TW487559B - A83543 compounds, their preparation process and their uses - Google Patents

Abstract

The compounds of the present invention are prepared directly or indirectly by modifying the compounds that are naturally produced from Saccharopolyspora spinosa. The compounds of the invention have been shown to have activity against insects and mites. The compounds are prepared by modifying the rhamnose sugar, modification of the forosamine sugar, or starting with pseuodoaglycone and then replacement with a nonsugar derivative or different sugar, modification of the 5,6,5-tricyclic and 12-membered macrocyclic lactone part of the compounds naturally produced or of the pseudoaglycone of the natural compounds.

Description

487559 A7 __B7 V. Description of the invention (1) Invention invention The present invention relates to the use of spinaldoxin (SP) produced by Spinaldo yeast (^^ nnharopoly-a.j > .Qr, as & jnosa). IHOSYN) Compounds produced by chemical modification. These compounds have insecticidal activity. Xue Mingbeishu U.S. Patent No. 5,362,634 confirms that the fermentation product A83543 is a family of related compounds produced by S. spp., Which is incorporated herein by reference. These compounds have been called A, B, C, D, E, F, printed by the Consumers' Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) G, H, J, K , L, M, H, 0, P, Q, U, S, T, U, V, W, Y and other factors or components (see also PCT WO 93/09126 and PCT WO 94/20518) and later傺 is called Spinozin A, B and so on. These Spinozin compounds are useful for the control of spiders, nematodes and insects. Spinocinol compounds that are naturally occurring are 5,6,5-tricyclic hydrazones, neutral sugars (rhamnose), and amines (f ο r 〇samine) fused to 12-membered gallide κ irst et al. (1991), Tetrahedron Letters 32 · 4839) If the compound does not contain amine sugar, it is called A, D and other pseudo-aglycone compounds. The preferred names for referring to pseudoglycoside ligands are Spinoxin A 9-Psa, Spinoxin D 9-Psa, and the like. Spinozin compounds generally have the following structure: R3 ’, .〇

This paper size applies to the Chinese Standard (CNS) A4 (210 X 297 mm) 4 ^ 7559 V. Description of the invention (2) Printing factors R1, R2, R3, R4, Rs of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ， R6, R7 / Spinozin A Η CHg C2H5 CH3 CH3 CHa Spinozin B Η CH3 C2Hs CH3 CH3 CH3 Spinozin C Η CH3 CH3 ^ Η5Ν " ^ λ_ C2Hs CH3 CHa CHa Spinozin D ch3 CHa C2Hs CH3 CHa CHa Spinoxin E Η ch3 CH3 CHa ch3 CH3 Spinoxin F Η CH (CH3) 2N-^^ l ^-^ C2H5 CH3 ch3 CHa Spinoxin G Η CH3 ch3 C2Hs CH3 CHo CH3 Spinozin Η Η CH〇CHn C2Hs H CH3 CH3 Spinozin J Η ch3 C 2 H 5 CH3 H CH3 Spinozin KK Η CHa CsHs CHg CHa H Spinozin L CHa CH3 (CH3) 2N- -^^ x ^^ C2Hs CHg H CHa Spinozin M Η CH3 (CH3) NH-^^^ C 2 H 3 CHg H CH3 Pack — (Please read the notes on the back before filling this page) Standards are applicable to China National Standard (CNS) A4 (210 X 297 mm) 487559 V. Description of invention (3) Printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs for consumer cooperation

Factors R1, R2, R3, R4, R5, Re, R7, Spinozin N CHa CHa (ch3) nh-^^^ C 2 H 5 CHa H CHa Spinozin 0 CHa CHg (CH3) 2N-- ^^ X ^^ C2H5 CH3 CH3 H Spinoxin P Η ch3 CaHs CHg HH Spinoxin Q Q3 CHa CaHs H CHa CH3 Spinoxin R Η CHa C2H5 H CHa CH3 Spinoxin S Η CH3 CH3 H CHg CHg Spinoxin T Η CHg C2H5 HH CH3 Spinoxin U Η CH3 C 2 H 5 H ch3 H Spinoxin V CHg CHa C 2 H 5 H CHa H Spinoxin W CHa CH3 (C H3 ) 2 N — C 2 H 5 CH3 HH Spinozin Y Η ch3 (CH3) 2N-^^^^ C2H5 CH3 CH3 H Pack — (Please read the precautions on the back before filling this page) The size of the paper is applicable China National Standard (CNS) A4 specification (210X 297 mm) 487559 A7 B7 V. Description of the invention (bucket) Printing factors R1, R2 '# R3, R5; RB, R7; Shi Bin Northyn A 17-Psa Η CH3 Η C2Hs ch3 ch3 CH3 Spinnock A 17-Psa Η CH3 Η C 2 Η 5 ch3 ch3 CH3 Spinnock B E 17-Psa Η CH3 Η CHa CHa CH3 ch3 Spinozin F 17-Psa Η Η Η CsHs CH3 CHa CHa Spinozin Η 17-Psa Η CHa Η C 2 H 5 H CHa CHa Spinozin J 17-Psa Η CHa Η C2Hs CH3 H CH3 Spino Xin L 17-Psa CHo CHa Η C2Hs CHa H CH3 (Please read the precautions on the back before filling out this page) -Packing-The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 487559— A7 B7 V. Description of the invention (left) R3 '.

Factor R1; R2, R3, R4 / Rs, Spinozin A 9 ~ Psa Η CHa (CH3) jN C 2 H 5 Spinozin D 9-Psa CH3 CHg (CH3) NH〇CsHs H Spinozin A with base CHa H CaHs H Spinozin D with base CH3 CH3 H CaHs H (Please read the precautions on the back before filling this page).

, 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the naturally produced Spinozin compounds can be produced by fermentation of strains NRRL 13719, 18 537, 18533, 18539, 1843 and 18823 ° These strains have been Deposited and made part of the collection of germ fungi of the USDA Agricultural Research Institute--S-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 * B7 V. Description of the invention (6) As mentioned above, Spino ¥ compounds are particularly effective against insects of the order Lepidoptera and Diptera. Spinozin compounds are quite environmentally friendly and have interesting toxicology graphics. However, in some applications, it is desirable to have a longer residual effect than the spinosinoxin disclosed in conventional patents and publications. Spinozin analogues with longer residual effects can be used to control mites on fruits and nuts or to control moths that affect pear fruit. Summary of the Invention The invention disclosed herein is a synthetic modification of a product produced by Saccharopolv-spora soinosa, thereby producing intermediate products and / or insecticidal products for the agricultural and animal health markets. Many synthetic modifications are performed on rhamnose and forosamine, through hydrogenation, epoxidation, primogenization, halogenation, oxidation, addition of alkyl groups, addition of nitrogen groups and macrolides. The addition and removal of the substituents are performed on the molecule. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are prepared directly or indirectly by modifying compound K, which is produced naturally by Spindowella yeast, see US Patent No. 5,362,634 issued to 0〇; ^ 1 心 (: 〇 No., the patent is incorporated herein by reference. The compounds of the present invention have been shown to have activity against insects, spiders and nematodes. Therefore, the compounds of the present invention can be used to make other compounds or the compounds of the present invention can be used by themselves Inhibits or deactivates phobias or mites. Contacts the inhibited or deactivated amount of compounds with the habitat of worms or mites. The "infestation" of insects refers to the presence of ring culture or their eggs inhabited by phobias or mites Place, the adjacent air or the air around it, the paper size of the food to be eaten by the worm or the mite applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)-Packing-(Please read the precautions on the back before filling This page) Order 4 487559 A7 __.____ B7, V. Description of the invention (7), or objects in contact with it / Generally these compounds are applied to the leaves of plants, which are born of pygma or mites Food. Unless specifically stated herein, the following words and terms have the following meanings: The term "haloalkyl" means an alkyl group having 1 to 4 carbon atoms, of which at least one halogen is bonded to a carbon atom. The word means C 1, F, Br, or I. The term "alkanolyl" means an alkyl group having 1 to 4 carbon atoms, of which at least one carbonyl group is attached to the alkyl group. The term "alkylhydroxylamine" Means the substituents with the following chemical formulas-equipment-(Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperation Department of the Central Standards Bureau of the Ministry of Economic Affairs where R1 * 1 and R11 are each independently 1 to 4 Alkyl groups having 1 to 5 carbon atoms, or alkanol groups having 1 to 5 carbon atoms. The term "protected hydroxyl" means substituted with a methyl ester, such as, but not limited to, methoxymethyl, tetrahydropyran , Substituted by ethyl ester, such as but not limited to 1-ethoxyethyl, substituted by anisole * such as but not limited to p-methoxybenzyl, substituted by silyl ether, such as but not limited to having Silyl ethers of 1 to 2 carbon atoms are generally ethers having 1 to 2 carbon atoms, generally Esters having 1 to 2 carbon atoms, more particularly formate or acetate, carbonates are generally carbonates having 1 to 2 carbon atoms, more specifically methyl carbonate, and generally having 1 to 2 2 sulfonate sulfonate, more specifically methyl sulfonate. These protecting groups are in Green, T.W · Wuts, PQ M * Organic Synthesis ^ Organic Groups in Organic Syntheses, John Wiley and Sons , New York, 1991, pp. 17-18) in more detail, the entire text of which is incorporated herein for reference. The term “protected amine group” means 10 and 4 (CNS) A4 specification (210X29 * 7 mm) 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7____ 5. Description of the invention (8) Refers to M-formate with 1 to 2 carbon atoms, with 1 The fluorene amines having 4 to 4 carbon atoms are generally η-methylamino and η-ethylfluorenyl, and imines such as η-benzylidene. These protective groups are further described in Greene's Organic Groups in Organic Syntheses. The term "inhibiting insects or mites" means a decrease in the number of living worms or mites' or a decrease in the number of eggs. "Deactivation amount" means the use of M to cause a countable decrease in the population of worms or mites being treated The amount of the compound. Generally, the compound used is about 1 to about 1,000 ppm (or 0.01 to 1 Kg / mu). These compounds are generally effective against Haploste les fascifrons aster leafhopper, Spodoptera ex i gua · beet armyworm), Meloidogyne arqnaria. peanutroot knot nematode), cotton (.Aphis gos 5; Y pii. cotton aphids), cotton leaf ride (Tetra-anychus ur ti ca ^. two spotted spider mite), eleven star claw leaf beetle (Diabrotioa undecimounctata howardi Southern corn rootworm), American cotton worm (He 1 i oth is cotton bollworm), Peregr i nus ma idis. corn p 1 an t hopper), American leaf moth (He 1 i oth is virescfin ^, T obbaccobudworm), German cockroach (B 1 a 11 e 11 agermanicus, German cockroach), Europe Gstrinia nubilalis. European cornborer, Neohotett ixc Ljlc iticepsi green rice leafhopper, Ni lapar ya ta__Lu gens. Brown planthopper »and Chilo suppressalis, rice stem borer) etc. 0 ____- 11 -_ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back 4 • Items and then fill in:: Write this page).

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 B7 V. Description of the invention (9 ·) Synthetic compounds are generally modified by rhamnose, amine sugar, or 9- or 17-pseudoglycoside compounds Is the starting point and then M rhamnose or amine sugar replaces non-sugars or different carbohydrates. Synthetic compounds are also prepared by modifying the 5,6,5-tricyclic and / or 12-membered macrocyclic pseudoglycoside compounds of naturally occurring compounds as described in the examples herein. The compounds requested herein include all isomers of the compound and any acid addition salts and isomers thereof. There are several non-mirromeric isomers of the compounds claimed herein. Because of the majority of stereogenic centers, non-mirromeric isomers can be expected to be active against the insecticide. Although some non-image isomers may be more effective than others, the present invention treats all non-image isomers equally. In the A portion of Example 17, the rhamnose at positions R5 ′, R6 ′, and R7 ′ of Chemical Formula I is obtained by adding a long-chain alkyl group, an aryl group, and / or a long-chain alkyl group having a halogen substituent, Addition modification of aryl. Esters can also be formed at R5 ', R6', and R7 'positions. Additional sugars can also be substituted at these positions. Another modification is to add substituents containing atoms such as nitrogen, sulfur, phosphorus, and silicon at these positions. In addition to the modification on rhamnose, the double bond between the C5 and C6 positions in Chemical Formula I is modified by epoxidation or hydrogenation. In Part B of Example 17, the amine sugar was substituted with a non-sugar substituent via an ester coupling. Esters generally have a nitrogen heterocyclic group, a halogen, or an amine group. In part C of Example 17, the amine sugar was changed from arsine or methyl to a long-chain alkyl group, a phenyl group, a quaternary ammonium salt, or an N-oxide by changing a substituent on the nitrogen. In the part D of Example 17, the molecule is modified by alkylation and nitrogen group at the double bond positions of C13 and C14 by hydrogenation, epoxidation, primogenization, and addition such as hydroxylamine and fluoride. In the part E of Example 17, the paper size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (21〇 '乂 297mm) --------- ^^ install-(please first Read the notes on the back and fill in this page), 1T Φ Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 487559 A7 B7 · V. Description of the invention (1) C17 substituent K removed from the macrolide was obtained with dihydrazone and / Or modify the C5 and C6 positions with halogen, epoxide and alkoxide. In part F of Example 17, at positions C5 and C6, they were modified by hydrogenation, epoxidation, halogenation, oxidation, and addition of heteroatom substituents and esters. In part G of Example 17, the other saccharides such as rhamnose derivatives are substituted amine sugars. In the part VII of Example 17, the Spinoxin starting material was alkylated or demethylated. The resulting material is preferably used as a starting material for the manufacture of other compounds. In Part I of Example 17, a deoxidized rhamnose analog and further M ester or heteroatom substitution modifications were prepared. In Part J of Example 17, the rhamnose is replaced with other sugars and non-sugars such as esters and ethers. In the K part of Example 17, the C9 position of the 5,6,5-tricyclic part in the molecule was modified by oxidizing a hydroxyl group to a ketone and then adding an alkyl group to a C-0 double bond. Furthermore, the hydroxyl group at the C9 position is deoxidized or substituted with an M nitrogen-containing group. The compounds disclosed herein are not only useful in the production of agricultural products, but acid addition salts of these compounds are also ideal products. Acid addition salts can be prepared from compounds disclosed by Chemical Formulae I, E, IV, VI, VI, and XV. The salts of the compounds use standard techniques for preparing salts, which are well known to those skilled in the art. Salts can be neutralized to form acid addition salts. Particularly useful acid addition salts include, but are not limited to, those formed by standard reactions of organic and inorganic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, t succinic acid, citric acid, lactic acid, cisbutane Glycolic acid, fumaric acid, cholic acid, paranaphthoic acid, galactic acid, glutamic acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, formic acid, laurel Acid, stearic acid, -13-This paper size applies Chinese National Standard (CNS) A4 (210X 297 cm) Γ Binding (please read the notes on the back before filling this page) Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed 487559 A7 B7___ V. Description of the invention (1 1) Salicylic acid, methanesulfonic acid, benzenesulfonic acid 'sorbic acid, picric acid, benzoic acid, lauric acid, etc. The steps and formulations on which the composition is prepared are conventional techniques in the field of conventional agricultural or pest control technology. The composition can be concentrated or dispersed in water, or it can be used in the form of a powder, bait or granule. Dispersions are generally aqueous suspensions or emulsions prepared from concentrated formulations of the compounds. Water-soluble or water-dispersible or emulsifiable formulations are solid, wettable powders, or liquids and are known as emulsifiable concentrates or aqueous dispersions. The wettable powder can be coagulated or crushed to form water-dispersible particles. These particles include a mixture of a compound, an inert carrier, and a surfactant. The concentration of the compound is generally between about 0.1% and about 90% by weight. Inert carriers are generally diatomite, montmorillonite and diatomaceous earth or purified silicate. The surfactant comprises about 0.5% to about 10% of a wettable powder, wherein the surfactant is generally a sulfonated lignin, a concentrated sulfonate, a naphthalenesulfonate, an alkyl benzenesulfonate, an alkylsulfonate, Or non-ionic defined active agents, such as ethylene oxide adducts of alkylphenols or mixtures thereof. Emulsifiable concentrates of the compounds of this invention generally contain from about 50 to about 500 grams of compound per liter of liquid, equal to about 10 to about 50% dissolved in an inert carrier, which is a mixture of solvents or emulsifiers that are immiscible with water. . Organic solvents include organics such as xylene and petroleum distillates, such as the high boiling naphthalene and olefin fractions of petroleum, including vermiculite and aromatic naphtha. Other available organics such as terpene solvent turpentine derivatives, such as cyclohexanone and complex aliphatic amidines and complex alcohols. All emulsifiers of emulsifiable concentrates are generally mixed ionic or non-ionic surfactants, as described in this article _______— 14 ~ ___ This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) ) I ----- N-^^ 依 衣 一 .----- 1Τ ------ (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs System 487559 A7 _____ B7___ V. Description of the invention (12) The author and its equivalent. ‘An aqueous suspension containing a water-insoluble substance may be prepared, in which the compound is generally dispersed at a concentration of about 5% to about 50% by weight in an aqueous medium. The suspension is preferably finely ground and vigorously mixed with a vehicle such as water, a surfactant, and a dispersant as described herein. Inert ingredients, such as inorganic salts and synthetic or natural gums, can also be used as needed to increase the density and / or viscosity of aqueous vehicles. The precipitated flowable material can be prepared by dissolving the active molecule in a solvent and a surfactant or a polymer that can be mixed with water. When these formulations are mixed with water, the active compound precipitate and the surfactant control the size of the resulting microcrystalline precipitate. The size of the crystals can be controlled by selecting a specific polymer and surfactant mixture. The compounds of the present invention can also be applied as granular compositions to soils. Granular compositions typically contain from about 0.5% to about 10% by weight of the compound. The compounds are dispersed in an inert carrier, which is generally clay or an equivalent. Generally, granular compositions are obtained by dissolving the compound in a suitable solvent and applying it to a particulate carrier that has been preformed into the desired particle size. The particle size is generally about 0.5 mm to 3 mm. The granular composition can also be formed into a pellet or paste-like carrier and compound, dried to combine the compounds, and pulverize the pellet or paste M to form a desired particle size. The compound may also be combined with a suitable organic solvent. Organic solvents are generally mild petroleum lubricants that are widely used in agriculture. These compositions are generally applied as a K spray. More particularly, the compound is applied as a dispersion of a M liquid carrier, which is water. Compounds can also be __- 15 _ This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210 × 297 mm)-Packing-(Please read the precautions on the back before filling this page), 11 487559 A7 B7 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards V. Invention Description (13 Application in the form of a sol composition. The compound is dissolved in an inert carrier, which is a propellant mixture that generates pressure. The aerosol composition is packaged in a M container, where the mixture It is dispersed through an atomizing valve. The propellant mixture contains a low-boiling halocarbon which can be mixed with an organic solvent or an inert gas or a gaseous halocarbon pressurized aqueous dispersion. The amount of compound applied to insects and mites It is not important and can be easily determined by those skilled in the art. Generally, the concentration that provides ideal control is about 10 ppm to about 5,000 ppm. For crops such as soybeans and cotton, the application rate is about 0.01 to about 11 ^ /} ^, The compound is applied in a spray formulation of 5 to 5083 / eight. The compound can also be applied to any place where insects or mites live. These places are generally cotton, soybean or Vegetable crops, fruits and hazels, grape vines, houses or decorative plants. The compounds of the present invention can also be used to treat animals M control arthropods, namely insects and spiders, which are pests on animals. These spider pests are generally Injures the host's external ("ect 0") surface; the agent used to control such pests is preferably an "external parasite killer." All animals are susceptible to such pests, although vertebrate hosts have the most serious problems. Humans are latent hosts for many parasites, and parasite infestation is a common medical problem in tropical regions and in areas where sanitary facilities are inadequate. In addition, those who are highly susceptible to parasite infestation are many livestock * such as cattle, sheep, pigs , Goat, buffalo, deer, rabbit, chicken, turkey, duck (, goose, ostrich, etc. Horses and other recreational animals are susceptible to parasites. Mink and other animals with fur for breeding purposes are also the same, and rats The same is true for rats, rats, and other experimental and research animals. For companion animals, such as dogs and cats, 16 paper standards are applicable to the Chinese National Standard (CNS) A4 specification (210X 297mm) 丨 _ Pack. Order (please read the precautions on the back before filling this page) 487559 A7 B7 V. Description of the invention (14) It is highly susceptible to parasite infestation, and because it is related to humans Intimacy 'This parasitic disease can also occur in humans who accompany these animals. Fish, crustaceans and other aquatic species are also vulnerable to parasites. In short, parasitic diseases involve mainly the entire animal range The economic cost caused by the spread of ectoparasites is considerable. In the field of livestock breeding, animals suffer from problems such as reduced feed efficiency and growth rates. The production of milk and wool is harmed and the production of wool, animal skins and fur is endangered. Animals become vulnerable to secondary microbial infections and parasites. Even when in vitro parasites do not endanger health and production, they can cause discomfort that cannot be ignored. Although many parasiticides are available, they have encountered various problems, including limited types of action, environmental toxicity, the need for repeated treatments, and in many cases resistance to ectoparasites. Therefore, there is still a need for new topical parasiticides. The compounds of the present invention provide a new tool for medical devices for controlling ectoparasites. In a specific example of the present invention, the present invention is directed to a method for inhibiting or killing an arthropod parasite on an active object, which comprises contacting the parasite with an effective amount of a compound of the present invention. Printed by the Consumer Cooperatives of the Central Associated Bureau of the Ministry of Economic Affairs The compounds of this invention can be used to control a wide variety of arthropod parasites. Representative parasites that can be controlled by the compounds of the present invention are the following: American flower ticks, stippled spotted ticks, Persian ticks, small bovine ticks, oxtail, itch mites, burdock mites, maggot dogs, and shortheaded tick , American tick, Goose skin mite, Ixodes sibiricus, Feather mite, Kestrel mite, Beak-eared tick, Horse tick,

Gujia County, Guanjia County (⑽ (2lQx 297 printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China, printed 487559 A7 B7) V. Description of the invention (15) Sheep itch mite, Sanguine red tick, cymbal copper, Aedes mosquito, Malaria mosquitoes, Culex mosquitoes, common mosquitoes, feather lice, spiral cone flies, spotted mosquitoes, temperate bed bugs, spiral cone flies, dog head flea, cat head flea, caterpillars, hairy pupae, pupae, sheep flea, skin flies , Red-tailed gastronomy flies, Gastrodia magna, Equine nose gastroflies, Tongue flies, Disturbing horn flies, Blind lice, Cattle blind lice, Body blind head I, Pig blind lice, Hydrota ^ a irritans, Bovine fly, Striated skin fly , Long-nosed lice, Li nognathus Pedalis, Membrane long-nosed mosquitoes, Cercospora melanogaster, Sheep lice fly, Housefly, Sheep fly, Lice, Hairy maggot, Black flower fly, Blood mosquito, Pubic lice, Hunting, Mosquito, Tube lice, buffalo blind lice, flies, pupae, mealworms, cone hunting. The in vitro parasiticidal activity of the compounds of the present invention can be achieved upon contact with parasites. The contact can be eggs, larvae, adults or other life stages. "Contact" involves the parasite ingesting a compound of the present invention. The delivery technology of a topical parasite killer is a hot habit. Those skilled in the art are well-known. In general, the compound of the present invention is applied to the surface of an animal, whereby the compound of the present invention can be contacted with the parasite already on the host and the parasite that will invade the host during the effective period. In general, compounds are formulated into liquid formulations that can be sprayed onto or poured onto the animal's body surface. Another traditional treatment is "immersion", in which the treated cattle are generally intoxicated. In the diluent of insecticide. For some hosts and parasites, the formula can be powder that can be spread on the host, or shampoo or lotion for animal bathing. Collars for cats or dogs can also be used as a topical delivery A parasiticidal method whereby topical parasiticides can be delivered directly to the surface of the animal. In other technologies, topical parasiticides are applied to places where animals often infest, so they are treated as if they were directly applied to the host. Can make compounds and send _______-18 _ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) _ installed-(Please read the precautions on the back before filling this page) Order d 7559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (16) Insect contact. As far as domestic animals are concerned, dusting bags are also known, and they are located in a way that cattle cannot avoid. The ground will rub against the bag to allow the compound to contact the parasites. In another embodiment, the compounds of the present invention can be used to control insects and spiders, which are parasites in cattle and other animal waste. In the present invention, In the embodiment, the compound of the present invention can be passed through the intestine through the oral administration and embedded in the feces. The control of parasites in the feces can indirectly protect animals from parasites. The compounds of the present invention are formulated Parasites can be used by methods known to those skilled in the art. In general, the formulations may include a compound of the invention and one or more physiologically acceptable adjuvants. The formulation contains a concentration agent, in which the active agent of the present invention is present at a concentration of K 0.001 to 98.0%, and the other contents may be physiologically acceptable carriers. Such formulations, especially those containing less than 50% of the compounds of the present invention, can sometimes be used directly, but these formulations can also be diluted with other physiologically acceptable carriers to form thinner therapeutic formulations. The latter formulations may contain the active agent at a lower concentration of from 0.001 to 0.1 percent. In another embodiment, the compound of the present invention can be effectively combined with other parasiticides or insect repellents, the latter being a conventional internal parasiticide ("endo" = internal, who controls internal parasites, the Parasites are generally flat worms and nematodes). Representative parasiticides for internal use include the following

Abamectin, thiotetrazol, avermectin, butylene naphtha, fly venom, dichlorvos, Doramectin, Epsiprantel, Febantel, benzenesulfur _____- 19-_ ^ Paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) ------ ： — ^^ 办 衣 ------ 、 Order ------ 0, (Please read the notes on the back before filling this page) 487559 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed A7 B7 V. Description of the invention (π) Olfactory azole, fluorobenzene_beer, Ivermectin, L-four-side beer, methylbenside beer, Mitr 〇scanate, _ hydrogen __, Μ ο X idecti η,

Netobimin, niclosamide, nitroisothiocyandiphenyl ether, sulfazolamide, oxybenzidine, six gas wells 0, 嗣, Clorsulon, Closantel, diacetaminophenoxy ether, nitroiodobenzonitrile Hydroxysalamine, mesylamine, triclosan. Representative parasite killers include:

Abamectin, Alphmethrin, Amitraz, Avermectin, fly poison Λ Cycloprothrin ^ Cyfluthrin ^ Cyhalothrin ^ Cype rmethrin, Cymazine, De 11 amethrin, Diaron, D if lubenzuron, dimorphine scale, Doramectin, oxygen yellow plate, metasulfide scale , Fenvalerate Λ F 1 ucythrinate, Flumethrin, Hexaflumuron, Ivermectin, hexachlorobenzene, Lufenuron, malathion, Methoprene, Metriphonate, Moxidectin, ¥ permethrin, Phosme, P rimiphos, Promramphos, fish Glycoledione, thiomethanil, fendicarb, trichlorfon, Z etacypermethri η, B · t · biotoxin and boric acid. Pipeline regulations Except for one shipment, unless otherwise stated, all reagents and solvents used were purchased directly from commercial suppliers and all reactions were performed at room temperature (20-22 ° C) using constant speed magnetic stirring. All reactions involving organometallic reagents, humidity sensitive reagents, or gold hydride reagents are performed in commercially available anhydrous solvents and under a dry nitrogen environment. Use of NaCl, NaHC〇3, NfUCl and other paper standards Applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm): Binding (Please read the precautions on the back before filling this page) Employees of the Central Bureau of Standards, Ministry of Economic Affairs Cooperative printed 487559 A7 B7____ V. Description of the invention (18) Salts for distribution, extraction, or washing_ means saturated aqueous solutions of these salts. The reaction is generally "gradually completed" by extracting the organic solution M of the product with a salt solution as described above; the organic layer is dried with K2CO3, Na2S04, or MgS04, evaporated and evaporated under reduced pressure. Reverse-phase thin-layer chromatography (RPTLC) was performed on a glass substrate combined with an octadecylsilane plate (0.2 mm from Whatman). Chromatography refers to flash chromatography and is performed on E. Merck Silicone 60 (20-400 mesh). Reverse-phase high-performance liquid chromatography (RPHPLC) was performed on a C18-bound sand gum (Rain Dynamax 60 A, 8wm). All melting points are measured in open capillaries and are uncorrected. The iHNMR and 13C NMR spectra were measured at 300 to 400 MHz and 75 or 101 MHz, respectively. Mass spectrometry data was measured by electrospray ionization (ESI). Elemental analysis was provided by Dowlanco or Midwest Micro labs' analytical laboratories. Ii) Example 1 Φ Kerosin A with _ Kiyoshi Synthesis A sample of Spinozin A (8,50 g, 11.61 mmol) was dissolved in EtOH (100 inL). Water (100 mL) was added, and a 4N Η 2 SO 4 (aq) solution (200 mL) was added to the solution while searching. The resulting mixture was heated to a reflux temperature under a nitrogen atmosphere for 4.5 hours. Cool to room temperature, dilute with toluene (250 mL) and ethyl acetate (300 mL), and add brine (300 mL). After extraction, the phases were separated. The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic layers were washed successively with diluted brine (3X) and 5% NaHC03 (2X) and then dried over anhydrous MgS04 and concentrated under reduced pressure. The residue was purified on a flash SiO 2 column (250 g; ethyl acetate). After concentrating the purified part on the chromatography to dryness, a glassy solid (4.08 g »87%) can be obtained» [a] 5 8 9 = -145.6 ° (MeOH) · [a] 5B9 = ____- 21 __ Paper Music scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) ------- 7--install ------ order ---------- (Please read the back first Please note this page, please fill in this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A 7 • B7 · V. Description of Invention (19) -131.7. (CHC13) 〇, Ramie Example 2 Indoxin A17-Psa synthesis

A sample of Spinozin A (20.0 gms, 27.4 mmol) was dissolved in 300 mL II H2SO4 and heated to 80 t using a magnetic stirrer: 2 hours. The reaction was then allowed to cool to room temperature. The precipitate was filtered through suction and washed with freshly prepared III H2SO4. The solid product was then dissolved in dichloromethane, washed with brine, dried over K2CO3, and evaporated under reduced pressure. Purification of M by silica gel chromatography using 70% EtOAc in hexanes gave spinoline 17-Psa (14.46 gms; 89%) as a colorless glass. Synthesis of Phenyloxin A 9-Psa in Example 3 A suspension of N-chlorobutanediimide (1.20 gm, 9.00 mmol) in dichloromethane (45 ml) was cooled to -78C under nitrogen. Pure diethylsulfur (1.07 ml, 9.90 mmol) was added to the suspension over 5 minutes, and the mixture was stirred at -781C for 0.5 hour. Spinoloxin J (2,15 gm, 3.00 mmol) dissolved in 8 mL of dichloromethane was slowly added to the mixture for 15 minutes and kept below -601: reaction temperature. When the addition is complete, stir the solution at _78 for 6 hours. Triethylamine (1.25 inL, 9.00 mmol) was then added dropwise and the solution was allowed to warm to room temperature. The reaction was diluted with 40 mL of dichloromethane and poured into 20 mL of 1N sodium bisulfate and 30 mL of water. The layers were separated and the organic layer was extracted with 30 mL of saturated sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in MeOH (100 ml). Anhydrous K2C0 3 (4.15 gm, 30.00 mmol) was added and the suspension was stirred at room temperature. After stirring for 2 hours, the reaction was cooled to 0 ° C and the water was evaporated to 1/5 of the reaction volume in a rotary evaporator. Add dichloromethane (100 mL) and water (This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) = binding (please read the precautions on the back before filling this page)) Staff of the Central Bureau of Standards, Ministry of Economic Affairs Consumption cooperatives print 487559 A7 ^ _ B7__ · — V. Description of the invention (20) 100 inL) and layered. The aqueous layer was extracted with 3 ^ 50 inL dichloromethane and combined with the organic extracts and washed with water followed by K saline solution. The solution was dried over sodium sulfate, filtered and concentrated in a rotary evaporator to obtain a viscous yellow oil. The product was purified by flash chromatography (250 gm silica gel, 0.5% concentrated sulfuric acid in 5% methanol in dichloromethane) to obtain Spinoxin A 9-Psa (1.52 gra; 93% "H NMR (CDCl3) 378 (br s, l, Η-13), 4.63 (ιη, 1, Η-21), 4.43 (m, 2, Hl", Η-9), 2.23 (s , 6, N (CH3) 2) 〇 Example 4 Preparation of A part of Zhong Nuoxin by using Sacnh aropo1yspota spinc ^ a) NRRL 1 8395 culture material Nine grains of freeze-dried or a suspension of S. polyspora yeast NRRL 18395 in the form of a suspension in liquid nitrogen is inoculated into a nutrient medium containing composition A and composition B (medium B is more suitable for large-scale production) The nutrient medium A contains (indicated by the content M%) pancreatic soybean medium M3. 0%, yeast extract 0.3%, MgS04.7.20.2%, glucose 0.5%, maltose 0.4%, deionized water qsl liter, Unadjusted pH ("purchased from Baltimore Biolabs") and nutrient medium B contains 3.0% of proteolytic enzyme peptone hydrolyzed by yeast, 0.3% of yeast extract, MgS04.7.20.2%, Glucose 1.0%, qsl liter of deionized water, pH was adjusted from 6.2 to 6.5 with sodium hydroxide ("purchased from NZ Amine A, Sheffield Products, P. Box 638, Norwich, NY 13815J. By adding 2.5 % Amaranth to nutrient seed fungus culture medium A or B to prepare slanted medium or plate medium. The inoculated slanted medium is cultured at 30 ° C. This paper size is applicable to Chinese national standards (CNS> A4 size (210X 297 mm) ) ------: ------- Order ----- (Please read the notes on the back before filling out this page) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ B7___ V. Description of the invention (21) 10 to 14 days. Scrape the mature slant culture medium M aseptically scrape the spores to loosen and remove and drench the mycelium plexus. The resulting loose spores and culture growth take about 1 / 4 Inoculation to the first-stage nutrient culture medium. In addition, it can be inoculated to the first-stage medium from liquid nitrogen ampoules. When the culture is maintained in liquid nitrogen, the ampoules use an equal volume of nutrient culture (cultivation 48-72) Hours, 30Ό) and suspension medium preparation Suspension medium contains lactose (100 g), glycerol (200 mL), and deionized water (qs to 1 liter). Inoculate liquid ampoule into a 500-mL Erlenmeyer flask containing 100 mL of nutrient medium (or 50 inL medium) 250-inL triangle bottle). The culture was placed on a shaker at a rate of M 250 γρππ around a circle of 2 inches (5.08 cm) at 30Ό 'for 48 hours. The inoculated culture (5% v / v inoculum) was inoculated into 100 inL of a productive medium having the following composition: (content indication) 4.0% glucose, partial enzyme hydrolysis "of plant protein 1.5-3.0 %, Cottonseed meal * Kl.〇%, CaC03 (test grade or industrial grade) 0.3%, soybean oil 1.0%, tap water lsl (pre-sterilized and pH adjusted to 7.0 with NaOH) »HSheftone HJ Sheffield Products» ^ 'Proflo »Traders Protein» P.0. BOX 8407 »Memphis» TN 38108. The inoculated production medium was placed in a 500-mL Erlenmeyer flask at 28-301C on a shaker at a rate of M 250 ΓΡίη at a rate of 2 Incubate for 6 to 8 days. B. 揋 zel 忒 Φ substance reverse membrane fermentation To provide a large amount of inoculum, inoculate 10 mL of the first stage culture medium prepared as described in Part A to 400 mL and the first The first stage culture medium has the same composition as the second stage culture medium. This second stage culture medium is _____- 24-This paper is in accordance with the Chinese National Standard (CNS) M specifications (210X 297 mm) (Please read first Note on the back, please fill out this page) 487559 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (22) 2-L wide mouth triangle flask, at 30t :, the rate of M 250 rpro on the oscillator is around a 2-inch circle, training 48 hours. Inoculate the prepared second-stage nutrient medium into 80-115 liters of sterile productive medium prepared as described in section A. If necessary, additional soybean oil K can be added to control foaming. Ferment the inoculated productive medium in a 165-L stirred bioreactor at a temperature of 28 ° C for 5 to 8 days. The air flow in the stirring tank and the speed of the agitator are controlled by a computer to maintain the dissolved oxygen content as 50% or more of air saturation.

Fenshi Example 5 Dioxin A, B, C, and D in the broiler were filtered with a filter aid (1% Hyflo), the fermentation medium (225 liters) prepared as described in Example 4, and M water (~ 50 L ) Wash the separated biomass. The biomass was then stirred with methanol (~ 100 L) for about 1 hour and filtered. The methanol solution was concentrated to a volume of about 1 liter. The concentrate was extracted 3 times with K ether (1 L each). The combined ether extracts were concentrated to a volume of about 200 niL. A portion of the concentrate (8 mL) was chromatographed on a silica gel column (RP-8 Lobar, size B, E.M. Science, E.M. Industries Division, 30 Inc,). Repeat this step a total of 12 times (cycles). The instrument setup and implementation steps for preparative chromatography are performed in the "Autoprep" mode as follows:-The complete "Autoprep" HPLX system contains three Rainin Rabbit HPX pumps, a pressure group, and a Gilson Model 20 1B HPLC section. Collector, an IsC0-v4 absorbance detector and an Apple Macintosh Plus computer. The complete system was configured according to the Dynaraax HPLC Method Administrator Manual from Rainiri Instruments. "-25-This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) ------- Γ-'batch clothes ------, order ------- 0 (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __B7 _, V. Description of the Invention (23)

"Autoprep" HPLC structure has the advantages of > automation, to allow repeated preparative separations under virtually identical conditions to have virtually identical results. Collecting and combining the corresponding portions obtained from multiple operations can be Provides chromatographic analytical quantities without the need for large columns. M-equivalent mode (ISOCRATIC) and flow rates of 0.8 mL / miri use two-solvent mixtures (A) and (B). Solvent system A contains 95 inL CH3OH, 95 mL CHaCN , 10 raL H2〇, and solvent system B contains 100 mL of CH3OH, 100 mL of CHaCN, and 0 mL of H2. The power equal mixture used contains 60% of solvent B. The duration of each dissolution cycle is 28.0 minutes The discarded solution was discarded 16 minutes before each cycle. The next precipitate was dissolved in 6 times, 2 minutes per tube (16 mL per tube). The lysis was automatically combined by each cycle (12 times in total). The final portion (chromatographic lysate) of 6 tubes was obtained by analyzing the activity of each final lysate on mosquito larvae and also the presence of active spinoxin compounds by analytical HPLC. Then based on the activity and HPL Figure C combines active eluates and further purification. The purification uses the same "Autoprep" HPLC and solvent system, but with high resolution and pre-packed 21.4imX25-Cm preparative column (Rain Dynamax) , M obtained Spinoxin A, B, C and D. Spinoxin A and D can be crystallized from CH3OH / H2O. Example 6 Φ Chernosin purification as described in part A of Example 4 Method To prepare a fermentation medium (10 L), but 1) use 200 mL of production medium in a 1-L flask; 2) remove soybean oil from the production medium; and 3) incubate at 30 for 4-6 days. Filter the medium .Discard the history containing 4 meg of historical Nosin A / inL and non-detectable amount ________- 26 _ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) I Binding (please read first Note on the back, please fill in this page again.) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 B7 _, one or five, description of the invention (24) Binoxin B, C, or D / mL of the filtrate. Wash with water Biomass and M methanol extraction for 1 hour. The extract (7 L) contains 72 meg Spinoloxin A / mL And 7 meg spinosinol D / mL. The methanol extract was concentrated to a volume of 5 L, and added to HP-20 resin (150 mL, Mitsubishi Chemical Industry Co., Ltd.) in water (2 L), Japan. ). The mixture was stirred for 1 hour. The HP-20 resin mixture was then placed in a glass column. The initial effluent and precipitation using methanol: water (1: 1, 1L) are not active. The second precipitate using methanol: water (7: 3, 1 L) contained a small amount of Spinoxin A. Subsequent precipitations using methanol (1 L) included spinoxin A and spinoxin D activity. The methanol eluate was concentrated and combined with 2 similar eluate fractions obtained from other dissolution operations and concentrated to dryness. The residue was dissolved in 75 mL of methanol: THF (4: 1) and precipitated by addition to 10 volumes of acetonitrile. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in methanol (25 mL) and placed in a 5.5X 90-cin column of LH-2 (/ Sephadex (Pharmacia LKB Biotechnology Company, U, S, A ·), which was prepared by M methanol. 125 HPLC fractions were collected and analyzed using the HPLC method described in Example 1. The fractions containing the desired compound were combined and concentrated. The residue was dissolved in methanol (10 mL) and placed in C- Preparative 41.1-mm x 25-cin prefilled tubing column filled with 18 reverse-phase silicone (Rainin Dynamax). The tubing system was adjusted under the conditions of methanol: acetonitrile: water (37.5: 37, 5: 25). After the sample, the sample was developed using a 180-mi η linear gradient of the following solvents: solvent system A: 37.5 mL CH3OH, 37.5 mL CH3N, 25 mL H2O, and solvent system B: 45 mL CH3OH, 45 mL CH3CN, 0 mL H2〇. Combined with Spinoxin Ai dissolving fraction, dry, soluble in t-Bu0H (5 ______- 27 ~ This paper size applies Chinese National Standard (CNS) A4 specification (21 OX 2W (Mm) 1 Binding (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7. V. (25) mL) and freeze-dried K to obtain 77, rag pure Spinoxin A. The spines containing Spinozin D and 6 similar separation operations were combined and concentrated and as described above. For general chromatography, the same column is used, but the solvents are different. The column system is adjusted under the conditions of methanol, acetol, water (40, 40, 20). The linear gradient of M 180-mi η in the column The solvent system used to develop the sample was: solvent system A contains 40 mL CH3OH, 40 niL CHaH, 20 mL H2O, and solvent system B contains 95 mL CHaOH, 95 mL CH3CN, 10 mL H2O. The fractions containing D were combined and concentrated. The residue was dissolved in t-BuOH (5 mL) and freeze-dried to obtain 212 mg of spinosinol D. 7 Example 7 indoxin F :, F, G Miscellaneous Miscellaneous of Η, Η and J and 中 窨 诺扎 A 17-Psa_ Treated according to the method described in Example 4 using a fermentation medium (8 L) prepared in a similar manner to that described in Example 4. The LH-20 Sephadex column will be used. The obtained lysate containing the desired compound is combined with the corresponding lysate obtained by other similar fermentations. Because the components E, F, G, Η, J, and A The amount of pseudoglycoside compound produced is very small and must be provided in sufficient quantities for further purification by multiple fermentations. A secondary factor collection portion prepared in this manner and containing approximately 1.6 g of solid 15 substance was placed in a M8 micron C-18 reverse phase silica (0DS) pre-packed HPLC column (Rainin Dynamx) as described in Example 4. The column system M CH3〇H: CH3CN: Η20 (75: 75: 50) adjustment, and the gradient system M The following solvent system from 100% solvent (A) to 50% (B): solvent system A 75% CHaOH, 75% CH3CN, 50% H2O and solvent system B95% CH3OH, 75% CH3CN, 50% H2O, M25-ml eluate were collected. Collected This paper size is applicable to China National Standard (CNS) A4 (210X 297mm) — Binding (please read the precautions on the back before filling this page) A7

V. Description of the invention (26) The lysate described in 30: The lysate is collected but separated 1 31-44 2 45-63 3 64-69 4 70-80 5 81-130 6 131-160 The collected part 5 (100 mL) was concentrated to a residue, dissolved in methanol (1 mL) and placed in a 21,4imX 250-nnn HPLC column (Rainin Dynamx) as described in Example 5. The column was adjusted using the following solvent system (A): Solvent system A 30: 30: 40 CH3〇H / CH3CN / H2〇 (1N NfUOAc, pH 5), and solvent B 95: 95: 10 CH3〇H / CH3CN / H2O (1N NH4OAc, pH 5), developed with a 120-minute linear gradient from 100% solvent (A) to 50% solvent (B), 15-mL eluate was collected at M7.5 mL / roin. Collection of the precipitate was continued for an additional 60 minutes at 50% (B). Collect the following solvents: _Collect part Dissolve ingredients

1 37 F 2 38-48 Ε 3 52-63 B′-G 4 65-70 ，, 丨 J Combine these collection portions with those obtained by other chromatography processes using starting materials. As described in this article, the paper size is applied to the Chinese National Standard (CNS) A4 specification (210X 297 mm) using the column layer. I ---- J-1 clothing ------, 玎 --- -(Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, the content of the dissolved fractions E 249 717 F 4 717 G 104 731, J 87 717 Fake A 288 590 487559 A7 _ B7 · V. Description of the invention (27) Analyze and further purify the combined part; demineralize in HP-20 resin using standard techniques; and concentrate and freeze-dry K to obtain the following components: ”Applied by mass spectrometry Example 8 Preparation of Zhongluoxin K, Zhongke Caoxinoxo 0, and Φ 窨 nuoxin Y_A using Peizhai NRRL 1 8743 The culture of Sporola multiflora NRRL 18743 in the form of a suspension was inoculated into a nutrient medium having the following composition: Peizhai base composition β (ζ) Pancreatic soybean medium "30 Yeast extract 3 MgS04 1Η20ο 2 glucose <5 maltose 4 deionized water q. S. 12 Autoclave for 30 minutes at 0TC. This paper size applies the Chinese National Standard (CNS) Λ4 specification (210 :, &lt; 297 mm) ^ Binding (please read the precautions on the back before filling this page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs Cooperatives Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives 487559 A7 B7, V. Description of Inventions (28)

• Baltimore Biolabs, tockeysville, MD can be used to prepare slanted or flat media by adding 2.5% agar to nutrient media. The inoculated slant medium is cultured at 30 ° C for about 10 to about 14 days. The heat-producing slant culture medium M is scraped off with a sterile instrument to loosen and remove the spores and soak the mycelium clumps. About 1/4 of the thus obtained pine spores and cultures were inoculated into 50 mL of the first-stage nutrient seed culture medium. Alternatively, the first stage culture medium can be inoculated from a liquid nitrogen ampoule. Liquid was prepared by homogenizing a nutrient medium, diluting with a sterile suspension M 1: 1 (volume: volume) of glycerol: lactose: water (2: 1: 7), and dispensing into a sterile tube (1.5 ml / tube). -Nitrogen-protozoa. The diluted culture is then stored under liquid nitrogen and in a suitable storage container as the original inoculum used for the culture of the shake-flask culture and the fermenter strain culture. Quickly thaw the liquid nitrogen ampoule and inoculate 0.5 mL In a 250-raL wide mouth Erlenmeyer flask containing 50 mL of nutrient medium. The culture was cultured at 32t! Around a 2-inch circle in a shaker at K 250 rpm for 48 hours. The cultured culture (5% v / v inoculum) was inoculated into 25 mL of a productive medium having the following composition: a fine ingredient of boiled pei village _ g (g) glucose, 80 adenized milk ”20 Cottonseed meal 11 30 Corn infusion 10 H-This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) ------ ΓΙ- ^ 批 衣 ------ 1T ---- --Φ (Please read the notes on the back before filling out this page) 487559 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7 V. Description of the invention (29) CaC〇3 (industrial grade) · 5 methyl oleate 30 tap water q · S · to 1-L "adenized milk nutrient, Sheffield Products» Norwich »HY ^^ Proflo» graders Protein Memphis TH cultured the inoculated productive medium in a 250-mL wide-mouthed triangle flask at 301C at a rate of M 250 ΓΡΠΠ around a 2-inch circle and cultured for 7 days. Provide a large amount of inoculum, inoculate 10 mL of the first-stage nutritional medium prepared as described above to 400 mL of the second-stage nutritional medium having the same composition as the first-stage nutritional medium. The second-stage nutritional medium Purity> 98%. The collected fraction containing Spinoxin K separated by the first preparative HPLC and the repurified Spinoxin 0 were combined and concentrated to 200 ml, and M was the same as Spinoxin 0 Desalting method. Collect the eluate containing purity> 98% of component K, concentrate to dryness, and obtain spinosinol K (11.1 g; &gt; 99% purity) from t-BuOH freeze-drying. Tube) 9 by M rank NRRL 1 8743 points Nosin Π and Zhongke Nosin Υ _ Approximately M. The fermentation medium (2 (30-L)) was prepared as described in Example B above. After adjusting the pH of M5N HC1 to 3.0, acetone (260-L) was added to the entire medium The obtained mixture was filtered through a ceramic filter to obtain a filtrate (480-L), and the filtrate was kept under refrigeration for another week. The medium / propionate filtrate was adjusted to pH 12 with 25% HaOH and the filler was flowed to a flow rate of 0.5 L per sample. Paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) ~ installed ------ order ----- see (please read the precautions on the back before filling this page) 487559 A7 B7 Economy Printed by the Consumers' Cooperatives of the Ministry of Standards of the People's Republic of China. 5. Description of Inventions (30)

A steel pipe column (10-L, 10 cmX 122 cm) containing HP-20ss resin (Mi tsubishi Chemical Industries, Ltd., Japan) was filtered twice before passing through a ceramic filter. MCH3CN-CH3OH-0.1% a q. NhOAc (adjusted to pH 8.1 with NH4OH) (25 ·· 25: 50; 20-L). Spinolsin K, CH3CH-CH3〇H-0.1% (adjusted to pH 8.1 with NFUOH) (95: 95: 10; 30-L) at a flow rate of 1-L / min. And Y. The concentrated precipitate (30-L) was redissolved in CHaOH, then concentrated to dryness, redissolved in CH30H (100 ml), and then precipitated in CH3CS (2-L). The resulting precipitate was removed by centrifugation, the precipitate was washed with KCH3CN, and the precipitate was discarded: the combined filtrate and washing solution (3-L) were concentrated to dryness. The obtained residue was re-dissolved in dichloromethane (50 ml) and placed in a column of silica gel (EM grade 62 · 60-200 mesh) equilibrated in acetonitrile (7.5crox50cm). The column system KCH3CN is the eluent, followed by (: [13 ^ (: [13〇1 ^ (9: 1: 2〇- [), followed by CH3CN-CH3〇H (8 ·· _ 2: 10- L), collect 1-L fractions. Collect fractions 11-30 and concentrate to dryness. Dissolve the resulting residue in CH3OH (50 mL) and place (10 times of dissolution operation) Phase HPLC 60A, 8 thick C18, 41.4 mm IDX25 cm and 41.4 mmX5 cm protective assembly), the column system is balanced with H2〇-CH3〇H-CH3CN; (50: 175: 175, containing 0.1% 閜 4 ( ^ 〇 :). The column system was changed from H2〇CH3〇H-CH3CH to (50: 175: 175; containing (K1; NfUOAc) to H2〇-CH3〇H CH3CN at a rate of 40111 / min and 60 minutes. (10:45:45; containing 0 · 1; / NH4〇Ac) linear gradient precipitation. The variable wavelength UV detector adjusted to 250 nra was used to monitor the separation process. The collection corresponds to a small amount of Spinozin Y (collect Part 1, hL), Spinoluo 'Sin K (collection Part 2, 8-L) and Spinn-33-this, · Zhang's scales are applicable to China National Standard (CNS) A4 specifications (210X29? Mm) one pack -(Please read the precautions on the back before filling out this page) Order the consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs The company printed 487559 A7 __B7_, V. Description of the invention (31) Nosin 0 (collection part 3, 4-L) The first 3 peaks of the depleted lysate (collection of 10 leaching operations) Sin K was concentrated to a small volume, and then desalted by re-chromatography in the same column, without the dissolution of Yuanyuan solution. The effluent corresponding to the absorption peak was concentrated to dryness, dissolved in t-BUOH, and frozen. Dry to obtain pure Spinoxin K (7.3 g). ^ Desalting Spinoxin 0 in a similar manner and freeze-drying K to obtain Spinoxin 0 (1.4 g). Spinoxin is obtained by similar chromatography. Ya desalting (Rainin Dynamax-60A 8 pm C18 column, 21.4 mm IDX25 cm, with 21.4 fflinX 5 cm protective components) and M similarly freeze-drying M to obtain pure Spinoxin Y (46 mg) Ο tube) Example 10 NRRL 18719 Preparation of Sinopinoxin J, Zhongpinoxin L, Zhongoxinoxin M, and Zhongwanoxin N. Spinacin polyspora soinosa NRRL 18719 culture M was used to obtain spinoxin J, spinn Nosin L, Spinozin M, and Spinnozin N. Α Buttering · Vibrating Wet Bottle A culture of Spinaldella yeast NRRL 18743 in suspension in liquid nitrogen was inoculated into a nutrient medium having the following composition: fluorescein-based component a (R) pancreatic soybean medium 11 30 yeast extraction Object 3 MgS〇4_H2〇 ° 2 This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) I .. Binding (please read the notes on the back before filling this page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumer Cooperative 487559 A7 ____._ B7___ V. Description of the Invention (32) Glucose '5 Maltose 4

Deionized water q.S.l-L

Autoclave at 120 ° C for 30 minutes. #Baltimore Biolabs, Cockeysville, MD Can be used to prepare slanted or flat media by adding 2.5% agar to nutrient media. The inoculated slant medium was cultured at 301C for about 10 to about 14 days. The mature slant medium culture K was scraped with sterile equipment to loosen and remove the spores and soak the mycelium clumps. About 1/4 of the thus obtained pine spores and cultures were inoculated into 50 mL of the first-stage nutrient seed culture medium. Alternatively, the first stage culture medium can be inoculated from a liquid nitrogen ampoule. When the culture is maintained in liquid nitrogen, use a homogeneous nutrient medium (cultivated at 301C for 48-72 hours), dilute with sterile suspension M1: 1 (volume: volume), and distribute into sterile tubes (1.5 ml / Tube) to prepare ampoules. The suspension contains lactose (100 g), glycerin (200 ml), and deionized water (q · S · to 1 liter). Inoculate the \ liquid nitrogen ampoule into a 500-inL Erlenmeyer flask (or a 250-ml flask containing 50 ml medium) containing 100 ml mL of nutrient medium. The culture was cultured at 301C in a shaker at a rate of M 260 rpia around a 2-hour (5.08 cm) circle for 48 hours. The cultured culture (10% v / v inoculum) of liquid nitrogen ampoule, depending on the size of the flask, is inoculated to a production medium containing 50 ml or 100 ml of the following composition: This paper size applies Chinese national standards (CNS) A4 specification (210X297 mm): Binding (please read the notes on the back before filling out this page) 487559 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention base

畺 glucose 80 adenized milk * 20 cottonseed meal h 30 corn infusion 10 CaC〇3 (industrial grade) 5 methyl oleate 30… tap water q · s · to 1-L MIN NaOH adjust pH to ρΗ7 · 0, at 120Ό Sterilize for 40 min. * Adrenalized milk nutrients, Sheffield Products, Norwich, HY 13815

MifProflo »graders Protein, Memphis TN 38018 The amount of methyl oleate is 30 rol. The inoculated productive medium was cultured in a 250-ml or 500-ml flask at a speed of M 260 rpm in a shaker at 2-371 (5.08 cm) circumference at 371C for 7 to 10 days. B. Zygophyllum inverse tendinosa: In order to provide a large amount of inoculum, inoculate 10 ml of the first-stage medium prepared as described in Part A above to 400 ml of second-stage nutrition that has the same composition as the first-stage medium Sex medium. This second-stage culture medium was cultured in a 2-L wide-mouthed flask, and was cultured for 48 hours at 30 ° C in a shaker at a rate of 260 rpm around a 2-inch circle. The cultured second-stage nutrient medium (2 L) is seeded to 80 to 115 liters as described in Part A-36 above.-This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) — r binding ( (Please read the precautions on the back before filling this page) 487559 Α7 Β7 V. Sterile production medium prepared by the method described in the description of the invention (34). The inoculated production medium was fermented in a 165-L stirred bioreactor at a temperature of 301C for 7 to 10 days. The air flow and the mixer speed in the mixing tank are controlled by a computer to maintain the dissolved oxygen concentration at or above 60% to about 80% air saturation. The following table illustrates the amount of Spinoxin J, Spinoxin L, Spinoxin M, and Spinoxin M, and Spinoxin N prepared from a culture of NRRL 18719. Table I Use NRRL 18719 The amount of spinosin compound produced by the culture by fermentation in a shake flask. i clothing-(Please read the precautions on the back before filling out this page) The amount of printing factors (mg / m 1) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Spinoxin J 661 Spinoxin L 133 Spinox Sin M NDH Spinozin N, ND * 1 ** Not detectable by HPLC analysis. 37 This paper size applies to Chinese National Standard (CNS) A4 specifications (M0X 297) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 1. Description of the invention (35) Section mutual table

I Amount of spinosin compound produced by NRRL 18719 culture fermentation by a stirred reactor. Amount of factor (mg / ra 1) Spinoxin J 5,282 Spinoxin L 2,487 Spinoxin M 136 Spinoxin N 71 Tube pus example 11 Preparation of Sinopinoxin J, Medium Chernosin K, Zhongluo Nuozai M, and Zhongluo Nuozai N_M prepared the fermentation medium (105-L) as described above, and the pH was adjusted to 10 by adding 5N Xin 0Η (initial pH 6.8). The resulting mixture was filtered through a ceramic filter. The filtrate was discarded, a mixture of acetone and water (1: 1, 50 L) was added to the mycelium solid, and the resulting mixture was filtered. A second mixture of acetone and water (1: 1, 50 L) was added to the mycelium solid, and the resulting mixture was adjusted to pH 3.0 with 25% sulfuric acid. The resulting mixture was filtered, and a third mixture of acetone and water (1: 150 L) was added to the hypha solid. The resulting mixture was filtered and the acidic filtrate was combined. . This paper size applies Chinese National Standard (CNS) A’4 size (210X 297mm)

Hi 'mu IK f ^ Jn ml mi · ϋϋ · ϋϋ —ϋ ϋ_ϋ ϋϋ VJ, — ^ ϋ —ϋ 1_ιϋ ml 1— ^^^ 1 tin— I f (Please read the notes on the back before filling this page) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China 487559 A7 B7 ^ V. Description of the invention (36) The combined filtrate M has been extracted (10 L). The phases were separated and a second portion of hexane (10 L) was added to the aqueous phase. The pH of the resulting mixture was adjusted to pH 10 using 5N NaOH. The emulsion was diluted with M50 L water. The phases were separated and hexane was extracted with a third portion of hexane (10 L). The phases were separated and the 2 and 3 hexane extracts were combined and concentrated to a volume of about 4 liters. When standing, the condensate is divided into three phases, an aqueous phase, an emulsified liquid phase, and an organic phase. The organic phase was freeze-dried to obtain 15.29 g of a crude product. The crude product was dissolved in methanol (500 mL), filtered, and concentrated to dryness under reduced pressure. Dissolve the residue in Part 2 of methanol (20 ml) and place in LH-20 SEPHADEX (Pharraacia LKB Biotechnology, Inc. Piscata way, NJ, 7.5 cmX46 cm), and dissolve in M methanol and collect 25 ml. Serving. The HPLC system was used to analyze the eluate M to determine the eluate containing the spinoxin compound. Fractions 18-50 were combined and concentrated to dryness. The residue was dissolved in a mixture of methanol, acetonitrile, and water (5: 5: 1) and a 1 ml portion was taken in a preparative reverse-phase HPLC column (Rainin Dynamax -60A, C18, 41.4 μm 300 ×, 8 mm particles, 60A holes, Woburn, MA). Column M was added with ammonium acetate to a final concentration of 0.1% (pH 7.6) in a mixture of methanol, acetonitrile, and water (87.5: 87.5: 25) to elute. The eluate fractions were analyzed using an HPLC system, and similar eluate fractions and concentrated M were combined to obtain three semi-pure concentrates A, B, and C. The semi-pure concentrate C was rechromatographed on the system described in the previous paragraph, and rechromatography was performed 10 times, with each rechromatography operation being filled with 200 ml. The elutions from each operation were combined and concentrated to obtain Preparations C1 and C2. Preparation C2 was subjected to the third chromatography; however, 0,1% ammonium acetate was replaced with water (desalted. The paper size is in accordance with Chinese National Standard (CNS) A4 size (210X 297 mm). Binding (please read the back first (Notes on this page, please fill out this page) 487559 A7 B7 'V. Description of the invention (37) Step). The fractions containing Spinoloxine 1 ^ with a purity of 1 卩 1 ^ to &gt; 99.5% were combined and concentrated. The residue was crystallized from K in ethanol / water (1: 1) to obtain 2.4 g of spinosinol L.

The preparation C2 and the semi-pure concentrate B are combined and desalted as described in the previous paragraph (12 X 200 inL operation); however, the desired compound is a mixture of methanol, acetonitrile and water (11: 11: 3) Dissolution. HPLC. Spinesin J-containing fractions with a purity of at least 99.5% were combined and concentrated. The residue was dissolved in hot t-butanol and freeze-dried to obtain 4.3 g of Spinoxin J 0. The semi-pure concentrate A was chromatographed as described above, but the desired compound was added with ammonium acetate to a final concentration of 0.1%. A mixture of methanol, acetonitrile and water (37.5: 37.5: 25) was eluted. The fractions from each operation (4 times in total) were combined and concentrated to obtain Preparations A1, A2 and A3. The above-mentioned column chromatography was used to prepare the food A 1; however, the column system was a mixture of K methanol, Ethan and water (2: 2 ·· 1) was eluted. Spinelin M-containing eluates containing at least 99.5% HPLC purity were combined and concentrated. The residue was dissolved in hot t-butanol and lyophilized to obtain 136 mg of spinosinol M. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Preparation A2 was chromatographed and processed according to the method described in the previous paragraph to obtain 71 mg Spinoloxin N.啻 Scenario 12: Utilization of NRRL 18823, Part of QA's Nuoxing QA • Zhenpan Style: Anger Bottle Fermentation ': Spinolae sp. Yeast NRRL 18823, freeze-dried 9 capsules or kept in liquid nitrogen The culture is inoculated into a nutrient medium with the following composition: ___- 40 -_ This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) 487559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (38) Firefly pieces _ Fanmou 1 _ composition _ most (g) pancreatic soybean culture medium "30 0 yeast extract 3

MgS〇47H2〇 2 glucose 5

Deionized water q.S.l-L

Autoclave for 30 minutes at 120TC &quot; Baltimore Biological Laboratories, Cockeysville, MD can be inoculated to the first stage medium from liquid nitrogen ampoules. This ampoule is a homogeneous one-pot culture (48-72 hours incubation, 301!), Diluted 1: 1 (volume: volume) with sterile suspension, and distributed into sterile tubes (1,5 ml / tube) )in. The suspension contains pore sugar (100 g), glycerol (200 ml), and deionized water (U.s. to 1 L). Liquid nitrogen ampoules were inoculated into a 250-ml wide-mouthed triangle flask containing 50 ml of nutrient medium. The culture was cultured at 32 ° C for 2 hours (5.08 cm) in a shaker at a rate of 250 rpm in a shaker, and cultured for 48 hours. The cultured culture (5% v / v inoculum) was inoculated into a 50-mL Erlenmeyer flask containing a productive medium having the following composition: 4: peizhai base composition, S (g) glucose 80 Adenized milk ”20 Cottonseed meal U • 30 -41-The paper scale is applicable to China National Standard (CNS) A4 (210X29? Mm) I ----- JI ----------- (Please read the notes on the back before filling this page) 487559 A7

5. Description of the invention (39) Corn infusion '10 CaCOa (industrial grade) 5 methyl oleate 30 tap water q · M1.N NaOH adjust the pH to ρΗ7 · 0 and sterilize at 120t! For 40 min. M glandularized milk nutrient, Sheffield Products, Norwich, HY HHProflo »graders Protein, Memphis, TH The amount of methyl oleate is 30 ml. The inoculated productive culture medium was cultured in a 250-mL Erlenmeyer flask at 30 ° C at a rate of M25〇ΓΡΐα around a 2-inch circle and cultured for 7 days. In order to provide a large amount of inoculum, 10 mL of the first-stage nutrient medium prepared as described in Part A above was inoculated to 400 mL, which is the same as the first-stage nutrient medium. Composition of the second phase of nutrient medium. The second-stage nutrient medium was cultured in a 2 L wide-mouthed Erlenmeyer flask, at 321: below, at a rate of 260 rpm around a 2-hour circle, and cultured for 48 hours. The cultured second-stage nutrient medium (2 L) was prepared by inoculating 5 L of sterile production medium as described in Section A above. The inoculated production medium was fermented in a 165-L stirred bioreactor at a temperature of 301 ° C for 7 days. The air flow and agitator speed in the mixing tank are dug by the computer to maintain the dissolved oxygen concentration at or above 60% to about 80% air saturation. Example 13: Spinozin Q, Spinn_Nosin R, Zhongxun Mou S, and Spinnoxin T from self-cultivation NRRL 18823_ -42-This paper is for Chinese country Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page}

Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed 487559 A7 _____ B7, V. Description of the Invention (40) Prepare a fermentation medium (100 L according to the method described in the above example); The potency of nosinol was 303 pg / ml, and the potency of Spinolol Q was 50 pg / ml), and it was refrigerated for 2 days before processing. After the pH was adjusted to 3.0 with 5N HC1, acetone (100 L) was added to the whole culture medium. The resulting mixture was filtered through a ceramic filter to obtain mash (170 L), which was kept under refrigeration until every other week. The medium / acetone filtrate was adjusted to pH 13 and passed through a ceramic filter before filling to steel tubing (10 L; 10X122 cm). The column contained HP-20SS resin (Mitsubishi Chemical Industries, Ltd., Japan) ) And the flow rate is 1 L / min. This column was mixed at a flow rate of 1 L / min using a solvent "A" (0.1% aq. NH4〇Ac, adjusted to pH 8.1 with NH4OH) and a solvent "B" (CH3CH CH3〇H 1: 1). Gradient, 4 L of eluate was collected. The pump system is programmed to generate a gradient from 0 to 50% Β within 1 minute, then a gradient from 50 to 100% Β within 90 minutes, and then 100% Β power is equally transmitted for 15 minutes. HPLC analysis indicated that the majority of the eluate 17 (4 L) was Spinoxin R and other more polar substances and a small amount of Spinoxin T and Y; the majority of the eluates 18-22 were Spinozinol and smaller amounts of Spinozin R and Q and a small amount of Spinozin S and more polar substances; eluates 23-24 contain Spinoxin and Q. The HPLC analysis of the collected part suggested the following total amount: Spinozin® 23.0 g; Spinozin® Q 3.4 g; Spinozin® R 2.0g; Spinozin® S 0.2 ?; Spinozin® T 0 , 2g. Iv) fe Example 14: Zhongke Nuoxin semi-blue orchid rank 冋 received Zhongke Nuoxin Q, Zhong Nu Nuo R, Zhong W Nuo Nu S, and Zhong Nuoxin T_ fermentation medium (85 L; Obtained Shibin-43-This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page) ---- Order the staff of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative 487559 A7 B7 V. Description of the Invention (41) The potency of Nuoxin is 302 pg / iil, and the potency of Spinol Q is 44ps / io1), and it is refrigerated overnight before processing. After the pH was adjusted to 3.0 with 5N HC1, acetone (90 L) was added to the entire medium. The resulting mixture was filtered through a ceramic filter to obtain mash (176 L), which was kept under refrigeration until every other week. Adjust the medium / acetone filtrate K 50% NaOH to pH 13 and pass through a ceramic filter (140L filtrate) before filling the steel tube (10 L; 10 X 122 cm). The column contains HP- 20SS resin (Mitsubishi Chemica 1 Industries, L td ·, Japan) and a flow rate of 1 L / min. This column was mixed at a flow rate of 1 L / min using a gradient of solvent "A" (0.1% aq • NfUOAc, adjusted to pH 8.1 with NH4OH) and solvent "B" (CHaCN CH3〇H 1: 1). Collect 4 L (approximate) eluate. The pump system is controlled by the program. M generates a gradient from 0 to 50% B within 1 minute, then generates a gradient from 50 to 100% B within 90 minutes, and then transmits 100% B power equally for 15 minutes. HPLC analysis indicated that fraction 1 (fractions 16-21; 24.5 L) contained spinoxin H (12.32g) and Q (0.34g); fraction 2 (fractions 22-25; 16 L) Contains Spinozinol (4.66 g), Q (2.06 g), R, S and T. A · The pure ingredients are mixed in a concentrated manner. The collected part 2 is concentrated to dryness, redissolved in dichloromethane (50 ml), and filled with silica gel (EM grade 62, 60-200 mesh), and the balance is equal to two. Glass columns in methyl chloride (5,5 cm X, 30 cm). The column was washed with M dichloromethane (2 L), followed by lysis with M dichloromethane-methanol (95: 5), and 250 ml of the eluate was collected. The fraction 3 obtained after 15 operations was combined and concentrated to a residue, and then dissolved in ethanol / water (400 ml) and allowed to be maintained at room temperature. ___-44 -___ This paper size applies Chinese national standards (CNS ) A4 size (210X 297mm) (Please read the precautions on the back before filling in this tribute)

# Printed by the Consumers' Cooperatives of the Central Prospective Bureau of the Ministry of Economic Affairs 487559 A7 _ B7 / V. Description of Invention (42) weeks. The obtained crystals were washed with cold ethanol / ice (1 ·· 1) and dried to obtain 6.1 g of dry crystals. The crystals were analyzed by HPLC and found that they contained 68.7% Spinoxin IX and 31.2% Spinoxin Q. The dry crystalline material 2 was dissolved in tetrahydrofuran / methanol (1: 1) and placed in a preparative reverse-phase HPLC column (Rainin D ynama X 6 0 A 8 pm C18, 41 · 4 m in ID X 2 in 12 operations). 5 cm with 41.4roinx 5 cm protective assembly). The column was dissolved and eluted at a flow rate of 50 ml / min, using a solvent "A" (H2O-CH3CN-CH3〇H; 30:35:35, containing 0.1% NH4OAc) and a solvent "B" (H2 〇-CH3CN-CH3〇H 10: 45: 45, containing a gradient of 0.1% NH4 (Ac). The pump system is programmed to produce a gradient from 50 to 100% B in 60 minutes. The separation process was monitored by a variable wavelength UV detector adjusted at 250 nm. Peak 1, containing Spinozin (Η) (99%; 6 L), followed by Spinozin Q. Combine all the operations (12 times) of peak 2 (containing 20% spinoxin Η, component Q 80%; 8 L) and concentrate to 500 ml, then put into the same column and under the same mobile phase conditions Operate 5 times. Part 2 (2 L) was collected and desalted by placing it in the same column M equilibrated in H2O-CH3OH-CH3CH (20:40:40) containing 99% pure Spinozin Q. The column system was eluted with 112-(: 113〇 [1-(^ 3〇 [&lt; (10:45:45)), and 10 lysates were collected (one every 3 minutes). The lysates were combined to 2 to 7. Concentrate to a residue and dissolve in hot ethanol (80 ml). Add an equal amount of Η20 and allow the solution to cool overnight. Collect the resulting crystals in a decanter and wash with cold EtOH-H2O (1: 1). And dried M to obtain 1.5 g of pure spinosinoxin Q. Tube pus example 1 5 killing Kuang insect sister A · Bing _ floating liquid. -—____-45-This paper size applies to China National Fresh (CNS) Λ4 specifications ( 21GX 297 public holiday)-(Please read the notes on the back before filling this page)

A7 __B7_ printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, V. Description of the Invention (43) Spinozin compound '12 .5¾ TERGITOL TMN-6 (non-ionic surfactant) 1.0% ZI0SYL 200 (silica) 1.0% AF-100 (Polysilicone-based defoamer) 0.2% Sanxan gum solution (3%) 10.096 ΜΑΚΝ 10 (10 mol ethylene oxide nonylphenol surfactant) 9.0% tap water 66.3% R · Emulsifiable Spinocin compound 12.4% EXXON (naphthalene solvent) 83.6% T0XIMUL Η (nonionic / anionic surfactant blend) 2.0% TOXIMUL D (nonionic / anionic surfactant blend) 2.0% Pipeline Example 1ft Inventive Formula A of the invention • Feed box warming substance Spinoxin compound 10% rice coarse bran 85% light mineral oil 5% R • Feeding mixture of Spinoxin compound, 25% Alfalfa flour 60% Powdered clay 5% Waste molasses 10% -46-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

， 1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Fifth, invention Ming (44) C · suspension · Spinoxin compound 30% naphthalenesulfonate 5% non-ionic surfactant 5% smoke Silica 1% Water 59% D · Drop solution Spinoxin compound 20% Nonionic surfactant 0.8% Propylene glycol 15% Water 64,2% E · Drop suspension Spinoxin compound 1096 Nonionic Surfactant 1% Light mineral oil 8996 F · Sprayable solution Spinoxin compound 15% Propylene glycol 85% G · Sprayable county liquid suspension Spinoxin compound 25% Propylene glycol, 1596 Water 60% Η ♦ 可 泮Spinococcus Spinocinus Compound. 30% -47-This paper size applies to China National Standard (CNS) Α4 size (210X29 * 7 mm) (Please read the precautions on the back before filling this page)

487559 A7 B7 V. Description of the invention (45) Polyvinylpyrrolidone '1% water 68% when oil Γ Example 17 Synthetic decoration effect Part A rhamnolide-modified derivative Printed by employee consumer cooperative of Central Standard Bureau of Ministry of Economic Affairs — (Please read the notes on the back before filling this page) _ 线 啻 敝 例 八 1- (Compound 9 邛-(2.3.4-Tri-0-ethyl- (14-rhamnosyl 5.6-II Gas-derived halves) Φ 窨 oxin A 9-Psa The compound 9-0- (2,3,4-tri-0-ethyl-oc-L-rhamnosyl) Spinoxin A 9-Psa (106 mg, 0,137 mmol) was dissolved in 5 mL of toluene. Phenyl-triphenyl temco (I) halide (11.9 mg, 0.0128 mmol) was evacuated. The head space of the flask was evacuated and nitrogen was introduced 3 times. Hydrogen was introduced 3 times. The flask was maintained in hydrogen using a spherical bottle and heated to 110-120 ° C. After 3.5 hours, the flask was cooled to room temperature and the oil-air hydrogen was replaced with nitrogen. The toluene solvent was evaporated and M20 inL Replace with ether. M3X 10 mL IN HC1 extract the ether solution. Combine the acid extract and M10 ml 4H NaOH to neutralize. M3x 10 mL ether extract the neutralized suspension, combine the ether extracts, and wash with M20 mL brine. MK2C03 was dried and evaporated under reduced pressure. Compound 9-0- (2,3,4-tri-0-ethyl-a rhamnosyl 5,6-dihydro derivative) was obtained. Nosin A 9-Psa compound 5,6-dihydro derivative, 39 ♦ 4Ing, 36.8% 1H-NMR δ6.84 (lH, bs), l01 (1H, m), 0.68 (1H , M) 〇

In the case of A 2 -2 Dioxin Z _ some intermediate Nuoxin Q, the compound Spinoxin Q (302 rog, 0.412 ππηοΐ) was dissolved in dry CH2C12 (8 ml). Stir the solution under nitrogen and add DMAP (diisoamylmethyl phosphonate, 269 mg, 2. "mmol). Then introduce dichloroacetic anhydride -48 ~ This paper applies the Chinese National Standard (CNS) Λ4 Specifications (210X 297mm) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economy, Yinjia 487559 A7 — ___B7___, one or five, invention description (46) (492 mg, 315 / i 1, 2.05 mmol). After 45 minutes, add Ptt Stir (1.5 ml), then add Et0Ac (50 ral) and toluene (50 ml). M5% aq. NaHC03 (3X) extraction solution. Manh · Ha2SO4 dried the organic phase and dried under reduced pressure. The residue was flashed Purify in a SiO2 column (30 g / EtOAc followed by 5% EtOH in EtOAc). Purely eluate the compound 2'-0-dichloroacetamispino Spinoxin Q; 310 mg, 89% Cl MS ro / z 844 (M + 3), 842 (M + 1); IR v 1772 cm "; 4 NMR (CDC13) δ 6.7Q (1H, bs), 6.0 (1Η, s), 5. · 43 (1Η, bs), 5.19 (1Η, dd: 3.1, 1.8 Hz), 1.67 (3Η, CHa, bs) ppm ° Example A 3 ~ 2'-0-Trimethylacetate Gibbs Spinoxin_Q The compound Spinoxin Cl (330 mg, 0.451 mmol) was dissolved in dry CH2C12 (10 ml). The solution was stirred under nitrogen and DMAP (diisoamylmethyl pentanoate, 306 mg, 2.50 mmol) was added. Then trifluoroacetic anhydride (473 rag, 320 // 1, 2.25 mmol) was introduced. After 14 hours, pyridine (1.5 ml) was added, followed by Et0Ac (50 ml) and toluene (50 ml). K5% aq. NaHCOa (3X) extraction solution. The organic phase was dried with Manh. Na2S04 and dried under reduced pressure. The residue was purified in a flashed SiO 2 column (100 g / EtOAc followed by 5% EtOH in EtOAc). Compound 2'-0-trifluoroacetamido-spinnockin Q obtained by pure dissolution; 199 mg, 54904 NMR (CDC13) δ 6.69 (1Η, bs), 5.43 (1Η, bs), 5 · 26 (1Η, dd: 2 ′, 1.6 Hz), 1.66 (3Η, CH3 'bs); 13C-HMR (CDC13) δ 156.7 (d: 32 · 5 Hz), 114.0 (q: 286 Hz) ppro 〇 When oil? Example A4-2’-Π- (to Sanqijia Mou) Cangjia Mou Zhongke Nuoxin Q Dissolve Spinoxin Q (i30 mg, 0.587 mmol) in dry -49-

Awl IT (Please read the notes on the back before filling out this page) The scales are applicable to China National Standard (CNS) A4 size 1 210X297 mm) &quot; 487559 Printed by A7 B7, Cooperative of Employees of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (47) CH2C12 (10 ml). DmAp (diisoamylmethylphosphonate, 367 mg, 3.0 mmol) was added, followed by trifluoromethylbenzyl chloro (613 mg, 440 ml, 2.94 mmol). After stirring at room temperature for 2 hours, M EtOA c (100 u 1) and toluene (30 ml) were used to dilute the reaction mixture, and the solution was washed successively with M saline and 5% aq, NaHC0 3 (3 ×). The organic layer was dried with Manh. Na2S04 and dried under reduced pressure. The residue was separated in a flashed Si02 column (100 g / E t0 Ac followed by 5% EtOH in EtOAc) to obtain the compound 2′-0-p-trifluoromethyl) benzylspinoxin Q ; 473 mg, 89% iH NMR (CDC13) 58,13 (1H, bd: 8.1 Hz), 7.68 (1H, bd: 8 · 2 Hz), 6.73 (1Η, bs), 5.45 (1Η, bs), 5.42UH, dd: 3.3, 1.8 Hz) '1.69 (3Η'CH3'bs); Element analysis: Estimated value of C43H68MO11F3: C 65.10, Η 7.58, N 1.55; Actual value: C 64.89, Η 7.55, N 1.56.

Example A 5 (S, 6R) -Cyclo (p-trifluoromethyl) cylamine 临 窨 窨 NuoQi Q Compound (5S, 6R) -epoxy-spinoxin Q (406 mg, 0.543 mrool) was dissolved in dry CH2Cl2 (10 ml). DMAP (diisoamylmethylphosphonate, 369 mg, 3.0 mmol) was added, followed by trifluoromethyl benzamidine chloride (623 mg, 445 w 1, 2.98 mmol). After stirring at room temperature for 14 hours, triethylamine (2 ml) was added and stirring was continued for 30 minutes. MEt0Ac (100 ml) and toluene (30 ml) were used to dilute the reaction mixture, and the solution was successively washed with brine, 5% aq. NaHC03 (2x) and water (IX). The organic layer was concentrated under reduced pressure. The residue was purified in a flashed Si02 column (80 g / Et0Ac) to provide the compound (5S, 6R) -epoxy-2'-0M-p-trifluoromethyl) benzyl spinol-50-Ben Paper size is applicable to China National Standard (CNS) A4 (210X 297mm) ------ * — packing— (Please read the precautions on the back before filling this page), ιτ • Ay 487559 A7 ____ _ ' B7, V. Description of the invention (48) Xin Q; 391 mg, 78% IR / 1728, 1664, 1324, 1272cm-1; 4 Hidden (CDCla) δ 8 · 12 (1Η, bd: 8 · 2 Hz), 7 · 67 (1Η, bd: 8.2 Hz), 6.54 (1Η, bs), 5.42 (1Η, dd: 3.2, 1.8 Hz), 131 (3Η, CH3, bs) 〇g Pus AR -2 '-(1-dioxoacetamidine, a certain intermediate, nosine) The compound spinoxin (170 mg, 0.237 ππποί) was dissolved in dry pyridine (3 ml). DMAP (diisoamyl) was added Methyl phosphonate, 30 mg, 2.46 mmol). Stir at room temperature and add dichloroacetic anhydride (0.077 ml, 120 mg, 0.50 mmol). After 30 minutes, add toluene (50 ml) and EtOAc (50 ml). The solution was washed with M water, and then washed with 5% aq. NaHC03 (3X). The organic was dried with MNa2CO3. And concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (15 g / Et0Ac) to provide the compound 2'-0-dichloroethenylspinoxine; 155 mg, 79% Cl MSm / z 830 (M + 3), 828 (M + 1); 4 NMR (CDC13) δ 6.70 (1H, bs), 5.99 (1Η, s), 5.18 (1H, s), 5.18 (1H, dd: 3 0, 2.0 Hz).

Case A 7-(Two-Z-based) Phosphorous Beverage _Zhongluo Nuoxin H Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs a, ----- (Please read the precautions on the back before filling this page) The compound spinoxin IX (351 mg, 0.489 mmol) was dissolved in dry pyridine (5 ml). Add DMAP (diisoamylmethylphosphonate, 62 mg, 0.51 mmol) and stir at room temperature under nitrogen for 5 minutes. Diethyl chlorophosphite (157 mg, 0,145 ml, 1.0 mraol) was added. After 30 minutes, toluene (50 ml) and Et0Ac (50 ml) were added. Flammy brine (2X) and 5% t β aq. NaHC0 3 were used to wash the solution and concentrated. The residue was separated in a flashed Si02 column (100 s / EtOAc) to obtain the compound 2'R- (diethyl) phosphite spinoxin; 306 mg, 75% CI MS m / z 838 (M + 1); 4 NMR (This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 Β7 V. Description of the invention (49) CDC13) δ 6.69 (1Η, bs), · 40 (1Η, ιη), 3.83 (4Η, 2X CH2, m), 1.18 (6Η, 2X CH3, m); Elemental analysis: For CuH72N〇12P The estimated value: C 63.06, Η 8.66, N 1.67; the actual value: C 62.94, Η 8.88, N 1.71. Example 1 A 8-(2 ′ R)-(di 7 ″) thionyl phosphorium

The compound spinoxin IX (261 mg, 0.364 mmol) was dissolved in dry pyridine (3 ml). DMAP (diisoamylmethylphosphonate, 60 rag) was added followed by diethyl chlorothiophosphate (152 mg, 125αζ 1, 0.80 rarool). The reaction mixture was stirred at room temperature under nitrogen. After 12 hours, toluene (5 ^ ml) and Et0Ac (50 ml) were added. The solution was extracted with M brine and then M5% aq. NaHC03. The organic layer was dried over MNa2SO4 and concentrated under reduced pressure. The residue was purified in a flashed SiO 2 column (30 g / Et0Ac) to obtain the compound 2'R- (diethyl) thiophosphate spinoxin; 8.4 mg, 27% CI MS m / z 878 ( M + l); UMR (CDC13) δ 6.74 (1Η, bs), 4.80 (1Η, m), 4.22 (4H, 2X CH2, m), 1.30 (6Η, 2X CH3, m). Example of tracheid A 9 -2 '-Π- (Z) Z dithio in hydraxin H The compound spinoxin IX (720 mg, 1.003 mmol) was dissolved in dry dichloroethane (15 ml). DMAP (diisoamylmethylphosphonate, 80 mg) was added, followed by dry triethylamine (2 ml). The reaction mixture was stirred at room temperature under nitrogen. Ethyl ethylenedifluoride chloride (1 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with M toluene (50 ml) and EtO Ac (100 ml). The solution was washed successively with M saline, 5% aq. NaHC03 (3x), and water (IX). The WMa2CO3 organic layer was dried and concentrated under reduced pressure. The residue was purified in a flashed Si0 2 column (110 g / Et0Ac) to obtain the compound Spinoloxine 2-This paper size applies the Chinese National Standard (CNS) Α4 size (210X297 mm) C— ( Please read the notes on the back before filling this page) Order 487559 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (50) 0- (ethyl) ethoxybenzyl Spinolox; 668rog 81% CI MS m / z81 8 (M + 1); i-HMR (CDC13) δ 6.69 (1H, bs), 5.22 (1Η, dd: 3.0, 1.8 Hz), 4.27 (2Η, q : 7.2 Hz), 1 · 29 (3Η, t ·· 7.2 Hz); Elemental analysis: CuHs 7 NO! 3 Estimated value: C 64.60, H 8.26, N 1.71; Actual value: C64.63, Η 8.41 , N 1,80.

Symptoms A10-2'-Π-Trisinoacetamidine Inoxin H was dissolved in Spinoxin (295 mg, 0.411 mmol) in dry pyridine (5 ml). Trichloroacetamido chloride compound (1 ml, excess) was added and the reaction mixture was stirred at room temperature under nitrogen for 14 hours. Add toluene (50 ml) and Et0Ac (50 ml). M5% aq. NaHC03 extraction solution. The organic layer was dried over MNa2SO4 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (60 g / EtOAc) to obtain compound 2'-0-trichloroethinyl spinosinoxine; 249 mg, 70% CI MS m / z 866 (M + 5 ), 862 (M + 1); LR (CDCla) δ 6.70 (1Η, bs), 5.18 (1H, / dd: 2.2, 1, 8Hz), 2.16 (6Η, 2x CH3, s) 〇 啻) Fe case A 11-2'_Π- 氡 7, a certain sinosome Η Η The compound spinoxin Η (306 mg, 0.43 ππηοΐ) was dissolved in dry pyridine (5 ml). Add chloroacetamidine (0.50 ml) dropwise. The reaction mixture was stirred at room temperature under nitrogen. After 3 hours, toluene (50 ml) and Et0Ac (50 ml) were added. Continuous M saline, 5% aq, NaHC03 and water washing solution. The organic layer was dried over 2 × 25 × 4 and concentrated under reduced pressure. The residue was purified in a flashed Si02 column (80s / Et0Ac) to provide compound 2'-0-chloroethenylspinoxine; 71 mg, 21% HMR (CDC13) 36, 72 (1H, bs ), 5.16 (1H, dd: 2.2 *, 1.8 Hz), 3,69 (2H, bs);-53-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) r-- ^ Yi ------ 1T ----- (Please read the notes on the back before filling out this page) 487559 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (51) &quot; C-NMR (CDCl3) d 169.9 ('C = 0), 41.4 (-CH2Cl) PPin. Example A 12- (3 'R) -2 fluorenone-3 methylarginyl-3'-(thiomethyl) methoxoloxinol _ The compound spinoxinol (3.10 g, 4.32 irnnol ) Dissolved in dry DMS0 (8 ml). This mixture was stirred at room temperature under nitrogen and triethylamine (3 g, 7 eq.) Was added, followed by Py-S03 complex (2.06 s, 12.9 mmol). The reaction mixture was stirred at room temperature for 14 hours. Add toluene (100 ml) and Et0Ac (100 ml). Flail Μ saline, 5% aq. NaHC03 and water extraction solution. The organic layer was dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (SiO 2 / EtOAc) and then separated by HPLC on a reverse phase C-18 column M 10% water in methanol as a mobile phase. The obtained pure eluate was evaporated to provide compound (3'R) -2'-keto-3'-methoxy-3 '-(thiomethyl) methyl spinosinol; 697 mg, 39% IR ν 1738, 1721, 1661, 1038 cnrhEI MS m / z 776 (M +); ^ H-NMR (CDC13) 5 6.71UH, bs), 3.99 (1Η, m: Wh / 2 = 18 Hz ), 3.53 (3H, CH3, s), 3.36 (3Η, CH3, s), 2.19 (6H, 2x CH3, bs), 2.08 (3H, CH3, s) 〇 Example A 13-2 醢 some -2'-Epicyclic Nuo Barrier H and 2'-Xuanzhong Nuo Xinxin _ The compound 2'-keto-spinoxin (2.95 g, 4.12 mmol) was dissolved in dry Et20 (60 ml). The solution was cooled to 0 ° C under nitrogen and Li (T-BuO) 3A1H (97%, 1.62 g, 6Λ8 mmol, 1.5 equivalents) was added. Stir for 20 minutes at 0T. The reaction mixture was carefully quenched with brine. Ether (50 ml) was added and the phases were separated. M5% aq.NaHC〇3 (4x) Cleaning Yes — -54 · This paper size is applicable to Zhongguanjia Standard (CNS) A4 specification (210X 297 public holidays)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 * B7_, V. Description of the invention (52) Machine layer, Manh. K2C03 dried the machine layer and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (SiO 2 / EtOAc). It is thus possible to obtain 2'-epimeric alcohols which are not separated on silica or by HPLC on 018 / acetonitrile-MeOH-water (60-30-10). 2'-Alcohols (1.84 g, 2.56 mmol) were dissolved in dry CH2C12 (10 ml). Add human pyridine (5 ml) and DMAP (80 mg), followed by Ac 2 0 (3 ml, excess). Stir at room temperature under nitrogen for 8 hours. The reaction mixture was diluted with MEtOAc (50 ml) and benzene (50 ml). The solution was washed successively with M saline (2X) and 5% aq. NaHC03 (2X). MNazSO * The organic layer was dried and concentrated under reduced pressure. The residue was elutriated (230-400 m, 120 g / EtOAc) in a flashed Si02 column to obtain the pure compound a) 2'-〇-ethylamyl-2'-epispinoxin; 1.176 g, 60%, iH-NMR (CDC13) 56.67 (1H, bs), 4.83 (1Η, d: 3.8 Hz), 4.52 (1H, dd: 10.0, 3 · 8 Hz), 3.47 (6Η, 2XCH3, s), 2.14 (6Η, 2XCH3, s), 2.01 (3Η, CH3, s) ppm. Compound 2'-0-Ethyl-2'-epi-Spinoxin h (280 mg, 0.368 mmol) was added to dissolve in EtOH (5 ml), followed by 10% CO3 solution (3 ml). The reaction mixture was stirred at room temperature under nitrogen for 15 minutes. Brine (10 ml) was added, followed by EtOAc (50 ml) nhe PhH (50 ml). The phases are separated. The organic layer was washed with M water (3X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified by flash distillation in a Si02 column (80 g / EtOAc) to obtain compound b) 2'-epi-Spinoxin; 228 mg • 86% ^ -NMRiCDClajSe.eTdH ^ bsi ^ .eSdH ^ S. eHz), 3.55 (3H, CH3, s), 3.46 (3Η, CH3, s), 2.14 (6Η, CH3, s) ppm; 13C-NMR (CDCl3) 5 203.2, 172.9, 147.9. 144 · 7, 144.5, 129.7, 120 · 3, 103.9, 97.6, 86.1, -55-This paper size is applicable to China National Standard (CNS) A4 (21 × X 297 mm) ^ Binding (please read the first Please fill in this page again for attention) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs for consumer cooperation 487559 kl ______ B7_, V. Description of the invention (53) 84 · 9, 81.1, 77 · 3, 77. Bu 74 · 1, 73.0 , 67.6, 65.4, 61.3, 61.1, 49 · 8, 48 · 2, 48.1, 46 · 5, 42.0, 41.7, 41.2 (2 × C), 37, 9, 37 · 0, 34 · 8, 34 · 6, 31.4, 30 · 6, 28 · 9, 22.2, 19.5, 18.9, 18.2, 16.6, 9,9ρριι.啻 Example A14-2Ό-Sandasinyl SpinolsinΗ The compound SpinolsinΗ (1.59 g, 2.21 nunol) was dissolved in CH2C12 (10 ml) and DMAP (0.80 g) was added. This mixture was searched at room temperature under nitrogen. TMS trifluoromethanesulfonate (0.90 ml, excess) was slowly introduced into the mixture via a syringe and kept stirring for 1 hour. EtOAc (50 ml) and PhH (50 ml) were added. M5% aq. NaHC03 (3x) washing solution. The organic layer was dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flashed Si02 column (100 g / EtOAc) to obtain the compound dimethylsilyl spinosynoxine; 1.615 s, 92% mP = 163 ° C (EtzO); EI MS 791 (M + ); 4-NMR (CDC13) δ 6.69 (1Η, bs), 3.81 (1Η, dd: 2.6, 2,0Hz), 3.46 (3Η, CHa, s), 3.38 (3Η, CH3, s), 2 "6 (6H, 2X CH3, bs) ppm 〇 Tube example A 15-2'-0-Ethyl acetonoxin H_ _ the compound Spinoxin H (2.21 g, 3.08 mmol ) Soluble in CH2C12 (60 ml), add 10% aq. NaOH solution (25 1111) and 1 (2 (: 03 solid (5 g), followed by diethyl sulfate (8 ml, excess). At room temperature under nitrogen The reaction mixture was stirred vigorously for 48 hours. H2O (50 ml) and CH2Cl2 (50 inl) were added, the phases were separated, the organic layer was washed with MgSO 2 (2 ×), dried with K 2 CO 3 and concentrated under reduced pressure. The residue It was separated by flash column 5 230 (250-400 μm, 250 g / Et0Ac). Pure eluent can provide compound -56-this paper size is applicable to China National Standard (CNS) A4 size (2KΓ × 297) Li)-Pack-(Please read the precautions on the back before filling this page)

、 1T meeting 487559 A7 ___ B7 _ 'V. Description of the invention (54) 2, -0-ethylspinoxine Η; 63¾ mg, 28¾ Cl MS ra / z 746 (M + 1); iH-HMR (CDCl3) 56.71 (lH, bs), 3.61 (2H, CH2, ra), 3.49 (3Η, CH3, s), 3.42 (3Η, CH3, s), 2.17 (6Η, 2xCHa, s), 1.18 (3H, CHa, t: 7 * 0 Hz) ppm; 13C-NMR (CDC13) δ67 · 0 (-CH2-), 16.0 (-CH3) ppm; Elemental analysis of C42HB7N010: Estimated value: C 67.61, Η 9 · 07, N 1 · 88; actual value: C 67.80, Η 1.87, N9.20 妩 Example A16-Nonoxin 1 ^ (2'R)-(ethyl) carbon _ Central Ministry of Economy Printed by the Bureau of Consumers of the Bureau of Standards I ^-clothing-(Please read the notes on the back before filling this page) # Dissolve triphenylphosphine (6,5 g, 24.8 mmol) in dry THF (30 ml) in. Diethyl azodicarboxylate (4.8 ml · 5.32 g, 30.5 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Add pure ethanol (1.43 ml ♦ 1. 14 g, 24.8 mmol). After stirring for another 5 minutes, the compound (1.20 g, 1.67 mmol) was introduced. Continue at room temperature under nitrogen. Stir for 24 hours. Add ethyl acetate (50 ml) and benzene (100 ml). K brine, 5% a, q. NaHC 03 (2X) and water (IX) successively washing solution. The organic layer was dried over MK2CO3 and concentrated under reduced pressure. The residue was separated in a flash SiO 2 column (120 g / EtOAc) to obtain Spinoloxine (2'R)-(ethyl) carbonate compound; 233 mg, 18¾ IR v 1747 &gt; 1720 &gt; 1645 &gt; 1263 cm'1; NMR (CDC13) δ 6.74 (1H, bs), 4.95 (1H, dd: 3.3, 1,8 Hz), 4.19 (2H, q: 7.1 Hz) ppm; Elemental analysis of C43Hs7N0i2: Estimated value: C 65 · 37, Η 8.55,, Ν 1.97; Actual value: C 65,44, Η 8.49, Μ 2 · 05 〇 Example A 17-2 III Pneumocarbamate, a medium carbamoxicin, _ Dissolve the spinocinol compound (〗. 12 g, 2.95 mmol) in dry 1, 2- _____ _ 57 _ This paper is suitable for Guancai County (CNS) A4 specifications (210X 297 Gongchu) 487559 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (55) in dichloroethane (3 ml). Add, tidine (3 ml). The solution was cooled to Ot: under nitrogen. Trifluoromethanesulfonic anhydride (1.20 ral, 7,0 mmol) was added. After 1 hour of incubation, PhH (50 ml) and Et0Ac (100 ml) were added. The solution was washed with 5% a.q. NaHC03 (3x). The organic layer was dried over MK2CO3 and concentrated under reduced pressure. The residue was separated in a flash SiO 2 column (160 g / EtOAc) to obtain 2'-0_trifluoromethanesulfinospinoxine; 1.77 g, 71% IR ν 1415, 1212, 1068, and 918 cm · 1; iH-NMIHCDClaMe ^ dH, bs), 4.93 (1H, dd: 2.8, 1.9 Hz) ppm. Example of tube △ 18-2'-〇1-propyl in the nucleus 1 ^ _ The compound spinoxin (1.22 g, 1.70 mmol) was dissolved in CH2C12 (20 ml) and 25% NaOH aqueous solution (15 ml), followed by K2CO3 (2 g), tetrabutylammonium chloride (1.2 g) and benzyltriethylammonium chloride (1.5 g). 1-iodopropane (10 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 48 hours. CH2C 12 (20 ml) was added and the phases were separated. The organic layer was washed with water (2X), dried over K2CO3 and concentrated under reduced pressure. The residue was separated by flash column chromatography (120 g / EtOAc). Concentrate of pure solubilized fractions can provide compound 2f-0-n-propyl spinosynoxine; 535 mg, 41¾) 1H-NMR (CDC 13) δ 6.67 (1H, bs), 2.13 (6H, 2xCH3, x ), 0 · 81 (3H, CH3, t: 7.4 Hz) ppm; Elemental analysis of CuHwNOiD: Estimated value: C 67.95, H 9.15, N 1.84; Actual value: C 67.74,, H9.37, H 1, 84. Case No. A 19-2 夂 〇1- 戍 基 的 诺诺 ΗΗ Dissolve the compound Spinoloxine (1.02 g, 1.42 mmol) in _________________- RO _ This paper size applies Chinese National Standard (CNS) A4 Specifications (210X 297mm) ------ ^ Installation ------ Order ----- Fee J 丨 丨 (Please read the precautions on the back before filling this page) Staff of Central Bureau of Standards, Ministry of Economic Affairs Printed by the consumer cooperative 487559 A7 _____ B7 V. Description of the invention (56) CH2C12 (20 ml) and added 25%, aOH aqueous solution (15 ml), followed by K2CO 3 (3.5 g), tetrabutylammonium chloride (0.8 g ) And benzyltriethylammonium chloride (1.3 g). 1-iodopropane (15 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 72 hours. CH2C 12 (20 ml) was added and the phases were separated. The organic layer was washed with K water (3X), dried over 1 (2: 0 and concentrated under reduced pressure. The residue was separated by flash column chromatography (200 g / EtOAc). Pure solvent Concentrate of the fraction can provide compound 2 'pentylspinoxine Η 559 mg, 50% iH-NMR (CDCI3) δ 6.69 (1H, bs), 2.16 (6Η, 2χ CH3, s), 0.82 ( 3Η # CH3, t: 7.4 Hz) ppm; Elemental Analysis: for C45H73NO10 calc. C 68.58, H 9.34, N 1.78; found C 68.29, H 9.32, N 1.80. Example A W Nosin in benzyl H _; _ The compound Spinoloxine H (1.48 g, 2,06 mmol) was dissolved in CH2C12 (20 ml) and 25% NaOH aqueous solution (15 ml) was added, followed by K2 CO a (3 g), tetrabutyl Ammonium chloride (0.85 g) and benzyltriethylammonium chloride (1.2 g). Add benzyl chloride (10 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 72 hours. Add CH2C12 (20 ml) The phases were allowed to separate. The organic layer was washed with water (3X), dried with MK2CO3 and concentrated under reduced pressure. The residue was separated by flash SiO2 column chromatography (200 g / Et0Ac). Pure dissolution Servings of the concentrate provide compound 2'-0- ¥ kispinoxine; 806 mg, 48% iH-NMR (CDC13) δ 7., 24 (5Η, m), 6.67 (1H, bs), 4.62 (2Η, m), 3.60 (1H, dd: 2.5, 1.6 Hz), 2.14 (6H, 2x CH3, s) ppm; Elemental Analysis: for C47H69NO10 calc. C 69.86, H 8.61, N 1.73; found C 69.78, H 8.93, N 1.81. __- 59 -__ This paper standard applies Chinese national standard ( CNS) A4 specification (210X 297 mm) ϊ AW · 1T (Please read the notes on the back before filling out this page) 487559 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (57) Regulations 221-2'-0-7, 醢 A Zhongke Nuoxin Q_ The compound Spinoxin Q (11.0 mg, 0.015 mmol) was dissolved in dry CH2CU (3 ml). Triethylamine (5 ml) was added. The solution was stirred at room temperature under nitrogen and Ac20 (0.70 ml, excess) was added. After 20 hours, EtO Ac (50 ml) and PhH (20 ml) were added. M saline, 5% a.q. NaHC03 (4X) and water (1x) were continuously washed. The organic layer was dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (5 g / EtOAc) to obtain the compound 2'-0-ethylspinoxin d; 11.0 mg, 95% iH-NMR (CDCI3) δ 6.74 (1H, bs), 5.46 UH, bs), 5.13 (1H, dd: 2.4, 1.8 Hz), 2.02 (3H, CH3, s), 1.70 (3H, CH3, bs) ppm. Trachea case A 22_3'-0 -n_ 丙 某 中 诺诺辛 J_ The compound Spinoxin J (331 mg, 0.433 mmol) was dissolved in CH2C12 (10 ml) and 15% NaOH aqueous solution (5 ml) was added, followed by K2 CO 3 (0.70 g ), Tetrabutylammonium chloride (0.3 g) and benzyltriethylammonium chloride (0.83 g). Add iodopropane (4.0 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 48 hours. Add CH2C12 (50 ml) and water (50 ml) and separate the phases. The organic 餍 M water (2X) was washed, the MK2C03 was dried and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (80 g / EtOAc). Concentrate of pure solubilized fractions can provide compound propyl spinosynoxin J; 156 mg »86¾ ^ -HMR (CDCla) δ 6.65 (1Η, bs), 2.11 (6H, 2x CH3, s), 0.84 (3H, CH3 , t: 7.3 Hz) ppm; 13C-NMR (CDCI3) δ72 · 4 (0-CH2-), 23.8 (-CH2-), 11.2 (CH3) ppm. When axillary case A 23-3 base Spinozin J__- 60-This paper size applies Chinese National Standard (CNS) M specification (21〇X 297mm) ------- il? ---- i ----- · (Please read the precautions on the back first Refill this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 ^ __ B7____ V. Description of the invention (58) The compound Spinoxin J (747 mg, 1.04 mmol) was dissolved in CH2C12 (20 ml) and added 15% NaOH aqueous solution (10 ml), followed by K2CO3 (1.10 g) and benzyltriethylammonium chloride (1.2 g). Add 1-iodoethane (5.5 ml) and stir the reaction mixture vigorously at room temperature under nitrogen fc for 48 hours. Add CH2C12 (50 ml) and water (50 ml) and separate the phases. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (100 g / EtOAc). Concentrate of pure solubilized fractions can provide a) compound Spinoxin J (192 mg) and b) compound 3'-0_ ethylspinoxin J; 401 mg, 70% 1H-NMR (CDCI3) δ 6.65 ( 1Η, bs), 3.53 (2H, q: 7.2 Hz), 2.12 (6H, 2x CH3, s), 1 · 14 (3H, CH3, t: 7.2 Hz) ppm; 13C-NMR (CDCI3) δ 66 · 1

(〇 一 CH2_), 16.3 (CH3) ppm; Elemental Analysis: for C42H67NO10 calc. C 67.62, H 9.05, N 1.33; found C 67.91, H 9.33, M 2.00. Cases A 24-3 '-0-7 In a certain sinomenoxin K___ The compound spinoxin K (30.6 mg, 0.043 mmol) was dissolved in CH2C12 (5 ml). A 15% aqueous solution of HaOH (5 ml) was added, followed by K2C03 (0.300 g) and benzyltriethylammonium chloride (0.41 g). Add 1-iodoethane (2.0 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 72 hours. Add CH2C12 (50 ml) and water (50 ml) and separate the phases. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (10 g / EtO ^ c). Concentrate of pure solubilized fractions can provide a) compound (15.1 mg) and b) compound 3'-0_ethylspinoxin K; 5.5 mg, 34%) 1H-NMR (CDCI3) δ 6.72 (1Η , bs.), 3.32 (1H, m), 3.57 (2H, m), 2.13 (6H, 2x CH3, s), 1.17 (3H, CH3, C: 7.3 Hz) ppm. (Please read the precautions on the back first (Fill in this page again)-The paper size of this paper applies the Chinese National Standard (CNS) A4 (210X 297 mm). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 487559 A7 ___ ^ B7 _, 5. Description of the invention (59) _ Example A 25-3 Glucoxanthinololone-A compound Spinoloxin L (330 mg, 0.451 mraol) was dissolved in CH2C12 (15 ml). A 20% aqueous NaOH solution (10 ml) was added, followed by K2CO3 (1.30 g) and benzyltriethylammonium chloride (1.1 g). Add 1-iodoethane (5.0 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 96 hours. CH2C12 (50 ml) and water (50 ml) were added and the phases were separated. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (85 g / EtOAc). Concentrate of pure solubilized fractions can provide compound 3'-0_ethylspinoxin L; 127 mg, 37% 1H-NMR (CDCI3) δ 6.64 (1Η # bs), 5.37 (1Η, bs), 3 · 60 (1Η, m), 2 · 12 (6Η, 2XCH3, s), 1 · 17 (3Η, CH3, t: 7.4 Hz) ppm; 13C-NMR (CDCI3) δ 66 · 1 (0-CH2- ), 16.3 (CH3) ppm. Enriched Example A 26-3'-0-Yan Bing, a sinomenox J_ The compound Spinoloxin J (370 mg, 0.515 ππποί) was dissolved in CH2C12 (15 ml). A 15% NaOH aqueous solution (10 ml) was added, followed by K2CO3 (1.40 g) and benzyltriethylammonium chloride (0.98 g). Bromoallyl (3.0 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 28 hours. CH2C12 (50 ml) and water (50 ml) were added and the phases were separated. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was dissolved in toluene (10 ml) and heated to reflux temperature for 10 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified in a flashed SiO 2 column (80 g / EtOAc). Concentrate of pure solubilized fractions can provide compound 3 ^ 〇-allyl Spinolsin J; 121 mg, 31% iH-NMR (CDC13> δ 6.67 (1H, bs), 5.77 (1Η, π \), 5.22 (1H, bd: 17.2 Hz), 5.03 (1H, bd: 10.3 Hz), 4.07 (2H, bd: 4.2 Hz), 2.13 (6H, 2x CH3, s) ppm; Elemental Analysis: for C43H67NO10 calc. C 68.14, H 8.91, N 1.85; found C 63.38, H 9.10, N 1.77. (Please read the precautions on the back before filling out this page) One Pack-Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 ______ ^ B7 V. Description of the invention (60) A detailed example of tube A 27-3 Neproxen J_ Norpin J_ Dissolve the compound Spinoxin J (392 mg, 0.546 mmol) in CH2C12 (15 ml). Add 15% HaOH aqueous solution (10 ml), followed by K2CO3 (1.50 g) and benzyltriethylammonium chloride (1 · 10 g). Added propargyl bromide (80% solution in toluene; 4.0 ml) and at room temperature The reaction mixture was stirred vigorously under nitrogen for 40 hours. CH2C12 (50 ml) and water (50 ml) were added. The phases were separated. The organic layer was washed with K water (2X), dried with WK2CO3 and concentrated under reduced pressure. The residue was dissolved in toluene (10 ml) and heated to reflux temperature for 20 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (80 g / Et0Ac). The concentrate of the pure eluate can be Provide compound 3 ^ 0-propargyl Spinolsin J; 138 mg, 33% λΗ-ΝΜΕ (CDCI3) δ 6.66 (1Η, bs), 4.22 (2H, m), 3.66 (1H, dd: 9.4, 3.3 Hz ), 2.37 (1H, dd: 2.4, 2.4 Hz), 2.12 (6H, 2x CH3, s) ppm; Elemental Analysis: for C43H65NO10 calc. C 68.32, H 8.57, N 1.85; found C 63.39, H 8.62, N 1.75 Case A 28-3'-0- (Cyclopropyl) Shen Zhongzhong Nuoxin J_ The compound Spinoxin J (470 mg, 0.655 mmol) was dissolved in CH2C12 (10 ml). 15% NaOH aqueous solution (15 ml) was added, followed by K2CO3 (1.50 g) and benzyltriethylammonium chloride (1.10 g). Add (cyclo / propyl) methyl bromide (.09 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 72 hours. Add CH2C12 (50 ml) and water (50 ml). The phases are separated. The organic layer was washed with water (22), dried with MKzCO 3 and decompressed under reduced pressure.

Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _____ B7 V. The description of the invention (61) is concentrated. The residue was purified in a flash SiO &gt; column (90 g / EtOAc). Concentrate of pure solubilized fractions provides a) compound Spinozin J (216 mg) and b) compound 3'_0_ (cyclopropyl) methyl Spinosin J; 25.1 rog, 9% IMR (CDC13) 3 6.71 (1Η, bs), 3.07 (1Η, in), 2.17 (6Η, 2XCH3, s), 0.48UH, m), 0.18 (1Η, m) ppm 2Q-3'-0- (氤) Tian Jizhong Onoxin J_ The compound Spinoxin J (510 mg, 0.71 mmol) was dissolved in CH2C12 (5.0 ml). K2CO3 (1.10 g) was added. The reaction flask was immersed in a water bath (10 ° C) and 10% aqueous NaOH (10 ml) was added with vigorous stirring, followed by benzyltriethylammonium chloride (1.20 g). Chloroiodomethane (5.0 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 72 hours. Add CH2C12 (100 ml) and water (50 ml). The phases are separated. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (70 g / EtOAc). The concentrate of pure solubilized fractions can provide a) compound (111 mg) and b) compound 3'U chloro) methyl spinosinol J; 120 mg, 28% "NMR (CDC13) δ 6.66 (1Η, bs) , 4.70 (2H, bs), 3.74 (1H, dd: 9.5, 3.4 Hz), 2.12 (6H, 2x CH3, s) ppm; Elemental Analysis: for C41H64NO10CI calc. C 64.25, H 3.42, N 1.83; found C 64.49 , U 8.37, N 1.74. Example A 30-Zhongtaoxin L-3'-0- (pentaphenyl) -thiocarbonyl carbonate _-_ ί The compound Spinoxin L (733 mg, (1.0 mmol) was dissolved in dry pyridine (5.0 ml). Stirred at room temperature (water bath) under nitrogen. Within 5 minutes, (pentafluorobenzyl) chlorothiocarbonyl carbonate (1.5 nil) was added dropwise. , Excess). At 10 -64-This paper size applies the Chinese National Standard (CNS) Α4 specification (21〇 &gt; &lt; 297 mm)-® Packing (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 ______ B7_ V. Description of the invention (62) minutes, add PhH (50 ml) and Et0Ac (50 ml). Solution K5! Caq.NaHC03 (3x). The organic layer was dried with Manh. Na2SO4 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (80 g / EtOAc) to obtain 3'-0- (pentafluorophenyl) -thiocarbonyl carbonate of Spinoloxin L; 712 mg, 74%, 4 -NMR (CDCI3) δ 6.69 (1Η, bs), 5.46 (1H, dd: 9.5, 3.2 Hz), 5.40 (1H, bs), 3.77 (1H, dd: 3.1, 2.0 Hz), 2.23 (6H, CH3, s) t 1.64 (3H, CH3, bs) ppm; 13C-NMR (CDCI3) δ 191.5 (C = S), 37.0 (C3.-O) ppm. Fen_Example A 31-.V-Deargon-China Passenger Nosin L_ The 3 ^ 0- (pentafluorophenyl) -thiocarbonyl carbonate (690 mg, 0.72 mmol) of the compound Spinoxin L was dissolved in dry toluene (10 ml). Hydrogenation was added at room temperature under nitrogen. Tri-η-butyltin (0.50 ml, 1.86 mmol). Then AIBN (20 mg) was added. The reaction mixture was heated to reflux temperature for 15 minutes. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was flashed Purification in a SiO 2 column (75 g / EtOAc) to obtain compound 3'-deoxybinoxin L; 236 mg, 46%, UMR (CDC13) δ 6.68 (1Η, bs), 5.39 (1Η, bs), 3.53 (2Η, m), 2.15 (6Η, 2xCH3, s), 1.63 (3Η, CH3, bs) ppm; Elemental Analysis: for C41H65NO9 calc. c 68.78, H 9.15, N 1.96 ; F ound C 68.70, H 8.87, N 2.03. Tube) fe Example A 32-neutral nosin. 1 eve: T-〇- (Mpropyl) 礆 casein _ will compound Spinozin J (330 mg, 0.46 mmol) was dissolved in dry HMP A (3.5 ml). Silver carbonate (0.66 g) was added. The reaction mixture was stirred at room temperature under nitrogen for 5 minutes. Introduce 2-iodopropane (1.5 ml). The reaction mixture was stirred for 18 hours. Et0Ac (20 ml) and PhH (100 ml) were added. _-65-The size of this paper is applicable to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) .-- «Handling-(Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 _ B7 V. Description of the invention (63) The organic layer was washed with water (3 X), 'MK2CO 3 was dried and concentrated under reduced pressure. The residue was separated in a flash SiO 2 column (20 g / EtOAc) to obtain a) a) compound (98 mg) and b) a 3'-0- (isopropyl) carbonate of the compound Spinoxin J; 87 mg t 34%) ^ MR (CDCla) δ 6.68 (1H »bs)» 4.84 (2H, m), 3,54 (3H, m), 2.14 (6Η, 2X CH3, s), 1.23 (6Η, 2XCH3, δ: 6.2 Hz) ppra; Elemental analysis: Estimated value of C44HG3NO12, C 65,73, Η 8.65, Η 1.74; Actual value, C 65.63, Η 8.78, N 1,75 〇 tube 敝Example A Dioxin I, XX, Nosin I, _ The compound Spinoxin L (244 mg, 0.33 mmol) was dissolved in dry pyridine (4 ml). Add dichloroacetic anhydride (0.50 ml, excess) and stir at room temperature under nitrogen for 16 hours. Et0Ac (50 ml) and PhH (100 ml) were added. The solution M5% a.q.HaHC03 (3x) was washed. The organic layer was dried over Manh. K2CO3 and concentrated under reduced pressure. The residue was purified in a flashed SiO 2 column (80 g / Et OAc) to obtain the compound 3 夂 0-dichloroacetamido Spinozin L; 129 mg, 46% El MS ιπ / ζ 342 (M +) ; 1H-NMR (CDCI3) δ 6.71 (1H, bs) # 5.93 (1H, s), 5.43 (1H, bs), 5.14 (1H, dd: 9.6, 3.2 Hz), 3.57 (3H, m), 2.13 ( 6H, 2x CH3, s), 1.66 (3H, CH3, s) ppm · Example A 34-3 ′ -0-Dimethyl Z 醮 a certain midoxin_ The compound Spinoxin J (302 mg, 0.42 mmol) was dissolved in dry pyridine (5 ml). Dichloroacetic anhydride (0.5 ml, excess) was added and stirring was continued for 16 hours at room temperature under nitrogen. EtoAc (50 ml) and PhH (100 ml) were added. Solution K 5% a. Q. NaHCOb (3 X) was washed. M anh. K2C〇3 Drying —_—_ __-66-This paper size is applicable to China National Standard (CNS) A4 (710 X 297 mm) one to one I — ^ ---- * ® batch clothing- ---- 1T ------ (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _ B7__; _ 5. Description of the invention (64)

The organic layer was dried and shrunk under reduced pressure. The residue was purified in a flash SiO 2 column (80 g / EtOAc) to obtain the compound 3 ^ 0-dichloroethenylspinoxin J; 293 mg, 84% 4-NMR (CDC13) δ 6.66 (1Η , bs) # 5.95 (1H, s), 5.07 (1H, dd: 8.7, 3.2 Hz), 3.52 (button, m), 2.15 (6H, 2x CH3, s) ppm; Elemental Analysis: for C42H63NO11CI2 calc, c 60.36 , H 7.66, N 1.70; found C 60.59, H 7.65, N 1.96. Tuberculosis Example A Keluozhai, J_ The compound Spinoxin J (296 mg, 0.41 mmol) was dissolved in CH2C12 (5.0 ml). K2CO3 (1, 10 g) was added. The reaction flask was immersed in a water bath (100P) and 15% aqueous NaOH (10 ml) was added with vigorous stirring, followed by benzyltriethylammonium chloride (0.88 g). Add iodobutane (3.0 ml) and stir the reaction mixture vigorously at room temperature under nitrogen for 40 hours. Add CH2C12 (100 ml) and water (50 ml). The phases are separated. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (60 g / EtoAc). The concentrate of pure solubilized fractions can provide a) compound (211 mg) and b) compound 3'butyl spinosinoxin J; 20.5 mg, 22% "NMR (CDCl3) S 6.71 (1H, bs), 3.58 (2H, m), 2.18 (6H, 2x CH3, s), 0.38 (3H, CH3, t: 7.3 Hz) ppm; 13C-NMR (CDCI3) δ 70.5 (0-CH2), 32.8 (CF'2), 30.4 (CH2), 14.5 (CH3) PPm. Example a. Butyridine y. Indoxazone j * The compound Spinoxin J (359 mg, 0.50 mmol) was dissolved in dry pyridine (4 ml). N was added , N-dimethylaminopyridine (66 mg) ◦The reaction was cooled to 10 ° C (water bath) under nitrogen. 'Isobutyl chloride (2.0 ml) was added. The Chinese standard (CNS) ) A4 size (210 X 297 mm) I 5 Binding (please read the notes on the back before filling this page) Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 5. The invention description (65) It was stirred at room temperature under nitrogen for 70 hours. EtOAc (50 ml) and PhH (100 ml) were added. The organic layer was M5% aq, washed with NaHC03 (3X). The organic layer was dried with Kan. K2CO3 and dried over Concentrated under reduced pressure. The residue was purified in a flashed Si02 column (80g / Et0Ac). Obtained 3 夂 0-Isobutyryl Spinozin J; 364 mg # 92% 1H-NMR (CDCI3) δ 6.70 (1Η, bs), 5.02 (1H, dd: 9.6, 3.2 Hz), 3.57 (2H, m ) # 3.49 (1H, dd: 3.2, 1.8 Hz), 2.16 (6H, 2x CH3, s), 1.15 (6H, 2x CH3, d: 7.0 Hz) ppm; Elemental Analysis: for C44H69NO11 calc. C 67.06, H 8.82 , N 1.78; found C 66.78, H 8.86, N 1.75. Examination example A Wnosin J in Tentamidine _ The compound Spinoxin J (426 mg, 0.59 nnnol) was dissolved in dry pyridine (4 ml) Add N, N-dimethylaminopyridine (116 rag). Cool the reaction to 101C (water bath) under nitrogen. Add pivalamidine chloride (2.0 ml, excess) and continue stirring at room temperature under nitrogen 70 hours. Add EtOAc (50 ml) and PhH (100 ml). The organic layer was washed with M5% aq. NaHC03 (3x). The organic layer was dried over anh. K2CO3 and concentrated under reduced pressure. The residue was purified K in a flashed Si02 column (80g / Et0Ac) to obtain 3'-0_t-pentylspinyl Spinoxin J; 433 mg, 91% El MS m / z 802 (M +); 1H- NMR (CDCI3) δ 6.65 (1H, bs), 4.94 (1H, dd: 9.8, 3.2 Hz), 3.52 (2H, 3.45 (1H, dd: 3.2, 1.8 Hz), 2.14 (6H, 2x CH3, s ), 1.14 (9H, 3x CH3, s) ppm. Example A. Ί8-5. Di-S-3'yl indoxoxine, J_ Compound 5,6-dihydro-spinoxin J (399 mg , 0.554 mmol) is dissolved in CH2C12 (5.0 ml). K2C03 (1.10 g) is added. The reaction flask is ____- 68 -_ This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)- Binding (Please read the precautions on the back before filling this page) Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 ------' B7 V. Description of the invention (66) Immerse in a water bath (10 ° C) With vigorous stirring, add 15% NaOH aqueous solution (10 ml), followed by tetrabutylammonium hydrogen sulfate (0. 90 g). Add 1-iodoethane (3 ♦ 0 m 1). The reaction mixture was stirred vigorously under nitrogen for 72 hours. CH 2 C12 (100 ml) and water (50 ml) were added. The phases were separated. Organic Water (2 fathers), 1 (2 (0) dried and (2 (: 12 (1001111)) and water (50 ml). The phases were separated. The organic layer was washed with K water (2X) and MK2C 〇3 was dried and concentrated under reduced pressure. The residue was purified in a flash SiO2 column (100 g / EtOAc). The concentrate of the pure eluate provided 5,6-dihydro-3'-0- Ethyl Spinozin J; 217 mg, 52% 丄 -NMR (CDCI3) δ 6.72 (1Η, bs), 3.57 (1H, m), 3.49 (2H, m), 2.13 (6H, 2XCH3, s), 1.14 (3H, CH3, t: 7.3 Hz) ppm; Elemental Analysis: for C42H69NO10 calc. C 67.44, H 9.30, N 1.87; found C 67.64, H 8.95, N 1.87. Tube) Example A 39-5.6-Diargon W'oxin J_ in 3'-propyl The compound 5,6-dihydro-spinoxin J (8 mg, 0.119 mmol) was dissolved in CH2C12 (3.0 ml). K2CO3 (0.68 g) was added. The reaction flask was immersed in a water bath (10t :) and 20% NaOH aqueous solution (6 ml) was added with vigorous stirring, followed by tetrabutylammonium hydrogen sulfate (0.81 g). 1-iodopropane (1.20 μm 1) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 20 hours. Add CH2C12 (100 ml) and water (50 ml). Separated phases. Organic layer M water (2X), MK2CO3 drying and CH2C12 (100 nil) and water (50ml). The phases are separated. The organic layer was washed with water (2X), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flashed SiO 2 column (25 g / EtOAc). Concentrate of pure solubilized fraction can provide 5,6-dihydro-3'-0-propyl spinolsin J; * ____- 69 -_ _ Applicable to this paper size} National National Standard (CNS) A4 Specification (2 ! OX 297 mm) &quot; I ------ =-I- ♦ -pack ------ order ----- (Please read the notes on the back before filling this page) Central Ministry of Economy Printed by the Consumer Bureau of Standards Bureau A7 B7 J ^ Invention Note (67) 55.0 mg, 60% 1H-NMR (CDCI3) δ 6.78 (1H, bs), 3.55 (3H, rn &gt;, 2 · 16 (6H, 2x CH3) , s), 0.89 (3H, CH3, t: 7.5 Hz) ppm; 13C-NHR (CDcl3) 572.5 (O-CH2-), 23.9 (CH2) and 11.2 (CH3) ppm. Tube Example △ 40-2 ' -表 -2 '-[1-71 中 中 诺辛辛 1 ^ _ Compound 2'-0-ethynyl-2'-spinoxin (502 ms, 0.664 mmol) was dissolved in CH2C12 4.0 ml). K2C03 (1.10 g) was added. The reaction flask was immersed in a water bath (10 ° C) and 20% was added with vigorous stirring.

Aqueous NaOH (10 ml) followed by tetrabutylammonium hydrogen sulfate (0.82 g). 1-Iodoethane (1.20 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 22 hours. Add CH2C12 (100 nil) and water (50 ml). Separated phases. The organic layer was K water (2x), dried with MK2CO3 and CH2C12 (100 ml) and water (50 ml). The phases are separated. The organic layer was washed with K water (2 ×), dried over MgSO 2 and concentrated under reduced pressure. The residue was flashed in a Si02 column (80g /

EtOAc). Concentrate of pure solubilized fractions can provide 2'-Table-2'-0-ethylspinoxine; 132 mg, 27% XH-NMR (CDCI3) δ 6.66 (1Η, bs), 4.70 (1H, d : 3.7Hz), 2.12 (6H, 2xCH3, s), 1.14 (3H, CH3, t: Hz) ppm; 13C-NMR (CDCI3) δ 66.8 (O-CH2-) and 16.2 (CH3) ppm. A 4 Bu 5.6-Digas' Vnn-butyl 窨 窨 窨 辛 xinoxin J__ Compound 5,6-dihydro-spinoxin J (93 mg, 0.129 mmol) was dissolved in CH2C12 (3.0 ml). Add &gt; K2C03 (0.70 g). The reaction flask was immersed in a water bath (10¾) and 20% NaOH aqueous solution (10 ml) was added with vigorous stirring, followed by tetrabutylammonium hydrogen sulfate (0,66 g). Add 1-iodobutane (2.0 m 1) and stir the reaction mixture vigorously at room temperature under nitrogen ___- 70 -____ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 11; —Aw · I order (please read the notes on the back before filling this page) 487559 A7 ____ B7 V. Description of invention (68) 20 hours. Add CH2C12 (100 ml) and water (50 ml). Separated phases. Organic layer M water (2X), dried with MK2CO3 and CH2C12 (100 ml) and water (50 ml). The phases are separated. The organic layer was washed with water (2x), dried over MK2CO3 and concentrated under reduced pressure. The residue was purified in a flashed SiO 2 column (25 g / EtOAc). Concentrate of pure solubilized fractions can provide 5,6-dihydro-3'-0-butyl spinosynox J; 63 mg, 63% ^ -H-NMR (CDCI3) δ 6.78 (1Η, bs), 3 .57 (3H, m), 2.16 (6H, 2x CH3 # s), 0.37 (3H, CH3, t: 7.2 Hz) ppm; Elemental Analysis: for C44H73NO10 calc. C 63.10, H 9.43, N 1.80; found C 68.23 , 9.65, N 1.33. Fenshi Example A 42 ~~ 2'-0- (S_methyl-N-ammonium carbodiimidothio) spinoxin Η __ Yu cold (0 ° C), after Properly stirred suspension of sodium hydride (50% in mineral oil, printed dispersion, 12.0 mg, 0.14 mmol) in the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, in 2-3 minutes of anhydrous THF A solution of spinosynox (0.1 g, 0.14 mmol) in THF (1.5 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 minutes, and then a portion of N-benzyl isothiocyanate (25 u 1,0.18 ππποί) was added by using a syringe. Remove the cooling bath and stir the mixture at room temperature for 4.5 hours. Then add a portion of methyl iodide (30 / i 1, 0.48 fflinol) and mix the mixture for 30 minutes. The solvent was then removed under reduced pressure and the residue was dissolved in anhydrous ether (20 inL). Any insoluble matter was removed by filtration through diatomaceous earth and rinsed with ethanol. The filtrates were combined and washed to leave 0.13 g of crude 2f-0- (S-methylbenzylcarbimidothio) spinosinol: IMIUCDCU δ 2.48 (s, 1, SCH3 as a colorless oil ), 5.40 (ιη, 1, Η-2,). This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 —-____. B7 V. Description of the invention (69) Decoration example A H2 夂 0 -Trimethylammonium dioxinoxine X504447 in cold (0 ° C), properly stirred sodium hydride (50% dispersion in mineral oil, 12.0 mg, 0.26 mmol) in anhydrous THF (2.0 mL) of the suspension, a solution of human spinoxin (0.1 g, 0.14 mmol) in THF (2.0 raL) was added dropwise over 2-3 minutes. Stir the mixture for 20 minutes, then add a portion of trichloroethane (20 to L'0.2 nunol) and stir at 0 ° C for 2 hours. 0 Then add a portion of glacial acetic acid (16 / i L'0 · 27 mmol) and the reaction mixture was allowed to cool for 10 minutes. The solvent was then removed under reduced pressure and the crude 2 \ -trichloroacetimino spinosinol was purified by flash chromatography on silica (40 mL) using 3% methanol in dichloromethane as the eluent. liquid. Pure white 2'-trichloroacetimidospinoxine (95 mg, 79%): iNMlUCDCh) δ 5.30 (m, 1, H-2 '), 8.36 (s, 1 , = ΝΗ); Mass spectrum (Cl, CHd, m / z (rel. Intensity) 861 (MtT, 4), 142 (100). Tube_Example A 44-3 W Nuo barrier in trifluoromethane group J_ Yu Cold (_10 ° C), properly stirred Spinoxin J (0.2 g, 0.28 mmol) and dry CH2Cl2 (5 roL) in dry Bit Vita (0.1 mL, 1.26 mmol) solution, add part by syringe triflic acid (60 μL, 0.35 mmol). The resulting orange-brown solution was stirred at -101C for 1.5 h, then diluted with CH2C12 (20 mL) and continuously K water (5 niL), saturated Na2CO3 (4 mL) , And then washed with K water (5 mL), and finally dried M (MgS04). The concentrate leaves 216 mg (91%) of 3'-0-trifluoromethanesulfonylstiloxine J, which is pure enough for use. Without further purification: lNMR (CDCl3) δ 4.98 (dd, 1, Η-3 ·).-72-This 氏 Zhang scale is applicable to the Chinese National Standard (CNS) Α4 specification (210X 297 mm 1 (please read the back first) Please note this page, please fill in this page) Clothing · Order 487559 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives A7 B7 V. Description of the invention (70) Example 8 4 5-Bu 0 (2.3 · 4-tri-0-71 radical-[-(^-rhamnosyl)) A 9-Psa: L-rhamnolide) in the case of oxoxin A 9-Pm 3: admixture of spinoxin A 9-Psa (2.1 g, 3.86) in cold (0 ° C), with appropriate stirring mmol) and pyridine p-toluenesulfonate (1.3 g, 5.17 mmol) in dry CH2C 1 2 (200 ml). The solution contains powdered 4A molecular sieves (2.6 g), dropwise within 20 minutes. Add a solution of 0_ (2,3,4_tri-0-ethyl-ct-L-rhamnylpyrimosyl) trichloroimine acetate (5.0 g, 12.75 mmol) in CH2C12 (20 mL) After 3 hours at 0 ° C, another portion of a solution of imidate (2.0 g) in CH2C12 (6 mL) was added. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. Then more was added Imide (0.8 g). After another 7 hours, the reaction mixture was filtered through diatomaceous earth, the diatomaceous earth was washed with CH2C12 (25 mL), and the filtrate was combined with K saturated Na2CO3 (2X 80 mL) and washed. Dry (MgS04). The concentrate left 11.5 g of residue, which was subjected to flash chromatography on silica (700 mL) using 3% MeOH in CH2C12 as eluent to give 2.0 g (67%) of compound a) 9 -0- (2,3,4-tri-0-ethyl-ct rhamnosyl) Spinoxin A 9-Psa: 9-0- (2,3,4-tri-0-ethyl- 々-1 ^ -rhamnosyl) Spinoxin A 9-Psa 3: 1 mixture. The mixture was separated by HPLC through a 21.4 nim (id) x 20 cm (l) Rainin reverse-phase C18 column using 4% H2O (containing 0.01% NH40H) in methanol as the eluent into about 200 rags. part. -Atropisomers first precipitate. Compound b) 9-0- (2,3,4-tri-0-ethyl- / 3-1 ^ -rhamnosyl) Spinoxin / \ 9-Psa: 0.35 g; colorless foam ; IMR (CDC13) δ 4.36 (s, 1, this paper size applies Chinese National Standard (CNS) A4 specification (21QX 297 mm) (Please read the precautions on the back before filling this page)

1T f 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (71) H-1 '), 4.45 (m, 2, Hl ", H-9). Compound c) 9-0- (2,3,4-tri-0-ethyl-α-L-rhamnosyl) Spinoxin A 9-Psa; 1.2 g, colorless foam; IMR (CDC13) δ 4.43 (bd, 1, Hl "), 4.47 (s, 1, H -1 '). Example A-Benzyl sulfoxanoxine A suspension of chloropreneimine (104.7 mg, 0.78 mmol) in dichloromethane (2.6 ml) was cooled to -78 ° C under nitrogen. Isopropyl sulfide (125 &quot; 1, 0.86 mmol) was added to the suspension and the mixture was stirred at -781C for 0.5 hr. Then a solution of Spinozin J (184. 6 rag, 0, 26 mmol) in dichloromethane (1 ml) was added. When the addition was complete, the solution was stirred at -78 ° C for 6.25 hr, and then triethylamine (109 L, 0.78 min. 1) was added, and the solution was added to room temperature to make the ochre red. After heating, Et20 (6 mL) in 5% MeOH in dichloromethane was added to purify the eluent, and M was obtained as a colorless semi-solid 3'-pentyl spinosin J (151.2 mg, 82%). 1NMR (CDCM δ 6.87 (bs, 1H), 5.88 (d, 1H); 5.81 (dt, 1Η); 5,03 (s, 1Η); 4.70 (m, 1Η); 4,44 (bd, 1Η); 4.35 (bd, 1H); 13HMR (CDC 13) δ 204,203 ppid 〇 Cyst example A 47- (4'R) _4'-dehydrohydrogen-4'_amino Nosin A · To a solution of 4'-ketospinoxin K (115.3 mg, 0.16 mmol) in methanol (2 m 1), add saddle acetate (149.3 mg * 1 · 9 mmo 1), followed by cyanoborohydride (10 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 7 hours. Then the mixture was diluted with M IN HC1 and washed with ether. Then extracted with fresh ether. KMgSO was dried and evaporated under reduced pressure at room temperature. Separate the crude product on silica by chromatography, in a single step M -74-This paper size applies to China National Standard (CNS) A4 specification (210. × 297 mm) I ----- If ( Please read the precautions on the back before filling this page), 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _____ B7 V. Description of the Invention (72) 10% methanol in dichloromethane solution and then 50% methanol The dichloromethane solution was eluted. (4 D-4 夂 desmethoxy-4'-aminospinoxin A (23.3 mg; 20% yield) is a colorless glass, which is the most polar substance after separation. FDMS, m / e ( Relative strength) 717 (60): 716 (M *, 100), 142 (35), 114 (30) 〇 啻 Detailed example A 48-2'-Chloro-3'-ene-Methyl-Methyl Argon-Middle Spinoxin 反应 was reacted according to the method described in Example 3 to prepare Spinoxin A 9-Psa. Spinoxin 与 was used with Spinoxin J (5.02gm, 7.0 mmol) and N-chloroprene respectively. Stilbene imine (2.88 gm, 20 mmol), chloroform (90 inL), dimethyl sulfide (3.1 roL, 42.0 mmol), triethylamine (2.8 mL, 21.0 mmol), and potassium carbonate (12 · 8 gm, 92.2 mmol) in a 35: 65 mixture. Spinozin A 9-Psa (2.32 gm; 94% yield based on Spinozin J) and 21-oxy-3 alkenyl 4 ' -Demethoxy-spinoxin k Η (290 mg; 55% yield, based on M-spinoxin Η), FDMS, m / e (relative strength) 684 (M +, 30), 683 (100 ) As a white solid.例 _Example A 49-2 (aL-2.3.4-Rhamnosaurus sylvestris) in Chinese 窨 Nosin Η 3 · -Tri--0-Rhamnos sylvestris in Chinese) tastes Nosin, 1 in Spinoxin And Spinozin J (35:65, 1.0 gm, 1.44 mmol, respectively) in a solution of anhydrous dichloromethane, and 1-bromo_2,3,4-tri-0-ethynylrhamnose 1 was added. (1.26 g, 3.57 mmol), followed by diisopropylamine (301 ml, 1.73 mmol) and then silver trifluoromethanesulfonate (456.8 mg, 1.73 mmol). The reaction mixture was stirred at room temperature and in a dark room for 2 days. The mixture was then diluted with dichloromethane and washed with water. Filter dichloromethane to remove insoluble matter, dry with MMgSO 4 and reduce the temperature at room temperature and minus -75-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 public celebration) | Clothing --- (Please read the back first Note: Please fill in this page again), 11 487559 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (73) It is concentrated under pressure. The crude product was separated from the unreacted starting material by chromatography on silica. The CH2C12 solution of M5% MeOH was the eluent. The crude product mixture was purified by preparative HPLC in a C18 column, K acetonitrile: methanol: 0.1% Xin 4 (^. (42.5: 42.5: 12.5 to 45:45:10 with a linear gradient of 90 minutes) as the elution Compound a) 2 '-(a -L-2,3,4-tri-0-methylrhamnosyl) Spinoxin (47 mg), FDMS, m / s (relative strength) 990 (ΙΓ, 100) and compound 1>) 3 '-(3-1 ^ 2,3,4-tri-0-methylrhamnosyl) Spinoxin J (16 mg), FDMS, m / e (relative intensity) 990 (M +, 25), 989 (70), 988 (70), as a white solid. iFisher, E .; Bergmann, M .; A. Chem. Ber. 1920, 53, 2363, Rich Example A 50-2 '-(H- 锊) Asia Defense W. NosingΗ in rough 2'- A solution of ketospinoxine (238.3 mg, 0.33 mmol) and hydroxylamine hydrochloride (24.9 mg, 0.36 mmol) in pure ethanol (10 ml) was added to anhydrous sodium acetate (60.0 mg, 0.73 nunol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then diluted with M dichloromethane, washed with water and brine, dried over KNa2S04 and evaporated at room temperature under reduced pressure. The product was purified by silica chromatography * M 5% methanol in dichloromethane was used as the eluent. The obtained 2 '-(N-hydroxy) imino-spinodinolide (73.9 rag) was a white solid, FDMS, in / e (relative strength) 731 (fT, 50), 73 (100) ° 啻 axillary cases A 51-4: A certain intermediate Nosin K was reacted using Spinozin K (1.49 gin, 2.07 nunol) according to the method described in Example A 46. Available 4'- 嗣 基 Spinozin K (1.48 gin; -76-This paper size is applicable to China National Standard (CNS) A4 specifications (2! 0X 297 mm) (Please read the precautions on the back before filling this page ) 、 · &Quot; 口 -—J— I HJ. · 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (74) about 100% yield), is a sticky white solid, FDMS, ro / e (relative intensity) 715 (M ♦, 100).例 _Example A 52-2 '-(N- via a certain) imine a-4' -nor-chloro-3 '4 · -to- 氲 neutronoxin ____ using 2-oxygen -3; -Alkenyl-4'-demethoxyspinoxine (579.8 mg, 0.85 nunol) was used as the starting material, and the reaction was carried out according to the method described in Example A50. 2 '-(N-Hydroxy) imino-4'-desmethoxy-33,4'-deargon spinosynoxine (223 mg, 42% yield, the starting material for K recovery is Benchmark) Slightly white solid. FDMS, m / e (relative intensity) 699 (M +, 70), 698 (100) 〇g _Example A 53-9-0-2 4-tri-0-ethyl-a-L-rhamnosyl spine Nuoxin A 9-Pm is an example of bis-butyric salt_ Compound 9-0-2,3,4-tri-0-ethyl-a-L-rhamnosyl) Spinoxin A 9-Psa (99.6 mg, 0.128 mmol) was dissolved in 2 mL of acetone and a solution of glutaric acid (8.5 mg, 0.064 mmol) in 2 mL of acetone was added. After the solution was stirred for 3 hours, the solvent was then removed under reduced pressure. Compound 9-0-2,3,4-tri-0-ethyl- (1-1 ^ rhamnospinyl spinosynin 9 bang 33 hemiglutarate * 105.7 mg can be obtained. C ^ HziNio · 1/2 (C5H0〇4): C 66.48, Η 8.99, Ν 1.67; actual value C 66.30, Η 8.58 * Ν 1.71; mp.76-82lC. Tube tender example A 54-3 '-Π-Z A certain midoxoxin J semi-analcoholic _ _ Compound 3'-0_ ethylspinoxin J (130.4 mg, 0.174 mmol) was dissolved in 2 mL of acetone and glutaric acid was added 2 inL acetone solution of acid (11.5 mg, 0.087 mmol). Stir the solution overnight. Evaporate the solvent to get 3'-0. A paper size is applicable to China Garden Standard (CNS) A4 (210X 297 mm). (Please read the notes on the back before filling this page)

487559 A7 __. B7 V. Description of the Invention (75) -Ethyl Spinosin J Hemovalerate, 131 mg. Analyze estimated values for CuHuNO &quot; · 1/2 (C5H0〇4): C 65.82, Η 8,81, Ν 1.72; actual value C 65 · 65, Η 8,46, Ν 1.72; mp.75-82QC . Example A 55-3 '-O-Fifteen deuterium Zn Some of the novosin J half a dioxin dissolves the compound 3'-0-pentadeutero ethyl spinosin J (97.4 mg, 0.129 mmol) To 3 mL of acetone and glutaric acid (8.6 mg, 0.065 mmol) in 2 niL of acetone was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to obtain the compound 3'-0-pentadecylethyl spinosin J hemiglutarate, 102 mg. Analyze the estimated values for C42HS2N (hQD5 · 1/2 (C5H8 (U): C 65 · 02, Η 9.27, N 1.70; actual values C 65.12, Η 9 · 01, Ν 1.85; mp.104-114〇 C. Examples of tube A 56-5. Dioxane-3 ^ 0-η-propyl chrysinoxine J semi-stilbene disulfonium salt_ Compound 5,6-dihydropropylspinoxin J (88.3 mg , 0.115 mmol) was dissolved in 3 inL acetone and a 2 inL acetone solution of glutaric acid (7.5 mg, 0,056 mmol) was added. The solution was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to obtain compound 5,6-di Hydrogen-3'propyl Spinocinol J hemiglutarate, 86,1 mg. Analytical estimate for C43H71NO &quot;-l / 2 (C5Ha〇4): C 65 · 99, Η 9.12, N 1.69; Actual Value C65 * 30, Η 10 · 00, Ν 1.77; mp. 74-84 ° C. 啻 _ Example A 57-.V-η-ζ group innosine L half rg di caseinate compound 3 ' -0-Ethyl Spinocinol L (84.2 mg, 0.10 mmol) was dissolved in 3 mL of propionate and 3 mL of a solution of propylene copper with glutaric acid (7.5 mg, 0. 056 mmo 1) was added. The solution is stirred at room temperature overnight. Steamed under reduced pressure. The paper is sized to the Chinese National Standard (CNS) A4 (210X 297 mm).

I- -1-II (Please read the precautions on the back before filling out this page), 11 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (76 ) Solvent, to obtain compound 3 * -0-ethylspinoxin L hemiglutarate, 91.0 mg. Analyze the estimated values for CnHsgNOiD · 1/2 (C5H8〇4) · C66.16, Η 8.90, N 1.69; actual values C65.43, Η 9.16, N 1.69; mp.77-82t! 〇

Example 8 58- (3,5) -4'-guanshen_: ^ -guanchloro-3,-"(1?)-(〇-methylchloro, α-propanyl chloride) methyl 1Φ 窨Norsin J and (3'S) -A1 Nor'V-Deargon'V-"(S)-(a -Methylarginyl, a -¾ 醯 chloro) methyl 1 Nornosine J will compound 3 *- 0-trifluoromethanesulfenylspinoxin J (488 ms, 0,574 ππηοΐ) was dissolved in dry DMF (20 niL). The phosphonium propionate compound and propionic acid (1.09 g, excess) were added. The reaction mixture was cooled to room temperature At the same time, 660 W ultrasonic vibration (55% amplitude) for 15 minutes. Add PhH (70 ml) and Et0Ac (70 ml). M2% aq. NaHC〇3 solution (2X) and saturated aq. NaHC〇3 (lx) The solution was washed. The organic phase MK2CO3 was dried and concentrated under reduced pressure. The residue was purified by Si02 flash column chromatography to obtain a mixture (275 mg). This sample was then repeated by repeating RF C-18 HPLC (MeOH-H20: 90-10) to obtain compound a) (3'S) -4'-nor-3 '-[(10-U-methoxy, cx-propionyloxy) methyl] Spinol Xin J; 62 mg, 23%): IMIU CDC13) 5 5.96 (1H, d: 9.2 Hz) 4.99 (lH, s) ppm and compound b) (3'S) -4 · -demethyl-3'-deoxy- 3 '_ [(S) ~ (oc-methoxy, oc-propylhydrazone (Oxy) methyl] Spinocinin J; 84 mg, 31%: IMMCDCIO δ 5.89 (· 1Η, dd: 9.4, 1.2 Hz), 4.99 (1Η, bs). Compound C (3 ' ) The stereoisomeric chemistry can be confirmed by NOEDS and molecular model results. -79-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page )

, 1T 487559 A7 B7 V. Description of the invention (77 group) Zoynin in compound Shen 3 dissolves compound 3'-0-trifluoromethanesulfonylspinoxin J (496 mg, 0.583 mraol) in dry DMF (14 mL). Add lithium chloride (1.80 g, excess). The reaction mixture was cooled to room temperature while K-ultrasonic (660 W, 52% amplitude) was oscillated for 7 minutes. The solution was washed with diluted saline (2X) and water (2X). The organic layer MK2CO3 was dried, filtered and concentrated under reduced pressure. The residue was purified on a short SiO2 / EtOAc column and then repeatedly purified by RP C-18 HPLC (MeOH-H20: 92-8). Epimeric (3'5) -4'-nor-3'-deoxy [1? / 5-3-chloro-3-methoxy) methyl] spinoxin produced by purification records J; 45mg, ll%: 5.02 (0.5H, s), 5,00 (0.5H, s), 4.57 (0,5 H, d: 9.5 Hz), 4.55 (0.5 H, d: 4.5 Hz), 2.16 (6 Η, 2x CH3, s) 〇 Rich example AfiO _ (: TS) _4'-nor-3 夂 argon "(R)-(rr-fluorine, α-methyl argon) methyl 1 methylpyridine Xin: [(3'5;)-4'-demethyl-3 ^ deargon f (S)-(cr-gas, σ-methylargon) Shen Ji 1 Zhong Nuoxin J_ Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumer Corporation (please read the notes on the back before filling this page) Dissolve the compound Spinoxin J (697 mg, 0.97 mmol) in dry toluene (10 mL). Stir under nitrogen and add pyridine (1 ml) and diethylaminethiotrifluoro compound (D AST; 0.70 mmol, 0.85 g, 5,2 ππηοΐ). The reaction mixture was immediately warmed to the boiling point. After 10 minutes, the solution was cooled to room temperature. Benzene (50 ml) and EtO Ac (75 ml) were added. M 5% aq. NaHCOa aqueous solution was washed. The organic layer MK2C03 was dried and reduced under reduced pressure. The residue was evaporated by flash evaporation. 2 column (80 g / EtOAc) separation to obtain a white solid (626 mg). A part of this sample (400 mg) is further optimized. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 80 487559 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (78) RF C-18 HPLC, (MeOH-H2O: 90-10) was used to isolate M to obtain compound a) (3'5) -4 '-Desmethyl-3'_deoxy [(1〇-(«-fluoro," -methoxy) methyl] Spinozin J; 82 rog, 21% · · IMIUCDCUSS. Uidd: 66 · 3, 5.4Hz) ppm and compound b) (3'S) -4'-nor-3-3-deoxy [(S)-(ct-fluoro, α-methoxy) methyl] Spinoxin J; 292 mg , 64%): ^ MRiCDCla) 5 5.26 (dd: 65.1 * 8.6 Hz) ppm 〇 Rich example AfU-H'S, 2'S) -n '-(2'S) lg radical_2'-to M-gas in the noroxin H_ The compound spinoline H (916 mg, 1.28 mmol) was dissolved in dry toluene (15 mL). Pyridine (1.8 ml) was added. The solution was heated to reflux temperature under nitrogen. At the beginning of the heating process, DAST (0.62 ml, 4.6 mmol) was added. After boiling for 10 minutes, the reaction mixture was cooled to room temperature and carefully quenched with K5% aq. NaHC03. Add benzene (50 ml) and EtOAc (75 ml). M5% aq. NaHC03 (3x) washing solution. The organic layer was dried over K2CO3 and concentrated under reduced pressure. The residue was purified by flashing a Si02 column (100 g / Et0Ac), and the eluate was collected to obtain the compound (l'S, 2'S)-[l- (2'S)] methyl-2'-deoxy-fluoro history. Binoxine Η; 992 mg, 72%: IMIU CDC13) δ 4.99 (dd: 52 · 8, 7.0 Hz) ppm. Example of tracheids A fi2-3 '(E)-(Nn-butyl) imine hydrazone oxoxine J_ Compound 3 ^ 0-trifluoromethanesulfonyl spinosinoxine J (591 mg, 〇 · 695 ιαπιοί ) Dissolved in dry DMF (20 mL). 15% TBAF / Al203 (2.7 g, excess) was added. The reaction flask was placed in a water cooling bath and sonicated (55% amplitude) at 660 W for 10 minutes. Et0Ac (50 ml) and PhH (70 ml) were added. The solution was filtered, extracted with K water (3x) and dried over MK2CO3. Organic layer _ 81 _ This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)-Installed · Printed by the Central Consumers Bureau of the Ministry of Economic Affairs 487559 A7 ___ B7__ 5. Description of the invention (79) Extraction under reduced pressure. The residue was separated by flash chromatography column (SiO2, 75 g / Et 0Ac) to provide compound (3 '((E)-(Nn-butyl) imino spinosinol J; 144 mg , 23%: IMRiCDCM 34 · 81 (1Η, d: 2.0 Hz) ppm 0

Honey bottle example A 63-3? I; deuterium Z in a certain unit of oxanosin J The compound spinoxin J (882 mg, 1.22 mmol) was dissolved in dichloromethane (5 ml). K2CO3 (1.42 g) was added. The reaction flask was placed in a water cooling bath (ca. 10 ° C). While stirring, 15% aq. NaOH (15 ml) was added, followed by ΤΒΑ-Π (0.92 g) and NBiuHSOWO. 30 g). C2D3I (5 g: 31 mmol) was then added and the reaction mixture was stirred vigorously at room temperature for 48 hours. Dichloromethane (100 ml) and water (100 ml) were then added. Phase separation was performed after extraction. The organic layer was washed with water (2X) and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (120 g / Et0Ac) to obtain the compound 3'-0-pentadecylethylspinoxin J; 815 rag, 88%: IMlUCDCla) δ 6.64 (1Η , Bs), 4.69 (1H, d: 1.2 Hz), 3.43 (3Η, CH3, s), 3.36 (3Η, CH3, s), 2.10 (6Η, 2x CH3 »s) ppm ° 啻Detailed example A 64-3 · -guan argin-3,-ΜMinosinoxin J (1: 1 3 'R and 3' S borohydride) and (: TS) -4'-demethyl_3 ' _Dechloro-3 '-[(RS) _ (a ~ Couple, a -methyl chloride) methyl 1 Spence

A Compound 3'-0-trifluoromethanesulfonyl (440'fflg, 0.518 mmol) was dissolved in dry DMP (20 ml). Sodium azide (1.44 g 'excess) was added. The mixture was sonicated (660 W, 55% amplitude) for 10 minutes at room temperature. -82-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) (Please read the notes on the back before filling out this page) • Equipment, vm 487559 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs A7 _____. B7 V. Description of the invention (80) Add Et0Ac (50 ml) and PhH (100 ml). With 5% aq. KHC03 solution (3 x). The organic layer, Manh. K2CO3, was dried, filtered and concentrated under reduced pressure. The residue was subjected to flash column chromatography KSiO2 (50 g / EtOAc) and by RPC-18 HPLC (MeOH-H20: 88-12) to obtain compound a) 3'_deoxy-3'- Azo Spinozin J ((1: 1 3'R and 3'S mixture); 40 mg, 10%: iNMlHCDCh) δ 4 · 83 (0.5Η, d: 2 · 4Η), 4.64 (0 · 5Η , D: 2 · 8 Hz), 3.95 (0.5Η, m), 3.85 (0 · 5Η, dd: 2.8, 4.0Hz), 3.81 (0.5Η, in), 2.17 (6H, 2XCH3, s ) ppro and compound b) (3'S) -4'_ nor-3'-deoxy-3 '-[(RS)-(a-azo, α-methoxy) methyl] Spinozin J ; 101 mg, 26%: IMR (CDCM 3 5.00 (0 · 5Η, s), 4.98 (0 · 5Η, s), 4 · 520 · 5Η, d: 9.9 Hz), 4,35 (0.5 H, d: 9.9 Hz), 2.14 (6 Η, 2X CH3, s) ppm 〇 啻 Case A 4'-nor-dehydro-fluorene, α-methylargonyl) methyl 1 in the noroxin. I Compound 3'-0-trifluorosulfonylsulfenylspinoxin J (448 mg, 0.574 mmol) was dissolved in dry DMF (20 ml). Add lithium chloride (1.80 g, excess). The mixture was cooled to room temperature while the mixture was sonicated (660W, 52% amplitude) for 7 minutes. Add PhH (70 ml) and Et0Ac (50 in 1). Rinse with saline (2 x) and water (2 x) diluted with solution K. The organic layer K K 2CO 3 was dried, filtered and concentrated under reduced pressure. The residue was purified on a short SiO2 / EtOAc column and then repeatedly purified by RP C-18 HPLC (MeOH-H20: 92-8). Purification records of the (3'demethyl-3'-deoxy-3 '-[(RS) -a-chloro, cx-methoxy) methyl] spinoisin J epimers; 45 mg, 11%: 5.02 (0.5H, s), 5.0 (0.5 H, s), this paper size applies Chinese National Standard (CNS) Α &lt; 4 size (210X 297 mm) (Please read first Note on the back, please fill out this page again) Binding-487559 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (81) 4 · 57 (0 · 5 H, d: 9.5 Hz), 4.55 ( 0,5 H, d: 4.5 Hz), 2.16 (6 Η, 2X CH3, s). When pus example A 66-5.fi-Diargon-2’-Π_B in a certain middle-nosinoxine_ Will the compound 5,6-dihydrospinoxin? 1 (462 1 ^, 0.64 111111〇1) was dissolved in dichloromethane (6 ml). Potassium carbonate powder (1.0 g) was added. Place the reaction flask in a water cooling bath (ca, 10 ° C). While stirring, 10% aq. NaOH (15 ml) was added, followed by NBiwHS04 (0.30 g) solid. Then add iodoethane (4.0 ml). The reaction mixture was stirred vigorously at room temperature under nitrogen for 46 hours. Dichloromethane (100 ml) and water (100 ml) were added. After extraction, the phases were separated. The organic layer ManheK2CO3 was dried and concentrated under reduced pressure. The residue was purified in a flash SiO 2 column (80 g / EtOAc) to obtain compound 5,6-dihydro-2.-0-ethylspinoxine; 336 mg, 70%: IMMCDCM δ 6.69 ( 1H, bs), 4.59 (1H, bs), 3.37 (3H, CH3, s), 3.30 (33, CH3, s), 2.06 (6Η, 2X CH3, s) ppm

O Example of tracheid A 67-5 · 6-Diqipan 2, _0_11- and Kezhongkexinuoxin _ Compound 5,6-dihydrospinoxine 488 (488 mg, 0.68 mmol) was dissolved in dichloromethane (8 ml). Add potassium carbonate powder (1.1 g). The reaction flask was placed in a water cooling bath (ca. 10 ° C). While stirring, 10% aq · Na0H (20 ml) was added * followed by NBluHS04 (0.95 g) solid. Iodine n-propane (4.0 in 1) was then added. The reaction mixture was stirred vigorously at room temperature under nitrogen for 46 hours. Dichloromethane (100 ml) and water (100 ml) were added. After extraction, the phases were separated. The organic layer Manh. K2CO3 was dried and concentrated under reduced pressure. The residue was purified in a flashed 3.02 column (80 s / EtOAc) to obtain Huayi 84 _ This paper size is applicable to the Chinese National Standard (CNS) Λ4 grid (210X 297 mm) (Please read the back (Please fill in this page again)

1T 487559 Economic Cooperative Standards Bureau Employees' Cooperative Cooperative Print A7 B7 V. Description of the Invention (82) Compound 5,6-dihydro-propylpropyl Spinocinol 355 mg, 69%: IMIHCDCla) δ 6 72 (1Η, bs), 4.63 (1Η, d: 1.3 Hz), 3.41 (3H, CH3, s), 3.34 (3Η, CH3, s), 2.10 (6H, 2x CH 3, s), 0.67 (3 Η, CH3, t: 7.4 Hz) ppm. Example A 68-3'-Table Caoxin J_ Compound 3'-keto-spinoxin J (3.61 g, 5.04 mmol)) was dissolved in ether (100 ml). The solution was cooled to 0 ° C under nitrogen. Add a portion of lithium di-t-butoxyhydrogen hydride (1.45 g; 97%, 5.53 mmol). Mixing was continued for 15 minutes at 0 ° C, and then the remaining LTBAH (105 g, 4.00 mrool) was introduced. Stirring was continued for another 35 minutes. Add benzene (60 ml). Slowly decompose excess hydride with saturated brine (20 ία 1) at 0 ° C. The phases are separated. The organic layer was successively M brine-H20 (8: 1), M10% aq. NaOH solution, and washed with water. The organic phase, Manh. K2CO3, was dried, filtered and concentrated under reduced pressure. The obtained product (3.215 g, 89%) was obtained by flash column chromatography (160 g, SiO2 / EtOAc) to obtain 95% pure compound 3'-epispinoxin J; 2.715 g, 75 %: ιΗ- NMR (CDCI3) δ 6.63 (1H, bs), 4.71 (1H, bs), 4.55 (1H, ra), 4.28 (2H, m), 4.04 (1H, m), 3.78 (1H, m), 3.49 (1H, m), 3.33 (3H, CH3, s), 3.31 (3H, CH3, s), 2.11 (6H, 2x CH3, s) ppm. Example A 69-3'- 恙-. VD-tri-arsenide is very good. T_ Compound 3'-epispinoxin J (1,53 g, 2.13 mmol) was dissolved in dry dichloromethane (20 ml). Add pyridine (5.0 ml, dry). The solution was cooled to 0 ° C under nitrogen. In the K syringe method, trifluoromethanesulfonic anhydride (1.0 ml, excess) was slowly introduced. Continue stirring at (TC for 16 hours. Add ________________-85-This paper size applies to Chinese National Standard (CNS) Λ4 specification (2! OX.297 mm) I -------- ^ ---- --1T ------ # (Please read the notes on the back before filling out this page) 487559 A7 B7 V. Description of the invention (83)

Et0Ac (50 ml) and PhH (100 1111). The solution was extracted with dilute brine (2 /) and 5% 39. KHC03 solution (2X). The organic layer was filtered with anh. Na2S04, and concentrated under reduced pressure. The residue was flashed in a Si02 column (100g / EtO Ac) to obtain the compound 3'-Table-3'-0-trifluoromethanesulfonylspinoxin j; 36 g, 75%) : 1H-NMR (CDCI3) δ 6.69 (1Η, bs), 5.03 (1H # dd: 3.2, 3.5 Hz), 4.63 (1H, bs), 3.90 (ih, dq ·· 3.9, 6.4 Hz), 3.39 (3H, CH3, s), 3.35 (3H, CH3, s), 2.13 (tSH, 2x CH3, s) ppm. Implementation diameter [A 70-3'-〇- (α, atrigas-butanyl) Spinosin J____ The compound Spinozin J (790 mg, 1.10 mmol) was dissolved in dry dichloromethane (5 ml). Potassium carbonate (1.1 g) was added, followed by 15% aq. Sodium hydroxide solution (15 1111 ), 811′1 ^ 〇4 (0,8〇8) and 4-bromo-1,1,2-trifluorobutene (3.0 g, excess). DMSOU. 0 ml was added). Stirring was continued at room temperature under nitrogen for 16 hours. Dichloromethane (100 ml) and water (100 ml) were added. After extraction, the phases were allowed to separate. The organic phase KK2CO3 was dried, filtered and concentrated under reduced pressure. The residue was flashed in a SiO2 column (100 g / EtOAc) to obtain the compound 3'-0-U, α, /?-Trifluoro-7-butene) -α-base Spino Central Bureau of Economics Printed by the employee consumer cooperative (please read the precautions on the back before filling this page) Xin J; 194 mg, 21%): [NMRiCDCl :!) 5 6.66 (1H, bs), 6.28 (1H # m: WH / 2 = 65 Hz) 5.43 (1H, m: WH / 2 = 60 Hz), 5.28 (1H, d: 17.4 Hz); 5.02 (1H, dd: 11.4, 1.4 Hz) # 2.13 (6H, 2x CH3 · s ) ppm and (b) recovered compound Spinosyn J (520 mg, 75%). and (b) recovered compound Spinosyn J (520 mg, 75%). Example A 71-2 'Very Zhongke Nuoxin J__ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 487559 A7 __ ~ B7 V. Description of the invention (84) Will 3' -_ Shi Binnuo Xin J (755 mg, 1.05 mmol) was dissolved in dry THF (10 ml). Tetraethylsilane (1.0 ml) was added followed by 15% BimNF / A1203 (0.55 g, excess). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Add benzene (70 ml) and EtOAc (30 ml). K 5% aq. KHCOa solution (2X). The organic layer was dried over KK2CO3, filtered and concentrated under reduced pressure. The residue was obtained by flash evaporation on a Si02 column (120 g / EtOAc) K) U ^ 3 ^ -ketospinoxin J (290 mg, 38%) and (b) compound 2'-Table-3'-one Base Spencer J; 375 mg, 50% UMlUCDCUSe.eOUH, bs), 5.06 (1H, d: 4.1 Hz), 3.39 (3H, CH3, s), 2.08 (3H, 2XCH3, s) ppm0 Rich examples A72-2'-Table-3 窨 Nanosin J_ Dissolve the compound Table-3'-keto Spinosin J (305 rag, 0.426 mmol) in dry THF (10 ral) and add dry ether (10 ml ). The solution was cooled to 0 ° C and stirred under nitrogen and a portion of Li (t-BuO) 3AlH (200 mg, 0.76 ππποί) was introduced. Stirring was continued at this temperature for 30 minutes. The M brine was then carefully quenched. The mixture was partitioned between Et20 and water containing 5% NaOH. Organic 餍 continuous K water containing 5% NaOH and 5% aq, KHC〇3 (2X) was washed, MK2CO3 was dried, filtered and concentrated under reduced pressure. K obtained only printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy (Please read the precautions on the back before filling this page) 2'-Table-3'-Table Spinocin J white foam; 303 rog, 99% 1H_ NMR (CDCI3) δ 6.61 (1Η, bs), 4.78 (1H, d: 3.3 Hz), 3.84 (1H, dq: 9.8, 6.3 Hz), 3.37 (3H, CH3, s); 3.35 (3H, CH3, s), 2.14 (6H, 2xCH3, s) ppm. Example A-Constitution-.V-Table-3--0-Ethyloxinoxin J_ Compound 2 *-Epoxyspinoxin J (250 ms, 0.348 mmo 1) was dissolved in dichloride Methane (5 m 1). Potassium carbonate (1.0 g) was added. Flask ___- 87 -__ This paper size applies Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy. 487559 A7-B7 ~ ______ 5. Description of the invention (85) In a cooling bath (10 ° C), 20% Ha0H (20 ml) was added, followed by BiuNHS04 (0.71 g), iodoethane (2.0 ml), and DMS0 (5 ml). The reaction mixture was stirred vigorously under nitrogen for 60 hours. Dichloromethane (100 ml) and water (100 ml) were added. After extraction, the phases were allowed to separate. The organic layer was dried over K2CO3, filtered and concentrated under reduced pressure. The residue was flashed in a Si02 column (30 g /

EtOAc) to provide 2'-Table-3'-epiethylspinoxin J, 43mg 17% 1H-NMR (CDC13) δ 6.72 (1Η, bs), 4.81 (1H, d: 4.0 Hz), 4.01 (1H , m) 3.36 (3H, CH3, s), 3.33 (3H, CH3, s), 2.16 (6H, 2xCH3 's) ppm. 啻 Case A 74-3' -Deargon-.V- Nuozai in the air (: TM compound ΐ. · 1 complex) _ 3'_ epispinoxin J (570 mg, 0.794 mmol) was dissolved in dry dichloromethane (10 ml). The solution was cooled to -25 ° C under nitrogen. Diethylamine thiotrifluoride (315 ml, 2.38 mmol) was introduced via an injector. Stir for 3 hours under -25 Torr and nitrogen, then raise the temperature within 30 minutes. Add pyridine (0.5 ml) and continue stirring for another 15 minutes at room temperature. The mixture was partitioned between CH2C12 (100 ml) and 5% aq. KHC03 (150 ml). The organic layer was washed successively with M5% aq.KHC03, dried with MK2CO3, filtered and concentrated under reduced pressure. The residue was flashed in a Si02 column (100s / EtOAc) and then compound 3f-deoxy-3 ^ fluorospinoxin J was obtained by RP C-18 HPLC (10% water in methanol), 3.-F: 1 ·· 1 mixture of 3'bF, 168 mg, 29%, M-MMIUCDCI:]) δ 6.68 (1Η, bs), 4.60 (1H, nm), 4.36 (0.5 H, ddd: 44.6 , 2.9, 2.5 Hz), 3.38 (1.5 H, CH3, s), 3.36 (1.5 H, CH3, s), 3.33 (1.5 H, CH3, s), 3.32 (1.5 H, CH3, s), 2.12 (6Ht 2x CH3, s) ppm. _ _-88 ~ This paper size applies to China National Standard (CNS) Α4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (86) g Case A 75-: T_n-Se a certain customer Nosing, J_ will be 3'-Table Spence Nosing J 14δ mg, 0.206 mmol) was dissolved in dry xylene (3 ml). The solution was stirred at room temperature under nitrogen and diphenylphosphine (118 mg, 0.45 mmol) was added, followed by fermentation (42.5 mg, 0.45 mmol). After stirring for 15 minutes, diethyl azobiscarboxylate (DEAD, 75 ml (95%) * 0.45 mmol) was added to the mixture. Stir at room temperature for 16 hours, then dilute with MPhH (70 ml) and Et0Ac (50 ml), wash with M5% aq. KHC03, and dry with potassium carbonate. The residue was purified on a flash SiO 2 column and then separated on an RP C-18 HPLC column (12% water in methanol) to obtain (a) the recovered 3'-epispinoxin J (101 mg (68%) and (b) compound 3'-0-phenylspinoxin J; 3.1 mg, 1.9% iH_NHR (CDCI3) 57.28 (2H, m), 6.99 (3H, m), 6.76 (IH.bs ), 4.84 (1H, d: 1.6 Hz) # 4.54 (1H, dd: 9.4, 3.1 Hz), 3.53 (3H, CH3, s), 3.46 (3H, CH3, s), 2.11 (6H, 2x CH3, s ) ppm. Symptomatic case A 7 Bu Zhongxinxin J Xi. Vn- (S-cage) dithiocarbazone Spinoloxin J (1.20 mg, 1.67 mmol) dissolved in dry dichloromethane (10 ml ). Pyridine (dry, 2 ml) was added followed by human DMAP (70 mg). The reaction mixture was stirred at room temperature under nitrogen and cooled in water. Slowly add phenylchlorodithioformate (1.80 ml, excess) via syringe. The mixture was then stirred at room temperature under nitrogen for 16 hours. Add PhH (70,

ml) and Et0Ac (70 ml). The organic layer was washed with M5% KHC03 (4X), and MK2CO3 was dried and concentrated under reduced pressure. The residue was separated by flashing a Si02 column (120 g / EtOAc). The compound 3'-0_ (S-phenyl) dithiocarbonate was provided; 780 mg, 54% lW NMR-89. National Standard (CNS) A4 Specification (210X 297mm) (Please read the notes on the back before filling this page) • Ze. 〇59 A7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of Invention (87) (CDC13) δ · 50 (2H, m), 7.33 (3H, ra), 6.63 (1H, bs), 5.73 (3H, m), 4.69 UH, bs) '3.32 (3H, CH3, s), 3.12 (3H, CH3 / s), 2.15 (6H, 2XCH3, s) ppm 窨 fe Case A 77- Spinozin J-3'-0 -(Pentafluoromacro) thiocarbonyl carbon_Horspinoxin J (1.52 mg, 2.12 mmol) was dissolved in dry acetonitrile (15 ml). DM AP (0.84 g, 6,88 mmol) was added and dissolved. The solution was cooled to 0 ° C under nitrogen. Pentafluorophenylchlorothiocarboxate (1.60 ml, 10.0 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 16 hours. PhH (70 ml) and Et0Ac (50 ral) cM5% KHC03 (3x) extraction solution were added and dried with MK2CO3. The organic layer was concentrated under reduced pressure. The residue was separated on a flash SiO 2 column (120 g / EtOAc) to provide compound 3'-0- (pentafluorophenyl) thiocarbonyl carbonate; 1.77 g, 88%, π-NM 1? (CDC13) δ 6.65 (1Η, bs), 5.42 (1H, dd: 9.4, 3.2 Hz), 3.41 (3H # CH3, s), 3.39 (3H, CH3, s), 2.10 (6H, 2x CH3, s) ppm · · A detailed example A 78'V -Π-Γ (: TR) 'V-dehydrogenation 窨 窨 Nuo barrier J 1 -3 ir nuosin · ι, (.vm and crskv-allyl' v-go Arsenic in argon syrup J 1: 1, and (: TS) 'V-allyl-3, _dechlorinated Caoxin J _ will be compound Spinozin J-3'-0- (Pentafluorophenyl) thiocarbonyl carbonate (1.65 g, 1.75 ramol) (1.52 mg, 2.12 mmol) dissolved in dry toluene (25 ml). Allyl tributyltin (1,70 nil, 5.32 mmol) was added Then, AIBN (180 mg) was added. The mixture was heated to reflux temperature under nitrogen for 20 hours. The mixture was cooled, concentrated and placed directly into a flash SiO 2 column (220 g / EtOAc). Purified fractions Further, RP C-18 HPLC (10% water in methanol) was used to provide compound 3) 3'-0-[(3 1) -3'-Go to __________ 90 _ _ This paper standard applies Chinese national standard (C NS) A4 specification (210X 297 mm 1 (Please read the precautions on the back before filling this page)

1T line 487559 A7 B7 V. Description of the invention (88)

Oxy Spinnoxin J] -3 ^ Spinnoxin J; 373 mg 30% iH-NMR (CDCI3) δ 6.66 (1Η, bs), 4.59 (1H, bs), 3.52 (2H, m), 3.28 ( 3H # CH3, s), 3.24 (3H, CH3, s), 2.12 (6H, 2x CH3, s) ppm; Elemental Analysis: for Ca〇Hi24N2019 calc. C 67.77, H 8.32; N 1.93, found C 67.69 , H 3.70; N 2.24, and compound b) (3'R) and (3'S) 3 allyl-3'-deoxyspinoxin J 1-1 mixture; 144 mg, 11%. The mixture was further compound C obtained by repeating RP C-18 HPLCK on a 5 micron Rainin column.) (3'S) -3'_allyl-3 夂 deoxyspinoxin J; 窨 Detailed Example A 79-H4R ) Digas-3 '(ΓΠ-(methylchlorocarbonyl) methylene-3'-deargon in oxoxine J_ The compound 3' (E)-(methoxycarbonyl) methylene-3'-spin Nosin J (308 mg, 0.39 mmol) was dissolved in Et20 (10 ml). Glacial acetic acid (5 ml) was added. The mixture was stirred at room temperature and 1 ^ 8 ^ 〇 ^ (180 1 ^, excess) was added. Economy Department of the Central Bureau of Standards Consumer Cooperative printed at room temperature and under nitrogen for 16 hours. PhH (100 ml) and EtO Ac (50 ml) were added. Diluted saline (2X), followed by M5% aq. NaHC〇3 Extraction. The organic layer was dried over Manh. K2CO3, filtered and concentrated under reduced pressure. The residue was purified by flashing a Si02 column (55 g, EtOAc) to provide compound (14R) -13,14 /?-II Hydrogen-3 * (E)-(methoxycarbonyl) methylene-3'-deoxyspinoxin J; 222 mg, 72%) INMR (CDC13) 5 6.13 (1H # d: 1.6 Hz), 4.89 (1H, d: 4.1 Ηζ) /4.3β (1H, d: 6.3 Hz), 3.79 (1H, dd: 1.7, 6.3 Hz), 3.61 (3H, CH3, s), 3. 39 (3H, CH3, s), 3.21 (3H, CH3, s)% 2.11 (6H, 2x CH3 # s) ppm. Example A 80-3 '(E)-(hydroxymethyl) Yashenguan argon窨 诺辛 J — '(14S, 21S,) -1 ·? Bu argon_l 3 · 1 4-Digas-1 -91 (Please read the precautions on the back before filling this page) The paper size is suitable Financial Customs House Standard (CNS) Α4 specification (H1GX 297 public) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (89)

.21-Difluorene'V (K)-(fluorenylmethyl) methylene-.V-Deargon-1.2 Benzanosin J Compound 3 '(E)-(methoxycarbonyl) Methyl-3'-deoxyspinoxin J (340 mg, 0.44 mmol) was dissolved in dry dichloromethane (5 ml). Add dry T HF (1.5 ml). The solution was cooled to 0 ° C under nitrogen and DIBALH (1.95 ml, 1.0 M solution in cyclohexane, 1.95 mmol) was added. Continue stirring for 45 minutes. A saturated solution of NH4OH-NH4Cl (1: 1) was added dropwise at 0 ° C. PhH (100 ml) and Et0Ac (70 ml) were added, and a solution of saturated heart 4〇11-NH4C1 (1 ·· 1) was added, followed by extraction with K2N aq. HaOH, and finally K5% aq. KHCOa solution (2X). The organic layer was dried over K2CO3, filtered, and concentrated under reduced pressure. The residue was separated on a flash SiO 2 column (30 g / EtOAc) to provide compound 8) 3 '(E)-(hydroxymethyl) methylene-3'-deoxyspinoxin J; 91 mg, 28% iHNMR (CDCl3) 56.71 (lH, bs), 5.87 (lH, t: 6.2 Hz), 4.51 (1H, d: 3.9 Hz), 3.33 (3H, CH3, s), 3.31 (3H, CH3, s), 2.16 (6Η, 2x CH3, s) ppra. And compound b) 13,14cc-dihydro-1,21S-dihydroxy-3 '(E)-(hydroxymethyl) methylene-3 · -deoxy1,2, Spinoloxin J; 104 mg, (CDC13) 55, 82 (1H, t: 6.1 Hz), 4.47 (1H, d: 3.9Hz), 3.29 (3H, CH3, s), 3.26 (3H, CH3), 2.78 (2Η, m ), 2.12 (6H, 2XCH3, s) ppm0 Tube Example A 81 -4 夂 fl-n-Bing Zhongzhong Nuozai K__ Spinoxin K (322 mg, 0.448 mmol) dissolved in dry dichloromethane (4 ml ). Add potassium carbonate (1.1 g). Place the flask in a water bath (ca. + 10 ° C). Add 15% NaOH aqueous solution (25 ml), and then add Bu4NHS〇4 (1.2 g) -92-This paper applies the Chinese National Standard (CNS) A4 specification (2 丨 0X 297 mm) according to the standard (Please read the notes on the back first Fill out this page again), τ

T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (90), iodine-propane (3.0 ml) and DMS0 (4 ml). After 16 hours, additional Bii4NHS04 (0.70 g) was introduced. Stir vigorously at room temperature under nitrogen for a total of 60 hours. Water (100 ml) and dichloromethane (100 ml) were added. After extraction, the phases were allowed to separate. The organic layer was dried with Manh. K2CO3, dried over Celite and dried under reduced pressure. The residue was separated in a flashed SiO 2 column (100 g / EtOAc) to provide the compound 4'-0-η-propyl spinosinol K; 225 mg, 66% M-NMR (CDCla) S6.66 ( lH, bs), 4.75 (lH, bs), 3.67 (lH, in), 3.39 (6Η, 2X CH3, s), 2.13 (6H, 2X CH3, s), 0.82 (3H, CH3, t: 7.4 Hz), 0.71 (3%, CH3, t: 7.4Hz) ppm ° Example 8 82_methyl-2.3.4-tri-0-ethyl-[-rhamnofur glucoside glycoside will be methyl L-rhamnopyranoside (Fischer, E, Chem. Ber., 189 5, 28, 1 158) is c (and / 3 glycoside isomers (21.0 s, 0.118 mole). % U / w) in a mixture of an aqueous sodium hydroxide solution, DMSO (100 rol) and tetrabutylammonium hydrogen sulfate (20.0 g, 0.059 mmol). Iodoethane (75.0 mL) was added to the mixture. A slight exothermic reaction can be seen within 20-30 minutes before the reaction (external cooling, ice bath system is used to maintain the reaction temperature close to 25 ° C). After 3 hours of reaction, an additional 75 ml of iodoethane was added. After another 3 hours, add 75 i of 1M ethyl iodide and more than 50% NaOH solution (200 ml). After another 3 hours, add 70 ml of iodoethane and more than 50% NaOH solution (100 ml), and stir the mixture overnight. The total reaction time is 24 hours. Dilute the mixture with K water (200 ml) and extract as much as possible with dichloromethane. The dichloromethane extract was washed with brine (200 ml), dried (MgSO4) and evaporated. Amorphous residue was developed with hexane (-93-This paper size applies Chinese National Standard (CNS) A4 specifications (210 &gt;; 297 mm)) (Please read the notes on the back before filling this page) Binding Line

487559 Lost blind support in print ¾ Printed by employee consumer cooperative A7 — ^ __ B7__ V. Description of the invention (91) 300 ml) and filtered. The collected solid M hexane (100 mL) and the combined filtrates were concentrated and concentrated to give 42.0 g of crude product. Flash chromatography was performed with 900 ml of silica, using 10% ethyl acetate in hexane as the eluent. After 800 ml of pre-precipitation, 200 ml of lysate was collected. The clean methyl 2,3,4-tri-0-ethylrhamnopyranoside (25.5 g, 82%) obtained from fractions 3-11 was a colorless oil: MNMR (CDCU) 3 4,64 (d, 1, H-1 (α-glycoside isomer)), 3.89 (dp, 1, H-5), 3.50-3.80 (m, 8), 3.33 (s, 3,0CH3) , 3.23 (t, 1, H-4), 1, 30 (d, 3, H -6), 1.15-1.25 (π, 9, CH2CH3). Vial example A 83-2,3.4-tri-fl-7, yl-1, rhamnose methyl 2,3,4-tri-0-ethyl-1 ^ rhamnopyranoside (11.0 (0.042 mol) in 110 ml of a 4: 1 (v / v) trifluoroacetic acid: water solution was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure (~ 1.0 mm, 30-35 ° C) to near dryness, and the residue was diluted with dichloromethane (200 inL). The aqueous and organic phases were separated and the saturated sodium bicarbonate solution (40 inL), brine (40 rnL), and the dry washed organic phase were then dried over magnesium sulfate, and concentrated to leave 11.0 g of crude product. 950 mL of silica was used for flash chromatography, and 25% ethyl acetate in hexane was used as the eluent to obtain 9.5 g (91%) of pure triethyl rhamnolide, which was α and / 3 epimers. Mixture and nearly colorless oily substance: iHNMlHCDCh) δ 5 * 18 (m, 1,)-1), 3.6 ~ 3.95 (π, 8), 3.25 (ιη, 1, Η-4 ), 2.48 (€ ΐ, 1,0Η), 1.15-1.35 (m, 12) 0 啻 _Example 8 84-0- (2.3.4-tri-0-ethyl- (7- 丨, rhamnolide Sugar Pyranosyl) -Sanmo imitate__ __- 94 -_ This paper size applies the Chinese National Standard (CNS) Λ4 specification (2! 0X297 mm) (Please read the precautions on the back before filling this page). Installation · -5Ϊ »Line 487559 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (92) Add a portion of freshly distilled trichloroacetonitrile (12.0 inL, 0 · 12 mmol) to cold (0-5 ° C), properly stirred solution of triethyl rhamnose (2,2 g, 8.86 mmol) in dry dichloromethane (80 inL). 60% sodium hydride in mineral oil (0.35 g) , 8.87 mmol is 100%) The solution is added to the solution within 1-2 minutes. (Note: foaming and hydrogen (Released). After 20 minutes of reaction, the cooling bath was removed and the mixture was stirred at room temperature for 5.5 hours. Then the mixture was cooled again to 0-5 ° C and a portion of silicone (6.0 g) was added. Stir for 10 minutes After that, the mixture was washed through the mixture and the collected solid was washed with dichloromethane (25 mL). The combined mash and washing solution were evaporated to dryness under reduced pressure (~ 25 mm, 30-35 ° C) and the residue was washed with hexane. Treatment with alkane (60 niL) to separate some flocculated solids. After holding for 30 minutes, the solid was filtered (diatomaceous earth) and washed with hexane (25 mL). The combined mash and washings were then decompressed (~ 25 nun, 30-35 ° C) and concentrated to dryness, leaving 2.9 g of crude imidate as a pale yellow oil. According to iHNMR spectrum analysis, it was found that it contained only epimers and was pure enough to be used directly without further purification 1 ( Note: i mi date cannot be subjected to silica chromatography and decomposed by short-circuit distillation under reduced pressure (~ 〇, 1 mm): iHNMR (CDCl3) 5 8.54 (s, 1 / NH), 6.22 (S / 1 , Hl), 3.6-3.95 (m, 9), 3.35 (tt 1, H-4) # 1.34 (d, 3, K-6), 1.1-1.3 (m, i 9).

Example A85-3 '(E)-(Methylchlorocarbonyl) Methylmethoxine'v-Deargonin Knosin J (3' (Z)-(Methylchlorocarbonyl) Yatianxi-.V-Apricotine Zhongke Nuoxin J Dissolve the compound 3'-ketospinoxin J (609 mg, 0.851 mmol) in dry toluene (25 ml). Add methoxycarbonylmethylenetriphenylphosphorane (___-95- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) --------- installed-(Please read the precautions on the back before filling this page)

Line 1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (93) 2.2g, excess). The reaction mixture was heated to reflux temperature under nitrogen for 2 hours. Cooled to room temperature and chromatographed directly on a flash SiO 2 column (220 g / EtOAc). The eluates having the desired polarity were combined and concentrated under reduced pressure to obtain a crude product (584 g). Samples were separated by repeated RP C-18 HPLC (12% H2O in methanol) to obtain: recovery of the starting 3'-keto spinosinol J (49 mg), compound a) 3 '(Z)-(methoxycarbonyl) ) Methylene-3'-deoxyspinoxin J; 45 mg »7.5% 1HNMR (CDCl3) d 6.68 (1H, bs), 6,13 (1H, bs), 3.68 (3H, CH3, s) , 3.33 (3H, CH3, s), 3.30 (3H, CH3 s), 2.16 (6Ht 2x CH3, s) ppm, and compound b), 31 (E)-(methoxycarbonyl) methylene-3 '-Deoxyspinoloxacin J; 242 mg »40% ^ NMR (CDCla) δ 6.64 (1H, bs), 6.16 (1H, 1.8 Hz), 3.58 (3H, CH3, s), 3.37 (3H, CH3 's), 3.19 (3H, CH3.S), 2.08 (6H, 2x CH3, s) ppm. In the example, Wnosin A 9-Psa and 3'-ketospinoxin J ( To a solution of 1.89 gm, 2.64 mmol) in methanol (100 ml), potassium carbonate (anhydrous; 1.82 gin: 13.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (100 ml) was then added and the mixture was filtered. The filtrate was evaporated at room temperature to obtain a yellow solid. The yellow solid was dissolved in dichloromethane and washed with water, followed by brine and dried over magnesium sulfate. Dichloromethane was then evaporated under reduced pressure to obtain a colorless semi-solid (1.53 gin). The semi-solid was purified by flash chromatography using a 5% methanol in dichloromethane solution and a 10% methanol in dichloromethane solution as a single step gradient to obtain Spinoxin A 9-Psa (1.09 gm, 76% product Rate), it is white. _____- 96 -_ This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions on the back before filling this page).

， 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __B7 V. Description of the invention (94) The glass object.

g. Example A 87 ′ ′-Amidyl-MesoWnosin Q was reacted according to the method described in Example A 46, M Spinoxin L (997.4 mg, 1.36 mmol) was used as the starting material and a colorless semi-solid 3 * -Ketospinoxin D (850 mg). NMR showed that the product contained impurities of diisopropylsulfur, but the product was used without further purification. Example A 88-Mesanosine D 9-Psa The reaction was performed according to the method described in Example A 86. M 3 ketospinoxin D (770 mg, 1.06 mmo 1) was used as the starting material, and Colorless glassy Spinoxin D 9-Psa (246 mg, 42% yield). Enriched Example A 89-2'yl-Stilanosin_Η Ethyl sulfide (1.8 mL, 16.74 mmol) was added dropwise to cold (-78 ° C), nitrogen-covered N over 2-3 minutes. -A suspension of chloropreneimine (1.7 g, 12.73 mmol). The resulting solution was stirred at _78 ° C for 30 minutes, and while maintaining the reaction temperature at &lt; -65 ° C, then spinosynoxine (3.0 g, 4.18 mmol) was added dropwise over 10 minutes. Dichloromethane (25raL). After maintaining at -78 ° C for 3 hours, while holding the reaction temperature at <-65 ° C ', diethylamine (4.1 ml, 29.47 mmol) was added dropwise over 5 minutes. The cooling bath was then removed and the reaction was allowed to warm to room temperature over a period of 20-30 minutes. Dichloromethane (80 ml) was added, washed with 0.2N HC1 (150 mL) and brine (100 niL), and dried over magnesium sulfate. The remaining concentrate was 4 · 2 g of semi-solid. After flash chromatography on silica (325 niL), K 3% methanol in dichloromethane was used as the eluent to obtain 2 (2 · 8 g, 93%) of spinosinol, a colorless foamed carcass. : WNMR (CDC13) 54.68 (S, l, Hl,), 4.12 (cl, This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page )

487559 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (95) 1, H-3 '), 3.97 (ιη, 1, H-5,). Tube_Example A 90-Mesanosin A 9-Psa, 2 * -ketospinoxin (1.0 g, 1.39 mmol), p-toluenesulfonic acid radon (0.32 g, 1.75 mmol), and tripropylamine ( A solution of 0.33 ml, 1.75 mmol) in 1,4-dioxane (40 ml) was heated to reflux temperature under nitrogen for 30 hours with stirring. The solvent was then removed under reduced pressure and the residue was chromatographed on silica (100 mL). Spinoloxin A 9-Psa (a colorless foam was obtained using 5% methanol in dichloromethane as the eluent M ( 0.39 g 52%): iHNMR (CDC13) δ 6.78 (br s, 1, H-13), 4.63 (m, 1, H-21) 4.43 (m, 2, H-l &quot;, H-9), 2.23 (s, 6, N (CH3) 2 · Fen Example A 91-Medium Wnosin R 9-Psa The reaction was performed according to the method described in Example 3, M Spinoxin M (199.3 mg, 0, 28 mmol) Is the starting material. After preliminary purification by chromatography on silica, in one step, M 7% methanol in dichloromethane solution followed by K 10% methanol in dichloromethane solution. HPLC separation on a C 18 column, acetonitrile: methanol: 0.1% ammonium acetate (a linear gradient of 60 minutes from 30: 30 ·· 40 to 32.5: 32,5: 35). Spinoloxine was obtained as a white solid. B 9-Psa (49 mg, 33% yield), FDMS, m / e (relative strength) 530 (M +, 60), 529 (100).

Bottle Example A Chloropropyl Spinolsin L and Argon Propyl Spinolsin L · Under a nitrogen atmosphere, the compound 3-0-η-propyl Spinolsin L (1.07 g, 1.38 nunol) was dissolved in dichloromethane. Methyl chloride (25 ml) and added m-CBPA (standard (called Α4 · (2ωχ 297 public holiday y -98 (Please read the precautions on the back before filling in this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (96) 50%, 1.88 g, 5.44 mmol) and stir the reaction for 24 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with a 10% sodium bisulfate solution (3 extraction, followed by extraction with a saturated sodium bicarbonate solution (3 X 25 ml). The organic layer was washed with brine (25 ml) and washed with Anhydrous potassium carbonate dried to obtain a yellow solid (0,80 g). The crude product K was purified by reverse-phase HPLC (methanol: 0.1% aq. Ammonium hydroxide, 90: 10) to obtain (5R, 6S) -5,6 -Ethoxy-3'-0-n-propanyl spinosynoxine L (26.6 mg, 2.4%): part 1HNMR δ 6.68 (bs, 1Η), 4.78 (s, 1Η), 4.67U, 1Η), 4.37 ( d, 1Η), 4,21 (q, 1H), 3.58 (m, 1H); and (5R, 6S) -5,6-ethoxy-3 · -0-n-propyl spinosinoxin L ( 114 mg, 10.4%): part 1HNMR δ 6,54 (bs, 1Η), 4.78 (s, 1Η), 4.63 (ιη, 1Η), 4 * 38 (d, 1Η), 4.20 (m, 1H), 3.60U, 1H).

In the case of Ife Example A93-3'-0.N-bis- (tri-deuteromethyl), sinoglutinol M was dissolved in spinoline J (1.34 g, 1.87 mmol) in dichloromethane (8 ml). Potassium carbonate (1.0 g) was added, followed by 20% sodium hydroxide solution (20 ml), tetrabutylammonium hydrogen sulfate (0,77 g), and deuterium methyl iodide (5.0 g). The reaction mixture was stirred vigorously for 20 hours. Upon completion, the crude mixture was suspended in m-xylene (25 ml) and heated to reflux temperature for 1 hour. The mixture was then cooled and chromatographed on silica gel (ethyl acetate) to provide Π, N-bis (trideuteryl) spinoxin M (0.883 g, 64%) as a white solid: MS m / z 737 . CuHhDsNOh analysis estimates: C, 66, 73; Η, 8.06; N, 1.90. Actual value: C, 66.92; Η, 7,84; Ν 2.13.

Case No. A 94-3 '-(Z)-(Carboxy) Yatian and Zhongzhong Nuozhai J ___- 99 -_ This paper's standard is applicable to China National Standard (CNS) A4 (210 X 297 mm) ( (Please read the notes on the back before filling out this page)

487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 V. Description of the Invention (97) (Methoxycarbonyl) methylene spinosinoxin J (80 mg, 0.104 mmol) was dissolved in THF (5 ml). Add methanol (3 ml) and saturated lithium hydroxide solution (3 ml). The mixture was stirred under nitrogen for 6 hours and ethanol (2 ml) was added, then the mixture was concentrated. The residue was dissolved in ethyl acetate (50 in 1) and washed 3 times with brine. The organic calendar was dried over sodium sulfate, concentrated and HPLC (80:20, methanol / water) was used to obtain a white off solid 3 '-(Z)-(carboxy) methylene spinosinol J (42 mg, 53%). ): iHHMRS 6 * 68 (s, 1H): 5.28 (s, 1H) »3.41 (s, 3H), 3.34 (s, 3H).啻 Detailed example A 95-4 窨 oxin K The compound 4'-keto spinosin K (235 mg, 0.328 mmol) was dissolved in dry THF (10 ml). Dry ether (10 ml) was added and the solution was cooled under nitrogen at 0 ° C. While vigorously stirring, lithium tri-tert-butoxide was added (1.94 mg, 0.74 mmo 1). After 30 minutes, saturated brine was carefully added, followed by ether (100 ral). The mixture was washed 3 times with M2N sodium argon oxide / saline solution, followed by K5% aqueous sodium bicarbonate solution. The organic layer was dried with potassium carbonate, filtered and concentrated under reduced pressure to obtain 4'-epispinoxin K (206 mg # 87%) as a white solid: 1H NMR 6 6.65 (s, 1 H), 4.84 ( s, 1 H), 3.64 (m, 2 H), 3.40 (s, 3 H), 3.34 (s, 3 H) 4 · -keto spinosynoxine K (149 mg, 0.20 7 mmo 1), and then heated to reflux temperature in m-xylene according to the synthetic compound 3'-0, N-bis (trideuterylmethyl) spine Northyn M, using uranium carbonate (1.2 g), 20% aqueous sodium hydroxide solution (25 ml), methyl iodide (5.0 ml), and tetrabutylammonium hydrogen sulfate (0.80 g). By HPLC on silica gel (ethyl acetate __________ ~ 100—1 paper size applies to Chinese national standards (〇call / \ 4 specifications (210 &gt; &297; 297)) '~~ — (Please read the precautions on the back first (Fill in this page again.) Packing, -ir Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, printed 487559 A7 B7 V. Description of the invention (98) Ester) Purified crude pyrolysis product and additional HPLC (86: 14, methanol / Water) purification. The obtained compound was 4 Table Spinoxin A (74 mg ') iH NMR δ 6.67 (s, 丄 H), 4.84 (s, 1 Η), 3.74 (q, J = 6.8, 1 Η), 3.46 (st 3 Η), 3.34 (s, 3 Η), 3.37 (S / 3 Η).

啻 Axillary case A 97 _4'-trifluoromethyl-4'_ In the table, Caoxin K was dissolved in compound 4'-keto spinosin K (170 rag, 0.2 37 mmol) in dry THF (10 ml). Stir under nitrogen at 0 ° C and add trifluoromethyl (trimethyl) silane (241 mg, 1.69 mmol). Continue stirring at 0 ° C for 6 hours. After gradual completion, the crude product was dissolved in dichloromethane (5 ra 1). Water (1 ml), benzyltriethylammonium chloride (100 mg) and KHF 2 (300 mg) were added and the mixture was stirred for 2 hours. The crude product K provided was generally purified on silica gel (ethyl acetate) and gradually purified by HPLC (88: 12, methanol / water) to provide 4'-trifluoromethyl-4'-episphin Northing K (65 mg, 35%) as a white solid: 1 · Η NMR δ 6.70 (s, 1H), 4.81 id, J = 2.2, 1H), 3.35 (q # J = 6.4, 1 H), 3.47 (S / 3 H), 3.44 (s, 3H); 13C NMR (APT) d 76.0 (q, J -26, quaternary).

啻 _ 例 / \ 叩-(? ^. 65) -3'-dechlorin-5,6-ethoxy-3'-methylene history 1 Mou J and (5S · 6R)-: Γ-dehydrogenation -5. Fi-Z Μ 'V -Yatian Shizhong Xanoxin J Compound 3 · -deoxy-3'-methylene spinosin J (640 mg, 0.896 mmol) was dissolved in dichloromethane ( 100 ml). Cool the solution to 0 ° C and —_______ ~ 101 -_____ This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

487559 A7 B7 V. Description of the invention (99) Add m-CPBA (1.06 g, ca. 3 πιηηΐ) part by part. Stirring was continued for 1 hour at 0 ° C. A 10% sodium bisulfite solution (100 ml) was added, followed by dichloromethane (150 ml). After extraction, the phases are separated and the organic phase is gradually reacted in a general manner. Purification of Μ silica gel column and

It was then separated by HPLC (88:12, methanol / water) to obtain a) compound (5R, 6S) -3'-deoxy-5, 6-ethoxy-3'-methylene spinosin J ( 20 mg, 3%) white solid: iH NMR δ 6.64 (s, 1 H), 5.23 (C, J = 1-7, 1 Η); 5.07 (d, J = 1.5; 1 H), 4.69 (d, J = 1.6, 1 H), 3.41 (s; 3 H), 3.26 (s, 3H); and (5 $, 6! 〇-3'-deoxy-5,6-ethoxy-3'-methylene "Kispinoxin" (170 mg, 26%) white solid: 1hNMRS6.47 (s, 1H), 5.18 (s, 1 H), 5.02 (S, 1 H), 4.64 (s, 1 H), 3.36 (s, 3 H), 3.20 (s, 3H). Rich example A 99-: r_ U &quot; '(((Φ (诺辛辛 J' V -0-) some) methyl) ¾ some 3W-three gases Methyl) H-cHaziHne converts 3- (4- (bromomethyl) phenyl-3-difluoromethyl-3 ^ (3 丨 32b) to (

6.0 g, 21.5 mmol) was dissolved in dichloromethane (6 ml). Add Spinozin J (1.75 g, 2.4 mmol) in dichloromethane solution (5 ml) to this solution. Printed in the printed bag of the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) ), Then add tetrabutylammonium hydrogen sulfate (1.1 g) and 25% aqueous sodium hydroxide solution. The reaction mixture was stirred vigorously for 20 hours. Gradually complete and chromatograph K on silica gel (, ethyl acetate) to provide compound (4 "'((((Spinoxin J_3'-0-) yl) methyl) phenyl 3W-trifluoromethyl))- 3wH-diazir ine (1.339 g, 62%) as a white solid: ESI MS m / z 916 (Μ + 1).

Anal. Calcd for C49H68F3N3O10: C, 64.24; H, 7.48; N, 4.58. Found: C, 64.13; H, 7.60; N, 4.69. _____- 102 -___ This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 487559 A7 ----- B7 V. Description of the invention (100) Printing and decoration of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 100-3'-Π-Μ Propylene Nosin J Spinnoxin J (3.74 g, 4.92 mmol) of 3'-0-acetate was dissolved in dry THF (50 ml). Dry pyridine (10 ml) was added and the solution was cooled to -78 ° C under nitrogen. Slowly add 0.5 M Tebbe reagent in toluene (25 ml, 12.5 mrnol). After stirring at -78 ° C for 30 minutes, the temperature was raised to + 25 ° C and stirring was continued for 1 hour. The mixture was cooled to 0 ° C and 15% aqueous sodium hydroxide solution (20 ml) was added very slowly. After that, diethyl ether (150 ml) was added. The reaction is generally carried out gradually and chromatography on silica gel (ethyl acetate) to provide the compound 3'-0_isopropenyl Spinozin J (1.99 g, 53%) as a white solid: INMR δ 6.65 (s, 1 Η ), 4.20 (m, 2H), 3.84 (m, 2H), 3.41 (s, 3 Η), 3.34 (s, 3H), 1.75 (s, 3H). Anal. Calcd for C43H67NO10: C, 68.13; H, 8.91; N, 丄 .85. Found: C, 68.10; H, 8,99; U, 2.09. Example A: Sylpropene Knozai J will be 3, -0- Propenyl Spinozin J ( 0.828 g, 1.09 mmol) was dissolved in dry toluene (12 ml). Triethylsilane (338 g, 0.9 ramol) was added. The mixture was cooled to + 10 ° C under nitrogen and TFA (91, 2 mg, 8fflinol) was added over 1 minute. Continue to search for 5 minutes, and then add triethylamine (1.5 ml). The reaction is generally performed gradually and chromatographed on silica gel (ethyl acetate) to obtain the product, which is additionally purified by HPLC (90:10, methanol / water) to provide 3, -0-isopropylspinoxin J ( 218 mg, 26%), is a white solid (please read the precautions on the back before filling in this page) • The size of the paper is applicable to China National Standards (CNS) A4 specifications (21 × 297 mm) ) -103-_ 487559 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (1〇1) 1H MMR 5 6.71 (s, 1Η), 3.73 (m, 1Η), 3.51 (s, 3 Η), 3.45 (s, 3H). Anal. Calcd for 1 C43H69NO10: C, 67.95; H, 9.15; N, 1.84. Found: C; 68.20; H, 9.03; N, 1.35. Spine case A 102-compound 3 :: Ίη-propyl borneoxine J and compound 3 V-0-n-propyl borneoxine L (40-15%) Evening compound will be Spinoxin J (60% -85% ) And the technical mixture of Spinozin L (40-15%) was dissolved in dichloromethane (50 ml). Potassium carbonate (12 g) and 20% aqueous sodium hydroxide solution (100 ml) were added, followed by η-propyl iodide (35 ml), tetrabutylammonium hydrogen sulfate (4.6 g) and DMS0 (50 ml). The mixture was stirred vigorously for 72 hours. The reaction is generally carried out gradually and chromatographed on silica gel (ethyl acetate) to provide compound 3'-0-11-propylspinoxin "(60% -85%) and compound 3'-0-n-propylspinol A mixture of nosin L (40-15%) (8.87 g) as a white solid: iHNMRSeJSU, 1H), 5 * 37 (s, ca. 0.2 Η), 0.85 (t, J = 7.4, 3H). Honeydew Example A 103-Compound 3 '-0-n_propyl Φ W Nosin J MO% -85%) and Compound: Γ-Π-n-propyl W Nosin L UO-15%) The salt of the acid salt compound 3'-0-η-propyl spinosynoxin J (60% -85%) and compound 3'-0-η-propyl spinosynoxin L (40-15%) The mixture (205 mg, 0.275 111111〇1) was dissolved in propyl (8 1111) and a solution of citric acid monohydrate (57.9 mg, 0.275 mmol) in acetone (3 ml) and the stirred solution were added for 2 hours. Borrow -104-(Please read the notes on the back before filling out this page)

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specifications [210X297 mm] 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (102) The solvent is removed by a rotary evaporator to obtain A mixture of compound 3'-propyl spinosinol J (60% -85%) and compound 3'-0-n-propyl spinosinol L (40-15%) citrate (254 mg). Example A 1 04-Compound 5. fi-Diargon-3 '-0-η-propyl midoxin J (60%-85%) and 3 η-propyl midoxoxin L (40-15%) ^ The compound will be compound 3'-0-n-propyl spinosynoxin J (60% -85%) and compound 3'-0-n-propyl spinosynoxin L (40- 15%) of the mixture (8.35 g) was dissolved in ethanol (250 ml). Cyclohexane (60 ml) was added. The mixture was cooled to 0C under nitrogen and 10% Pd / C catalyst (7.0 g) was added. The reaction mixture was heated to reflux temperature for 3 hours. It was then cooled to 0 ° C and Hbitidine (2 ml) was added. The catalyst was filtered and the filtrate was concentrated and then dissolved in ether (300 ml). Generally gradually completed can provide compound 5,6-diargon-3'propyl spinosinoxin '(60% -85%) and compound 3'-〇1-propyl spinosinoxin 1 ^ (4〇-15%) Mixture (7.40 g) as a white solid: 1H NMR δ 6.73 (s, ca. 0.8 Η), 6.63 (S / ca. 0.2 H) # 5.37 (s, ca. 0.2 H), 0.84 (t, J = 7.4, 3 H). Fen Example A Compound 5.6-Digas' V_n-n-propyl W-Nosin J (60% -85%) and Compound: Γ-Π-η-propyl-Moroxine T 』U0-15%) Neem tree meeting will compound 5,6-dihydro-3'-0-n-propyl spinosinol J (60% -85%) and compound-propyl spinosin L (40-15%) of the mixture (205 mg, 0,269 mmol) was dissolved in acetone (8 ml) and a solution of citric acid monohydrate (56.7ms, 0.269 mmol) in acetone (3 ml) and the stirring solution 2- 105-This paper size applies Chinese National Standard (CMS) A4 specification (210 乂 2 () 7mm) (Please read the precautions on the back before filling out this page)-° ^ Printed by Qilang Zhongyugou Consumer Cooperative System 487559 A7 B7 V. Description of the invention (103) hours. The solvent M was removed by a rotary evaporator to obtain the compound 3'_0-η-propyl spinosynoxine J (60% -85%) and the compound 3'-0-η-propyl spinosynoxine L (40-15% ) A mixture of salt of manganese (211 mg). Example A 106-Compound 5 Diargon-3 '-Π-μ-Mpropyl Propoxynol J J 3'-0_isopropenyl Spinozin J (280 mg, 0.369 mmol) in 20 minutes Interaction with triethyl charcoal (110 mg, 0,94 mmol) and TFA (340 mg, 3.0 mmol), following the procedure of compound 3f-0-isopropylspinoxin J (Example A 101). After separation of the crude product by HPLC (90:10, methanol / water), 5,6-dihydro-3'-0 &quot; ^-isopropylspinoxin "(47 mg, 17%) was obtained as a white solid : ESI MS m / z 763 (M + 1). Fen Example A 107-3 Ethyl-N-formyl-Chokenoroxine M and Compound 3 ^ 0-Zyl-Chrysene NozzleM 3'-0-Ethyl Spinoxin J (2.20 g, 2.95 mmol) was dissolved in ether (25 ml). The solution was then added to a solution of sodium acetate (10.3 g) in ethanol (50 ml) and water (20 ml) pre-refluxed under nitrogen for 30 minutes. Next, iodine (4.8 g) was added, and after 5 minutes, 0.2N aqueous sodium hydroxide solution was added. Stirring was continued for 10 minutes at 50 ° C. The reaction mixture was combined with a saturated sodium bisulfite solution (200 ml) and the reaction was gradually performed in a general manner. Flash chromatography (ethyl acetate) on silica gel followed by 30% ethanol in ethyl acetate to provide a) 3'-0-ethyl-N-formyl-spinoxin M (0.380 s , 17%) is a yellow glassy solid: ESI MS π / ζ 760 (M + 1); and compound b) 3'-0-ethylspinoxin M (0.799 g, 37%), as a white off solid: ESI MS m / z 732 (M + 1). Example A 1 08-N- "2W-(methyl argonyl) 7. Alkenyl 1-3 '-0-ethyl-Shi Cao ______- 106 -_ This paper applies the long-term standard of China ( CNS) A4 size (210X.297 mm) gutter (please read the notes on the back before filling this page) 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (104) Nosin M will 3 · -0-Ethyl Spinoxin M (455 mg, 0.622 mmol) was dissolved in dry dichloromethane (20 ml). Methyl propionate (2.20 ml, excess) was added and the mixture was stirred at room temperature and Stir under nitrogen. After 18 hours, 'react gradually and purify on a silica gel column (ethyl acetate) to obtain [2 ~-(methoxycarbonyl) vinyl] -3'-0-ethyl-spinnow Sin M (454 mg, 89%) as a white solid: ESI MS m / z 816 (M + 1). Example AH) 9- (4W (((中 窨 诺辛 Η -2 · -0-) Group) methyl) cage 1 &quot; -trifluoromethyl) -3wH-diazirine Spinoloxine (1.40 g, 1.95 mmol) and 3- (4- (bromoethyl) phenyl-3-difluoro Methyl-3 [1- € 1133, {1 ^ (2.7〇8, 9.7 111111〇1) in accordance with 3 ...- (4W (((Spinnock J-3 Methyl) phenyl 3 &quot; '-trifluoromethyl)-3 &quot; Ml-diazirine method step reaction. 3W- (41 ((Spinoxin A-2 -methyl) methyl) phenyl 3 &quot;# _Trifluoromethyl) -31- diazirine (251 mg, 14%) is a white solid: ESI MS m / z 916 (M + l) 〇 Example A 110-3W- (4W (((3 '-0 -Z group Φ W Nosin M -N-) yl) methyl-) phenyl-3 &quot; '— ^ Gas methyl)-miazirine 3'-0-ethyl Spinoxin M (79 mg, 0.108 mmol ) Dissolved in dry DMF (5 ml). Triethylamine (0.50 ml) was added, followed by 3- (4- (bromomethyl) phenyl-3-trifluoromethyl-H-diazirined.O g, 3.6 mmol) of dry dichloromethane solution (4 ml 1). The mixture was stirred at room temperature in a dark room and chromatographed on silica gel (ethyl acetate) to obtain 3W- (4W (((3 '-0-ethyl Binoxin MN-) yl) methyl-) phenyl-trifluoromethyl) -3 ... Η- -107-This paper size applies to Chinese National Standard (CNS) Λ · 4 specification (210 × 297 mm) (Please (Read the precautions on the back before filling out this page.)

Yuanzhai Yinzhong _ Mai ¾ member X. Consumption combined with fi print 487559 A7 ___ B7 V. Description of the invention (105) diazirine (90 mg, 90%), yellow glassy solid: ESI MS m / z 930 (M + 1). Example A 1 1 1 -3'-Allylpyrene-Xinzhong Nosin. 1-3-Ketospinoxin J (3.40 g, 4.799 mmol) was dissolved in ethyl ether (40 ml). Stir the solution vigorously under nitrogen at + 10 ° C and add allyltributyltin (4.0 ml, excess). After 5 minutes, lithium perchloride (20.0 g) was introduced slowly. Maintain vigorous stirring for 20 hours. More ethyl acetate (100 ml) was added and the reaction was allowed to proceed gradually. The crude product was chromatographed on silica gel (ethyl acetate) to obtain 3'-allyl-3'-epispinoxin J (2.32 g, 62¾) as a white solid: mMR δ 6.66 (s, 1 Η), 5.72 (m, 3 H), S.09 (m, 2 H), 3.4S (s, 3 Η), 3.35 (s, 3 H) ESI MS m / z 753 (M + 1)窨 敝 例 A 1 1 2-(14R / S -3 f -Allyl-Ή. 1 4-Diargon-3 '-Minodon in the table 3'-Allyl-3'-Table history Binoxin J (1.14 g, 1.50 mmol) was dissolved in dry dichloromethane (12 ml). The solution was cooled to -78 ° C under nitrogen and a portion of diphenylsulfanyl chloride (650 mg, 3.32 mmol) was added. ). After 10 minutes, the mixture was heated to 0 ° C. After another 10 minutes, triethylamine (0.50 ml) was added and the mixture was stirred at 0 ° C for 10 minutes. The reaction was gradually carried out and the reaction was carried out in silicone (ethyl acetate Esters) were chromatographed on K to obtain a white solid (1.028 g). This material was dissolved in dry toluene (20 ml). Tri-n-butyltin argon (1.80 'ml, excess) and AIB (110 mg) were added. The mixture was heated to reflux temperature under nitrogen for 15 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by silica gel (ethyl acetate) chromatography. Then separated by HPLC (92: 8 -108 _ this paper size Guanjia County (CNS) A4 size (21G X .: W mm) ~~--batch of clothes-(Please read the precautions on the back first (Fill in this page again)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T line 487559 A7 _____ B7 _ V. Description of the invention (106), methanol / water) M Provide (14R / S-3'-allyl-13,14- Dihydro-3'-epispinoxin J (188 rag, 16%) as a white solid: iHNMR δ 5.45-5.75U, 3H), 5.04 (π, 2H) .ESI MS m / z 760 (M + 1).

Example A 1 iKh compound 5,6-diargon-.V-non-N-.V-propyl midoxine J and compound 5. fi-digas 'V-羌' V -propyl Panaxine J Compound 3'-allyl-3'-epispinoxin J (218 mg, 0.28 7 mmol) was dissolved in ethanol (30 ml). The solution was cooled to 0 ° C under nitrogen. Add 10% Pd / C (911 mg), followed by cyclohexane (10 ml, unpurified before use). The mixture was heated to reflux temperature for 3 hours under nitrogen. Add triethylamine (1 ml). After gradual reaction and analysis on silica gel, the crude product was separated on HPLC (94: 6, methanol / water). A) Compound 5,6-dihydro-3 夂 epipropylspinoxin J (28 mg, 12¾) was obtained as a yellow glassy solid: k NMR δ 8 · 04 (s, 1H), 6.31 (s, 1 H), 3.47 (S, 3 Η), 3.39 (S / 3 Η), 2.71 (S / 1.5 Η), 2.19 (s, ca. ca. 1.5 H), ESI MS m.'z 7ό (M + 1) (M + l) and compound b) 5,6-dihydro-3'-epi-3T-propyl spinosinol J (94 mg, 43%) is a white solid: XH NMR δ 6.75 (s, 1 Η), 3.42 (s, 3 Η), 3.34 (s, 3 Η), 2.13 (s, 6 Η).

Example A 114-3 ′ -Ω-7ιene Sinokinexin J Spinoxinine J (1.2 g, 1.67 mmol) was dissolved in ethyl vinyl ether (50 ml, excess). Add mercury acetate (3.5 g). The mixture was heated to reflux temperature under nitrogen for 4 hours. In the process of gradual reaction and silicon rubber (ethyl acetate-109-this paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) (Notes for filling in this page)

1. 1T line 487559 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (107). VO-vinyl Spinozin J (163 mg, 13¾) can be obtained after chromatography. It is white. Solid: ESI MS ιπ / ζ 744 (M + 1). Example A 1 1 5-3 '-Ο- (N-oxazole) fluorenyl in glutinosin J Spinoloxin J (2.40 g, 3.34 mmol) was dissolved in dimethylformamide (15 ml). The solution was cooled to 0 ° C under nitrogen and imidazole (6.8 g, excess) was added. The mixture was stirred for 10 minutes. Then, thionine chloride (1.90 ml) was slowly introduced through a syringe, and the mixture was warmed to room temperature and continuously stirred for 16 hours. The reaction is generally carried out gradually and chromatographed on silica gel (ethyl acetate). M provides imidazole) sulfinospinoxin J (1.52 g, 54%) as a white solid: ESI MS m / z 848 (M + 1). Full example A 1 4T-Nor-3 '-(R) (methyl) methylene in a certain harmful Nosing J J 3'-0- (N-imidazole) sulfonyl Spinoxin J (1.21 g , 1.43 mmol) was dissolved in dry toluene (20 ml). Benzyltriethylamine chloride (5.0 g, excess) was added and the solution was added to reflux temperature under nitrogen. After 5 hours, the mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate) and then separated by HPLC (90: 1, methanol / water) to obtain 4 夂 nor-3 *-(E) (methoxy) methylene Kespinoxin J (61 mg, 6¾) as a white solid: η NMR δ 6.70 (s, 1 Η), 6.15 (d, JT = 2.0, 1 Η), ς.ΟΟ (s, 1 Η), 4.68 (q, J = 6.6, 1 H), 3.60 (s # 3 H), 3.20 (s, 3 H).

Example A 1 17-5.6-Diargon'VOZene in a certain guest Nosin. J Dissolved 5,6-di-M-spinoxin J (1.85 g, 2.57 mmol) in vinyl ether (50 ml, filtered ). Add mercury acetate (4.2 g, excess). The reaction mixture was heated to reflux temperature for 4 hours. Then add sodium carbonate solids (10 ____-110-towels suitable for this paper size) A4 size (2i () x 297 public dust ~~ —-(Please read the precautions on the back before filling this page)

487559 Printed by the Consumers' Cooperative of the Central Economic Standards Bureau of Economic Lang A7 B7 V. Description of Invention (108) g). The reaction is generally carried out gradually and chromatographed on silica gel (ethyl acetate) to provide 5,6-dihydro-3,0-vinyl spinosinol] (1.02 8,53%): 1U NMR δ 6.74 ( s, 1 Η), β.31 (da, Ji = 16.9, = 6.5, 1 Η), 4.30 (m, 2 Η), 3.90 (m, 2 Η), 3.38 (s, 3 Η), 3 · 3ό (s,: ·· H) _ Cell example A 118-2 Dioxin, a moderately harmful oxinol. Follow the steps described in 5,6-Dihydro-3'-0-ethylene Spinoxin J to make Spinox Octane (2.03 g, 2.83 mmol) was reacted with butyl vinyl ether and separated from the reaction mixture. The resulting 2 &apos; -0-vinyl spinnosin H (1.09 g, 52¾) was a white solid: ESI MS m / z 744 (M + 1). Tube_Example 6 119-Zhongguoxin ,; [(Dimethyl) phosphate Shiluoxin J (0,903 g, 1.26 mmol) was dissolved in dry pyridine (2.5 ml). The solution was cooled to Ot under nitrogen: and carbon tetrabromide (0.91 g, 2.75 mmol) was added. After stirring for 5 minutes, trimethyl phosphorus P (0Me) 3 (0.38 ml, 3.12 mmol) was slowly introduced via a syringe. The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The reaction is generally carried out gradually and chromatography on silica gel (15% ethanol in ethyl acetate) K provides Spinoxin J 3'-〇- (dimethyl) phosphate (0.910 g, 88¾) as a white solid ^ ESI ME m / z 826 (M + l) ° Pipe oil; Example A120-Zhongke Nuoxin 1 &quot; [of 2'-0- (dimethyl) phosphate will be Spinoxin Η (0.65 g, 0.905 mmol) with carbon tetrabromide (0.63 g, 1.90 mmol) and trimethyl scale (0 · 30 ml, 2 * 46 mmol) 'Espinoxin J-3'-0- (dimethyl) phosphate The steps react. This • Provides 2 (-(dimethyl) phosphate (0.230 g, 31%) of spinosinol, as a white solid: ESI MS ro / z 826 (M + 1). _- 111 -_ This paper size applies to Chinese National Standard (CNS) A4 (210X 29 * 7 mm) I binding line (please read the precautions on the back before filling this page) 487559 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Print A7 _______ B7_ V. Description of the invention (109) Example A 121- (148) -13.14_ Diargon-: ^ -0-ethyl-sufunoxin 4) 3'-0_b Kirspinoxin M (810 mg, 1.106 ππηοΐ) was dissolved in dry ether (80 ml). A portion of lithium tri-tertiary aluminum butoxide (97% powder), 1.48 g, 5.6 mmol) was added. The mixture was stirred under nitrogen at room temperature for 5 hours. The solution was then cooled to 0 ° C and slowly quenched with saturated saline (5 ml). More diethyl ether (100 ml) was added and the mixture was extracted with M 2N aqueous sodium hydroxide solution (twice) and extracted with saturated sodium bicarbonate solution (once). The organic layer M was dried over anhydrous potassium carbonate, filtered and concentrated. The crude product was chromatographed on silica gel (20% ethanol in ethyl acetate) to obtain (MS) -13,14-dihydro-ethyl-spinoxin M (766 mg, 94%) as a white solid.丄 H NMR δ 4.68 (s, 1 H), 4.60 (m, 1 H>, 3.42 (s, 3 H), 3.35 (s, 3 H), 2.29 (s, 3 Η), 0.98 (d, J = 3 Η). Example A 1 22-4-dihydro-3 · -o-ethyl-spinoxin M (14S) -13,14-dihydro-3 ^ 0-ethylspinno Octane (326 mg, 0,444 mmol) was dissolved in dry dichloromethane (10 ml). Triethylamine (3.0 ml) and iodoethane (2.0 ml, excess) were added. The mixture was stirred under nitrogen at room temperature 4 Hours. The reaction is generally performed gradually and chromatographed on silica gel (15% ethanol in ethyl acetate) to provide (14S) -13,14-dihydroethyl-spinoxin M (337 mg, 99%), As a white solid: ESI MS m / z 762 (M + l). Example 1 2 · ν Π 4S) -13. 14-di-M_3'di-Q-propyl spinosyn J fh compound (1R / 1S · 15R · — 21S) -15-Dechlorin-1,15-Argon-3, -0-n-Bingmou-12 Bu-Junu Nuozai J 1-Entropy and ih compound Π 5 R)-15 -Dehydro-1 5 -fluorenyl: Γ--112-(Please read the precautions on the back before (Fill in this page) • Binding-Binding This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 487559 A7 s ^ __: __ ^ __ 5. Description of the invention ("〇)

0-n-Cinnosine tJ within 16 hours, according to the steps of (14S) -13,14-dihydro-3 ^ 0-ethylspinoxin M, make 3'-0-n -Propyl Spinozin J (1.87 g, 2.46 mmol) was reacted with a solution of lithium tri-tertiary aluminum butoxide (97¾ powder, 2.02 g, 7.71 mmol) in ether (100 ml). The reaction is generally carried out gradually and chromatography on silica gel (ethyl acetate) to provide a) (14S) -13, 14-dihydro-3 f -0_n-propyl Spinozin J (1. 19 g, 63¾), As a white solid: 1H NMR ^ 4.70 (s, 1H), 4.64 (m, 1H), 3.43 (s, 3 H), 3.41 (s, 3 H), 2.15 (s, 6 Η), 1.04 ( Shan J = 6.8 '3 H); and b) a mixture of compounds (0.66 g), which was further analyzed by HPLC (88:12, methanol / water) to obtain c) (1R / 1S, 15R, 21S) -15 -Deoxy-1, 15-oxy-3 * -0-n-propyl-1,21-branched-spinoxin J 1-hemiacetal (77 ms, «) as a white solid: h NMR δ 5.38 (s, 0.5 Η), 5.03 (d, J = 7, 0.5 Η), 3.49 (s '3 Η), 3.40 (s' 3 Κ), 2.15 (S / 6 Η), 1.02 ( broadened d, J = 6.8, 3 Η). ESI MS m / z 764 (M + 1);, and d) (15R) -15-deoxy-15-hydroxy 3'-0-n-propyl spine Northing J (44 rog, 2.3¾), white solid: Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) NMR δ 5.79 (d, J = 9 · 8, 1 Η), 5.72 (s' 1 Η), 5.70 (d, J = 9.3, 1 Η), (s, 1Η), 4.64 (m, 1Η), 3.47 (, s, 3 Η), 3.42 (s' 3 Η ), 0 · 90 (d; J = 6.6, 3 H)., Within 3 hours, according to d4S) -13, 14-dihydro-3, -0-B-------- ------- 113 -___ The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210: &lt; 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __ _ B7__ V. Description of the invention (111) The steps described for spinosynoxine M include 5,6-dihydro-3'-O-n-propyl spinosinin J (1.88 g, 2.47 min) and lithium lithium tri-butoxide (97% powder, 2.40 g, 9.16πππο1) in ether (100 ml) was reacted. Upon gradual reaction and chromatography on silica gel (ethyl acetate), (14S) -5,6,13,14-tetra M-3'-〇-n-propyl spinosinoxin J (1.440 g, 76¾), white solid: INMR δ 4.66 (d, J: 丄 .4, 1 Η), 4.64 (m, 1 Η), 3.41 (s, 3 Η), 3.34 (s, 3 Η), 2.09 (s, 3 Η), 1.00 (d, J = 6.6, 3 Η).

g bottle example A 125-3f-0- (2-methylhydrozyl) _Zhongcaoxin J Dissolve Spinozin J (718 mg, 1,00 ππποί) in DMS0 (1.4 ml) and dichloromethane (1.4 ml). Add potassium carbonate (0.90 g, 6.5 mmol), 20% aqueous sodium hydroxide solution (5.2 ml), tetra-η-butylammonium hydrogen sulfate (339 mg, 1.00 mmol) and 2-methoxyethyl bromide Base (1.00 ml, 10.6 mmol). The mixture was partitioned between ether and water. The organic layer was extracted with ether. The combined organic layers were washed with water (3 times) and washed with saturated sodium bicarbonate, dried over anhydrous potassium carbonate and evaporated to give a yellow oil. This oil was chromatographed in a reverse-phase column (Kromasil 'C18, oxidized sand ODS, 100A, 10ra, spherical, 25cmX 20 nun) using 88¾ methanol and 12¾ water (containing 0.1¾ v / v cone. Ammonium hydroxide aqueous solution ) M yielded a white amorphous solid (249 mg, 32¾). iHNMR d 3.78 (m, 2H), 3.38 (s, 3H). ,

啻 Example A-methylarginine and even-nosinoxin J Spinnoxin J (359 mg, 0.500 mmol) was dissolved in dichloromethane (2 ml) and the resulting solution was cooled to 0 ° C. Adding diisopropylethylamine (105 ml, 0.600 mmol) in a single part and binding it in several parts (please read the notes on the back before filling this page) This paper size applies Chinese national standards ( CNS) Λ4 specification (210X297 mm) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 ____ ___ V. Description of the invention (112) Added bromomethyl methyl ether (9 (U, 50 ml, 0 ♦ 5 mmol) ). The immediately formed precipitate can be reconstituted after a few minutes. The mixture is stirred for 2.5 hours at 0¾ and 2.5 hours at room temperature. The mixture is cooled to 0 ° C and additional amine (0.32 ml) is added. , 1.8 mmol) and bromide (0.15 ml, 1.7 mmo 1). The mixture was stirred for an additional hour. A saturated aqueous sodium bicarbonate solution (3 ml) was added and the mixture was stirred at room temperature for 17 hours. The mixture was washed with sodium bicarbonate solution, water (twice), saturated sodium bicarbonate solution, and brine (twice). The mixture was dried with anhydrous potassium carbonate and evaporated to form a yellow oil. This oil was placed on a reverse-phase UromasiT C18 , Silicon Oxide 0DS, 100A, ΙΟπι, spherical , 25cm × 20 nun), using 85¾ methanol and 15¾ water (containing 0.1% v / v cone. Ammonium hydroxide aqueous solution) to produce a white glassy solid (87 rog, 3S!). INMR d 3.45 (s, 3Η); MS 111 / 2762.6 (^ 1 咄 estimated value is 762.5).

Enrichment example A 127-5. Dig -.V-methylchloromethyl-Φtanoxine J 3 methoxymethyl-spinoxin J (243 mg, 0.319 mmol) and palladium / activated carbon ( 10%, 200 mg) in a 25-ml round bottom flask. Ethanol (7.25 ml) and cyclohexane (1.75 ml, 17.3 mmol) were added and the resulting solution was heated to reflux temperature for 3 hours. The mixture was filtered through diatomaceous earth and a PTFE membrane (Gelman, Acrodisc 13CR, 0.2mro). The mixture was concentrated under reduced pressure and the residue was chromatographed in a reverse-phase column (Kromasil 'C18, silica 0DS, 100A, 10m, spherical, 25cm × 20 mm) using 85¾ methanol and 15¾ water (containing 0.1¾ v / v cone. Aqueous ammonium hydroxide) K produces an amorphous solid (68 mg, 28 »:). MS π / ζ 764.7 (estimated value of M + 76 764.5). ____- 115 -_ Zhang scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) (Please read the precautions on the back before filling this page) • Binding and ordering A7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1. Description of Invention ("3)

Current example A128-: Γ-0- 氤 methyl-Zhongke fortune [and 3’_0-trimethyl silicon

Spinoloxine L (366 mg, 0,500 mmol) was dissolved in DMF (1 ml) and the solution was cooled to -15 ° C. 1.0 M photoresist adhesion promoter (0.53 ml, 0.53 πιποοΚ was added dropwise to produce a very dark solution that was allowed to stand at 0 ° C for 65 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate The organic layer was washed with a dilute aqueous solution of sodium bicarbonate, a dilute solution of sodium thiosulfate and brine. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a dark oil (380 mg). Phase column Uromasil · C18, silica ODS, 100A, 10m, spherical, 25cm X20 mro) chromatography, using 90¾ methanol and 10¾ water (containing 0. U v / v con c. Ammonium hydroxide aqueous solution) Μ Two products were produced, 3 cyanomethyl-spinoxin L (48 mg, 12V), MNMR d 4.25, 4,44 (abq, J = 14.9, 2 [〇;} ^ 1! 1/2 771.6 (^ 1 + 1) (771.5); and 3'-0-trimethylsilyl-spinoxin L (241 mg, 60%), iHNMR d 0 · 19 (s, 9H); MS m / z 804.7 (Estimated value of M + H is 804.5). Example A 129'VO-Carbon-t-Butylchloromethyl-Mesanosin J J Spinoxin J (718 mg, 1.00 mmol) and four _n_ Butyl ammonium hydrogen sulfate (34 mg, 0.10 mmol) was dissolved in dichloromethane (3. 5 ml). T-butyl bromoacetate (2.95 ml, 20.0 ππηοΐ) and powdered potassium hydroxide (1.0 g, 15 ininoDM) were added continuously in one portion and the reaction mixture was stirred at room temperature. For 40 minutes After that, tetra-n-butylammonium hydrogen sulfate (64 mg, 0.2 mino 1) was added. After 60 minutes, the mixture was diluted with water and extracted with methylene chloride (once) and ethyl acetate (once). .The combined organic layer K water (2 paper sizes applicable to Chinese National Standards (CNS) Λ4 specifications (210 × 297 mm) I gutter (please read the precautions on the back before filling this page) 487559 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 B7 5. Description of the invention (114 times), saturated sodium bicarbonate and brine cleaning, drying and evaporation of potassium potassium carbonate and magnesium sulfate to produce a yellow oil (4.13 g). This oil was placed under reduced pressure Oil (2.3 g) was produced at 2 hours under K (0.9 torr). The oil was chromatographed on silica gel (165 g) with ethyl acetate followed by a 10¾ methanol in ethyl acetate solution to give a white foam (295 mg , d 4.24, 4.19 (ab q, J = 16.5, 2H), 1.49 (s, 9H); MS m / z 832 · 7 (Μ + The estimated value of Η is 831.5). Bottle Example A 1 30-4 "-N-desmethyl-4" N_ (2-Gasethyl) 5 · 6_Digas-3'-0-propyl Zhongnosin J According to Example CZ Methods: Bromo-2-fluoroethane (0.20 ml, 0.34 2.7 mmol), sodium iodide (0.04 g, 0.3 mmol), (i-Pt) 2NEt (0.4〇1111,0 * 3〇8) , 2.3 111111〇1), 4 "-1 demethyl-5,6-dihydro 3'_0-propyl spinosinol J (0.300 g, 0.401 mmol), and DMF to prepare compounds. MPLC (25: 7 to 50:50 ethyl acetate / cyclohexane) to obtain 4 "-fluorene-desmethyl-4" N-(2-fluoroethyl) 5,6-dihydro-3propylspinoxin as a white powder J. 啻 Example A 131-4 "-N-" 3'-Π- (9-A certain methyl argonyl group) θ-propylamine hydrazone Jinoxin J and: Γ-ί!-(Θ -propylamine hydrazone ) Spino · Trimethylamine (0.25 ml, 0.18 g, 1.8 mraol) and HC = C (Me) 0C0Cl (0.10 ml, O.llg, 0.92 mmol) were sequentially added to Fmoc-N (H) -b- Ala-C00H (0.26 g, 0.84 minol) 0 ° C, Spinozin J (0.502 s, 0 · 699 ππηοΐ), and DMAP (0.02 g, 0.2 nun 〇1) in dichloromethane solution (4 in 1) Zero solution. After 2 hours, it will be mixed _- 117 -__ This paper size applies Chinese National Standard (CNS ) A4 size (210 乂 297 mm) (Please read the notes on the back before filling out this page)-Assembling and routing Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 487559 A7 • B7 V. Description of the invention (115) The contents were heated to room temperature for 20 hours. The mixture was allowed to evaporate. MPLC (SiO 2, 0: 100 to 20: 80 methanol / dichloromethane) to obtain 0.17 g (243 4 of 4 ”U 3, -0- (9- Fluorenylmethoxycarbonyl) cold-propylamine fluorenyl] Spinoxin J is white powder: 1 ^ (111 +} ^) expected value: 1011.6. Actual value: 1011.6 and 3'-0-(/ 3- Alaninyl) Spinozin J, 0.21 g, (38¾), white powder: MS (ra + H + &amp; m + 2HM Expected value: 789.5 &amp; 395.2. Actual value: 395.5. Fmoc group is reacting It is easy to be deprotected under the conditions and can be regarded as the product of the present invention. Example A U2_4 ”-N_desmethyl U-digas-propyl Zhongcaoxin

A Add F-TEDA (0.98 g, 2.8 mmol) to a solution of CH6-CN (10 m) in 5,6-dihydro-3f-0-η-propyl spinosinol J (0.94 g, 1.23 mmol). After 10 minutes, the organic layer was partitioned between ethyl acetate and 0.1 M hydrochloric acid. The organic layer was washed sequentially with sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. MPLC (SiO 2, 5:95 to 10:90 methanol / dichloromethane) M 0.64 g (70%) of 4 ”demethyl-5,6-dihydro-3,0-propyl spinosyn J, which is a white powder, can also be recovered (5,6-dihydro-3'-0-n-propyl spinosinol J 0.25 g (27%)).

啻 Example A 1H1 Table-Mesanosine K within 15 minutes, 0- (2,3-bis-0-methyl-4-0-benzylidene-L-rhamnosyl-Dttan Glycosyl) trichloroacetamide imidate (5.5 g, 11.5 roraol) in dichloromethane solution (60 ml) was added dropwise with properly mixed Spinoxin A 9-Psa (1.25 2.30 rorool) and pyridine anchor The powder containing methanesulfonate (0.815 g, 3.24 mmol) in dry diqijiayuan (120 ml) ____- 118 ~ ___ This paper size applies the Chinese National Standard (CNS) Α · 4 specification (2i〇 X 297 mm) (Please read the notes on the back before filling this page)

487559 A7 ______ B7 V. Description of the invention ("6) Finalized 4A molecular sieve (2.0 g) solution. Stirred at room temperature for 4 days, filtered the mixture diatomaceous earth, M dichloromethane (100 ml) Wash the diatomaceous earth and M saturated sodium carbonate (2X60 ml) and brine (75 ml) and wash the combined filter (please read the precautions on the back before filling this page) and the washing solution. After concentration, 8.2 g of residue is left. The K silica (650 m 1) was subjected to flash chromatography using 3¾ methanol in dichloromethane to produce a coupling product of 1.18 (58¾), a 3α: 1/3 epimer of a colorless foam. This material was dissolved in methanol (30 in 1) and anhydrous calcium carbonate was added to the solution (0.98 g, 7.1 mmol). The solution was stirred at room temperature for 6 hours, and 2N hydrochloric acid (6.8 in 1) was added dropwise. M acidified and then concentrated to near dryness under reduced pressure. The residue was partitioned between water (40 ml) and dichloromethane (150 ml). The organic extract was followed by M saturated sodium bicarbonate (40 ml) and brine (40 ιαί ) Washed and dried with magnesium sulfate. After concentration, 0.72 g of crude debenzylated product remained. By flash of silica (80 m 1) Purification by chromatography, using 0.5 M methanol in dichloromethane solution to produce 0.5 g of clean product, which is a 3: 1 mixture of Spinoxin K and 1'-epi 'Spinoxin K. By HPLCM 41.4 mmx 25 cm (l)

Rain in reverse-phase C18 (8_) column, using 15% water (containing 0.0U ammonium hydroxide) in methanol as the eluent, the product was separated into three parts of about 180 mg. Lu-Epimer, Table-Spinnockin K first precipitated: 110 mg; colorless foamed carcass printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; 1η NMR (CDC13) 5 6.79 (st 1, H-13 ), 4.63 (m, 1, H-21), 4.45 (m, H-l1, H-1 &quot;,H-9); MS m / z 435 (10), 175 (5), 142 (100), 71 (90).

Example A 134-4 'A certain middle-aged patient, Kronozo K, added a portion of propionic anhydride (0.1 ml, 0.77 πιπιοί) at room temperature to Spinozin K (72 rag, 0.1 mmol) and DMAP (~ 2 -119-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 487559 A7 _B7 _ _ V. Description of the invention (117 ) mg) of dry pyridine (1.0 ml), and the mixture was stirred for 20 hours. Pyridine was removed under reduced pressure, the residue was dissolved in dichloromethane (25 ml) and the dichloromethane solution was washed with water (5 ml), saturated sodium carbonate solution (25 ml), brine (5 m) and sulfuric acid Dry with magnesium. After filtering off the drying reagent, the dichloromethane solution was concentrated to about 6 ml and K polyvinylpyridine (0,3 g) was stirred for 15 minutes to neutralize any residual propionate in the product. Filtered on the resin After the action, dichloromethane was evaporated and 85 mg of crude product remained. Purified by flash chromatography using silica (30 m Π, using 3¾ methanol in dichloromethane solution M to produce 71 mg of 4'- colorless foam). 0-Propanyl Spinozin K ^ ΗΝΜΙίδ 6.76 (s, 1, Η-13), 5.02 (t, 1, Η-4 ·), 4.87 (s, 1, Η-1 ·), 4.66 ( m, 1, Η-21), 4.42 (br d, 1, H-1 &quot;), 4.32 (m, 1, H-9); MS m / z 773 (2), 231 (15), 142 (70), 71 (100). 窨 Analogous compounds of Knosin A (9_0- (2,3,4'tri-0-methyl-buchacha_nH: brain 煻) analog compounds 9-0- (2,3,4-tri-0-methyl-D-rhamnosylpyranosyl) Spinoxin A, position 1 1 of 3 · 5 a: 1/3 differential Mixture of isomers Example A45 was prepared in the same procedure with a yield of 82¾, which was made up of 0.54 g (1.0 mmol) Spinoxin A 9-Psa, 0.35 g (1.4 mmol) Utt pyridyl p-toluene sulfuric acid and 2.0 g ( 5.7 mmol) 0- (2,3,4-methyl-α-D-rhamnopyranosyl) -trichloroacetamide imidate. ° ^ and 々 epimerization, the system is by the reverse phase HPLCK C18 combined with silica gel was performed using 10¾ water (containing 0.1% ammonium hydroxide) in methanol. The cold epimer was first precipitated. / 3 epimer: 85 mg; colorless foamed body; 1HNMR ( CDCU56.78 (s, 1H, Η-13), 4.66 (m, 1H, H-21), 4.40 (m, 3H, H- -120-This paper size applies to China National Standard (CNS) A4 specifications ( 210X 297 mm) (Please read the notes on the back before filling this page)

487559 A7 B7 V. Description of the invention (118 1 ", Η-1 ', Η-9). Alpha epimer: 270 mg; colorless foam; ^ HMRCCDCla) 5 6.76 (s, 1H, H-13) , 4.82 (m, 1H, H-21), 4.40 (m, 3H, Hl ”), 4.28 (m, 1H, H-9); MS m / z 499 (2), 189 (10), 142 (70 ), 71 (100). Symptomatic case 8 136-Plant-0- (2.2.2-Trifluoro71) ¥ Nosin 3 A part of a suspension of 60% sodium hydrogenated mineral oil (224 mg, 5.6 mmol of 100¾) was added to the cold ( 0-5 ° C), in a solution of Spinozin J (500 mg, 0.7 mmol) in anhydrous THF (20 ml) after proper mixing. When it had stopped (after about 10 minutes), trifluoroethyl triflate (J. Org. Chem * 1973, 38, 3673; Tetrahedron 1965, 21, 1) (0.9 g, 3.2 mmol) was added dropwise. The cooling bath was removed after 1 hour, and the reaction was still stirred at room temperature for 4 hours. The mixture was cooled to 0-5 ° C and water (20 ml) was added dropwise over 15 minutes. The mixture was extracted with ether (2 X 50 ml). The organic extract was washed with brine (25 ml) and dried over magnesium sulfate. Purified by flash chromatography on silica (120 ml) using 3¾ methanol in dichloromethane as the eluent. Partially purified product (150 mg) was purified on a 41.4 rain (i.dJX25 mm (l) Rainin reverse-phase C8 (8 ° 1)) column using 10% water (containing 0.1 ammonium hydroxide) in methanol as Dissolve to produce 58 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) mg of clean 3'-0- (2,2,2_trifluoroethyl) Spinozin J product as a colorless foam: 。. 1H NMR (CDC13) δ 6.7.6 (S / 1H, H-13), 4.81 (s, 1H, H-1 '), 4.67 (m, 1H, H-21), 4.42 (d, 1H; H-1M), 4.30 (m, 1H, H-9), 4.06 (m # 2H, CF3CH2O). Example A 137r.m2, 3,4- Three-0-Z a certain α-rhamnose pH; sleepy-121-This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 487559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (119!) Base) Zhong Nuo Zai 1 and: Γ-Π-(2. 3 · 4-Tri-Π-Z Moubu / 3-Rhamnus bran pH; sulfanyl) W Nuoxin J in position Γ &quot; α: / 3 of 9: 1 epimer mixture (0.33 g, 62¾ yield) was obtained from Spinoxin J (0.4 g, 0.56 mmol), Btt dark Iron p-toluenesulfonate (0.18 g, 0.72 mmol) and 0- (2,3,4-tri-0-ethylα-L-rhamnylpyranosyl (0.18 g, 0.72 mmol) and 0_ (2,3,4-tri-0-ethyl-oc-L-rhamnosylpyranyl) trichloroacetimidate (1,6 g, 4,08 mmol) The same procedure is used for A45. The mixture is a silica (8 mm) column (41 · 1 mro (id) X25 cro (l)) combined with reverse phase HPLCMC18, using 6¾ water (containing 0.15¾ ammonium hydroxide) in methanol The solution was used as the eluent. The epimers were first precipitated. / 3 epimers: 5 mg; colorless foam; 4 cores! (00 (: 13) 56.76 (3, 1H, H-13 ), 4.81 (d, J = 2.2, 1H, Η-1Ί, 4.67 (m, 1H, H-21), 4,49 (s, 1H, H-l &quot;), 4.42 (dd, J = 8.8 , 1 · 4, 1H, Η-Γ '), 4 · 30 (m, 1H, H-9). Alpha epimer: 85 mg; colorless foam; 41 — 1? (00 (: 13) 36.76 (3,1H, H-13), 5.02 (d, J = 1.5, 1Η, Η-1 &quot;), 4.79 (d, J = 1.5, 1Η, Hl ”), 4.67 (m, 1H, H-21), 4.42 (dd, J = 8.5, 1.5, 1H, H-1, T), 4.27 (in, 1H, H-9); MS m / z 948 (100).

Tracheostomy case A Degassing and Chlorine-.V-alkenyl-Spinoxin J Add a portion of 2,2,2-trifluoroethanol (15a 1, 0.21 roraol) to cold (0 ° C) 60% hydrogenated A suspension of mineral oil (7.5 mg, 0.188 mmol, 100%) in dry DMF (2.5 ml) was stirred under refrigeration for 20 minutes. A part; Γ-0-trifluoromethanesulfonyl-3'-epi-Spinoxin J (100mg, 〇 ″ 18 -122-This paper size applies to China National Standard (cns) A4 specifications (2 丨 〇: &lt; 297 mm) (Please read the notes on the back before filling out this page) 1) Add to currently clean solution and stir the mixture at room temperature for 18 hours. Silicone (200 in g) was added, and the mixture was stirred for 10 minutes, and then the collected silica was washed with dichloromethane. The filtrate and washings were combined and concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate (20 ml). Then, the ethyl acetate solution was washed with brine (10 ml) and dried over magnesium sulfate. The solvent left 76 mg of the residue, and its K silica (10 ml) was flash-chromatographed to obtain 43 mg of 4′-dehydro-3′-deoxygenate using 3¾ methanol in dichloromethane as eluent K. -3'-alkenyl-Spinostin J, a colorless foamed carcass. Y NMR (CDC13) δ 4.72 (d, J = 3.3, 1H, H-31); 13C NMR (CDCI3) δ 160 · 0 (C-4 丨), 87.9 (C-3 ·).

A 例 A 139-3 ^ 0-propyl hydraxoxine L powdered potassium hydroxide (lg) was added to spinosynoxine L (0.732g, 1.0 mmol), tetrabutyllithium bromide (0.1 ππηοΐ ) And a solution of n-propyl bromide (2.7 22.0 mmol) in dichloromethane (3 ml) and stirred under nitrogen at 25 ° C for 1.5 hours. Water (10 ml) was added and the layers were separated. The aqueous layer was extracted with K dichloromethane (3 X 20 ml) and the combined extracts were dried over sodium sulfate, filtered and concentrated. Milled with pentane to obtain propyl spinosinol L (0.72 g, 93¾) as a colorless glass. EMI MS, m / z 774.7 (Mf).

例 _ Example A Propoxoloxin J &amp; L Powdered potassium hydroxide (U) was added to Spinoxin J &amp; L (0.732 g, 1.0 mmol), tetrabutyllithium bromide (〇 · 〇32 g, 0.1 μm of bromopropane (5 ml)) solution and stirred for 3 hours under nitrogen and 25¾. Ether (20 ml) and water (10 ml) were added and the phases were separated. The aqueous layer was extracted with ether (2 × 20 rol) and dried over magnesium sulfate. The combined ether extracts were filtered, and concentrated. This paper applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) on a long scale (please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _ B7__ V. Description of the invention (121) Alkane grinding to obtain 3'-0-propyl Spinozin J &amp; L (0.71 g, 92! Ϋ), colorless glass Thing. 3’-0_propyl spinosinoxin ”^ [^, 111/2 760.2 (1 ^). EMI MS of 3'-0-propyl Spinozinol L, π / ζ 774.3 (MM.

Example / V 141 -3 'Kezhongnuol K Add powdered potassium hydroxide (lg) to spinoxin L (0.732 g, 1.0 mmol), tetrabutyl lithium bromide (0.032 g, 0.1 mmol) in ethyl bromide (5 ml)) and stirred under nitrogen at 25 ° C for 0.5 hours. Ether (20 ml) and water (10 ml) were added and the phases were separated. K ether (2 X 20 ml) extraction The water calendar and dried over magnesium sulfate The combined ether extracts were filtered, and concentrated. K was milled with pentane to obtain 3'-0_ethylspinoxin L (0.72 g, 94¾) as a colorless glass. EMI MS of 3 &apos; -0-propyl Spinozinol J, m / z 760.3 (MM.

When Example A 141-3,-0 -propyl sinotropin Q

Spinoloxin Q (732 mg, 1 mmol), tetrabutyllithium bromide (34 mg, 0.1 mmol), 1-bromopropane (4 ml, 24 mmol), and digas methylbenzene (1 ml) into a 50 ml round bottom flask equipped with a magnetic stirrer. Stir the solution at room temperature and in a water bath and add a portion of sodium hydroxide (500 rag, 7.5 mmo 1, M 85¾ pure, mainly mechanically powdered before use). The resulting mixture was stirred for 2 hours, and then the reaction was gradually completed by partitioning between 25 ml of ethyl acetate and 5 ml of water. The phases were separated and washed with M 1 X 5 m 1 water, 1 X 5 m 1 saturated sodium chloride. The ether phase was dried over K magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was chromatographed using 30 g of silica gel with ethanol / ethyl acetate / hexane (2: 50: 50) as the eluent to obtain compound 3 Propyl Spinoxin Q _________; _ ~ 124 I_____ The wave scale applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

487559 A7 B7 V. Description of the invention (122) 'It is a white brittle foam (β10mg, purity 97.5%, analyzed by HpLC, Part B is modified by M non-derivative half-degraded amines to modify the pseudochrysalis. A detailed example of a compound compound tube B1-1 fluorenyl-Φ-kerosin A 1 7-Psa Heat the solution of Spinozin A (2.00 gin, 2.73 mmol) in glacial acetic acid (50 ml) to reflux temperature for 5 hours and It was then stirred at room temperature for 12 hours. The reaction mixture was evaporated to a small volume, and then poured into a planer and sodium bicarbonate solution. The ethereal mixture was extracted with ether. The ether portion was washed with brine, dried with potassium carbonate and at room temperature. And evaporation under reduced pressure to obtain a yellow glass (1.48 gm). The product was separated by chromatography on silica, and the ethyl acetate solution of M40% methylhexane was the eluent. 17-0 -Ethyl-Spinoxin A 17-Psa (478,9 mg, yield 28¾) is a white solid, FDMS, m / e (relative strength) 632 (M + -H, 100), and the history of separation Binoxin A 17-Psa (846, 2 mg, 52% yield) is a colorless glass. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first) Please fill in this page again.) 窨 Detailed example B2-17-0- (3-Dimethylamine propionyl) inoxoxine A 17-Psa The compound 17-0- (propionyl) spinoxin A 17-Psa (206.3 mg, 0.32 mmol) was dissolved in dimethylamine (5 ml) in an ice bath and the reaction mixture was capped and allowed to stir at -5 ° C for 2 hours. Then, when dimethylamine was passed through an acid wash, During the distillation, the reaction mixture was allowed to warm to room temperature. The residue was dissolved in HC1 aqueous solution and washed with ether. M 5N aqueous sodium hydroxide was basified and extracted with fresh ether. The ether obtained from the alkaline extract was washed with brine, and M Sodium carbonate was dried and dried at room temperature under reduced pressure. The resulting 17-0- (3-dimethylaminopropylammonium) spinosin A 17-Psa (177.1 mg, 80¾ yield) was a colorless glass Material, FDMS, m / e (relative strength) 689 (M, 100). -125-This paper size applies to China National Standard (CNS) A4 (210X 297 mm). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 487559 A7 B7 _ V. Description of the invention (123) In the example (3-propionyl), anoxine A 17-Psa in spinoxin A 17-Psa (364.3 mg, 0.61 mmol) in chloroform ( 10 ml) Add propionyl chloride (75 ml, 0.92 mmol) followed by diisopropylethylamine (160 ml, 0.92 nunol). The reaction mixture was heated to reflux temperature for 6 hours, followed by addition of propylammonium chloride (75 ml, 0.92 nnnol), and diisopropylethylamine (160 ml, 0.92 ππηο 1) and the mixture was refluxed for another 12 hours. The reaction mixture was then cooled to room temperature and diluted with dichloromethane. The dichloromethane was washed with saturated sodium bicarbonate, dried with potassium carbonate and evaporated at room temperature under reduced pressure. The ancestral substance was chromatographed on silica, and M2 (U ethyl acetate in dichloromethane solution was eluted. The obtained 17-0- (3-propanyl) spinosin A 17_Psa (322 mg, 82% product Ratio), is a colorless glass, FDMS, m / e (relative strength) 643 (M ~ H, 100). Life-rich example B4-17-CI-(Acetofluorene) Zhongkexin A 17-Psa The reaction was carried out as described in Example B3. M Spinoxin A 17-Psa (205.4 mg, 0.35 mmol) was used as the starting material, and chloroacetamido chloride, and 40¾ ethyl acetate in hexane solution was used as a layer. The leaching solution was separated. The obtained 17-0- (chloroethenyl) spinoxin A 17-Psa (194.7 mg, 83¾ yield) was white and deviated from glass, FDMS, m / e (relative strength) 666 (tT-Η, 100), 190 (20) 〇 Example of tube-(4-Air but @@) Zhongke Nuoxing A 17-Psa The reaction was performed as described in Example B3, M Spinoxin A 17 -Psa (206.4 mg, 0.35 mmol) as the starting material, and chlorobutyryl chloride, and the use of 35¾ ethyl acetate in hexane as the chromatographic eluate. The obtained 17-0- (chlorobutanol group) history Binoxin A 17-Psa (224.3 mg, 92¾ Yield __- 126 -_ This paper size applies to China's national standard rate CNS) A4 size (210X 297 mm) &quot; &quot; &quot; &quot; &quot; a (please read the Notes on the back to fill out this page)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 _ B7__ V. Description of the invention (124)), white deviation from glass, FDMS, m / e (relative intensity) 696 (M +, 100), 189 (20 ). Example of flask B6-17-Π-(dimethylamine Zfluorenyl) Φ Kerosyn A 17-Psa The reaction was performed as described in Example B2, and 17-0- (chloroethenyl) spinosyn A 17_Psa (99.4 mg, 0.15 mmol) was the starting material. The obtained 17-0- (dimethylamine ethylammonium) spinosyn A17_Psa (79.1 mg, 78¾ yield) was a beige glass, FDMS, m / e (relative strength) 675 (M * -H , 100). Cases of struggling pus B7-17-Π-U-iodine) indoxoxine A 17-Psa in 17-0- (4-chlorobutanol group) spinoxin A 17-Psa (91,9 mg, 0 · To a solution of 13 mmol) in acetone (3 ml) was added sodium iodide (198 rag, 1.3 mm). When a precipitate formed, the reaction mixture was heated to reflux temperature for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with methylene chloride. The dichloromethane was dried over potassium carbonate and evaporated at room temperature under reduced pressure. 17-0- (4-iodobutanol) Spinoxin A 17-Psa (94.7 mg, 93% yield) was obtained as a beige glass, FDMS, m / e (relative strength) 832 ( ! _0), 786 (M, H, 100), 704 (20), 377 (30).啻 Example B8-17-0- U-dimethyl antibutanol) Cao Nuoxing A 17-Psa The reaction was carried out as described in Example B2, with a history of 17-0- (4-iodobutanol)) Binoxin A 17-Psa (216.9 mg, 0.28 mmol) was used as the starting material. The obtained 17-0-U-dimethylamine butanol) Spinoxin A 17-Psa (155.7 mg, 79¾ yield) was a beige glass, FDMS, m / e (relative strength) 704 (r , 100) 〇 Example B9-17-0-(N '_ Jiashi-(I Chunji Z brew ester) in the Cao Nuo Xing A Π ________ ~ 127 —___ This paper size applies to China National Standard (CNS) A4 specifications (210X 297mm) (Please read the notes on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 — a _ B7__ V. Description of the invention (125) -Psa at 17-0- (4-chloroethenyl) Spinoxin A 17-Psa (150.5 mg, To a solution of 0.23 mmol) in chloroform (7 ml), diisopropylamine (59 β 1, 0.34 mmol) was added, followed by pemipine HQ (38 y 1, 0.34 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour and then heated to reflux temperature for 2,5 hours. The mixture was cooled to room temperature for 3 days. Then 1-methylpiperazine (0.5 ml) was added and the mixture was heated to reflux temperature for 4 hours. The reaction mixture was then cooled to room temperature and poured into a saturated sodium bicarbonate solution and extracted with ether. The ether portion was washed with M brine, dried over magnesium sulfate and evaporated at room temperature under reduced pressure. The crude product was purified by chromatography on silica. M 7¾ methanol in dichloromethane solution and M 20¾ methanol in dichloromethane were precipitated (single step). The obtained 17-0-(^ 1'-methyl 4-piperidylacetic acid) spinosinol &amp; 17-Psa (63.1 mg, 38¾ yield) is a colorless glass, PDMS, m / e (relative Intensity) 730 (M \ 100), 731 (80). Example: Dinoxyl ZSg ester) Benoxin A 17-Psa was reacted as described in Example B9, K 17-0- (chloroethenyl) spinoxin A 17-Psa (152.3 mg, 0.23 mmoi), and morpholine (add 0.5 ml at a time) as starting materials. Reflux for 14 hours and extract with K dichloromethane. The obtained 17-0- (N-morpholinoacetate) Spinoxin A 17-Psa (141.3 mg; 86% yield) is white and off-glass. , FDMS, m / e (relative intensity) 717 (ΪΓ, 100). Example 1 ^ 1-17-0- (2- (1-Mi_yl) Z) Mr. Nosin A 17-Pμ in sodium hydride (50% mineral oil suspension; 15.81 ^, 0.33111111. 1) To a solution of THF (5 ml), imidazolyl (23.1 mg, 0.34 mmol) was added. -128 · * This paper size applies to China National Standard (CNS) A4 (210X 297 mm) — (Please read the precautions on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (126) Add 17-0-bromoethenyl spinosyn A 17-Psa (201, 1 mg, 0.28 mmol) to the mixture, and The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water. The methylene chloride portion was then washed with salt, dried over potassium carbonate, and evaporated at room temperature under reduced pressure. The crude product was purified by chromatography on silica, eluting with 5% ethyl acetate in ethyl acetate. The obtained 17-0- (2- (oxazolyl) ethynyl) spinoxin / \ 17bang 53 (117 mg, 60¾ yield) is a colorless glass, FDMS, m / e (relative strength ) 699 (M *, 100), 698 (40), 189 (40), 101 (70).

Rich bottle example B1 2-17-0- (2- (4- (2-pyrimidinyl buhexyl Dlt. P well-based) ethicinyl) Zhongnosin A was reacted as described in Example B11, M 17-0- (bromoethenyl) Spinoxin A 17-Psa (209.6 mg, 0.29 mmol), and 2- (buhexahydropyridyl) pyrimidine as starting materials, and 5% methanol Dichloromethane is a chromatographic eluate. The obtained 17-0- (2- (4- (2-pyrimidinylbubuhexylpyridinyl) ethanyl group_spinoxin A 17-Psa ( 233.6 mg, 97¾ yield), white off-glass, FDMS, m / e (relative strength) 717 (M, 60), 794 (100).

啻 Example R1 3-17-0- (2-U-Metoprolidine) Zirconium) Indoxacin A was reacted as described in Example B11, M 17-0- (Bromoethenyl) Spinozin A 17-Psa (201.8 mg, 0.28 mmol), and 4-dimethylamine piperidine as starting materials, stirred at room temperature for 3 days, and using a solution of 10¾ methanol in dichloromethane and then 100¾ Methanol (single step) was the eluent. The obtained 17-0- (2- (4-methylamino-1-eridinyl) ethenyl) Spinoxin / \ 17 卄 ^ _- 129 -_ This paper size applies to Chinese national standards ( CNS) A4 specification (210X297mm) &quot; (Please read the precautions on the back before filling this page)

Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 ____ B7 V. Description of the invention (127) (104.2 μ, 49¾ yield), white solid, FDMS, m / e (relative intensity) 759 (M *, 100) . Example B1 4-1 7-0- (4-Pyridinylcarbonyl) Sporoxin A 17-Psa in a suspension of isonicotinic acid (50.7 rag, 0.41 mmol) in dichloromethane (10 ml) , DMAP (18.5 mg, 0.4 mmol) and Spinoxin A 17-Psa (202.1 mg, 0.34 ππποί) were added, followed by DCC (107.8 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 2.5 days, and then diluted with ether and filtered. The filtrate was evaporated at room temperature under reduced pressure. The residue was purified by chromatography on silica, and 50% ethyl acetate in hexane was eluted. The obtained 17-0- (4-pyridylcarbonyl) spinosyn A 17_Psa (116 * 1 mg, 7 «yield) is a colorless glass, FDMS, ra / e (relative strength) 696 (M, 100 ), 694 (40). Rich example B15-17-Π- (Six-gas trap Z 蚍 group) Φ 窨 Nosin A 17-Psa The reaction was carried out as described in Example B11, M17-0- (Bromoethenyl) Spinoxin A 17-Psa (206.4 rag, 0.29 mmol), and hexahydropyridine P were the starting materials. The obtained 17-0- (hexahydropyridine ethylspinyl) spinosyn A 17-Psa (127,1 mg, 61% yield) was a beige solid, FDMS, m / e (relative strength) 791 ( 40), 718 (40), 717 (M +, 65). In the rich case (N-methyl Ubutyrate), W Nuoxin A 17-Psa was reacted as described in Example B14. K Spinoxin A 17-Psa (20 7.7 mg, 0.36 mmol) and methyl Amidine (63.7 mg, 0.43 mmol) was the starting material. The obtained 17-0- (1methyl-L-amidate) Spinoxin A 17-Psa (65.9 mg, 43% yield, based on Spinoxin A 17-Psa recovered by K), FDMS , m / e (relative strength) 703 (95), 702 (-130 _ This paper size applies to the Chinese National Standard (CNS) Λ · 4 size (210X297 mm) (Please read the precautions on the back before filling this page)

487559 Printed by A7 __B7, Employee Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs V. Description of Invention (128) M *, 100) Fluorenylspinoxin A 17-Psa The reaction was performed as described in Example B14, using 17-0-bromoethylspinoxin A 17-Psa (205.1 mg, 0.29 ππηοΐ) and 1- (2-aminoethyl ) -Hexahydropyridine as the starting material. After chromatography on silica, K 10¾ methanol in dichloromethane was dissolved as the eluent. The product was further subjected to reverse phase HPLC on a C18 column. M acetonitrile: methanol: 0.1 ¾ Ammonium acetate (35:35:30 to 45:45:10, linear gradient within 60 minutes) M obtains 17-0- [N- (2-hexahydropyridylethyl)] amine ethylspinoloxin A 17-Psa (11 mg, 5% yield), a white solid, FDMS, ro / e (relative strength) 760 (90), 759 (M +, 100). Tube) B18-17-0-( Z hydrocarbonylethinyl) Spinoxin A 17-Psa The reaction was performed as described in Example B3, M Spinoxin A 17-Psa (207.7 mg, 0.35 mmol) and diethyl chloride malonate ( 484 ml, 3.78 mmol; added only a wide number of times). 17-0- (ethoxycarbonylethenyl) obtained Spinozin A 17-Psa (153.6 mg, 62¾ yield), a colorless solid, FDMS, m / e (relative strength) 704 (M +, 100), 189 (51). The reaction was performed as described in Example B3, M Spineau Octyl A 17-Psa (4.06 g, 6.9 ππηοΐ) and bromoacetamidine are used as starting materials, and a dichloromethane solution of 10¾ ethyl acetate is used as a chromatographic eluate. The obtained 17-0M Ethyl bromide) Spinoxin A 17-Psa (2.92 g, 59¾ yield), white deviation from solid, FDMS, m / e (relative intensity) 712 (M \ 50), 713 (85). -131 -(Please read the notes on the back before filling this page)

Order. ¾. This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (129) Example B20-17-Π- ( P-Amine cage (Zylenyl) Sinokine A 17-Psa Dissolve the compound 17-〇- (p-nitrophenylethylethyl) spinoxin A17-Psa (101 · 6 mg, 0.134 mmol) in ethanol (5 ml) and tin chloride (11) (142.6 mg, 0.75 ml) was added. The yellow color of the solution quickly disappeared and replaced with a white suspension. The reaction was heated at reflux temperature for 3.5 hours, cooled to room temperature, and allowed to stand overnight. After a gradual reaction to form a residue, the residue was purified by chromatography on silica gel (ethyl acetate / hexane). K provided 17-0- (p-aminophenethylfluorenyl) Spinoxin A 17-Psa (45.3 mg, 46¾ yield) as a white solid, FDMS m / z 723. CuHwNOi 〇 Estimated value of analysis: C, 68.03; Η, 7.94; Ν, 19.3 ·. Actual value: C, 67.53; H, 7.91; Ν, 2.41. Benoxin A 17-Psa in Fen Example B2 ((鄱-氡 氡 甲 醮 基)) was prepared as described in Example B46, using 郯 -chlorobenzoic acid (51 mg, 0.332πππο1), DMAP (47 mg , 0.38 mmol), Spinozin A 17 ~ Psa (135 mg, 0.228 mmol), and DCC (49 mg, 0.23 mmol). The obtained 17-CM-o-chlorobenzylidene) Spinoxin A 17-Psa (69 rag, 41¾) was a white solid with FDMS m / z 729.啻 Example B22-17-0- (m-Phenyl cage 7, fluorenyl) Phenoxin A 17-Psa The compound was prepared as described in Example B46, using m-chlorophenylacetic acid (42.3 mg, 0.24 mmol ), DMAP (45.2 mg, 0.37 mmol), Spinoxin A 17-Psa (134 «4 mg, 0.22 mmol), and DCC (51.2 mg, 0.24 mmol). The obtained 17-0- (m-chlorophenethylfluorenyl) spinosin A 17-Psa (101.5 mg, 60¾) was a white solid. FDMS π / ζ 742. Example B23-17-0-Woxining A 17-Psa of a middle school in the first grade This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

487559 Employees' Cooperative Cooperative A7 B7 of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) The compound Spinoxin A17-Psa (104 mg, 0.18 mmol) was dissolved in benzene (5 ml) and dimethylformamide was added. Amine dimethyl acetal (0.10 g, 0.84 mmol). The solution was heated to reflux temperature for 2 hours, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate / hexane gradient, 20:30 to 50:50), and M provided 17-0-formamyl spinosin A 17-Psa (35.8 mg, 32.8¾ ) As a white solid: FDMS ιη / ζ: 618. Example B24-17-0-(Acetylenyl) Cryptamino) Φ g Nosin A Ϊ7_Ρ s_a The compound was prepared according to the procedure described in Example B46, using 2-benzoic acid (83 mg, 0.3 6 mm ο 1), DMAP (3 8 mg, 0.31 mm ο 1), Spinozin A 17-P sa (15 0 mg, 0 ♦ 2 5 mmo 1), and DCC (5 8 mg, 0 ♦ 2 8 mmo 1) . The obtained 17-0- (o-benzylidene) benzylidene) Spinoxin A 17-Psa (37.6! 1 ^, 18.5%) was a white solid:? 01 ^ 111/2 799.例 _Example B25-1 7-0-(鄱 氪 醯 Z 醯 A certain kenosine A 1 7-Psa According to the procedure described in Example B46, the compound was prepared using 2-chlorophenylacetic acid (69 mg, 0.4 mg ), DMAP (38 mg, 0.31 mmol), Spinoxin A17-Psa (148 mg, 0.25 mmol), and DCC (64 mg, (K31 mmol). Nosin A 17-Psa (92 mg, 49¾), white solid · FDMS m / z 743, 745. CuHssCh 〇Cl analysis estimated value ♦♦ (:, 66 · 25; Η, 7.46. Actual value: C , 66.23; Η, 7.36 〇

A case of back pus. IT nosin A in a mesityl in a cage. Compounds were prepared according to the procedure described in Example B46. 2-Phenylbenzoic acid (78 mg, 0.39 mmol) and DMAP (37 rag, 0.30 mmol) were used. , Shibin applies China National Standards (CNS) 8 4 specifications (ZIOXN7 mm) (Please read the precautions on the back before filling out this page) Order 4, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _: ____ ^ __ V. Description of the invention (131) Nosin A17-Psa (142 mg, 0.24 mmol), and DCC (60 mg, 0.29 mmol). The obtained 17-0- (o-phenylbenzylspinyl spinosin A 17-Psa (70 mg, 38¾) was obtained as a white solid: FDMS ιη / ζ 770. As an example B27-17-Π- (鄱. P-Dichlorophenethylsulfonyl) Spinois prepared by the procedure described in Example B46 using 2,4-dichlorophenylacetic acid (66 mg, 0.32 mmol), DMAP (52 mg, 0,26 mmol ), Spinozin A17-Psa (142 mg, 0.24 romol), and DCC (55 mg, 0.26 mmol). The resulting O- (o-, p-dichlorophenethylfluorenyl) spinosin A 17-Psa (108,5 mg, 57.9%), as a white solid: FDMS m / z 777 〇 Example B28-17-Π- (fluorenyl-propylpropylcarboxamidine) Spinozin A_ 17τ. P_M The compound was prepared according to the procedure described in Example B46, using 2-isopropyl · benzoic acid (72 rag, 0.43 mmol), DMAP (43 mg, 0.35 mmol), spinosin A17-Psa (171 mg, 0.28 mmol), and DCC (72 rag, 0.35 mmol). The resulting 17-0- (o-isopropylbenzyl) spinoxin A 17-Psa (76.7 mg, 36 * 0S 〇, is a white solid: FDMS ro / z 737 ... (: nHeQ (estimated value of ha analysis · C, 70.0δ; Η, 8.21. Actual value: C, 70.33; Η, 8.28. 啻 敝 Example B2Q-17 -0-(%! 3 · 鄱-二氡 cage ^ base) Shi Caoxin A 17-Psa Compounds were prepared according to the procedure described in Example B46, using 2,6-dichlorobenzoic acid (61 mg, 0.30 mmol), DMAP (40.6 mg, 0.332 mmol), Spinozin A17-Psa (131 mg, 0.22 romol), and DCC (59 rag, 0.28 mmol). The resulting 17-0- (o-, pyrene-dichlorophenethylfluorenyl) spinosin A17-Psa (101πιg, 58.5¾), white solid: FDMSIn / z777 _- 134 -_ This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm 1 (Please read the notes on the back before filling (This page)

Order 487559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _ B7 V. Description of the invention (132) Example of pus pus B30-ΐ7-Π- ¥ Jinzhong Nozai A 1 7-Psa Will be compound Spinozin A 17 -Psa (120 mg, 0.20 mmol) was dissolved in 5 ml of dimethylformamide and silver oxide (50 mg, 0.21 nunol) and benzyl bromide (120 mg, 0.70 mraol) were added. The reaction was stirred for 1 hour and additional benzyl bromide (200 mg, 1.4 mmol) and silver oxide (40 mg, 0.42 mmol) were added during this period. The reaction was stirred for another 12 hours, after which the reaction was heated to 80-90 ° C and benzyl bromide (100 mg) and silver oxide (20 mg) were added every hour for 3 hours. The reaction was cooled to room temperature, and the filtrate was washed with ether (50 ml), filtered, and deionized water, and then with brine. The ether solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate / hexane gradient, 20:80 to 50:50) to provide 17-0-benzyl spinosin A 17-Psa (6.3 mg, 4.5%) , Is a colorless glass: FDMS m / z 618: partial NMR 5 7.41-7.36 (m, 5Η), 6.78 (bs, 1Η), 5.90 (dd, 1H), S.BKdt, 1H), 5.18 (dd, 2H); 4.90 (m, 1H), 4.86 (dd, 1H), 4.68 (m, 1H), 4.33 (q, 1H)茏 Acetyl) Φ Binoxin A 17_Psa The compound was prepared according to the procedure described in Example B46 using 3,4-dichlorophenylacetic acid (136 mg, 0.66 mmol), DMAP (70 mg, 0.57 mmol), Spinol Sin A17-psa (170 mg, 0.29 mraol), and DCC (70 mg, 0.34 mmol). The resulting 17-0- (y, m (dichlorobi ethenyl) spinoxin 8 17 bang 33 (171.2 1 ^, 76.5%) is a white solid: "Estimated value of 776, 777, 778, 779, 780, C4iH52〇Cl2 Cl2 analysis in 01 ^ 111/2: C, 63.32; H, 7 * 00; C1, 9.12. Actual values: C, 63, 37; Η -135-This paper size applies to China National Standard (CNS) Α4 specifications (2 丨 ox297 mm) 1 ~ (Please read the precautions on the back before filling this page )

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487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (133) 6.91; C1, 9.31. Example R22-1 7-0- (p- (H-dimethylamine) benzylidene) Chernosine A 17-Psa The compound was prepared according to the procedure described in Example B46, using 2,6-dimethylamine Benzoic acid (30 mg, 0.18 mmol), DMAP (22 mg, 0.18 mmol), spinoxin A17_Psa (98 mg, 0.16 mmol), and DCC (40 mg, 0,19 mmol). The resulting 17-0_ (p- (N, N-dimethylamine) benzylidene) Pinocinin A 17-Psa (39.5 mg, 32¾) was a white solid: FDMS ιη / ζ 777. Estimated value for C42H53N0iQ analysis: C, 68.36; Η, 8.06; N, 1.90. Actual values ♦ C, 68.20; Η, 8,28; N, 2.12. Example B33-17-0- (p-methylarginylmethylfluorenyl) Phenoxine A 17-Psa The compound was prepared according to the procedure described in Example B46 using 4-methoxybenzoic acid (44 mg, 0 * 29 mmol), DMAP (41 mg, 0.33 mmol), Spinozin A17-Psa (108 mg, 0.18 mmol), and DCC (44 mg, 0.21 nunol). The obtained 17-0- (p-methoxybenzyl) binnosin VI 17-Psa (101.7 Iπg, 76.4¾) was a white solid: FDMSπl / z 724, 725. Rich Example R: U-17-0- (¾ 酼 酼 V 客 V oxinoxin A 1 7-Psa The compound was prepared according to the procedure described in Example B46, using benzoic acid (33 mg, 0:27 mmol), DMAP ( 28 mg, 0.23 mmol), Spinoxin A1 7-Psa (98 mg, 0.17 mmol), and DCC (41 mg, 0.20 mmol) 0 A 17_Psa (71.0 mg, 61.7¾) is a white solid: FDMS m / z 695 ° C40H54 ° i Estimated value for analysis: C, 69.14; 11, 7.83. Actual: (:, 69.35; 1 ^ 7.69.窨 Confirmation-Li Bingmou Shen Choumou) Nuoxin A 17-Psa __-136-This paper size is applicable to China National Standard (CNS) A4 size (210X297). (Please read the precautions on the back first (Fill in this page again)

487559 A7 ____ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. B7 V. Description of the Invention (134) The compound was prepared according to the procedure described in Example B46, using 4-isopropylbenzoic acid (58 mg, 0.35 mmol), DMAP ( 51 mg, 0.41 mmol), Spinozin A 17-Psa (129 mg, 0.21 mmol), and DCC (80 mg, 0.38 nunol). The obtained 17-0- (p-isopropylbenzyl) binoxin A 17-Psa) (33.1 mg, 20.5¾) was obtained as a white solid: FDMSIn / Z 736. Cell example R ^ -1 7- (1-¾ 7, 臓 cazonoxin A 17-Psa The compound was prepared according to the procedure described in Example B46, using phenylacetic acid (30 mg, 0.22 mmol), DMAP (4 mg , 0.34 mmol), Spinoxin A 17-Psa (121 mg, 0.21 mmol), and DCC (47 mg, 0 * 22 mmol). The resulting 17-0-phenethylbinoxin A 17-Psa (86.0 rag, 59 · 3 t), white solid: FDMS m / z analysis estimate: C, 69 · 47; Η, 7.96. Actual value: C, 69 · 28; Η, 7.94. Cell Examination Example B 37-17-Π-(p-Tyridine ethylacetinyl) Spinoxin A 17_Psa The compound was prepared according to the procedure described in Example B46 using 4-methoxyphenylacetic acid (39 mg, 0.23 mmol), DMAP (45 mg, 0.36 mmol), Spinoxin A 17-Psa (123 mg, 0.20 mmol), and DCC (67 mg, 0.32 mmol). The resulting 17-0 -(P-methoxyphenethylfluorenyl) Spinozin A 17-Psa (97.8 mg, 63.5¾) as a white solid: FDMS ro / z 739. Tube chest B38-17_n-(p-methylphenethylacetin) Based) stropoxin A 17-Pm The compound was prepared according to the procedure described in Example B46, using 4-nitropolyacetic acid (86 mg, 0.47 mmol), DMAP (66 mg, 0.54 mmol), Spinol Xin A 17-Psa (255 mg, 0.43 m mol), and DCC (100 rag, 0.48 mmo 1). The obtained p-nitrophenylethyl donkeyyl) Spinozin A17-Psa (194.1, 59.6%), as a white solid: FDMS m / z 753. _- 137 -__ This paper size applies to Chinese National Standard (CNS) A4 (21 OX 297 mm) (Please read the precautions on the back before filling this page)

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Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of Invention (135)

Estimated value for CnH55N012 analysis: c, 65 · 32; Η, 7.35; Ν, 1.86. Actual values: C, 65 · 58; Η, 7.54; H, 2.05. Purulent Example 7-η- (meta-sayl ^ ethynyl i. Spinoxin A 17-P ... α Compounds were prepared according to the procedure described in Example B46 using 3-nitrophenylacetic acid (86 mg, (Κ37 mmol), DMAP (62 mg, 0.50 mmol), Spinoxin A 17-Psa (185 mg, 0.31 mmol), and DCC (83 mg, 0.40 mmol). The resulting 17- 0- (m-nitrophenylethylethyl) Spinosin A 17-Psa (166, l, 70.3%), white solid: C4iH55N12 Estimated value for analysis: C, 65.32; Η, 7.35 N, 1.86. Actual values: C, 65.13; H, 7.49; N, 1.92. Example of tube B40 -17_0_ (between— * ▲ 甲 甲 本 B5 ^ 基) history province ifexin A 17_Psq according to the example The compound was prepared according to the procedure described in B46, using 3-trifluorotolylacetic acid (101 mg, 0.49 mmol), DMAP (64 mg, 0.52 mmol), spinoxin A 17-Psa (274 mg, 0.005) 46 mmol), and DCC (109 mg, 0,52 mmol). The resulting 0- (m-trifluorotoluylacetamido) spinoxin A 17-Psa (302.2 mg, 84.6%) was obtained as a white solid: 〇42 Heart 5 〇10 Factory 3 analysis estimated value: C, 64.93; Η, 7. 14. Actual value: C, 65 ♦ 07; Η, 7.39 〇 Rich example B41-17- heart-0- Methyl Spinozin A 17-P, a The compound was prepared according to the procedure described in Example B47, using 17-epi-Spinoxin A 17-P sa (20 in g, 〇 ♦ 〇3 3 mm ο 1), P "〇t ο n S p ο nge ® (5 ms, 0,03 mmol) and trimethyloxy tweezer tetrafluoroborate (14 mg, 0.065 mmol). The resulting 17-epimethylspinoxin A 17-Psa (7.1 mg, 35¾ ), Is a white solid: part of the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

、 -Ιτ 487559 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (136) NMR δ 6.71 (bs, 1H), 5.88 (dd, 1H), 5.81 (dt, 1H), 4.90 (m, 1H), 4.84 (s, 1H) '4.32 (q, 1H)' 4.77-4.62 (m, 2H) # 3.56 (s, 3H), 3.50 (s, 6H) / 3.45 (s, 3H). Example R42-17-D- (m-Methylchlorophenethylfluorenyl) stronocin A 17-Psa The compound was prepared according to the procedure described in Example B46, using 3-methoxyphenylacetic acid (98 mg, 〇. · 59 mmol), DMAP (71 mg, 0 * 58 mmol), Spinoxin A 17-Psa (290 mg, 0.49 mmol), and DCC (112 mg, 0.54 nunol). The obtained 17-0- (m-methoxyphenethylfluorenyl) Spinozin A 17_Psa (308.7 mg, 85.1¾) was a white solid: estimated value of C42H58〇h analysis ·· C, 68 · 27; Η , 7.91. Actual value: C, 68.25; Η, 7.92. Example B4Π7-0- (Four-gas D-Franan-2-yl) SHINOXIN A C-17-Psa will be Spinoxin ^ \ 〇17bang 53 (0.50 ^ 0.85 111111〇1), 3, A solution of 4-dihydro-2H-H® (0.45 mL, 0.41 g, 4.9 mmol) and TsOH · HC1 (0.01 g, 0.05 mmol) in dichloromethane (4 ml) was stirred for 24 hours. The mixture was partitioned between ether and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. MPLC (silicon dioxide, 50: 50, ether / hexane) yields 0.35 g (61%) of 17-0- (tetrahydropiperan_2_yl) Spinoxin A C-17-Psa, 1: 1 mixture of non-mirror isomers and clean, colorless glass. Example of tube B44-17-Π- (4-nitrocagerazinyl) -17-fluorene-midinoxine A 17 z £ sa Dimethylazocarboxylate (0.4 ml, 2.49 nunol) Add benzene solution to Spinozin A 17- -139-_ at room temperature within 2-3 minutes (Please read the precautions on the back before filling this page)

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This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 —____ B7_ V. Description of the Invention (137)

Psa ((K3 g, 0.51 mmol), triphenylphosphine (0.65 g, 2.49 mmol) and p-nitrobenzoic acid (0.37 g, 2.20 mmol) in benzene solution (12 ml). The resulting solution was at room temperature Stir for 48 hours. Remove the solvent and perform flash chromatography on silica (150ml) using 2.5¾acetone in dichloromethane as the eluent to obtain 110 mg of 17-0- (4-nitro Benzamidine) -17-epi-Spinoxin A 17-Psa. A sample recrystallized from acetone / water in 2: 1, the sample is a colorless needle. Mp 159-1QOC; NMR (CDC13) δ 7.32 (s, 1Η, Η-13), 5.59 (m, 1Η, Η-17), 4.97 (m, 1Η, Η-21), 4.87 (d, 1Η, Η-1 ·), 4.34 (m, 1H, H-9); MS m / z 740 (100) · Rich Example B45-Ϊ7-0-(4-Nitrogen in a cage 7, 艢 a) -1 7- 羌-中 窨 诺辛 A A 1 7-Psa will A portion of 1,3-dicyclohexylcarbodiimide (21 mg, 0.11 mm〇1) was added to a properly mixed 4-nitro-phenyllactic acid (20 mg, 0.11 mmol) at room temperature, 4 -A solution of dimethylamino Dttidine (3 mg, 0.024 mmol) and 17-epi-Spinoxin A-17-Psa (59 mg, 0.1 mmol) in dichloromethane (2 ml). The resulting mixture was placed in a chamber Stir at temperature for 2 hours, It was then diluted with more dichloromethane (2.0 ml) and filtered to remove insolubles. The filtrate was evaporated and the residue was subjected to flash chromatography on silica (25 ml) using 25¾ ethyl acetate in methane as the eluent. Μ obtained 17-0- (4-nitrophenethylhydrazone,)-17-epi-spinoxin A 17-Psa (70 mg), as a colorless foam: 1 {NMR (CDCI3) δ 8.23 (d, 2H), 7.S0 (d, 2H), 7.12 (s, 1H, H-13), 5.28 (m, 1H; H-17) # 4.90 (m, 1H, H-21), 4.84 ( d, 1H, Hl *), 4.30 (m, 1H, H-9), 3.78 (s' 2H, CH2C〇2); MS m / z 752 (100) · This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 1 (Please read the precautions on the back before filling this page)

487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (138) Case B46-17-0- (Pair _ 氡 乙 乙 _ 基) Cao Nuoxin A 17-Psa The compound is- Chlorophenylacetic acid (50 mg, 0.29 mmol) and dimethylaminopyridine (DMAP, 50 mg, 0.40 mmol) were dissolved in dichloromethane (8 ml), and Spinoxin A 17- Psa (164.7 mg, 0.279 mmol), followed by dicyclohexylcarbodiimide (DCC, 66 mg, 0.32 mmol). The reaction was stirred overnight. The reaction was filtered to remove solids and chromatographed on silica gel (ethyl acetate / hexane gradient, 20:80 to 50:50) to provide 17-0- (p-chlorophenethylfluorenyl) Spinoxin A 17 -Psa (128.4 mg, 61.8%), as a white solid:? 〇} ^ 111/2 743. 〇411155〇1〇 (: 1 Estimated value of analysis: C, 66.25; Η, 7.46. Actual value: C, 65.98; Η, 7.31 °. Examination example B47-1 7-0-A Zhongzhong Nosin A Ϊ7-Psa Dissolve the compound Spinoxin A 17-Psa (267 mg, 0,452 mmol) in dichloromethane (5 ml) and add Proton Sponge® (107 mg, 0,50 mmol) and trimethyl oxygen Sickle tetrafluoroborate (104 mg, 0.702 nunol). The mixture was stirred for 3 hours and gradually reacted to form a white fluffy solid (0.20 g). The solid was purified by reverse phase chromatography (methanol / water 90: 1) K to provide 17-0-methyl spinosin A 17-Psa (135.8 mg, 49.6%) as a white solid: 1 foot (film) 2969 , 2933, 2825, 1722, 1661, 1458, 1377, 1103, 1034 cnT1; 13C NMR δ 202.80, 172.31, 147.01, 143.71, 129.15, 123.73, .95.22, 82.19, 32.09, 30.86, 77.53, 76.05, 75.86, 67.75, 60.73, 53.30, 57.51, 57.33, 49.33, 47.42, 46.55, 46.11, 41.23, 40.91, 21.22, 36.11, 34.24, 30.93, 30.39, 27.88, 20.19, 17.61, 17.02, 9.19., Part Ⅱ: Amine supplementation to replace meat meat evening Decorate the rich and detailed example of Kenosin B in Spinozin B (200 mg, 0.28 nunol) in a solution of nitrogen (5 ml) and add diisopropylethylamine (72.7 "1, 0.42 mmol) And then add acetyl chloride (30 μ 1, 0.42 mmol). The reaction mixture at room temperature _-141 -_ This paper size applies to China National Standard (CNS) A4 size (210X297 mm) (Please read the note on the back first) (Fill in this page again)

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487559 Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (139) Stir for 0.5 hours. The mixture was then diluted with M dichloromethane and diluted with saturated sodium bicarbonate. The methylene chloride portion was dried over potassium carbonate and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and eluted with 5¾ methanol in dichloromethane. N-Ethylspinoxin B (239 nig, about 100¾ yield) is obtained as a colorless vitreous body, FDMS, π / e, (relative strength) 759 (M + -H, 10), 714 (60), 189 (50), 170 (50), 101 (100). Enrichment example: (2) Cinnamoxib, a certain midoxinoxine B was reacted according to the procedure described in Example C1. Spinoxin B (200 mg, 0.28 mmol) and benzamidine chloride were used as starting materials. N-benzyl spinyloxin B (227.4 mg, about 100¾ yield), pale yellow glassy body, FDMS, m / e (relative strength) 821 (M + -H, 5), 776 (20), 232 (30), 189 (35), 103 (100). For example, m-Allyl was treated with oxoxin B according to the procedure described in Example C1. Spinoxin B (200 mg, 0.28 mmo 1) and The allyl bromide was the starting material. The reaction was stirred at room temperature for 4 days, then evaporated at room temperature and under reduced pressure, and a hexane solution of 40¾ ethyl acetate was used as the chromatographic eluate. The obtained allyl spinoxin B (148.9 mg, 70% yield) was a colorless glass, FDMS, m / e (relative strength) 757 (M + -H, 100). Acetone B was reacted according to the procedure described in Example C1. Spinoxin B (200 mg, 0.28 mmol) and benzyl bromide were used as starting materials. The obtained N-benzyl spinosin B (216.6 mg, 96¾) Yield) is a colorless glass, FDMS, ra / e (relative strength) 807 (Μ ^ Η, 100). -14 2-(Please read the notes on the back before filling this page)

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This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 487559 A7 B7 Printed by Economic Consumers Central Sample and Staff Bureau Consumer Cooperatives V. Description of the invention (140) Rich _ Example "RN-Methyl Zano Acetone A iodide in Spinoxin A (111 · 6 mg, 0 · 15 mmol) in chloroform (5 ml), methyl iodide (200 ^ Π was added. The reaction mixture was stirred at room temperature for 24 hours and then added Methyl iodide (200 ^ 1), and stirred at room temperature for a further half of the reaction mixture for 24 hours. Then the solvent was evaporated at room temperature under reduced pressure and the residue was triturated with ethyl ether. The resulting N-methyl spinoline Octane A iodide (101 mg, 76¾ yield), white deviation from solid, FDMS, m / e (relative strength) 747 (M +, 100) 0 Melamine Example Hydrogenated Schistoxin A at 81.2% pure Spinolol The ice-cooled solution of 2 * 07 3111, 2.83 111111〇1) in dichloromethane (100 ral) was added, and m-chloroperoxybenzoic acid (450 mg, 2.57 mmol) was added. The reaction mixture was allowed to warm to room temperature for 1 hour. And then the reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched by the addition of sodium bicarbonate solution. The organic phase was separated and sulfur was added. The magnesium acid was dried, and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica, and eluted with M10% methanol in dichloromethane. The resulting N-oxyspinoxin A (1.59 gm , 92¾ yield), M light yellow glass, FDMS, m / e (relative strength) 762.9 (20), 731.8 (M ~ 0, 40), 686.8 (100), 401.7 (25). The following example was performed: The reaction was performed as described in Example C13, and MN-oxysporoxin A (509 · 8 mg, 0.68 mmol) was used as the starting material. A white precipitate was formed during the reaction. Separated by filtration. The precipitate was then triturated under ether. The ether was evaporated at room temperature under reduced pressure and the residue was dissolved in methanol (20 οι 1) and added with boron argon-143-(Please read the precautions on the back before (Fill in this page)

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This paper size applies to China National Standard (CNS) A4 specifications (21〇: &lt; 297 g t) 487559 A7 B7 V. Description of the invention (1 ^) Printed by the Ministry of Standards, Bureau of Standards and Consumers Cooperative (258) mg, 6.82 mmol) and the reaction mixture was stirred at room temperature for 7 hours. The mixture was then evaporated to a small volume at room temperature under reduced pressure and diluted with K ether. The ether portion was washed with water, brine, dried over potassium carbonate and evaporated at room temperature under reduced pressure. The product was separated by chromatography on silica and the hexane solution of M70ΪK ethyl acetate was eluted. The obtained 4 ”-hydroxyspinoxin A (92.1 mg, 19¾ yield) is a colorless glass, a 3: 1 isomeric mixture, FDMS, ra / e (relative strength) 704 (M, 80), 591 (30), 190 (70), 115 (100). Rich travel example C8-3 ". 4" -dihydro-4 "-deamine W-nosin C N-oxyspinoxin A (505.9 nig, 0.68 mmol) was heated to 120 ° C under nitrogen. The gas began to release at 115 ° C, and continued to heat the chamber gas to stop the release (about 15 minutes). The mixture was then slowly cooled to room temperature. The product was separated by chromatography on silica, K 5% methanol in dichloromethane. The obtained 3 ”, 4” -dihydro-4 ”-deamine spinosynox C (91 mg, 19¾ yield), FDMS, m / e (relative strength) 696 (M +, 80), 589 (20), 189 (50), 101 (100), formamyl spinosin B (43.3 mg; 9¾ yield), spinosin M102.1 mg; 21¾ yield), and spinosin B (114.5 ms; 23¾ yield), all of them are colorless glass. 啻 敝 Example C9-N-(fT -benzyl-3-㈣ 丨 share methyl) Φ Trioxin C in Spinoxin C (213.6 mg, 0.3 nunol) in methanol (2 ml), N-benzyl-3-indole carboxylic aldehyde (83.7 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours, and sodium cyanoborohydride ( 43.5 mg, 0.7 ππηοΐ). Incubate for another 2 hours at room temperature. TLC (dissolved in 10% methanol in dichloromethane solution) showed incomplete reaction. However, in the chamber -144-Chinese paper standard applies to this paper size. (CNS) Α4 specification (210X 297mm) (Please read the precautions on the back before filling in this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of Invention (142)

The solvent was evaporated to a small volume under mild reduced pressure. The mixture was then diluted with M dichloromethane. The dichloromethane portion was washed with water, brine, dried with potassium carbonate, and distilled under reduced pressure at room temperature. The product was separated by chromatography on silica, M7 (U ethyl acetate in hexane solution. The resulting N- (N, benzylfluorenylmethyl) spinosin C (83.8 mg, 30¾ yield) , Is a light yellow glass, FDMS, m / e (relative strength) 1140 (15), 923 (M, 100). 啻 Example C10-H-desmethylformyl group Cao Nuoxin J Yu Shibin To a solution of Nosin J (990.4 mg, 1.38 ππηοΐ) in anhydrous dichloromethane (25 ml) was added Pt-pyridinium dichromate (622.6 mg, 1.65 mmol). The reaction mixture was stirred at room temperature for 3.75 days and It was then filtered through celite. K was washed with fresh methylene chloride. The methylene chloride portions were combined and the methylene chloride was evaporated at room temperature under reduced pressure. The product was separated by chromatography on silica, ethyl acetate. Eluate. The obtained N-desmethyl-N-methylspinyl spinosin J (360 mg, 36¾ yield) is a white solid, EIMS, ro / e (relative strength) 732 (M +, 40), 715 (100), 175 (20), 101 (25) 〇 Example No. 1-N-benzyl in the W-Nosin A 痗 ih Han reaction was carried out as described in Example C5, M Spinoxin A (100 mg, 0,14 mmol) and benzyl bromide as starting materials, and refluxed for 6 days. The obtained benzyl spinosin A bromide (86.6 mg, 69¾ yield.) Was a white off solid, FDMS, m / e (relative strength) 976 (10), 822 (Mf, 100), 189 ( 60), 142 (100).

窨 Detailed examples of demethyl- (dimethyl-prevent) -4 ”-azacyclopropene S. Caoxin A ________- 145 -_ This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions on the back before filling out this page) Order% 487559 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (143) Acetonitrile in Spinozin C (205.2 mg, 0.29 mmol) (2 ml) solution, monochloroacetaldehyde (39,1 mg, 0.62 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. Reverse-phase HPLC (M4 «Ethyl, 44¾ methanol and 12¾ (0.5¾ ammonium acetate solution) Dissolution) showed that the reaction was incomplete. The mixture was then diluted with sodium bicarbonate solution and sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane part was washed with brine, dried with potassium carbonate and evaporated at room temperature under reduced pressure. It is a colorless glass (199 mg). The product was separated on a C18 column by preparative HPLC. M ethyl acetate · methanol: 0.1¾ ammonium acetate (35:35:30 to 45:45:10 90 minutes linear Gradient elution). The obtained 4 ”-desmethyl- (dimethylamine) -4” _azacyclopropenyl spinoxin A (30 mg , 1 «yield), as a white solid, EIMS, m / e (relative strength) 729 (M '100). 啻 Example C12-4" -desmethyldimethylprene) -4 "-argon Panaxine A in benzene (10 ml) solution of N-oxyspinoxin A (203.8 mg, 0.27 mniol), and acetic anhydride (500 ml) was added. The reaction mixture was stirred at room temperature for 5 days. The mixture was then stirred at Evaporate at room temperature and under reduced pressure. The residue (after standing at room temperature for 6 days) was separated by chromatography on silica with K and M 2. 5¾ methanol in dichloromethane. The resulting a) 4 ”- Demethyldimethylamine) -4 ”-oxyspinoxin A (59.9 mg, 32¾ yield), a restless, colorless glass, FDMS, m / e (relative strength) 704 (MH, 10) , 592 (90), 190 (95), 101 (100), and compound b) N-acetylspinoloxin B (69.2 mg, 34¾ yield), which is a colorless glass. 例 _Example (: 14 -) ^-^-Methylamine, methylamine, and some) Caoxoxin 8 Spinoxin B compound (200 mg, 0.278 mmol) and methyl isocyanate ____- 146-_- This paper is applicable to China National Standard (CNS) A4 Specification (2 丨 〇 &lt; 297 mm) (Please read the precautions on the back before filling in this page)

487559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (144) Esters (0.30 g, 5,26 mmol) were combined in 10 ml of toluene and the mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ether / water and the layers were separated. The extracted aqueous layer was extracted with 3 × 25 ml of ether and the ether extracts were combined. The ether extract was washed with 5 ml of a saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica column (230-400 in, dichloromethane: methanol, 95: 5, v / v) under moderate pressure to obtain N- (N'-methylaminomethylmethyl). Spinozin B (0.14 g, elemental fraction

Analysis: Estimated value C, 65.09; Η, 8.31; N 3.31; Actual value C, 64.80; Η, 8.31; Η, 3.34; FAB MS (m / z) 775 (M + 1) 〇 Example of cell Cl 5-N -Methocarbinol B, Spinoxin B (200 mg, 0.279 mmol) was dissolved in 5rol dichloromethane, and methanesulfonyl chloride (0.11 0.96 mmol) and diisopropylethyl were added. Amine (0.13 g, 1.00 mmol). Stir at room temperature for 2 hours, then pour 10 ml of ether and water each. The layers were generated and the aqueous layer was extracted with M2 X 10 ml water. The ether extracts were combined, washed with 10 ml of a saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed in a silica column (230-400 m, dichloromethane: methanol, 95: 5, v / v) under moderate pressure to obtain compound N-methanesulfonylspinoxin B (0.14 g). Element analysis of SOcCuHssNOhS, 63: estimated value C, 61.86; Η, 8.23 i_N 1.76; actual value C, 61 · 73; Η, 7.83; Ν, 1.65.

Example C16-NZ Chlorinyl R in chlorocarbonyl group Spinoloxin B compound (214 mg, 0.298 mmol) was dissolved in 5 ml of dichloromethane and ethyl chloroformate (0.15 g, 0.14 mmol) was added with diiso Propylethylamine (0.12 g, 0.93 mmol). Stir the reactants at room temperature -147-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 male f) (Please read the precautions on the back before filling this page)

Printed by 1T Central Laboratories of Ministry of Economic Affairs and Consumer Cooperatives 487559 A7 B7 V. Description of Invention

Stir for 2 hours. The reaction was poured into 10 ml of water / 10 ml of ether and the layers were separated. The aqueous layer was extracted with M2 X 10 ml ether. The ether extracts were combined and washed with 10 ml of saturated sodium bicarbonate followed by M 10 in 1 brine. The ether solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography on a medium pressure silica column (230-400 in, dichloromethane: methanol, 95: 5, v / v) to obtain N-ethoxycarbonyl spinosyn B (0.19 g, 80¾ ). Elemental analysis of C43Hb7N012 · Estimated value C, 65 · 38; Η, 8.55; Ν 1.77; actual value C, 64,80; Η, 8.53; Ν, 1.24; FAB MS (m / z) 790 ( M + l) 〇 Rich bottle example C17-N-trifluoromethyl histanosin B. Spinoxin B compound (118.9 mg, 0.165 mmol) was dissolved in 5 ml dichloromethane and diisopropylethyl was added. Amine (0.10 g, 0.77 mmol) and trifluoroacetic anhydride (0.10 g, 0.48 mmol). The reaction was stirred at room temperature for 20 hours. The reaction was poured into an ether / saturated sodium carbonate solution and the layers were separated. The aqueous layer was extracted with M2X 10 ml ether. The ether extract and the K30 ml 1 saline solution were combined to wash the extract, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chromatography K on a medium pressure silica column (230-400 ro, dichloromethane / hexane, 40:60, v / v) yielded the compound N-trifluoromethylacetamido binoxin 8. 〇42 ^ 2 Sichuan 11 "3 element analysis: estimated value C, 61 · 97; H, 7.52; Ν 1.31; actual value C, (30.88; Η, 7.60; Ν, 1.46; FAB MS ( m / z) 813 (M + 1).

Cell Example C18-N-Pyridoxine W-Nosin B Add the Spinoxin B compound (107.3 mg, 0.150 Γπιοί) to 10.0 ml of ethyl formate and heat the mixture to reflux temperature. After 1 hour at reflux temperature, cool the reactants to room temperature and remove the solvent under reduced pressure. The paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X2 () 7 male chelate) (Please read the precautions on the back first) (Fill in this page again)

487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (146)

. Chromatography on a medium pressure silica column (230-400 μm, dichloromethane / methanol 9 5: 5, v / v) to obtain the compound dimethoxenyl spinosin B; 103.1 mg, 92,3%. 〇41 ^: ^ 〇11 Elemental analysis: estimated value C, 66.02; H, 8.51; Ν 1.88; actual value C, 64.67; Η, 8.75; Ν, 2.03; FAB MS (m / z) 745 (M + l). Example: CIQ-N-flg methyl formamidine Shenuoxin C. Silver cyanate (3.7 g, 24 mmol) was suspended in 10 ml of benzene and silicon tetrachloride (1 g , 5.8 ιηπιο 1). The reaction changed color immediately, from light gray to dark purple suspension. The reaction was heated to reflux temperature for 1 hour, cooled to room temperature and any solids were filtered off. The filtrate was concentrated under reduced pressure to obtain silicon tetracyanate as a colorless oil. Dissolve all silicon tetracyanate in 10 ml of benzene and add a solution of the compound Spinozin C (93 mg, 0.132 ππποί) in 2 ml of benzene. The resulting solution was heated to reflux temperature for 30 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. 20 in 190¾ isopropanol / water was added to the residue and the reaction was heated to reflux temperature for 30 minutes. Cool to room temperature and concentrate under reduced pressure. The residue was suspended in dichloromethane and filtered to remove solids. The residue was chromatographed on a gravity silica column (230-400 m, dichloromethane / methanol 95: 5, v / v) to obtain the compound aminoformyl spinoxin C (28.2 mg, 28.6¾). ) Hs2N2〇ii elemental analysis: estimated value c, 64 · 32; Η, 8.37; N 3.75; actual value C, 64.04; Η, 8.12; Ν, 4.04; FAB MS (m / z) 746 (Ml ). Example: C20-N-Sanqi Shenjiji Dissolve Spinoxin B compound (136 mg, 0.189 mmol) in 5 ml of dichloromethane and add diisopropylethylamine (0.10 g, ( K77 ramol) -149-This paper size is applicable to China National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7 V. Description of the invention (147) and trifluoromethanesulfonic anhydride (0.10 g, 0.35 ππηοΐ). The reaction was stirred at room temperature for 1 hour. The reaction was poured into a 20 ml each of ether / saturated sodium carbonate solution. The layers were separated and the aqueous layer was extracted with M 2 X 10 in 1 ether. The ether extract and the K 25 m 1 saline solution were combined to wash the extract, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chromatography K on a medium pressure silica column (230-400 m, dichloromethane / hexane, 50:50, v / v) yielded the compound N-trifluoromethanesulfonyl-spinoxin 8. 〇41 心 2_12 $ "3 element analysis: estimated value (:, 57 · 94; Η, 7.35; N 1.65; actual value C, 58.07; H, 7.52; 1.70; FAB MS (ιη / ζ) 849 (Μ + 1). Example C2 Buenosae A (E) -propane-1 &quot; M: Greek casein: T-ammonium. And W. nosin B methyl (Z) -acrylic acid in ethyl f 3W-ammonium salt Spinoxin A compound (0.68 g, 0.929 mmol) was dissolved in dichloromethane (3 ml) and water (50 ml) was added. The mixture was stirred at 0¾ and a portion of ethyl propionate (Aldrich, 2.20 g, 22.4 mmol). Remove the cooling bath and stir the reaction mixture for 30 minutes, then sonicate it (at a 50 W Fishers ultrasonic washer) for 12 minutes. After that, add dioxane (400 m 1 ) And the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 m, 80 g / THF, followed by methanol, followed by 15¾ water in methanol). The pure solution obtained by chromatography Fractions can be obtained a) ethyl [Spinoxin B N-2W-methyl U) -acrylic acid] -3 &quot;, ammonium salts (296 mg, 38! U: IR v 1720, 1635, 1645 and 1610 cnr1; 4-NMR (CDCla) d 7.35 (1H, bs), 6 * 70 (1H, bs), 2,60 (3H, CH3, bs), 1.9 5 (3H, CH3, s) ppiu; and compound b) Spinozin-150-This paper size is applicable to China National Standard (CNS) A4 (2i0X 297 mm) (Please read the notes on the back first (Fill in this page again)

-I-Repeated---I set the impression of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _ B7___ V. Description of the invention (148) A N-[(E) -propyl-Γ〃-enoic acid] _3 &quot; '-$ Ann salt (316 mg, 42%): IR η 1720, 1655, ΙΘΟδοιπ · 1 ^ H-NMRiCDCla) d 7.04 (1H, d: 17 Hz), 6.72 (1H, bs), 6.47 (1H, d: 17 Hz ), 3.35 (3H, CH3, bs), 3.28 (3H, CH3, bs) ppm. Example C22- »Phenoxin B N_ (2W-methyl- (Z) _prop-Γ &quot; -enoic acid on m. Spinoxin B compound (192 mg, 0.267 nunol) was dissolved in dry dichloromethane (25 ml). A portion of methyl propionate (Aldrich 1.80 s, 21.4 1) was added. The reaction mixture was stirred at room temperature under nitrogen for 5 hours. The solvent and excess ethyl propionate were removed under reduced pressure. The residue The product was purified on a flashed silica gel column (230-400 m, 50 g / THF). The pure eluate was used to obtain Spinoxin B methyl- (Z) -propyl-Γ &quot; -enoic acid) -3 ... -S purpose (205 mg, 95¾) ^ H-HMRCCDCla) d 7.38 (1H, d: 12.8Hz), 6.70 (1H, bs), 4.50 (1H, d: 12.8 Hz) ppm.

Example of tube [23-N- (氤 a) methyl Φ 窨 oxinol B] Spinoxin B compound (263 mg, 0.370 mmol) was dissolved in dry dichloromethane (7 ml). The solution was stirred at room temperature under nitrogen. Triethylamine (1.0 ml) was added, followed by bromoacetonitrile (1.2 ml, excess). The reaction mixture was stirred at room temperature for 3 days. Ethyl acetate (50 ml) and PhH (50 ml) were added, and the solution was washed successively with M water (3 x) and 5¾ sodium bicarbonate (2 x). The organic layer was dried over anhydrous potassium carbonate and concentrated under reduced pressure. The residue was then dried at 0.005 Torr for 3 hours to obtain the compound (cyano) methyl spinosin B (260 mg, 9 «): 13OHMR (CDCl3) d 117.8 (CN) and 43.8 (N-CH2- CN) ppm 0 -151-The standard of this paper is applicable to China National Standards (CNS) Λ · 4 specifications (: M〇x 297 mm)

In ϋ ^ ϋ — ^ ϋ · — t --y .1 Hall (J- .1 *,.! Λ:-·· 1111 n (Please read the precautions on the back before filling this page)

1T ψ 487559 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (149)

Key Example Π24-4 "-N-Ethylinosinoxine B Alkylation Step A: Stir a solution of Spinoxin B compound (0.50 g, 0.70 mmol) in DMF (1.5 ml), and place the solution in Sequential M iodoacetam (0.11 m 1, 0.21 g, 1.4 mm ο 1) and (i-P r) 2 NE t (0.36 mL, 0, 27 g, 2.1 mmol) in sequence under nitrogen Treatment. After 20 hours, the mixture M ca.linL in 1M sodium thiosulfate solution treated K to decompose any residual iodine. The resulting mixture was partitioned between ether and saturated brine. The organic layer was washed with brine, dried over magnesium sulfate, and filtered And concentrated under reduced pressure to yield 0.61 g. The residue was purified by MPLC (silica, 5:95 methanol / ethyl acetate) to obtain 0.47 g of (9 (U) 4 ”-N-ethylspinoxin B White powder. Analytical estimate of C42Hb7N010: C, 67.62; Η, 9.05; 1.88. Actual: C, 67.11; Η, 9.73; Ν, 1.92 and C, 67 · 17; Η, 9.54 ; Ν, 1.98 ...

Real bottle example C.P.) Intermediate Nosin B was prepared according to the alkylation step A of Example 24 using Spinoxin B (0.50 g, 0.70 ιαιαοί), DMF (1.5 mL), 1 -Iodopropane (0.14 mL, 0.24 g, 1.4 mmol), and (i-Pr) 2NEt (0.36 ml, 0.27 s, 2.1 mmol). Purified by MPLC (silica, 2:98 methanol / ethyl acetate) to obtain 0.41 g (77%) of 4 "-N- (1-propyl) spinoxin B as a white powder. C43HSsNO1Q Analyzed estimated value: C, 67,96; Η, 9,15; Ν, 1.84. Actual value: C, 68 · 06; Η, 9.25; Ν, 1.97 〇 Real-fe case (] 2β ~ 4 ”-Ν ~~ (2-Methyl-propyl) Shenke Nuoxing B The compound was prepared according to the alkylation step A of Example 24, and the history of its use --- -152-This paper is in accordance with the Chinese National Standard (CNS) Λ4 specification (210X297 mm)

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、 1T 487559 A7 B7 V. Description of the invention (150) Binoxin B (0.95 g, 1.3 mmol), DMF (2.8 mL), 1 ~ Iodine-2-methylpropane (0.32 iuL, 0.51 g, 2 8 mmol), and (i-Pr) 2NEt (0.73 ml, 0.54 g, 4.2 mmol). Purified by MPLC (silica, 50:50 methanol / ethyl acetate) to obtain 0.07 g (7¾) of 4 "-N-Π-propyl) Spinoxin B as a white powder. C 4 4 Η 7 Analyzed estimated value of i NO i (]: C, 68.28; Η, 9.25; N, 1.81. Actual value: C, 68.33; Η, 9.26; Η, 1.88.

For example, [27-4 "-N- (2-methyl-propanyl-boxy) was prepared in accordance with Example 24. The compound was prepared according to the alkylation step A described in Example 24 using Spinoxin B (0.95 g, 1.3 mraol), DMF (2.8 mL), cyclopropane methyl bromide (0.27 mL, 0.38 g, 2.8 raraol), sodium iodide (0.05 g, 0.3 mmol), and (i-Pr ) 2NEt (0.73 ml, 0.54 g, 4.2 mmol). Purified by MPLC (silica, 2:98 methanol / ethyl acetate) M to obtain 0.3 g (33%) of 4 "-N- (2-formaldehyde) (Propyl-prop-1-yl) spinosyn B, a white powder. CuHhNOh analytical estimates: C, 68.45; Η, 9.01; Ν, 1.81. Actual values: C, 68 · 36; Η, 9.22; N, 1.76.

Example C28 ~ N- (N '-(1. 1 -DimethylZargonylcarbonyl) glycinamido) Shi Nuoxin R Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the Note: Please fill in this page again) Peptide coupling step A: Boc-Gly-〇H (0 ♦ 16g, 0.91 ππηοΐ) and B0P-C1 (0.23 g, 0.90 mmol) which are stirred at -15 ° C The solution of chloroform (7 ml) was treated with N-methylformmorpholine (0.12 ml, 0.11 s, 1.1 mia〇Π) under a nitrogen atmosphere. After 1.5 hours, the mixture was sequentially treated with Spinosin B (0.550 s, 0.70 mmol) and N-methylformmorpholine (0.12 ml, 0.11 g, 11.1 mmol) were treated. The temperature was maintained at -15 ° C for 4 hours, and then the substance was removed gradually. The paper scale is applicable to the Chinese National Standard (CMS) A4 specification (210X297 public holiday) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Invention Description (151)

Gradually warm to room temperature for 10 hours. The mixture was evaporated under reduced pressure, and the residue M was purified by MPLC (silica, 50:50 to 100: 0 ethyl acetate / hexane) to provide 0.61 g (99¾) of N- (N ′-(1, 1-Dimethylethoxycarbonyl) Glycinamido) Spinoxin is a white powder. Ah 4 71] 74 丨 12〇13 Analytical estimates: C, 64.51; Η, 8.52; Η, 3,20. Actual values: C, 63.76; Η, 8.62; Ν, 3.29, and C, 63.78; Η, 8.60; N, 3.43.窨 Example (N ′-Π. 1 -Dimethylethylargonylcarbonyl)-3 -propylamine fluorenyl) oxoxine B This compound is a compound prepared according to the hydrazine coupling moiety described in Example 28, wherein Use a solution of ^ (:-/ 3 413-(^ (0.178, 0.9〇111111〇1) and 8 (^-Cl (0,23 g, (K90 mmol) in dichloromethane (7ml) under a nitrogen atmosphere with N -Methylformmorpholine (2X0.12 ml, 0.22g, 2.2 mmol) and Spinoxin B (0.50 g, 0.70 mmol). By MPLC (silica, 70:30 to 100: 0 ethyl acetate / Hexane) purification residue M provided 0.62 g (99¾) of N- (N '-(1,1-dimethylethoxycarbonylpropylamidinyl) spinosin B as a white powder. Analysis of C4BH76N203 Estimated value: C, 64 · 84; H, 8.62; N, 3.15. Actual value: C, 64 · 38; H, 8.67; N, 3.22. Rich cases C30-N- (N '-(Sg) Argonyl carbonyl X-propanyl) stilano S-β This compound is a compound prepared according to the peptide coupling portion described in Example 28, which is based on (^ 2 ^ 13-011 (0.218, 0.94 111111〇1 ) And 80 卩 -Cl (0 * 2 34g, 0.94 mmol), dichloromethane (7ml), N-methylformmorpholine (2X0.12 ml, 0.22g, 2.2 mmol), and spinosyn B (0 50 g , 0.70 mmol). By MPLC (silica, 75:25 ethyl acetate / hexane) -154-Λ-- «(Please read the precautions on the back before filling this page), \ ''卩 The paper size is applicable to China National Standard (CNS) A4 (210X 297mm)

487559 A7 B7 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (152) Purification residue M provides 0.68 g (99%) of (phenylmethoxycarbonyl) -L-propylamine fluorene Neusin B is a white powder ° CsiH / iNJu Analytical estimated value: C, 66.36; Η, 8.08; N, 3.03. Actual value: C, 2 rotamers ^ H-NMIUCDCI:]) 7 · 3-7 · 4 (M, 5Η), [5 · 06 + 5 · 10 y 5.04 (5 + 2d, J = 12.23 y 12.3 , Σ = 2H], 2,87 y 2.76 (25, Σ = 3Η).

Example C3: N- (N '. N * -dimethylglycine donkey. Gaspinoxin B. This compound was prepared according to the peptide coupling moiety described in Example 28, where H (Me2) was used. Gly-0H (0,09 g, 0.9 ππποί) and Chuan Cl (0.254g, 0.98 mmol), dichloromethane (7ml), N-methylformoline (2X0.12 ml, 0.22g, 2.2 mmol ) And Spinozin B (0.50 g, 0.70 mmo 1) 0 The residue was purified by MPLC (silica, 5:95 methanol / dichloromethane) to provide 0.23 g (41¾) of dimethylglycine醯 Base Spinozin B, a white powder. Analytical estimated value: C, 65.8UH, 8.79; N, 3, 49. Actual value: C, M + H + Estimated value 803.5 Actual value 803.6.

Example I C32-N- (Nf-methylsothioaminomethylamido) Spinoxin B Spinoxin B (203 mg, 0.28 mmol) was dissolved in 10 ml of toluene and methyl isopropyl was added Nitrate (100 mg, 1.36 mmol), and the solution was stirred for 1 hour. After the reaction gradually proceeded, the crude mixture was chromatographed on silica gel (1: 1, ethyl acetate / hexane) to provide N- (r-methylthioaminomethylmethyl) spinosin B (0, 14 g, 64%), as a white solid, MS m / z 791.)-L-propylaminomethyl) Spinoxin 8 as a white powder. 〇421 ^ 6 «2〇1. Analytical estimates of $: 0, 63.77; Η, 8.41; N, 3.54. Actual value ·· (:, 63.57, Η, 8.42 -155-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) η--W-^^ clothing-(Please read the (Please note this page and fill in this page again)-Yikou 487559 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (153) N, 3.63 〇

Serotonin cm (N '· N dimethylformyl) Spinoloxacin C Spinoxin C (102 mg, 0.14 mmol) dissolved in dimethylformamide dimethyl acetal (5 ml ) And the solution was heated to reflux temperature for 30 minutes. The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (95: 5 rolol / ethyl acetate) to provide N- (H ', N'-dimethylmethylimidyl) spinosin B (56 · 2 rog , 5150, as a yellow-brown solid: FDMS m / z 758.

Example C34-N- (N'N'-dimethylaminoformamidine) in oxoxine B

Spinozin B (0.10 g, 0.14 mmol) was dissolved in dimethylaminomethylamidinyl chloride (0.1 g, 0.93 nnuol), and N, N-diisopropylethylamine (0.10 g , 0.77 mole) was dissolved in dichloromethane (10 ml) and stirred for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (95: 5 ethyl acetate / methanol). Available as N- (hT, N'-dimethylaminomethylamido) binoxine B (76.8 mg, 70¾) as a white solid: FDMS π / ζ 788. Casein C35-N-Zepinyl Spinoxin B (98 mg, 0.14 mmol) was dissolved in dichloromethane (5 nil) and N, N-diisopropylethylamine ( 26 mg, 0.2 ππηοΐ) and octyl chloro chloride (30 0.18 ππηοΐ) were added and the reaction was stirred for 20 hours. After the reaction was gradually completed, the residue was purified by chromatography on silica gel (95: 5 methanol / ethyl acetate) to provide N-octyl spinoxin B (61.9 mg, 53 · 8! 〇: FDMS m / 2 8 4 4 · C 4 β Η 7 7 Ν 0 1 1: C, 6 8. 2 9; Η, 9 ♦ 19; Ν, 1.6 5. Actual value: C, 68.03; Η, 9.29; Ν, 1.84.啻 敝 Gangya S Shangji Zhongnuo Xinxin __Β This paper size applies Chinese National Standards (CNS) Λ4 specifications (21GX 297 mm) (Please read the notes on the back first and fill out this page) Fee · 059 059 Economy Printed by A7 B7, Consumer Cooperatives of the Ministry of Standards, Ministry of Standards 5. Description of the invention (154) Spinoxin B (1.01 mg, 1.40 mmol) was suspended in water (10 ml) and cooled to 0 ° C in an ice bath. To this cold suspension was added 1N H 'C 1 (10 m 1) and the reaction was stirred until all the solids were dissolved. (Caution ... A little heating is necessary, and M will dissolve all solids). Cool the solution down to 0 ° C and add sodium nitrate (500 mg, 7.2 nunol) and stir the reaction at 0 ° C. During the reaction, a white precipitate formed during the reaction. After 2 hours, additional nitrous acid was added (500 mg, 7.2 πιπιοΓ) and stir the reaction for an additional hour. The solid was collected by vacuum filtration and washed with cold water (2X). The solid was air-dried to obtain N-nitroso spinosinoxin B (1.00 g, 95¾), as a white solid: FDMS m / z 748. Estimated value for analysis: C, 64 · 32; Η, 8.37; Ν, 3.75. Actual value: C, 64 · 52; Η, 8.26; Ν, 3.45 Life-enriching example C37-N-Sg Mesocene Sinopinoxin B The compound was prepared according to the method described in Example C78, using Spinoxin B (109 mg, 0.152 mmol), Ν, Ν-diisopropyl di Ethylamine (0.1 g, 0.8 mmol) and benzyl chloride (26.3 mg, 0.15 mmol). N-benzylidene spinosyn B (78.6 mg, 60.5¾) was obtained as a white solid: FDMS m / z 857 〇

Cellar Example C38-N-Subcage Dikenoxin C Compound Spinoxin C (106 mg, 0.15 mmol), benzaldehyde (0.1 g, 0.9 mmol), and camphorsulfonic acid ( 5 mg) was dissolved in benzene (15 ml) and the reaction was heated to reflux temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate / hexane gradient 20:80 to 40:60) to provide N-benzylidene spinosin C (65.5 rag, 55.0%) as a white solid: FDMS ηη / ζ 746,791. ______; _- 157 -_ This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2i0X 297 mm) ---- r--y ---- (Please read the notes on the back before filling in this Page) 487 559559 A7 B7 V. Description of the invention (155) Cell example C39-N, N-diethyl, a certain nuocoxine Γ Compounds were prepared according to the method described in Example C78, using Spinoxin C (102 mg, 0.144 mmol), Ν, Ν-diisopropyldiethylamine (0.1 g, 0.8 mmol), and ethylammonium chloride (0.1, 1 mmol). N, M-diethyl donkey base Spinoxin C was obtained as a white solid: FDMS m / z 787. Analyze the estimated value of CuHbs ^ 〇12: (:, 65.54; 夂 8.31. Actual value: (:, 64.64; 1 8.08.) _ Example C40-N. N-two 7, 醯 in the base to taste Nuoxin ：: according to the implementation The compound described in Example C79 was prepared using spinoxin C (81 mg, 0.11 mmol) and methyl isocyanate (0.5 g, 0.9 mmol). Compound N, N-diethylspinyl Octyl C (61.8 mg, 71.0¾) as a white solid: FDMS m / z 760. Estimated value of C41Hb4N2Oh: C, 64.71; Η, 8.48; N 3.68. Actual: C, 64 · 48; Η , 8,70; Ν 3,59. Example C41-4 "-Demethyl- (dimethylamino) -4"-(N- (Sulmonium- (2-hydroxy.3. 5-di- t_cobenzylidene) iminosufunoxine desmethyldimethylamidoamine) -4 "-hydroxy.5-di-t-coke cage 荜) imine 客 kenoxin A compound Spinozin C (0.55g, 0.78ππηο1) was dissolved in methanol / tetrahydrofuran (6: 1) and added with 1,3-di-t-butyl-1,2-benzoquinone (228 mg, 1.03 ramol) and The reaction was stirred for 24 hours. During this reaction, the reaction changed from dark red to pale yellow-green. The solvent was removed by a rotary evaporator and the solvent was removed by silica gel (ethyl acetate / hexane, 1: 1). A crude green solid was isolated and purified to provide compound 4 "-desmethyl- (dimethylamino) 4"-(N- (E)-(2-diameter group, -158-____ ---- a --- ---- 0 II (Please read the notes on the back before filling this page) Order the paper size printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to apply the Chinese National Standard (CNS) A4 (210X 297 mm) ^ 7559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (156) 3,5-Di-Bocylphenyl) Imino Spinosin A (228 mg, 32.2%): Part 1H- NMR d 6.78 (bs, 1Η), 6.65 (s, 1Η), 6.62 (s, 1H), 5.88 (dt, 1H), 5.80 (dt, 1H), 4.86 (s, 1H), 4.67 ( m, 1H), 4,63 (d, 1H), 4.32 (q, 1H), 4.15 (bs, 1H), 3.70-3 · 62 (m, 2H); and 4 ”-desmethyl -(Dimethylamino) -4 &quot;-( N- (Z)-(2-hydroxy, 3,5-di-t-cophenylphenyl) imino spinosin A (343 mg, 48 · 51): Partial 1H-NMR δ 6.78 (bs, 1H), 6.74 (s, 1H), 6.63 (s, 1H), 5.88 (dd, 1Η), 5.δ1 (dt, 1H), 4.86 (s, 1H), 4.69 (m, 1H), 4.63 (d, 1H), 4.32 (q, 1H), 3.68 (m, 1H).例 Example C42-4 &quot; -Demethyl- (dimethylamino) -4 "-Chlorinozepine A The compound 4" -desmethyl- (dimethylamino) -4 " -[N- (E)-(2-hydroxy, 3,5-di-t-butylphenyl) imino spinosin A (204 mg, 0.225 mole) suspended in methanol / tetrahydrofuran Λκ, 6: 1 : 1 (8 roL), and the compound was dissolved by adding tetrahydrofuran (6 mL). To this solution was added oxalic acid dihydrate (60 mg, 0.47 ππηοΐ) and the reaction was stirred for 20 hours, followed by heating at 50-60 ° C for 4 hours. After the gradual reaction was completed, the residue was purified by cyclotron chromatography on silica gel (ethyl acetate / hexane, 1: 1) to provide compound 4 "-desmethyl- (dimethylamino) -4" -Spinoxin 6 (43.2 11 ^, 27.3%) as a white solid: part 1 [11 (^ 56.75 (bs, 1Η), 5.86 (dd, 1Η), 5.77 (dt, 1Η), 4.96 (dd, 1H), 4.82 (s, 1H), 4.65 (m, 1H), 4.29 (q, 1H), 4.00 (q, 1H), 3.70 (m, 1H). Example [ 43- -4 ”-desmethyl- (dimethylformate Sg) -4”-锊 基斯宾 ________- 159 -__ This paper size is applicable to China National Standard (CNS) A4 (21〇X 297 mm) ) —------ 4 ----- (Please read the notes on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative 487559 A7 B7 • __ 5. Description of the invention (157)

Nuozai A Compound 4 "-desmethyl- (dimethylamino) -4" -oxyspinoxin A (78 mg, 0,11 mmole) was dissolved in ether (10 niL) and placed in an ice bath Cool to 0 ° C. To this cold solution was added lithium tertiary butyl butoxide (48 mg, 0 * 19 mmol) and the reaction was stirred for 20 minutes. The reactant M was quenched with saturated sodium chloride (3 ml), the reaction was gradually performed, and the residue M was purified by cyclotron chromatography on silica gel (ethyl acetate / hexane, 1: 1) to provide compound (4 "S ) -4 "-desmethyl- (dimethylamino) -4" -hydroxyspinoxin A (46.6 mg, 59.7%, colorless glassy: part 1H-NMR δ 6.78 (bs, 1H) , 5.88 (dd, 1H), 5.81 (dt, H), 4.86 (s, 1H), 4.67 (melon, 1H), 4.50 (d, 1H), 4.32 (q, 1H), 3.66 (m, 1H ), 3.34-3.23 (m, 3H) ί 13C-NMR δ 202.81, 172.55, 147.54, 144.12, 129.33, 128.80, 103 · 14, 95.45, 82 · 27, 81 · 06, 80 · 85, 77,72, 76.68 , 76.06, 75 · 71, 71.54, 67.94, 60.94, 59.01, 57.70, 49.44, 47.60, 46 · 04, 41.52, 41 · 16, 37 · 38, 36 · 28, 34 · 32, 34 * 19, 31.42, 30.62 , 30.12, 28.39, 21.53, 8.01, 17.80, 16 · 21, 9 · 35 ·

Example of cellar C44-Normone- (Dimethylammonium 4 &quot; -Z-Chlorochlorinoxine A * The compound (4 "S) -4" -desmethyl (dimethylamino) -4 ”-hydroxyspinoxin A (10 mg, 0.14 mmol) was dissolved in dichloromethane and added with acetic anhydride (0.05 g, 0.5 mmol) and pyridine (0.1 g, 1 mmol) and the reaction was stirred for 2 hours. Gradually complete the reaction to obtain the compound (4 "S) -4" -desmethyl- (di-160 _ This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back first (Fill in this page again)

487559 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (158) Methylaminob 4 ”-acetoxyspinoxin A (5 · 7 mg, 57¾), a colorless glass ; Part 1H-NMR5 6.75 (bs, 1Η), 5.86 idd '

1H), 5.77 (dt, 1H), 4.83 (s, 1H), 4.66 (m, 1H), 4. 49 (dd, 1H), 4 • 42 (ddd, 1H, cf = ll • 0, 9.4, 4 • 7), 4.29 (q, 1H), 3.63 (m, 1H); 13C-NMR δ 147 • 64, 129 * 33, 128.77, 103 · 02, 95. 39, 82. 24, 81.01, 80.74 &gt; 77.68, 76.77, 76.01, 73.13, 72.82, 67.92 »I 60.95, 59 • 01, 57 .71, 49 .42, 47 • 58, 46. .01, 41. 48, 41 • 14, 37 .35 , 36 • 25, 34 • 27, 34 ♦ 17, 30. t 12, 30. 03, 29 • 68, 28 ♦ 39, 27, 76, 21 • 53, 21 ♦ 17, 17,, 99, 17 · 79 , 16 .13, 9. 34 〇Example C45 -N-Nordinyl-N Monomethyl Hua-Nacoxine D The compound N-desmethyl_N_methylmethyl-spinoxin I 1 · 08 g; 1.47 mmol) was dissolved in ethyl formate (25 ml) and the solution was heated at reflux temperature for 14 hours. The solvent was evaporated by a rotary evaporator and N-desmethylformyl-spinoxin D (645.6 mg, by a reverse phase HPLC (methanol / 0.1¾ aq. Hydroxide, 85:15) K 57.6%), as a white foam: Partial 'H'NMR δ 8,09 &amp; 8.06 (s, 1H), 6.77 (bs, 1H), 5.49 (bs, 1H), 4.86 (s, 1H), 4.67 ( m, 1H), 4.50 (d, 1H), 4.30 (q, 1H), 3.60 (m, 1H). Cases of Lulun (: 4 (^ 4 "-1" (2.4-diazepine) ) Amoximine Carboximide 1 Intranoxine 8 According to the method of Example C80, 2,4-difluorophenyl isocyanate (78 ml, 98 mg, 0.63 nunol) and Spinoxin B (0.30 g, (K42 mmol) to prepare the compound. MPLC (Si〇2, 50:50, EtOAc / Hexane ΪΚ obtained -161-This paper size applies to China National Standard (CNS) A4 size (2 l0x 297 mm) (Please read first (Notes on the back then fill out this page)

Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7' B7 _ 5. Description of the invention (159) 0.36 g (99%) 4 ”-N-[(2,4-difluorophenyl) aminocarbonyl] Pinoxin B, a white powder. MS (ιπ + ΗΟ expected value: 873.5 ° actual value: 873.8) Example (3.4-difluorobenzyl) aminocarbonyl] Spinoxin B according to Example C80 Method: Compounds were prepared from 3,4-difluorophenyl isocyanate (0.12 g, 0.64 mmol) and spinosyn B (0.30 g, 0.42 mmol). MPLC (SiO2, 64:40 to 100: 0, EtOAc / hexane) M to obtain 0.38 g of (99¾) 4 ”-N-[(3,4-difluorophenyl) aminocarbonyl] spinosin B, as a white powder: MS (iu + H +) Expected value: 905.4. Actual value: 905.6. 啻 Bottle example C48-4 "-N-" (4- Tian argon. ¾) amine carbonyl 1 Φ 窨 Nuoxin B According to the method of Example C80, from 4-A Compound was prepared with oxyphenyl isocyanate (81 ml, 93 mg, 0.63 mmol) and spinosyn B (0.30 g, 0.42 mmol). MPLC (SiO2, 64:40, EtOAc / hexane) Μ 0.36 g (99%) 4 "-N-[(4-methoxyphenyl) aminocarbonyl] Spinoxin B, white powder: MS U + HM expected value: 867,5. Actual value: 867.8 〇

啻 Nosin B in the detailed example (Bu Bingmou) According to the method of Example C81, bupropion (0.14 ml, 0.24 g, 1 · 4 mm ο 1), (i-P r) 2 HE t (0 · 36 m 1, 0 ♦ 2 7 g, 2 ♦ 1 mm ο 1), Spinoxin B (0.50 g, 0.70 nunol), and DMF (1.5 ml) to prepare the compound. MPLC (SiO2, 50:50, EtOAc / hexane) M to obtain 0,41 g (77¾) 4 &quot; -N- (l-propyl) spinosin B, as a white powder. Analysis of C43HhN0iq: Estimated value · C, 67,9δ; Η, 9.15; _____- 162-Chinese National Standard (CNS) Α4 specification (210X297 mm) for paper size iA &quot; (Please read the note on the back first (Fill in this page again)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559. A7 B7 V. Description of Invention (16) N, 1.84. Actual values: C, 68 · 06; Η, 9.25; N, 1,97. Example C 5 〇-4 · "-Ν--methyl-1 -propyl) stronoxin B According to the method of Example C81, 1-iodo-2-methylpropane (0,32 ml, 0.51 g, 2.8 mmol), (i_Pr) 2NEt (0.73 ml, 0.54 g, 4.2 mmol), spinosyn B (0.95 g, 1.3 mmol), and DMF (2.8 ml) Compound. MPLC (Si〇2, 50:50, EtOAc / hexane) M to obtain 0.07 g (7¾) 4 "-N- (2-methyl-propyl) spinosyn B, white powder (can also be recovered Spinozin B, 0.71 g (75%)): MS (in + HM expected: 774.5. Actual: 774.8. Analysis of CuHmNOh: estimated value: C, 68.28; Η, 9.25; Ν, 1,81. Actual value: C, 68.33; Η, 9.25; Ν, 1.88.

Example C51 f (Cyclopropyl) Methyl 1 曹 Cao Xingxing R According to the method of Example C81, (Bromomethyl) cyclopropane (0.27 ml, 0.38 g, 2.8 mmol), Nal (0.05 g, 0.3 ιιιιηηΓ), (i-Pr) 2 -NE t (0.73 m L, 0 ♦ 5 4 g, 4 ♦ 2 mmo 1), Spinozin B (0.9 5 g, 1.3 mmol), And DMF (2.8 mL) to prepare the compound. MPLC (50:50, EtOAc / hexane) K to obtain 0 * 34g (33¾) 4 ”-N-[(cyclopropyl) methyl] spinosyn B, a white powder (also spinosin) B, 0.40 g (42%) Spinozin B) Analysis of cC44Hs3N0Q: Estimated value C, 68.45; Η, 9.01; N, 1.81. Actual value: C, 68.36; Η, 9.22; N, 1 · 76.

Example C52-4 "-NZ and even -fS.fi-Nanoze R in diargon According to the method of Example C81, ethyl bromide (60 ml, 0.12 g, 0.75 mmol), (i-Pr ) 2-NEt (0.20 mL, 0'15 g, 1.1 mmol) The paper size is applicable to China National Standard (CNS) A4 specification (210. × 297 mm) I ---,-1 --- -(Please read the notes on the back before filling this page)

, 1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (161), 5,6-dihydrospinoxin 8 (0.27 light, 38 111111〇1), and 0 {^ (2 11 ^) Cooking compounds. MPLC (40:60, EtOAc / hexane) M obtained 0.22 g (79¾) 4 "-N-ethyl-5,6-dihydrospinoxin B as a white powder. Analysis of CuHhNOh: Estimated value: C , 67.44; H, 9.30; N, 1.87. Actual values: C, 67 · 52; H, 9.07; Ν, 1.78. Cases of L2 gas (2-methyl-propyl) Β According to the method of Example C81, diiodo-2-methylpropane (0 · 10 ml, 0.16 g, 0.8 7 mm ο 1), (i-P r) 2-NE t (0.2 3 in L , 0 ♦ 17 g, 1.3 1 «〇1), 5,6-dihydrospinoxin 8 (0.318, 0.43 111111〇1), and DMF (2 roL) cooking compounds. MPLC (Si〇2, 40 : 60, EtOAc / hexane) M to obtain 0.16 g (48¾) 5,6-dihydro-4 "-N- (2-methyl-butylpropyl) spinosin B as a white powder. Analysis of C44H73R〇1Q: Estimate: C, 68.10; H, 9.48; N, 1.80. Actual values: C, 68.10; H, 9.37; N, 1.87. Cell Example C! U-4 &quot; -N- (2-Fluoro 7 "yl) Spinoxin B According to the method of Example C81, Br--2-gasethane (0.10 nil, 0.17 g, 0 · 3 mmol), Nal (0.04 g, (K67 mmol), (i-Pr) 2NEt (0.36 rarool, 0.27 g, 2.1 mmol), spinosyn B (0.48 g, 0.67 fflinol), and DMF (2 raL) to prepare the compound. MPLC (30:70 to 40:60, EtOAc / hexane) K yielded 0.30 g (5M) of 4Ί (2-fluoroethyl) spinoxin B as a white powder. C ^ H ^ NOh analysis: Estimated values: C, 66.03; H, 8.71; N, 1.83. Actual values: C, 65 · 89; Η, 9.11; Ν, 1.92. Rich bottle example m4 ”-N- (2.2, 2-Trifluoroethyl) Spinoxin B _ 164 A paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210.X 297 mm) ----.-- ϊ ----- ( (Please read the notes on the back before filling out this page)

、 1T 487559 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (162) According to the method of Example C81, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.34 g, 1.5 mmol), (i-Pr) 2NEt (0.36 mmol, 0.27 g, 2.1 roraol), spinosyn B (0.38 g, 0.53 mraol), and DMF (2 mL). MPLC (30:70, EtOAc / hexane) to obtain 0.32 g (76¾) 4 "-H- (2,2,2-trifluoroethyl) spinosin B as a white powder. C42Hb4N〇1d Analysis: Estimated value: C, 63.06; Η, 8.06, · Ν, 1.75. Actual value: C, 62.78; Η, 7.97; Ν, 1.66. Example "! ^-4" -1 "2- ( ^ '. 丨 1'_Dimethyamino group) Zomoxin 1 in Yimou 1 ^ According to the method of Example C81, Me2 (CH2) 2Cl · HC1 (0.30 g, 2 ♦ 1 ra m ο 1), (Bu P t) 2 NE t (0 · 50 m L, 0 · 3 7 g, 2 · 9 mm ο 1), Spinozin B (0.50 g, 0.70 mmol), and DMF (2 mL) Compound. MPLC (20:80, Me0H / CH2Cl2) M to obtain 0,04g (7¾) 4 ”-N- [2- (N, H′-dimethylamino) ethyl] spinoxin B, as White powder (0.44 g (88%) Spinoxin B can also be recovered). MS (m + FT) expected: 789.5. Actual value: 789.8.

According to the method of Example C81, Fenxiong Example "57-4"-(2-propyl) was prepared from 2-iodopropane (0.11 ml, 0.19g, 1 ♦ 1 m ra ο 1), (i -P t) 2 NE t (0 ♦ 3 0 m L, 0 · 2 2 g, 1 ♦ 7 in m ο 1), Spinozin B (0.40 g, 0.56 nunol), and DMF (2 mL ) Preparation of compounds. MPLC (Si〇2, 50:50, EtOAc / hexane) M to obtain 0.09 g (21¾) 4 "-N- (2-propyl) spinosyn B, white powder: MS (m + H +) Expected value: 760.5. Actual value: 760,6. Analysis of CuHhNOh: Estimated value: C, 67.96; H, 9,15; N, 1.34. Actual value: C, 68.04; Η, 9.32; Ν, 1.85 . -165-1 This paper size applies to China National Standard (CNS) Α4 size (21QX297 mm) (Please read the precautions on the back before filling this page)

1T ^ 7559 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (163)

Rich Nosin B in Example C58-4 "-N- (l-Butyl) According to the method of Example C81, 1-iodobutane (0.13 ml, 0.2U, 1.1 mmol), (i- Pr) 2NEt (0.30 mL, 0.22 g, 1.7 mmol), Spinoxin B (0.40 g, 0.56 mmol) and DMF (2 oil) were used to prepare the compounds. MPLC (Si〇2, 50:50 EtOAc / hexane) K to obtain 0.41 g (95¾) butyl) Spinoloxine B as a white powder. MS (π + Η〃) expected: 774.5. Actual: 774.7. Fen example C59-4 "U ”-N- (butyl-1. 4-diyl) Φ Caoxin B iodide salt According to the method of Example C81, 1,4-diiodobutane (0.11 ml, 0.26 g, 0.83 mmol) was obtained. ^ (I -Pr) 2NEt (0.30 raL, 0.22 g, 1 * 7 mmol), spinosyn B (0.30 g, 0.42 mmol) and DMF (1 ml) to prepare the compound. MPLC (Si〇2, 25: 75 methanol / di Chloromethane) M obtained 0.18 g (47¾) 4 ”_ ^, 4” -11- (butyl-1,4-diyl) spinosin 8 iodized salt, which is a yellow-yellow powder. Rich example MO-nd -(Penta-1 · 2-diyl) sinozoline RM salt According to the method of Example C81, 1,5-diiodobutane (0.12 ml, 0.26 g, 0.81 mmol) ^ (i-Pr) 2 HE t (0.30 inL, 0.22 g, 1.7 mmol), Spinozin B (0.30 g, 0.42 mmol ) And DMF (1 ml) to prepare the compound. MPLC (Si〇2, 25:75 methanol / dichloromethane) to obtain 0 · 10 g (26¾) 4 "^, 4" called-(penta-1,2-di Base) Spinozin 8 iodized salt, as a yellow-brown powder. Examples of nfib d. 4 'Ί (_ Ding :: L4-diyl) in the Nuozai according to the method of Example C81, from 1, 4-Diiodobutane (0.22 ml, 0.52 g, 1.7 mmol) ^ U-P r) a NE t (0.44 inL, 0.33 g, 2.5 -166-This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X 297 mm) I --- *-S ----- (Please read the notes on the back before filling this page) Order 487559 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explain (164) mmol), Spinozin C (0.60 g, 0.57 mmol), and DMF (4 ml) for cooking compounds. MPLC (Si02, 5:95 methanol / dichloromethane) M obtained 0.10 g (23%) 4 "^, 4"-[Bu (Ding-1,4-diyl) Spinozin ( : White powder. MS U + HM Expected: 758.5. Actual: 758.6.

Rich Example Γ: 62-4 ”-N. 4” _N_ (pent.budiyl) Spinoxin C According to the method of Example C81, 1,5-diiodopentane (0.25 ml, 0 * 54 g, 1.7 mmol) Λ (i-Pr) 2NEt (0.44 mL, 0.33 g, 2.5 mmol), Spinoxin C (0.60 g, 0.57 mmol) and DMF (4 ml) were used to prepare the compound. MPLC (Si〇2, 50:50 ethyl acetate / hexane) K obtains 0.31 8 (70%) 4 "_ 夂 4" called-(penta-1,4-diyl) spinosinol (:, is White powder. MS (m + HM expected value: 772.5. Actual value: 772.7.) Ife example (^ 3-4 "called .4" -1 2 71-base nuoxin (according to the method of Example C81, Made from iodoethane (0.23 ml, 0.45 g, 2.9 mmol), (i_Pr) 2NEt (0,60 mL, 0.45 g, 3.4 mmol), spinosin C (0.40 g, 0.57 mmol) and DMF (2 ml) cooking compound. MPLC (SiO 2, 50: 50 ethyl acetate / hexane) K to obtain 0.38 g (88%) 4 ”1,4”-^-diethylspinoxin (:, White powder: 1 ^ (111 + ^) Expected value: 760.5. Actual value: 760, 7. C43Hs3N01Q2 Analytical value: C, 67.96; Η, 9.15; Ν, 1.84. Actual value: C, 68.01; H, 9 * 47; Ν, 1.83. Examples of CiU-4 &quot; -N.4 "U2-butene-1.4-II) Sinokine C and ^:-Ν.ΠΜ butadiene- 1.4-diyl) Φ Caoxin C According to the method of Example C81, 1,4-dichlorobut-2-ene (0.10 ml, 0.12 g, 0.95 mmol) ^ Nal (0.02 g, 0 * 1 mmol), (i-Pr __-167 -__ ^^ 7 degrees apply Chinese national standard (〇? ^) / \ 4 specifications ( 210/297 mm) ~~ .— ^ — (Please read the notes on the back before filling this page)

, 1T 487559 A7 ________B7_ 5. Description of the Invention (165)) 2NEt (0.22 mL, 0.16 g, 1.3 mmol), Spinoxin C ((K29 g, 0.41 mmol) and DMF (1.5 ml) to prepare these compounds. MPLC (Si02, 20:80 ethyl acetate / dichloromethane) M obtained 0.11 g (35%) of 4 "-N, 4" -N- (2-butene-1,4-diyl) history Binoxin C, is a white powder: MS (π + Η expected value: 765.5. Actual value: 756.6, and 4 "-N, 4M-N- (butadiene-1,4-diyl) spinosin C: 0.11 g (35¾), white powder: MS (m + H +) Expected value: 754.5. Actual value: 75.8. Mild room temperature oxidation has shown the formation of this product.

Example: C65-4 "-N-" (6-fluoren-3-PH; pyridinyl) methyl] Spinoxin B According to the method of Example C81, from (6-chloro-3-pyridinyl) Chloromethane (0.14 g, 0 * 86 mmol), (i-Pr) 2 NEt (0.22 inL, 0.16 g, 1.3 mmol), Spinoloxin B (0.30 g, 0.42 nnnol), and DMF (1 ml) Preparation of compound. MPLC (Si02, 25:75 to 75:25 ethyl acetate / hexane) K to obtain 0.30 g (86%) 4 ”-N-[(6 · • chloro-3-utt Acryl) Methyl] Spinoxin B, a white ochre powder.

Fen example C66-4 "-N-" N ·-(2.2-dimethylethylchlorocarbonyl) -propylamine riding 1 printed by Cao Nuoxin B Central Consumers Bureau of the Ministry of Economic Affairs employee consumer cooperatives --------- -· ----- (Please read the precautions on the back before filling this page) According to the method of Example C77, Ν # (2χ0 · 12 ml, 0.22 g, 2.2 mmol), Boc ~ N (H) _ / 3 -Ala-C〇2H (0.17 g, 0.90 mmol), BOP-C1 (0.23 g, 0.90 nnnol), Spinoxin B (0.50 g, 0.70 mmol) and CH2C12 (7 ml) to prepare the compound. MPLC ( Si〇2, 70: 30 to 100: 0 ethyl acetate / hexane) K to obtain 0.62 g (99! U4 "-N- [N '-(2,2-dimethylethoxycarbonyl)- / 3 -propylamine base] Spinoxin B, white ochre powder: MS (m + H MM expected value: 889 ♦ 5. actual value: 889 · 7 -168-This paper size applies to Chinese national standards (CNS ) A4 specification (2ί〇 × X 297 mm) 487559 A7 B7 V. Description of the invention (166) ° Analysis of C4BH7BN2013: Estimated value · C, 64,84; H, 8.62; N, 3 · 15. Actual value : C, 64 · 38; Η, 8.87; Ν, 3.22. (Please read the notes on the back before filling this page)

Example C67-Π-fN ·-(Methylmethylchlorosulphonate) -i-Protein Bronze 1Zonoxin B According to the method of Example C77, NMM (2x0.12 ml, 0.22 s, 2.2 mmol ), Boc ~ N (H) -LA 1 a-CO 2 Η (0.21 g, 0.94 niinol), B0P-C1 (0 · 24 g, 0,94 mmol), Spinosin B (0 · 50 g, 0.70 nmol) and CH2C12 (7 ml). MPLC (Si02, 75: 25, ethyl acetate / hexane) to obtain 0.68 g (99ίϋ) Π- [N '-(phenylmethoxycarbonyl) -L-propylaminofluorenyl] Spinoxin B , Is a white powder: MS (m + HM expected value: 923.5. Actual value: 923.7. Example α8-4 "-N-" ΝΉ '-dimethylglycine in a certain zonoxin B according to Example C77 Method: NMM (2x0.12 ml, 0 * 22 g, 2.2 mmol), Ν (Me) 2 ~ G1y-CO2Η (0.09 g, 0.9 mmol)-Β0Ρ-C1 (0.25 g, 0.98 mmol), Spinoxin B (0.50 g, 0.70 mmol) and CH2C12 (7 ml) were used to prepare the compound. MPLC (Si〇2, 5:95, Me0H / CH2Cl2) K yielded 0.43 g (77S04 ”-N- [fT, N'-Dimethyl Ethylene Glycoxyl, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs)] Spinoxin B, white powder: MS (m + H ') Expected value: 803.5. Actual value: 803.6. 啻Example "N, · N '-(pent, 5-diyl) -β-propylamine i-group.] History

Binoxin B was prepared according to the method of 洌 C77 by NMM (2χΟ · 12 ιηΐ, 0.22 g, 2.2 mmol), N, H (CH 2) 5-/ 3-A 1 a-CO 2 H (0. 14 g, 0.89 niinol), B0P-C1 (0.26 g, 1.0 mmol), Spinozin B (0, 50 g,-169 -__ This paper size applies to China National Standard (CNS) A4 specification (2i〇: &lt; 297 Gongguang) 487559 A7 ___. B7. V. Description of the invention (167) 0.70 mmol) and CH2C12 (7 ml) to prepare the compound. MPLC (Si〇2, 5: 95 to 10:90, MeOH / CH2Cl2) M to obtain 0.54 g (90%) 4 "-N- [N ', IT- (penta-1,5-diyl) -/ 3 -Propanamidinyl] Spinoxin B, white powder: MS (ιη + Η *) Expected value: 857.6. Actual value: 857.8. Rich Example C70-4 "4." N ·. ^- Di-Z-based-theta-amidino] Spinoxin E According to the method of Example C77, NMM (0.24 ml, 0.22 g, 2'2 mmol &amp; 0.12 ml, 0.11 g, 1.1 mmol), H, N (Et) 2- / 3 -Ala-C〇2H · HC1 (0.16 g, 0,88 mmol), BOP-C1 (0.26 g, 1.0 mmol), history Compounds were prepared with binoxin B (0.50 g, 0.70 mmol) and CH2C12 (7 ml). MPLC (Si〇2, 5:95 to 10:90, MeOH / CH2C12) K yielded 0.46 g (78¾) 4 "- N- [N ', N'-Diethyl-propylaminopropyl] Spinosin B, white powder: MS (m + H +) expected: 845.6. Actual value: 845.δ. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (eg 7: 4 "咄-[« '-(9-Watki Methane)-) 3-propylamine 8? 1 base 1 Β and propylamine 窨 窨 窨 窨 宰 宰 B according to the method of Example C77, from NMM (2x0.12 ml, 0.22 g, 2.2 mraol &amp; 0.12 ml, 0.11 g, 1.1 mmol), Fmoc-H (H)- / 3 -Ala-C0H (0.26 g, 0.84 mmol), BOP-C1 (0.23 g, 0.90 nunol), spinosyn B (0.502 g, 0.699 mmol) and CH2C12 (7 ml) to prepare the compound. MPLC ( Si〇2, 0: 100 to 20:80, MeOH / CH2C12) M to obtain 0.03 g («) 4" -N- [N '-(9-fluorenylmethoxycarbonyl)-/ 3-propylaminofluorenyl] Spinozin B, white powder: MS (m + ΙΓ) Expected value: 1011.6. 4 "1-(/ 3-propylaminofluorenyl) Spinozin 8 0.278 (49%), white powder: MS ( m + HM expected value: 789.5. Actual value: -170-This paper size applies Chinese National Standard (CNS) A · 4 specifications (21QX 297 mm) A7 · B7 V. Description of the invention (168) 789.7. Under reaction conditions The mild deprotection of the Fmoc group has demonstrated the formation of this product.

For example, C72-4 "-N- (diethylhydrophosphinofluorenyl), Kenozo R will be (Et0) 2P (0) Cl (91 ml, (Kll g, 0.63 mmol) and (i- Pt) 2NEt (0.22 ml, 0.16 g, 1.3 mmol) was sequentially added to a solution of Spinoxin B (0.30 g, 0.42 mmol) in CH2C12 (4 ml). After 2 days, the mixture was mixed with (^ 2 (: 12 and "}] (: O3. The organic layer was washed with brine, M (Na2SOd was dried and dried and evaporated. MPLC (SiO2, EtOAc)) 0.27 g (75%) 4"- N- (diethoxy-o-fluorenyl) Spinozin B is a white powder. Example C73-N-Three gas generation Z-fluorenyl-N-Guan Jia, an employee of Sinok Norsk, Ministry of Economic Affairs, Central Standards Bureau Printed by Consumer Cooperatives ------- i ----- (Please read the notes on the back before filling this page) Add a part of trifluoroacetic anhydride (0.16 ml, 1,1 mmol) to the cold ( 0 ° C), properly stirred N-desmethylspinoxin D (0,4 g, 0.54 mmol) and triethylamine (0.2 ml, l \ 5 mmol) in ethyl acetate solution. Remove and cool Bath and stir the solution at room temperature for 40 minutes, then poured into ice water (40 ml). The product was extracted in ethyl acetate (3x15 ml) and saturated with NaHC03 (6 ml) and brine (6 ml). clear The organic extract was dried over (MgS04). The solvent was evaporated to leave 0.4 g of clean M-trifluoroacetamido-N-desmethylspinoxin D as a colorless foam MΗ-NMR ( CDC13) δ 6.76 (s, 1Η, Η-13), 5.49 (s, 1Η, Η-5), 4.86 (d, 1Η, Η-1 ·), 4.66 (,, 1Η, Η -21), 4.51 (d, 1Η, Hl ”), 4.30 (ιπ, 1Η, FM, 3.0 and 2.88 (s, total 3Η, N (CH3)); MS m / z 139 (70), 224 (100). Example C74-N- (2.2. 2-Three-Gas Z-Hydrogenated) Hydroxylamine-N-Norca-Zhongke-171-The standard of this paper is applicable to Chinese national standards (CNS) Λ4 specification (210. × 297 mm) 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (169)

Novozymes Anhydrous f (2CO3 (0.12 g, 0.87 mmole) was added to Spinozin A (1.5 g, 2.0 nunol) and 2,2,2-trichloroethylchloroformate, which had been properly stirred (0.8 ml, 5.5 mmol) of dry benzene (20 ml). The resulting mixture was heated at reflux temperature for 48 hours, then cooled to room temperature and poured into ice water (100 ml). The product was extracted in ethyl acetate ( 3x40 ml) and washed the organic extract with brine (40 ml), and dried M (MsSO4). The solvent residue (2.7 g) M silica (170 ml) was subjected to flash chromatography using 2: 1 hexane / ethyl acetate was used as the eluent to obtain NM 2,2,2-trichloroethoxy) carbonyl-N-desmethylspinoxin A (1.3 g) as a colorless foamed carcass: NMR (CDCla) δ 6.76 (s, 1H, H-13), 4.86 (d, 1H, Hl,), 4.75 (m, 3H, C13CCH2, H-21), 4.48 (m, 1H, Η-ΓΊ, 4.32 (m, 1H, H-9); MS m / z 189 (100), 302 (28), 591 (32), 893 (77). Example of a flask C7LN- (2.2.2-tris (2,4-methyl) ethane) ) Carboxamole-N-desmethyl in W Nuozai, in 2-3 minutes, the solution of 2,2,2-trichlorochloroformate (0.07 ml, 0.51 nunol) in CH2C12 (2 ml) Add dropwise N-desmethylspinoxin D (0.15 g, 0.20 mmol) and pyridine (0.3 ml) in a solution of CH2C12 (4 ml). The solution was stirred at room temperature for 6 hours and then diluted with water (5 ml). The organic layer was separated and washed successively with 1H HC 1 (5 ml), saturated NaHC0 3 (5 ml) and brine (5 ml), and dried over (MgS04). The remaining residue was concentrated (0.42 g) The residue was subjected to flash chromatography using silica (90 ml), and 2: 1 hexane / ethyl acetate was used as the eluent K to obtain the paper size applicable to the Chinese National Standard (CNS) A4 (210X 297) %) I--......-4—-In, &gt; &gt; I— I--_ -in (Please read the notes on the back before filling this page)

1T 487559 A7 ____ _-B7 V. Description of the invention (170) 0 · 15 g (803〇N- (2,2,2-trichloroethoxy) carbonyl-N-desmethylspinoxin D, colorless foam: iH_NMR (CDC13) 5 6.76 (s, 1H, Η-13), 5.48 (s, 1H, H-5), 4.86 (d, 1H, H_l,), 4.76 (m, 2H, C13CCH2), 4.66 (m, 1H, H-21), 4.48 (ro, 1H, H-1 ”), 4.30 (m, 1H, H-9), 2.37 and 2.85 (s, total 3H, NCH3).

Rich case C76-H- (2, 2, 2-Tris (3,2'-ethoxy) yl) carbonyl-N-nor-methyl-7-Zenji Zhongyinxinxin D Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1 :: II I ..... 1 called i-I — y- —-I--I (Please read the precautions on the back before filling out this page) 5¾ 36 on silicon oxide (0 · 21 g) A suspension of 2 and a third butyl hydroxyperoxide (90%, 0.07 mmol) in CH2C12 (3 ml) was stirred at room temperature for 15 minutes. To this mixture, N-tri-chloroethoxycarbonyl-N-desmethylspinoxin D (0.15 g, (K16 ππηοΐ)) CH2C12 (2 ml) was added dropwise over 2-3 minutes. The solution. The mixture was stirred at room temperature for 1.5 hours and then filtered. The collected solid KCH2C12 (10 ml) was washed and the filtrates were combined and washed with water (5 ml) and brine (5 ml) and dried over M (MsS04). The remaining 0.11 g of the residue was concentrated. The residue was subjected to flash chromatography with silica (90 ml), and 63 mg of N- (2,2,2-trichloroethoxy) carbonyl was obtained by using CH2C12M of methanol. -N-desmethyl-7-hydroxyspinoxin D, a white foam ^ H-NMR (CDC13) δ 6 * 76 (s, 1H, H-13), 5.58 (s, 1 Η, Η- 5), 4 · 6-4.9 (m, 4H, Η-1 ,, H-21, C13CCH2), 4.48 U, 1H, Hl "), 4 · 40 (m, 1H, H-9).

Fulleren Case C77- "N '-(2,2-Dimethyl Z Hydrogen Bran) Glycine 醯 1 1 Coke Mou B B 4-methylmorpholine (NMM) (0.12 ml, 0,11 g, 1.1 mmol) This paper is compatible with the Chinese National Standard (CNS) A4 specification (210X 297 mm) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (171) Add to -15 ° C in Boc-N (H) -GIy-C〇2H (0.16 g, 0,91 mraol) and B 0P-C1 (0.23 g, 0.90 mmol) in CH2C12 (7 ml). In 1 After 5 hours, the volume was reduced by about half under reduced pressure. Spinoxin B (0.50 g, 0.70 mmol) and NMM (0.12 ml, 0.11 g, 1.1 πιηο 1) were added sequentially. The mixture was added Warm to room temperature for 20 hours; evaporate the mixture. MPLC (SiO2, 50:50 to 100: 0, EtOAc / hexane) M to obtain 0.61 g (991) 4 "-N- [N '-(2, 2-dimethylethoxycarbonyl) glycinamido] Spinoxin B, white powder: MS (m + HM expected: 875.5. Actual: 875.9)

Example C78-KM Substituted for Aethynyl W Nuoxin B Spinoloxin B (104.4 mg, 0.145 mmol) was dissolved in dichloromethane (5 ml) and Ν, Ν -diisopropylethylamine ( 0.1 g, 0.8 mmol) and dichloromethane f (0.1 g, 0 * 9 mmol) and the reaction was stirred for 1 hour. After the residue was gradually formed, the residue was purified by silica gel (ethyl acetate / hexane, 50:50) chromatography to provide N-chloroethynylspinoxin B (79.1 mg, 68¾) as a colorless glass. Object: Analysis of FDMS ra / z 794 CC42HWN0HC1: Estimate: C, 63.50, H, 8.12; 1.76. Actual values: C, 63.32; H, 8.04; M, 1.58. Enrichment example C7Q-N- (N'-Z a thioamine and a formamidine) Cao Nuoxin_ Compound Spinoloxin B (97.8 mg, 0.136 mmol) was dissolved in toluene (4 ml) and added Ethyl isothiocyanate (0.05 g, 0.6 nunol) and the reaction was heated at reflux temperature for 2 hours. The toluene solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, gradient 20:80 to 50:50) to provide the compound N- (Nethylthioaminomethyldonyl) ） History _____- 174 -_ This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X29 * 7mm) ---------- 0-- (Please read the notes on the back before filling This page), 11 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 * B7 _ V. Description of the invention (172) Binoxin B, a colorless glass: FDMS m / z 804, 805.

Example CS0-4 "-N-" (4- (trifluoromethyl arginyl) cage 1 amine certain furfuryl kenoxin B will be 4 (trifluoromethoxy) phenyl isocyanate (94 ml, 0.13 g, 0.63 mmol) and DMF (3 ml, 3 mg, 0,04 mmol) were sequentially added to a solution of Spinozin B (0.30 g, 0.42 mmol) in ether (4 ml) at 0 ° C. The mixture was heated 15 minutes to room temperature. Decompose excess isocyanate by adding methanol (1 ml) and evaporate the mixture. MPLC (SiO2, 50: 50, ethyl acetate / hexane) to obtain 0 * 37§ (971) 4 "- ^ [(4- (trifluoromethoxy) phenyl] aminocarbonyl spinosyn B, white powder: MS (m + H +) expected value: 921.5. Actual value: 921.6.

Casein C81 Funosin B Iodine Ethyl Complex (0.11 ml, 0.21 g, 1.4 mmol) and (i-Pt) 2NEt (0.36 ml, 0.27 g, 2.1 mmol) were sequentially added to the history A solution of binoxin B (0.05 g, 0.70 mmol) in DMF (1.5 ml). The progress of the reaction was monitored by TLC (SiO2) and HPLC (C1B). After showing sufficient conversion (1-5 days), the reaction was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over K (MgS04), filtered and evaporated. MPLC (SiO2, 50: 50 ethyl acetate / hexane) M obtained 0.55 g (89! U4 "-N-ethyl spinosin B, white powder: MS (m + H +) expected value: 746.5 Actual value 746.7. -175-This paper size is applicable to China National Standard (CNS) Λ4 specification (2 丨 0X297 Gongqing 1 ------- a ---- clothing-(Please read first (Notes on the back then fill out this page)

、 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559, A7 — B7 V. Description of Invention (173)

Enrichment example C82-U "S) -4" -desmethyl- (dimethylamino)-4 "-methylargon (Dimethylamino) -4 "-hydroxyspinoxin A (2.21 g; 3.08 mmol) was dissolved in CH2C12 (60 ml). Water (20 ml), 10¾ aq · NaOH (25 ml) and K2CO3 solids (5 g) were added, followed by dimethyl sulfate (8 ml, excess). The reaction mixture was stirred vigorously at room temperature under atmosphere for 48 hours. Water (50 ml) and CH2C12 (50 ml) were added, and the layers were separated. The organic layer was washed with H20 (2X), dried over K2CO3, and concentrated under reduced pressure. The residue was separated by flash column chromatography (230-400 m, 250 g / ethyl acetate).

Fenshi C83-4 "-(S)-4" -desmethyl_ (dimethylamine a) -4 "-^ 窨 Φ 窨 窨 A A compound (4” S) -4 ”-to Methyl- (dimethylamino) -4 "-hydroxyspinoxin M2.21 g; 3.08 mmol) was dissolved in CH2C12 (60 ml). Water (20 ml), 10¾ aq. NaOH (25 ml) and K2CO3 solid (5 g) were added, followed by diethyl sulfate (8 ml 1, excess). The reaction mixture was stirred vigorously at room temperature under nitrogen for 48 hours. Water (50 ml) and CH2C12 (50 ml) were added to separate the layers. The organic layer was washed with H2O (2x), dried over K2C03 and concentrated under reduced pressure. The residue was separated by flash column chromatography (230-400 m, 250 g / ethyl acetate).

Example C84-4 "-(S) -4T'_ Jian Shenmou-(dimethylamine a certain)-4"-propyl argon, but also amidin A compound 4 "-(S)-4"- Demethylated- (dimethylamino) -4 &quot; -hydroxyspinoxin Ml. 22 g, 1.70 mmo 1) Soluble in CH2C ί 2 (20 ml): The paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) (Please read the notes on the back before filling in this page) Revision 7559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (174) Water (20 ml), 1 0% NaOH aqueous solution (25 ml), followed by K2CO3 (2 g), tetrabutylammonium chloride (1.2 g) and benzyltriethylammonium chloride (1.5 g). Diiodopropane (10 ml) was added and the reaction mixture was stirred vigorously at room temperature under nitrogen for 48 hours. Dichloromethane (20 ml) was added and the phases were separated. The organic layer was washed with water (2x), dried over K2CO3 and concentrated under reduced pressure. The residue was purified by flash column chromatography (120 g / ethyl acetate). Example C85-4n-)-4 "-Normone- (Nita-amine)-4" -Qi Shenmou

Shi Xingxin A Compound 4 ”-(S) -4” -desmethyl- (dimethylamino) -4 ”-hydroxyspinoxin M510 mg, 0.71 mmol) was dissolved in CH2C12 (5.0 rol) K2C03 (110 g) was added. The reaction flask was immersed in a water bath (i (TC)) and an aqueous solution (10 ml) was added with vigorous stirring, followed by benzyl triethyl saddle chloride (1.20 g). Added Chloroiodomethane (5.0 ml) and the reaction mixture was stirred vigorously at room temperature under nitrogen for 72 hours. Dichloromethane (100 ml) and water (50 ml) were added. The phases were separated. The organic layer was washed with water (2x), Dry over K2CO3 and concentrate under reduced pressure. The residue was purified by flash Si02 column chromatography (70 g / ethyl acetate).

Example C 8 6-4 n _ (S)-4 ”-Norso- (diphosphonium amine) -4” -trimethylsane argonyl sulphone A A compound 4 ”-(S ) -4 "-desmethyl_ (dimethylamino) -4" _hydroxyspinoxin A (510 mg, 0.71 mmol) was dissolved in CH2C12 (10.0 ml). Dimethylamine pyridine (〇 · 80 g). Stir the mixture at room temperature under nitrogen. Slowly introduce trimethylsilyl trifluoromethanesulfonate (0.99 U excess) through the syringe and continue to mix for 1 hour. Ester (50 m 1) _ 177-This paper size is applicable to the Chinese national standard rNS) A4 size (210X 297 mm) ~ (Please read the precautions on the back before filling out this page) ·· Packing. + Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 487559 A 7 _ B7 V. Description of the invention (1M) and benzene (50 ml). Wash the solution with 5¾ aq. NaHC〇3 solution (3x). Dry the organic layer with K2C03 Dry under reduced pressure. The residue was purified by flash column chromatography (100 g / ethyl acetate).

Example C87- (4 "S, 4" -normethyl- (dimethylamino) -4 "-ethyl base, arginine, amidin, A, compound (4" 3) -4 "-to Methyl- (dimethylamino) -4 ”-hydroxyspinoxin A (10 rag, 0.14 mraol) was dissolved in dichloromethane and acetic anhydride (0,05 g, 0.5 mmol) and pyridine (0.1 g, 1 mmol), and the reaction was stirred for 2 hours. The reaction was gradually obtained to obtain the compound (4 "S) -4" _desmethyl- (dimethylamino) -4 "_acetamoxyspinoxin A. 窨Example C88-4 "-Demethyl- (dimethylamino group 4" _

g very neutral g nosin A Soluble compound 4 "-(S) -4" -desmethyl- (dimethylamino) -4 "-hydroxyspinoxin A (306 mg, 0.43 mmo 1) in Dry pyridine (5 ml). Chloroacetic acid chloride (0.50 μm 1) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen. After 3 hours, toluene (50 ml) and ethyl acetate (50 ml) were added. ). The solution was successively washed with brine, 5¾ NaHC〇3 (2X) and water. The organic layer was dried over anhydrous Na2SO4 and dried under reduced pressure. The residue was subjected to flash Si02 column chromatography (80 g / Ethyl acetate). 窨 Example Compound 4 "-Dichloro-4" -Deamin-5,6-Digas Speen

Phenoxin A 5,6-dihydrospinoxin A N-chloride (1.26 g, 1.68 mmol) was dissolved in dry THF (10 ml). Cool the solution to _78 ° C and add pyridine (5 ml) ·: · While stirring, add three gas acetic anhydride (1.8 ml, 2.67 g, 12.7) This paper size applies Chinese National Standard (CNS) A4 specifications ( 210 X 297 mm) (Please read the notes on the back before filling out this page). Packing. Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 —____ B7___ 5. Description of the Invention (10fc) mmol). After 16 hours, diethyl ether (120 ml) was added and the mixture was extracted with dilute brine (2x), followed by extraction with 10¾ KHC03 (2X), dried with K2CO3 and concentrated under reduced pressure. The residue was separated by flash column chromatography (ethyl) to obtain compound 3 ", 4" -dihydro-4 "-deamin-5,6-dihydrospinoxin A ( 122 mg, 10.5%) as a white solid: l-NMR δ 6.82 (bs, 1Η), 5.61 (m, 1Η), 5.53 (bd, J = 10 HZ, 1Η), 4.66 (q, J = 6 HZ, 1H), 1.23 (d, J 6.3 Hz, 3H), 1 · 19 (d, J = 6 · 6 H z, 3 H), 1 · 15 (d, J = 7.0 H z :, 3 H ) Examination of the history of CQ0-complex 5, fi-dichloro-N-formamine-Zhongke Mou Xing R and complex 4 ”-deamin-5,6-digas-4” Panaxine C Dissolve 5,6-dihydrospinoxin AC (1.43 g, 1.95 mmol) in dichloromethane (25 m 1) and add pyridine (6.0 m 1). Cool the flask to + 10 ° C Bromine (3.0 ml) was added with vigorous stirring under nitrogen. Water (2.0 ml) was added and stirring was continued for 1 hour. Ether (200 ml) was added, and the mixture was continuously mixed with a solution of water (10% NaHS〇3), water and 10%. 1 ^ (: 〇3 aqueous solution was extracted with anhydrous! (2 (: 〇3 dried, filtered and concentrated. The crude product was divided into 2 equal parts. One part was purified by flash chromatography (Si〇2 / Et2〇) and borrowed. Repeated RP (018) HPLC (92 ^: δ, MeOH / H2〇) To obtain compound 5,6-dihydro-N-methylamidino-spinoxin B (230 mg, 31¾) as a white solid-NMR δ. 7.95 (bs) and 7.93 (bs, total 1H) , 6.74 (bs, 1H), 2.64 (s, 3H), 1.14 (d, J = 5.8 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 1.02 (d, J = The 6 · 3 H z, 3 H) and b) fractions were concentrated to about 50% 4 n -deamino-5,6-dihydro-4 ”-ketospinoxin C (16 8 mg, about 1 2 ίϊί) -179-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 ___ B7 V. Description of the Invention (177) The above steps were repeated on a scale 5 times larger, which resulted in the production of pure 4 "-deamin-5,6-dihydro -4 ”-ketospinoxin C (212 mg, 3.1¾) as a white solid &quot; H-NMR 0 '6,79 (bs, 1H), 4.90 (dd, J = 8.2 Hz, 2.5Hz ), 3.95 (q, J = 6.7 HZ); 13C-NMR d 208.7, 203.2, 172.6, 149.6, 145.1, 100.9, 95.4, 17.6 (CHa), 16.1 (CH3), 15.3 (CH3), 9.2 (CH3 ) ·

Enriched Example C9 Compound 4 "-deaminase-5 · dihydro-4 H) -C4" -deaminyl-5,6-dihydro-4 "-keto Spinolol Octyl C (192 mg, 0.273 mmo 1) was dissolved in dry ether (50 ml 1). The solution was cooled to 0 ° C and a portion of lithium tri-butyl aluminum hydride (97%, 145 mg, 0,55 mmol) was added. Stirring was continued for 15 minutes at the same temperature. Then the reaction mixture was carefully quenched with brine. Diethyl ether (100 ml) was added and the mixture was extracted with NaOH (2x), followed by extraction with 10¾ KHCCh aqueous solution, dried with K2CCh and Concentrated. The crude product was purified by flash chromatography on a Si02 column (Et0Ac) and separated by RP (018) HPLC (92: 8, MeOH / H20) to obtain compound 4 "-deamino-5, 6-Dihydro-4ff (S) -hydroxyspinoxin C (91 ms, 47%) as a white solid: 'H-NMR d 6.81 (bs, 1 Η), 4.43 (bd, J = 7.4 Hz, 1H), 3.57 (m, 1 H), 1.21 (d, J = 6.1 Hz, 6H), 1.12 (d, J = 6.9 Hz, 3H).

Is it rich? -Compound 4, '-guanamine oxygen_4 "(S"' hydrazone i Fusinocin C 4 "-deamin-5,6-dihydro-4" (Sb-Spinyl Spinocin C (66 mg, 0 · 093 mmo 1) dissolved in dichloromethane (1.5 ιη 丨) ° Added to Iodine Academy (2 · 0 m 1 -180-. This paper size applies to Chinese National Standard (CNS) A4 specifications (Issued by 210X 297) 丨 f i--yi-- (please read the precautions on the back before filling out this page),-487559 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description ), Followed by 40 ¾ NaOH aqueous solution (3.0 ml) and tetrabutyl iron phosphate bromide (320 mg). The reaction mixture was stirred vigorously at room temperature under nitrogen and powdered KOH (10 ml) and Et 20 (100 ml) were added. The mixture was washed with water, followed by 10¾ KHC03 aqueous solution (2x). The organic layer was dried over anhydrous K2CO3, filtered and dried under reduced pressure. The residue was flashed in a Si02 column (CΗ2) (C12-Et2 0) purified to provide compound 4 "-deamin-5,6-dihydro-4" (S) -methylchlorospinoxin C, as a white solid ^ H-NMR δ 6.82 ( bs, 1H), 4.43 (dd, J = 9.4 Hz, 1.9 Hz), 3.52 (s, 3H) , 3.46 (s, 3H), 3.45 (s, 3H), 3.32 (s, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.1, 3H), 1.14 (d, J 6.8 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H).

Part D illustrates the third part of the compound of formula I. The modified cell of h 1 3 · Dan 1 4 ′ is an example of old- (14R) -13, 14-diazepine-Φ. In a solution of Spinozin A (1.0 gms, 1.37 mmol) in pure ethanol (20 ml), sodium borohydride (520 mg, 13.7 mmo 1) was partially added within 0.5 hours. The reaction mixture was stirred at room temperature for 45 minutes, and then quenched by the addition of a saturated aqueous ammonium chloride solution. It was then diluted with water and extracted with dichloromethane. The dichloromethane portion was dried over K2CO3 and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica, diluted with 5¾ methanol in chloroform. Because the obtained separation effect was not good, the chromatography was repeated. After the product was recovered, it was diluted with ethyl acetate. The obtained (14R) -13,14-dihydro-spinosin A is a colorless glass, FDMS, m / e (relative strength) 734 (M, 100), 733 (60). Example D2-(14S)-5. 14-tetrachloro-Zhongfu-181 _ This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1 &gt; ϋϋ 'II i ^^ F · — · Ϋι n &gt; i— ^ ϋϋϋ I ml i (Please read the notes on the back before filling this page), -s'tv 487559 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (179) According to The reaction was carried out as described in Example D5, and Spinoxin A (106.8 mg, 0.15 mmol) was used as a starting material. The obtained (14S) -5,6, 13, 14-tetrahydro-spinoxin A (85.5 mg; yield 80%) was a colorless, slightly viscous solid, FDMS, m / e (relative strength) 736 (M +, 100).

Examination Example 03- (Ί 4R) -5, 6.13. 1 4-tetrachloro-spinoxin A at (14R) -13,14-dihydrospinoxin A (210.3 mg, 0.29 mmol) (9 ml) solution, tris (triphenylphosphine) rhodium (1) (47.2 mg, 0.05 mmol) was added and the reaction mixture was placed under a hydrogen atmosphere. The mixture was stirred at room temperature for 4 days, and then the solvent was evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and released with 5% methanol in dichloromethane. The product was further purified by chromatography on silica and diluted with 70¾ ethyl acetate. The obtained (14R) -5,6,13,14-tetrahydro-spinozin A was a colorless glass, FDMS, π / e (relative strength) 735 (M '100).

Example [) 4- (13R. 14S) 3. 14-Chlorine-Medium Moxin A In an ice-cold solution of Spinoxin A (200.7 mg, 0.27 mmol) in methanol (3 ml), add 30¾ solution of hydrogen peroxide (41 ml, 1.35 mmol) followed by sodium hydroxide (19 mg, 0.33 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and then heated to room temperature: after stirring at room temperature for 3 hours, the mixture was diluted with dichloromethane. Then, dichloromethane was washed with water, washed with 5% sodium thiosulfate, dried over K2CO3, and evaporated at room temperature under reduced pressure. The obtained (13R, 14S) -13,14-epoxy-spinoxin A (200 · 2 mg, 99%) was a colorless glass, FDMS, m / e (relative strength) 747 (M, 100). Fen Heng Example H Π 4S)-Γ).. U. 14-tetra-argon-de-argon-132-This paper size is applicable to Chinese National Standard (CNS) Λ4 size (21GX 297 mm) (Please read the note on the back first) Please fill in this page for further information), 1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (18〇) in 3, -Deoxyspinoxin J (108.8 mg, 0.16 mmol) To a solution of ethyl acetate (50 m 1), alumina / barrel (1000 mg) was added. The reaction mixture was placed under hydrogen of 60 ps i and stirred at room temperature for 8 hours. After the catalyst was filtered, the solvent was evaporated at room temperature under reduced pressure. The residue was purified by chromatography on gasified silicon and diluted with 2.5% ethanol in ethyl acetate. The obtained (14S) -5,6,13,14-tetrahydrodeoxy Spino sheep J is a white solid, FDMS, m / e (relative strength) 707 (65), 706 (MH +, 100).

Example D6-(14S, 14-Dihydro-Spinoxin A, Spinoxin A (454 mg, 0.620 mmol) was dissolved in ether (50 ml). Under nitrogen and room temperature, vigorously To this solution was added lithium tributoxy aluminum hydride (475 mg, 97%, 1.81 mmol). Stirring was continued for 18 hours. Then diluted with ethyl acetate (70 m 1) and toluene (50 m 1) and carefully It was quenched with brine. The resulting mixture was washed with brine (2X) and then with 5¾ sodium bicarbonate aqueous solution (2x). It was dried over anhydrous K2CO3 and concentrated under reduced pressure. By flashing a Si02 column (30 g, 0.05% Dttidine in ethyl acetate), purify the residue to obtain compound (14S) -1 3,14-dihydro-spinoxin A (421 mg, 92%) needles (ethyl acetate Ester-hexane). 111.9.150-152 ° C; [a] 589 = -77.4 ° (CHCl3); ^ -NMR (CDCla, 300 MHz) d 3.56 (1H, m), 3.00 (1H, dd: 9.0 , 9.0 Hz), 2.32 (1H, m), 2.14 (6H, 2xCH3, s) ppm; MR FAB MS (

MfT) Analysis of C41FU8N0la: Estimated value: m / z 734.4843; Actual value: m / z 734.4853; CnHuNOi. Analysis: Estimated value: C 67 · 09, Η 9 · 20, N 1.91; Actual value: C 67 · 30, Η 9 · 39, Ν 1 · 95 -183-This paper size applies to China National Standard (CNS) Α4 Specifications (210 × 297 mm)-· 11 n mj ^ n ^ i ϋ ^, ιϋ 11. ^ 1 i 1 ^ 1 (Please read the precautions on the back before filling this page) Order the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printing 487559 A7 B7 ----------------- 5. Description of the invention (181)

For example, (N-fluorenyl) amino-13, 14-alkenyl, luckily A. Spinoxin A (3.54 g, 4.71 nunol) was dissolved in ethanol (80 ml), and 10 was added. % Sodium hydroxide aqueous solution (15 m 1), and then immediately added hydroxyammonium hydrochloride (2.0 g, excess). The reaction mixture was stirred for 45 minutes. Then add ethyl acetate (50 ml) and toluene (100 ml). Extract with brine, followed by 5¾ sodium bicarbonate (3x). The organic layer was dried over K2CO3 and dried under reduced pressure. The residue was completely dried under reduced pressure and CH2C12 (50 ml) was dissolved. Add triethylamine (5 m 1 :) followed by methanesulfonyl chloride (2 * 5 m 1 :). After stirring for 30 minutes, toluene (70 ml) and ethyl acetate (50 ml) were added. Wash the solution with 5¾ sodium bisulfate (3x). The organic layer was dried over K2CO3 and concentrated under reduced pressure. The residue was dissolved in anhydrous toluene (30 ml), DBUU (0 ml) was added and the reaction mixture was heated under reflux (under nitrogen) for 30 minutes. The solution was cooled, toluene (50 ml) was added and the solution was extracted with water (4x). Dry over K2CO3 and concentrate under reduced pressure. Separate by flash column chromatography (Si〇2 / Et0Ac) and connect by preparative HPLC (silica-coated 018, 10% water in methanol solution as mobile phase) to obtain compound 13 Hydroxyl) amino-13, 14-alkenyl spinosyn A (1.45 g, 40¾) IR v 1722, 1618, 1120 cml, Cl MS m / z 763 (M + l); UMR (CDCI3, 300 MHz ) d 3.55 (1H, m), 2.60 (1H, dd: 9.0, 9.0 Hz), 2.36 (1H, bd: 5.0 Hz), 2 * 13 (6H, 2x CH3, s) ppm; 13C-HMR (CDCIg, 300 MHz) d 200 · 7 (conjugated 0〇), 166.5 (fourth stage C), 107.8 (fourth stage C) Ppm °

) n 5 (e) -enex-nn-trimethyl sulfide A-184-I-: 1-i- -I In I i · 1 vn urn— ϋϋ ϋ (Please read the Note: Please fill in this page again.) The size of the paper used for this edition is in accordance with the Chinese National Standard (〇 知) 8-4 specifications (210 \ 297 mm). Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _____ B7_____ 5. Description of the invention (182) The compound Spinozin A (5.68 g, 7.76 mm ο 1) was dissolved in DMS 0 (40 ml). The solution was stirred at room temperature (water bath) under nitrogen. Add trimethylsilyl cyanide (3.0 m 1). After stirring for 5 minutes, add Li CN (1. 1 g, excess) part by part. Continue mixing for 30 minutes and add ethyl acetate (50 ml) and PhH (100 ml). Extract with 10¾ aq · K2CO3 (3X) solution. The organic layer was dried over anhydrous K2CO3 and concentrated under reduced pressure. The residue was purified on a flash SiO 2 column (220 g / EtOAc). The pure eluate was evaporated to provide compound (13R) -13-fluorenyl-14, 15 (E) -alkenyl-15-0-trimethylsilyl spinosin A; 5.33 g, 82¾) 4 -NHR (CDC13, 300 MHz) d 5.73 (2H, m), 4.74 (2H, m), 4.22 (2H, m), 3.53 (1H, m), 3.14 (1H, bs), 2.13 (6H,. 2xCH 3, s), 0.09 (9H, 3xCH3, s); CwHriKhQSi: Estimated value: C 65.03, Η 8.97, N 3.37; Actual value: C 64.88, Η 8.95, Η 3.68 Examination Example Dfl-(13R 1 4R &gt; -13-fluorenyl-17-de-g-1-1 4-digas-16 • 17 (F:) -alkenyl mesityl A X509471 and (1 2R · 1 4R) -13- Qi even -1 3,14-digas 窨 谌 A π 488 will compound (13R) -13-cyano-14, 15 (fluorene) -alkenyl-15-0-dimethylsilyl spinosin H (557 mg, 0.67 mmol) was dissolved in CH2C12 (30 ml). Water (50 ml) and KHF2 (5.0 g) were added, followed by tetrabutylammonium chloride (1.36 g). At room temperature under nitrogen The mixture was stirred for 1 hour. Dichloromethane (70 ml) and water (50 ml) were added. The phases were separated and the organic layer was washed with water (2x), dried over K2CO3 and concentrated under reduced pressure. The residue was flashed $ 1〇2 column (230-400 m, 100 g / EtOAc) Compound a) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notice on the back before filling out this page), v &quot; 487559 Printed by A7, Consumers Cooperative of Central Standards Bureau, Ministry of Economic Affairs B7 V. Description of the invention (183) (13R, 14R) -13-cyano-17-deoxy-13, 14-dihydro-16, 17 (E) -alkenyl spinosin A; 132 mg, 33¾ ) UMR / CDCh, 300 MHz) d 6.80 (1H, dd: 10.2, 4.4 Hz), 4.30 (3H, m), 3.00 (1H, dd: 9.2, 9.3 Hz), 1.69 (3H, CH3, s); Analysis of C34H43N〇8: estimated values C 68.09, H 8.23, N 2.33; actual values C 67 · 87, H 8.42, N 2.48 and compound b) (13R, 14R) -13- Cyano-13,14-dihydro Spino &amp; 290 1 ^, 57%) 1 [| -_1? (〇0 (: 13,300 MHz) d 4.26 (4H, m), 2.96 (1H, dd: 9.3 , 9.1 Hz), 2.06 (6H, 2x CH3, s), 〇88 (3H, d: 6.4 Hz); Analysis of C42HmN20h: Estimated value: C 66 * 46, Η 8.76, N 3 · 69 •, Actual values: C 66,62, Η 8.39, N 3.64. Example CM 0-(1 M)-H 氲 even -14, 15 (E buene a -2 1 -0-dimethylmethane S group 醸 a -15-0-trimethyl a alkane-Zhongkemou Xin _X 507995 Dissolve compound 2'_0_trifluoromethanesulfonyl spinosinoxine H (663 mg, 0.78 mmol) in dry DMS0 (7 ml): stir the solution at room temperature under nitrogen and add cyanide Trimethylsilane (1.0 m 1, excess). At this time, it is necessary to cool the reaction mixture to room temperature. After stirring for 5 minutes, a portion of anhydrous lithium halide powder (310 mg, 9.4 mmo 1) is added. Again Stirring was continued vigorously for 30 minutes. Ethyl acetate (50 ml) and PhH (100 ml) were added. The solution was continuously extracted with brine, diluted with brine and 5% aq. NaHC〇3 (2X). Flashed Si02 column (100 g / EtOAc) The residue was purified to obtain compound (13R) -13-fluorenyl-14, 15 (E) -alkenyl-2, -0-digasmethanesulfonyl-15-0-trimethyl Silyl-Spinoxin H, 507 mg, 69¾ IR v 2238, this paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 g t) ----.----.--- 0! (Please read the notes on the back before filling this page)

、 1T 487559 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (184) 1734, 1670, 1206, 1149, 1066cm · 1; 'H-NMR (CDCIg, 300 MHz) d 5.76 (2H, m ), 4.80 (3H, m) &gt; 4.24 (2H, ra), 3.19C1H, bs), 2.18 (6H, 2XCH], s), 〇14 (9H, 3xCH3, s) °

Rich stealing example f) 1 1-(m 1 41? Bu 1 3 · 1 4-dichloro-1 3 棊) Lingji-Spinocin A A compound Spinopin A (1.0 g, 1 · 3 mmol) was dissolved in 10 ml of methanol and hydroxyammonium hydrochloride (0.23 g, 3.3 mmo 1) was added. Potassium hydroxide (0.15 g, 2.6 mmol) was added to the solution and the reactants reacted at room temperature. Within a few minutes, the colorless solution then turned into a cloudy white sink. The reaction was stirred overnight at room temperature. After stirring at room temperature for 18 hours, the white suspension was poured into a night funnel containing 30 ml of a saturated sodium hydrogen sulfonate solution and 30 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with 2x50 ml of 1 ether. The ether extracts were combined, decanted with 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained compound was (13R, 14R) -13,14-dihydro-13- (hydroxy) aminospinoxin A; 0.92 g, 8S% as a white solid. Analysis: estimated value · C 64.37, Η 8.96, N 3.66; actual value: C 64.12,

Η 8.84, Ν 3.50; MS m / z (FD) 764 (63, 2936, 2972, 1722; ^ -NMR (CDCla, 300 Mz) d 5.81 (1H, d), 5.75 (1H, dd) 4.81C1H, s ), 3.22 (1H, d), 3.06 (1H, t). Example D12-(1 3R · 1 4R) -1 3 · 1 4-Difluorene · Ί-(N-Tian-N-Hydroxy) Ammonium Kemuxin A The compound Spinoxin A (1.01 g , 1.36 mmol) dissolved in 5 ml of methanol and added N-methylhydroxyammonium hydrochloride (0.23 g, 3.3 mmo 1): the hydrogen-187-this paper wave standard applies the Chinese Garden Standard (CNS) A4 specifications (2! 0 X 297 mm) 1- i I mi 1 mp ^ m —ϋ I (Please read the precautions on the back before filling out this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 B7 5. Description of the invention (185) Potassium vaporized (148 mg, 2.63 mmol) was added to the solution and the reaction was stirred at room temperature. After 1 minute, the reaction became cloudy. The reaction was stirred at room temperature for 18 hours, and the ingredients were poured into a separatory funnel containing 30 m 1 of a saturated sodium hydrogensulfonate solution and 30 m 1 of dichloromethane. The layers were separated and the dichloromethane layer was extracted with 2 × 50 m 1 of dichloromethane. The dichloromethane extracts were combined, washed with 30 m of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained compound was (13R, 14R) -13, 14-dihydro-13-(N-methylhydroxy) amino spino sheep A; 0.89 g, 83%, as a white solid. Analysis of C42H70N2O11 ·· Estimated value: C 64.76, Η 9.06, N 3.60; actual value: C 64.88, Η 9.03, Ν 3.78; MS m / z (FD) 779 (M + 1). Example D13-( UR · 1 4R) _13 · 1 4-Dichloro is called X 镡 镡) amine very rich Fuxin A 17-Psa According to the procedure described in Example D11, Spinoxin A 17-Psa (207 mg, 0.35 mmol) , Hydroxyammonium hydrochloride (96.0 mg, 1.38 mmol), potassium hydroxide (74.6 mg, 1.32 mmol), and 5 ml of methanol. Analysis of the obtained compound (13R, 14R) -13,14-dihydro-13- (hydroxy) aminospinoxin A 17 -Psa, 115 mg, 53% cC33H53N01Q. Estimated value: C 63.54, Η 8 · 56, N 2.25; actual: C 62.66, Η 9.76, Ν 2 · 11 · MS m / z (CI) 624 (M + 1). LR (CDC13, 300

Mz) d 5.90 (1H, d), 5.77 (1H, dd), 4.85 (1H, s), 4.83 (1H, m), 4.34 (1H, m), 3.80 (1H, m), 3.30 (1H, d) 〇Examination example f) 1 4- (1 3R, 1 4R) -U · 1 4-dichloro-13- (N-diasinyl-M-gas

&gt; Amine Zhongxinxin A -188-This paper size applies Chinese National Standard (CNS) Λ4 specification (21OX297 mm) —-(Please read the precautions on the back before filling this page) IL, Order

i 'Explanation of the invention (186) Compound (13R, 14R) -13, 14-dihydro-13- (hydroxy) aminostilbenexin A (139 mg, 0.181 mmol) was dissolved in 5 ml toluene and benzaldehyde (44 mg, 0.41 mmo 1). The reaction was heated to reflux temperature for 1 hour, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by S i 02 column (CH2Cl2: CH3OH, 97: 3 (V / V)) under moderate pressure to obtain compound (13R, 14R) -13, 14-dihydro-13- (1 Benzyl-N-oxo) Amino Spinozin A 84 mg, 54¾. Analytical value of ^ Estimated value: C 67.58, Η 8.51, 丨 '丨 3.28; Actual value: C 67.31, Η 8.43, N 3.11; ^ -NMR (CDCla, 300 Mz) d 8.26 (2H, m) , 7.44 (3H, 4), 5.90 (1H, d), 5.76 (1H, dt), 4.84 (1H, s) ϋ 'ml In: = * ϋ— — ^ u ... ϋϋ I ( Please read the precautions on the back before filling out this page) Example D15-Π 3R · 14R of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-m 4-Dichloro-13-(N-methyl-N- 珲(A) Aminospoxifen I) Suspoxifen D (0.53 g, 0.71 mmol) was suspended in 10 ml of methanol, and amidine-methylhydroxylamine (103 mg, 1.24 mmol) was added. To this suspension was added potassium hydroxide (103 rag, 1.83 mmol) and stirred at room temperature. After stirring for 1 minute, the reaction changed from visible to more turbid. The reaction was stirred at room temperature for 48 hours. The reaction was poured into a separatory funnel containing 25 m 1 of dichloromethane and 30 m 1 of saturated sodium bisulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (C18, CH3OH: H2O, 95: 5 (Va)). Resulting compound (131 ?, 1410-13, 14-dihydro-13- (N-methylhydroxy) amino spinosinoxin D; 180 mg, 32% ·: · Note: During the chromatographic purification, the compound ( 13R, 14R.) -13, 14-dihydro-13-(N-methylhydroxy) amino spinosinoxine D will be partially decomposed into the compound Spinozin. The paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economy, Yin Chang 487559 A7 B7 V. Invention Description (187) Xin [). (: Analysis of 43 1172 ^ 12〇11: Estimated value: 0 65.12, [19.15, N 3.53; Actual value: C 64.96, Η 8.97, N 3.32. 4-NMR (CDC13, 300 Mz) d 5.43 (1H, bs ), 4.86 (1H, s), 4.80 (1H, m), 4.42 (1H, in.), 4.28 (1H, m), 3.68 (1H, m). Example of old β-(14S) -1 3 1 4-Diarginoxin A 1 7-Psa Suspend compound (14S) -13,14-dihydrospinoxin A (380 mg, 0.518 mmol) in 10 ml of water and add 2 ml IN H2SO4. No change was observed when the acid was added to the solution. The reactants were heated to 95-100 ° C, during which the solids dissolved to obtain a colorless solution. After heating for 1 hour, a white precipitate formed and the reactants were cooled to room temperature. Warm. The solid was collected by filtration under reduced pressure, washed with 3x10 ml of cold water and air-dried. The resulting compound (14S) -13,14-dehydrogen-spinoxin A 17-Psa, 284 mg, 93¾. (: 33H52〇3 of Analysis: Estimated value: C 66.86, Η 8.84; Actual value: C 66.29 9.19; ^ -NMR (CDCI3, 300 Mz) d 5.90 (1H, d), 5.79 (1H, dt), 5.85 (1H, s) , 4 · 76 (1H, m), 4 · 32 (1H, q), 3 · 82 (1H, m). Example D1 7-(1 4R) -1 L 1 4-Secondary-Φ Harm Sim A 17-Pm will be (14R) -13,14-dihydrospinoxin A (397 mg, 0.541 mm 0 1) suspended in 10 m 1 of water and added 2 m 1 1 NH 2 S 0 4: 'After adding acid No change was observed when it reached the solution. The reactant was heated to 95-100 ° C, during which the solid was dissolved to obtain a colorless solution. After heating for 20 minutes, a white precipitate began to form, and the precipitate was redissolved after 1 hour. The reaction was cooled to room temperature and formed a glassy solid. The glassy was extracted with 2x25 m of ether

This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) ---- · &lt; _ 丨 • 衣 —I (Please read the precautions on the back before filling this page)

, 1T 487559

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs I A7 B7 V. Description of the invention (188) Solid, washed with 20 m I of brine, dried over anhydrous sulphuric acid I and concentrated under reduced pressure. The compound (14R) -13,14-dihydro-spinoxin A 17-Psa, 226 mg, 71¾ was obtained. (: Analysis of 33H52〇3: Estimated value · C 66.86, Η 8.84; Actual value: C66.84, Η 8.90; M-NMR (CDC13, 300 Mz) d 5.88 (1H, dj, 5.67 (1H, dt), 4.85 (1H, s), 4.83 (1H, m), 4.34 (1H, q), 4.01 (1H, m).

Rich example D1 8-1 4S) -1 1 4-digas-13-methyl spinosin A A cuprous iodide (1.34 g, 7.0 mmo 1) was suspended in a nitrogen atmosphere at 20 m 1 Anhydrous ether. The reaction was cooled to 0 ° C in an ice bath and a 1.4 M solution of methyl lithium in ether (9.0 ml, 12.6 mmol) was slowly added over 3 minutes. A solution of the compound Spinozin A (2.04 g, 2.δ0 mmol) in 5 ml of ether was slowly added to the reaction over 10 minutes. A bright yellow solution is obtained, which will gradually lose its color and a precipitate will be obtained. After 30 minutes, the reaction was poured into a separatory funnel containing 25 ml of a saturated sodium bicarbonate solution and 25 ml of ether. The layers were separated and the aqueous layer was extracted with 2x50 ml of ether. Filter B »to remove suspended solids and wash with 25 ml of brine, dry over magnesium sulfate and concentrate under reduced pressure. The obtained residue was subjected to HPLC (C18, CH3OH: H2O, 95: 5, V / V) to obtain a compound (13R, 14S) -13, 14-dihydro-13-methylspinoxin A, 56 g, 27¾. (: Analysis of 42HG3N01Q · Estimated value: C 67.44, Η 9.30, Ν 1.87; actual value: 67 · 47, Η 9.20, N 1.93. MS m / z (Cl) 748 (M + l); LR (CDC 1 3, 300Hz) d 5.85 (1H, d), 5.80 (1H, dt), 4,85 (1H, s),

4.78 (1H, m), 4.42 (1H, d), 4.33 (1H, q), 3.66 (1H) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ------ Mr- ---- (Please read the notes on the back before filling out this page) Order the Consumers' Cooperatives Seal of the Central Bureau of Standards of the Ministry of Economic Affairs — 487559 A7 ____ B7 _ 5. Description of the Invention (189) Example D19-(13R, 14S)- 13. 1 4-DiM -1 Ding Shizhong Kemuxin A A cuprous iodide (1.0 g, 5.2 mmo 1) was suspended in 20 m 1 of anhydrous ether under an atmosphere. The reactants were Cool to 0 in an ice bath and slowly add a 1.4 M solution of η-butyllithium in hexane (7.0 ml, 11 mmol) over 5 minutes. Stir at 0 ° C for 30 minutes to obtain a dark brown solution. 5 ml of ether solution of the compound Spinozin A (2.13 g, 2.9 mmol) was slowly added to the reaction within 5 minutes. After stirring for 15 minutes, the reaction was poured into 50 ml of 50 ¾ concentrated ammonium hydroxide The separating funnel of the aqueous solution was extracted with 3x30 ml of ether. The ether extracts were combined, washed with 50 ml of concentrated saddle hydroxide and 30 ml of a saturated sodium bicarbonate aqueous solution. The ether solution was dried over magnesium sulfate and reduced in water. It was concentrated under reduced pressure. The obtained compound: (13R, 14S) -13,14-dihydro-13-n-butyl-spinoxin A, 0.53 g, 23%. Analysis of C45H75〇1Q: Estimated value: C 68 · 41, Η 9.57, N 1,77; actual value C 68.07, Η 9.51, N 1.82; MS m / z (DCI) 790 (M + l); LR (CDC 1 3, 300Μζ) d 5.85 ( 1H, d), 5.80 (1H, dt), 4.85 (1H, s), 4.79 (1H, m), 4.43 (1H, d), 4.29 (1H, q), 3.67 (1H, m). Example 1)? 0- (145,15 ^)-13,14-digas-15-hydroxyl-Hydroxy-Hydro-Synthesis_Spinoxin M600 mg, 0.820 mmol) was dissolved in dry ether (100 ml) . Add lithium tri-t-butoxyaluminum hydride (296 mg, 97%, 1. 13 ππηο 1). After stirring for 5 minutes under nitrogen, the reaction mixture was cooled to 78 ° C and a portion of LiAlH4 (29 mg, 0.763 mmol) was added. Stir under -7810 / nitrogen for 25 minutes. Then change the cooling bath to and continue stirring for 2 hours. Then, saline (10 ml) was slowly introduced and diethyl ether (70 ml) was added. After separating the extracted phases, wash the organic layer with brine (3x). -192-This paper size is in accordance with Chinese National Standards (〇 ^> 8 4 specifications (210: &lt; 297 mm) (Please read the precautions on the back first) (Fill in this page again). Tr. 487559 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (19) Drying with K2C03, filtering and concentrating under reduced pressure. The residue is flashed Si 〇2column (202 / ethyl acetate) was purified and followed by (: ^ 〇111 to 〇1; "(^ separation (1.0m, 10% EtOH / EtOAc). These steps provided the compound (14S, 15 S) -13,14-dihydro-15-hydroxyspinoxin A, 78 mg, 13%: π-ΝΜΙί (CDCIg, 300 MHz) d 4.80 (1H, d: 1.2 Hz), 4.37 (2H, m ), 4.25 (2H, m), 3.62 (1H, m), 3.51 (3H, CH3, s), 3.45 (6H, 2xCH3, bs), and 2.19 (6H, 2xCH3, s ) ppm.-(14S. 1 5S. 1 7S. 21S) -1, 21-Deargon-1 3. 1 4-dihydro-1, 21-Off-1. 1 5, 2 g 谌 Xin A and Π 15S)-粹--Zhong Mo Mou Li A Spinaloxin A (446 rog, 0.610 mmol) was dissolved in dry Et2O (60 m 1). Stir at room temperature under nitrogen with stirring add Lithium tri-t-butoxyaluminum hydride (148 mg, 0.583 mmol). After 10 minutes, LiMHa (19 mg, 0.50 nunol) was added and stirring was continued for 50 minutes at RT / M2. The mixture was cooled to 0 ° C and brine was added dropwise to quench the remaining hydride. Et20 (70 ml) was added and after separation of the extracted layers, the organic layer was washed with brine (3x), dried over K2CO3, filtered and under reduced pressure. Concentrated. The residue was separated on a flashed Si02 column (25 g / 5¾ Et0H in Et0Ac) to obtain compound a) (14S, 15S, 17S, 2IS) -1,2 Budeoxy-13, 14 -Dihydro-1,21-Breck-1, 15, 2, 2 Trispinoxin A, 71 mg, 15%: UMR (CDC13, 300 MHz) d 4.86 (1H, d: 1.2 Hz), 4.48 ( 1H, bd: 7.5 Hz), 4.30 (2H, m), 3.84 (1H, m), 3.45 (3H, CH3, s), 3.46 (3H, CH3, s), 3.52 (3H, CH3, s) And 2.21 (6H, 2 x C Η 3, s) ppm, and the compound (3 1 3 mg) of the compound b) product, the paper size of this paper shall apply the Chinese National Standard (CNS) A4 specification (210X297 mm) ) ------- ^-yi-- (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 B7 V. Description of Invention (19)

Further separation was repeated on a Chromatotron rotating disk (1.0 mm, 15% EtOH / EtOAc). These separations provided compound b) [(15S) -Hydroxy Spinolometer A, 79 mg, 17¾: 13C-NMR (CDCU, 75 MHz, low magnetic field region) d 172.22, 144.73, 130.94, 129.73, 128.70, 103.37, 95.47, 84.49, 82.25, 81 · 01, 79 · 03 and 77.70 ppm. Examination Example D22-(14R) -13, 14-Digas Hydroxyl Chloroxine A Dissolve Spinoxin A (2.17 g, 2.96 mmol) in ethanol (75 ml) and be careful within 5 minutes Add sodium borohydride (1.1 g, 29 mmo 1). The reaction mixture was stirred for 3 hours and carefully quenched with 1 N HC 1 (15 m 1). After the gradual reaction was completed, the crude material (1.68 g) was chromatographed on silica gel (dichloromethane / methanol, 95: 5) to provide (14R) -13,1 4-dihydrospinoxin M635 mg , 29.2%) and (14R) -13,14-dihydro-15-hydroxyspinoxin M317 rag, 14.6%), as a white solid. Compound (141? 13,14-dihydro-15-hydroxyspinoxin A: 13C-NMR d 174.75, 131.52, 128.50, 104.16, 95.34, 83.28, 82.26, 80.99, 77.74, 76.15, 76.15, 73.66, 70 29, 67.80, 64 · 82, 60 · 83, 58.94, 57.66, 44.90, 44.54, 44.54, 44.26, 42.93, 40.65, 40.38, 39.89, 37.74, 36.84, 34.91, 34.41, 33.84, 31.65, 31.17, 28.07, 19.06 , 19.06, 18.36, 17.75, 9.51, 8.77; part 1H-NMR d 7.31 (s, 1Η), 5.75 (dd, 1H), 5.87 (dr, 1H), 4.81 (s, 1H), 4.80 (m, 1H), 4.40-4.25 (m 2H), 3.95 (ηι, 1H). Examination example-(13R, r) R / S) -l 5-a certain -KΊ, 14-ring argon A shopper

Moosin A -194-The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm)

1T 487559 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (192) Compound (13R, 14S) -13, 14-methoxyspinoxin A (0.53 g, 0.71 mm. l) Dissolved in ethanol (10 ml) and added sodium borohydride (36 mg, 0.96 mmol) and stirred the reaction for 3 hours. Additional sodium borohydride (100 mg, 2.64 mmol) was added and the reaction was stirred for 72 hours. The reaction was quenched with acetone (5 ml), then IN HC1 (1 ml) was added and the reaction was gradually completed to obtain a residue, which was subjected to reverse phase HPLC (methanol / 0.1% aq. Ammonium hydroxide, 90%) : 10) Purified. The obtained compound (13R, 14S, 15S) -15-hydroxy-l3,14-epoxy spinosinol / \ (78.9Ing, 14.8%): part 1H1MR d 5.8 (d, 1H), 5.60 (dt, 1H) , 4.80 (s, 1H), 4.43 (d, 1H), 4.30 (ς, 1H), 4.09 (d, 1H), 4.01 (m, 1H), 3.78 (111,1 []); and (131 ^ 14 $, 151〇-15-hydroxy-13,14-epoxy Spinosin A (70 mg, 13¾): MS m / z 750.6. Example Π 4S) -1 3. 14-dichloro Nosin D 'The compound Spinozin D (1.00 g, 1.34 nunol) was dissolved in anhydrous tetrahydrofuran (25 ml) under nitrogen and lithium tri-t-butoxyaluminum argon (1.01 g, 3.97 mmol) was added and The reaction was stirred for 24 hours. The reaction was quenched with ethyl acetate (40 ml.) And brine (10 ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate (25 ml) and the layers were separated after filtration through filter paper. The ethyl acetate extracts were combined and washed with brine (25 ml), dried over anhydrous potassium sulfonate and concentrated under reduced pressure. The residue (360 mg) was purified by reverse-phase HPLC (methanol / 0.1¾ aq · ammonium hydroxide, 95: 5) to obtain (14S) -13,14-dihydrospinoxin DU89 mg, 18.9% ), As a white solid: MS m / z 748.7 〇42 ^ 3 Shuai 10 analysis: estimated value: (:, 67.44; 19.30; «, 1.87. Actual value: (:, 67.21; 19.20; 11, 1.69 .: . This paper size applies Chinese National Standard (CMS) A4 specification (210XM7mm) (Please read the precautions on the back before filling this page)

487559 A7 B7 V. Description of the Invention (193) Rich Example D25-1, 21-Deargon-1, 2 Bu Broken-1, 1 5, 2 Bu Sanya A. (1 5R / S)- 1 k 铮 Intermediate Novo Axin, (14R. 1 6.6.1 77 /) -17-Deargon-1fi, 17-Degas-13, 14-Di 中 Intermediate Retin A 17-Psa. And (14R) -13, 14-Dipyridine A. Dissolve Spinoxin A (5. 12 g, 7.00 mmol) in anhydrous ether (75 ml) and cool to 0 ° C. Methyl ether (15.0 ml, 7. 5 mmol) was added to a solution of lithium aluminum hydride (0.5 M) in ethylene glycol and immediately quenched by adding water (0.30 m 1 :), followed by 1 5% hydroxide Aqueous sodium solution and water (1.0 m 1). The suspended solid was filtered off and the filtrate was rotary evaporated under reduced pressure to provide a white solid (4.62 g). By reverse phase HPLC (methanol / 0.12 aq. Sodium hydroxide, 90: 10) to provide the compound 1,2 budeoxy-1,21-bran-1, 15, 2, 2 trishydroxyspin A ( 792 mg, 15 · «) · Part of 1H-NMR δ '5.88-5 · 72 (m, 2H), 4.82 (s, 1H), 4.40 (d, 1H), 4.35-4.23 (m, 2H) , 4.13 (m, 1H), 3.85-3.67 (m, 3H); MS m / z 738.7 (M + l), and (15R / S) -15-hydroxyspinoxin AC 1.13 g, 22.1%) : (First isomer) part 1H-NMR d 5.89 (dd, 1H), 5.78-5 · 72 (Please read the precautions on the back before filling this one hundred.

, 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (m, 2H), 4 • 81 (s, 1H), 4.44 -4 · 31 (m, 2H), 4. 26 (q, 1H), 4 • 04 (t, 1H), 3.83 (m, 1H); 1 3C-NMR 0 '173.53, 145.22, 132. 34, 130.14, 128. 29, 103.01, 95 • 46, 82. 26, 81. 03, 77. 72 , 76.24, 73 • 76, 67 • 89, 64 • 78, 60. 89, 58. 97, 57. 66, 47.65, 46 • 91, 46 • 90, 41 • 39, 40. 64, 39. 62, 37 39, 36.39, 31 • 20, 30 • 73, 28 .37, 27. 21, 20. 68, 19.0, 18.33, 17. 75, 10. 15, 9.80; MS m / z 734 • Ί (m + 1) ° Analysis of C41HG7NO1ϋ: Estimated value c, -196-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 Gongcheng) 487559 A7 • B7 V. Description of the invention (194) 67.09; H , 9.20; N, 1.91. Actual values: C, 66 · 96; H, 9.14; Ν, 1.94; (second isomer) part 1H-NMR δ 5.89 (d, 1H), 5.85-5.74 (m , 2H), 4.84 (s, 1H), 4.46- 4.35 (tn, 2HJ, 4.33-4.25 (m, 2H), 3.67 (m, 1H); 13C-NMR &lt; 5 172.24, 144.75, 130.96, 129.77, 128.69 , 103 .80, 95 .40, 84 • 50, 82.27, 81 .03, 79 .35, 76.71 9 76 · 20, 73 · 80, .67 · 83, 64 .65, 60.87, 58.95, 57. 66, 48. 00, 47. 78, 46. 54, 44.71, 41 · 27, 40. 63, 37 • 44, 36 · 94, 36. 36, 32. 02, 31 .36, 29. 65, 27 · 10, 19 .54, 19 · 05, 18. 34, 17 · 73, 10. 15. 7, 7; 40; MS m / z 734. 7 (m + 1) ° Analysis of C41 Η 8 7 N 0 1 0: Estimated value: C, 67 · 09; Η, 9. 20; N, 1.91-actual value: C, 66.65; Rhenium, 9.16; N, 1.85, and (14R, 1 6, 17Z) -17-deoxy-16,17-dehydro-13,14-dihydrospinoxin A 17 --- ------- This-(Please read the notes on the back before filling out this page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy-Psa (54 mg, 1.0%): Part 1H-NMR5 (5.78 ( dd, 1H), 5.86 (d, 1H), 5.66 (dt, 1H), 4.83 (s, 1H), 4.55 (m, 1H), 4,30 (q, 1H), 3.91 (m, 1H); MS (El) m / z 574, and (14R) -13,14-dihydrospinoxin A (901, 17.6¾). Example 1) 2Γ)-(1 5R. 1 4S) -1 5-dehydrogen-15-Pingshi-Γ), 6 ″ 3. 1 4-Tetrazine A and compound (1 R / S, 14S, 15R, 21 S) -1 Γ) -Deaminase-1. 1 5- 暌 -1, 2- 断 -5, Γ). 1 3. 1 4-Tetrachlorochloronoroxine A 1-Half-condensed smoke (14 $, 5,6,13,14-tetrahydrospinoxin / \ (2.6〇8, 3.53 mmol) was dissolved in dry Et20 (: 90 ml). The solution was under nitrogen Cool to 0 ° C and add Li A1H4 (951 powder, 268 mg, 6.8 mmol): the mixture applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) at the paper size 487559 A7 B7 t-Central Standards Bureau, Ministry of Economic Affairs Printed by the staff consumer cooperative V. Description of the invention (195) Stir for 10 minutes and then carefully quench it with saturated NH4CI in 10% ammonium hydroxide aqueous solution (10 ml). Generally the reaction is gradually completed and the reaction is completed in silicone (ethyl acetate, Then 15% ethanol in ethyl acetate) was chromatographed to provide a) (15R, 14S) -15-deoxy-15-hydroxy-5,6,13,14-tetrahydrospinoxin A (1. 261 g, 48%) as a white solid: NMR δ 4.71 (d, J = 1.2, 1H), 4.47 (d, J = 7.5, 1H), 4.17 (m, 1H), 4.08 (m, 2H), 3.43 (s, 3H), 3.37 (s, 6H), 0.72 (d, j = 6.8, 3Hj, CuHmNOh analysis: Estimated values: C, 66.73; H, 9.70; N, 1.90. Actual values: C, 66.44; H, 9.71; N, 1.82; and b) Compound (1R / S, 14S, 15R, 21S) -15-deoxy-1, 15-oxa-1,2-bran-5,6, 13,14-tetrahydrospinoxin A 1-hemiacetal (0,561 g , 21%) as a white solid d: ESI MS m / z 740 (M + 1). Fen Shi Example [) 27-Π 4S) -15-Go to "even -15,16 (F:)-ene" '), 6. HI 4-

1 14-tetrahydro intermediate trial IS Xin A. And deargonium-1 Γ). 1 (UR) -ene even-Γ). Fi · 1 3 _, 1 4-tetrahydro mid trial Nosin A (15R, 14S) -15-deoxy-15-hydroxy-5,6,13,14-tetrahydrospinoxin MO (484 g, 0.65 mmol) was dissolved in dichloromethane (4 ml). The solution was cooled to 0 ° C under nitrogen and morpholine sulfur trifluoride (

0. 50 m 1, 4.1 mmo 1). Remove the cooling bath and continue stirring for 4 hours at room temperature. The reaction was generally completed gradually and chromatographed on silica gel (ethyl acetate :) to provide the product mixture, which was further separated by HPLC (90:10, MeOH / H2O). Obtained: a) (14S) -15-Deoxy-15,16 (E) -alkenyl-5,6,13,14-tetrahydrospinoxin A (48 mg, 10%), white Solid ·· UMR _ 198-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) ----.-- L --------- 1T ------ IP -. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 ___ B7 ______ Master and Invention Instructions (196) 5 5.28 (d, J = 9.9, 1 Η) , 4.83 (s, 1Η), 4.72 (m, 1Η), 4.21 (m, 4Η), 3.52 (s, 3Η), 3.47 (s, 3Η), 3.46 (s, 3Η), 1 41 (s, 3H); 1 &gt;) (14 $, 151 ^ / 3) -15-generation-5,6,13,14-tetrahydrospinoxin A (60 mg, 12¾), white Solid: 'H-NMR ό' 4.96 (d, J = 46.8, 0.4H), 4.19 (dd, J1 = 66, J2: 9, 0.6 H), 4.83 (d, J 2.2, 0.6 H), 4.31 (d, J = 1,2, 0.4 Η), 3.53 (s, 3 Η), 3.46 (s, 6 H); and (14S) -15 -deoxy-15,16 (E ) -Alkenyl-5,6,13,14 -Tetrahydrospinoxin A (152 mg, 32%), white solid crossbone UMR δ 5.24 (d, J = 10.8, 1H) &gt; 4.80 (d, J = 1.2, 1H), 4.79 (m, 1H), 4.34 (d, J = 7.4, 1H), 4.20 (m, 3 H), 3.51 (s, 3H), 3.45 (s, 6H), 1.66 (s, 3H). Fen 旃 Example [^ only -1: ^ 141-Shinolyl-Zinobinoxine Eight sodium hydride (60¾ distributed in oil, 52 mg, 1.3 mmol) was weighed into a flask and placed in a nitrogen ring gas . The suspension was mainly stirred with pentane (2 ml) and the pentane was removed by a pipette. Removal of residual pentane by evaporation under a stream of nitrogen. Suspend the dried MaH in DMS0 (4 ml), cool the resulting slurry to 15 ° C and add iodide dimethyl oxide mirror in a single portion (caution-initial vigorous gas generation). (286 mg, 1.3 mmo 1). The reaction mixture was stirred at this temperature for 40 minutes while the mixture was a clear solution. A solution of Spinolsin Aug? Mg, 1.13 mmol.) In dry toluene (1 ml) and DMS0 (1 ml) was added dropwise over 5 minutes. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C, diluted with Et20 and quenched with saturated sodium bicarbonate solution and water. The mixture was partitioned between Et20 and a saturated sodium bicarbonate solution. Extraction with Et2〇 ------.---- (Please read the precautions on the back before filling this page)

、 1T This paper size applies Chinese National Standards (CNS) Λ4 specifications (210X 297 mm) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (197) Water layer and combined ether phase and washed with water (3 times), diluted with sodium hydrogen sulfonate and salt. The mixture was dried over anhydrous sodium sulfonate and the solvent was removed under dry nitrogen to give a white solid (812 mg). The solid was chromatographed on silica gel (81 g) with EtOAc followed by 2% MeOH in EtOAc as the eluent to give a white solid (785 mg, 93¾). UMR S loss 6.85 (br s, 1H); MS m / z 746.5 (M + H estimate, 746.5).

Rich example [) 29-13. 14-cycloargon-15-hydroxyspinoxin J compound 13,14-epoxyspinoxin with 25〇11 ^, 0.3. 111] At Et 2 0 (20 m 1). The mixture was stirred vigorously under nitrogen at room temperature and lithium tri-t-butoxyaluminum hydride (153 mg, 0.6 mmol) was added. Continue stirring for 18 hours. The reaction mixture was quenched with brine and extracted with ether (3 X 20 ml). The ether extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on preparative TLC (EtOAc) to provide compound 13, 14-epoxy-15-hydroxyspinoxin M140 mg, 56%) as a white solid. mp 90-91〇C; MS m / z 750; ^ -NMR (CDC 1 3, 300 MHz) 5.81 (1H, d), 5.62 (1H, d), 4.80 (1H, s), 4.42 (1H, d ), 4.30 (1H, m); 13C-NMR (CDCla, 300 MHz) 172.2 (lactone C = 0), 85 · 2 (C-OH.).

Examination example [) 30-1 · 3 · 14-dichloro-2- 荥 ffi ffi g Φ g 1 ¾ A Ambient at -30 ° C bisisoamphenicol (1.01 ml, 7.7 mmol) To THF (20 ml) solution was added η-butyllithium (4.8 ml, 7.7 mmol) and HMPAU.O ml) and cooled to -4 (TC. Spinoloxin M.O. g, 1.4 mmol) in THF (10 ml) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was quenched with ammonium chloride solution (10 ml). The paper size is in accordance with Chinese National Standard (CNS) A4 specification (2 丨 0χ 297 mm) ---- · --ϋ ----- (Please Read the notes on the back before filling this page), 1T 487559 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (post) and extraction with ether (3x40 ml). The ether extracts were combined and dried over anhydrous ^ 2304 and concentrated under reduced pressure. The residue was chromatographed on a preparative (1:18) column and diluted with a methanol solution of 10¾ water (0.1¾ NHJH) to obtain compound 13,14-dihydro-2-phenylselenospinoxin Mo · 24 g, 19%), as a white off solid. 1Η-NMR (CDC 1 3, 300 MHZ) 7.55 (2H, m), 7,25 (3Η, m), 6.01 (1H, m), 5,85 (1H, m), 3.97 (1H, d ).

Example of richness ΓΚΉ 富 Funosin A in U-DiM. Compound (2Z) -2,3-dihydrospinoxin A (20 mg, 0.03 mmol) was dissolved in Et 2 0 (5 mL). The mixture was stirred vigorously under nitrogen at room temperature and lithium tri-t-butoxyaluminum hydride (7.6 mg, 0.03 mmol) was added. After stirring for 18 hours, lithium tri-t-butaneyl aluminum hydride (7.6 mg, 0.03 μm) was added. Stirring was continued for 1 hour. The reaction mixture was diluted with brine and lifted up with ether (3x15 ml). The ether extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on a 018 column of preparative HPLC and eluted with 10% water (a methanol solution containing 0.1! ^ [14〇 [〇 to obtain compound 3,14-dihydrospinoxin Mil mg, 50¾), Off-white flake solid. 1Η-NMR (CDCl 3, 300 MHz) 5.95 (2H, m), 4.91 (1Η, s), 4.70 (1H, s); 13C-NMR (CDCla, 300 MHz) 206.1 (C = 〇 &gt;, 168, 9 (lactone C = 0), 144.7 (fourth-order C &lt;), 138.0 (fourth-order C =); MS m / z 732 〇F: Partially-formed g formula ^ ^ Sanjiao's 017 position BR-based decoration example FJ -17- argon _17_ amine very intermediate test A 17-Pm -201-· This paper size applies Chinese National Standard (CMS) A4 specification (210X297 mm) (please (Please read the notes on the back before filling out this page)

Five Λ invention notes (whistle) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was added to a 17-Pistol Spinoxin A 17-Psa (318.7 mg, 0.54 mmol) in methanol (6 m 1) solution, and ammonium acetate ( 417 · 1 mg, 5 · 4 in m ο 1) and then add sodium borohydride (45 mg, 0 · 76 mmo 1). The reaction mixture was stirred at room temperature for 5 days. The solvent was evaporated at room temperature under reduced pressure. The residue was dissolved in IN HC1 and washed with ether. The aqueous layer was then basified with 5N HaOH and saturated with sodium chloride. The aqueous layer was then extracted with fresh ether. The ether portion was washed with brine, dried over K2CO3 and evaporated at room temperature under reduced pressure. The obtained 17-deoxy-17-aminospinoxin A 17-Psa (68.2 mg; yield 21¾) was a colorless glass, a 7: 1 mixture of isomers, FDMS, π / e (relative Intensity) 744 (5), 591 (20), 590 (MH +, 40), 112 (100). Example E2_ (1 β. 1 7Z) -1 7-deargon and even osmium 6. 1 7-deargon octyl A 17 -Psa in M-methyl spinosin A iodide (203.7 mg, To a suspension of 0.23 mmol) in THF (9 ml) was added sodium hydride (50¾ of mineral oil suspension, 42.9 mg, 0.89 mmo 1). The reaction mixture was heated to reflux temperature for 1 hour, and then extracted with ether. The ether portion was washed with brine, dried over K2CO3 and concentrated under reduced pressure at room temperature. The crude product was chromatographed on gasified silicon, hexane and then 40% ethyl acetate in hexane, and then dissolved in one step. The resulting (16,17Z) -17-deoxy -16, 17-dehydrospinoxin A 17-Psa (89.5 mg, yield 67¾), white glass, FDMS, m / e (relative strength) 1 144 (20), 573 (M +, 60 ), 〇1 (100) 〇 Example E3-(16, 17E) -17- deargon -16, 17- desulfonate inoxin A 1J -Psa, _ (17, 18F :) -17- Fengqi -17. 18- 关 Ｍ 客 谌 •-202-The paper size is in accordance with the Chinese National Standard (CNS) Λ4 specification (210 X 297 mm) 丨 rf I (Please read the precautions on the back before filling in this Page) __a ·

1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (2 (70) Xin 17- 卩 ^ and (16,172) -17-Dehydrogen-16.17-Nuoxin A 17 -Psa The reaction was carried out as described in Example E2, starting with Spinozin A (5.1 gm, 6.97 mmol). The product was separated on a C18 column by preparative HPLC and acetonitrile · methanol : 0.1% NH 4 0Ac (20: 40: 40). The obtained (16, 17E) -17-deoxy-16, 17_dehydrospinoxin A 17-Psa (119 mg; yield 3%), FDMS, m / e (relative strength) 572 (M, 100), (17, 18E) -17-deoxy-17, 18-de. Hydrogen Spinozin 17-Psa (634 fflg; 16% yield), FDMS, m / e (relative strength) 572 (M, 100), and (16,17Z) -17-deoxy-16,17-dehydrospinoxin A 17-Psa ( 6 89 mg; yield 17t) are all white solids. Rich example E4- (5R. FiR) -5- (2-fluorenylethylarginyl 6-bromosulfonyl A-1_7-P sa Yu Shibin To a suspension of norsin A (154.1 mg, 0.21 mmol) in ethylene glycol (5 ml) was added N-bromosuccinimide (79.8 mg, 0.45 mmol). The reaction mixture was heated to 80 ° C for 1.5 hours And then cooled to room temperature

The mixture was diluted with dichloromethane and washed with water. The dichloromethane portion was then washed with brine, dried over K2CO3 and evaporated at room temperature. The product was separated by chromatography on silicon chloride and eluted with 70% ethyl acetate in hexane and then with 5% methanol in dichloromethane. The obtained compound a) Spinoxin A 17-Psa (41.7 mg; yield 34¾) was a colorless glass. (5R, 6R) -5- (2-Hydroxyethoxy) -6-bromospinoxin A 17-Psa in 70% ethyl acetate in hexane was further purified by chromatography on silicon chloride. Dissolution. Resulting compound b) (5R, 6R) -5- (2-hydroxyethylamino) -6-bromo spinosinoxin A -203-This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the notes on the back before filling out this page), τ printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 * B7 V. Description of the invention (2001) 17-Psa (50.2 mg, yield 33¾), It is a colorless glass, FDMS, m / e (• relative strength) 734 (~ 5), 732 (MH +, 60), 189 (100). Fushi Example H (5R. 6R) -5. Fi-fluorenyl-1-7-0-dimethyl-1, S-pentane, and 17-Psa in (5S, 6R) -5,6-epoxy Nosin A 17-Psa (503.7 mg, 0.83 mmol) in diethyl ether (20 ml) was added with chlorotrimethylsilane (211 ml, 1,66 mmol) and diisopropylethylamine (289 ml, 1.66 miu 〇1). The reaction mixture was stirred at room temperature for 23 hours, and then additional chlorotrimethylsilane (105 ml, 0.83 1 «〇1) and -diisopropylethylamine (144 ml, 0.83 mmol) were added. The reaction mixture was stirred for an additional 18 hours at room temperature. The ether was decanted and the residual precipitate was triturated with fresh ether. The ether portions were combined, washed with saturated aqueous NaHC03, dried over K2CO3 and evaporated at room temperature under reduced pressure. The crude product was purified by chromatography on silica and eluted with 50¾ ethyl acetate in hexane. The obtained (5R, 6R) -5,6-epoxy-17-〇-dimethylsilyl spinosin A 17-Psa (521.1 mg; yield 92¾) was a colorless glass, FDMS, m / e (relative strength) 679 (75), 678 (M, 100), 190 (30), 100 (35.). Fenshi M-(5R, 6R) U- 甚 "Verydroxin A 17-Psa in a solution of Spinozin A 17-Psa (1.0 gm, 1.71 mmol) in dichloromethane (45 ml), Add m-chloroperbenzoic acid (591.7 mg, 3.34 mmol). The reaction mixture was stirred at room temperature for 23 hours. The mixture was diluted with dichloromethane and washed with saturated NaHC03, dried over K2CO3, and evaporated at room temperature under reduced pressure. The crude product was purified by chromatography on silica and eluted with 15% acetone in dichloromethane. The obtained (5R, 6R) -5,6-epoxy '-204-The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

1. 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 * B7 ______________- V. Description of the invention (202) Kespinoxin A 17-Psa (1.04 gm; yield about 100¾), colorless glass Object, FDMS, m / e (relative intensity) 607 (M, 70), 190 (100), 101 (99). Enrichment Example E7-1 7-keto-Zinobinoxine A iUsa Suspension of N-chlorobutanediimine (108,6 mg, 0.81 mmol) in dichloromethane (2.6 ml) at -78 ° C Add isopropyl sulfide U25 ml, 0.86 mmol). Stir the reaction mixture at -78 ° C for 30 minutes, and then slowly add pentospinoxin A 17-Psa (150 · 1 mg, 0.25 mmol). Dichloromethane solution (1 ffl 1). The reaction mixture was stirred at -78 ° C for 3 hours, then triethylamine (109 ml, 0.78 mmol) was added and when the color turned red, the reaction mixture was warmed to room temperature and then the mixture was diluted with dichloromethane, It was washed with 0.1N HC1, brine, dried over MgS04 and evaporated at room temperature under reduced pressure. The crude product was purified by chromatography on silica and eluted with 40¾ ethyl acetate in hexane. The obtained 17-keto-spinoxin A 17-Psa (84.7 mg; yield 58¾) was a colorless glass, FDMS, m / e (relative strength) 588 (M, 100). Enriched Example E8 -1 7-Dehydrogen-1 Γ). 17-Degassed Spinoxin_A Ag The reaction was performed as described in Example 3, using Spinoxin J (15.02 gm, 21 mmol) as Starting material. After the methanol solution of K2CO3 was treated, the reaction mixture was filtered and evaporated at room temperature under reduced pressure. The residue was kept at room temperature for 24 hours without further purification, followed by trituration with dichloromethane followed by evaporation of the dichloromethane at room temperature under reduced pressure. The crude product was purified by chromatography on silica and eluted with 5¾ methanol in dichloromethane. The obtained crude 17-deoxy-16, 17-dehydrospinoxin / \ Ag, is a yellow semi-solid and the history of -205-The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2l0x 297) ）) 丨 * (Please read the precautions on the back before filling out this page) Order 487559 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (203) Binoxin A 9-Psa (1.02 gm Yield: 9%) as a colorless glass. Crude 17-deoxy-16,17-dehydrospinoxin A Ag was further purified by preparative HPLC on a C18 column with acetonitrile: methanol: 0.1% NH4〇Ac (35:35: 30) Dissolution. The pure 17_deoxy-16, 17-dehydrospinoxin A Ag (1.81 gm; 224 yield) was obtained as a white glass, FDMS, m / e (relative strength) 460 (10), 385 ( M +, 55), 384 (100). Enriched Example M-17-Deargon-17-Hexan-13, 14-Dichloro-13-Gag Nosin A 17-Psa Dissolve the compound Spinoxin A (97 mg, 0.13 mmol) To 5 mL of methanol, potassium cyanide (59.8 mg, 0.92 mmol) was added and the reaction was stirred overnight. After the gradual reaction was completed, the crude product (0.05 g) was chromatographed on silica gel (ethyl acetate / hexane 20 · 80 to 50 · 50 gradient) to provide compound 17-deoxy-17-cyanide Base-13, 14-dihydro-13-fluorenyl spinosyn A 17-Psa (18,9 mg, 20.2¾) as a white solid: IR (KBr) 3019, 2971, 2933, 2823, 2240, 1723, 1481, 1104, 1038, 732 cm-1; 13C NMR (5 171.86, 131.87, 126.64, 121.49, 120.18, 96.01, 82.72, 81.61, 78.36, 75.98, 68.65, 61.42, 59.61, 58.36, 56.37, 48.30, 47.09, 46.75 , 44.58, 43.41, 41.80, 37.48, 36.57, 34.15, 33.53, 30.23, 28.63, 27.47, 22.97, 22.22, 18.32, 13.26, 10.42; FDMS m / z 628. C42H88N2O1Q analysis: Estimated value: C, 66.46; Η, 8.76 · Actual value: C, 65.84; Thallium, 8.14. Example Π0-17- Deodorant, -η-"? 〃 '-(dimethylformate even) ethyl ester 16, 17- (7. Bu Jingxun Zhongke Xing J 17-Psa This paper size is applicable to Chinese National Standard (CNTS) A4 (210 X 297 mm) (Please read the notes on the back before filling this page) Order 487559 Central Bureau of Standards, Ministry of Economic Affairs A7 B7 printed by employee consumer cooperatives Ming (204) Spinoloxin J (1.20 g, 1.67 mmol) was reacted with 1-chloro-2-dimethylamineethane (the hydrochloride was formed in situ), followed by 3, -0, N -The procedure described for bis (trideuteryl) spinoxin M. Chromatography on silica gel (ethyl acetate) and HPLC separation (88:12, MeOH / H20) to provide 17-deoxy-3 [2W-(dimethylamino) ethylbulfene 16, 17- (Z) -alkenyl spinosinol J 17-Psa (: 109 mg, 101), as a white solid: UMR δ 6.39 (s, 1 Η), 5.63 (m, 1 H), 2.18 (s, 6Η), 1.84 (s, 3Η). Examination example Π 1-(13R. 14S) -13. 1 4- 璟 《中 中 柒 柒 辛A, Compound 1 3R · 1 4S) -16, 1 7-Deuterium-1 7-Sadium Argon-1 · 17 (Z) -—— ene-1 3.14-Sadium Arsenic A 1 7- Psa, and chemical compounds (1 3R, 1 4S. 1 M. 1 7R) -1 7-desarginyl-13, 14-cycloargon and even -1 β "7-ammonium acetamidine A 1 7-Psa Dissolve Spinoxin A (5.06 g, 6.91 mmol) in ethanol (35 mL). Then tetrahydrofuran (15 mL) was added, followed by 10% aqueous NaOH solution (15 mL.) And 30% aqueous hydrogen peroxide solution (6 mL, excess). Stir at room temperature for 4 hours. Generally, it is gradually formed and chromatographed on silica gel (ethyl acetate) to obtain: a) (13R, 14S) -13,14-epoxy spinosin A (3.18 g, 61.5%), as a white solid: ESI MS m / z 748 (M + l); and b) a mixture of less polar compounds, which was subjected to flash silica gel column chromatography (7¾ Et20 in dichloromethane) to obtain: c) (13R, 14S) -16, 17-dehydro-17-deoxy-16, 17 (Z) -alkenyl-13, 14-epoxy Spinozin A 17-Psa (280 rag, 6 · «), White solid ^ H-NMR δ 5.40 (m, 1 Η), 3.45 (s, 3H), 3.39 (s, 3H), 3.38 (s, 3H), 1.72 (s, 3H); and d) (13R , 14S, 18S, 17R) -17-Degas-based-13 -207-The size of this paper is applicable to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page) Order 487559 A7 B7 V. Description of the invention (205), 14-epoxy-16, 17-epoxy spinosin A 17-Psa (97 mg, 2.34), white solid: iH-NMR δ 4.47 (οι, 1H), 3.81 (s, 1Η), 3.43 (s, 3Η), 3.38 (s, 6Η), 1.37 (s, 3Η). Example N12- (2 R / S ')-m7-dihydro-17-dechloro-16 · 17 (E / Z) _ 悌 中 中 蒈 谌 辛 F__17-Psa diisopropylamine (0.658 mL, 5.0 mmol) was dissolved in dry THF (10 niL.). The solution was cooled to -23 ° C under nitrogen and n-BuLi (2.5 mL of a 2.5M hexane solution, 2.0 mL, 5.0 mmol) was added dropwise. Stir at -23 ° C for 30 minutes and cool the mixture to -78 ° C. Spinoloxin F (1.03 g, 1.434 mmol) of dry THF (3 niL) was added dropwise to the reaction mixture. After 5 minutes, the reaction temperature rose to -23 ° C. After 48 minutes , Iodoethane (1.25 m L, 15.6 mm 〇1) was introduced. Use the sensation to allow the temperature to rise to room temperature within 2.5 hours. Usually gradually formed by reaction and chromatography on silica gel (ethyl acetate) to obtain the product (441 mg). Repeat chromatography on silica gel (ethyl acetate). (2R / S) -16,17 provided -Dihydro-17-dechloro-16, 17 (E / Z) -alkenyl-2-ethylspinoxin F 17-Psa (152 mg, 18%) as a white solid: lH-NMR δ 6.60 (m, 0.33 Η), 6.50 (s, 0.33 Η), 6.29 (s, 0.33 Η), 5.60-6.05 (m, 3Η), 4.78 (s, 1H), 3.46 (s, 3H), 3.40 ( s, 6H), 0.75-0.92 (3 xt, 6H). ESI MS m / z 587 (M10 1) 2 mg, 0 · 37 mmo 1) Add to cold (-20 ° C) 17-ketospinoxin A 17-psa (220 mg, 0. 37 mmol) and Aromatic (III) heptahydrate ( 140 mg, 〇 · 37 mmol) of methanol This paper size is applicable to Chinese National Standards (CNS) A4 (2 丨 0X 297 mm)--* ί Ⅱ ^^ I (Please read the precautions on the back before (Fill in this page) Order Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumers' Cooperatives of the Central Standards Bureau 487559 A7 ___ B7 V. Description of the Invention (206) (6 mL) solution (note: foaming and H2 release). This mixture was stirred at _2 ° C for 20 minutes, then quenched at this temperature by adding IN HC1 (0.5 mL) dropwise over 2-3 minutes. Then the mixture was diluted with ether (40 mL) and brine The organic layer was washed with (2x5 niL) and dried over MgSO. After concentration, 290 mg of a solid residue was left, which was flash-chromatographed with silicon chloride (40 ml) using 3¾ MeOH (^ 2 (: 12 The eluate was obtained to obtain 220 mg of a white powder, which was a 4: 1 mixture of 17-epi-Spinoxin A 17-Psa and Spinoxin A 17-Psa. C18 was bonded by reverse phase HPLC Silica column (41.4 mm (id) X 25 cm (1)) was separated and 15% H2O in MeOH was used as the solution. Spinozin A 17-Psa was first precipitated. 17_ 表-Spino Semi A 17-Psa: 106 mg; white powder; 1H MMR (CDCh) δ 6.78 (s, 1Η, Η-13), 4,86 (d, 1Η, Η-1,), 4.83 (m, 1Η, Η -21), 4.32 (m, 1Η, H-9), 3.90 (m, 1Η, Η-17). In the F part of the compound, the 谌 (Α, 夕, 璟, 璟) part f &gt; 5 and 0Γ) position Ffe 的 ffe Decorative Example FI-(! 5R. FiR)-5- (2- 锊 some 7, «even)-Brbrinobinoxin A in Spinoxin (1.0 gml 1,37 mmol) and M -Bromobutene To a suspension of hydrazone (289.5 mg, 1.63 mmol) in ethylene glycol (20 ml), 5 N HC 1 (29 5 ui, 1.47 mmol) was added. The reaction mixture turned yellow and stirred at room temperature for 1 5 hours, during which the color fades to clear. The mixture is poured into saturated aqueous NaHC0 solution and extracted with ether. Ethyl acetate is dried over MgS04 and evaporated at room temperature under reduced pressure. Crude (5R, 6R .)-5- (2-Hydroxyethoxy-6-bromo spinosinoxin A (896 · 8 mg, yield 75%). || The compound was purified by chromatography on gasified silica with 5% methanol Dichloromethane solution solution of this paper applies the Chinese National Standard (CNS) A4 specification (2 丨 ϋ χ 297 mm) ----- ^-* --- clothing-(Please read the precautions on the back first (Fill in this page)

, 1T 487559 A7 B7__ V. Description of the invention (20) Analysis of (5R, 6R) -5- (2-hydroxyethoxy) -6-bromo spinosinol as white glass, FDMS , m / e (relative intensity) 873 (100),

871 (Μ, 80K

Example F2- (5S. M)-5,6-dipyridine-5,6-diargonoxine A in spinoxin A (487.8 mg, 0.67 mmol) and trimethylamine-N-oxidation Dihydrate (108 .mg, 0.97 mmol) in aqueous (0.5 ml) t-butanol (3 m 1) suspension, add Dtt spin (60 m 1, 0.7 4 mm ο 1) and then add Iron tetraoxide (0.1 M; 40 m 1, 0.0 0 4 mm ο 1) ϋ The reaction mixture was heated to a reflux temperature under a nitrogen atmosphere for 19 hours. The dark mixture was then cooled to room temperature and poured into an aqueous solution of NaHSO3 and extracted with ether. The ether portion was washed with brine, dried over MgS (U, and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and eluted with 7¾ methanol in dichloromethane. The resulting (5S, 6R :)-5,6-dihydroxy-5,6-dihydrospinoxin A (282.1 mg; yield 55%), beige solid, FDMS, m / e (relative strength) 766 (M +, 60 ), 765 (100). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). Example F3- (5R)-5- (2-Wait 7 argon)- fi. 7-guan chloride in hydraxine A in (5R, 6R) -5- (2-hydroxyethoxy) -6-bromo spinosyn A (299.9 mg, 0.34 mmol) in anhydrous THF ( 10 ml) solution, sodium sulfide (50% mineral oil dispersion; 69.3 mg, 1.4 4 mm ο 1) was added and the gas was released. The reaction mixture was stirred at room temperature for 3.5 hours, and then poured into Water. The water portion was extracted with ether. The ether portion was washed with brine, dried over K2CO3 and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica, 5% methanol in dichloromethane Elution. (5R) -5- (2-Hydroxyethoxylate) ) -6,7-Dehydrospinoxin A (123.9 mg; yield paper size applies to Chinese National Standard (CNS) Λ4 specification (210.X 297 mm) ^ 7559 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (208) 50%, based on the recovered starting material), light yellow glass, FDMS, m / e (relative strength) 791.8 (M, 100) ， 419.5 (30) 〇 Rich Example F4- (5S · flR) -Zhongpinoxin A carbon p pi is intended for (5S, 6R) -5,6-dihydrospinoxin A (85 mg, 0.11 mmol) and ethylene carbonate (109.2 mg, 1.2 mmol) in benzene (3 ml), anhydrous K2C03 (40.2 mg, 0.29 m π 1) was added, and the mixture was heated to reflux temperature at 2.5 After hours, the mixture was cooled to room temperature and diluted with dichloromethane. The dichloromethane portion was washed with water, brine, dried over K2CO3 and evaporated at room temperature under reduced pressure. The layer was passed over silica The purified product was separated and eluted with 7% methanol in dichloromethane. The obtained (5S, 6R) -spinoxin A carbonate (65.1 mg; yield 75%) was a white solid, FDMS, m / e. (Relative strength.) 792 (Mf, 70), 791 ( 100).

富 例 例 F5- (! 5S. Μ) -5-Ethylpyridine and Zhang Kexinxin A and (5R, 6R) -5 -Ethyl Chloride-5.fi -Dihydro History Trial Xin A In a solution of Spinozin A (511.7 πδ, 0. 7 ιπιποί) of Bing Jue η S12 (〇in 1), N-bromosuccinimide (152.9 mg, 0.86 mmol) was added at room temperature. Stir for 24 hours and slowly pour 5Np NaOH (35 ml). The aqueous mixture was then saturated with NaC 1 and extracted with ether. The ether portion was extracted with brine, dried over K2CO3 and evaporated at room temperature under reduced pressure. A crude mixture was obtained (544.2 mg). The mixture was purified by chromatography on silica, eluted with 7% methanol in dichloromethane, and the isomers were separated by preparative HPLC on a C18 column with acetonitrile: methanol: 0.1¾NH4〇Ac (41: 41: 18 to 42: 42: 16, at 60 minutes linearity). Result (5S -211-This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

, 1T

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs of the Employees' Cooperative of the Invention (29.0), 6S) -5-Ethoxy-6-bromospinoxin A, FDMS, m / e (relative strength) 874 (50) , 873 (98), 872 (48), 871 (Mf, 100) and (5R, 6R) -5-ethoxyl-6-bromo-5,6-dihydrospinoxin A, FDMS, m / e (relative strength) 874 (60), 873 (90), 872 (45), 871 (Μ, 100), as a white solid. Fenxi F6-5. 6-dioxopineoxine A 1 7-Psa In a solution of spinosyn A (257.2 mg, 0.35 mmol) in tetrakis tetrachloride (10 ml), add bromine (18 ml , 0.3 5 mmol). The reaction mixture was stirred at room temperature for 20 hours, during which the color of the reactants faded to pale yellow. The solvent was evaporated at room temperature and under reduced pressure, however, TLC (dissolved in 1 (U methanol in dichloromethane)) showed incomplete reaction. The residue was redissolved in carbon tetrachloride (10 ml) and bromine ( 18 ul, 0.3 5 mmol). The reaction mixture was stirred at room temperature for 3 days, during which the color of the reactants faded. Then it was diluted with dichloromethane and washed with 5% sodium thiosulfate. The dichloromethane portion was dried with MgSO 4 And evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and eluted with 3¾ methanol in dichloromethane. The resulting 5,6-dibromospinoxin A 17-Psa ( 142.9 mg; yield 5 «) as a white solid, FDMS, m / e (relative strength) 750 (M +, 10), 189 (30), 101 (100). Case Study Dihydrohistory Nosin A ( 246088) Spinoline A (5 0 4 mg; 0 · 6 9 m in ο 1) of dry benzene (3 0 m 1), with the addition of the atmospheric tris (triphenylphosphine) hook I (50 · 6 mg; 0 · 055 mmol) and the mixture was placed in an atmospheric generator under hydrogen. Stirred with magnet (not monitored temperature) for 6 hours and then maintained under nitrogen environment for 19 hours. A small amount of NMR showed anti-212-paper size Applicable in China Home Standard (CNS) Α4 size (210X297 mm) ----.-- W ----- (Please read the Notes on the back to fill out this page)

1T 487559 A7 B7 V. Description of the invention (210) 2/3 should be completed by appointment. Additional tris (triphenylphosphine) phosphonium chloride (50 rog; 0. 055 mmol) was added and the mixture was replaced with hydrogen. The magnet was stirred for another 24 hours and evaporated at room temperature under reduced pressure. The residue was initially subjected to flash chromatography on silica using 5¾ MeOH in dichloromethane. The resulting product (489. 1 mg) was a yellow glass 9 substance. The product was further purified by delta-preparative reverse-phase HPLC with CH3CN [38%] · MeOH [38%]: 0.005% NM40AC [24%] to CH3CH [45%] · MeOH [45%]: 0.05¾ NH4〇Ac [10%] gradient elution. The obtained 5,6-dihydrospinoxin A (246088) (275.4 mg; yield 54%) was a pale yellow-white glass. Partial ^ -NMR (CDCla δ 6.82 (1H, bs), 4.79 (1Η, s), 4.61 (1Η, m), 4.39 (1Η, bd), 4.17 (1Η, bq), 3.23 (1Η, m), 2 · 90 (1Η, m), 2.76 (1Η, m), 2.50 (1Η, in), 0.97 (1Η, m), 0.64 (1Η, ι).

Example FS- (5S, BR) -5. Β-cycloargonyl keinoxine A and (T) R. (KS)-璟 g A kekexin A of the Central Government Bureau of Consumer Affairs, Ministry of Economic Affairs System ---- *-m ----- (Please read the precautions on the back before filling this page) Under nitrogen, (5S, 6R) and (5R, 6S) -epoxy Spinozin A To a 6: 1 mixture of 300 ml chloroform solution of N-oxide (2.6 gms; 3.4 mmol), triphenylborane (823 mg, 3.4 mmol) was added and stirred at room temperature for 6 hours. The reaction was diluted with dichloromethane and washed with IN NaOH. The dichloromethane portion was dried with 1 (2: 03 and evaporated under reduced pressure to obtain a white off-glass (2.57 gins). The crude material was purified by delta preparative reverse-phase HPLC with MeOH [42%]: CH3CN [42¾]: 0.25% NlUAc [16¾] was eluted for 22 minutes and then MeOH [45%]: CH3CN [45%]: 0.25% NH4OAc [10¾] was eluted for 14 minutes. The obtained ( 5S, 6R), 5,6-Ring-213-This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) ^ 59 ^ 59 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs i. Invention Explanation (211) Oxy Spinnoxin A (0.26 gms, 11¾), some UMR (CDCla) d 6.71 (1Η, bs), 4.86 (1Η, s), 4.71 (1Η, m), 4.42 (1Η, bd), 4.30 (1Η, bq), 2.56 (1Η, dr), 2.47 (1Η, dd), and (5R, 6S) _epoxy Spinozin A ( 1.3 gms; yield 54%) 1H-NMR (CDCla) δ 6.59 (1H, bs), 4.86 (1Η, s), 4.68 (1Η, m), 4.42 (1Η, bd), 4.23 ( 1Η, bq), 2.59UH, dt), 2.45 (dd) are all white solids.

Example F9-JR)-argon argonium g oxin D and (5R, 6S)-cyclolanthyl g oxin D D The reaction was performed as described in Example F9, with (5S, 6R) and (5R, 6S) ) _A mixture of 6: 1 epoxy-spinoxin D, N-oxide (450 mg, 0.58 mmol) was used as the starting material. The obtained (5S, 6R) -epoxy spinosinol D (16 · 4 mg, «) 1H-NMR (CDC13) 0 '6.71 (1Η, bs), 4.53 (1H, m), 1.40 ( 3H, s), and (5R, 6S) -epoxy Spinolol half 0 (82.1 mg; yield 191) part 1H-NMR (CDC13.) Δ 6.59 (1Η, bs), 4.85 (s), 4.6S (1H, m), 4.42 (1H, bd), 4.23 (1H, bq); 2.56 (1H, dt), 2,41 (1H, dd), 1.39 (3H, s) are all white solids. Low yields are due to loss on reverse phase HPLC columns. Example F1 0-(55:. 6R) and (5R, 6S) diepoxy 棊 Spinolol A, Nτ ·. Oxide compound in Spinoloxin A (212 · 2 mg, 〇 · 238 mmol; 82.1¾ purity) in 10 ml of dichloromethane, add m-chloroperoxybenzoic acid (135 mg, 0.771 mmol) and stir at room temperature for 3 hours. Partitioned between saturated NaHCO3 and dichloromethane: The phases were separated and the aqueous layer was extracted with fresh dichloromethane. Consolidated paper standards are applicable to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the notes on the back before filling out this page),-ιτ 487559 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-A7 B7 V. Description of the invention (212) The organic layer was dried over MgS04 and evaporated under reduced pressure to obtain a white solid (246.3 mg). Chromatography on silicon chloride to purify the crude product, using 10¾ MeOH in dihydromethane solution to 20% Me0H in dichloromethane solution in one step. The obtained (5S, 6R) and (5R, 6S) _cyclochlorospinoxin A, N-oxide 6: 1 mixture was a white solid (181.2 mg; about 100%); part 1H-NMR (CDC13) δ 6.71 and 6.60 (1Η, s), 4.87 (1Η, s), 4.76 (ra, 1Η), 4.70 (1H, m), 4.32 (1H, m), 4.26 (1H, m), 3.42 (s), 3.31 (s), 3.24 (s). The rich example m- (5S, 6R) and fluorene arginyl Φ binosin D, N-chloride were reacted as described in Example F10. Spinoloxin D (517.9 mg, 0.70 mmol) was used as the starting material. . The obtained (5S, 6R) and (5R, 6S) -epoxy Spinoxin 6: 1 mixture (450.4 mg; yield 83%) of the spinoxin D, N-oxide was yellow glass. Partial l-NMR (CDC13) 0 '6.71 and 6.60 (1H, s), 1.40 (3Η, s) ‘

Fen Lu Case Π 2-(5R. 6R) -Γ), β-Dibromo-4 ”-Breed 1 Very Zhong Ke Mou Xin A and (5R, 6 R) -5. Fi-Er Chun Zhong Xiu Xin B The compound Spinozin M1.98 g, 2.70 mmol) was dissolved in CH2C12 (90 m 1). Triethylamine (10 m 1) was added and the reaction mixture was cooled to 0 ° C.丨 Half added odor (5.0 s, 27.8 ιπιποΐ.). After 15 minutes, increase the temperature to room temperature and continue to stir for 30 minutes. Dilute the mixture with CH2C12 (100 m 1) and continue with water (2x) And 10iUlaHS〇3 aqueous solution were serially diluted: the organic layer was dried with K2C03 and concentrated under reduced pressure. The residue was flashed in a Si02 column (230-400 m, 120 g / Et0AC, followed by EtOH) to obtain the Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) ---- ί -------- (Please read the precautions on the back before filling this page), 11 487559 Central Standard of the Ministry of Economic Affairs A7 _. B7___ printed by the Bureau ’s Consumer Cooperatives V. Description of the Invention (213): a) Compound (5R, 6R) -5,6-dibromo-4 ”-_ kispinoxine A (342 mg, 15¾) IR (KBr) v 1720, 1660, 740, 595 cm'1; 1H-NMR (CHClo) d : 6.70 (1H, bs), 4.90 (1H, dd: 7.7, 2.9 Hz), 4,72 (3H; m: WH / 2 = 12 Hz), 3.95 (1H, q: 6.6 Hz) and b) Compound (5R, 6S) _5,6_ dibromo-spinoxin B; 1.22 g, 51%) IR (Or) v 3410, 1720, 1665 cm · 1; 1H-NMR (CHCla) δ: 6.71 (1H, bs ), 4.78 (3H, m: WH / 2 = 12 Hz), 2.50 (3H, CH3, s).

Enriched Example FH5-Chloroxine A in Chlorine and Fisoxoxoxin A A. Spinoxin A (2.62 g, 3.58 mmol) was dissolved in dry CH 2 C 12 (30 m 1 :). The solution was allowed to cool to 0 ° C under nitrogen. A portion of the phenylselenylene chloride (Aldrich, 98%; 0.909 g, 4.6 5 mmol) was added with vigorous stirring. After 7 minutes, a portion of m-CPBA (Aldrich, 50%; 4.46 g, 12.9 mmol.) Was introduced. Add CH2CI2 (50 ml) and continue stirring at 0 ° C for 15 min. After that, Et3N (5.0 ml) was added, and the mixture was stirred for 10 minutes, and then the reaction mixture was further diluted with C Η 2 C 1 2 (100 m 1.). Wash the solution with 10% HaHS03 (2x). The organic phase was washed successively with water (1x), 5% MaHC03 (3x), 5% K2CO3 (1x) and water (1x), then dried over anhydrous K2CO3, filtered and concentrated under reduced pressure. The residue was purified using a flash column (230-400 m, 120 g; EtOAC as eluent). The homogeneous eluate was concentrated under reduced pressure by TLC to provide a white solid (2.23 g). This material was then subjected to preparative reverse-phase HPLC [2 Millipore RCM 40 mm centimeter, C18-coated 6 ir oxidized sand; eluate · 10% water (containing 0.05 v / v% NFUOH) in MeOH solution ] Purification ·: · The collected lysate can be collected--216-The paper scale is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page) 487559 Printed A7 B7 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (214) 5-Chloropsinosin A was obtained as a white glassy solid (1.188 g, 43%). HMR and osmium, osmium-COSY spectroscopic analysis showed that this substance was a mixture containing about 15% 6-ammonium Spinoxin A 6. 235 mg of Rain η reversed phase column (with spherical 5m, 100Α, 018 coated) was used as the mobile phase with 15¾ water (containing 0.05 ν / ν% ΝΗ4〇Η) in methanol as the mobile phase. Separation of samples. The obtained compounds are as follows: Compound a) 5-chlorospinoxin A (91 mg, 39%) CT MS m / z (M + 3): 769.25, (M + 2): 768.10, (M + l) 767.10; ^ -NMR (CDCia) δ 6.71 Hz (1H, bs), 5.96 (1H, bs), 2.86 (dd: 14.2, 3.2 Hz) ρριϊι; IR (CM. C13) v 1721, 1663, 1 100, 605 cnr1, and compound b) 6-chlorospinoxin A (35 mg, 15¾) Cl MS: m / z 766 (M + 1), 768 (M + 3). M-NMR (CDC13) d: 6.65 (1H, bs), 5.84 (1H, dd: 3.1, 3.1 Hz). Elemental analysis of C41HhN〇1qC ·· Estimated value · C 64 · 25, Η 8.42, Ν 1.83; actual value: C 64.29, Η 8.41, Ν 1.79-窨 旆 Example F1 4U-cis two-base -Γ). Dioxin R (respectively 5 5S · 6R) and (US) isomers ^ 2: 1 mixture in dichloride The compound spinoxin A (3.26 g, 4.45 mmol) was dissolved in acetone ( 70 ml). Water (30 ml) was added, followed by N-methylmorpholine-N-oxide * (645 mg, 5.5 mmo 1). After the N-oxide was dissolved, OsCU (2.5 U-BuOH solution 2.5%, 0.0015 mmol) was added. The reaction mixture was stirred at room temperature. After 24 hours, EtOAc (100 ml) and benzene (100 ml) were added. The mixture was washed successively with 10% NaHSOy_K solution (1x), water (1x) and 5% NaHC03 (li &lt;). The organic layer was dried over K2CO3 and dried under reduced pressure. By flash steaming This paper size applies Chinese National Standard (CNS) A4 specification (210; &lt; 297 mm) (Please read the precautions on the back before filling this page)

1T 487559 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (215) S i02 column (EtOAc, followed by HUMeOH in EtOAc). Hydroxyl-5,6-diargon Spinoxin A mixture ((5S, 6 [〇 and (51 ^, 6 $) isomers of 2: 1 mixture, 2.236 8,66; 1;) and 5,6 -Cis-dihydroxy-5,6-dihydrospinoxin is a 2: 1 mixture of (5 $, 6! 0 and (51?, 63) isomers (339 mg, 10¾). UMR (CDCl13) d: 6.72 (1Η, bs), 4.76 (1H, bs), 3.92 (0.65 H, m;), 3.85 (0.35 H, m), 2.34 (3H, CH3, s).

Examination example F15-(5s. FiR) -5,6- Erhuamou A conspiracy A &gt; Dioxin ethylene_ fuming and (r) s, 6R) -5. Γ)-equal s (trichloromethane Arsenic) Spinelin A (5s, 6R) -5,6-dihydroxy-5,6-dihydrospirinoloxin A (376 mg, 0.491 mmol) was dissolved in dry CH2C12 (10 ml). Pyridine (3 ml) was added, followed by N, N-dimethylamino Dttidine (600 mg). The reaction mixture was stirred at room temperature under nitrogen and trichloroacetamido chloride (1,000 m 1, excess) was added. After 1 hr, the mixture was diluted with EtOAc (100 ml) and PhH (50 ml). The solution was washed successively with brine (1x) and 5% NaHC03 aqueous solution (2x) and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The residue was separated on a flashed Si02 column (60 g / Et0Ac) to obtain: compound a) (5s, 6R) -5,6-dihydroxyspinoxin A dichlorovinyl acetal (104 mg, 25¾) IR (CHCla) V 1805, 1722, 1660 cm &quot;1; 'H-NMR (CDCla) d: 6.62 (1H, bs), 4.96 (1H, dd: 7.8, 3.3 Hz), 4.85 (1H, dd: 7.8, 3.9 Hz), 2.20 (6H, 2xCHa, s) and compounds b.) (5s, 6R) -5,6-bis-s (trichloro-acetoxy) spinosinoxin A (129 mg , 25%) IR (CHCla) v 1772, 1720, 1662 cm'1 I ---.------- (Please read the precautions on the back before filling out this page) The standard of the paper is applicable to Chinese national standards (CNS) A4 specification (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7. B7_ ___ V. Description of the invention (216); ^ -HMR (CDCIa): 6.76 (1H, bs), 5.66 ( 1H, in: WH / 2 = 8 Hz), 5,50 (1H, dd: 5.7, 3.3 Hz) 2.19 (6H, 2x CH3, s) ppm; Cl MS m / z 1056 (M + l).例 Your example "16-5-_some-6.7-enesome-6- 镡 中 中 窨 谌 辛 4 will (5 $, 6 feet) 311 € 1 (51 ^, 6 $) 5,6-cis A 2: 1 mixture (1.51 g, 1.97 mmol) of Benzyl-5,6-dihydrospinoxin A was dissolved in dry CH2C12 (5 ml). Separately, N-aminobutanediamine (0.793 g, 5.91 mmol) was dissolved in dry CH2C12 (15 ml). Ethyl sulfide (0.83 ml, 7.68 mmol) was added to the NCS solution at -78 ° C and stirred at -78 ° C for 30 minutes. Alcohol solution and continuous stirring at -78 ° C for 1.5 hours. Then triethylamine (2 ml, dry) was added and the solution was allowed to slowly simmer to room temperature under nitrogen over 2 hours. EtOAC (50 ml ) And PhH (100 ml). The solution was washed successively with 5¾ NaHC03 (3x) and water (1x), then dried over K2CO3 and concentrated under reduced pressure. A flashing Si02 column (230- 400 m, 120 g, EtOAC, followed by purification of the residue with 10% Et0H in EtOAc) to obtain 1.20 g slightly intercalated, which can be easily crystallized from Et20 to obtain 5-keto-6,7-alkenyl -6-Hydroxy Spinocinol &amp; (1.01§, 674) 11? ((: 11 (: 13) v 1720, 1665, 1648 cm'1; 'H-NMR (CDCI3) d: 6.68 (1H, bs ), 3.84 (1H , dd: 9.2, 9.0 Hz), 2.13 (6H, 2x CH3, s); Cl MS m / z 762 (M + l).

Examination Example FI 7- R. 6R)-5,6-Dibromostiloxine A Dissolve Spinoxin A (1.59 g, 2.17 mmol) in dry CH 2 C 1 2 (3 m 1). The solution was stirred at room temperature. Add a part of phenylselenylene bromide (98%, 1.05 g, 4.34 mmol): After stirring for 30 minutes, the paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the back (Please fill in this page again for attention)

1. 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7. B7 5. Description of the invention (217), the solution is cooled to 0 ° C. MCPBA (2.5 g, about 7 mmol) was added. Stirring was continued for 30 minutes at 0 ° C. Add triethylamine (3 ml) and stir for 10 minutes. Dilute the mixture with benzene (150 ml) and EtoAc (50 ml). The solution was successively cleared with 10% NaHS03 (2x) aqueous solution, saline (1x) and 5% NaHC03 (2x). The organic phase was dried over K2CO3 and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2 / EtOAC) and then subjected to HPLC (018 coating, 6m, 100 A filling; 5¾ H20 in MeOH solution as mobile phase). Purely soluble fractions can provide a) unreacted compound Spinoxin A and b) compound (5R, 6R) -5,6-dibromo spinosinoxin A (297 mg, 16%) M-NMR (CDC13 ) d: 6.69 (1H, bs), 4.74 (3H, m: WH / 2 = 12 HZ), 2.17 (6H, 2xCH3, s) ppm; Cl MS m / z 894 (M + 3), 882 ( H + 1) 〇 Example: 8-5-_yl-fi, 7-ene, -fi- (p-gas) benzyl argon, and even octyl octyl A. 5-keto-6,7-ene 6-hydroxyspinoxin A (556 mg, 0.73 mmol) was dissolved in dry CH2C12 (10 ml). Add pyridine (5 ml) and DMAP (300 mg). The solution was stirred at room temperature under nitrogen and p-chlorobenzyl chloride (1.0 ml, excess) was added. After 15 minutes, the reaction mixture was diluted with Et0Ac (50 ml) and PhHUOO ml). The solution was serially diluted with brine (2x), water (1x) and 5% NaHC03 (2x) aqueous solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si 〇2 / E tO Ac) to obtain the compound 5-keto-6,7-alkenyl-6- (p-chloro:) benzyl spinoxin AC634 mg, 96¾) NMR (CDC13) d: 8.03 (2H, bd: 8.4 HZ), 7.41 (2H, bd: 8.4 Hz), 6.73 (1H, bs), 4.09 (lH, dd: 9.3, 9.0 Hz), 2.20 (6H, 2x CH3, -220-This paper size applies to Chinese National Standard (CNS) A4 size (210 × 297 mm)) ---- 1 --.--- ^^ clothing-(Please read the note on the back first (Fill in this page again)

、 1T 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (218 s) s ppm 0 窨 Example Π9-5. Conspiracy

Norsin A The compound 5-keto-6,7-alkenyl-6-hydroxyspinoxin A (91.40 g, 1.84 mmol) was dissolved in dry CH2C12 (15 ml). The solution was stirred at room temperature under nitrogen and triethylamine (dry, 3 ml) was added. After 15 minutes, trimethylsilyl trifluoromethanesulfonate (1.5 ml) was introduced and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with PhH (50 ml) and EtoAc (100 ml). The solution was successively extracted with brine (1x), 5¾ NaHC03 aqueous solution (3 fathers), and [] 20 (^). The organic layer was dried over K2CO3 and concentrated under reduced pressure. The residue was separated on a flashed Si02 column (120g / EtoAc + 0.2¾ Py) to obtain the compound 5,6-bis (trimethylsilyloxy) -5,7 (8) -diene spino Northin A (1.312 g, 794.) lH-NMR (CDCla.) D: 6.69 (lH, bs), 5.48 (1H, dd: 1.9, 0.7 Hz), 0.13 (9H, 3xCH3 s), 0.04 (9H, 3xCH3, s); Elemental analysis of C47U〇12Si2: Estimated value: 62 · 29, Η 8.79, N 1.55; Actual value: C 62.10, Η 8.84, N 1.41 〇

Example of a ketooctyl A in a -6,7-enylbutadiene-dioxanyl argonyl group. The compound 5-keto-6,7-alkenyl-6-hydroxyspinoxin A (1 · 02έ g, 1 · 3 4 5 mm ο 1) Dissolved in C Η 2 C 12 (dry, 20 m 1) ':' Add pyridine (2 ml). Stir the solution at room temperature under nitrogen and add t-BDMS trigas mesylate (98%, 471 ml, 2.01 mmol) ': Stir continuously for 14 hours and mix the mixture with EtoAc (80 ml) and PhH (50 ml) dilution. Based on 5% NaHC〇3 -221-This paper size is applicable to Chinese National Standard (CNS) A4 (21 〇 X 297 mm) (Please read the precautions on the back before filling this page)

Yin Chang, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (219) (2x) cleaning solution. The organic layer was dried over K2CO3 and concentrated under reduced pressure. The residue was purified by flash column chromatography (230-400 m SiO 2, 100 g, EtOAc) to obtain compound 5-keto-6,7-alkenyl-6 -1 -butyldi-methyl sand Alkoxy Spinozin M 1.030 g, 874) UMR (CDC13) d: 6.66 (1H, bs), 3.81 (1Η, 9.5, 9.3 Hz), 0.84 (9H, 3x CH3, s), 0 · 09 (3H , CH3, s), 0.05 (3H, CH3, s).

Example F21-(5S) β-Difluorene-5-Hydroxyquinone A (Rd-R, A-Difluorene-6-Dimethylsulfonyl-Axin A (6R &gt; -5, 6_II Value-fi-fluorenyl Φ 窨 谌 A A Suspend triacetic acid (1 · 12 g, 2 · 6 2 mm ο 1) suspended in 30 m 1 of THF: water, 2: 1 (V / V) Spinoloxin M 0.98 g, 1.34 mmol) was added to this yellow suspension. The reaction was then stirred at room temperature for 30 minutes. The reaction was treated with 7 mL IN NaOH and then 2.5 mL of 0.5M NaBH4. Treated with 3M NaOH solution. The reaction turned black and supported the precipitate. The solid was allowed to settle to the bottom of the flask and the liquid was poured into a separatory funnel containing 50 ml of ether. The layers were separated and the aqueous layer was extracted with 2x25 niL ether. The ether was combined The extract was washed with 30 niL of saturated aqueous NaHC03 solution, dried over K2CO3 and concentrated under reduced pressure. By medium pressure liquid chromatography (230-400 m, CH2Cl2: Me0H, 95: 5 (V / V) ) The residue was purified to obtain compound a) (5S) -5,6-dihydro-5-hydroxyspinoxin A (349.7 mg, 30 · «), part of UMR (CDC13) d 6 · 80 (1H, bs ), 4.00 (1H, m.), 2.95 (1H, m) 0.68 (1H, m); part of 13C-NMR (CDCla) d 148.64, 6 7 · 40, 45 · 79, 43.01 35.16 and (6s) -5,6-dihydro-Phoenix Spinoxin A and (6R) -5,6-dihydro-6-hydroxy Spinosin A -222-This paper size applies to China National Standards (CNS) Λ4 specifications (210X 297 public holidays) (Please read the precautions on the back before filling this page)

^ 〇 / 559 A7 B7 V. Description of the invention (22〇) Mixture, (6s) -5,6-dihydro-6-hydroxyspinoxin A and (6R) -5,6-dihydro-6-hydroxyl Spinozin A can be prepared by HPLC (C-18 coated, 6m, 100 A filling; 10% Η20 in MeOH solution as mobile phase.) To provide compound b.) (61〇-5, 6- Hydrogen-6-Hydroxy Spinocinol &amp; (7.11 ^, 1%) Part 11 ·! -NMRiCDClo) d 6.84 / 1H, bs), 3.48 (1H, m) 2.92 (1M, m) 0.55 (1H, m ); 13C-NMR (CDCla) d 148.64, 72.66, 44.86, 43.96, 34.52 and compound c) (6S) -5,6-dihydro-6-hydroxyspinoxin A (11.4 mg, 1¾) 1H-NMR (CDC13) d 6,80 (1H, bs), 4.11 (1H, m) 2.78 (1H, m) 1.40 (1H, m); 13C-HMR (CDCla) d 148.46, 66.52, 38.18, 37.65, 32.95 〇 Enriched Example F22- (5R. 6R) -5-Ethyl argon A 6-thiomethyl argonyl group A compound Spinoxin A (2.64 g, 3.61 mmol.) Solution CH3CN (Dry, containing 1¾ ethylsulfur ffi; 30 m 1,). This solution was held at room temperature and dimethyl (methylthio) pyrene tetrakis borate was added <1.10 g, 5.61 mmol) and the mixture was sonicated (50 W ultrasonic cleaner) 1 0 minutes. Add anhydrous sodium acetate powder (2.5 g, excess) and sonicate for 1 hour. The solution was diluted with EtoAc (50 ml) and PhH (100 ml) and the solution was washed with 5% K2CO3, 5% NaHC03 aqueous solution and ^ 0. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO 2 and preparative HPLC (C-18 coated, 6 m, 100 A ballast; 8¾ H2O in MeOH as mobile phase). Purely soluble fractions can provide compound (5R, 6R) -5-ethoxyl-6-thiomethylaminospinoxin M2.07 g, 68¾) UMR (CDCla) d: 6.89 (1H, bs.) , 5.31 (1H, dd: 2.4, 2.2 Hs) This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)-Binding line 487559 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (221)), 2 · 16 (6H, 2xCH3, s), 2 · 11 (3H, CH3, S.), 2 · 01 (3H , CH3, s); Elemental analysis of C44H71N12S: Estimated value: C 63,06, Η 8.54, N 1.67; Actual value: C 63.15, Η 8.77, Μ 1.76 〇

Channeling F23- (5R · RR) 酦 気 砀 基 窨 窨 窨 窨 窨 窨 Rosin A A compound (5R, 6R.)-5-ethoxy-6-thiomethoxy sparoxin A (1 · 〇 5 g, 1.25 mmol) was dissolved in CH2CU (100 ml). The solution was cooled to 0 ° C with stirring, and m-CPBA (50%, 1.95 g, 5.6 μο1) was partially added. After 40 minutes, the reaction mixture was diluted with CH2C12 (50 ml). The solution was washed successively with 10% NaHS03 aqueous solution (2x), water (1x) and 5¾ NaHC03 aqueous solution (2x). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (230-400 m Si〇2 / Et0Ac, followed by KUEtOH in EtOAc) to obtain compound (5R, 6R) -5-ethoxyl-6-methylsulfonium Kirspinoxin A (966 mg, 89%) IR (CHCla) v 1740, 1724, 1662, 1320, 1135 cm'1; 'H-NMR (CDCla) d: 6.57 (1H, bs), 5.52 (1H, dd: 4.5, 4.0 Hz), 2.78 (3H, CH3, s), 2.17 (6H, 2xCH3, s), 1.98 (3H, CH3, s)

Example F24- (5R, fiR) -Γ) -chun-Γ)-锊 A guest guest J dissolved the compound Spinoxin AU.33 g, 1.32 nunol.) In DMS0 (1 5 m 1) . Water (5 m 1.) was added, causing precipitation. Concentrated H 2 SO 4 (1 · 8 mmo 1 :) was introduced while stirring. The precipitate was allowed to dissolve immediately. The solution was cooled to 0 ° C and N-bromosuccinimide (322 mg, 1.8 mmol :) was added. After stirring for 15 minutes at 0 ° CM, the reaction mixture was poured into 50 m 1 of a saturated NaHCO 3 aqueous solution -224-. ^ The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (21〇 &lt; 297 mm) '' (Please read the notes on the back before filling out this page)

487559 A7 ____: _ B7__ 5. In the description of the invention (222): extract the mixture with Et 2 0. The combined organic extracts were decanted with brine, dried over K2CO3 and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C-18 Dynamax column, 20¾: water in MeOH solution as mobile phase) to obtain compound (5R, 6R) -6-bromo-5-hydroxyspinoxin J (1 · 30 g, 86%) Cl MS m / z 828 (M ^ l); 'H-NMR (CDCla) d: 6.56 (1H, bs), 4.24 (2H, m: WH / 2 = 14 Hz), 3.85 (1H, dd: 3.5, 3.5 Hz), 2.05 (6H, 2xCH3, s). Rich example F25U-Dioxin A 9-Psa in dihydrogen. The compound Spinoxin A 9-Psa (46.5 mg, 0.0856 mmol) was dissolved in 5 mL of toluene. Phenyl-triphenylphosphine phosphonium (I) chloride (8.5 mg, 0.0092 1) was added to the solution. Vacuum the top area of the flask and introduce the atmosphere 3 times. Evacuate and introduce hydrogen 3 times. The spherical flask was maintained under hydrogen and heated to 110-120 ° C. After 3.5 hours, the flask was cooled to room temperature and the hydrogen was evacuated and replaced with an atmosphere. The toluene was evaporated and replaced with 20 m 1. Extract with 3x10 mL of 1M HC1 ether solution. The acid extracts were combined and neutralized with 10 ml of 4N NaOH. The neutralized suspension was extracted with 3x10 mL of ether, the ether extracts were combined, washed with 20 mL of brine, dried over 1 (2 (: 03) and concentrated under reduced pressure. The resulting compound 5,6-dihydrospinoxin A 9_Psa (29 · 5 mg, 63¾) part 1H-NMR (CDC13) d 6.84 (lH, bs), 1.01 (1H, m), 0.68 (1H, m). Storage Example F26-5,6- Dipyridine A 1 7-Psa According to the procedure described in Example F25 above, the compound Spinoloxin was used. "17_ Psa (270 · 8 mg, 0.458 mmol) to 32.8 mg [(Ph) 3P] 3RhCl Dispose. After evaporating toluene, use medium pressure liquid chromatography (230-400 m -225-this paper scale is applicable to China National Standard (CNS) A4 specification (210 × 297 mm)) (Please read the precautions on the back before filling (This page) -pack-

1T line 487559 A7 —__ _ B7__ V. Description of the invention (223)

The compound was purified by SiO2, CH2Cl2: MeOH, 95: 5 (V / V). The obtained compound 5,6-dihydrospinoxin 17-? 53 (188.1! 1 ^, (39.2%) part ^ -NMR (CDCI3) d 6.84 (1H, bsj, 3.63 (1H, m), 1.02 (1H M), 0.68 (1H, m); partial 13C-NMR (CDC13) d 149.28, 72.48, 46 · 55, 27 · 00.

Example F27-5.fi-g Nosin J in dioxin Follow the procedure described in Example F25 above to treat the compound Spinoxin with 91.3 mg [(Ph) 3P] 3 RhCl in 20 mL of toluene solution. g, 1.39 mmol). The obtained compound 5,6-dihydrospinoxin J (0.70 g, 70%) part 1H-NMR (CDC13) d 6.84 (1H, bs) 3.82 (1H, dt), 1.01 (1M, m), 0 · 69 (1Η, m).

Example F28-H. Fi-dihydrodioxine H Dissolve the compound Spinoxin H (2.57 g, 3.58 mmol) in a round bottom flask containing 20 ml of toluene. A 5 inL toluene solution of [Ph3P] 3RhCl (169.2 mg, 0.183 mmol) was added to the colorless solution. The flask was fitted with a reflux condenser and the top area of the flask was evacuated 3 times and nitrogen was introduced. The nitrogen was evacuated 3 times and hydrogen was introduced. The flask with a spherical shape was maintained under 1 atm of hydrogen and heated to 100-1 10 ° C in an oil bath. After 10 hours, the heat source was removed and the flask was evacuated 3 times and nitrogen was introduced after each vacuum. The contents of the flask were filtered under hot air through a 3 "diatomite column & washed with 100 mL of ether to dissolve out the remaining compounds. The filtrate was extracted with 3 x 50 mL IN HC1. The acid extracts were combined and 25 mL Ethyl ether reverse extraction and alkalization with 50 mL 4N NaOH. The white solid of the satin was extracted into ethyl acetate (2 X, 25 mL) and the ether extract was washed with 25 mL of saline solution. The paper dimensions are applicable to Chinese national standards ( CNS) Α4 specification (2 丨 0 × 297 mm) (Please read the precautions on the back before filling this page).

1T 487559 A7 s _._; _ [___ V. Description of the invention (224) The ether solution was filtered through a plug of diatomaceous earth and concentrated under reduced pressure. The obtained compound 5,6-dihydrospinoxin [1 (2.24 8,87.14) :(: 4 () ^ 5_1 (1Analyzed value ·· Estimated value: C 66.73, Η 9.10, N 1.95; actual value · · C 66 · 31, Η 9 · 01, Ν 2 · 02 · Cl MS (m / z) 721 (M + 1). Example F29-5, β-dioxin intermediate beta glutamate A semiglutarate Dissolve compound 5,6_dihydrospinoxin A (232.2 mg, 0.316 mmol) in 3 mL of acetone. Add 3 mL of glutaric acid (20,8 mg, 0.157 mmol) in acetone and at room temperature The solution was stirred and the solution was separated. The solvent was removed under reduced pressure to obtain the compound 5,6-dihydrospinoxin A hemiglutarate (250.8 mg). Analysis of C41HS7NO1Q · 1/2 (CsH8〇4): Estimated value : C 65 · 31, Η 8.94, N 1 · 75; actual value: C 65 · 14, Η 8.78, Ν 1.87; mp · 83-92 ° C.

Example F30U-Dioxin R hydrogenation step A: Spinmexine B (1.10 g, 1.53 mmol) and (Ph3P) 3RhCl (0.05 g, 0.09 nunol) in PhMe (15 mL) solution were dissolved in Parr The device was kept in a hydrogen environment (45-50 ps i), 104-107 ¾ for 2 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure and the residue was decolorized (Et20 / charcoal) and filtered. The filtrate was evaporated under reduced pressure and purified by MPLC (SiO2, 5:95 to 10:90 MeOH / CH2Cl2) to obtain -0.90 g (82%.) 5,6-dihydrospinoxin B, is a white powder. Analysis of C40Hs5N0ia: Estimate: C, 66.73; Η, 9.10; N, 1.95. Actual values: C, 66.53; hydrazone, 9.14; K, 2.15: 'Example F3 Compound m Bu 擐 某-Shishenoxin 0 ^ Synthesis Spinoloxin Q (970 mg, 1.32 mmol) was dissolved Dichloromethane (150 -227-This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

CPlease read the precautions on the back before filling out this page}

487559 A7-B7 V. Description of the invention (225) 150 ml). The solution was cooled to 0 ° C and a portion of ni-CPBA (1.19 g of about 50¾ reagent, about 3.45 mmol) was added. After m-CPBA was dissolved, the reaction mixture was immediately placed in a refrigerator. After 40 hours, the reaction mixture was extracted with 10: UlaHS03 (2) O, water (1x), and 5¾ NaHC03 (2x) aqueous solution. The organic layer was dried over anhydrous K2CO3, filtered and concentrated under reduced pressure. The residue was separated on a flash SiO 2 column (230-400 m, 70 g / EtOAc). The chromatographically homogeneous fraction was concentrated under reduced pressure to obtain a white solid (.694 mg). A white solid (88 mg) precipitated from this substance was precipitated with dry Et20. Diethyl ether solution, after evaporation, compound (5S, 6R) -epoxy-spinoxin Q, 606 mg, 61%) lH-NMR d 6.51 (1H, bs), 4,73 (1H, d: 1.2 Hz), 3.87 (1H, dd ^ 1.21 1.8 Hz), 2.16 (6H, bs 2xCH3), 1.31 (3H, s, CH3) ppm.窨 旆 例 F32- (5S. FiR) Ί β-Dihydro-5,6-Secondary Gnosin (65¾) Good (r) R. FiS)-5,6-Di-hydro-5,6 -Erzen very middle hydrazine (M ^ 5%)) mixture Spinoloxin A (3.26 g, 4.45 ππηοΐ) was dissolved in acetone (70 mL). Water (30 mL) was added, followed by N-methylmorpholine N-oxide (645 mg, 5,5 mmol), and tetraoxine (2.5¾ in 2-methyl-2-propanol solution; ^ 160 mg, 〇. 〇1 5 mm ο 1.) ϋ After 1 hour, add another part of 0 s 0 4 ϊ (300 mg). After 24 hours, the mixture was combined with 1 (UNaHS0 3 (200 mL) 7 I aqueous solution and gradually reacted. The crude product was mixed with silica gel (10% Me0H

L ?: EtOAc solution.) Purified on a short flash column to provide unseparated (5S, 6R).

I] 5,6-dihydro_5,6-dihydroxyspinoxin (65¾) and (5R, 6S) _ 5,6-dihydro ^ -5,6-dihydroxyspinoxin A (35 ; Mixture of n (35¾) (2.24 g, 66¾) -228-This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T line 487559 A7 —— ^ _: ____ V. Description of the invention (226) is a white solid: iH-NMR d 6,71 (s, 1 H), 3.93 (m , 0.65 Η), 3.88 (m, 0.35 Η), 2.11 is, 6 Η).

For example, m-5.fi-Secondary R is a PhMe (15 mL) solution was placed on a Parr device under H2 gas environment (45-50 ps i) and 104-107 ¾. After 2 hours, the reaction was filtered and evaporated. The residue solution Et20 was slurried with charcoal. The slurry was filtered and evaporated. MPLC (5:95 MeOH / CH2Cl2) yielded 0.90 g (82%) of 5,6_dihydrospinoxin B as a white powder. Analysis of C40Hs5N0i: estimated value C, 66.73; H, 9.10; 1.95, actual value: C, 66.53; H, 9.14; N, 2.15. Example F34-5.fi- 二 気 Φ 窨 谌 辛

In a 100 ml Parr container, 10 ¾ Pd / C and hexane were added to a solution of pure ethanol (60 mL) in Spinoxin D (2.5 g, 3.4 nun 〇1). This suspension was heated at 120 ° C for 48 hours. After cooling, the reaction mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure to obtain 2.4 g of a 2: 1 mixture of Spinoxin D and Spinoxin D. The residue (200 mg) was dissolved in dichloromethane (20 mL) and cooled to 0 ° C. MCPBA (95 mg, 0.45 mmol) was added to the reaction mixture and stirred at 25 ° C for 16 hours. The reaction mixture was quenched with sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted with dichloromethane (2x20 mL). The combined extracts were stirred with 10% NaHC03 for 3 hours, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on preparative HPLC using a C18 column and eluted with 101¾ water (0,1¾ NH4OH) in methanol to obtain compound 5,6-dihydrospinoxin D (10 mg): MS -229-Ruler Zit uses Chinese National Standard (CNS) 8 4 specifications (210X297 mm) ---- 1 ---- clothing-(Please read the precautions on the back before filling this page), \-'口487559 A7 B7 V. Description of the invention (227) m / z 748〇'H-NMR (CDCla, 300 MHz) 6.85 (1H, s), 4.82 (1H, S), 4.65 (1H, m), 4.42 ( 1H, d.), 4.20 (1H, m), 0.95 (3H, d). D-SLiLj has different meanings, substituted with amine sugar, modified -1-7-Π- (buiodine-2_defiethoxyl-a-L-rhamnose, and even oligoxin A 17-Psb in Spinoline A 17-Psa (105.4 mg, 0.18 mmol) in acetol (0.86 ml) was added with 3,4-di-0-acetamido-6-deoxy-L-hexane Sugar (A 1 drich, 5 2 u 1, 0.3 5 mm 〇1) and then added N-iodobutanyl te (80.5 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 19 hours. Then The dark mixture was diluted with dichloromethane and washed with aqueous NaHSO 3 solution, followed by 5% sodium thiosulfate. The dichloromethane portion was dried with MgSO 4 and evaporated at room temperature under reduced pressure. The product was purified by HPLC, and the 17-0- (2-iodo-2-deoxy-3,4-di-〇-acetamidine) obtained by eluting the amidine with 45: 45: 10 / acetonitrile: methanol: 0.05¾ NIUOAc aqueous solution was obtained. -Α, L-rhamnosyl)] Spinoxin A 17-Psa (49 mg; yield 29%), colorless glass, FDMS, m / e (relative strength) 930 (M ~ H , 20), 929 (30), 190 (100). Enriched cases G2_ 17-0- (2- Quanxi-α -1, Rhamas basket, Shi Shiyao Xin A 1 7 -Psa as follows Example G3 The reaction was performed with 17-〇 ~ (2-deoxy-3,4-di-0-acetamido-a-L-rhamnosyl) Spinoxin A 17-Psa (271.2 mg, 0.34 mmol.) As starting material: · Π ~ 〇- (2-desoxy-α-L-rhamnosyl) Spinoxin A 17-Psa (l87 Saki; 77: ¾ yield) -230 -This paper size applies to China's National Standard (CN'S) A4 size (210X 297mm) (Please read the precautions on the back before filling this page)

1. 1T line 487559 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (228), white glass, FDMS, m / e (relative strength) 1432 (20), 752 (30), 720 (M'100), 206 (50). Example of Fenxiong (λνΐ 7-0--2-guanyl group-L two mouse-plum sugar curtain) Shi Weiyixin A 17-Psa on 17-0- (2-iodo-2-deoxy-3,4 -2 -〇-Acetyl-a-L-rhamnosyl) Spinoxin A 17_Psa (107.8 mg, 0.12 mmol) in methanol (9 m 1) solution, and a saturated ammonia solution of methanol (2 π 1) was added ° The reaction mixture was capped and stirred at room temperature for 19 hours. The mixture was evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and eluted with 5% methanol in dichloromethane. The obtained 17-0- (2-iodo-2-deoxy-a-L-rhamnosyl) Spinoxin A 17-Psa (74 mg; yield 75%) was a colorless glass, FDMS , m / e (relative intensity) 848 (MH, 20), 591 (100), 189 (65), 101 (90).窨 例 G4 -17-0- (2- 关 気 可 -3,4-bis-0-ethyl salt-a-L-rhamnolide) Zhongxin A 17-Psa on 17-0-(2 -Iodo-2-dechloro-3,4-di-0-ethenyl-a-L-rhamnosyl) Spinoxin A 17-P sa (5 15 · 3 mg, 0 · 5 5 mm ο 1) in toluene (85 ml) solution, add tri-n-butylsilane (780 ul, 2.85 mmo 1). Then add a small amount of A IBN. The reaction mixture was heated to reflux temperature for 30 minutes, and then cooled to room temperature for 1.5 hours. The mixture was evaporated at room temperature under reduced pressure. The mixture was evaporated by chromatography on silica and eluted with 40¾ ethyl acetate in hexane: the resulting 17-0- (2-deoxy-3,4-di-0-acetamido-a rat Liglycan) Spinoloxine A 17-Psa ((321.5 mg; yield 73¾), white glass, FDMS, m / e (relative -231-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297mm) (please read the precautions on the back before filling this page),-? ^ / 559 A7. B7 V. Description of invention (coffee), strength) 804 100), 190 (55), 101 (70).

Enriched example G5-.V-Norchlorochlorohistamine C. The reaction was performed as described in Example H1 below, starting with 3'-demethoxyspinoxin B (240 mg, 0.35 mmol).始 物。 Starting material. The obtained 3'-demethoxyspinoxin C (126.1 mg; yield 54%) was a pale yellow solid, FDMS, m / e (relative strength) 676 (40), 675 (100), 674 (1T , 80), 673 (35). Fenshi Example M′ν-Demethylchloro-1yl Kexin A A 7-Pα The reaction was performed according to the method described in Example E7 above, and 3 demethoxyspinoxin A 17-Psa (809.8 mg, 1.4 mmol). The obtained 3'-normethyl-17-keto spinosinoxin A 17-Psa (501.4 mg; yield 64¾) was a colorless glass, FDMS, m / e (relative strength) 559 (M +, 45), 558 (100), 159 (10). Examination Example G7-1 7-Π-(2-Ethylamine -2-dehydrogen'3. 4,6-tetra-0-Ethyl thio-theta-type »Glucose Acetone A 17-Psa will be Spinoxin A 17-psa (1.00 1.70 mmol), 2-methyl_-(3,4,6-tri-0-ethenyl_1,2-didechloro_ 〇 (-0-11 Moran-type grape-based)-[2, ld] -2-i®_l # (Nakabayashi, S .; Warren, CD ·; Jeanloz, RW Carbohydr. Res. 1986, 150, C7) ( 0.56 g, 1.70 mmol) and 1,2-dichloromethane (65 mL) solution of iron pyridine-p-toluate_ (75 mg, 0.30 mraol) was heated and stirred at reflux temperature for 48 hours, and then cooled to room temperature Warm. Then add saturated Na2CO3 (2 mL) and stir the mixture at room temperature for 5 minutes and then dilute with water (15 mL) and CH2C12 (30 mL) .: Separate the aqueous layer and CH2C12 (30 mL) ) Washing and washing-232-This paper size is applicable to Chinese National Standard (CMS) A4 specification (210X 297mm) (read the precautions on the back of the chain before filling this page) • Binding line 487559 Α7 Β7 V. DESCRIPTION OF THE INVENTION The (23) solution was combined with the organic layer. The combined organic layers were then washed with brine (25 mL), dried (MgS04), and concentrated. The residue (1. 4 g) flash chromatography with silica (160 mL), using 3% MeOH in CH2C12 as eluent, to obtain 0.6 g of crude glycosylation product. 200 mg of the product was divided into three parts by reverse phase HPLC to Rainin 徼 absorption C18 column (41.4 nun (idU25 cm (1)) purification, using MeoH eluate of 10¾ water to obtain 151 mg 17-0-(2-acetamido-2-deoxy _3,4,6-tetra-0-acetamido- / 3-D-piperanylglucospinyl spinosin A 17-Psa. The sample recrystallized from 1: 2 EtOAc / hexane was colorless needles. , Mp 199-200 ° C; UMR (CDC13) d 6.76 (s, 1H, H-13), 5.66 (d, ΙΗ, ΝΗ), 5.18 (dd, (Please read the precautions on the back before filling this page) • Equipment-1H, F (3 ”), 5 • 02 (t, 1Η, Η-4”), 4.83 (d, 1H, H-1 4.62 (m, 1H, Η -21), 4.60 (d , J ~ 8.2, 1H, Η-1 ”), 4.28 (m, 1H, Η -9), 4.14 (m, 2H, H-6”), 3.98 (m, 1H, H-2 ”) 〇 Comments Example G 8-17- 0- (2 'Alkylamino-2-desarginyl-3-Dd Zeranose Glucose) Benzene A 17-Psa Ordered at 17-0- (2-ethyl Amido-2_deoxy-bD-piranyl «glucosyl] Spinoxin A17-psa (35 mg, 0.038 mmo l) in MeOH (5 mL), and a portion of 60% Na N (2 mg) of mineral oil dispersion was added. The resulting solution was stirred at room temperature for 25 minutes and then neutralized with glacial acetic acid. The solvent was evaporated and the residue was flash-chromatographed with silica (25 mL) using 12% MeOH in CH2C 12 as the eluent to obtain 17-0- (2 acetamido-2-deoxy- / 3 -〇-Piranyl glucosyl) Spinoxin / \ 17- 卩 33 (27 11 ^), a colorless foam: UMR (CDC13) 5 6.83 (s, 1H, Η-13), 4.83- 233-This paper size applies the Chinese National Standard (CNTS) A4 specification (210: &lt; 297 mm) Line Wah Qiyin t! Fc ticket support staff 1. Night fee ^ 阼 fi, 1000 軚 〇59

Description of the invention (231) (s, 1H, Η-Γ), 4.63 (in, 1Η, H-21), 4.58 (d, 1H, H-1 "), 4.32 (m, 1H, H-13 ); MS m / z 102 (100), 189 (75), 573 (30), 794 (Mf + H, 12). Example of the case 09-2-()-acetamidine-α_budose Dibromide 気 Zhang 酴 B aims to diethyl sulfonyl glycosamine hydrochloride (Flynn, EH; Sigal, Η. V., Jr .; Wiley, PF; Gerzon, KJ Am. Chem. Soc. 1954, 76, 3120) (0.9 g, 3.05 mmol) was added to a solution prepared from acetic anhydride (0.75 inL) and 30% HBr in acetic acid (3.75 mL) at room temperature. Stir for 1 hour, and then add diethyl ether (45 ml) in 4-5 ml portions in 10 minutes to precipitate the hydrobromide product; the oil is initially allowed to flow out but solidified by scraping and stirring continuously. This hygroscopic hydrobromide was filtered under an atmosphere, washed with ethyl K (3x40 mL), and then dried in a rotary evaporator at 30 ° C and reduced pressure (-30 mm) to produce 2-0- Acetyl-a dextrose amino bromide hydrobromide (1.1 g) is a white off-white powder. This powder can be used directly in glycosylation reactions 1 [\ -WM (C DCla) δ 6.67 (d, 1H, Hl), 4.92 (dd, 1H, H-2), 2.84 (d, 6H, N (CH:)) 2), 2.33 (, 3H, d 0) , 1.37 (d, 3H, H-6) · Examination Case G 1 0-17- (1- (β-D-Detamine) and Chinese Kexin A 17-Psa will be part of 2-0-acetamidine -A Desaminoglycine bromide hydrobromide (1.1 g, 3.0 nunol) was added to the well-stirred Spinozin A 17-Psa (0.5 g, 0.85 mmol) and dimethylpyridine ( 0.26 mL, 2 · 2 mmol) of a 1,2-dichloromethane solution. The solution was heated to 60-65 ° C and held at that temperature for 24 hours, cooled to 25 ° C and treated with 0.5 N HC1 (5 · 2 mL) treatment -234-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the Invention (232). The mixture was stirred at 25 ° C for 10 minutes and then diluted with CH2C12 (20 mL). The organic layer was separated and washed with water (5 mL), saturated NaHC03 (¢ 3 mL) and saline (5 mL) and dried (MgS04). Flash chromatography on silica (150 mL) to leave 0.6 g of concentrate, using 3% MeOH in (: [] 2 (: 12 solution as eluent to obtain 0.25 g 17-0-(/ 3 -D-deglycosamine) Spinozin A 17-Psa, 4/3: 1c (a mixture of allomeric isomers, as a white foam. It was dissolved in MeoH (7 mL) and added 0.1M NaOMe in MeOH (1.5 mL). Stir the solution for 6 hours at room temperature, then add acetic acid (10 mL) and stir the solution for 10 minutes. Evaporate the solvent and leave 200 mg of 17-0-(/ 3-D- Desaminol) Spinoxin A 17-Psa, a 4: 1 /? / Α alloisomer mixture.-Alloisomers (80 mg, white foam) by reverse phase HPLC with 3 Partially separated on a Rainin 018 column (41.4 mm (id) X 25 cm (1)), using 45:45:10 CH3CN / MeOH / 2% NH4〇Ac as eluent MH-NMR (CDC13) δ 6.78 (s, 1H, Η-13), 4.84 (s, 1Η, Η-ΙΊ, 4.66 Cm, 1Η, Η-21), 4.36 (d, J = 7.1, 1Η, Μ-ΓΊ, 4.30 (m, 1H, H-9); MS m / z 748 (2), 329 (30), 313 (50), 218 (45), 200 (100), 189 (15), 158 (70), 147 (20) Examination Example CM1-a -D-Amine-Etheramine Gas Bromide Esters D- Sugar (B oeck, L · D ·; C hi ο, Η ·; E at ο η, T · E ·; Godfrey, 0. W., Jr .; Michel, KH; Nakatsukasa, W • M .; Yao, R. CF. European Patent, 0375 316 A1 (1990)) (0 · 1 g, 0.6 3 mmo 1) Add 1 in L Jihan cut sensation companion, refrigerate (about 10 ° C.) 5 ·· 1 (v / v) of 30¾ HBr of acetic acid: acetic anhydride mixture ': will -235-This paper size applies Chinese National Standard (CNS) A4 specifications (] 1〇 &gt; &lt; 297mm) (Please read the back first (Notes for filling in this page)

T &gt; 487559 Muqilang Chuo 矂 隼 ^ Printed by the employee consumer cooperative A7 B7 V. Description of the invention (233) The resulting solution was stirred at the cooling temperature for 10 minutes, and then stirred at room temperature for 1 hour. Diethyl ether (7 ml) was then added in portions of 1.0 ml in 5 minutes. The oil in the hydrobromide product was initially allowed to flow out but solidified by scraping and continuous stirring. This hygroscopic hydrobromide was filtered under nitrogen and washed with diethyl ether (4 × 10 mL), and then dried in a rotary evaporator at about 30 ° C under reduced pressure. It can be used immediately for glycosylation. Yield (I-D-amine sugar bromide hydrobromide: 0.17 g (89¾) as a white deviation powder: tH-NMR (. CDCI3) 8 6.60 (s, 1H, Hl), 4.22 (m, 1H, H -5),

2.94 (d, 3H, HCHa), 2.87 (m, 1H, H-4), 2.83 (d, 3H, HCHa), 2.30 (m, 4H, H-2, H-3), 1.68 (d, 3H, H-6) 旆 Example CM 2-1 "-Shou-Zhongxunuoxin A HgBr2 (0.1 g, 0.28 mmol) in CH2C12 (10 mL) suspension was quickly stirred at room temperature for 10 minutes. Dissolve about 2/3 HgBr2) during this period. Powdered with 4A molecular sieve (0.15 g) and added Spinoxin A 17-P sa (0 · 11 g, 0 · 18 mm 0 1) and mix the mixture 10 Minutes, and then within 1 hour, a solution of a glucosamine bromide hydrobromide (0.17 g, 0.56 ππηοΠ in CH2C12 (4.0 mL) was added dropwise. After stirring for another 3 hours, saturated Na2CO3 (4 mL) was added and Μ Mix the mixture for 10 minutes. Filter the mixture through diatomaceous earth and wash the collected mixture with CH2C12 (15 mL) and water (5 mL). Combine the organic layers of the filtrate and separate the washings and wash with CH2C12 (15 mL) Water layer. The combined organic extracts were washed successively with 10¾ KI aqueous solution (2 X 4 mL), 10% HaHC03 (5 mL) and brine (10 mL) and dried (MgS04). After evaporation, 0.15 was left g residue, which was subjected to flash chromatography on silica (40 mL) using 4¾ MeOM (: 1 ^ (: 12 Eluate to get clean -236-This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page),-Central Bureau of Standards, Ministry of Economy Printed by the Consumers' Cooperatives 487559 A7 * B7 ------------ V. Description of the invention (234) Glycosylated product (49 mg), 1 ”-Table-Spinnock A and Spinnock 3: 1 mixture of Sin A. This mixture was dissolved in CH3CN (1.5 niL) and analyzed by HPLC in a continuous arrangement in dioxin 4 · 6 mm (i · d ·) X 2 50 mm (1) A pe X Separation of isomers with a phenyl column, 40:40:20 CH3CN / MeOH / 2% Ν Η 4 0 A c was used as the eluent and the flow rate was 1.5 m L / mi η. About 30 injections 4 0-4 5 uL each containing about 1.5 mg of the prepared mixture. The obtained 1 "-epispinoxin A is a colorless foam: l-NMR (CDCla) 56.75 (s, 1Η, Η -13), 4.80 (s, 2Η, Hl, Hl ”), 4.59 (m, 1Η, H-21), 4.28 (m, 1H, H-9); MS m / z 732 (M + l, 1) 189 (25), 142 (100).富 例 例 G13_1 7-Π-(2,3 · 4 · Busi-0-Ethyl- / 3-D-DfiH South type gi grape)) g 1¾A A 17-Pα Spinozin A A solution of 17-Psa (0.3 g, 0.5 mmol) and HgBr2 (90 mg, 0.25 mmol) in 1,2-dichloromethane (20 mL). The powder containing 4A molecular sieve was heated and heated to reflux temperature and collected by distillation. 3 mL of solvent. In this refluxing mixture, 2,3,4,6-tetra-0-acetamyl-a glucosyl bromide (0.48 g, 1.17 mmol) in dichloromethane (5 mL) solution. Collect more solvent (3 mL) and continue refluxing for 20 hours. Then more bromide (0.15 d and HgBr2 (90 mg) were added and refluxed for 5 hours. The reaction mixture was then cooled to room temperature and filtered through celite. The collected solids were CH 2 C 12 ( 20 mL) was washed and the filtrate and washings were combined and washed successively with 1 (UKI (2 X 10 mL), water (15 mL) and brine (15 mL) and then dried (MgS04). Evaporation left 0.7 5 g Residue, flash chromatography on oxidized sand (90 m L), '-237-This paper wave scale applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions on the back first (Fill in this page again) • Binding and binding 487559 Printed A7 B7 by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (235) Use CH2C12 of 3¾ MeOH to obtain 0.2 g 17-0- (2,3,4,6 -Tetra_0-ethanylpiranose-type glucosyl) Spinozin a 17-Psa, a colorless foam: UMR (CDCM 6 6.78 (s, 1H, H-13,), 5.20 (m, 1Η, Η-3 '), 5.05 (m, 1Η, Η-4 ”), 4.86 (d, lH, H-l'), 4.66 (m, 1Η, Η-21), 4.59 (d, 1Η , Hl "), · 4.30 (m, 1H, H-9), 4.14 (m, 2H, H-6M); MS m / z 921 (M + l, 2), 331 (100), 189 (90).. Glycosyl groups, pseudosaccharides, and other compounds are produced by other compounds

Example H1-Synthesis of Zhongkemouxin C from Zhongkeqinxin B. A solution of Spinoxin B (1,000 gms, 1.4 mmol.) In methanol (45 ml) was cooled to 3 ° C under nitrogen. A freshly prepared methanol solution of 1 M sodium methoxide (7.1 ml, 7.1 mmol) was added and then a portion of the iodine solid (1.8 8 melons 3, 7.1111111101) was added. The reaction was stirred at 3 ° (4.5 hours. (1 ^ 1 ^ shows that the reaction was completed 80¾) and poured into 5¾ sodium thiosulfate / diluted ammonium hydroxide solution and extracted with ether. The ether extract was washed with brine, Dry (CKO3) and concentrate at room temperature under reduced pressure. The crude product was purified by reverse phase HPLC on a Cl8 column and eluted with methanol: acetonitrile: 0.05% ammonium acetate (45:45:10) The obtained product (MS, and 1H-NMR) of Spinoxin C (361 mg) ° is the same as that of Spinoxin C produced in nature. To a solution of D 9-Psa (132 mg, 0.24 mmol) in water (5 ml), 1 N Η 2 S 0 4 to P Η 1 · 7 were added dropwise and the mixture was homogenized. The solution was heated to 8 ( TC 3 · 75 hours, during which oil and solution are separated -238-This paper size applies Chinese National Standard (CNS) A4 specifications (2! 0X_297 public housing) (Please read the precautions on the back before filling this page )

487559 A7 B7 5. Description of the invention (236). The mixture was cooled to room temperature and dichloromethane was added to dissolve the oil. The aqueous phase was separated and extracted with fresh dichloromethane. The dichloromethane fractions were combined, washed quickly with IN H2SO4, dried over K2CO3 and evaporated to room temperature to obtain a pale yellow glass (82.9 mg). The product was purified by flash chromatography with 5¾ MeOH in dichloromethane to obtain Spinoxin D Ag (63.6 mg, yield 63¾) as a colorless glass.

例 例 H3- Synthesis of Zhongxinxin R from Zhongliyaoxin A Spinyloxine A (5.0 gms, 5.13 mmol) and acetic acid trihydrate (4.68 gms, 34.4 mmol) in 80% methanol / water ( 125 ml) solution was heated to 47 ° C under nitrogen. After adding a portion of iodine in solid form (1.75 gms, 6 8.0 in m ο 1), the pΗ value was reduced from 10 to 8 to obtain brown. The pH was maintained at 8-9 by adding 1N sodium hydroxide at a fixed time. The reaction was heated for 2.5 hours (during which time the color faded to pale yellow) and then cooled to room temperature. The solution was poured into a solution of water (250 ml) and ammonium hydroxide (50 ml) and extracted with ether. The ether extract was washed with brine, dried (U2CO3), and concentrated under reduced pressure at room temperature. The crude product was purified on a C18 column by reverse-phase HPLC, and eluted with methanol · · acetonitrile: 0.054 ammonium acetate (45:45:10) to obtain Spinoxin B (2.52 gms), which (MS , UMR, 13C NMR, IR, and OR) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The same as Spinozin B produced by nature. Examination Example H4-N-Normosome 窨 Mou Li, 1 The reaction was performed as described in Example H3, with Spinozin J (105.4 mg, 0.15 mmol) as the starting material; however, the extraction operation was pseudo-two Chloromethane is carried out instead of ether. The resulting N-desmethylspinoxin J (57.3 mg; 54%) was a pale yellow glass. -239-This paper size applies to Chinese National Standards (CNS) ^ \ 4 specifications (210X 297 mm) 487559 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (237), Example H5-N -Demethylspinoxin was reacted as described in Example H4, starting with Spinoxin L (102.5 mg, 0.14 mmol). The resulting N-desmethylspinoxin L (66.5 mg; 664) was a white glass.

In the cellar case, Hfi-N-desmethylsigmaoxine K was reacted as described in Example H4, with Spinoxin U101.5 mg, 0.14 nunol) as the starting material. The resulting N-desmethylspinoxin K (79.3 mg; 81%) was a white glass.

Example F7: H7-H-desmethylspinoxine D. Spinoxin D (5 · 10 gms, 6.8% mm ο 1) and sodium acetate (10.3 gm, 125 mmol) in 80% methanol / water ( 500 ml) suspension was heated to 50 ° C while blowing nitrogen through the liquid for 15 minutes (pH = 8.96). When a part of the iodine (3.15 gms, 12.4 mmol) was added in a solid form, the pH was reduced to pH 8 to obtain a brown color. The pH was maintained at 8-9 by adding IN sodium hydroxide over time. The reaction was heated for 1.5 hours (during which time the color faded to pale yellow) and then cooled to room temperature. Add 10% sodium bisulfite (100 mL) to neutralize unreacted iodine. The reaction was concentrated on a rotary evaporator to a total volume of 150 mL and the solution was extracted with 3 x 100 mL of ethyl acetate. The ethyl acetate extracts were combined and washed with saline solution (100 mL). The ethyl acetate solution was dried over potassium carbonate and concentrated in a rotary evaporator. 5.0 gm yellow oil was obtained. The crude product was purified by flash chromatography (500 mL SiO2, CH2Cl2: CH3OH, 95:05) to obtain N-desmethylspinoxin D (3.79 g ms, 75.8%): part 1H- KMR (CDC 1 3, 300Mz) 6.68 (1H, bs), 5.50 (1H, bs), 4.86. (1R, s), 4.67 (1H, m), 4.46 (1H, bd -240-unit Paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) ----: --------- 丨 (Please read the precautions on the back before filling this page) Order 487559 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative A7 B7 V. Description of the invention (238) ·), 4 · 30 (1H, bd), 2 · 43 (6H, s), 1 · 72 (3Η, s ”啻 旆 Example 8-Ν, Ν -Didemethylspinoxine! (The reaction was performed as described in Example HI, starting with desmethylspinoxine K (891 mg, 1.27 mmol); however, the extraction was performed with ethyl acetate It was not carried out with diethyl ether. The obtained N, N-didemethylspinoxin K (463.6mg) was a colorless glass. Fenxiong H9-zhongkepinxin F 17-Psa espinoxin E 17- The compound was prepared from 35 mg (0.049 mmol) of Spinoxin F as described in Psa (Example H10). The obtained Spinoxin F 17-Psa 24 mg (88%) was obtained as none. Foam · HMR (CDCls) δ 6.75 (br s, 1H, H-13), 5.83 (d, 1H, H-5), 5.75 (dt, 1H, H-6), 4.82 (s, 1H, H -lf) 4.65 (m, 1H, H-21), 4.28 fm, 1H, H-9), 4.15 (m, 1H, H-17), 3.52 (s, 3H, 4, -0CH3), 3.46 (s, 6H, 2,-, 3'-0CH3), 1.25 (d, 3H, H-6 '); MS m / z 576 (2). Examination example H1 0 -Zhongxinxin R 1 7- A pseudoglycoside compound was added to a 35 mg solution of spinosinol E in water (0.7 mL) with appropriate stirring, and a portion of IN H2SO4 (0.1 mL) solution was added. The resulting solution was heated to 90-100 ° C and then The temperature was maintained for 24 hours. The resulting pseudoglycoside compound was isolated during this time. The mixture was then cooled to room temperature and the crude product was extracted into methylene chloride. The organic extract was then washed with saturated NaC U and dried ( MgS04 :). After evaporation, the crude 17-pseudoglycoside compound was purified by chromatography on silica gel using CH 2 C 12 solution of methanol as the eluent to obtain 26 mg (92¾) Spinoxin E. 17-Pseudoglycoside compound, -241-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) ---- Γ --.---- (Please read the precautions on the back before (Fill in this page) D, Yan 487559 A7 _ B7 _ V. Description of the invention (239) · 1 Colorless foam: 4_〇 !? (00 (: 13) 0'6.74 (1 ^ 3,11), [1- 13), 5.83 (d, 1H, H-5), 5.75, (dt, lH, H-6), 4.81 (s, 1H, H-1 ') 4,72 (m, 1H, H-21), 4.28 H-9), 3.52 (s, 3H, 4, -0CH3), 3.46 (s, 6H, 2,-, 3, -0CH3), 1 · 13 (d, 3H, H-22) ; MS m / z 576 (2). Part I Deargon Demonstration and Enlightenment of Beef Demonstration Example T1 Demethylphenidate-2 Deuterium and Demonstration No. 1 Printed by the Consumers' Cooperative of the Central Economic Standards Bureau (Please read the precautions on the back before filling out this page) Compound 2'-deoxyspinoxin Q (940 mg, 1.31 mmol) was dissolved in hot 70% Me0H / 30% pH 9 buffer (40 ml). Add sodium acetate trihydrate (1.3 gms, 9.6 mmo 1) and heat the suspension to 47 ° C. Then add iodine (438 mg, 17 mmol) as a solid. After stirring for 4 hours at 47 ° C, additional iodine (150 · 8 mg, 0.59 mmo 1) was added. The mixture was stirred for an additional 4 hours at 47 ° C, then cooled to room temperature and stirred for another 12 hours. The solution was poured into 5% sodium thiosulfate and extracted with Et20. The Et20 portion was washed with brine, dried (K2CO3), and evaporated at room temperature. The residue was chromatographed on a silica gel column (5% MeOH / CH2Cl 2) and provided N-desmethyl-2 ^ -deoxyspinoxin QU62.7 mg; yield 56% to recover the starting material As a reference), a light pink solid; FDMS, m / z (relative intensity) 702 (100), 159 (10). Example I2-N-Normo-3'-demethyl-based Shimou sheep, f reacted as described in Example II to 3'-deoxy. Spinozin J (1.51 gms, 2.16 mmol ) Is the starting material. The obtained N-desmethyl-3'-deoxyspinoxin J (937.6 mg; yield 63%) was a white solid; FDMS, m / e (relative strength) 687 (100) 159 (10).- 242-This paper size is in accordance with Chinese National Standard (CNS) A4 (2 丨 0X297 mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __B7___ 5. Description of the Invention (24〇) Example 13-3, Deargonization Very Medium Inoxanosin J 17-Psa 3'-Deoxyspinoxin J (25,7.2 mg, 0.37 mmol) was suspended in an IN H2SO4 (5 ml) solution and heated to reflux temperature for 2.25 hours. The mixture was then cooled to room temperature, diluted with CH2C12 and washed with water. The CH2C12 portion was washed with brine, dried (K2CO3) and evaporated at room temperature. The residue was chromatographed on a silica gel column (50% EtOAc / hexane) to provide 3 deoxyspinoxin J 17-Psa (112 rag; yield 54%); FDMS. M / e, (relative strength) 560 (100), 159/16). Fushi Example T4-9-0- (1-tetrakis-amino group) Spinozin A 9-Psa (a mixture of α and / ¾ oligomeric compounds) The compound Spinozin A 9-Psa (106.6 mg , 0.20 mmol) was dissolved in benzene (10 ml) and added with diqirmaine (21 ml, 0.23 mraol) and then a catalytic amount of p-toluenesulfonic acid was added. The mixture was heated to reflux temperature for 16 hours. Since no reaction was observed, more dihydropiran (200 ml) was added. The mixture was refluxed in a Dean / Stark trap for 6 hours and then cooled to room temperature. The mixture was released with CH2Cld # and washed with IN NaOH. The CH2C12 portion was washed with brine, dried (K2C03) and concentrated at room temperature. Dissolve the residue (105 mg, mostly spinoxin A 9-Psa) in benzene (10 ml), add dihydropiperan (200 ml, 2.2 mmol), and then add p-toluenesulfonic acid (42.9 mg, 0.23 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with Et20. The Et20 portion was washed with saturated NaHC03, brine, dried (U2CO3) and evaporated at room temperature. The residue was chromatographed on a silica gel plate (100% EtOAc, then 10% Et0H / E, t0Ac, then 100% MeOH, performed in 2 steps) to provide 9-0- (tetrahydroeranyl) spine Northing-243-'This paper's standard is applicable to China National Standard (CNS) A4 specification (2i0x 297 male thin) ----: ----- II (Please read the precautions on the back before filling this page )

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 B7 V. Description of the invention (241) A 9-Psa (a mixture of α and / 3 isomers :) (116.8 mg; yield 93¾); FDMS m / e (relative intensity) 628 (109), 142 (5).

Example T.H ′ -Π-Ethyl Acetate Li J. The compound Spinoxin J (207.9 mg, 0.29 mmol) was dissolved in Ottidine (2 ml) and acetic anhydride (140 ml, 1.5 mmol) was added. The mixture was stirred at room temperature for 24 hours, and then evaporated at room temperature. The residue was chromatographed on a silica gel column (7¾ MeOH / CH2Cl2) to provide 3 夂 -ethylstilpinoxine J (148.8 mg, yield 68%) as a colorless glass. FDMS, ro / e (relative strength) 759 (100 :), 283 (4), 142 (7). ψ Example 窨 旆 -0-Ethylpyridinium oxoxine The reaction was carried out as described in Example 15, starting with spinosynoxine (211.9 mg, 0.29 mmol). The obtained 2T-0-acetylspinoxin H (175.2 mg, yield 801) was a colorless glass. FDMS, m / e (relative intensity) 759 (100), 142 (6).

Fu Shi Example 17-4 'Acetyl mesitycin K was reacted as described in Example 15 with Spinoxin K (207.0 mg, 0.29 mmol) as the starting material. The obtained 4'-0-acetylspinoxin K (204.9 mg, yield 93%) was obtained as a white glass. FDMS, m / e (relative strength) 759 (100).

Examination example T8-4 Γ (S-methyl) dithiocarbonyl 1 in spinoxin K (201.0 mg, (L28 mmol) and oxazole (catalytic amount) was dissolved in anhydrous THF (2 m 1), and stirred at room temperature under nitrogen. Sodium hydride (50¾ in mineral oil solution; 25 mg, 0.52, mmol) was added to the solution, followed by sulfur disulfide (90 ml, 1.5 mmol) and then added Methyl iodide (90 paper sizes applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) ----: --.---- (Please read the precautions on the back before filling this page)) Order 487559 Ministry of Economic Affairs A7 B7 printed by the Consumer Standards Cooperative of the Central Bureau of Standards 5. Description of the invention (242) ml, 1.44 mmol). After stirring at room temperature for 1 hour, add acetic acid (90 ml) and pour the mixture into saturated NaHC0,3. The aqueous layer was then extracted with (: [12 (: 12. The CH2C12 portion was washed with brine, dried (MgS04) and evaporated at room temperature to provide a 4'-0-[(S-methyl) dithiocarbonyl] history. Binoxin K (218.1 mg, yield 97%) is a yellow glass. FDMS, m / e (relative strength) 808 (100).

Example Tfl -.vnr (s-methyl) dithiocarbonyl 1) Noxin J was reacted as described in Example 18 with Spinoxin J (207.1 mg, 0 · 2 9 in m ο 1) is the starting material. The obtained 3 夂 0-[(S -methyl) dithiol)] Spinoxin J (224.0 mg, yield 96¾) was a yellow glass. FDMS, m / z (relative intensity) 808 (100). Example 110-2'-0-[(S._Methyl) dithiocarbamate, 1 in the case of Kouxin Xin, the reaction was performed as described in Example 18, with Spinoxin H (204.0 mg, 0.2δ mmol ) Is the starting material. The resulting 2 ^ 0-[(S-methyl) dithiocarbonyl] spinosinol (218 · 8 mg, yield 97¾) was a yellow glass. FDMS, m / z (relative intensity) 808 (100).

Example 11 1 -2 '-Q-[(S -methyl) dioxocarboxan 1 in ketoxin Q The reaction was carried out as described in Example 18, with Spinoxin Q (1.00 gms, 1.4 nunol ) Is the starting material. The obtained 2'-0-[(S-methyl) difluorenylcarbonyl] spinoxin Q (1.13 gras, yield 98%) was yellow glass. FDMS, η / ζ, (relative intensity) 822 (100).

Fenshi Example II2-3'-0- (S-A) dithiocarbonyl and even ketoxin L dissolved Stronoline L (1.65 gms, 2.2, mmo 1) in anhydrous THF1 (50 m 1) And cooled under nitrogen and in an ice bath. Add oxazole (21.2 mg, 0.3-245-this paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) _ '----: ----- Φ clothing-( (Please read the notes on the back before filling out this page)

1T 487559 F-A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (243) mmo Γ) into the solution, followed by sodium hydride (60¾ mineral oil solution; 105.0 mg, 2.6 mmol) and then added Carbon disulfide (700 ml, 11.64 mmol) and iodotin (700 ml, 11.1 mmol). The mixture was stirred at room temperature for 1 hour, then a small amount of NaH was added and stirring was continued for 1 hour. The mixture was poured into a saturated ammonium chloride solution and extracted with CH 2 C 12. The CH2C12 portion (K2C03) was dried and evaporated at room temperature to provide 3'-0- (S-methyl) dithiocarbonyl) Spinoxin L (1.86 mg, yield 100%) as yellow Solids FDMS, m / e (relative strength) 821 (100), 160 (4).

Example Example 3-4'-Dehydrogeno-Mesanosine K Dissolve the compound 4'-0-[(S-methyl) dithiocarbonyl] Spinosin K (182.5 rag, 0.23 mmol) in toluene (10 ml). Add tributyltin hydride (93 ml, 0.35 mmol) and AIBN (catalytic amount) and reflux the solution. After another 2 hours, more tributyltin hydride (100 ml) was added. The mixture was refluxed for another 12 hours and stirred at room temperature for 5 hours. The solvent was then evaporated to a small volume and then chromatographed on a silica gel column (80¾ EtOAc / hexane) to provide 4'-deoxyspinoxin K (59.9 mg, yield 37%) as a colorless glass Thing. FDMS, m / e (relative intensity) 702 (100).

Fenshi Example Π 4-3'-Dearginyl Pyridoxine J Compound 3 '-0- [(S -methyl) dithiocarbonyl] Spinoxin J (849 · 1 mg, 1.0 5 mm ο 1) Dissolved in anhydrous toluene (50 m 1). Fresh tributyltin hydride (500 ml, 1.6 mmol) and AIBN (10.2 mg) were added and the mixture was refluxed. After 8 hours, add A IBN (32.8 mg) and continue refluxing for 2 hours. After standing at 5 ° C for 48 hours, the lysate was evaporated to a small volume. The residue was chromatographed on a silica gel column (3.5% Me0H / CH2C 12) to provide 3'-deoxygenation. This paper is sized to the Chinese national standard (CNS> A4 specification (210X 297 mm)). · —— (Please read the precautions on the back before filling this page),-Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, printed by 487559 A7 B7 V. Invention Description (244) The rate is 76t), which is a colorless glass. FDMS, m / z (relative strength) 701 (100) ,. Fen example T1 5-2'-guan g is very Chinese guest 谌 Xin Η will compound 2 '-0- [ (S_methyl) dithiocarbonyl] Spinoxine (1 · 15 gms, 1.4 mmol) was dissolved in anhydrous toluene (50 ml). Fresh tributyltin hydride (750 ml, 2.8 mmol) and AIBM 30 mg) were added and The mixture was refluxed. After 2.5 hours, add AIBN (20.5 mg) again and keep refluxing for 5 hours. After stirring at room temperature for 11.5 hours, the solvent was evaporated to a small volume and the residue was chromatographed on a silica gel column (3.5% MeOH / CH 2 C 12) to provide 2′-deoxyspinoxin H (821.5. mg, yield 84: i)) as a colorless glass. FDMS, m / z (relative intensity) 701 (100).

Fuyu Example T16-2'-Old, a certain 窨 柒 窨 柒 octyl Q dissolves the compound 2 '-0- [(S -methyl) dithiocarbonyl] spinoxin Q (1.08 gms, 1.3 mmol) In anhydrous toluene (50 ml). Fresh tributyltin hydride (750 ml, 2.8 mmol) and AIBNC 47.5 mg) were added and the mixture was refluxed for 2.5 hours and then cooled to room temperature. After 20 hours, the solvent was evaporated and the residue was chromatographed on a silica gel column (3.54 MeOH / CH 2C 12) to provide 2'-deoxyspinoxin Q (912.9 mg, yield 98¾) as a colorless glass Thing. FDMS, m / Z (relative intensity) 716 (100).

Fenshi Example Π7-: Γ-Qiqinqinqinxin L was reacted as described in Example 116, with 3 ^ 0- (3-methylthiocarbonyl) spinoxin L (1.85 gms, 2.25 mmol) . 3'-Deoxyspinoxin L (1.16 gms, yield 7 «) is a colorless glass. FDMS, m / e (relative intensity) 716 (100). -247-This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 Public Holiday 1 I ------: ---- (Please read the precautions on the back before filling this page) Order 487559 A7 B7 V. Description of the Invention (245) Rich Example I18-9-Π- (ητ-L-3,4-Diethyl Twisted Rhamnoside) Zhongbin Mooxin A 9'Psa, Spinozin A 9 -Psa (1.56 gms, 2.9 mmol) and bromo-2, 3,4-tri-O-ethynyl rhamnoside 41.52 gms, 4.3 mmol) were dissolved in CH2C12 (75 ml; anhydrous). Tetramethylurea (1.0 ml, 8.4 mmol) was added, followed by silver trigas methanesulfonate (823.8 mg, 3.2 mmol), and the reaction flask was covered with aluminum foil. After stirring for 24 hours, the reaction mixture was filtered through celite at room temperature and in a dark room, and the celite was washed with CH2C12. The filtrate was collected and washed with saturated NaHC03, dried (MgS04) and evaporated at room temperature. The residue was placed under high vacuum to produce a viscous yellow oil 3.29 gins. This material was chromatographed on a silica gel column (5% E tOH / CH 2C 12, followed by washing the column with 10 ΟίϊΕ tOH) to provide the product 9-0- U -L-3,4-di-0-acetamidine Base rhamnosyl) Spinozin A 9-Psa (259,6 mg, 15¾ based on recovered Spinozin A 9-Psa, a colorless glass). IR (KBr, cm-1) 3480.99 (OH), 2938.92, 1747.73, 1661.89, 1457.41, 1373.49, 1232.67, 1164.19, 1125.61, 1042.66, 988.64, 902 · 80 · FDMS (m / z, relative strength) 774 (100) ': Analysis of (C42H63N〇12): Estimated value · C: 65.18, Η: 8.20, the policy of employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ι_ϋ ml II ml n_ · ^ I m mu · ϋϋ —Hi ml ml · 11_1 TJ, \ '彡 (Please read the notes on the back before filling this page) Ν: 1.81; actual value ·· C: 64.94, Η: 8 · 28, Ν: 1.97. Example of Ning 9-3.4-Di-6-6

Add iodoethane (32 mL, 0.40 mol), 3,4-di-0-acetamido-6-deoxy-L-glucoside (4.28 g, 0.20 mol), 50% Na0H aqueous solution (43 mL , 0 · 81 mol) and DMS0 (11.4-mL, 0.16 mol) were sequentially added to a 300-mL round bottom three-necked flask equipped with a top M device: Start M-248-This paper is scaled to Chinese National Standard Soap (CNS) Λ4 specification (210X297 mm) economic, printed by the Central Standards Bureau ’s consumer cooperative 487559 A7 ________ B7_ V. Description of the invention (246) Mix and add tetrabutylanhydrosulfate (2.04 g, 0.006 mol). Continue mixing for 66 hours. The mixture was equilibrated between water and Et20. The aqueous layer was extracted twice with Et20 (20 mL) and the last one was extracted with Et20-CH2C12 (20 mL). The organic layers were combined, washed successively with water, a dilute aqueous solution of sodium thiosulfate, water and brine, dried over sodium sulfate and potassium carbonate, and concentrated under reduced pressure. A white solid precipitated during evaporation. The mixture was diluted with pentane and the solids were removed by filtration. The solvent was removed from the filtrate under reduced pressure to give a pale yellow oil (3.2 g, 87%), which was sufficiently homogeneous for subsequent reactions without additional purification. 1H-NMR d 6.32 (dd, J = 6.1, 0.6, 1H), 4.78 (dd, J = 6.1, 1.2, 1H), 1.36 (d, J = 6.4, 3H), 1,22 (t, J = 7.0, 6H). Enriched Example 120-3,4-Di-il-n-propan-fi-deargon-L-gi-permethenol Iodine n-propane (39 mL, 0.40 mol), 3,4-di-0 -Acetyl-6-Degassed-LS glucose (4.28g, 0.20 mol), 50% Na0H aqueous solution (43 mL, 0.81 mol) and DMS0 (11.4 mL, 0 · 16 mol) are added to the equipment in order A 300-mL round bottom three-necked flask with a top stirrer. Start stirring and add tetrabutylammonium hydrogen sulfate (2.04 g, 0.006 mo 1) in a single portion. The mixture was stirred at room temperature for 17 hours. The mixture was equilibrated between water and pentane. The aqueous layer was extracted with additional pentane. The organic layers were combined and washed successively with water (three times), diluted sodium thiosulfate, diluted sodium hydrogen sulfonate and brine. The solvent was removed under reduced pressure (20 Torr then 0 · 1 Torr) to obtain a pale yellow oil (4.0g, 94: ¾), which was used without further purification. HMR d 6.31 (dd, J = 6.1, 1.4, 1H), 4.78 (dd, J = 6.1, 2.4, 1H), 1.60 (m, 4H), 1.37 (d, J = 6.4, 3H), -249-this Paper size applies Chinese National Standard (CNS) A4 (2iox mm) (Please read the precautions on the back before filling this page)

V. Description of the invention (247), Economy, that printed by the Consumer Standards Cooperative of the Central Bureau of Standards 0.93 (t, J = 6.3, 3H), 0.94 (t, J = 6.3, 3H). Example 12: 3,4-di-0-i-propyl-fi-dioxane, even-LS glucose and iodine i-propion (40 mL, 0.40 mol), 3,4-di-〇 -Ethyl &quot; * 6 -Deoxy-L-® Glucose (4 · 28 g, 0.20 m ο 1.), 50% N a 0 Η Water soluble makeup (43 juL, 0 · 81 mol) and DMS0 (11 · 4 mL, 0.16 mol) were added to a 300-mL round bottom three-necked flask equipped with a top stirrer. Start stirring and add tetrabutylammonium hydrogen sulfate (2.04 g, 0.006 mol) in a single portion. The mixture was stirred at room temperature for 67 hours and at reflux temperature for 24 hours. The mixture was cooled to room temperature and equilibrated between water and pentane. The aqueous layer was extracted with pentane. The organic layers were combined and washed with water (4 times), diluted sodium thiosulfate, water, and saturated sodium bisulfate. The solvent was removed under reduced pressure (first 20 Torr to 0.1 Torr to give a pale yellow oil (1.2 g, 28%)) which was used without further purification. 1H-NMR d 6.29 (dd, J = 6.1 , 1.4, 1H), 4.70 (dd, j = 6.1, 2.4, 1H), 1.35 (d, J = 6.4, 3H), 1.21 (d, J = 6.4, 3H), 1.18 (d, J = 6.4, 6H ), 1 · 17 (d, J = 6.4, 3H). Example T22 · 9_ (2 -Deammine-3_0,4-0-di-n-propyl-rhamn I. Gengshibuzhongzhong谌 辛 A 9-False 茌 BR, a certain chemical compound, and 9- (2-degassing group-3- 〇 · 4-〇- 二-η- 丙 某-Bu; 3 -rhamnose) -Zhong Phenocin A 9-Pseudoxanthine K uses a chemical compound with the same procedures and reactants as described in Example 129, and the amount used is as follows: Spinoxin A 9-pseudoglycoside (544 mg, 1.00 mmol ), CH2C12 ligand compound (4 mlj, 3,4-di-0-n-propyl-6-deoxy-L-grapeline (429 mg, 2.00 mmol) and camphorsulfonic acid (-250-present Paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) I ---.-- ^-蝼 II (Please read the notes on the back before filling this page), 11 487559 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives A7 B7 , Described the invention (248)

279 mg, 1.20 mmol). The crude product was chromatographed on silica gel (80 g), eluted with 3% MeOH in CHC13, and reversed phase (Kroroasil 'C18, siliconized silicon ODS, 100A, 10 m, spherical, 25 cm X 20 mm ), With 90% Me0H and 10¾ water (containing 0.2 · v / v concentrated NH4 0H aqueous solution) to provide alloisomers which are all white foams; α-alloisomers (307 mg, 41% ) 4-NMR d 4.85 (br d, J = 2.9, 1H), 0.94 (t, J = 7.5, 3Η), (K92 (t, J = 7.5, 3Η), and / 3- allomers (80 mg, 1 (U) LR d 4 · 42 (m, 2H), 0 · 93 (t, J 2 7.3, 3H), 0 · 92 (t, J = 7.3, 3H). Example 123- 9- (To "Mizyl-3-0.4-0-Di-i-Bingmou-1a-Rhamnine")-Zhongxinxin A 9-Puppet with a servant and use Example 129 The same steps and reactants were used as follows: Spinoxin A 9-pseudoglycoside (543 mg, 1.00 mmol), CH2Cl2 (4 mL), 3,4-di-propyl-6- Deoxy-L. Glucosulose (428 mg, 2.00 mmol) and camphorsulfonic acid (279 mg, 1.20 mmol). The crude product was chromatographed on silica gel (100 g) using Eto Ac chromatography and on a reverse-phase column (Kromasil '' C18, Silicon Oxide 0DS, 100A, 10 m, spherical, 25 cm X20 mm) with 90% MeOH and 10¾ water (containing 0.1¾ v / v concentrated NH4〇H in water) to produce a white powder (306 mg, 40¾). UMR d 4.84 (br d, J = 2.9, 1H) , 1.40-1.13 (m, 25 Η;) 〇 Example T2H-(0 · (!-Diethyldithiogalanose) deargonate-2 ~~ • Ethanol-rhamnose will be 3, 4-Di-0-Ethyl-6-deoxy-L-glucoside (2.14 g, 10.0 mmo 1) dissolved in benzene (20 mL) Within 5 minutes, 〇-〇- diethyl / -251-This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) I -—I-----. -I —-1- I I--·-_ ..... (Please First read the notes on the back #Fill in this order) Order 487559 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (249) A solution of thiophosphoric acid (1.96g, 10.5 mmol) in benzene (10 mL) and The resulting mixture was stirred at room temperature for 18 hours. Further, dithiophosphoric acid (0.10 g, 0.54 mmol) was added and the mixture was stirred for another 20 hours. The mixture was extracted with dilute aqueous sodium hydrogen sulfonate (twice), water and brine. The mixture Na2S04 and MgS04 was dried. The solvent was removed under reduced pressure to give a yellow oil (4.03 g, 101%). Example F25-9- (2-Dehydro- 3-0 · 4-0-Diethyl a certain α-rhamnolide) -Zhongxuan Mixin A 9-Pseudosugar The powder of 4A molecular sieve (500 mg) and AgF (685 ms, 5.40 mmol) were suspended in acetonitrile (2 inL). Add a single portion of 1- (0,0-diethyldithiophosphoranyl) -2-deoxy-3,4-di-0-ethenyl-rhamnose (400 mg, 1.00 miiio 1) Acetonitrile solution. The resulting dark green-brown mixture was stirred at room temperature for 6 days. The mixture was filtered through celite to remove black precipitate, the solvent was evaporated and the residue was dissolved in a 1: 1 mixture of EtOAc-Et20 (20 fflL). The mixture was washed successively with NaOH (2 times), water (2 times) and brine. The solvent was evaporated and the residue was placed on a reverse-phase column (KromasiT C18, silica 0DS, 100A, 10 m, spherical, 25 cm × 20 mm) using 90% MeoH and water (containing 0.1% v / v concentrated NH4. H solution) was chromatographed to give an amorphous white solid (36 mg, 9¾). tH-NMR d 4 · 85 (br d, J 2 2 · 9, 1 Η), 2 · 08 (s, 3 Η), 2 · 01 (s, 3H). Example 126-9- (2H-5-RZ, argon-5.6-dichloro-β-S-methyl -__ 2jia-P-Jinan) -Zhongkexin Abu pseudo-BP-based compound Spinoloxin A 9-pseudoglycoside compound (272 mg, 0.500 mmol) and 3,4-di-0-acetamido-6-deairyl-L-®glucone (214 mg, / -252-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297mm) ----;-,-(Please read the precautions on the back before filling this page), ^ τ Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 487559 A7 B7 _ V. Description of the invention (250) 1 · 00 mmo 1) Dissolved in CH2C 12 (3 mL), adding substances that passed through molecular sieves (4 A, 40 mg) and camphorsulfonic acid (12 8 / ng, 0.55 0 mm ο 1). After 18 hours, add camphorsulfonic acid (20 mg, 0.086 mmol). The mixture was stirred for 3 days. The mixture was diluted with CH2Cl2 (10 mL) and diluted with a 1: 1: 1 mixture of water-saturated aqueous sodium hydrogen carbonate solution-1.0N NaOH. The aqueous layer was extracted with CH2C12 (twice) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate and evaporated to obtain a dark oil. The residue was placed on a reverse-phase column (Kromasil 'C18, silica ODS, 100A, 10 m, spherical, 25 cmX 20 mm) using 90% MeoH and 10% water (containing 0.1% v / v concentration NH4OH solution) was chromatographed to give a white foam (44 mg, 11%). HMR d 5.92-5.73 (m, 4H), 5.01 (br s, 1H), 2.09 (s, 3H)

O Fenshi Example T27-5 "-Diqi-9- (2-guan argan-3-0.4-0-diethyl-1 -a-rhamnoside, a Chinese guest Li A 9-pseudosugar BR A certain compound will be 9- (2-deoxy-3-0,4-0-diethyl-1-a-rhamnosyl) -spinoxin A 9-pseudoglycoside compound ( 200 mg, 273 mmol) and cyclohexane (0.40 inL, 3.95 mmol) were dissolved in pure ethanol (4 mL). Carefully add charcoal / charcoal (10%, 20 mg / 19 mmol) and the resulting mixture at reflux temperature Heat for 3 hours. Stir the mixture for another 17 hours at room temperature. Filter the mixture through diatomaceous earth and evaporate under a stream of nitrogen. The residue is placed in a reverse-phase column (Kromasil 'C18, silica 0DS, 100A, 10 m, Sphere, 25 cm × 20 mm), chromatographed with 90% MeoH and 10¾ water (containing 0.1¾ v / v concentrated NH4OH solution) to give a glassy solid (45 mg, 22%). 4-NMR d 6.83 (br s, 1 H), the lack of 2H-multiple spectral lines in 5.9-5.7 asks ^-253-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X297 mm) -----,-,- ---- (Please read the notes on the back before filling this page) Order 487559 A7 B7____ V. Description of the invention (251), 0 Example T28U-Dichloroguanyl-3: ι0 · 4-0-bis-η-propyl, 1-α-rhamnose, Kekexin A 9-pseudosugar BR-based compound will be cyclohexane (3 0 mL, 28.6 mmel) and rake / charcoal (10%, 43 mg) were added to pure ethanol (3 mL). 9- (2-deoxy-3-0,4-0-di-η-propyl was added -I-a-rhamnosyl) -Spinoxin A 9-pseudoglycoside compound (188 mg, 0.248 mmol) in ethanol (2 niL) and the mixture was heated at reflux temperature for 5 hours. At 1 At the hour and 4.5 hours, 38 mg and 67 mg of rake / charcoal were added to the reaction mixture. The mixture was cooled, filtered through diatomaceous earth and concentrated to a thick oil. The residue was dissolved in Et20 and concentrated concentrated acid. Wash with sodium bicarbonate and brine, dry with anhydrous potassium sulfonate and evaporate to produce a light gray foam. The material was placed on a reverse-phase column (Kromasil 'C18, silica 0DS, 100A, 10 m, spherical, 25 cmX20 mm) , Using 92% MeoH and 8% water (containing 0.1 2 v / v concentrated NH 4 0 H aqueous solution) chromatography to produce an amorphous powder (80 mg, 42¾). 1 ^) ^ d 6.73 (br s, 1H), The lack of 2H-multiline between 5.9-5.7. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 窨 旆 例 T29-9- (2_ 去 g 某 -3-Π. 4-Π- 二 7. Even- 1-α -Rhamnosyl) -Chokepin A 9 -PseudoI Tang Zhi with a (h-complex dissolved Spinoxin A 9-pseudoglycoside compound (136 mg, 0.250 mmol) in CH2C12 (1 mL). A single portion of 3,4-di-0-ethyl-6-deoxy-L- »glucose (93 mg, 0.50 mmol) and camphorsulfonic acid (70 mg, 0.30) were added sequentially. roraol). Stir the reaction mixture at room temperature for 1 hour. Add a saturated aqueous sodium bicarbonate solution and dilute with E t0 Ac (5 mL), -254-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 (Mm) 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (252) · Things · The mixture was sold in saturated hydrogen sulfonate (10 mL) and l. ON MaOH (2 mL) and EtOAcUO mL ) Between the mixture ,. The aqueous layer was extracted with additional EtOAc. The combined organic layers were successively washed with saturated sodium bisulfate and brine and dried over anhydrous Na 2 SO 4. Remove the solvent under reduced pressure and place the residue on a reverse-phase column (Kroroasir C18, silica 0DS, 100A, 10 m, spherical, 25 cmX20 mm) using 90% MeoH and 10¾ water (containing 0.1% v / v Concentrated aqueous N H 4 0 H) was chromatographed to give an amorphous white solid (74 mg, 40¾). 'H-NMR d 4.84 (br d, J = 2.9, 1H), 1.21 (t, J = 7.1, 3H), 1.20 (t, J = 7.2, 3H). Part J is modified by rhamnose; &gt; Substitute modification of pseudofluorene, BF, and compound A2. Example of enrichment. 11-9-0- "(1'5,2 ^ 1) -2- 甲某 -4 -(] '. 2 夂 Etc.-Ethyl argonyl-3' _ 锊 锊 丁丁) -5- 锊 --K 二 -Diargon ring-2-11 Φ 窨 谌 辛 A Q-Psa # 二Argon Krypton: &gt; A mixture of krypton 2 and 5 in a solution of Spinozin A 9-Psa (100.8 mg, 0.19 mmol) in dichloromethane, 1-bromo-2, 3,4-tri-0 was added _Ethyl-rhamnose 1 (67.9 mg, 0.19 mmol), followed by trigas silver methanesulfonate (52.3 mg, 0.2 mmol) and then diisopropylethylamine (35 mg, 0.2 mmo 1) . The mixture was stirred at room temperature and in a dark room for 3.5 hours. Then the mixture was diluted with dichloromethane and washed with water. The methylene chloride portion was then washed with brine, dried over MgS04 and concentrated at room temperature under reduced pressure. The product was separated from unreacted starting materials by chromatography on silica, and eluted with 5% methanol in dichloromethane. The obtained 9-0- [(1 f S: 2 'S, 3' S) -2-methyl-4- (1,2, -2, -bis-acetoxy-3'-hydroxybutylbenzene 5 -Hydroxy-1, 3 -dichloropentane '-255-This paper size applies to China National Standard (CNS) A4 (210X297 mm)） · ϋϋ ϋϋ · ί m »ϋϋ I— ϋϋ —I- (please Read the notes on the back and fill in this page) Order the printed bag 487559 A7 B7 of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (253) 2-based] Spinoxin A 9-Psa Mixture of positions 2 and 5 (75 · 2 mg; yield 49%), FDMS, m /, e (relative strength) 816 (M, 70), 815 (100), 585 (10). Example J _._ 2 2. 2.-0-[(1 '?; · 2' S.iVS)-?-Tianmou-4-Π ', 2,' V -tris (^ butylbutyl 5-fluorenyldi) ft 璟- The 2- and 1-membered mixture of ^ 9-Psa in the digastric position 詈 2 and 5 is 9-0-[(l's, 2'S, 3'S) -2-methyl-4- (1 ', 2'-Bis-Ethoxy-3-hydroxybutyl) -5-hydroxy-1,3-dioxolane-2-yl] Spinoxin A 9-Psa at position 2 and 5 (104.2 mg, 0.12 mmol) in methanol (4 ml) A small amount of hydrogenated M (a mineral oil dispersion of 60¾) was added and gas was generated. The reaction mixture was stirred at room temperature for 15 minutes. The mixture was then diluted with dichloromethane and washed with a saturated aqueous ammonium chloride solution. The dichloromethane portion was washed with brine. , Dried over MgS04 and concentrated under reduced pressure at room temperature. The obtained 9-0-[(11,2'5,31) _2-methyl-4- (1 ', 2', 3 trihydroxybutyl [5-Hydroxy-1,3-dioxolane-2-yl] Spinoxin A 9-Psa A mixture of positions 2 and 5 of dioxolane (44.2 mg; yield 50¾), beige Solid, FDMS, m / e (relative strength) 733 (95), 732 (M +, 100), 543 (10). Example of arsenoxine A fl-Psa in history To a solution of Pinoxin A 9-Psa (474.3rag, 0.87 mmol) in dichloromethane (20 ml) was added diisopropylethylamine (225 / i 1, 1.3 mmol) and 2-methoxyethyl Oxymethyl chloride (100 ul, 0.87 mmol). The reaction mixture was heated to reflux temperature for 2'4 hours and then stirred at room temperature for 2 days. Then dilute the mixture with dichloromethane and saturated NaHCO 3 water; -256-This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) I.. --II (Please read the back Note for re-filling this tribute), 1TT printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (254) · Solution cleaning. The dichloromethane portion was dried with K2CO3 and concentrated under reduced pressure at room temperature. The product was separated from the unreacted material by chromatography on silica, and then eluted with 4% methanol in dichloromethane followed by 10¾ methanol in dichloromethane. The obtained 9-0- (2-methoxyethoxymethyl) spinoxin A 9-Psa (226.5 mg; yield 56%, based on the recovered starting material) was a colorless glass , FDMS, ra / e (relative intensity :) 632 (M, 40), 631 (100).例 Example J4-9_0-Methyl Shig Xing A A-Pu To a solution of Spinola A 9-Psa (200.1 mg, 0.37 mmol) in THF (2 m 1), add sodium hydride (50% of Mineral oil dispersion; 34.6 mg, 0.72 mmol), followed by methyl iodide (90 ul, 1.4 mmol). The reaction mixture was stirred at room temperature for 3.5 hours while performing a slow evaporation. The mixture was diluted with ether and washed with water. The ether portion was then washed with brine, dried over K2CO3 and concentrated at room temperature under reduced pressure. The product was separated from unreacted material by chromatography on silica and eluted with 7% methanol in dichloromethane. The obtained 9-0-methyl spinosin A 9-Psa (75.6ing; yield 37%) was a white glass, FDMS, m / e (relative strength) 558 (M +, 60), 557 ( 100)-窨 旆 例 J5-9-0- f (2R · 3S. 4S. 5R. 9R &gt;-2-formamidine SS argon j-dimethylamine and even -7-methyl-1, 6.8- Trioxo L01, dicyclocycloalkane-7-even1, mesooctane A 9-Psa_- Yuspinoxin A 9-Psa (564.5 mg, 1.04 mmol) and 1-bromo-2,4 -Di-0-acetamidosulfonyl hydrobromide 2 (487.4 mg, 1.15 mmol) in anhydrous dichloromethane (30 ml), and tetramethylurea (358 ml, '-257- This paper size applies to Chinese national standards · (CMS> A4 specification (2 丨 〇X297mm) (Please read the precautions on the back before filling in this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __ · B7__ V. Description of the invention (255) 3.0 mmol) and silver trifluoromethanesulfonate (298.4 mg, 1.18 mmol). The reaction mixture was stirred at room temperature and in a dark room for 20 hours. The reaction mixture was then diluted with dichloromethane and washed with IN NaOH. The dichloromethane portion was then washed with brine and dried over K2CO3 and evaporated at room temperature under reduced pressure. The product was separated from unreacted material by chromatography on silica and eluted with a 5% methanol in dichloromethane solution. The obtained 9-0-[(21?, 35,43,51?, 91〇-2-methyl-3-ethoxy-4-dimethylamino-7-methyl-1,6, 8-trioxo [4.3.〇] bicyclononane-7-yl] Spinoxin A 9-Psa (101.9 mg; yield 13¾, based on the recovered starting material), which is the Mixture. FDMS, m / e (relative strength) 828 (20 :), 800 (M + -H, 100), 759 (20), 543 (30).

Enriched Example J6-9-0-Ethylpyridinium A in a solution of Spinoxin A 9-Psa (167.3 mg, 0.31 mmol) in chloroform (5 ml) and diisopropylethylamine (220 til, 1.26 mmol) and then ethyl chloride (220 ml, 3.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ether and decanted with 1N NaOH, dried over K2CO3 and evaporated at room temperature under reduced pressure. The product was purified by chromatography on silica and eluted with 50% ethyl acetate in hexane. The obtained 9-0-acetylspinoxin A 9-Psa (110.6 mg; yield 61%) was a white off-glass object, FDMS, m / e (relative strength) 586 (50), 585 (M, 100). Example J7-9-0-carbon 7: argon, acetone, selenium, tungsten, etc. A q-Pu The reaction was carried out as described in Example J6, with Spinoxin A 9-Psa (177 mg, 0.333 mino 1) and Ethylmalonyl Chloride as starting materials ': · Earned' -258-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before (Fill in this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __B7_ V. Invention Note (256) of 9-0-Carbonethoxyacetamido Spinoxin A 9-Psa (124.4 mg; Yield 57%), as White deviates from glass, FD, MS, m / e (relative intensity) 658 (MH +, 100). Fenxiong J8-9-0. N-Nitaji Binbinxin A 9-Psa iodide in DMF (0.5 ml) solution of Spinoxin A 9-Psa (101.1 mg, 0.19 mmol) Add silver oxide (11) (81.9 mg, 0.35 mmol) and methyl iodide (35 ul, 0.56 mmol). The reaction mixture was stirred at room temperature in a dark room for 7 days. The mixture was then diluted with ether and filtered. The precipitate was dissolved in water and washed with fresh ether. The aqueous layer was partially lyophilized and the residue was triturated with ether and dried under a stream of nitrogen. The obtained 9-0, N-dimethylspinoxin A 9-Psa iodide (13.5 mg; yield 10¾) was a tan solid, FDMS, m / e (relative strength :) 761 (10), 573 (30), 572 (M '100), 188 (25). Example of JQ-9-0-"(S-methyl) dithiocarbonyl" in the crystals of acetoxine A 9-Psa in spinoxin A 9-Psa (205.5 mg, 0.38 mmol) and oxazole Anhydrous THF (2 ml) was added with sodium hydride (50% mineral oil dispersion; 33.8 mg, 0.7 mmol), followed by carbon disulfide (90 til, 1.5 mmol) and then methyl iodide (90 ul, 1.4 mmol). The reaction mixture was stirred at room temperature and then added, glacial acetic acid (90 u 1). The reaction was then poured into saturated aqueous NaHCO 3 solution and extracted with dichloromethane. The dichloromethane portion was washed with brine, dried over MgSO 4 and Evaporate at room temperature under reduced pressure. 9-0-US-methyl) dithiocarbonyl) Spinoxin A 9-Psa (230 mg; yield 95%) was obtained as a yellow glass, FDMS, m / e (relative strength) 634 (60), 633 (100), 142 (50)., -259-This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ^ (Please read the precautions on the back first (Fill in this page again)

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _____ B7 V. Description of Invention (257), 1 Example &lt; 110-9-0- "(21 ^, 35,45.51 ^ Training Proposal?-田某-: ^ 锊-^: 1: 2 Rylamino-7-methyl-1, 6.1 dihydrazyl U · 3-01 ditg nonyl_7-7-yl 1 historical trial rumor Α Ώ-Ρμ according to implementation The reaction was performed as described in Example J2, with 9-0-[(2R, 3S, 4S, 5R, 9R) -2-methyl-3-ethoxy-4-dimethylamino-7-methyl- 1,6,8-trioxo [4.3.0] bicyclononane-7-yl] spinoxin A 9-Psa (40 mg, 0.05 mmol) was used as the starting material. The obtained 9-0 -[(2R, 3S, 4S, 5R, 9R) -2-methyl-3-hydroxy-4-dimethylamino-7-methyl-1,6,8-trioxo [4.3-0] Bicyclononane-7-yl] Spinoxin A 9-Psa (15.2 mg; yield 40¾), FDMS, ni / e (relative strength) 759 (M +, 100), 543 (35). Rich examples J1 1 -9-Πι-methyl argon benzyl hydrazine Ί 窨 柒 窨 柒 窨 柒 窨 柒 窨 柒 窨 柒 假 A 9-pseudoglycoside complex compound '_; _ same steps as described in Example J18, but immediately add pyrrolidine and pyridine and in The reaction was replaced by EtOAc with Et20. The same chromatographic conditions were used to give an amorphous white solid (110 mg, 54%), M-NMR d 7.61 (dd, J 7 · 7, 0 · 9, 1 Η), 7.54 (4, J = 2 1Η) 7.34 (t, J = 7.8 1Η), 7.10 (dd, J = 8.2, 2.0), 3.86 ( s, 3 Η) 〇 2 Tatsuka, KK .; Tanaka, A .; Fujimoto, K .; Kinoshita, M .; Umezainwa, SJ Am. Chein. Soc. 1977, 99 (17), 5826 〇 富 例 例 J1 2- 9- (1-p-Methyl argon benzyl gyl group_Zinobinoxine A 9-Pseudosaccharide_ffi compound_Di___ Follow the procedure described in Example J 18, but immediately add pyrrolidine and 11 ratio This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) I ---.-- 1 ---- (Please read the notes on the back and fill in this page) Staff of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Consumer Cooperative _ 487559 A7 B7____ 5. Description of the Invention (258) Pyridine and Et2O instead of EtOAc in the reaction. The same chromatographic conditions were used to produce an amorphous white solid (100M, 49%), iH -NMR d 7 · 98 (d, J = 8.9, 2Η), 6.92 (d, J = 8.9, 2Η), 3.87 (s, 3H ”stealing case, Π 3-9-Table- 9- (1-Pyridoxine SI group-Spinoxin A 9-False: Expanding glycoside with a chemical compound _-__ Spinoxin A 9- pseudoglycoside with fluorene compound (544 mg, 1.0 〇mmol) and three Phenylphosphine (525 mg, 2.00 mmol) was dissolved in benzene (5 mL) and the solution was cooled to 4 ° C. Diethyl azocarboxylate (0.31 mL, 2.00 mmol) was added dropwise at a rate such that the temperature was maintained below 5 ° C and the color of the reagent disappeared between drops. While holding at 5 C to 11 ° C, the mixture was stirred for an additional 20 minutes and stirred for 60 minutes without cooling. The reaction was quenched with water and diluted with aqueous sodium bicarbonate solution and partitioned between EtOAC and the diluted aqueous sodium bisulfate solution. The aqueous layer was extracted with Et0Ac solution (twice). The combined organic layers were washed successively with diluted sodium bisulfate (2 times) and brine. The mixture was dried over anhydrous sodium sulfate and evaporated to give an oily solid. This solid was dissolved in Et 2 0 and extracted with diluted HC 1 (3 times). The milky aqueous layers were combined and extracted with Et20. The pH of the aqueous layer was adjusted to approximately 10 with 1.0 N NaOH. The combined EtOAc portions were washed with brine (2 times) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on a reverse-phase column (KromasiT C18, silica 0DS, 100A, 10m, spherical, 25 cm X 20 nun) with 90% Me0H and 10¾ water (containing 0.1% v / v concentration NH4〇H aqueous solution) to give a white amorphous solid (0.54 g, 79%) lH-NMR d 7.26 (t, J = ^ .4, 2 H), 6.95 (t, J = 8.4, 1H), 6 · 87 (d, J = 8.4, 2H), 5.35 (br q, J =: -261-This paper size applies to China National Standard (CNS) A4 specifications (2l0 &gt; &lt; 297mm) ~- --- ·-^ ----- (Please read the notes on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Invention Description (259) 6 · 〇, 1H), 4.58 (s, 2H) Example J14-9-0- (2,3,5-tri-II-A) -a -LD 1-Nucin A 9-Psa and 9- 0- (2,15-tri-0-methyl-zhao 4 dinopyranosine A 9-Pm in di-P-ribofuranosyl yield of 84% α: Lu 9_0- (2, 3, 5- Tri-O-methyl) -α-L-ribofuranosyl) Spinoxin A 9-Psa 9: 1 mixture is commonly obtained from Spinn M Semi-A 9-psa (0.33 g, 0.63 mmol), Dtl: Rotary p-toluene mineral salt (0.2 g, 0.8 mmol) and 0- (2,3,5 -Di-O-methyl-1 / 3-D-enantiribosyl) trichloroacetimide salt (1.6 g, 4.75 mmol), the reaction was performed in the same manner as in Example J18. Α And 3 isomers 傺 separated by HPLC on a reverse phase C18 column of 41.4 mm (id ·) X 25 cm (1). Α-Aromeric isomers first precipitated. Α-Aromeric isomers : 100 mg; colorless foam; UMR (acetone-d6, 400 MHz) δ 7.06 (s, 1H, H-13), 5 · 10 (d, J = 4.1, 1H, H-1 '), 4. · 66 (in, 1H, H-21), 4.47 (dd, J = 10, 2, 1H, Hl ”), 4.32 (ιη, 1H, H-9); MS m / z 719 (100) ./ 3-rotomers: Π mg; colorless foam; 1H-NMR (acetone-d6, 400 MHZ) δ 7.05 (s, 1H, Η -13), 4.99 (d, J = 1.2, 1H, 4.66 ( m, 1H, H-21), 4.47 (dd, J = 10, 2, 1H, Hl ”), 4.32 (m, 1H, H-9); MS m / z 719 (100). Enriched cases J15-9-0- (2,3, k6-tetra-0-a certain bua-bu Ganlin p reported ranose nosin_A 9-Psa and Qn- (2.3.4.R -Tetra-0-A-Mou- / 3-L-mannose and glucomannan)) Chinese passenger luck A 9-Psa 〇 &gt; 99-0- (2,3,4,6-tetra-0-methyl Bu "-1- Ganlu Anan: -262, this paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) ----.-- Ί, ---- (Please read the back Please fill in this page for further information)-1 Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 ___ B7 ___ V. Invention Description (260) · Basic) Spinozin A 9-Psa 1.9: 1 changes The structure mixture (0.4 g, yield 71Γ) was obtained from Spinoxin A, 9-psa (0.4 g, 0.74 mmol), nth iron p-toluenesulfonate (0.25 g, 1.0 mmol ) And 0- (2, 3,4,6-tetra-0-methyl-a-L-mannanuranosyl) tri-chloroacetimide salt (1.7 g, 4.49 mmol), the reaction Pseudo-preparation was performed by the same procedure as described in Example J18. The isomers were converted by reverse-phase HPLC using 2 parts of C18-bound silica (8Que I) column (41.4 mm ( id)) x 25 cm (1)), with 10% H2〇 (containing 0.1% ΝΗ40Η) in MeOH solution is the eluent. The metameric isomers are first precipitated./3 metameric isomers: 18 mg •, colorless foam; 1H, H-13), 4.63 (m, 1H, H-21), 4.42 (m, 2H, H-9, H- lft), 4.38 (s, 1H, H-l '); MS m / z 762 (100). Alpha isomers · 95 mg; colorless foam; UMR (CDC13) S6.75 (s, 1H, M-13), 4.93 (d, J = 1.2, 1H, H-lf) , 4.63 (m, 1H, H-21), 4.42 (d, J = 7.5, 1H, Hl ”), 4.34 (ra, 1H, H-9); MS m / z 762 (100). Rich Example J1-(N_Norso-N- (2.2, 2-trichloroethylargonylcarbonyl)-γυ -D-aminoglycosyl) octyl A Q-Pm and 9-0- (N -Demethyl-N-2.2,2-trifluoroethane (1) -D-Amine) (2) -Nanoxin A 9-Psa

Add a portion of trimethylsilyl trigas methanesulfonate (0.7 mL, 3.6 nunol) to cold (_40 ° C), properly stirred N-desmethyl-N- (2,2, 2-trichloro Ethoxy) carbonyl-1-0-(4-nitroamidooxy) amine sugar (a mixture of allomeric isomers of about 6 a ·· 1/3) (0 · 7 g, 1. 49 mmo 1 ) And 4A; -263-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 Gong ^^ I. ί ϋ ^ ϋ ϋϋ ϋϋ ι_ι— m ^ —ϋ ι_1 (Please read the notes on the back first Fill out this page again), 11 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 • B7__ V. Description of the Invention (261), Molecular Sieves (Beads, 8-12 Mesh, 2.0 g) CH2C12 (30 mL) and Et20 (30 mL) mixture. Heat the mixture to -10 ° C for 20 minutes, then maintain the temperature of the reactant at -10 ° C, and add the dropwise Spinol over 20 minutes. A solution of octane 9-Psa (0.5 g, 0.92 mmol) in CH2C12 (30 mL). After stirring at 10 ° C for 4 hours, the entire mixture was poured into saturated agitated NaHC03 (240 mL) and ice. (About 100 g) in a mixture. The organic layer and the aqueous layer were extracted with CH2C12 (2 X 75 mL). The combined organic layers were washed with saturated NaHC03 (75 roL), then washed with brine (75 mL) and dried (MgS04). Concentrated 1.1 g of the residue remained, and the residue was subjected to flash chromatography with silica (175 mL), and the eluate with 3% MeOH in CH2Cl2g was used to obtain 0.6 g (77¾) of clean glycosylation 9-0 -(N-desmethyl-H- (2,2,2-trichloroethoxycarbonyl-a-D-aminobenzyl) Spinoxin A 9-Psa, α to / 3 3: 1 change The mixture of the isomers was a colorless foam. The mixture was separated by reverse-phase HPLC, and a C18-bound silica column [41 · 4 fflmU.d.) X 25 cro (l)) was used at 5% Η20. A solution of MeOH (containing 0.15% NH 4OH) was used as the eluent to obtain individual pure metamorphic foreign matter. /?-Anomer is first precipitated. / 3-arachimer: 140 mg; colorless foam; 1H-NMR (CDC13) δ 6.77 (s, 1H, H-13),

4.74 (m, 3H, H-21, CC13CH20), 4.40 (m, 3H, M-9, H-I ', HI "), 2.87 and 2.83 (s, total 3H, 4'-N (CH3)). oc-rotomers: 285 mg; colorless foam K; HMR (CDCl3) S 6.75 (s, 1H, H-13), 4.75 (m, 4H, H-1 ', H-21, CCl3CH2. ), 4.43 (d, lH, H-1 ”), 4.30 (m, 1H, H-9), 2.87 and 2.85 (s, total 3H, 4'-N (CH3)): |: -264-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mmΊ ------- &gt; ---- (Please read the precautions on the back before filling this page) Order 487559 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China A7 B7 V. Description of the invention (262) Implementation _ Example J17H- (N-Deryl-D-Face Sugar) y 谌 xina Q-Psa i By way of example The compound was prepared using the procedure used in J20. 100 mg of 9 0 [H-desmethyl-N- 2,2,2-dichloroethoxymine-aminoglycosyl) Schinoparox A 9-Psa obtained 37 mg of 9-0- (M-desmethyl-yS-D-aminoglycosyl) Spinoxin A 9-Psa, as a white foam: ih-NMR (CDC13) 0 '6.78 (s, 1H, H -13), 4.66 (m, 1M, H-21), 4.42 (m, 2H, H-1 ', H-1 ”), 3.62 (m, 1H, H-9), 2.42 (s, 3H, NH (CH3)), 2.23 (s, 6H, N (CH3) 2); MS m / z 671 (1ΓΗ, 10), 377 (100), 3S7 (95), 336 (24). Example J18m -Methylbenzyl argon in a certain compound A Q-Pseudoglycoside Bff compound__ Spinoloxin A 9-pseudoglycoside compound (163 mg, 0.300 mmol) was dissolved in CH2C1 2 (0.6 inL) Medium. Add 0-methoxybenzyloxy chloride (56 ul, 0.38 mmol) and triethylamine (53 ul, 0.38 mmol). After 3 hours, add 4-pyrrolidinopyridine (3 mg, 0.02 mmol) ) And stirred for 15 hours. The reaction was partitioned between EtOAc (5 mL) and 0.5 N NaOH aqueous solution (5 mL). The organic layer was washed successively with 0.5 H NaOH aqueous solution and brine, dried over anhydrous M g S 0 4 and under reduced pressure. The concentrated radon residue was chromatographed on a reversed-phase column (KromasiT C18, oxo-DS 0DS, 100 A, 10 m, spherical, 25 cm X 20 nun) using 90% Me0H and 10% H2O (containing 0.14 v / v concentrated N Η 4 0 Η water soluble makeup) to produce an amorphous white solid (110 ms, 54%), 'H-NMR d 7.76 (dd, J = 8.0 Γ.8, 1H), 7.47 (t, J = 8. 0 1 H), 3.90 (s, 3 H). ： -265-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297mm) I ---: --.-- · yi — (Please read the precautions on the back before filling this page), 11 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 _ B7 _ ^ V. Description of the Invention (263), Fen Shi J19-Q_n- (2.4-Three-Π- 甲某 -I. • 难 苏 _ 兰 耱 很) Spinoxin A 9-Pm _ Spinoxin A 9-Psa (0.4 g, 0.74 mmol) and pyridinium p-toluenesulfonate (0.25 g, 1.0 containing powdered 4 A molecular sieves) To a solution of the fraction (0.8 g) in dry CH2C12 (50 mL), 0- (2,3,4-tri-0-methyl-aL-lysupranyl) tri-chloro was added dropwise over 20 minutes. A solution of acetamidine salt (2.3 g, 6.8 mmol) in CH2C12 (10 mL). The reaction mixture was stirred for 72 hours, then filtered through celite, the collected solids were washed with CH 2 Cl2 (25 mL), and the combined filtrates were combined. It was washed with saturated Na2CO3 (2x 20 ml) and brine (20 mL), and dried (MgSO 4). After concentration, 2.8 g of the residue was left, and the residue was flashed with silica (240 mL). Analysis, using 3¾ MeOH (: 112 (: 12 solution, To produce 0.45 g (85%) of a clean coupling product as / 3: a 9-0- (2, 3,4-tri-0-methyl-L-lysupranosyl) Spinoxin A 9-Psa 1.5: 1 mixture of allomeric isomers. The mixture was separated by HPLC and 3 parts of about 150 rag were used for 41.4 mm (i · d ·) X 2 5 cm (1) reverse phase C18 Column, using 10% Η 2 0 (containing 0.15¾ ΗΗ 40Η) of MeOΗ solution as the eluent.-Metamer isomers first precipitate. &Gt; 9-metamers: 102 mg; colorless foam; HMR (CDCla) d ^ .78 (s, 1H, H-13), 4.68 (m, 1H, H-21), 4.55 (d, J = 1.4, 1H, Η-Γ), 4.44 (d, J = 7.7 , 1M, El, f), 4.38 (ία, 1H, H-9); MS m / s 435 (2), 175 (10), 142 (30), 71 (100). A-aramer 60mg; colorless foam; 1H-NMR (CDC13) d 6.79 (sr 1M, H-13), 4.84 (d, J = 2.9, 1H, Hl,), 4.67 (m, 1H, M -21), 4.41 (d, J-, -266-The paper scale is applicable to China National Standard (CNS) A4 (210x297 mm)---1--II 1--II I ί--:- -I (Please read the notes on the back before filling out this page), 11 487559 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs System A7 B7 V. Description of the invention (264) -7.3, 1H, Η-Γ?), 4.31 (m, 1H, H-9); MS m / z 435 (2), 175 (10), 142 (50) 71 (100) 〇; Example J20-9-0- (N-desmethyl-aD-amine sugar) in the noroxin A 9-Pm activated Zri powder (0.4g) was added to the appropriate stirring 9-0- (N-desmethyl (2, 2,2-trifluoroethoxycarbonyl) -aD-aminobenzyl) Spinoxin A 9-Psa 0.1 g, 0.12 mmol) THF (3 mL) solution, MeOH (0.5 mL) and 1M NH40Ac were added and the mixture was stirred at room temperature for 3 days. The solid was removed by filtration and washed with THF (5 mL). The filtrate and washings were combined and evaporated to dryness and the residue was collected in CH2C12 (30 inL). This CH2C12 solution was washed with saturated Na2CO3 (5 mL) and brine and dried (MgS04). After concentrating, 66 mg of residue was left. The residue was chromatographed on silica (20 mL) using CH2C12 solution of MMeOH to obtain 9-0- (N-desmethyl-aD-aminoglycosyl) ) Spinozin A9-Psa, white foam, UMR (CDC13) 5 6.76 (s, 1H, M-13), 4.78 (d, J = 1.9, 1H, H-l ':), 4.66 (m , 1H, H-21), 4.41 (d, J = 8.1, 1M, H -1 ”), 4 · 28 (m, 1H, H-9); MS m / z 671 (M + H, 12), 544 (20), 377 (44), 357 (100), 336 (40). K-part A8MM: &gt; Tri-part pseudo-molecular compound I C9 h ^ modification Example K1-9-Table history Binoxin A 9-Psa To a solution of 9-ketospinoxin A 9-Psa (207.9 mg, 0.38 mmol) in anhydrous methanol (10 ml) was added sodium borohydride (23 mg, 0.61 ππηο 1) The reaction mixture was stirred at room temperature for 40 minutes, then diluted with dichloromethane and washed with water. The methylene chloride portion was washed with brine, and the Chinese National Standard (CNS) A4 specification (.21) was applied to this paper scale. X 297 mm) mai «ιϋ_1 ml 111 mu ϋ—ϋ l ^ n ίϋ Λιβββ tt 1 (Please read the precautions on the back before filling this page) Order Central Printed by the Standards Bureau Consumer Cooperative 487559 A7 B7___ V. Description of the invention (265) K2C03 is dried and dried at room temperature and under reduced pressure. The product is separated on a C18 column by preparative HPLC with acetonitrile: A pH: 0.1¾ NfU0Ac (35 ·· 35: 30 to 40:40: 20, linear gradient within 60 minutes.) Dissolution. The obtained 9-epi-spinoxin A 9-Pea (57 mg; yield 28%), FDMS, m / e (relative strength) 1084 Λ15), 544 (M, 45), 543 (100) and spinosyn A 9-Psa (42 mg; yield 20¾). Example K2 -(9S &gt; and (9R) a Spinozin A 9-Psa_ in a solution of 9-keto Spinosin A 9-Psa (336.8 mg, 0.62 mmol) in anhydrous THF (7 ml), add chlorine Methyl magnesium (3.0 M; 250 ul, 0.75 ππηοΐ). During the Grignard reagent addition, the reaction mixture was heated to reflux temperature, followed by stirring at room temperature for 1 hour. Methyl magnesium chloride (500 ul, 1.5 mmol) was added and the mixture was stirred at room temperature for another hour. The mixture was diluted with ether and washed with water. The ether portion was filtered through celite to remove magnesium salts, washed with brine, dried over K2CO3, and concentrated at room temperature under reduced pressure. The product was separated on a C18 column by preparative HPLC and eluted with acetonitrile: methanol: 0.1% NH40Ac (30:30:40 to 45:45:10, linear gradient for 60 minutes). The obtained (9S) -9-methylspinoxin A 9_ Psa (93 mg; yield 27%), FDMS, m / e (relative strength) 558 (M +, 30), 557 (100) and (9R )-9-methyl spinosinol A9-Psa (55, g; yield 16%), FDMS, m / e (relative strength) 558 (M +, 40), 557 (100). Example 1 (3-9-Dechloroyl-Benzoxin 9-? 53 and 9-Desmoyl-8.9-Fu Shi Shi Mou Xin A · in 9-0-[(S-methyl .) Dithiocarbonyl] Spinoxin A 9-Psa (219.7 /-268-This paper size is applicable to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling out this page )

487559 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (266) mg; 0.3 5 mm ο 1) In the original (10m 1) bath makeup, dibutyltin hydride (2 5 0 m 1, 1.0 mm ο 1) and trace A IB N. The reaction was heated to reflux temperature for 20 hours without significant reaction. Add A IBN (trace) and continue heating for 28 hours. The mixture was then stirred at room temperature for 4 days and the solvent was removed at room temperature under reduced pressure. The product was initially purified by chromatography on silica, eluted with 5% methanol in dichloromethane, and then separated from unreacted starting material by preparative HPLC on a Π8 column with acetonitrile: methanol: 0.14% NH4〇Ac (40:40:20 to 45:45:10, linear gradient of 90 minutes). The obtained 9-deoxy-8,9-dehydrospinoxin &amp; 9- 卩 33 (8 11 ^; yield "), FDMS, m / e (relative intensity) 526 (M +, 65), 525 (100) and 9-deoxy-spinoxin A 9-Psa (34 mg; 18¾ yield), FDMS, m / e (relative strength) 528 (MS 55), 527 (100), all are white solids . Fenxiong IU-Q-Π-A, a certain Pinoxin A Ακ was reacted as described in Example 2, starting from 9-0-methyl Spinoxin A 9-Psa (188.8 mg, 0.34 mmol)始 物。 Starting material. The obtained 9-0-methyl spinosyn A Ag (126.9 mg; yield 90¾) was a white solid, FDMS, m / e (relative strength) 417 (M +, 40), 416 (100).例 Examples of deargonization-QNd, Ma Plinci) Φ 窨 Norsin A 9-Pm in 9-ketospinoxin A 9-Psa (154.4 mg, 0 · 28 mmol) solution in anhydrous methanol (7 ml) , Add morpholine (244 ul, 2.8 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then sodium cyanoborohydride (84.5 mg, 1.3 mrool) was added, and stirring was continued at room temperature for 7 hours, followed by diluting with ethyl acetate. The ether portion was washed with water, washed with brine, dried over MgS04, and concentrated at room temperature under reduced pressure. With the upper layer of silicon oxide '-269-This paper size applies Chinese National Standard (CNS) A4 specification (.210 X 297 mm) (Please read the precautions on the back before filling this page), ιτ A7 487559 B7 V. Description of the invention (267) (Please read the precautions on the back before filling in this page) The product is separated from unknown impurities, and the product is eluted with 51 methanol in dichloromethane. The obtained 9-deoxy-9HS phthaloline _) Spinoxin A 9-Psa (48.5 mg; yield 28%), a mixture of isomers, FDMS, m / e (relative strength :) 614 (30 ), 613 (M +, 50), 612 (100). Examination Example κβ-9-Dehydroxanthylmoxixin A Ag The reaction was performed as described in Example 2 with 9-deoxyspinoxin 9-P sa (3 3 5 mg, 0.6 3 mm ο 1) Is the starting material. The obtained 9-deoxybinninoxin A Ag (129.5 mg; yield 53%) was a white solid, FDMS, m / e (relative strength) (M +, 45), 386 (100). Fen Example K7-9-_Vidinoxanthine A 9-Psa Suspend N-chlorobutanediimide (1.4 g, 10.5 mmol) in CH2C12 (35 ml) and cool to -70 ° under nitrogen C. After adding ethyl sulfide (825 ul, 11.2 mmol) and stirring at -70 1C for 30 minutes, slowly add Spinoxin A 9_Psa (2.0 g, 3.7 mmol) in CH2C12 (13 ml). . After stirring at -70 ° C for 2 hours, triethylamine (1.4 ml, 10 mmol) was added and the reaction was warmed to room temperature. After stirring at room temperature for 20 hours, it was left at 0 ° C for 24 hours. The solution was diluted with CH2C12 and washed with Η20. The CH2C12 portion was then washed with brine, dried (MgS04), and concentrated at room temperature under reduced pressure. The residue was chromatographed on a silica gel column (7% MeOH / CH2Cl2) to provide 9-ketospinoxin A 9-Psa (1.83 g, 91%) as a white glass. FDMS, m / e (relative strength) 541 (100): Channeling example K8-K- αZ ^ -9-〇-Moqi qi-Zhongxinxin A false sugar 15-base compound f. -270- ^ Zhang scale is applicable to Chinese National Standard (〇 奶) 8 4 specifications (21〇 &lt; 297 km) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (268) Will Spinozin A 9-Pseudoglycoside (163 mg, 0.300 mmol) and 4-pyrrolidinopyridine (6 mg, 0.04 mmol) were dissolved in CH2C12 (1 mL). Add benzylacetamidine (55 mL, 0.40 1) in a single portion. The mixture was stirred at room temperature for 18 hours. The mixture was quenched with solid sodium bicarbonate and partitioned between EtOAc and aqueous sodium bicarbonate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a reverse-phase column (Kromasir C18, silica ODS, 100A, 10m, spherical, 25 cm X 20 mm), and 90% MeOH and water (containing 0.1% v / v concentrated solution) NH4OH solution) to obtain a white solid (108 mg, 53%). UMR d (t, J = 8.4, 2 Η), 6.95 (E, J = 8.4, 1 Η), 6.87 (d, J = 8.4, 2 Η), 4.85, (br s, 0.5 Η), 4.61 (s, 2 Η), 4.42 (br d, J = 7.8, 0 · 5 Η). Fen example Κ9_9- 耒-中 窨 诺辛 A A 9-False 搪 Hin BR BR compound will be 9- Table-9-0-phenoxyethenyl-spinoxin A 9-pseudoglycoside compound (0.44§ , 0.65 1 «〇1) suspended in a mixture of 1 ^ (^ (9 11 ^) and water (11 ^.). Potassium carbonate was added to the slurry obtained (135 mg, 0.97 mmo 1). 3 was added along the beaker wall Ml 9: 1 MeOH-water. After 4 hours, the homogeneous solution was equilibrated between EtOAc and 1: 1 water-saturated sodium bisulfate aqueous solution. The aqueous phase was extracted with EtOAc and successively dilute sodium bisulfate (2 times) The combined organic phases were washed with brine and dried. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a glassy solid (366 mg, 104%). M-NMR d 4 · 50 (br q, J = 6 · 0, 1 Η) 0 Example KlO-fl-Zhong U2-0. 3-0.4-Ch ~ Triethyl-1-a -rhamnosyl) -Medium glyoxin A False BP and ih complex and 9 -Table-9- '-271-. This paper size applies to China National Standard (CNS) A4 (210X297mm) ---- ΊΙ1ΙΦ! (Please read the notes on the back before filling this page) Order 5 Ministry of Economy A7 B7 printed by the Consumer Standards of the Central Bureau of Standards (269) β-η. X). 4-0-III π-l-/?-rhamnolide) -Spimidine AQ ... Pseudo-Ethanol Compound 9-Epi-Spinoxin A 9-Pseudoglycoside (340 mg, 0.625 mmol) In CH2C12 (6 mL). To this solution was added molecular sieves (4A; 420 mg) and pyridinium iron tosylate (210 mg, 0.837 mmo 1). This mixture was cooled to 0 ° C and maintained at this temperature, while l- (a / / 3) -2-0,3-0,4-0 -triethyl-rat was added dropwise over 10 minutes. A solution of glycosyl-trichloroacetimide salt (1.23 g, 3.13 mmol) in CH2C12 (5 mL). The mixture was stirred at 0 ° C for 40 minutes and at room temperature for 1 δ hours. The reaction mixture was partitioned between CH2C12 and aqueous sodium hydrogen sulfonate. Wash the organic layer with dilute sodium bisulfate aqueous solution, water (twice) and brine. Remove the solvent under reduced pressure and place the residue on silica gel (60 g) with 3¾

CHaCldS liquid chromatography with MeOH. The eluate containing the product was collected and the solvent was removed under reduced pressure. The residue was chromatographed on a reverse-phase column (Kromasir C18, silica ODS, 100A, 10m, spherical, 25 cm X 20 mm) with 92¾ MeOH and 8¾ water (containing 0.1¾ v / v concentrated NH4〇H aqueous solution). :) Dissolved to obtain two isomers of amorphous white solid, α-(142 mg, 29¾) LR d 4.75 (d, J = 1.4, 1 Η), 1.32-1 · 15 (m, 22 H); / 3- (70 mg, 14%) ^ -NMR d 4.31 (br s, 1 H), 1.35-1.13 (m, 22 H) ·: 'ϊ, part of 蕻The quaternary plum dimer was formed to be quasi-modified. Fuyu Example 1 "-Double Π Zhongkemou Shibantetan f Tianterin (Zhongbinnuo-Xin J-3, 1 Knee, according to compound 3 '-0, N-Bis (tris-deuterated methyl) spinosinoxin M, -272-This paper size applies Chinese National Standard (CNS) A4 specification (noX 297 mm) (Please read the precautions on the back before filling in this page)

487559 A7 B7 ____ V. Description of the invention (27〇). Using potassium sulfonate (3.0 g), tetrabutylammonium hydrogen sulfate (1.80 g), 15% MaOH aqueous solution (50 mL) and CH2Br &gt; 2 ( 4,5 roL> Spinolsin J (0.93 g, 1.29 mmol) was reacted with CH 2 B 2. After the gradual reaction was completed, the crude product was purified by chromatography on silica gel and then by HPLC (88: 12, MeOH / H20) was isolated to provide formaldehyde bis (spinoxin acetal (47 mg, 54) as a white solid: ESI MS m / z 1448 (M + 1). Example L2_ "SI R / S-Bi-Phi 窨 Mouxin J-3 'yl 1 sulfide — Spinozin J (2.70 g, 3.76 mmol) was dissolved in dry pyridine (10 mL). Dry dichloromethane (4 mL). Stir the mixture under nitrogen and cool-78 ° C. Slowly add thionyl chloride (0.90 raL, 12.3 mmo 1) ° Warm the mixture to room temperature and stir for 20 hours. Generally the reaction is gradually completed And chromatographed on silica gel (ethyl acetate, followed by 10% Et0H in EtOAc) to provide [S] R / S-bis [(Spinoxin J-3f-0-) yl] sulfide (1180 mg , 42¾), as a white solid: ESI MS m / Z 1482 (Μ + 1).窨 rumin B dimer 孖 4 ″ -Ν, 4 di-N- (pent-l · k Ermou) Intermediate review 柒 Bin Chun _ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-I .... .. ——I— I— I 1 &quot; ί: · In nn I (Please read the precautions on the back before filling this page) According to the method of Example C24, 1,5-dibromopentane (38 mL, 64 mg, 0.28 mmol), (i-pr) 2NEt (0.30 mL, 0.22 g, 1.7 mmol), spinosyn B (0.40 g, 0.56 mmol), and DMF (1.5 mL ) To prepare the compound. MPLC (0: 100 to 20:80 Me0H / CH2Cl2) can obtain 0.07 g (17¾) of 4 ”-N-pentamethylene bridged spinoxin B dimer as a white powder (also Recovery of Spinozin B, 0.16 g (40%)). MS (πΤΗ + &amp; m * 2H + / 2) Expected value 1504.D &amp; 752.5. Actual value: 1504.1 &amp; 753.1 and 4 ”-N, 4” -N- (Pei) tl, 5-Secondary) History Λ-273-This paper size applies to China National Standard (CNS) Α4 specification (2! 0 × 297 public celebration) _ 487559 Central Standard of the Ministry of Economic Affairs A7 B7 printed by the Bureau's Consumer Cooperatives V. Description of the Invention (271) Binoxin B bromide, 1.7 g (35%): MS U-Br-) Expected value: 786.5. Actual value: 786.7. ′ Ｍ 部 Chemical formula; I ^ 大 璟 部 上 詈 2 ^ Modification

Example M1 Ethyloctyl A in ethyl. According to the process of 2-methyl analog of Spinoxin A as described in Example M23, replace with ethane iodide (1.0 g, 6.4 mmol) Methyl iodide. Therefore, 1 gram of Spinoloxin A in preparative reverse phase chromatography can produce 0.35 grams of pure isomeric 2-ethyl Spinoloxin A〇C43He3N〇10. The analytical evaluation value is: C, 67 · 96; M, 9.15; Ν, 1.84. Actual value is C, 67 · 65; Η, 9,01; Ν, 1.96.

Examination Example M2-2-Z-Hydroxycarbamidine A. According to the process of 2-methyl analogue of Spinoxin A as described in Example M23, cyanoformate (0.69 g, 6.98 mmol) was substituted for electrophile. Preparative reversed-phase chromatography (C-18, flushing with 85-98% methanol: 0.1¾ of NH40H / water) to produce 0.14 g of 2-ethoxycarbonyl Spinoxin AOC44H ^ Analyzed and estimated values for No. 2 are: C, 65.72; M, 8.65; N, 1.74. Actual values are ···, 65 · 77; Η, 8.38; N, 1.79.

Examination Example H2-Methyl sulphur Φ guest A certain A According to the process of 2-methyl analog of Spinoxin A as described in Example M23, it was replaced with dimethyl sulfide (0.66 g, 6.98 mmol) It is an electrophilic reagent. Preparative reversed-phase chromatography (018, 85-98¾ methanol: 0,1% HH40H / water gradient rinse) Γ can produce 0.20 g 2-methylthiospinoxin A. 1 H-NMR (300 MHz, CDC U) d 2.2 (s, -274-This paper size applies Chinese National Standard (CNS) Λ4 specification (ZlOX 297 mm) —ml · ϋϋ ϋϋ I ϋϋ--Μ ^ ϋϋ n · ^ n ( Please read the notes on the back before filling this page), 11 Printed by the Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, printed 487559 A7 B7 V. Description of the invention (printed) 3H, cis CH3), C44H63N02 The estimated analytical value is C, 65.72; M, 8.65; N, 1.74. Actual values: C, 65.77; H, 8.38; N, 1.79. The estimated analytical value of S is C, 64.83; Η, 8.68; Ν, 1.80; S , 4.1. Actual values are: C, 65.18; Η, 10.43; M, 1.76; S, 3.66 〇 Trial example M4-2-bromohistohistory Nosin J J According to Spinoxin A 2 as described in Example M23 -Methyl analogue production process, substituted with 1,2-dibromotetrakiethane (0.9 g, 3.47 mmol) as electrophilic reagent at -70 ° C. Rinse with preparative reverse phase chromatography -18, with 85-98¾ methanol: 0.1% NH4Η / water gradient :) can produce 0.5 g of 2-bromospinoxin ^. 〇41 [^ 4 卩 〇11 ^ "The estimated analytical value is: (:, 60.73; Η, 7.95; Ν, 1.72. Actual value is C, 62.14; Η, 7.93; Ν, 1.79. Examination example M5 -2- (2): The R and S complexes of methanosin A in ethyl are prepared according to the 2-methyl analogue of spinosin A as described in Example M23, at -70 ° C. In the following, 1,2-dibromotetrafluoroethane (0.9 g, 3.47 mmol) was used as the electrophilic reagent. Preparative reverse phase chromatography (C-18, 85-98% methanol: 0.1¾ NfUOH / water rinsing) can produce R and S isomers (0.25 g per 克) that produce two 2- (2-hydroxy) ethyl spinosyn A. The estimated value of the analysis of isomers is C, 66.55 ; H, 8.96; N, 1.80. Actual value: C, 66 · 48;;, 10 · 6; N, 1.84, isomer 2: C 4 3 H s 3 MO: i : C, 66.55; Η, 8.96; N, 1.80. Actual values: C, 65 · 82; H, 10.07; Ν, 1,72 〇; -275-This paper size applies to Chinese National Standard (CNS) Α4 Specifications (210 × 297 mm) —t-IL—m_ | (Please read the precautions on the back before filling out this page),?! Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 48 7559 A7 ____ B7 _ 5. Description of the invention (still)

Place oxosulfan in noroxin A according to the process described for the 2-methyl analogue of oxin. Noroxin A as described in Example M23, using dimethyl sulfide (1.52 g, 6.98 8 mm ο 1) instead of electrophilic reagents. Preparative reverse phase chromatography (018, flushing with 85-98¾ of methanol: 0.125 NfUOH / water at 0.5 °) yielded 0.71 g of 2-phenylthiospininoxin A. Analytical estimates for C4 7H6 sNOi 0S are: C, 67.19; H, 8.28; N, 1.67; S, 3.81. Actual values: C, 67.12; Η, 8.51; Ν, 1.65; S, 3.34.

Example M7-2-Tianxixi Mouxin A This compound was prepared similarly to Example M23, except that ethyl formate (0.56 ml, 6.98 mmol) was substituted as the electrophilic reagent at -70 ° C. Preparative reverse-phase chromatography (C-18, 85-98% methanol · 0.1% NH4OH / water gradient washing) can produce 0.1 g of 2-formamyl spinosin AqCuHwNOh The estimated value of the analysis is · '(:, 66.37; H, 8.75; N, 1.84.7; S, 3.81. The actual value is ·· C, 63.77; Η, 8.46; N, 1.88. Example M8-?- The 2-methylthiospinoxin A. Ν-α-bismuth solution, the well-stirred 2-methylthiospinoxin A solution (1.0 g, 1.3 mmol) was cooled to 0 ° C in 10 ml of anhydrous methanol. And add m-chloroperbenzoic acid (50¾, 0.67 g, 1 · 9 in portions. Observe it exotherm to 10 ° C. After stirring for 1 hour, pour the reaction mixture into 10% HC1 and wash with ether 2 Times': The aqueous layer was basified with NaHC03 and concentrated to a solid under reduced pressure, and then triturated with 25 ml of ether three times and 25 ml of EtoAc to form a powder. The organic layer materials were combined and concentrated. •-276-This paper size applies Chinese National Standard (CNS) A4 specification (21〇 &gt; &lt; 297mm) -----.---- #! (Please read the notes on the back before filling in this page)

, TT 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, A7 B7 V. Description of the invention (office) Phase chromatography (〇18, gradient washing with 85-98% methanol: 0.1¾ NΗ4〇Η / water) This gave 0.36 g of pale yellow, 2-methanesulfenylspinoxinol, an oxide solid foam. 〇42 [^ 7 卩 〇12 $ Analyzed estimated value: C, 62 · 27; Η, 8.34; 1.73; S, 3.95: actual value: C, 58.63; Η, 8.07; Ν, 1.64 ; S, 4'12.

MLMJL9-2-Tian Yajiu Zhongzhong Kexin A A 10-mL anhydrous methanol solution of 2-methylthiospinoxin A solution (0.5 g, 0.6 65 mino 1) was cooled To -30 ° C and add 5 · 5 M of m-chloroperbenzoic acid (50%, 0.67 g, 1 · 9 mmo 1) in methanol via syringe. Concentrate via a rotary evaporator, then the residue is dissolved in 10 ml of 10! KHC1 and washed twice with 30 ml of Et20. The aqueous layer was basified with NaHC03 and extracted 3 times with ether / EtOAc, dried, and concentrated on a rotary evaporator to give 0.45 g of an oil. Preparative reverse-phase chromatography (C-18, flushing with 85-98¾ methanol: 0.1% NIUOH / water gradient) yielded 0.36 g of 2-methylsulfinylspinoxin A. 〇421 ^ 7guan 113 analysis and estimated values are: C, 63.53; H, 8.50; N, 1.76; S, 4.02. Actual values are: C, 63.17; Η, 9.50; 1.77; S, 4.02.

Example M10-2-Hydroxymethyl Amino Acid A and A? -N-P Pyridine Chisinocin Acetoxin A Piperidine (0.06 g, 0.7 mmol) was added to 2-methylamidomethylspinoxin A (25 mL) 0.44 g, 0.6 mmol). After 15 minutes, the solution was cooled to 0 ° () and sodium cyanoboride (0.5 g, 0.9 mmo 1) was added in portions to maintain its temperature below 10 ° C. After 20 minutes, Add 10¾ HC1 to this reactant and wash twice with Et20: .-277-This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) HI.--N ml nn -J-- n ϋϋ I (Please read the notes on the back before filling out this page)

1T 487559 A7 ____ B7_______ 5. Description of the invention (Shen). The aqueous layer was basified with HaHCCh and extracted three times with EtOAc. The combined organic layers were dried and concentrated to a godlike appearance via a rotary evaporator. Preparative reverse-phase chromatography (C-18, washed with a gradient of 85-98% methanol: 0.1% NH40H) can produce 0.1 g of 2-hydroxymethyl spinosin A and 2-n -Piperidinylmethyl spinoxin A vs. 2-hydroxymethyl spinoxin A. Η Analysis

Estimates are: C, 66.19; Η, 8.86; N, 1.84. Actual values are: C, 6 4.95; H, 8.65; N, 1.83. For p-n-piperidinylmethyl spinosin A. The estimated analytical value of 〇47 ^ 2〇1〇 is: (:, 68.08; 19.24; only, 3.38. · Actual value: C, 67.89; H, 9.31; N, 3.13. Example M1Ϊ-2- (1- Tian Clousi-1-Mr. Shen Shen) Printed by I --- ^-J --- 0II of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page) Spinoloxin enol (4.1 mmol) can be prepared according to the general procedure described in Example M23. Ethyl formate (1.5 g, 20 mmol) is added dropwise for more than 10 minutes, and cooled down here. (-70 ° C) solution, and then allow it to slowly warm to -30¾. Then pour this solution into a stirred, cooled (0 ° C) saturated NH4C1 (75 ml) and B_ ( 75 ml) aqueous solution. The organic layer was separated and washed with brine, dried and concentrated to an oil. Reverse phase chromatography (35-98% methanol: 0.1% NH4OH) by HPLC yielded 1.5 g Of pure hemiacetal. (: The analytical estimate of 4 3 H s 3 N0 ί 2 is: C, 65.12; Η, 8.78; Ν, 1.77. Actual value: C, 65.16; Η, 8.65; Ν, 1.83 〇

Fen Ϊ 例 MΪ2-2-Rong? In addition, according to the procedure of 2-methyl analogue of spinosin A as described in Example M23, methylocenyl chloride was replaced with methylselenyl chloride (0.26 g ·, 1.37 mmol). In this way, by preparative reverse phase chromatography (〇18, 85-98% -methanol '-278-this paper size applies the Chinese National Standard (CNS) A4 specification (210X: 297 mm) economic, that central standard Printed by the Bureau ’s Consumer Cooperatives 487559 A7 B7 V. Description of the Invention (: 0.1% NFUOH gradient washing) 1 gram of Spinoxin A can produce two isomers of 2-phenylselenyl Spinoxin A (R and S) (0.19 g and 0.06 g) main isomers ^ H-NMR (300 MHz, CDC13) d 7.7 (m, 2H); 7.25 (ra, 3H); 4.05 (br s, 1H) ^ The analytical estimated value of C47 Ηb9N0 i 〇Se is: C, 63 · 64; Η, 7.84; N, 1.58 · actual value: C, 63.57; Η, 7.85; M, 1.53. Trace isomers: ΐΗ-NMM300 MHz, CDC13) d 7.6 (m, 2H); 7.25 (m, 3H); 6.82 (brs, 1H); 4..55 (d, J = 4.2 Hz, 1H).

Rich Example MU- (R and S) 2-Ethylchlorocarbonylmethylspinoxine A Spinoxin Aenol (1.37 mmol) can be prepared according to the general procedure described in Example M23. Add ethyl bromoacetate (0.76 g, 4.5 mmol) at -60 ° C, then allow it to slowly warm to 0 ° C. This solution was poured into a saturated aqueous solution of NH4C1. It was extracted twice with 50 ml of Et20, and the combined organics were extracted again with 50 ml of 0.1N HC1. The aqueous layer that produced the acid was then basified with saturated NaHC03, and extracted twice with 50 ml of EU0. The combined organic layers were dried and concentrated to give one gram of oil, which was then subjected to reverse phase chromatography. With the extraction degree of 85-98% methanol: 0.1UH4OH, two 2-ethoxymine-methyl spinosin A isomers (0.17 g, 17% and 0.13 g, 131) can be produced. Spinozin A (0.2g) can also be recovered.窨 旆 例 -M1 4-2- 荥 selenium argon in a certain amount of A and A? 2-Phenylselenospinoxin A (main isomer; 0.20 g, 0.22 minol) in 10 ml of anhydrous MeOH, and cooled to N2 and magnet ift /-279-, This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page), 11 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Explanation of the invention (&gt;, 7) -60 ° C, and simultaneously add three portions of MCPBA (0.06 g, 57-35% pure MCPB A at about 0.25 mmol) for more than 15 minutes. The solution can be heated to room temperature for more than 1 hour, and then washed with 50 ml of Et20 diluted, saturated NaHC0 solution. The organic layer was extracted with 30 ml of 1N HC1. The acidic aqueous layer was basified (pH 9) with a saturated NaHC03 solution and extracted twice with 25 ml of Et20. The organic layer was dried over MgS04 and concentrated to an oil. Two substances were produced by chromatography (C-18, using an extraction degree of 85-90¾ methanol: O.UNH4OH). The first (0.06 g) was 2-phenylselenoxy spinosinoxin A. The second product (0.02 g) was 2,3-dehydrospinoxin A. Add selenium oxide (0.4 g, 0.44 ηπα〇1) to 10 ml of toluene and heat at reflux for 30 minutes. After cooling, wash with ethyl dilute, 25 ml of 1H HC1. The aqueous layer was separated, and the pH was adjusted to 9 with an aqueous solution of NaHC0, and then extracted twice with 50 ml of Et20. The combined organic layers were dried, concentrated, and chromatographed (018, using an extraction gradient of 85-90¾: methanol: 0.12 Shuai 4〇10 produces 0.1〇2 of 2,3-dehydrospinoxin A · ΐΗ-NM! Ϊ (300MHz, CDCM δ 7.9- 8.0 (m, 2H); 7.45 (m, 3H ); 6.77 (br s, 1H); (br d, J = 11Hz, 1H); 5.05 (br d, 5.05 (br d, J = 11 Hz, 1H); 4.87 (m, 1H); 4.75 (s, 1H); 4.4 (d, J = 7Hz, 1H); 4 · 18 (m, lH). For 2,3-dehydrospinoxin &amp;: 111-_1? (300 〖丨 [^, 00 ( : 13) 5 6.85 (br s, 1H); 5.97 (br d, J = 10 Hz, 1H); 5.82 (br d, J = 10 Hz, 1H); 5.65 (s, 1M); 4.82 (s , 1H); 4.65 (d, J = 7Hz, 1H); 4.25-4.4 (m, 2M); 4.1 (m, 1H); 4.87 (in, 1H; 4.75 (s, 1M); 4.4 (d, J = 7Hz, 1H); 4 · 18 (m, 1M) .MS M + H 730 * 9. '' -280-This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) I --- ·- ------ (Please read the precautions on the back before filling out this page),?! 487559 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, A7 B 7 V. Description of the invention (office) Examples of Ml-M15-2-phenylselenium chloride in the p-octyl A and? .H degassing guest translation Li price, 2-phenylselenium in 10 ml of anhydrous MeOH Solution of oxyspinoxin A (sub-isomer; 0.20 g, 0.25 mmol), cooled to -60¾ with N2 and magnetic stirring, and added three portions of MCPBA (0.065 g, approximately 0.25 mmol of 57- 85¾ pure MCPBA) for more than 15 minutes. The solution can be heated to room temperature for more than 1 hour, and then washed with 50 ml of Et20 diluted, planed and NaHC03 solution. The organic layer is extracted with 30 ml of IN HC1. The acidic aqueous layer is planed It was basified with a solution of NaHC03 (pH 9) and extracted twice with 25 ml of Et20. The organic layer was dried over MgS04 and concentrated to an oil. A portion of this selenide (0.2 g) was purified by chromatography (018, using an elution gradient of 85-9 8¾ methanol: 0.1% NH4OH). CarHi ^ NOnSe analytical estimates: C, 62.51;;, 7.70; · N, 1.55. Actual values are: C, 62.13; Η, 1.64; Ν, 7.73. This remaining crude selenide (0.2 g) was heated in 10 ml of benzene for 45 minutes, and after cooling, it was concentrated and chromatographed (C-18, using an extraction gradient of 85-98 ¾ methanol: 0.1 ¾ 1 ^ 40). . Generates 0.078 of 2,3-dehydrospinoxin &amp; yellow foam. This material decomposes at room temperature. 1H-NMR (300 MHz, CDC13) d6.85 (br s, 1H); 5. · 97 (br d, J = 10 Hz, 1Η); 5.82 (brd, J = 10 Hz, 1H); 5.65 (s, 1H); 4.82 (s, lH); 4.65 (d, J = 7Hz, 1H); 4.25-4.4 (ιη, 2H); 4.l (m, 1H) .; 4.87 (in, 1H; 4.75 (s, 1H); 4.4 (d, J = 7Hz, 1H); 4.18 (m, 1H). · Fen Example M 1 Γ) -China Kexin A. T-Butyl Dimethyl Silane Condensation _ /-281-This paper size applies Chinese National Standard (CNS) A4 specification (21 OX297 mm ) --- ^ ---- (Please read the notes on the back before filling out this page), 11 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (state) Add 2 ml of HMP A And 1 g of t-butyldimethylsilyl chloride (6.9 mmol) into a magnetic stirrer and cooled at 40 ° C (20 ° C) in LDA (6.8 mmol) to dissolve In. Then spinoxin A (1.0 g, 1.36 mmol) in 2 ml of THF was added for more than 2 min, and the solution was allowed to slowly warm to 0 ° C. The resulting solution was poured into 50 ml of water and 50 ml of ether. After the layers were separated, the organic phase was washed with brine, dried and concentrated. Lamination (85-98% MeOH / H2O extraction gradient) yielded 0.55 g of pure spinoxin A, t-butyldimethylsilyl ketal. 1H-NMR (300 MHz, CDCla): d 6.78 (br s, 1H); 8.83 (m, 2H); 4,82 (s, 1H); 4.15-4.32 (m, 2H); 4.05 (d, J = 6Hz, 1H); 3.83 (m, 1H); 0.9 (s, 9H); 0.2 (d, J = 11Hz, 6H) 〇 Analytical estimates of CrHuNUi: C, 66.71; H, 9.41; N, 1.66. Actual values: C, 66.54; H, 9.50; N, 1.64. Examination example M1 7-2-Chloroxanthinol and TBS shrinking of binoxin A (O.lg, 0.12mmon 5 ml anhydrous THF solution was stirred with magnet and cooled to _78 ° C Add a portion of N-chlorobutanediimide (15 mg, 0.125 mmol.) Allow the solution to slowly warm to room temperature, and allow it to distinguish between 30 ml of diethyl ether and 30 ml of saline solution The organic layer was dried and concentrated to an oil, and then chromatographed (reverse phase, gradient of 85-98% Me0H / H2) to obtain 40 mg of 2_ (R buclispinoxin tH-NMR (300 MHz , CDC13) d 4.68 (S, 1H; C2-H). MS M + H 766: Examination case M1 8-?-Arsenine A in Spinium · Spinosin A TBS ketal (0.05g, 0 · 06 mmol) of 5 ml paper without this standard is applicable to China National Standard (CNS) A4 specification (210X297 mm) I ---.--; ----- (Please read the precautions on the back before filling this page ) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, printed 487559 * A7 B7 V. Description of the Invention (Tear) After the water THF solution was stirred with a magnet and cooled to -78 ° C, a portion of XeF2 (15 mg, 0.09 mm〇l). Allow the solution to slowly warm to room temperature It was separated between 30 ml of diethyl ether and 30 ml of saline solution. The organic layer was dried and concentrated to an oil, and then chromatographed (reverse phase, 85-98% MeOH / H2 gradient of extraction) to obtain 18 mg 2-Gas Spinoxin A. ^ H-NMR CSOO MHz, CDCla) d 5.12 (d, J = 50Hz, 1H; C2-H) OM M + H 750.

Example Ml 9-2- (Dimethyl, argon, argon) imine Tianzhong Kemouxin A 2-Spinoxin (1-methoxy-buhydroxymethyl) (0.1 g, 0.13 mm ο 1 ) In 3 ml of Me 0 Η solution, 11 mg (0 · 18 mm ο 1) of N, N-dimethylhydrazine was added. It was then heated in a steam bath for 2 hours, then cooled and concentrated. The residue was chromatographed (reverse phase, eluent gradient of 85-98% MeOH / H20) to produce 3 mg of rhenium. 1H-NMR (300 MHz, CDC13) d 6.65 (d, J = 7 Hz, 1H; C2-CH = NNMe2); 4. 1 (dd, J = 7, 4 Mz, 1H; C2-CH); 2.78 ( s, 6H). M, S · M + H 802 · 8.

Fenshi Example M20-2-Hydroxyiminomethoxine A 2-Spinoxin (1-methoxy-1-hydroxymethyl) (0.06 g, 0.08 mmol) in 3 ml of MeOH 10 mg (0.14 nunol) of hydroxylamine hydrochloride was added. It was then heated in a steam bath for 2 hours, then cooled and concentrated. The residue was filled up with Et20 and washed with NaHC03 solution. After drying and concentrating the organic eyebrows, 0.05 g of the cis and trans isomers of the oxime were produced.

M-NMR (300 MHz, CDC13) d 7.55 and 6.95 (double front J 2 6 Ηζ, 1Η; C2-CH = N0H); 4.15 and 4.72Ί: two dd, J = 6, 4.5 Hz, IN; CS-CHhCnHesNsOH Analytical estimated value: C, 65 · 09; Η, 8.58 '-283-· This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -----; —J —-- ----— Order ------—: (Please read the notes on the back before filling this page) Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7_ V. Description of the invention (but) N, 3, 61. Actual values C, 65.10; H, 8.86; N, 1.57. Example M2 In a solution of 1-amino radical acetoxin A, 2- (1-methoxybutyromethyl) spinoxin A (0.4 g, 0.5 mmol) in 5 ml of MeOH, M, N was added. Dimethyl hydrazine (0. 05 g, 0. 8 mmo 1), heated at reflux for 1 hour, then cooled and concentrated in vacuo. The residue was covered with 1 ml of MeOH and stirred, and cooled (-4 0 ° C) to monoperphthalic acid ij | (m ο η 〇perphtha 1 ate) (MMPP, 85%; 0.5 g, 0.8 mmol ) Of 3 ml of MeOH. The solution can be warmed at room temperature and stirred overnight, after which it is poured into 10 ml of NaHC03 aqueous solution, and extracted twice with 25 ml of Et20. After drying the organic solution and concentrating, chromatography (reverse phase, 85-98% MeOH / H20 stripping gradient) yielded 85 mg of 2-cyano Spinosin AM + H 757.5. ^ -NMR (300 MHz, CDC13) to 4.43 (d, J = 4.7 Hz, 1H; C2-CH). Analytical estimates for C42HB4N2Olfl: C, 67.81; H, 8.81; N, 1.88. Actual values: C, 67 · 68; Η, 9.05; N, 1.73.

Ning Yiming M22-2- 氡 -2-Arsenoxine A in argon Under N2, 4 ml of a cooled (_40 ° C), stirred anhydrous THF solution in a 25 ml flask was added with butyl lithium (1 · 6 M, 0.1 ml, 0.16 mmol) and diisoxyl (30 ul, 0.2 mmol). After 30 minutes, add 0.5 ml of a solution of 2-cyano Spinosin A (0.105 g, 0.14 mmol) in anhydrous THF. This solution can be stirred for another 0.5 hours, then N-fluorobenzenesulfenimide (NFSi; 50 mg, 0.16 mmol) is added, stirred at -40 ° C for 0.5 hours, and then allowed to slowly warm to 0¾, It was then poured into Et20 and washed with saline solution. After drying and concentration, one is obtained; -284-This paper size applies the Chinese National Standard (CNS) A4 specification (210x297). _ I --- ::-^ --- Φ-- (Please read the Note for refilling this page),? Τ 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (2 纟 i) Light yellow oil, chromatographed (reverse phase, 85-98¾ MeOH / H20 stripping gradient) yielded 35 mg of 2-cyano-2-fluorospinoxin A «: MS · M + H 775.6. Example MM? -A very structure

Place the N2 inlet in a 50 ml 3-neck round bottom flask, add a funnel and thermometer, and pour 15 ml of anhydrous THF. The solution was stirred magnetically and cooled to -40 ° C. Additional butyllithium (1.6 M in hexane, 4.5 mL, 7.2 mmol) was added followed by diisopropyloxy (1.0 mL, 7.2 romo 1) dropwise over 2 minutes. After the addition was complete, the solution was cooled to -70 ° C, and HMPA (1.2 mL) and Spinoxin A (1.0 g, 1.37 mmo 1) in 3 mL of anhydrous THF were added. The solution can be slowly warmed to -40 ° C for more than 1 hour, then cooled to _70 ° C, and the methyl iodide (1 g, 7 mmol) in 2 ml of THF is added dropwise to maintain the temperature during the addition Below -60 ° C. Remove the cold bath and allow the solution to slowly warm to -10 ° C (estimated 45 minutes). The solution was poured into ice water and extracted twice with 50 ml of diethyl ether to obtain an organic product. Combine the organic layers and wash with saline solution. MgS04 was dried and concentrated to a light yellow gum. Two prepared 2-methylspinoxin A analogs (162.9 mg and 69.8 mg) isomers were prepared by reversed-phase chromatography (C18, extraction gradient with 85-98% methanol: 0.1¾ NfUOH). . The remaining material was isolated Spinozin A. Major isomers: 'H-NMR (300 MHz, CDCla) d 6.79 (br s, 1H), 1 * 4 (d, J = 10 Hz, 3H). The analytical estimates for C42Hs7N01Q are: C, 67.62; Η, 9.05; N, 1.88. Actual, values are: (:, 67.49; Η, 3.50; Ν, 1.86. This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) I ——— If II ----, 玎—----- (Please read the notes on the back before filling out this page) Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (Mi) Sub-isomers:' H-NMR (300 MHz, CDCls) d 6.71 (br s, 1H), 1.25 (d, 3H). The analytical estimate of CuHszNOiQ is: the actual value is: C, 67.20; Η, 9.31; Ν, 2.12. Ι \ ί 邬Formula I, the three tri-parts of the compound: &gt; Modification of the enriched example N1-5-Hydroxyglycinoloxine D. 7-formylol, "Very Influential D. 7.8-Degassed Influent D" And 7, dioxin in argon [] Spinoxin D (7.5 g, 10 mmol) dissolved in 20 ml of dioxane and 40 ml of formic acid (90%), cooled to -10 ° C and magnetically stir while adding a part of selenium dioxide (2.3 g, 2.1 mmol) to maintain the solution at this temperature for 4 hours, and then concentrate under vacuum, at this time the temperature is maintained at 0 ° C Or below. This reddish residue was then covered with ether (250 ml) and saturated NaHC03 100 ml was added. Those accumulating fluids were carefully shaken until the end of the gas generation, then filtered through diatomaceous earth and separated into layers. The organic layer was washed with brine, dried, and concentrated to a semi-solid substance. Recrystallization from MeOH yielded 4.5 g of a mixture of 5- and 7-hydroxyspinoxin D formate esters. Recrystallization from MeOH yielded pure 7-formamyl Spinozin D, rap. 184 ° C. M.S. M + H 790.8. The residue (estimated 2.5 g) was covered with 30 ml of THF and a 0.5 g solution of LiOOH in 10 ml of water was added. This solution may be allowed to stir magnetically at room temperature for 3 hours, then distinguish between EtOAc and water. The organic layer was dried (MgS04) and concentrated. The first major slope of the residue obtained by chromatography (reverse phase, 80-98% MeOH / H20 gradient) was from '5- and 7' Mixture consisting of Kirspinoxin D. Removal of (a small amount) of 7-isomers with MeOH -286-* This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) I ---; I -.- I 丰 --- --- 1T ------ 0 (Please read the precautions on the back before filling out this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (Break 0 and produce pure 1.4 grams Pure 5-hydroxyspinoxin D, mp. 115¾. M. SM + Η 762 · 4. The second major slope is 7,8-dehydro Spinoxin D, mp · 150 ° C M S. M + H 744.4. Analytical estimates for C4 2Hg sNOi 〇 are: C, 67.81; H, 8.81; N, 1.88, actual values: C, 67.60; H, 8.81; N, 1.88. A small slope peak separated by the 7,8-dihydro isomer was extracted and determined to be 7,11-dihydrospinoxin D, mp · 160 ° C 0M.S. 744.7: C42HssM0ifl The estimated value is: C, 67.81; Η, 8.81; N, 1.88. The actual value is: C, 67 · 68; Η, 9.05; Ν, 1.73 Ο

Examination Example NS7. 1 1 · 1 2 · Bis-Hydrogen (X543351) in the ballad D D. Spinoxin D (3.5 g, 9 mmol) dissolved in 10 ml of dioxane and 20 ml of formic acid (905Π, cooled to -10 ° C and magnetically stirred, while adding a part of Se02 (2.3 g, 2.1 mmol) to hold the solution at this temperature for 4 hours, then allowed to warm to room temperature. Stir continuously overnight, after which the reddish residue was covered with diethyl ether (250 ml) and 100 ml of saturated NaHCCh was added. The layers were carefully shaken until the end of gas generation, then filtered through celite and separated. The organic layer was washed with brine, dried, and concentrated. The residue was collected by chromatography (reverse phase, stripping gradient from 85 to 98¾ MeOH in 0.1¾ NH4OH aqueous solution), 7, 11, 12, 5 -Micro-dissolution fractions of bis-dehydrospinoxin 0 (3010 ^) at 320.111). M.S_ M + H 742.7.

Example N3-5- 酾 7-dehydrohistoroxine D magnetically stir the 5- and 7-hydroxyspinoxin D isomers (0.60 g, 0.79 mmol), and '-287-This paper size applies Chinese National Standard (CNS) A4 specification (21〇 &gt; &lt; 297mm) -----.--.-- 19 ^ --- --- 1T ------ 0 (Please read the notes on the back before filling this page) 487559 Α7 Β7 V. Description of the Invention (2 Ting) Join PDC (1.6 ίπιαοί). After 1 hour, the solution was separated between water and Et OAc, the organic layer was separated and washed with salt #, dried, and concentrated. The residue was stripped. First, the chromium salt was removed through a silica gel column with Et2O, and then through a reverse phase column (80-98% MeOH / H2O stripping gradient) to obtain 60 mg of the title compound, mpl 48 ° C. . .M.S.M + H 760.7. Fenyu example H4-5-argon-ft. 7-dehydromidazoxin [) and 7-argon very midazoxin D. Magnetic stirring of 5- and 7-hydroxyspinoxin D isomers ( 1.0 g, 1.34 mmol) in a mixture of 8 ml of CH2C12 and cooled to 0 ° C under nitrogen. Then add DAST (0.32 g, 1.5 eq) dropwise over 5 minutes. After 30 minutes, it was poured into 25 ml of a hydrogen sulfonate aqueous solution and extracted with 30 ml of CH 2 C 12. The organic layer was dried and concentrated, and then passed through a reverse-phase column (80-98% MeOH / H2. The degree of extraction) produces 4 brain distillates. The first product isolated was recrystallized from MeOH to give 0.16 g of 5-amino-6,7-dehydrospinoxin D, mp. 165 ° C. M.S. M + H peaked at 764.7. The second part of the distillate was 7-fluorospinostinosin D, with MS M + H peaking at 760.8. The remaining distillates were mainly unsaturated (7, 8- and 7, 11-go Hydrogen) Substance ϋ I --- Ίί .--- 0—I (Please read the precautions on the back before filling this page)

， 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper is printed in accordance with the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Employees Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7___ 5. Description of the invention (say) Xiao Example M- 5 · 6-Digas-β · 7-Dehydrospin-Nosin D and 5, 6-Dihydro-.711-Desmodium Nosing [], at 0.2 g (0. 27 mmol) of 7,8-dihydrospinoxin D in 5 ml of ethanol solution was added with 0.5 m 1 of cyclohexane and 50 mg (cat) of moist Pd (0 Η) 2 / C. The solution was heated at reflux temperature for 2 hours, then it was cooled, over-expanded and concentrated to an oil. Chromatography (reverse phase column, 80-98% methanol / water gradient solution) provided two new products. The first (40 mg) was 5,6-dihydro-7, 11-dehydrospinoxin D, rap · 166 ° C. UMRUOO MHz, CDC13) 5 1.0 (d, J = 7 Hz, 3H; C-6 methyl). Analysis of C42HuN (h〇: required value: C, 67.62; Η, 9 · 05; N, 1. 88. Actual value: C, 66.65; Η, 9.07; N, 1.73. The second (60 mg) is 5,6-dihydro-6,7-dehydrospinnoxin DUp · HSChUMRUOOMHz, CDC13) 56.73 (br s, 1H); 4.9 (s, 1H); 4.63 (m, 1H); .4.42 (d, J = 6 Hz, 1H); 4.15 (m, 1H); 1.67 (d, J = 2Hz, 3H); t-6 propenylmethyl). Example 18-Utilization of Insecticides and Acaricides The compounds of the present invention show activity against various migratory insects and mites. More particularly, the compound of the present invention exhibits an activity against watermelon aphids, which is a member of Homoptera. Other members of the order Homoptera include leafhoppers, planthoppers, pear yellow planthoppers, apple worms, pupae, whiteflies, mochi, and many other host aphids. Activity on thrips Wynn was also observed, which is a member of the order Homoptera. The compounds of the present invention are also resistant to subtropical armyworms, which are members of the order Lepidoptera. Other typical members of this order each contain Apple maggot moth, ground tiger, clothes moth, Indian valley maggot, leaf curler, cotton bollworm, European corn _, vegetable -289-This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) -----:-^ --- ΜΨ-- (Please read the notes on the back before filling out this page) Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to print 487559 A7 __B7_ 5 2. Description of the invention (must) maggots, crickets, cotton woolworms, bag moths, canopy caterpillars, sod webw omm, grasshopper worms; the compounds of the present invention can be used to reduce insects and mites, and can be used for A mime or mite-inhibiting population comprises applying a compound of the present invention as described in the above examples in an effective deactivating amount of a mime or mite to a place where the mime or mite is infested. The results are reported in the following table, where the following are the abbreviations used in the table: ALH means purple cicada leafhopper BAW means beet leaf moth CA means cotton aphid MEM means peanut root knot nematodes SCRW means eleven star melon Leaf beetle TBW means Tobacco leaf moth TSSM means cotton leaf weave GECR means German cockroach In the evaluation of insecticidal activity, each test compound was prepared into a 400 ppm solution, and the solution was then diluted to a lower concentration with water . The 400 PPm solution was prepared by mixing an aqueous solution of 19.2 ml of 0. 05% Tween 20 (polyvinyl chloride (20) sorbitan monolaurate) with 8 mg of a compound of the invention 8 ml of a solution of acetone / ethanol (9/1). The activity against the purple leafhopper was determined as follows. This test was performed using 400 ppm and 50 ppm concentrations. The plastic cup of 1 cup Division contains a cotton core coated with 0.4 ml of formulated substance using a fan-shaped mist cone nozzle. Allow excess water to evaporate. Put 5 to 10 carbon dioxide anesthetized adults into each cup. Cover the cup and apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) in the paper size of the room. ----- Ί — ^ --- MW-- (Please read the notes on the back before filling This page) Order printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 B7 V. Description of the invention (into) Keep at temperature for 24 hours. Calculate mortality. The activity against beet leaf moth was evaluated as follows. This test was performed at a concentration of 400 ppm and 50 PPIU. General purpose Lepidoptera artificial food is diluted with 5 liters of non-nutritive agar gelatin to half strength. 8 m 1 of food material is distributed in a 1-ounce feeding cup. One hour before treatment, 35-40 eggs were distributed on the surface of the food. The cup is then sprayed with the formulated substance through a fan-shaped mist cone nozzle. The treated cups were allowed to air dry before being sealed with a plastic lid, and the cups were left at room temperature for 6 days. Active 傺 depends on the total number of live and dead larvae and the size of live larvae. The activity against cotton aphids and cotton leaf moths was evaluated as follows: ° G ο 1 d e n c r ο k neck Pumpkin plants grew to extend the cotyledon stage (about 6 to 8 days). Before applying the test substance, the plants were infected with cotton aphids and cotton leaf moths by cutting off a transfer sheet of the pest swarm by preserving the strains for 16-24 hours. Before spraying the test substance, the transfer flakes were quickly removed from the pumpkin plant. The test was performed at 400 PPm and 50 ppm. Plants were sprayed with the test substance using a spray atomizer at 17 psi. Both the leaf surface and the back of the leaf are coated until they are flowable and then allowed to dry. The activity of each compound was measured 3 days after treatment. Activity is based on the number of mites or cicadas appearing on plants sprayed with solvents only. The activity against peanut root-knot nematodes was evaluated as follows. Five untreated cucumber seeds were placed on the bottom of a clean 1 ounce cup, 20 g of clean white sand was added, and the bottom was rotated while spraying the cup so that a solution of 1.0 ppm of 400 ppm could be placed on the sand. Add 2 · 5-3 · 0 ml deionized water containing 300 to 500 nematodes per 1 cup. Place the cup in the environmental growth room -291-This paper size applies to Chinese National Standard (CNS) Α4 size (210X297mm) I --- ^ ------- 0-- (Please read the precautions on the back first (Fill in this page again)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 487559 A7 B7_ V. Description of the invention (翊) Within 10 to 12 days, at a temperature of 76 to 856T and an atmospheric humidity of 50 to 60%. After 10 to 12 days, 'evaluate by inverting the cup and observing the nematode mortality rate and the degree of damage to cucumber plants ° The activity against the eleven star melon leaf beetle is by 1 in 1 containing a predetermined concentration of the test solution Added to 16g of lean soil containing corn kernels for evaluation. The resulting soil concentration was 24 ppm. After drying for 1.5 to 2 hours, the eleven star melon leaves of five fourth instar larvae were placed in each cup. After 3 to 4 days, check the number of live insects in the soil by emptying the cup on a plate. The activity system against American tobacco leaf moth was evaluated as follows. The general purpose Lepidoptera artificial food was diluted to half strength with 5¾ non-nutritive agar gum. Take 8 m 1 of food material and distribute it in a 1 ounce feeding cup. One hour before the treatment, 35-40 eggs were distributed on the surface of the food. The cup is then sprayed with the formulated substance via a fan-shaped mist cone nozzle. The tests were performed using 400 ppm and 50 ppm. The treated cups were air-dried before being sealed with a plastic lid, and the cups were left at room temperature for 6 days. The active pseudonym depends on the total number of live and dead larvae and the size of the live larvae. The activity against German cockroaches was evaluated as follows. Place 8 alfalfa, which is dominated by green pest food, into a 1-ounce cup of hungry food. The cup is then sprayed with the prepared substance via a fan-shaped mist cone nozzle. The test was performed using 400 ppm and 50 P in concentrations. The test cup was air-dried for 24 hours and infected with German cockroaches that were five and four years later than the third age. The cup was kept on top and kept in an environmental growth chamber for 10 days at a temperature of 76-85 ° C. The activity was evaluated in terms of the total number of surviving and dead insects. Acaricide ^ Using birch-292-This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297mm) ----- ^-IJ --- ΦII (Please read the precautions on the back before filling in this Page), tr Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 487559 A7 __B7_ 5. Description of the Invention (do), The method of the present invention is implemented according to the standard technology of acaricide application. In general, good weaving activity can be expected on the order of 1 _ 10 1 b s / a c r e. The compounds may be formulated in the forms described herein. When formulated as a dispersion, the acaricide is generally applied in the form of an infusion in the vicinity of the growing plant or is enhanced by stimulating the system. When used in granular form, the acaricide can be mixed with the soil before cultivation, or applied in bands on the surface of the seed row, the sowing area and then mixed with the soil, or it can be applied sideways to the grown crop. The following activities were discovered by the following compounds: This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

487559 A7 B7 V. Description of the invention）) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs% Sample No. Worm t Dagger Λ Rate Mortality A1 T3W 400, 100 A1 TSSM 400 100 A2 TBW 400 100 A3 T3W 400 100 A4 TBW 400 100 A5 T3W 400 100 A6 TBW 400 100 A7 TBW 400 100 A9 TBW 400 100 A10 TBW 400 100 All TBW 400 100 A12 TBW 400 100 A13a TBW 400 100 A13b TBW 400 100 A14 T3W 400 100 A15 TBW 400 100 A16 TBW 400 100 All TBW 400 100 A18 TBW 400 100 A13 TSSM 400 100 A19 TBW 400 100 A20 TBW 400 100 A21 TBW 400 100 A22 TBW 400 100 A22 TSSM 400 100 A23 TBW 400 100 A23 TSSM 400 100 A24 TBW 400 100 A24 TSSM 400 100 A25 TBW 400 100 A25 TSSM 400 100 A26 TBW 400 100 A26 TSSM 400 100 A27 TBW 400 100 Λ23 TBW 400 '100 -294-(Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 487559 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (printed) A29 Λ29 A3 0 A31 A3 2 A3 3 Λ3 4 Λ3 5 A3 6 A3 7 A3 3 A3 3 A3 9 A3 9 A40 1 A41 A42 A43 A44 A45a A4 5c A45c A45b A4 6 A43 A49a A49b ASO A51 A52 A53 A53 A54 A54 A55 A5 5 Λ5 6 Λ5 5 T3W 400 100 T3SM 400 100 T3W 400, 100 TBW 400 100 TBW 400 90 T3W 400 100 T3W 400 10C TBW 400 100 TBV / 400 100 T3W 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TSSM 400 100 T3W 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TBW 30 100 TBW 400 100 TBW 400 30 TBW 64 25 TBW 400 100 Intiermed TBW 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TSSM 400 100 TBW 400 '100 TSSM 400 100 295-— ^ ϋ · im §§1 ϋ_ι ml —ϋ Βϋ—i -ϋ ^ I (Please read the notes on the back before filling this page) The paper size of the paper is applicable to the Chinese national standard (CNS) A4 specifications (210X297 mm) 487559 A7 B7 V. Description of the invention (M3) Λ57 A53a A53b A59 AoOa A50b Λ 51 A62 A53 A53 A64a A〇4b A65 Αββ Αβ β Α67 Α67 Α63 Λ69 Α7 0 Α71 Α72 4 Α7 5 Α7 6 Α77 A73a A7 3b A7 3c A79 A80a A8 0b A31 A31 AS 5 A3S Λ37 TSSM 400 100 T3W 400 100 TEW 400 100 T3W 400 100 TBW 400 100 TBW 4〇p 100 TBW 400 1G0 TBW 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 T3W 400 100 T3W 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 T3W 400 100 TBW 400 100 TBW 64 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 丄 00 TBW 400 100 GECR 400 20 TBW 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TBW _ 100 T3W 400 100 296------, --1-- -(Please read the precautions on the back before filling out this page) Order the paper printed by the Central Consumers Bureau of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 487559 A7 B7 5 Description of the invention (2 materials) Printed by A3 3 CLH 400 20 A3 9 T3W 400 100 A91 Incarmed i B1 TSSM 400 90 B2 T3W 100 100 B3 TSSM 200 40 B4 TSSM 100 50 35 TSSM 100 65 B6 TBW30 100 B7 CA 200 60 B8 TBW 400 100 B9 TBW 400 100 B10 .TBW 400 100 B11 TBW 400 60 B12 TSSM 400 90 B12 TBW 400 100 B13 TBW 400 100 B14 TBW 400 100 B15 TBW 400 '100 B16 TSSM 400 100 B16 TBW 400 100 B17 TBW 400 100 B19 Incermed C1 TBW 80 100 C1 TSSM 400 100 C3 TBW 400 100 C3 TSSM 400 100 C4 TBW 80 100 C5 TBW 400 100 C6 TBW 80 60 C7 TBW 80 100 C7 TSSM 40 97 C3 TSSM 200 50 C9 TBW 400 100 C10 TBW 400 100 C11 TBW 400 * 100 C12 TBW * 400 100 C12 TSSM 400 100 297-(Please read the precautions on the back before filling this page)

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 487559 A7 B7 V. Description of the invention (Chao), C13a C14 C15 CIS CIS C17 C13 C13 C19 C19 C20 C21a C21b C22 C22 C23 C23 C24 C25 C26 C27 C23 C29 C3 0 C31 D1 D2 D4 D4 D5 D6 D7 D8 D9 DIO Dll Dll DI2 TBW 64 100 T3W 21 42 TBW 400 100 TSSM 400 100 TBW 64 54 TBW 400 70 T3W 400 100 TSSM 400 100 T3W 400 100 TSSM 400 100 GECR 400 20 TBW 400 100 TSSM 400 100 TBW 400100 TSSM 400 100 T3W 400 100 TSSM 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 64 100 TBW 400 30 TBW 64 • 22 TBW 400 100 TBW 30 33 TBW 80 90 TBW 400 100 TSSM 400 100 TBW 64 95 TBW 400 100 TBW 64 58 TBW 400 100 TBW 400 100 TBW 400 80 TBW400 100 TSSM 400 90 TBW 400 100 (Please read the notes on the back before filling this page)

1T 4 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -208-This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 487559 A7 B7 V. Description of the invention (Employment Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed D13 _ GECR 400 40 D14 TBW 400 100 D15 TBW 400 100 DI5 TSSM 400 100 D16 Incermed D17 3AW 400 60 D18 TBW 400 100 D19 TBW 400 30 D20 TBW 400 100 D21a GECR 400 2G D21b TBW 400 100 ALΙ ALH 400 100 Ε2 GECR 400 20 E4b TBW 400 100 E4b TSSM 400 60 E5 TBW 30 35 Eo NEHA 400 100 E7 TSSM 200 100 E3 BAW 400 30 FI TBW 400 100 F2 TBW 400 100 F3 TBW 400 100 F3 TSSM 64 24 F4 TBW 64 24 F5a TBW 400 100 F5b TBW 400 100 F7 TBW 64 100 F7 TSSM 400 100 FBa TBW 400 100 F3a TSSM 400 90 F8b TBW 400 100 F9a TBW 400 100 F9a TSSM 400 90 F9b TBW 400 100 F9b TSSM 400 90 F10 Incermed Fll Incermed F12a BAW 56 SO 299-I ---:-I ^ —MmII (Please read the notes on the back before filling this page)

、 1T This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 487559 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (d?) F12b F13a F13a F13b F14 F15a Fl5b Flo F17 F18 F19 F20 F21a F22 F23 F24 F25 F26 F27 F23 F29 F29 F30 F3 0 F31 G1 G2 G4 G5 G6 HI HI H2 H3 H3 H4 H5 TBW 400 100 TBW 400 100 TSSM * 400 100 T3W 400 LOG T3W 400 100 T3W 400 10C T3W 400 o 0 TBW 400 100 T3W 400 60 T3W 400 10C T3W 400 100 T3W 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 T3W 400 100 BAW 400 100 TBW 400 100 TBW 400 100 TBW 400 100 TSSM 400 100 TBW 400 100 TSSM. 400 100 TBW 400 100 Intermed TSSM 200 20 Incermed TBW 400 100 Incermed TBW 400 100 TSSM 400 100 Incermed TBW 400 100 TSSM 400 100 TBW 400 100 TSW 400 100 TBW 400 100 300------;-^ --ΑΨ —— (Please read the notes on the back before filling out this page) The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 487559 A7 B7 Ming (2 Lang) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs H6 TSSM 400 100 H7 TBW 400 100 H3 T3W 400, 100 H3 TSSM 400 100 11 TBW 400 100 11 TSSM 400 100 12 T3W 400 100 12 TSSM 400 100 13 TBW 400 100 13 TSSM 400 90 14 TBW 400 100 14 TSSM 400 30 15 TBW 400 100 15 TSSM 400 100 TBW 400 100 16 TSSM 400 30 17 TBW 400 100 17 TSSM 400 100 13 TBW 400 100 13 TSSM 400 100 19 TBW 400 100 110 TBW 400 100 111 Incermed 112 Incermed 113 TBW 400 100 113 TSSM 400 100 114 TBW 400 100 114 TSSM 400 100 115 TBW 400 100 116 TBW 400 100 117 T5W 400 100 113 BAW 400 30 J1 BAW 400 30 J2 TBW 400 40 J3 TBW 400 100 J4 TBW 400 100 J6 GECR 200 20 301 — I ---'--? ---- (Please read the precautions on the back before filling out this page) The paper size for this edition applies the Chinese National Standard (CNS) A4 Specifications (210X297 mm) 487559 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (introduction J7 GECR 200 20 K1 TSSM 400 100 K2a CA 400 50 K2b TBW 64 15 K5 CPH 400 10 0 Example 19 The Spinoxin derivative of Example 19 and the preparation method of Example 17 are as follows: The compound to be evaluated is dissolved in 1 part of acetone and 1 part of ethanol to provide a stock solution of the compound at a concentration of 5000 ppm. . The solution was shaken for 15 minutes in an ultrasonic wave. Place a portion of the stock solution in a 15 ml tube and add a portion of bovine serum to provide the desired compound dilution. Place the dental floss core in each tube to allow the serum to shave the core. For the test of the fly, about 20 fly larvae are placed in the center of the top of the saturated dental floss core, and the test tube is stuffed with cotton and cultured at 27 ° C and 70% humidity for 24 to 48 hours. Count the larval mortality and adjust the mortality with the control medium to determine the percentage efficiency against Lividae. For the test of adult flies, a saturated core was placed on a filter paper in a petri dish, and about 10 chilled and live flies were placed in the center of the bottom of the dish. Cover the petri dish and incubate at 27 ° C and 60% relative humidity for 48 hours. Mortality readings were recorded at 24 and 48 hours, respectively, and any mortality rate was adjusted with the control vehicle to determine the effectiveness against the flyfly cover adult. The result report is as follows: 、 -302-This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297mm) '— ------ I ^ -IdwII (Please read the precautions on the back before filling this page ) Order 487559 A7 B7 V. Description of the invention (3) The animal family age of the cockroach 颔 compound in the present invention Example No. When the number of the present invention is 100 ppm, the percentage of ASF killed is 10 PP m. When the percentage is at 100 ppm, the percentage of LBF killed is at 10 ppm. The percentage of LBF killed is Λ2 A3 100% Α5 100% Α6 100% Α7 100% Λ9 100% Λ10 100% All 100% A12 100%- (Please read the notes on the back before filling this page) 1.

、 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -303-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 487559 A7 B7 V. Description of the invention (others) Employee Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Printed A13a 100% A13d 100% Λ14 100%) ΛΙ5 100% A17 100% A13 100% Λ19 100% Λ2 0 100% Λ22 100% A23 100% Λ2 5 100% A27 100% A23 100% A29 100% A3 0 100 % A3 1,117 100% A3 2 丄 00% A3 3 100% A3 4 100% A3 6 100% A3 7 100% A4 0 100% A4 6 100% 100% A47 &lt;: 50% A43 100% &lt; 5G% A49b &lt;: 50% A50 100% A52 100% A53 100% A54 100% A55 100% A56 100% A57 100% A53a 100% AS 3 b 100% A59 100% Ao 0 &lt; a 100% A60b 100% A6 丄 30% Λ62 100% Λ63 100% Ao4a 100% (Please read the notes on the back before filling this page) • ϋ nmmm m. ·

， 1T -304-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) 487559 A7 B7 V. Description of Invention (302) Printed by A6 4b 100% A5 6 100% Λ67 100%; Λ63 100% A59 100% Λ7 0 100% A71 100% Λ72 100% A7 3 &lt; 50% A7 4 &lt; 50% Λ7 6 100% Λ77 100% A7 8a 100% A7 3b 100% A7 3c 100% A7 9 100% Λ3 0 &lt; a 100% A3 Ob &lt; 50% A31 100% Λ36, Λ90 &lt; 50% A3 7 100% A3 3 &lt; 50% A3 9 100% Λ9 I &lt; 50% B1 90% &lt; 50% 100% 32 60% &lt; 50% 53 &lt; 50% &lt;: 50% B4 &lt; 50% &lt; 50% B5 &lt; 50% &lt; 50% Bo &lt; 50% 75% 37 &lt; 50% •: .50% 33 100% 30% 39 30% 100% 310 &lt; 50% •: 50% 3 丄 丄 &lt; 50% &lt; 50% 312 &lt; 50% BI3 30% S 丄4, 50% &lt; 50% 315 100%, 50% 〇16 90% 50% BIT 100% BI3 90¾ -305-I --- 1-^ --- 0 ^-(Please read the note on the back first Please fill in this page for the matters) Chinese National Standard (CNS) A4 size (210X297 mm) 487559 A7 B7

(Milk) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

319 &lt; 50% Cl # C13b 100% 80% 100% &lt; 50% C2 60% &lt; 50% &lt; 50% v50% C3 100% 100% 100% 100% C4 100% 100% &lt; 50% &lt; 50% C5 100% &lt; 50% 100% &lt; 50% C5 90% 100% C9 90% CIO 100% C1I 100% 9 0% C16 &lt; 50% C17 70% C19 100% C20 &lt; 50% C21a 100% C21b 90% C22 &lt; 50% C23 100% C24 100% C25 100% C26 100% C27 100% C28 60% C29 100% C3G &lt; 50% C3i 100% D1 &lt; 50% &lt; .50% D2 100% &lt; .50% D3 100% &lt; 50% D4 100% D5 100% D6 100% D7 100% DB 100% D9a &lt; 50% D9b 100% DIO &lt; 50% D12 100% 100% D13 .50 % D17 70% D 丄 3 100¾ £ 1 90 ° ό SO '%,-306-隼 (CNS) A4 size (210X297 mm)

--- ^ ----! (Please read the notes on the back before filling this page), 11 487559 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs

-—— Oh! (Please read the precautions on the back before filling out this page) ΜΨ Order ------ 487559 B7 Five Invention Instructions (3β) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy H5 100% 100%} H6 100% 100% H7 100% 100% 100% 100% H8 100% 11 100% Job 2 100% Job 3 &lt; 50% 15 100% Job 6 100% 17 100% 19 100% Job 11 100% 114 100% 115 100% 100% 116 100% J1 90% 100% J2 &lt; 50% J3 &lt;: 5Ό% J4 100% J5 &lt;: 50% J6 &lt;: 50% &lt; 50% J7 &lt;: 50% &lt;: 50% J10 &lt; 50% K1 &lt;: 50% K2a &lt; 50% K2b &lt; 50% K3b &lt; 50% K4 90% Κ5 &lt; 50% Κβ &lt; 50% Κ7 &lt; 50% &lt; 50% (please first Read the notes on the reverse side and fill out this page) Order # This paper size applies to China National Standard (CNS) Α4 size (210X297 mm)

Claims (1)

487559 C8, ,, 1:… D8 Γ ^ _-t. Application for Patent Reexamination No. 083102553A01 Application for Revision of Patent Scope Amendment Date: June 1990 1. A compound selected from the following group Group: 3'-〇-11-propyl spinosinoxine (3 mouth 丨 1105; 711)]; 3'-〇-ethyl spinosinin J; 3'-0-ethyl spinosinin K; 3'-〇-Ethyl Spinoxin L; 3'-0-n-Butyl Spinozin J; 3, 0-isobutyridinyl Spinozin J; 5.6-Dihydro-3'-0-B Base Spinoxin J; 5.6-Dihydro-3'-0-n-propyl Spinoxin J; 5.6-Dihydro-3'-0-n-butyl Spinoxin J; 3'-〇-B Spinylspinoxin J hemiglutarate; 3'-0-pentadeuteryl ethylspinoxin J hemiglutarate; 5.6-dihydro-3'-0-n-propyl spinoxin J semipenta Diacid salt; 3'-0-ethylspinoxin L hemiglutarate; 3'-0-penta-deuterated ethylspinoxin J; 3'-0-isopropylspinoxin J; 3 ' -On-propyl-spinoxin J, 3'-0-n-propylspinoxin L; 5.6-dihydro-3'-0-n-propyl-spinoxin J; 3'-0-propyl Binoxin J citrate; 3'-0-propyl spine Nosin L citrate; 5.6-dihydro-3'-0-n-propyl Spinozin J citrate; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)- ---------------- Order --------- (Please read the precautions on the back before filling out this page) Intellectual Property Cooperative of Intellectual Property of the Intellectual Property Bureau of the Ministry of Economic Affairs 487559 A8 B8 C8 Sixth, the scope of application for patents is 5.6-dihydro-3'-〇-isopropylspinoxin j; 3'-0.-ethylspinylspinoxin μ; (Please read the precautions on the back before filling in this Page} 3'-0-Ethyl Spinoxin μ; 5.6-monohydro-3-epi-N- 3'-methylamido-propyl Spinoxin 5.6-dihydro-3-epi-3'-propyl Base Spinoxin j; (14S) -13,14-dihydroethyl Spinoxin μ; (14S) -13,14-dihydro-3'-〇-η-propyl Spinoxin j; (1R / S, 15R, 21S) -15-deoxy-1,15-oxy-3'-0-η-propyl-fluorene, 2 hydrazine-Nosin J1-hemiacetic acid; (1511) -15- Deoxy-15-hydroxy-3'-0-11-propyl spinosynoxine; (143) -5,6,13 ,! 4-tetrahydroxy-3'-〇-11-propyl spinosynoxine 1 ; 3'-0-propyl Spinoxin L; 3'-0 -propyl Spinoxin J; 3'-0-ethyl Spinoxin L; 3'-0-η-propyl Spinoxin Q 4 ”-Hydroxy Spinoxin A; (4 S) -4 -Defluorenyl- (difluorenylamino) _4, '_ Chenyl Spinoxin α · 4" -Deamino-5, 6 -Dihydro-4 "(S) -Jing Shi Bin Zhu Xin c; Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, Yin Yuyi 9-0- (2,3,4-triethyl-L-rhamnose 5,6-dihydrogen derivative) Spinozin A Psa; (5S, 6R) -epoxy-2'-0- (p-trifluorofluorenyl) benzyl spinosin ^^ 5.6 -Dihydro-3'-0-ethyl Spinozin j; 5.6- dihydro-3'-0-n-propyl Spinozin j; 5.6- dihydro-3'-0-n-butyl Spinn Northyn j; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Employees 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 487559 A8 B8 C8 D8 VI. Application for patent scope 5.6- Dihydro-3' -0-n-propyl Spinocinol J hemiglutarate; 5.6-dihydro-2'-0-ethylspinoxin H; 5.6-dihydro-2'-0-n-propylspinodin Octane H; (5R, 6S) -5,6-epoxy-3'-0-n-propyl Spinolsin L; (5S, 6R) -5,6-epoxypropyl Spinolsin L; ( 511,63) -3'-deoxy-5,6-epoxy-3'-methylene spinosinol; (5S, 6R) -3, deoxy-5,6-epoxy-3 ' -Arylene Spinnockin J; 5.6-dihydro-3'-0-n-propyl Spinnockin J; 5.6-dihydro-3'-0-n-isopropyl Spinnockin J; 5, 6 · Dihydro-3'-epi-N-fluorenyl-3'-propyl spinosinoxin J; 5.6- Dihydro-3'-epi-3'-propyl spinosinol J; 5.6- two Hydrogen-3'-0-vinyl Spinozin J; (143) -5,6,13,14-tetrahydro-3'-0-11-propyl Spinozin 1; 5.6-dihydro-3 ' -Phenoxyfluorenyl-Spinoxin J; 4 "-N-Defluorenyl-4" -N- (2-fluoroethyl) -5,6-dihydro-3'-0-propyl Spino Sin J; 4 "-N-desmethyl-5,6-dihydro-3'-0-propyl Spinozin J; 5.6-dihydro-N-Spinnoxin B; 4" -Go Amino-5,6-dihydro-4 "-ketospinoxin C; 4" -deamino-5,6-dihydro-4 "(S) -hydroxyoxyspinoxin C; 4" -to Amino-5,6-dihydro-4 "(S) -methoxyspinoxin C; (143) -5,6,13,14-tetrahydrospinoxin VIII; (14R) -5,6 , 13,14-tetrahydrospinoxin A; (143) -5,6,13,14-tetrahydro-3'-deoxyspinoxin 1; This paper size applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) (Please read the notes on the back before filling out this page) Packing · 487559 § ^ Application for patents printed by (5R, 6R) -5- (2, ethoxy) Dongmo Shibin materials a 17_Psa; (5S, 6R) -5,6-B Oxy_17_〇-trimethylsilyl spinoxin a 17-Psa; (5S, 6R) -5-epoxy spinoxin Al7-Psa; (5S, 6R) _5- (2-hydroxy (Ethoxy) _6_bromo-spinoxin a; (5S, 6R) -5,6-dihydroxy_5,6_dihydro-spinoxin a 17_psa; (5S, 6R) -spinoxin a Carbonate; (5S, 6S) -acetoxy-6-bromo-spinoxin a; (5R, 6R) -acetoxy-6- ,; odorant-spinozin a; 5.6-dihydrospino Octyl a; 5.6-dibromospinoxin A17Psa; 5.6-dihydrospinoxin a; (5S, 6R) -5,6-epoxyspinoxin a; (5R, 6S) -epoxy (5R, 6S) -i-Spinoxin d; (5S, 6R) -epoxy-Spinoxin a, N oxide; (5R, 6S) -epoxy-Spinozin a, N oxide; (53,611) -epoxy spinosinoxin, &gt; 1 oxide; (5S, 6R) -epoxy spinosinoxin d, N oxide; (5R, 6S) -5, 6-dibromo-4 "-ketospinoxin a; (5D61 ^)-5,6-di &gt; stinky-6-jingspinoxin 3; 5. 6-cis-dihydroxy-5,6-dihydrospirinoloxin b; (5S, 6R) -5,6-dihydroxyspirinoloxacin dichloroketal acetal; (5S, 6R) -5,6-Bis (trichloro-ethoxyl) Spinoloxine a; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) AWI ^ -------- ^ --------- (Please read the notes on the back before filling in this page) -4- 487559 A8 B8 C8 D8 The scope of patent application (5R, 6R) printed by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs- 5,6-Dibromosphinx. Nosin A; (5S) -5,6-dihydro-5-hydroxyspinoxin A; (6S) -5,6-Diaza-6-jingshi negative Octyl A, (6R) -5,6-dihydro-6-hydroxyspinoxin A; (5R: 6R) -5-ethoxyl-6-thioxanthyl spinoxin A; (5R , 6R) -5-Ethyloxy-6-methylsulfonylspinoxin A; (5R, 6R) -6-bromo-5-hydroxyspinoxin J; 5.6-dihydrospinoxin A 9-Psa; 5.6-dihydrospirinoxin A 17-Psa; 5.6- dihydrospirinoxin J; 5.6- dihydrospirinoxin Η; 5.6- dihydrospirinoxin A hemipentane Acid salt; 5.6-dihydrospinoxin B; (5S, 6R) -epoxy-spinoxin Q; (5S, 6R) -5,6-dihydro-5,6-dihydroxy Kirspinoxin A; (5R, 6S) -5,6-dihydro-5,6-dihydroxyspinoxin A; 5.6-dihydrospinoxin D; 9- (2H-5-R- Acetyloxy-5,6-dihydro-6-S-methyl-2-A-piperanyl) -Spinoxin A 9-pseudoglucosyl compound; and 5.6-dihydro-9- (2-Deoxy-3-0,4-0-diethyl-l-α-rhamnosyl) Spinoxin A 9-pseudoglucosyl compound. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------------- Order -------- (please first (Read the notes on the back and fill out this page)