TW389768B - Cephem compound and pharmaceutical composition containing the same - Google Patents

Description

5. Description of the invention (

A7 B7

(In the formula, X means CH or N; Y means protected or unprotected amine group; Z means substituted or unsubstituted fluorenyl group). In addition, Het represented by the above formula I or II means a trivalent heterocyclic group containing a 5 or 6-membered ring selected from N, 0, and S with 1 to 4 痼 identical or different atoms, and M formula The pyrrolyl structural formula shown in IV is better: --------- CII (Please read the precautions on the back before filling this page), ys

Printed in the central part of the Ministry " quasi-industrial consumer cooperation. Furthermore, in the above formula I or II, A series μ single bond or alkenyl is preferred, B series M single bond is preferred, and D is also a single bond. Better.

More suitable compounds can be in the above formula I, Acyl is the formula III 111 (where X is CH or N; Y is amine group with or without protection; Z is hydrogen or substituted or unprotected Substituted hydrocarbon group), the group shown, Het is a heterocyclic ring containing 5 or 6 members of the same or different atoms selected from 1 to 4 of N, 0 and S, A single bond or alkenyl, B A single bond, D is a single bond compound or its esters, salts, or its water and compounds as examples. Under K, first define K for the terms used in the description of this case. This paper is based on the Chinese National Standard (CNS) A4 (210X297 mm) standard printed by the Central Government Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs and Consumer Cooperatives. A7 B7 5. Description of the invention (1) The present invention provides a cephalosporin compound and The term "Containing the compound" specifically refers to a novel cephalosporin strip compound, a method for cracking the compound, and its intermediates, and a drug B containing the compound. According to the literature of the compound substituted or unsubstituted with a pyridyl anchor methyl group at the third position of the cephalosporin ring, it has been known that such as JP 60-237090 (W0 8505106, EP160969A2), especially fair 1-4419 0 and special fair 6-70068 (EP 64740B1.USP 5071979), special fair 2-44476 (EP 159011B1, USP 4833242) and other patent applications are prior. However, on pyridine anchor rings, compounds with -CONHN or heterocyclic substituents of similar substituents have not been reported to date. Although many cephalosporin compounds are on sale in the market, with the emergence of multiple doses of resistant bacteria or the diversification of treatment types, it is necessary to develop compounds with superior anti-killing activity and make them Characterization, especially the long-term half-life period in one blood, and the in vivo dynamics such as migration to tissues, etc. The two rounds of broad-spectrum cephalosporin compounds that are well-being, the demand is even greater. Therefore, the inventor of this case developed a new cephalosporin compound with superior properties for the purpose. After in-depth research, it was finally found that there is a pyridine box methyl group at the third position of the cephalosporin ring, and the pyridine Heterocyclically substituted cephalosporin compounds with -C0NHCN or similar substituents on the anchor ring have good dynamic characteristics in vivo. That is, the present invention provides a cephalosporin compound or a salt thereof, or a water compound thereof (M hereinafter referred to as "the present compound"), which has the following formula II at the third position of the cephalosporin hydrazone. The basis of the display: This paper size is applicable to the Chinese National Standard (CNS) Α4 specification (ZIOXW7 mm) 5 ---- r --.--- 7 * ^ 装 ------ Order ----- --- Quan (please read the notes on the back before filling this page) V. Description of the invention (4) A7 B7 # 5 Supplementary seal printed by the Shellfish Consumer Cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs First, in this note "The cephalosporin compound j is a compound group named based on the fCephe · described in The Journal of the American Cheaical Society, 8A, 3400 (1962 >" * means the third, A compound having a double bond at the S position at the four position. The compound of the present invention refers to a compound containing the general formula I, or a compound acceptable in the manufacturing process, or a salt thereof, or a water compound (the ester of the compound I , A salt of the compound I, a salt of the ester of the compound I, or a water compound thereof>, and -C0 in the fourth position of the compound represented by the formula I The upper right (-) in 0_ refers to the carboxylate anion, and forms a pair with the pyridine andrion on the substituent at the third position to form an intramolecular salt. In addition, if the carboxyl group has not been ionized, the pyridine anchor Samarium ions form salts with the anions or relative compartments present on Samarium. However, regardless of any of the above types, it is within the scope of the present invention. In addition, S at the first position of the cephalosporin compound is also May be oxidized. He mono- or polycyclic heterocycle j read in the definition of Heti refers to two kinds of monocyclic or polycyclic heterocyclic rings of aromatic and non-aromatic bars, and Adjacent three-valued groups are bonded to each other. However, in the case of a monocyclic heterocyclic ring, if it is an aromatic heterocyclic ring, it is preferably a 5 to 6 benzyl group, such as Furyl, sulfanyl, tetrazolyl, oxazolyl, oxazolyl, doxazolyl, pyridyl, oxazinyl, or triazinyl, etc., and in the case of non-aromatic triazines, then M 5 to 7-membered ring groups are preferred, such as pyrrolidinyl, doxazolyl, alkynyl, | imidazolidinyl, doxazolinyl, ipoxolinyl, and oxazole Group, eridyl, piperidinyl, morpholinyl, thiomorpholinyl, δ! Oxadiazolinyl and difluorenyl, etc. Among them, especially containing 1 ~ 2 艟 N or S ---- ----- Γ 泰-(Please read the note on the back before filling in this page) bj Γ This paper size applies to Chinese national standards (CNS > A4 size (21 OX297 mm)

, Invention description u)

Het-A-B-CO-D-NHCN, Ri

II (where Het is a monocyclic or polyfluorene heterocyclic ring containing the same or different atoms selected from N, 0 and S on a fistula M; R1 is a fluorene, a substituted or unsubstituted lower alkane Or lower alkenyl; A is substituted or unsubstituted lower alkylene, lower alkenyl, or single bond; B is substituted or unsubstituted imino or single bond; and, A and B are also Can be combined with each other to form a single key; D is a single key or (please read the precautions on the back before filling this page) "

NH

.5T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Η

The compound provided by the present invention is particularly preferably a compound represented by the following structural formula I, or an ester thereof, or a salt thereof, or water and a substance:

Het-A-B-CO-D-NHCN, R1

I (In the formula, Acyl refers to amidino; Het, R1, A, B, and D have the meanings as defined above. ° In the above formula I, wherein the Acyl is shown in formula III The basis is the best paper size applicable to Chinese national standards (CNS > A4 specifications (210X297 mm)-East, A7 B7 revised supplementary molybdenum " '-Ministry Central ^ 4, · ^ Only industrial and consumer goods cooperation agricultural printing $? V. Description of the invention (Sulfur atom and other heterocyclic atoms of 1 to 4 of 5 to 6 ring aromatic heterocyclic groups, etc. or benzofuranyl, isobenzofuranyl, benzo [b] sialazyl, B5I bite Base, isoearmyl, 1H-mutetyl, benzoxazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzimidazolyl, 1,2-benzoisothiazolyl Base, 1H-benzotriazolyl, quinolinyl, isoquinolinyl, fluorenyl, quinazolinyl, quinololinyl, perylene, naphthyridinyl, fluorenyl, pyridinyl, pyrene Oxazolyl, α-folinolinyl, / 9-humolinyl, 7-pyridinyl, acridinyl, phenanthryl, phenanthryl, phenanthryl, phenidazolyl, doperyl, pyridyl , Fluorenyl, 'Β§1 spelling group, pyrrolo [1,2-b] daponyl, Bftazolo [1,5-a ] Pyridyl, oxazolyl [1,2-a] pyridyl, oxazolyl [1,5-a] pyridyl, oxazolyl [1,2-b] dacrotyl, oxazolyl {1,2-a] Pyrimidinyl, 1,2,4-triazolo [4,3- &] pyridinyl, 1,2,4-triazolo [4,3-»>] daikonyl, etc. contain nitrogen atoms, 1 to 4 of 5 to 6 heteroatoms such as oxygen atom and sulfur atom, aromatic heteropyrene or benzene ring 1 to 2 are condensed to contain 1 to 5 heteroatoms including nitrogen atom, oxygen atom, sulfur atom, etc. Di- or tricyclic aromatic condensed heterocyclic groups, etc.), non-aromatic heterocyclic groups (such as ethylene oxide, oxetanyl, oxetanyl, oxetanyl, Bft pyridinyl, tetrahydrofuranyl, thiopropyl glycine, hexahydropyridyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, hexahydropyridinyl, etc. contain gas atoms , Heteroatoms such as oxygen atoms, fluorene atoms, etc., 4 to 6-membered rings, non-aromatic heterocyclic groups, etc.), amine groups, mono- or di-lower alkylamino groups (eg, methylamino, ethylamino, di Mono- or di-"-B alkylamino groups such as methylamino groups, etc.), tri-lower alkylammonium groups (such as trimethylammonium group, triethylanhydro H-6 alkylammonium, etc.), methylammonyl, fluorenyl (such as methylammonyl, ethylammonyl, propylammonium, etc. (: hydrazine; alkylmethane), aminomethyl paper Standards General Chinese National Standards (CNS) Α4 specifications (210X297 mm) 10 --------------- Order (Please read the precautions on the back before filling this page) V. Invention Description (

A7 B7

(In the formula, X means CH or N; Y means protected or unprotected amine group; Z means substituted or unsubstituted fluorenyl group). In addition, Het represented by the above formula I or II means a trivalent heterocyclic group containing a 5 or 6-membered ring selected from N, 0, and S with 1 to 4 痼 identical or different atoms, and M formula The pyrrolyl structural formula shown in IV is better: --------- CII (Please read the precautions on the back before filling this page), ys

Printed in the central part of the Ministry " quasi-industrial consumer cooperation. Furthermore, in the above formula I or II, A series μ single bond or alkenyl is preferred, B series M single bond is preferred, and D is also a single bond. Better.

More suitable compounds can be in the above formula I, Acyl is the formula III 111 (where X is CH or N; Y is amine group with or without protection; Z is hydrogen or substituted or unprotected Substituted hydrocarbon group), the group shown, Het is a heterocyclic ring containing 5 or 6 members of the same or different atoms selected from 1 to 4 of N, 0 and S, A single bond or alkenyl, B A single bond, D is a single bond compound or its esters, salts, or its water and compounds as examples. Under K, first define K for the terms used in the description of this case. This paper is in accordance with China National Standards (CNS) A4 specification (210X297 mm).

. Month A A7 B7 V. Description of the invention (I5) (wherein R1, A, B, D and Het have the same meanings as above) The pyridine derivative or its salt is reacted, and the protecting group is removed as needed to obtain 0 This reaction This is a method for synthesizing compound I by reacting M compound V or its hydrazone (M hereinafter referred to as compound v) with a pyrimidine derivative VI or a salt thereof (hereinafter referred to as compound VI) and nucleophilic substitution reaction. Compound V can be easily produced by a known method, such as the method disclosed in Japanese Laid-Open Patent Publication No. 60-231684, Japanese Patent Application Laid-Open No. 62-149682, or a method slightly adjusted according to the methods. In addition, compound VI can be produced, for example, by the method disclosed in the examples described later. * The nucleophilic substitution reaction of M compound VI to compound V is usually performed in a solvent. The solvents used in this reaction can be ethers (dioxane, tetrahydrofuran, diethyl ether, etc.), S-classes (ethyl formate, ethyl acetate, n-butyl acetate, etc.), halogenated hydrocarbons (digas methane, gas simulation , Tetrachloride, 1,2-digasethane, etc.), hydrocarbons (n-hexane, benzene, toluene, etc.), ammonium (methaneamine, Ν, Ν-dimethylamidamine, etc.), ketones (Acetone, methyl ethyl ketone, etc.), S Tang (acetic acid, propionitrile, etc.), etc., dimethyl sulfene, tetrahydropyridine, hexamethylphosphotyramine, water, etc. can be used alone Can also be mixed. Furthermore, alcohols such as formazan, ethanol, n-propionase, isopropionate, ethylene glycol, and 2-methoxyethanol can also be used. When compound VI is a liquid, compound VI may be made much larger than compound V (for example, 10 to 200 times) and used as a solvent. In this case, the above-mentioned solvent may not be used, or a mixed solution of the above-mentioned solvent and compound VI may be used. In V, the paper size of RB ^ 醯 oxy, carbamate, and substituted carbamate is applicable to the Chinese National Standard (CNS) A4 (210X297 cm) ml .n I ^^^ 1 HI —HI— • 一t (Jing first read the notes on the back and then fill out this page) Printed by the Ministry of Justice and only printed by J. Consumption in combination with bamboo. V. Description of the invention (4) A7 B7 # 五 Supplied by the Central Ministry of Economic Affairs Consumption cooperative seals First, in this description, "cephalosporin compound j is a compound group named based on fCephe · described in The Journal of the American Cheaical Society, 8A, 3400 (1962 >" * It means a compound having a double bond at the third and fourth positions of the cephalosporin ring. The compound of the present invention refers to a compound containing the general formula I, or a _ class permitted by the manufacturing process, or a salt thereof. Or water and substances (esters of compound I, Salts of compound I, salts of esters of compound I, or water and compounds thereof> In the compound represented by formula I, the -C00_ at the fourth position in the upper right (-) refers to a carboxylate It is an anion, and forms a pair with the pyridine andrion on the substituent at the third position to form an intramolecular salt. In addition, if the carboxyl group has not been ionized, the pyridine anchor ions are related to the anion or Salts are formed in the opposite compartment. However, regardless of any of the above forms, it is within the scope of the present invention. In addition, S at the first position of the cephalosporin compound can also be oxidized. Read in Heti definition ΓSingle or polycyclic heterocyclic ring j refers to two kinds of monocyclic or polycyclic heterocyclic rings of aromatic and non-aromatic strips, and the adjacent three-valued groups are combined with each other. However, in the case of a monocyclic heterocyclic ring, if it is an aromatic heterocyclic ring, it is preferably a 5 to 6 benzyl group, such as furyl, sulfanyl, tetrazolyl, fluorene An oxazolyl, oxazolyl, doxazolyl, pyridyl, pyrazinyl, or triazinyl group, etc. In addition, in the case of a non-aromatic triazine, it is a group of 5 to 7 members. It is preferably, such as pyrrolidinyl, dozozolidinyl, sulfonyl, oxazolyl alkyl, doxazolinyl, HPPolinolyl, oxazolinyl, eridinyl, piperidyl, Porphyrinyl, thiomorpholinyl, δ! Oxadiazolinyl, and difluorenyl, etc. Among them, especially containing 1 ~ 2 艟 N or S --------- Γ Thai-(Please Read the notes on the back before filling in this page) bj Γ This paper size applies to Chinese national standards (CNS > A4 size (21 OX297 mm) V. A7 ~ ___________ B7 Description of invention (21) For example, Escherichia, Enterobacteriaceae, Myxobacteria, Proteus, etc.) are highly active. In particular, in the past, Pseudomonas aquatic organisms have been treated with aminoglycoside strip antibiotics such as aminohydroxybutyl kanamycin A, gentamicin, and the like. The compounds of the present invention not only have amino groups similar to these. The antibacterial power of glycosides is comparable, and the toxicity to humans and animals is much lower than that of amine glycosides, which has the advantage of being extremely temporal.

After the Ministry of Justice of the People's Republic of China «. 芈 Bureau only works and cooperates with consumers to print and print the compound of the present invention can be formulated with a scientifically acceptable carrier, and M tablets' agents, capsules, granules, powders, and other solid agents, Or, liquid preparations such as syrups and injections are administered orally or parenterally. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. In the case of K solid preparations, excipients, slip agents, binding agents, and disintegrating agents can be appropriately formulated; in the case of M liquid preparations, solvents, dissolution aids, suspension agents, isotonic agents, and buffers can be appropriately formulated. Agents, painless agents, etc. If necessary, tincture additives such as preservatives, antioxidants, colorants, and sweeteners can also be used in the usual manner. Suitable examples of the excipients are as follows: lactose, white sugar, D-mannitol, starch, crystals, light anhydrous silicic acid, and the like. Suitable examples of the slip agent are as follows: magnesium stearate, calcium stearate, talc, silica colloidal particles, and the like. Suitable examples of the binding agent can be exemplified as follows: crystal crystalline vitamins, sucrose, D-glycosyl sugar alcohol, dextrin, hydroxypropyzanol, hydroxypropylmethyldividin, polyvinylpyrrolidone, etc. . Suitable examples of the disintegrating sheet 1 are exemplified as follows: starch, carboxymethyl-inosin, calcium carboxymethyl-inosin, calcium levanisole sodium, carboxymethyl starch sodium, and the like. Examples of suitable solvents are as follows: water for injection. Order (#Read the notes on the back before filling this page)

This paper size applies to the Chinese national standard (CNS > Α4 size (210 × 297 mm) 25 printed by Shelley Consumer Cooperative of Central Standards Bureau of the Ministry of Economic Affairs A7 _B7_ V. Single ring of invention description (5) is better, especially M pyrrolyl is the best. ”For the squid polycyclic heterocyclic ring, the preferred examples are benzalphenyl, vermidol, benzylthiazolyl, benzylfuranyl, benzimidazolyl and the like. The heterocyclic group is condensed with a benzene ring, a pyridine ring, a pyrazine ring, a phytazine ring, a pyrimidine ring, and the like. Among them, M Het is preferably bound to the fourth position of the pyridine ring. R1 ^ In the definition, the so-called Γ-lower alkyl j refers to straight or branched.-Alkyl, such as methyl, ethane, propyl, isopropyl, butyl, isobutylfluorenyl , Sec-butyl, tert-butyl, pentyl, isopentyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 3.3-dimethylbutyl, 2- Diethylbutyl, etc., especially MG- * alkyl, such as methyl, ethane, propyl, isopropyl, butyl, isobutyl, etc. In addition, these are low Higher alkyl groups can also be substituted by the following groups, such as lower alkenyl (such as vinyl, propenyl, butenyl, etc. Ca-e alkenyl, etc.), cycloalkyl (such as ethyl propyl , C3-T 环 alkyl such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), aromatic groups (such as Ce-ie aromatic groups such as phenyl and naphthyl, etc.) MH, alkyl such as methyl, ethane, and other groups such as alkoxy such as methoxy and ethoxy), aromatic ring groups (such as bifurenyl, sialyl, pyrrolyl, and fluorene) Oxazolyl, isoxazolyl, sialazolyl, isialazolyl, imidazolyl, pyrazolyl, 1,2,3-meldiazolinyl, 1,2,5-diazidazole, 1, 2,3-Syrazinyl, 1,2,4-Sialazolinyl, 1,3,4-Sialazolinyl, 1,2.3-Triazolinyl, 1,2,4-Tris Oxazolinyl, tetrazolinyl, ft-pyridinyl, «azinyl, pyrimidyl, erazinyl, trisino, etc. contain a fluorene atom, an oxygen atom, (please read the precautions on the back before filling this page) · Ding Dong. This paper size applies to China National Standard (CNS) A4 (210X297 mm) 9 The central government only copied and printed ^ A7 B7 V. Description of the invention (89), the original supplement 2 (lH, s), 7.85 (lH, s), 7.50 (2H, dd, j = '6.4, 1.8 Hz), 4.41 (2H, q, J = 7.4Hz), 1.42 (3H, t, J = 7.2Hz) IR (CHC13) van-1: 2970,1700,1600,1430,14 1 8,128 0,125 0,1080 ( 7) Suspend 2.33 g (10 nmol) of 1 10 in 50 ml of methanol, and then add IN NaOH 20nl (20ininol) at room temperature, stir at 50 ° C for 25 minutes, and then, under ice cooling After adding IN HC1 20sil, the formate was decanted under reduced pressure, and the precipitated solid matter was filtered, washed with M isopropanol and ether in order, and dried to obtain 1 1 1 2.028 (985 :). Melting point: 300. (: Above. 111: NMR (d6-DMSO) o: 8. 6 l (2H.d. J = 6 Hz). 8. 5 l (lH, s), 8.27 (lH, s), 7.77 (2H, d, J = 6Hz) I RCNujoDi / cin-1: 3336,3080.1699.1611.1296, 1211,106 5,1026 (8) Dissolve 246mg (5.84ffimol) of HSNCN in 15ml of anhydrous DMF and add 602NaH 214mg (5.36mmol) to it , And stirred at room temperature for 20 minutes to prepare a Na * [NH-CN]-/ DMF solution. Next, 1.0 g (4.87m «i 01) of I_LJJra was placed in 20 ml of anhydrous DMF, and carbonyldiimidazole was further added. 1.03 g (5.36 mm), and after stirring at room temperature for 95 minutes, 逑 Na * [NH-CN]-/ DMF solution was added dropwise under ice cooling, followed by stirring for 1 hour under ice cooling, and IN HC1 14.6 was added. ml. DMF was distilled off under reduced pressure, 30 ml of water was added to the obtained residue, and the precipitated solid matter was collected by filtration, washed sequentially with M isopropanol and ethyl, and dried to obtain a white powder 1 1 921 ng (82 X). Melting point 249 ~ 2 51 ° c. 112: NMR (d6-DMSO) (5: 8. 8 2 (2 H, d, J = 6. 0: Hz). 8. This paper standard is in accordance with China National Standard (CNS) A4 Specifications (2IOX297 mm)-^ 袈 — (Please read the note f on the back before filling in this page)-* A7 B7 Correction Molybdenum " '— Central ^ 4, · ^ only industrial and consumer goods cooperation agricultural seal $? V. Description of the invention (Sulfur atom and other heterocyclic atoms 1 to 4 of 5 to 6 ring aromatic heterocyclic groups, etc. or benzofuranyl, iso Benzofuranyl, benzo [b] sialazolyl, B5I bitenyl, isoearmyl, 1H-dutyl, benzoxazolyl, benzoxazolyl, 1,2-benzoisoxazole Base, benzozolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolinyl, isoquinolinyl, fluorenyl, quinazolinyl, quinololinyl, fluorene Aryl, naphthyridinyl, fluorenyl, pyridinyl, oxazolyl, α-folinolinyl, / 9-humolinyl, 7-purinyl, acridinyl, morphinyl, morphinyl, Morphogenyl, phenidazolyl, benzyl, pyridinyl, fluorenyl, 'β§1, pyrrolo [1,2-b] dacrotyl, Bftazolo [1,5- a] pyridyl, oxazolyl [1,2-a] pyridyl, oxazolyl [1,5-a] pyridyl, oxazolyl [1,2-b] dacrotyl, oxazolyl {1,2-a ] Pyrimidinyl, 1,2,4-triazolo [4,3- &] pyridinyl, 1,2,4-triazolo [4,3-»>] daponyl, etc. contain nitrogen atoms 5 to 6-membered ring aromatic heterofluorene or benzene with 1 to 4 heteroatoms such as oxygen, oxygen and sulfur atoms 1 to 2 condensed to contain 1 to 5 heteroatoms containing nitrogen, oxygen, sulfur, and other heteroatoms such as bi- or tricyclic aromatic condensed heterocyclic groups, non-aromatic heterocyclic groups (such as rings Oxane, oxetanyl, oxetane, oxetanyl, Bft pyridinyl, tetrahydrofuranyl, hydrosulfanyl glycine, hexahydropyridyl, tetrahydro Hexyl, morpholinyl, thiomorpholinyl, hexahydropyridyl and other heteroatoms containing gas atoms, oxygen atoms, fluorene atoms, etc. 3 to 4 to 6-membered non-aromatic heterocyclic groups, etc.) , Amine, mono- or di-lower alkylamino (for example, mono- or di-"-B alkylamino, such as methylamino, ethylamino, dimethylamino, etc.), tri-lower alkylammonium ( For example, trimethylammonium, triethylammonyl, tripropylammonium, etc., h-6 alkylammonium, etc.), formamyl, fluorenyl (eg, methylammonyl, ethylammonyl, propionyl, etc.) (（〃 "; Alkyl group>), Amine paper standard common Chinese national standard (CNS) A4 specification (210X297 mm) 10 --------------- Order _ · ( Please read the notes on the back before filling P) A7 B7

+ N

CONHCN Printed by the Central Ministry of Economic Affairs and only printed by the Consumers' Cooperatives. V. Invention Description (1 5 3 8,134 1,124 5,115 1.1034 (2) Same as before, from 335mg (〇.388iniB〇l > I- 丄) to obtain a yellow-white powder I 1.8 '25eg (10%) 〇I-U': NMR (d6 — DMSO) o: 1 4. 0 9 (lH, bs), 9.6 0 (1 H, d, J = 8.4 Hz) n 8. 9 2 (2H, d, J = 6. 9Hz). 8. 5 1 (2H.d, J = 6. 9Hz), 8.12 (2H, s), 7.47 (lH, s), 5.91 (lH, dd, J = 8. 4, 4'8Hz), 5.5 2,5.3 8 (2H, ABq, J = 14.9Hz), 5..19 (1 H, d, J = 5. 1Hz), 4. 1 4 (2H, q, J = 7. 2Hz). 3.56, 3.4 1 (2H, ABq, J = 15.5Hz), 1.2 l (3H, tf J = 7. 0 5Hz) I RCKBOi / cm-1 : 2 9 7 0, 2 1 5 8, 1 7 7 4.1 6 7 1, 1 6 3 6, 152 6,140 3,134 5,115 4,1036

V- £

1-19 'This paper size applies Chinese National Standard (CNS) A4 (210X 297mm) -133 (Please read the precautions on the back before filling this page)

V. Description of the invention (7) A7 B7 • Printed by the Ministry of Economic Affairs of the Central Bureau of Standards, Industrial and Consumer Cooperatives, trimethyl, mono- or di-lower trimethylaminomethyl (such as methylaminomethylmethyl, ethylaminomethylmethyl) , One of dimethylamine formamidine, etc. or di-Ci-e alkylamine formamidine group, etc.), amine sulfonyl group, mono- or di-lower alkylamine sulfonyl group (for example, methylamine sulfonyl group, ethyl group) Mono- or di-Cil alkylsulfonyl groups such as sulfamoyl, dimethylaminosulfonyl, etc.), carboxyl groups, lower alkoxycarbonyl groups (eg Ci-s alkoxy groups such as methoxycarbonyl, ethoxycarbonyl, etc.) Carbonyl, etc., hydroxyl, lower alkoxy (for example, h- ·; alkoxy of methoxy, £ oxy, etc.), lower alkenoxy (for example, allyloxy, 2-butenyloxy) Ca-s alkenyloxy, etc., cycloalkyloxy (such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, fluorheptyloxy, etc.) C3-T alkylalkyloxy), aralkyloxy (such as benzyloxy, phenethyloxy, etc. C7-1D aralkyloxy, etc.), aryloxy (such as phenoxy Ce-tD aryloxy, etc., hydrogen CT-t, aralkylthio (such as methylthio, ethylthio, etc.), aralkylthio (such as benzylthio, phenethylthio, etc.) Etc.>, arylthio groups (such as phenylthio, naphthylthio, etc., C6-ie arylthio groups, etc.), sulfonate, fluorenyl, azido, nitro, nitroso, halogen (such as fluorine, Helium, bromine, etc.), etc. The number of these substituents is preferably 1 to 3, and if the substituents are in the majority, M may be the same or different. The lower alkenyl J means straight_ Or branched C »-e alkenyl, such as allyl, propenyl, butenyl, pentenyl, etc. Among them, M allyl is preferred. They may also be the same as those in the lower alkyl group described above Substituted by a substituent. Γ lower alkylene in the meaning of A means a group derived from a lower alkyl group, such as methyl, ethyl, butyl, butyl, etc. Among them, M and M are preferred. M can also be the same as the above-mentioned lower grades. (---- Please read the note on the back before filling this page) Order: Quan ·. This paper size applies Chinese national standards CNS > A4 specification (210 × 297): -11-11 V. Description of the invention (8) A7 B7 Substituted by substituents in printed alkyl groups of the Central Ministry of Economic Affairs, Zhungong Consumer Cooperatives. So-called "lower elongation" "Medium" means a group derived from the above-mentioned lower alkenyl group, such as vinylidene, butenyl, propenyl, etc. Among them, vinylidene is preferred. They may also be substituted with the same as above-mentioned lower alkyl. The Γ 醢 group represented by KAcyl means the conventional fluorenyl group substituted at the amine group at the 6th position of the cyanohydrin derivative or the fluorenyl group substituted at the 7th position of the cephalosporin compound, Examples include the following: a fluorenyl group derived from an organic carboxylic acid group, such as methyl fluorenyl, alkylcarbonyl (alkyl fluorenyl), and more preferably an alkyl-carbonyl group (such as ethyl fluorenyl, propyl fluorenyl) Base, butyryl, isobutylamyl, pentamyl, isoamyl, trimethylethylamyl, hexamyl, etc. >, C3- »alkenyl < such as acryl, crotonyl, apple Fluorenyl, etc.), C3-t. Alkyl-carbonyl (e.g., propylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, octylhexylcarbonyl, cycloheptylcarbonyl, gold alkyl alkyl, etc.), Co-B pinenyl-carbonyl (e.g. Cyclopentenyl carbonyl, pentadienyl carbonyl, cyclohexenyl acryl, cyclohexadienyl carbonyl, etc.), aryl carbonyl (arylene) &MC; especially aryl-carbonyl (e.g. benzene Formyl, 1- or 2-naphthylmethyl, etc., aralkylcarbonyl, especially aralkyl-carbonyl (e.g., phenylethylfluorenyl, phenylpropanyl, cc, a, a -Triphenylethenyl, 2-phenethylcarbonyl, 2- or 2-naphthylmethylsulfanyl, benzhydrylcarbonyl, etc.), 5 ~ 6 shell aromatic heterocyclic carbonyl (such as 2- or 3-thiophene Formamyl, 2- or 3-furanmethylfluorenyl, nicotinylfluorenyl, isoniazidyl, 4- or 5-thiazolylcarbonyl, 1,2,4-pyridazol-3- or 5-yl Carbonyl, etc.>, 5 to 6 aryl aromatic fluorenyl acetamyl (for example, 2- or 3-thiapanyl fluorenyl, 2- or 3- thiofuranyl fluorenyl, 4-thiazolyl ethyl}, 4 -Sepazolyl acetofluorenyl, 1,2,4-sleepdiazol-3-ylethane in 1 ^ 1 Γ (Please read the precautions on the back before filling in this page) «I—J— ff— ^ 1 *

、 TT Standard paper size: Chinese National Standard (CNS) A4 (210X297 mm) 12 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) Benzene, 1-tetrazole Ethoxyl, etc., alkoxycarbonyl, especially C, ~ ce alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxyhexyl, isopropoxycarbonyl, H aryloxycarbonyl groups such as butoxycarbonyl, isobutoxycarbonyl, and tertiary butoxycarbonyl, especially MCe ~ C14 aryloxycarbonyl are preferred < e.g., Phenoxycarbonyl, oxo or 2-naphthyloxy Carbonyl, etc.), aralkyloxycarbonyl, especially MCT ~ C1S aralkyloxy-carbonyl is preferred < such as benzyloxycarbonyl >, aminoalkylalkyl (such as glycamine, Alanine, isovalanyl, leucine, isoleucine, serine, hydroxybutylamine, cysteamine, cystamine, methionamine, Asparagine, glutamine, lysine, glutamine, phenylglycine, phenylpropylamine, tyrosine, histamine, tryptamine, hydrazone Amine Amine group, 2-amino ethyl amine group (\ -6 alkyl-carbonyl group, etc.), monoalkylamino alkyl carbonyl group (such as methylaminomethyl) One of carbonyl, 2-ethylaminoethylcarbonyl and the like (: 〃 ;; alkylamino (^-, fluorenylcarbonyl, etc.), dialkylaminoalkylcarbonyl (such as dimethylaminomethyl Carbonyl, diethylaminomethylcarbonyl, and other di-Ct-β alkylamino groups Ci-e alkyl-carbonyl groups, etc.) These fluorenyl groups can be replaced by groups 1 to 3 under KM, such bases include : Amine, Nitro, Halogen (such as fluorine, gas, O, etc.), hydroxyl, oxy, carbamoyl, C, ~ U alkyl < such as methyl, ethyl, propyl, isopropyl , Butyl, etc.), Ci ~ alkoxy (such as methoxy, ethoxy, propoxy, butoxy, etc.), esterified or unesterified carboxyl (such as methoxycarbonyl, ethoxycarbonyl) Alkyl alkoxy group, etc., alkoxyimine groups substituted or unsubstituted by carboxyl or halogen (such as methoxyisocyanate paper standards are applicable to China National Standard (CNS) A4 specifications ( 210X297 mm) 13 --------.--- 7 *. -(Please read the precautions on the reverse side before filling out this page) Order five. Description of the invention (i〇) A7 B7 Printing of amines, ethoxyimines, and carboxymethoxides by the Shelley Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Amino group, p-carboxy-1-methylethoxyimino group, fluoromethoxyimino group, cyanoethoxyimino group, etc.), hydroxyimino group, 4-ethyl-2,3-dioxo Hexahydropyridylcarbonylamino and the like. In addition, the above-mentioned heterocyclic groups in the 5 to 6 aryl aromatic heterocyclic carbonyl group and the 5 to 6-membered aromatic heterocyclic ethyl group mean that they contain 1 to 4 nitrogen atoms. {Also, 0 is an oxidized one), an oxygen atom, a sulfur atom (also an oxidized by one or two oxygen atoms), and other heterocyclic aromatic heterocyclic rings. In addition to the examples on M, the following can be exemplified, Di: pyrrole, oxazole, pyrazole, pyrimidine, pyridine, dagen, verdole, isothiazole, oxazole, isoxazole, triazole and so on. The above-mentioned group represented by Acyl above formula III (X is CH or N;; is a protected or unprotected amine group; Z is hydrogen or a substituted or unsubstituted hydroxy group) is preferred. The protective group of the amine group in the definition of Y can be suitably used, for example, those which can be used in the field of / 8-lactam and peptides, among which M formamyl, chloroethenyl, tertiary butoxycarbonyl, benzyl Phenyloxycarbonyl, p-methoxybenzyloxy, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trifluoroethoxy Carbonyl, trityl and the like are preferred. The hydrocarbon group in the definition of Z may be, for example, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a fluorenyl group, an aralkyl group, a di- or triaryl-methyl group, an aryl group, or the like. The lower alkyl group may be linear or branched, especially those having a number of 1 to 6, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Dibutyl, tertiary butyl, n-pentyl, n-hexyl and the like. The lower alkenyl group may be straight or branched, especially those having an iodine number of 2 to 6, such as allyl, propenyl, butenyl, pentenyl and the like. Lower alkynyl (please read the precautions on the back before filling this page). ··· τ. 泉. This paper uses China National Standard (CNS) Α4 size (210X297 mm) -14-14 Ministry of Economic Affairs Printed by the Central Government Bureau of Shellfish Consumer Cooperatives A7 ___B7_ V. Description of the invention (11) Those with straight or branched shape, especially those with a number of 2 to 6 are preferred, such as propynyl, butynyl, Pentynyl and the like. The cycloalkyl group is preferably one having a halogen number of 3 to 6, such as fluorenyl, cyclobutyl, cyclopentyl, and hexyl. The aralkyl group is preferably one having a sulfonic number of 7 to 10, such as benzyl and the like. Di- or triaryl-methyl is preferably di- or tri-C ,. Aryl monomethyl, etc., such as benzhydryl, di < P-tolyl > methyl, trityl, tris (P-tolyl > methyl, etc.) The aryl group can be as large as 6 to Aryl groups such as 10, such as phenyl, etc. The fluorenyl group represented by MZ, for example, may be substituted by the substituents 1 to 3 under M, for example: carboxyl; methoxycarbonyl, ethoxycarbonyl, etc. Alkylamino-carbonyl group of 6, carbamoyl group; alkylthio groups of 1 to 6 with methylthio, ethylthio, etc .; sulfamoyl group; amino group • hydroxyl group; amine group Fluorenyloxy; fluorene, gas and other dentin. Among them, Z M hydrogen, (^ ~ (:, lower alkyl or M halogen or carboxyl substituted 1 or 2 lower alkyl (such as fluoromethyl, fluorine Ethyl, carboxypropyl, etc. are preferred. The ester derivative of the compound or intermediate of the present invention means an ester formed by carboxylation of a carboxyl group contained in the molecule, which can be used as a synthetic intermediate and an ester that can be used as a synthetic intermediate. Water-soluble and non-toxic metabolic esters are added in the warm. The esters that can be used for the synthesis of intermediates can be: substituted or unsubstituted Cl-β vinegar, Ca-β vinegar, C3-1. Ring press vinegar , C3- 1. Rare vinegar Cl-6 alkyl ester, substituted or unsubstituted cs-lD aryl ester, substituted or unsubstituted CT-ie arane deer, di Ce-ι. Aryl methyl ester, tri-c «-,. Aryl methyl esters, substituted silyl esters, etc. Metabolic ester residues, for example: ethoxymethyl acetate, ethoxymethyl, 1-ethoxy Propyl, trimethyl ethoxymethyl, bu (please read the precautions on the back before filling this page) ^ / * \ order ^ · This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) Printed by ABC, Consumer Product Cooperation, Central Bureau of Standards, Ministry of Economic Affairs A7 B7 V. Description of the Invention (12) Isopropyloxycarbonyloxyethyl, 1-cyclohexyloxyxiang (yloxyethyl, Fluorenyl, (2-oxo-5-methyl-1,3-dioxetan-4-yl) methyl, etc. When -coo- at the fourth position of compound I is acetated, the fig residue may be An example is as follows, for example: Formula νιπ —CH-O-COR8 R7

VIII [wherein RT is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R · is hydrogen, alkyl, cycloalkyl, alkoxy, cycloalkyloxy, cycloalkylalkyl, Alkenyloxy or phenyl] group, fluorenyl, (2-oxo-5-methyl-1,3-dioxetan-4-yl) methyl ester, alkoxyalkyl, alkyl fluorene Alkyl, tertiary butyl, 2,2,2-trihelyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trityl, triphenyl Methylsilyl, allyl, etc. Herein, the alkyl group of M, * cycloalkylalkyl, alkoxyalkyl and alkyl hindering alkyl is a straight or branched alkyl group having a fluorene number of 1 to 6 (for example, methyl Alkyl, ethyl, propyl, isopropyl, butyl, 2,2-dimethylpropyl, etc .; etc .; cycloalkyl and cycloalkyloxy or cycloalkylalkyl cycloalkyl, for example It may be a cycloalkyl group of 3 to 7 (for example, propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), etc. Alkoxy, and alkoxyalkyl The oxy group may be a straight or branched alkoxy group of 1 to 10 (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, decoxy, etc. ), Etc. In addition, the alkenyloxy group may be a straight bond or branched alkenyloxy group having a number of 2 to 7 (for example, allyloxy group, etc.). This paper size is applicable to China National Standard (CNS) A4 specifications ( 210X 297 mm) cf— (Please read the notes on the back before filling in this page) Ordering wood · V. Description of the invention (13) A7 B7 The "M Pharmaceutically acceptable salts are preferred In other words, it can be composed of salts with inorganic age, salts with organic sickle, salts with inorganic acid, pyrene with organic acid, salts with aging or acidic amino acid, intramolecular salts, and the like. And inorganic articles! Appropriate examples of the salts can be: sodium salt, potassium salt, etc .; gold salt, calcium salt, magnesium salt, etc .; earth salt, M and * aluminum salt, ammonium salt, etc. and organic Appropriate examples of the tested salts may be trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethylenylamine, triethylenylamine, diethylhexylamine, N, Γ-diphenylmethylethane Salts of methyldiamine, procaine, 2-phenylethylbenzylmethylamine, trimethylolaminomethane, polyhydroxyalkyl limbs, N-methylglucosamine, etc. Suitable examples of the salt are: salts of hydrochloric acid, hydrobromic acid, nitric acid, xuan acid, phosphoric acid, etc. Suitable examples of the salt formed with an organic acid may be: osmic acid, acetic acid, tricyanoacetic acid, fumarate Acid, oxalic acid, tartaric acid, maleic acid, gallic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Salt. Salts formed with aging amino acids, suitable examples may be: salts of fish box amino acids, lysine acids, maleine acids, histidine acids, etc .; salts composed of acidic amino acids, suitably Examples can be: aspartic acid, glutamic acid, and the like. Among these salts, the salt formed by Yu Si (the salt formed by Di Yu Wuyan, the salt formed by organic age, and the age The salt composed of a basic amino acid) means a carboxyl group at the fourth position of the cephalosporin 瑷 of the compound of the present invention, or a salt that can be formed when an acidic group such as a pouch group, a sulfonic acid group, or a hydroxyl group is present on the side chain. The salt formed with an acid (that is, the salt formed with an inorganic acid, the salt formed with an organic acid, and the salt formed with an acidic amino acid) means the compound of the present invention ----.---.- --Installation ------ I order ------- β, ^ Γί :: (Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) Α4 specifications ( 210X297 mm) 17 V. Description of the invention (14) A7 B7

Salts that can be formed in the presence of amine, monoalkylamino, dialkylalkylamino, cyclic aminoamino, arylamino, aralkylamino, and heterocyclic groups . In addition, the acid-added salt refers to a portion that forms an intramolecular salt in the compound of the present invention * also a carboxylic acid ester portion < C00 at the fourth position) and a pyridinium cation portion on the side chain of the third position The organic or inorganic acid to which 1 is added includes, for example, a salt having a counter ion such as a gas ion, a bromide ion, a sulfate ion, a p-toluate ion, a methanesulfonate ion, and a tricyanoacetate ion. The water and matter in the present invention, for example, means mono-water and di-water, and are obtained by adjusting by an appropriate drying method. The compound of the present invention can be produced by a method known in the field of / 3-lactam. The following is a representative method. (Preparation method 1) Compound I, an ester thereof, or a salt thereof can be represented by Formula V

R5

V (Please read the precautions on the back before filling out this page)-Binding and ordering

(Wherein * 1 ^ is a carboxy protecting group, is a hydroxyl group, a fluorenyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group, or a halogen) The cephalosporin compound or a salt thereof is represented by Formula VI

Het-A—B-CO-D-NHCN This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 18 Amendment Supplement

. Month A A7 B7 V. Description of the invention (I5) (wherein R1, A, B, D and Het have the same meanings as above) The pyridine derivative or its salt is reacted, and the protecting group is removed as needed to obtain 0 This reaction This is a method for synthesizing compound I by reacting M compound V or its hydrazone (M hereinafter referred to as compound v) with a pyrimidine derivative VI or a salt thereof (hereinafter referred to as compound VI) and nucleophilic substitution reaction. Compound V can be easily produced by a known method, such as the method disclosed in Japanese Laid-Open Patent Publication No. 60-231684, Japanese Patent Application Laid-Open No. 62-149682, or a method slightly adjusted according to the methods. In addition, compound VI can be produced, for example, by the method disclosed in the examples described later. * The nucleophilic substitution reaction of M compound VI to compound V is usually performed in a solvent. The solvents used in this reaction can be ethers (dioxane, tetrahydrofuran, diethyl ether, etc.), S-classes (ethyl formate, ethyl acetate, n-butyl acetate, etc.), halogenated hydrocarbons (digas methane, gas simulation , Tetrachloride, 1,2-digasethane, etc.), hydrocarbons (n-hexane, benzene, toluene, etc.), ammonium (methaneamine, Ν, Ν-dimethylamidamine, etc.), ketones (Acetone, methyl ethyl ketone, etc.), S Tang (acetic acid, propionitrile, etc.), etc., dimethyl sulfene, tetrahydropyridine, hexamethylphosphotyramine, water, etc. can be used alone Can also be mixed. Furthermore, alcohols such as formazan, ethanol, n-propionase, isopropionate, ethylene glycol, and 2-methoxyethanol can also be used. When compound VI is a liquid, compound VI may be made much larger than compound V (for example, 10 to 200 times) and used as a solvent. In this case, the above-mentioned solvent may not be used, or a mixed solution of the above-mentioned solvent and compound VI may be used. In V, the paper size of RB ^ 醯 oxy, carbamate, and substituted carbamate is applicable to the Chinese National Standard (CNS) A4 (210X297 cm) ml .n I ^^^ 1 HI —HI— • 一t (Jing first read the precautions on the back and then fill out this page) Only approved by the Ministry of the Central Government and only printed by J. Consumption and Bamboo Printed by the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Shellfish Consumer Cooperative A7 _____ B7_ V. Description of the Invention (16 ) When base is made, the preferred solvent is water or a mixed solvent of water and an organic solvent that can be mixed with water, and the use of the organic solvent is preferably acetone, methyl ethyl ketone, acetamidine, etc. The use of compound VI is relative to 1 deuterium of compound V is usually 1 to 5 ears, especially M1 to 3 ears are preferred. The reaction temperature M 10 ~ 100 ° C, especially M30 ~ 80 ° C is preferred. The reaction time depends on the compound V and compound VI, 棰, M and lyr, and reaction temperature There are differences between degrees, usually from «10 minutes to several hours, especially M1 to 5 hours. The pH during the reaction is 2 to 8, especially near M neutral, that is 5 to 8. Also, this reaction is usually If it is easier to perform in the presence of 2 to 30 iodide or thiocyanate, such salts can be exemplified as follows: sodium iodide, potassium sulfonate, sodium cyanate, potassium cyanate, etc. In addition to the above-mentioned salts, sometimes fourth-level ammonium salts with interfacial activity can be added to make the reaction progress smoothly, such as: trimethylbenzyl bromide, triethylbenzyl bromide Ammonium, triethylbenzyl ammonium oxide, etc. If Re in the compound V is a hydroxyl group, it can be used as described in Japanese Laid-Open Patent Publication No. Sho 58-43979 (USP 4642365, USP 4801703) and the like. It is carried out in the presence of a phosphorus compound. The solvents used in the reaction are preferably ethers, cools, halogens, halogens, amidines, ammoniums, ketones, nitriles, and other compounds, which can be used alone or in combination. ; Especially the use of dichloromethane, acetamidine, dimethylformamide, dimethylformamide, dimethylformamide and acetamidine Good effects can be obtained by using a combination solvent, a mixed solvent of dichloromethane and B brand etc. The amount of compound VI or its salt and organic phosphorus compound used is about 1 to 5 moles per mole of compound M or compound V. Ears, the latter is about 1 to 10 ears, especially about 1 to 3 ears, and this paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 mm) (please read the precautions on the back before filling this page) -Packing. Order five. Description of the invention (π) A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

About 1 to 6 ears. The temperature range of the reaction is about -80 ~ 50eC, especially about -40 ~ 40eC. The reaction time is usually about 30 minutes to 48 hours, especially about 1 to 24 hours. Organic age can also be added to the reaction system. Examples of such organic bases include triethylamine, tri (n-butyl) amine, di (n-butyl) amine, diisobutylamine, and dicyclohexylamine. And other amines. The amount of sickle is about 1 to 5 ears per mole of compound V. If R »in the compound V is a tooth atom (especially an iodine atom is preferred), the more suitable sol is the aforementioned ethers, hydrocarbons, halogenated hydrocarbons, hydrocarbons, amidines, germs, etc. Shaw, yeast, water, sub-class, etc. The amount of compound VI used, K compound V is added to about 1 to 5 ears, especially about 1 to 3 ears per 1 ear. The temperature range of the reaction Around 0 ~ 80eC, especially about 20 ~ 60 ° C. The reaction time is usually 30 minutes to 15 hours, especially about 1 to 5 hours. In order to promote the reaction, the reaction can be carried out in the presence of dehalogenated argon. Alas, these dehalogenated tinctures can use inorganic residues (sodium dibasic acid, potassium osmate, calcium osmate, sodium dihydrogen, etc.), tertiary amines (triethylamine, tri-n-propylamine, tri-n-butylamine, Diisopropylethylamine, hexyldimethylamine, pyridine, dimethylpyridine, etc.), alkylene oxides (propylene oxide, epichlorohydrin, etc.) and other deoxidizers. Compound VI itself can also be used as a deoxidizer. Hydrogen halide is thin (in this case, compound VI on 2 ears must be used for each compound V. (Cracking method 2) Acyl in formula I is the compound shown in formula III , You can type VII

Het_A-B-CO-D-NHCN V VII This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 21 (Please read the precautions on the back before filling this page) Γ _ Central of the Ministry of Economic Affairs Printed on A7 B7 printed by Zhunzhu Bureau Consumer Cooperative V. Description of the invention (18) (wherein the symbols have the same definitions as above) The hydroxyimine derivative or its ester or salt shown in the formula has the general formula ZOH Former) The compound shown or its reactive derivative is reacted and esterified to produce it. As long as the reactive derivative of ZOH is a hydrogen atom capable of substituting Z for the hydroxyimine compound VII, for example, the general formula ZRB (Re stands for a halogen atom, a monosubstituted substituent group such as alkoxy, etc.) The compounds shown below, etc. One example of the substitution of the "alkoxy" group is as follows, Di: CH2 alkyl, ethane alkyloxy, benzene alkyl, p-methyl, etc. Gas group, aryl alkoxy group, etc. The hydroxyimine compound VIII can be synthesized by the method contained in the description of this case or the method known in the technical field. The compound ZOH and its reactive derivative can be easily prepared by known methods, For example, it is synthesized by the method disclosed in Japanese Patent Laid-Open No. 60-231684, and Japanese Patent No. 62-14 9683, or a slightly adjusted method. When using 20Η, use appropriate dehydration to make hydroxyl groups. Imine compound VII reacts with Z0 to synthesize compound I. A dehydrating agent that can be used for this purpose can be exemplified by: oxyammonia-containing phosphorous acid, sulfinic sulfonium gas, and rabbit dicarboxylic acid dialkyl ester ( It is usually used under the conditions of coexistence, Ν, Ν'-dicyclohexyl Diimine, etc., especially those who use the hydrazine dicarboxylic acid 'diethylsulfonium' coexisting with triphenylphosphine ", and the coexistence of triethylphosphine diethyldicarboxylate with triphenylphosphine, It is usually carried out under anhydrous solvent, such as the above-mentioned _ class, hydrazone, etc. For each mole of hydroxyimine VIII, compound Z0Η, ethyl azodicarboxylate, triphenylphosphine are used. It is about 1 to 1.5 ears. It needs to be reversed for about tens to several hours under the temperature range of 0 ~ 501 (please read the precautions on the back before filling this page) -installation.

* tT square · This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) V. Description of invention (19) A7 B7 Printed by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. When ZRe is used, the reaction between ZR * and the hydroxyimine compound VII is a normal esterification reaction, and it is carried out in a solvent. Solvents can be solvents or mixed solvents such as ethers, esters, halogenated halogens, amidines, amidines, amidines, bladder, yeasts, water, etc. * Especially solvents that can be mixed with water A mixed solvent of water (for example, hydrous methanol, hydrous ethanol, hydrous acetone, hydrous dimethylene). The present invention can also be carried out in the presence of a suitable salt. These bases, for example, can be : Sodium Sulfate, Sodium Sulfate, Sodium Sulfate, Potassium Sulfate, etc .; and, can also be: Sodium hydroxide, potassium argon oxide, etc. Halogen Au Fluoride Hydrochloride, etc., etc. without eaves Ift. Also, this The reaction can also be carried out in a button solution (phosphate buffer solution, etc.) at pH 7.5 to 8.5. The mole numbers of the compounds ZR · and jfe are about 1 to 5 and the raw material compound VII per ear. About 1 to 10, especially about 1 to 3 and about 1 to 5. The reaction temperature is about -30 to 100 ° C, especially in the range of 0 to 80 ° C. The reaction time is about 10 minutes to 15 hours, especially It is about 30 minutes to 5 hours. When performing each of the above reactions, if necessary, the amine group, the hydroxyl group, the carboxyl group and other functional groups, and the M protecting group When it is protected, the removal method and purification method of the protecting group when manufacturing the compound of the present invention will be described below. 0 The removal method of the protecting group: for example, monohaloethenyl (chloroethenyl, bromoethenyl, etc.) can be borrowed from thiourea. Removal; alkoxy group {methoxy (carbonyl, ethoxycarbonyl, oxycarbonyl, etc.) > removal of acetic acid (such as hydrochloric acid, etc.); aralkyloxycarbonyl (benzyloxycarbonyl, p-methylbenzene Methyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) can be removed by contacting with rhenium; 2,2,2-trichloroethoxy (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 23 A7 B7 V. Description of the invention (2) The carbonyl group can be zinc and acid (such as osmic acid, etc.) removed; 2-methyl ground Ethyl esters can be removed; arylfluorenyl esters (benzyl esters, p-methoxybenzyl esters, p-nitrobenzyl esters, etc.) can be borrowed from acids (such as formic acid, trifluoroglyceric acid, A1C1 ,, T iCl *, etc.) or by removing plums; 2,2,2-trifluoroethyl esters can be removed by zinc and acids (such as K acid, etc.); silyl esters (trimethylsilyl) Alkyl esters, tert-butyldimethylsilyl esters, etc.) can be removed only by water. K fine cracking method: the compound of the present invention obtained by the above or other manufacturing methods, or its synthetic intermediate, can be borrowed Known processing methods such as extraction method, tube chromatography method, precipitation method, recrystallization method, etc., are isolated and separated. In addition, isolated compounds can be converted into desired physiologically acceptable salts by known methods. The compound of the present invention has peony activity, especially broad-spectrum antibacterial activity, and has a long half-life period in blood and excellent in vivo dynamic characteristics. Therefore, it is a practical and valuable antibiotic that can be used directly or indirectly in humans. And mammals (such as rats, wild rats, rabbits, dogs, cats, cattle, pigs) caused by pathogenic bacteria of various diseases, such as airway infection, urinary tract infection prevention and treatment. As for the special antibacterial activity, the following points can be cited: (1) Highly active against various gram-negative bacteria. Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) )

, TT ^ · (2) Highly active against Gram-negative bacteria (3) Highly active against Staphylococcus (MRSA) with resistance to dimethyl benzylcyanin (nethiciliiO) (4) Relative to The general effect of cephalosporin antibiotics produced by non-sensitive Pseudomonas aeruginosa has a significant effect (5) on many Gram-negative bacteria with / 8 -endolimb-enzyme production (this paper standard applies to Chinese national standards ( CNS) A4 specification (210X 297 mm) 24-24 V. A7 ~ ___________ B7 Invention Description (21) For example, Escherichia, Enterobacteriaceae, Myxobacteria, Proteus, etc.) are highly active. Especially In the past, for Pseudomonas aquatic organisms, aminoglycoside strip antibiotics such as aminohydroxybutyl kanamycin A, gentamicin, and the like were used. The compounds of the present invention not only have aminoglycosides such as these Unmatched antibacterial power, and its toxicity to humans and animals is far lower than aminoglycosides, which has the advantage of being extremely temporal

After the Ministry of Justice of the People's Republic of China «. 芈 Bureau only works and cooperates with consumers to print and print the compound of the present invention can be formulated with a scientifically acceptable carrier, and M tablets' agents, capsules, granules, powders, and other solid agents, Or, liquid preparations such as syrups and injections are administered orally or parenterally. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. In the case of K solid preparations, excipients, slip agents, binding agents, and disintegrating agents can be appropriately formulated; in the case of M liquid preparations, solvents, dissolution aids, suspension agents, isotonic agents, and buffers can be appropriately formulated. Agents, painless agents, etc. If necessary, tincture additives such as preservatives, antioxidants, colorants, and sweeteners can also be used in the usual manner. Suitable examples of the excipients are as follows: lactose, white sugar, D-mannitol, starch, crystals, light anhydrous silicic acid, and the like. Suitable examples of the slip agent are as follows: magnesium stearate, calcium stearate, talc, silica colloidal particles, and the like. Suitable examples of the binding agent can be exemplified as follows: crystal crystalline vitamins, sucrose, D-glycosyl sugar alcohol, dextrin, hydroxypropyzanol, hydroxypropylmethyldividin, polyvinylpyrrolidone, etc. . Suitable examples of the disintegrating sheet 1 are exemplified as follows: starch, carboxymethyl-inosin, calcium carboxymethyl-inosin, calcium levanisole sodium, carboxymethyl starch sodium, and the like. Examples of suitable solvents are as follows: water for injection. Order (#Read the notes on the back before filling this page)

This paper size applies to the Chinese national standard (CNS > Α4 size (210 × 297 mm) 25 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7__ V. Description of the invention (22), alcohol, propylene glycol, polyethylene glycol , Flax oil, corn oil, etc. Appropriate examples of soluble rib supplements include the following: polyethylene glycol, propylene glycol, mannitol, benzyl benzoic acid, ethanol, triaminomethane, cholesterol, triethinylamine , Sodium osmate, sodium betulinate, etc. Examples of hanged «Didang" can be given as follows: namely, hard wax triethylamine, sodium lauryl sulfate, lauryl amino propionic acid, lecithin, alkylbenzene Methyl dimethyl ammonium, benzyl ethoxylated ammonium, glyceryl monostearate and other interfacial activities; polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl carbamazepine sodium, methyl carbamazepine, hydroxypropyl Hydrophilic macromolecules such as chrysogen etc. Suitable examples of isotonic M can be given as follows: Digassed sodium, glycerol, D-glycosyl alcohol, etc. Suitable examples of buffering agents can be given as follows *: phosphate, Buffers, such as sugar salts, gallate salts, betulin salts, etc. Suitable examples include the following: dibenzyl alcohol, etc. Suitable examples of the preservatives include the following: dibenzoate, helium butanol, benzoin, acetoin, dehydrated acetic acid, sorbid, etc. Suitable examples of the oxidizing agent may be as follows: sulphate, ascorbic acid, etc. In addition, other active ingredients can also be mixed in the preparation, such as osmium-lactam antibiotics, etc. ° The compound of the present invention can be used as a therapeutic agent for bacterial infections, for example, for respiratory infections, urinary tract infections, urinary tract infections, endodontic infections, intestinal infections, and obstetric infections in humans and other mammals. And prevention of oedema, otococcal infections, surgical septicemia, etc. The administration of diabetics varies depending on the patient's status, weight, and method of administration. For parenteral administration, the appropriate method is that every adult 0.5 to 80 Bg of active ingredients are administered in kilograms, especially M2 to 40m, divided into 1 to 3 times a day, administered by intravenous or intramuscular injection (please read the precautions on the back before filling out this page)-Packing · , 11-^. Paper size Use the Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (23). In addition, the oral administration is administered 1 to 3 times per day, and the adult is administered approximately 1 to 100ig per kg of body weight. , Especially the active ingredient of 2.5 to 50 ng. The best form for carrying out the present invention, the meaning of the slang used in the manufacturing examples and the examples of the present invention. ^ ?: tetrahydrofuran; 0811: 1.8-diazo-bisamidine [5,4,0] Undecylene; DMF: dimethylformamide; DMS0: dimethylimide®; DIBAH: diisobutylphosphonium ¥ aluminum; TMS: trimethylsilyl; Me: Methyl; Et: ethyl; iPr: isopropyl; tertiary butyl; Ph: phenyl; MsCl: methanyl. (Protecting group) B0C: third butyloxycarbonyl group IB ·· oxazolyl group BH: diphenylmethyl PMB: p-methoxybenzyl P0M: third butyl group Indication, for example, it means compound "1", and others are the same. ^^ 1 '-I BJI---I-I 1 ^ 1 I — n (Please read the notes on the back before filling this page) Λ Economy The Central Bureau of Prototyping and Bakery Consumption Co-operation of DuPont Printing Co., Ltd. This paper is produced in accordance with the Chinese National Standard (CNS) A4 (2 丨 〇297mm) 27 A 7 B7 V. Description of the Invention (24) Ί COCH3

2 1 COCH2CH = NCH (COOEt2)

--------.--- M Pack-, ^ ΓΓί-- < Please read the precautions on the back before filling this page)

1T £ (1) Dissolve 7_ 7.74 · 1 (70 ·· 〇1 > ethyl formate 11 · 3 · 1 (0.14 · 〇1 >) in 150 · of benzene and add 7.6g of MeONa powder (0.14 ^ ol), stirred at room temperature for 1.5 hours, and then rolled back for 30 minutes, and then under reduced pressure to remove the stupidity in the reaction solution, dissolved the obtained residue in 150 · 丨 THF, and added 8.6.1 (0.15.001) of K acid, 14.8 g (70,01) of diethyl aminomalonate was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into NaHC03-ice water to Ethyl Acetate Extraction * After washing with water and dry bath, it is concentrated and the residue is crude. _ Using a silicone tube analysis method (CHaCU / ethyl acetate, 3/1), this residue is refined to obtain 14.0 ( Yield: 65.3X) 3: NMR (CDC13) 5: 1.33 (6H, t, J = 7. 0 Hz), 4. 3 2 This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Central Bureau of Prospecting and Consumers Cooperatives 28 A7 ____B7 V. Description of the invention (25) (4H, q, J = 7.0Hz), 4.65 (lH, d, J = 8.4Hz), 5.86 ( 1H, d, J = 7.8Hz), 6.99 to 7.10 (1Η, π〇, 7.10 (2H, d, J = 5. 6Hz), 8.73 (2H, d, J = 5.6Hz). (2) At 21.56 «(70.7 抑 〇1) ^ 3 Φ 詈 λ, warm on the oil bath of C for 1 hour. After the reaction solution is cooled, add ice water and neutralize with NaaCOa, then The insoluble matter was collected by filtration, dissolved in ethyl saccharate, and dried with anhydrous sulfuric acid g to reduce scratching. The obtained crystalline residue was washed with ethyl acetate to obtain 6.02 g of crystalline powder (received). Rate: 39.5Z > 1: NMR (CDC13) 1. 2 9 (3H, t, J = 7. OHz). 4.2 3 0 (2H, q, J = 7.0Hz), 6.44 (lH, bs), 7.01 (lH, bs), 7.59 (2H, d, J = 5.6 Hz), 8.60 (2H, d, J = 5.6 Hz) IR (Nujol) vcnr1: 1 7 0 2, 1 5 9 9. (3) Dissolve 2.58 g of sodium amaranth (0.1Uol > in anhydrous acetic acid 250 · 1), and then add a solution of 15.588 (51 «1« 〇1) suspended in acetic acid 70 * 1 under ice cooling. The reaction solution was heated to reflux for 9 hours, and then the reaction solution was decompressed under reduced pressure. After the obtained residue M1 Ν-hydrochloric acid was neutralized, the precipitated inferior material was filtered, washed with water and dried, and then recrystallized with M isopropanol to obtain 3 .Og's life. (Yield ·· 27.3%) ° (Please read the notes on the back before filling out this page) Strictly installed Social printout paper scale applicable Chinese National Standard (CNS) A4 size (210X 297 mm) 29 A7 B7 V. invention is described in (26) mmm p.

6 (1) Add 6.02g (27.8M0l) of i to 60g1 of ethanol containing 60al and NaOH 6.8g (0.17 * ol>), and roll it back for 1 hour. Ethanol in the reaction solution should be removed and then added It is neutralized with sugar acid. Insoluble matter is collected by filtration, washed with water, and dried to obtain 4.53 (yield: 86.6Z). _5: NMR (de-DMSO) δ: 6. 4 2 (lH, bs) N 7. 0 4 (1 H , bs), 7.56 (2H, d, J = 5.6Hz), 8.52 (2H, d, J = 5.6Hz). (2) Add 3.28g (17.4M0l) of 5JS to DMF 30 · 1, add 0.6 12Ha〇, heated to reflux overnight. The reaction solution was condensed under reduced pressure, and the residue was recrystallized from methanol to obtain 1.28 g (yield: 51.0Z). · —-I-1 i I HJ ^^ 1 1 ^ 1 ^^ 1 —1 1 n (Please read the notes on the back before filling this page) 6 .: NMR (de-DMSO) < 5: 6. 5 8 (lH, bs), 6. 8 6ClH, bs). 7.49 (lH, bs), 7.00 (2H, d, J = 6.2Hz), 8-41 (2H, d, J = 6.2 Hz) I RCNujoDvcnr1 ·· 3144, 3104, 3024, 1704, 1605. This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 30 A7 B7 V. Description of the invention (27)

mmm ^ CHO ό i? CH = CHCOOEt

(EtO) 2PCH2COOEt I l lBuOK 9 ---- ^ ^ ΓΥ-r-{CH3'O ~ s ° 2CH2NC ^ Jl .COOEt 10 11-〇χ · /

COOH --- «--- τ --- pack-Γ (Please read the notes on the back before filling this page) ίί 11 '(1) will be: Σ_ 10_7 (0. 1ι〇υ and _a_ 22.4g (0. Uol) was dissolved in 220 · 1 in THF, Ha 30 · 1 was added, followed by KaC03 (16.6 g, 0.12 ^ 1), and stirred overnight at room temperature. The reaction was carried out under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, dried in a bath, and decompressed under reduced pressure. The obtained residue was crystallized from ethyl K-n-hexane to obtain 15.61 g (yield: 88.U) of 3%. 1: NMR (CDCls) δ: 1. 3 5 (3 H, t J = 7 Ηζ) N 4.2 8 (2 H, q, J = 7 Hz), 6.60 (lH, d, J = 16 Hz), 7.38 (2H , d, J = 6 Hz), 7.60 (lH, d, J = 16 Hz), 8.65 (2H, d, J = 6 Hz). IR (CHCUhcnr1: 1711, 1645, 1597, 1551. (2) t-Bu0K12_5g < 0.106iol) suspended in 150al of THF, and THF150 containing 15.61g (88m «ol > and 18.92g (97naol > 1_CL) was added dropwise over 40 minutes under ice-cooling, taking care not to exceed the reaction temperature 30 < »C, after the dropwise addition, the reaction solution was further stirred at room temperature for 1 hour, *? Τ printed by the Central Bureau of the Ministry of Economic Affairs Applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 31 _ Ο 1 _ V. Description of the invention (28) A7 B7 neutralized with HC1 of M10 1Ϊ. After removing the THF in the reaction solution, it was dissolved in acetic acid. After washing with water, drying, and sterilizing the concentrated residue. After the residue M was finely cracked by silica gel tube chromatography (ethyl acetate), the residue of the eluate was washed with ethyl acetate to obtain 13.9 g (received). Rate: 73; 0 to 1. 1. If the product is treated in the same manner as in Manufacturing Example 2, the corresponding carboxyl 1 1 z 〇 馎 诰 Μ 4 · COOEtN-^ N:

(Please read the precautions on the reverse side before filling out this page) Equipment · Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, 12 ... .- · Hanging UA1H * of 12.14g (0.32 «〇l >) at 500 · 1 in THF, add 1 34.55g (0.16 · 〇Π in THF500il solution slowly under ice cooling, reflux for 1 hour and 30 minutes, then cool it, add NaaS0 «and 4N-NaOH, that is, oily insoluble matter is precipitated" After decanting the mother liquor, the insolubles were washed with MTHF, combined with the mother liquor, and decompressed. After removal, decompression box desilicon gel chromatography (methanol / ethyl acetate, 1/9) was used to treat the eluate. The residue was treated with ether and Washing with hexane gave 21.01 g of pale yellow crystals of 丄 _2_ (yield: 83JO.bp 152 ~ 155 ° C. 12: NMR (de-DMSO) 5: 2.22 (3H, s), 6.66 (1H, bs), 7.2 5 (1H, bs), 7.4 3 (2H, d, J = 6.0Hz), 8.4 3 (2H, d, J = 6. 0Hz). IR (KB r) ycm-1: 3 4 6 1 6 0 0. This paper size is applicable to Chinese national standard (CNS > A4 size (210X 297 mm) -32 32 A7 B7 V. Description of invention (29

N ^^ ~ CHO I ^^ COCH3 13

! M

Ac2Q OAc

DBU

(Please read the notes on the back before filling in this I)-Binding and binding (1) Add Ph3P = C0CH3 < 55g > to a solution of Z_ (18.53g) (173M〇l) in THF 250 · 1 at room temperature. (173 MOL) and stirred for 1 hour. Reduce the concentration of the house, and add toluene (50 · 1) and hexane (20 «〇, filter out the precipitated Ph, P = 0, and entangle the filtrate to obtain crude 1_3_ (34.2 g, containing Ph, P = 0). Oily} 〇 1 3: NMR (CDC13) 5: 2.4.4C3H.S), 6. 8 6 (1 H, d, J = 1 6.4 Hz), 7,45 (lH, d, J = 16.4 Hz ), 7.35 (2H, dd, J = 1.4, 4Hz), 8.69 (2H, dd, J = 1.4, 4Hz) (2) Under ice cold, at a temperature of M20 ~ 25 ° C, at 90U-Bn0K (21.5 9g, 173.17mo1VTHF added crude reaction before 20 ° C d. Printed on the paper standard of China National Standard (CNS) A4 (210X 297 mm) -33-33 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (3〇) and p-toluenesulfonylmethyl isominerals < 33.81g, 173.17 · Β〇υ / THF (300 · υ The resulting mixed solution was stirred at 25eC for 1 hour, then acetic acid (0.5 · 1 >) was added, and then water (300 · 1) and ethyl acetate (700 · 1) were added to separate the organic layer. After washing with water, the pressure was reduced. It was concentrated, and the residue was crystallized from toluene to obtain 21.38 g of a crude product of 14. The yield from 2L was 66.4S; Mp 177-194. Co.14: NMR (d6-DMSO) (5: 2.3.9 (3H, s), 7.19 (lH, bs), 7.45 (2H, dd, J = 1.6,4.6 Hz), 7.80 (lH, bs), 8.43 (2 H.dd, J = 1. 6, 4. 6 Hz) 0 (3) in 1 4 (20.9 g, 112 · 3 · βο1) in ethanol (200 nl > solution Add 1 ^ 811 * (4.258) / 11,0 (15 | «1 > to the solution and stir overnight at room temperature. The excess NaBH * was decomposed with» acid and concentrated under reduced pressure. Water / ethyl acetate was added to the residue. After the ester and water mushroom were adjusted to KaC03, the eaves layer was separated, washed with saturated brine, and concentrated. The residue was crystallized from toluene / ethyl acetate (ι / υ) to obtain 15 (14.76 sip 153-156 ° C 〇15: NMR (d6-DMSO) 5: 1.38 (3H, d, J = 6.2Hz), 4. 7 8_4.9 5 (lH, m), 6.84 (lH, bs), 7.2 0 (lH, bs), 7.60 (2H.dd, J = 1. 6, 4. 6 Hz), 8. 4 3 (2 H, dd, J = 1. 6, 4. 6 Hz) .IR ( Nujol) v cm · 1: 3 3 08, 1596, 1530, 1418, 1213, 1 0 5 8, 9 79〇 (4) To 丄 _5_ (9.03g, 48.03 · 〇1 >) add anhydrous acetic acid (40鼸 1), stir at 90 ° C for 1 hour. Remove the remaining anhydrous sugar acid under reduced pressure, add water (30ml) / K acid ethyl ester (150 · 1) to the residue, and add KaC03 until it is verified, separate the organic layer, wash and reduce Compressed, the paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) -34 (Please read the note on the back before filling this page)-Binding and ordering A7 ____B7_ V. Description of the invention (M) -1 < oily > < 9.14 g). This was dissolved in THF (50el), DBU < 12.1 > was added, and the mixture was refluxed at 70 ° C for 8 hours. It was concentrated under reduced pressure, dissolved in ethyl gluconate, and washed with water. The concentrated kneaded residue was dissolved in methanol (30b1), and 2N-NaOO (20 · 1 >) was added, followed by stirring at room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure to about 25 · 1, and ethyl acetate was used. Ester extraction. The residue was crystallized from toluene, m 1 6 (3.7 3 g, yield from 45.710. Ρ 159-160 ° C. 16: NMR (de-DMSO) 5: 5.00 (lH, dd, J = 4.0, 10.8 Hz). 5. 4 2 ClH, dd, J = 4, 1 7. 4 Hz), 6. 7 0 (1 H, dd, J = 1 0.8, 17.4 Hz), 7.09 (lH, bs), 7.17 (lH, bs), 7.36 (lH, d, J = 5.8Hz), 8.47 (lH, d, J = 5.8), IR (Nujol) y cm-1: 271 6,193 2,159 9,152 0,14 1 2, 1 2 1 1, 1 0 7 6, 9 8 6〇 (Please read the precautions on the back before filling in this page) • Packing. WC Industry Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs prints a sheet of paper for standard use in the country Shiyi centimeter 7 9 2 V. Description of the invention (32 〇 • ί A7 B7 CICH2OCH2Ph Ο υ

JB CH2OCH2Ph 18 Ο OL Άοηο CH2〇CH2Ph 19 (Please read the notes on the back before filling out this page)-Packing. Ο τχ N ^ CHO Η 20 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (1) will be 1.44g & lt l0M〇l) in DMF 20.1, add 0.42g NaOH (10.5M0U) under ice cooling, and stir for 30 minutes under room temperature, then cool the reaction solution to -30 ° C * add gas Substituted methyl benzyl ether (ClCHe〇CHa Pl0.46 · 1 (10.5 ·· ο1>, at the same temperature and mixed for 30 minutes), the reaction solution was poured into ice water, extracted with ethyl acetate, and then washed with water After drying, it is decompressed under reduced pressure, and the resulting residue is purified by silica gel tube chromatography (CHaCla / ethyl acetate = 9/1 ~ I / O) to obtain 2.31 g (yield 87.4Z) of 丄 _8_. 18 · NMR (CDC13) < 5: 4.4 46 (2H, s), 5. 2 9 (2H, s), 6. 5 9 (lH, bs), 6.67 (lH, bs), 7.26 ( lH, bs), 7.3 to 7.4 (5 H, m), 7.41 (2H, d, J = 6Hz), 8.51 (2H, d, J = 6Hz). This paper size applies the Chinese National Standard (CMS) A4 specification ( 210X297 mm) 36 A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (33) (2) 26_9g < 0.U〇l) JL_SL was added in DMF 150 · 1. Under ice cooling, the oxygenated phosphorus oxygenated 27.7 · 1 (0.3 · 〇1 >) was added dropwise at 25 ° CM below the reaction temperature, followed by heating and stirring at 40 ~ 45eC for 3 hours. The reaction solution was poured into water 500 · 1 containing K, Co. 3127g under ice-cooling, followed by extraction with MK acid, ethyl acetate, water washing, drying, and concentration reduction. The resulting residue was crystallized with ether to obtain 17.15g. (Yield of _2_2_ of 60.010. Denier: NMR (CDC13) < 5 · 4.60 (2H, s), 5.85 (2H, s), 7.33 (6H, m), 7.41 (2H , D, J = 5.6Hz), 7.54 (lH, bs), 8.60 (2H, d, J = 5.6Hz). (3 > 7.8g (27.7mo1) of JLEJS in methane 150 · To 1 and methoxybenzene 15.1, 11 g of aluminum helium (83.1 mol) was added at room temperature, and after stirring for 4 hours, 7.4 g (55.4 mol) of aluminum helium was further added, followed by stirring for 1 hour. The reaction solution was poured into ice water, and dilute hydrochloric acid was further added to prepare a clear solution. The aqueous solution was washed with ether, the pH was adjusted to 8 with 4N NaOH, and then extracted with methyl ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The crystalline residue was washed with diethyl ether-n-hexane to obtain 3.56 g of 2_0_ with a yield of 74.3% 〇2 0: NMR (CD3OD) 5: 7. 5 l (lH, bs), 7.65 (2H, d, J = 6.0 Hz), 7.79 (lH, bs), 8.44 (2H, d, J = 6.0 Hz ), 9.5 5 (lH, bs). 20: NMR (DM SO) 5: 7.5 7 (1 H, bs). 7. 6 4 (2H, d, J = 6.2Ηζ), 7.97 (lH, bs), 8.49 (2H, d, J = 6.2 Hz), 9.5 5 (lH, bs) 0 I R (Nujol) van * 1: 167 1, 165 5, 160 3. (Please read the precautions on the reverse side before filling out this page)-Binding and binding d. This paper uses the Chinese national standard (CNS specification (210X297 mm)) -37 _ A7 B7 V. Description of the invention (34) Boli 7 〇〇N Η π 'N' ^ CHO Η 6 20 Dissolve 5_77g (4〇M〇l > tS_ in DMF 70 · 1, add oxyazaphosphon 14.5 · 1 (0 16 · ο1), followed by stirring at 130eC for 5 hours, poured into ice water, neutralized with sodium hydrogen acetate, and then added ethyl gluconate. After the insoluble matter was filtered off, the organic layer was washed with saturated brine. After drying, the solution was concentrated under reduced pressure, and the obtained residue was recrystallized from methanol to obtain 0.97 g of 2 "L · in a yield of 14.01.

N

N

POM (Please read the notes on the back before filling out this page) -Ji n IJ.-Binding and binding Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Me N

(1) Break 21.0 (0.131 «〇1> of: 1_2 ^ in 0 >> 2501« 1, add 60: ^ & 0115.723 (0_1431 «〇1) under ice cooling, and stir at the same temperature for 20 minutes 100 ml of DMP was forced, the reaction solution was cooled to -45 ° C, and POM-Π (Π (: Ηβ0 (: 0Βιι) 20 · 6.1 · (0.143B〇1 >) was added, and stirred at the same temperature for 30 minutes, The obtained reaction solution was poured into water (700 · 1 >), and extracted with ethyl acetate. The paper size was applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 38 d_ Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 _B7___ 5. The invention was described (35) twice. The ethyl gluconate layer was washed with water, washed with saturated brine, dried over MgS04, and then removed under reduced pressure. Residue K silica gel tube chromatography (toluene / acetic acid) Ethyl ester = 1/2) treatment * to obtain 2 2 white crystals 33.73¾, yield 95Z. Ρ42 ~ 44 ° C 〇2 2: NMR (CDCU) 5: 1.1 · 9 (9H, s), 2. 2 4 (3H, s), 5. 7 5 (2H, s), 6. 6 8 (lH, d, J = 2. 4Hz), 7. 〇 7 (lH, d, J = 2. 4Hz), 7. 3 4 (2H, d, J = 6.2 Hz), 8. 5 3 (2H, d, J = 6.2 Hz) 〇IR (CHC13) ι / cm · 1: 1732,1602〇 (2) Will 150 DMF of 1 was cooled to -20 ° C, and after adding POCl 3 45.9 · 1 (0.49 Teng1), 33.4 (0 · 12 >) of DMF 40 · 1 was added dropwise and stirred under a chamber ancestor for 15 After a few minutes, stir 80 minutes at 60eC, pour the resulting reaction solution into 1000 · 1 ice water, add 102 g of KaC03 (0.74aol), add ethyl acetate 700 · 1, and neutralize with sodium hydrogen acetate; ethyl acetate The ester layer M was washed with water, and then washed with brine, dried over magnesium sulfate, and removed under reduced pressure. Ether and hexane were added to the obtained residue, and the precipitated crystals were filtered to obtain 27.6 g of pale yellow crystals with a yield of 75¾. Up 76 ~ 78eC. 23: NMR (CDC13: 1. 1 8 (9H, s), 2.5 1 (3H, s), 6. 2 4 (2H, s), 7. 2 9 (2H, d , J = 6. 4Hz), 7. 3 3 (1 H, s), 8. 6 2 (2H, d, J = 6. 4Hz), 9. 9 0 (lH, s). IR (CHCU) ㈣1 ·· 1731, 1657, 1603. This paper size applies to China National Standard (CNS) A4 (210X297 mm) 39 m -f 1 ini -iI In I 1- ^ ϋ \ ι I--II (Please read the precautions on the back before filling this page) d. A7 B7 V. Description of the Invention (36)

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Dissolve 20.0g (66.6uol > of 2_3JS in methanol 500 · 1, add NaOH 13.3g (0.33nol) in water 200 · 1 solution, and stir for 1 hour under room rent; after concentrating the reaction solution under reduced pressure, The precipitated insoluble matter was filtered to obtain white crystals ll.Og, yield P214 to 216. 02 4: NMR (d6-DMSO) 5: 2.50 (3H, s). 7.50 (2Η, d, J = 6. 0Hz), 7.65 (lH, bs), 8. 5 3 (2H, d, J = 6. 0Hz), 9. 7 3 (lH, s), 12. 2 4 (H, bs) .IR (KB r) vor1: 1 6 5 5, 1 6 0 4〇 (Please read the precautions on the back before filling this page),-·--1 iiy -pack.

.IT 0. The paper size of the printed papers of the China Standards and Quarantine Bureau of the Ministry of Economic Affairs of China is applicable to Chinese National Standards (CNS). M specifications (210X297 mm) -A (\ 40 V. Description of the invention (37) mmmio 〇IX , N CHO Η 20 A7 B7

26 Ο Ή I Boc 27 ΝΗ 2 NHCOIm (please read the precautions on the back before filling this page).

Boc 28 4l ^.: / ~ Βλχ The policy of employee consumer cooperatives in the Central Standards Bureau of the Ministry of Economic Affairs

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Boc 29 Dissolve 3.46 g (20 «ol > of 2_Q_ in DMF 20 · 1, add (Boc) a〇 (5.1ml, 22anol), and stir for 1 hour under room rent; the reaction solution is applicable to the Chinese standard of this paper) Standard (CNS) A4 specification (210 × 297 mm) 41 — a I — ___B7 V. Description of the invention (38) Injected into ice water and extracted with ethyl acetate; the organic layer was washed with water, dried, and concentrated under reduced pressure. The obtained The residue was recrystallized from toluene to obtain 5.24 g of 96.2 Z. 25: NMR (CDC13) 5: 1. 6 8 (9 H, s), 7. 4 3 (2H, d, J = 6.0 Hz) ) n 7. 5 l (lH, d, J = 2. OHz), 7. 8 2 (1 H, d, J = 2. 0 Hz), 8. 6 2 (2H, d, J = 6. 0 Hz ). IR (CHC13) vcnr1: 1755, 1666, 1604. (2) 2.72 g (10 mol) of 2-5_ was dissolved in formazan 50.1, and 0-methylhydroxylamine hydrochloride 0.92 was added. g (llmol), stirred at room temperature for 1 hour: the reaction solution was reduced by S, the residue obtained was dissolved in water, neutralized with sodium hydrogen nitrate, extracted with ethyl acetate, washed with water and dried, It was concentrated under pressure to obtain 2.99 g of a crystalline residue with a yield of 99.2 ×. 2 6: NMR (CDC 1 3 (syn / anti® mixture)) 6: 1. 6 4, 1. 6 5 (9H, s + s), 3.9 6 / 4.0 8 = 5 / l (3H, s + s), 7.09 / 7.45 = 5 / l (lH, bs + bs), 7.43 (2H, d, J = 6.2Hz), 7.68 / 7. 72 = l / 5 (lH, bs + bs), 8.58 (2H, d, J = 6.2Hz), 8.28 / 8.64 = l / 5 (lH, s). IR (CHCldycnr1: 1747, 1605. Central Bureau of Standards, Ministry of Economic Affairs Printed by Bei Gong Consumer Cooperative (please read the precautions on the back before filling this page) (3) Try to make 6.Og of zinc powder in 20 · 1 sugar acid, stir vigorously under ice cooling, and add M2_6_ 3.01 g (10 mol) of the solution formed by dissolving in sugar acid 20 · 1, keeping the temperature at 30 ° CM * After stirring for 30 minutes, the zinc powder was filtered off, the mother liquid was decompressed, and the residue was reduced. Dissolved in water, neutralized with sodium hydrogen nitrate, added ammonia, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain 2.63 g of the crude product. The paper size is applicable. Chinese National Standard (CNS) A4 specification (210 > < 297 mm) A7 B7 V. Description of the invention (39) This crude product 2JZJS was added to THF 50 · 1, and 2.43 g (15M0l) of carbonyldioxazole was added. , And stirred for 1 hour in a chamber. The reaction solution was concentrated and the crystal residue was washed with water and ether and dried to obtain a yield of 3.02 g 82.2X. 28: NMR (d6-DMSO) δ: 1.58C9H, s). 4.66 (2H (d, J = 5Hz), 6.85 (lH, s), 7.05 (lH, s), 7.68 (2H, d, J = 6Hz ), 7.75 (lH, s), 8.01 (lH, s), 8.33 (lH, s), 8.50 (2H, d, J = 6Hz), 9. 93 (lH, t, J = 5Hz). IR (Nujol ) vcnr1: 3 183, 1 7 4 6, 1 7 0 4, 160 1. Dissolve 2__a_ 3.02g (8.22iBOL) and cyanamide 0.69g (16.4ia0U) in DMP 50b1, and add sodium argon. .33g < 8.22M0l). At 60 ° C *, heat the reaction solution »stir for 30 minutes, add acetic acid 0.5 · 1, and concentrate it under reduced pressure. Add ice water and ether to the residue, and stir Adjust the pH to 6 with dilute hydrochloric acid, filter out the precipitated insoluble crystals, wash with ethyl ether and water, and dry to obtain 1.37 g of 2Ja, yield 48.8: S. 2_9: NMR (CDC 1 3 + CD3OD) (5: 1 .6 δ (9 Η, s) n 4. 5 7 (2H, s), 6.62 (lH, d, J = 2Hz), 7.43 (2H, d, J = 6Hz), 7. 6 0 (lH, d , J = 2Hz), 8. 5 0 (2H, d, J = 6Hz). IR (CHClOvcnr1: 2260, 2155, 1740, 1610) printed by the Consumer Cooperatives of the Central Sample Bureau of the Ministry of Economic Affairs. Elemental analysis (C17H19N503 · 1.5H20 ) Calculate 値: C, 5 5.4 3; H.6.02; N, 19.01 Asset test 値: C, 5 5. 3 5; H, 5 · 7 3; N, 1 8. 6 3 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 43 A7 B7 V. Description of the invention (4〇) Manufacturing example 11 IX, N CHO Η Ο 20

FjL, Ν CN Η 30

• HCI Ν C = NH Η I 0CH3 31

(Please read the notes on the back before filling out this page) Binding and ordering Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

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νη2 NC0NHCN 34 This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) -44 44 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (41) (1) Will be 864ag No. 2_QJ§ In formic acid 10.1, hydroxylamine hydrochloride 417 »g (6mol) was added, followed by stirring at 110eC for 6 hours. The reaction solution was depressurized and the residue was dissolved in water. The sodium sulfonate was neutralized and the precipitated crystals were filtered and recrystallized from formazan to obtain 394ng of 30 with a yield of 46.6ϋ. 3 0: NMR (de-DMSO) < 5: 7. 5 6 (lH, bs). 7. 6 1 (2 H, d, J = 6.2Hz), 7.91 (lH, bs), 8.49 (2H, dJ = 6.2 Hz). I R (Nujol) vcm · 1: 311 2, 2210, 160 2, 153 5. (2) Dissolve 6.858 (40.5 acid 〇1> of _3_〇_ in 500ml of methanol, and introduce hydrochloric acid tritium under cooling with ice water until saturation; after stirring at the same temperature for 1 hour, further in the room Stir at room temperature for 1 hour; concentrate the reaction solution by reducing K to obtain the crude product 31 of crystalline residue. To this residue was added a solution of methanol 100 · 1 and ammonia in methanol (5.3 · ο1) 160 ·! The mixture was stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water of 150%. The M2N was argon-neutralized to neutralize it. The precipitated insoluble crystals were filtered, washed and dried to obtain 6. 788 之 _2_2_ ， Yield 89.9: 1: 3: NMR (de-DMS0) δ: 7.34 (lH.s). 7.34 (2Hfd, J = 6Hz), 7.49 (lH, s), 8.32 (2H, d, J = 6Hz ) 0 IR (Nujol) ycnr1: 166 7, 160 2, 155 0. (3) Put 931 · Η < 5 · βο1) in DMF 10 · 1, and add carbonyldioxazole 89lBg (5.5nmol) with stirring. ), And stirred at room temperature for 2 hours. Next, firstly dissolve 0.42 g of cyanamide (10H »nol> in DMF 6il, add NaH 0 · 〇 (10 ·· 1), and stir in the room for 30 minutes. ”To make a monocyanocyanine”, add this monona salt, in the room After stirring for 3 hours, it was further stirred for 1 hour at 501. The reaction solution was concentrated under reduced pressure, and the paper size was applied to the national standard (CNS) A4 specification (210X297 mm) (please read the note on the back first) (Please fill in this page for more details.)

> 1T 45 A7 ____B7_ 5. Description of the invention (42) After the residue was dissolved in water, 1N-hydrochloric acid 10.1 was added to neutralize it, and the precipitated crystals were collected by filtration. This crystal was dissolved with IN-NaOH, and part of the insoluble matter was filtered off. The mother mash was neutralized again with dilute hydrochloric acid, and the precipitated crystal was filtered and dried to obtain 51.8 g of _a_4L, yield 40.8:!;. 3 4: NMR (d6-DMSO) 5: 7. 5 8 (2 H, d, J = 6 Hz) s 8. 0 6 (lH, s), 8.11 (lH, s), 8.56 (2H, bs). I R (Nujol) ycm-1: 218 0, 162 6, 159 7. Please read the back Φ page binding first

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, which belongs to the Industrial and Consumer Cooperatives. This paper uses Chinese National Standards (CNS) A4 (210X297 mm) 46 A7 B7 V. Description of the Invention (43) Tong Li 12 〇

V ^ CHO POM 35

CH3 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

UvCH3 POM 0 』〇 w_ POM 〇 37 38 ^ ^ jLyCOOH 39 ΙΙνχ ^ ΟΟΟΒΗ 40 \ Ο S ^ YC00H / ° ch3 41 / ° ch3 42

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44 This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) ---- * --------; = ^ 装-Γ (Please read the precautions on the back before filling in this page)

、 1T d -47-Printed by A7 ____B7_ by Shelley Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (44) (1) 14.32g (50M〇l) of _3_5JID was thermally dissolved in THF 24〇1 Cool to -70 ° C. MeMgBr's THF (0.9 Uol > Soluble IOObI) was added dropwise at a temperature of -60 ° CM. After 1 hour at the same temperature, the same solution was further added 20 · 1. After 1 hour, helium-containing solution was added to the reaction solution. 18g of ammonium in aqueous solution 100 «1, followed by concentration reduction. The residue was extracted with ethyl acetate, washed with water, dried, and then decompressed under reduced pressure. The obtained crystals were crystallized from diethyl ether-n-hexanol to obtain 14.0g of 3 6, yield 86.5X. 3 6: NMR (CDC13) 5: 1. 4 9 (9H, s), 1. 6 8 (3H, d, J = 7Hz), 5.02 (lH, q, J = 7Hz) , 5.97, 6.03 (2H, ABq, J = 8.0Hz), 6.51 (lH, d, J = 2Hz), 7.28 (lH, d, J = 2Hz), 7. 3 5 (2H, d, J = 6Hz) , 8. 4 8 (2H, d, J = 6 Hz). (2) Dissolve 14.0 (46.3 Tengu 0 1) of _2_6_ in digas methane 250 dew 1 and add 14 g of gadolinium dioxide, while stirring Under heating and refluxing for 1.5 hours, and then add 7 g of manganese dioxide per hour, add 5 times, and then add 14 g of hafnium dioxide, stir overnight, add rent and roll back; further add 1.4 g of manganese dioxide, under stirring Heating and refluxing for 7 hours; then filtering off the manganese dioxide, M dihelium methane and formazan in the reaction solution, and then washing The mother liquor was concentrated under reduced pressure, and the residue M isopropanol was recrystallized to obtain 11.6 g of 2_S_Z_ with a yield of 83.4 ×. 37: NMR (CDC13) 5: 1. 18 (9H, s), 2.5 3 ( 3H, s), 6.29 (2H's), 7.30 (lH, d, J = 2Hz), 7.40 (2H, d, J = 6.0 Hz), 7.51 (lH, d, J = 2Hz), 8.58 (2H, d, J = 6.0 Hz). IR (Nujol) vcnr1: 1718, 1 6 4 6, 1 6 0 2. (3) 11.2 笤 (39〇1 »〇1> of _2_2_ was dissolved in pyridine 12〇181 In addition, selenium dioxide was added for 9.6s (86 «ol >), and the reaction solution was depressurized after rolling for 7 hours. The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) -ΑΆ-~- --------- Equipment-yf \ (Please read the notes on the back before filling in this page) Order — 7 A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ) Concentration; add sodium carbonate aqueous solution to the residue, mix it, and then filter out insoluble matter, and at the same time, active sulfonic acid treatment. Adjust the pH of mother tincture to 5 with dilute hydrochloric acid, filter out the precipitated crystals, wash and dry, 8.05 g of _a_8_ was obtained with a yield of 62.5¾ 〇 3 8: NMR (de-DMSO) (5: 1. 1 l (9H, s), 6. 2 l (2H, s), 7.71 (2H, d, J = 6.0 Hz), 7.78 (lH, d, J = 1.6 Hz), 8. 2 9 (lH, d, J = 1.6 Hz), 8. 5 6 (2H, d, J = 6. OHz). (4) Dissolve _2_ £ _ of 5_98 volume (18.1 Housing 〇1) in 100 channels of formazan, add 45ml of 2N NaOH, and stir at room temperature for 2 hours. Remove the formazan from the reaction solution, add 5NHC1 18 · 1 to the solution to neutralize it; filter out the precipitated crystals, and dry to obtain 4.8 g of 3 9 〇 3 9: NMR (d6-DMSO) d: 7. 7 l (lH.bs). 7. 7 9 (2H, d, J = 6.0 Hz), 8.11 (lH, bs), 8.55 (2H, d, J = 6.0 Hz). (5) Put 4.8g (22.2 houses · ο1) of turbidity in methanol and 150al and dichloromethane 150g, and add 5.5g (28.3nmol) of diphenyl heavy hydrazine and stir at room rent for ^ night. The reaction solution was concentrated and concentrated to obtain residue M silica gel tube chromatography (digas methane / »Acetylacetate = 2/1 > spermidine, to obtain 3.92 g of raw _Q * yield 56.6;!:. 4 0: NMR (CDC13) 5: 7. 1 2 (lH, bs), 7, 3 to 7.5 (1 2 H, m), 7.56 (lH, bs), 7.63 (lH, bs), 8.58 ( 2H, d, J = 6.0 Hz) IR (Nu jol) van-1: 3386, 1725, 1645, 1603. (6) Add 2.72 g (7.1 ImoI) to methane 50 · 1, add 〇-methylhydroxylamine * hydrochloride l_78g (21.3Biol > formazan 15al soluble (please read the precautions on the back before filling this page) _ It— 11 HI · -Binding • This paper size applies Chinese national standards ( CNS) A4 size (210X297 mm) 49 A7 B7 Printed by the Industrial and Consumer Cooperatives of the Shiyang Municipal Standards Bureau of the Ministry of Economic Affairs

V. Description of the invention (46) The solution is stirred at room temperature for 3 days. The reaction solution was concentrated and warmed, and the residue was neutralized by adding an aqueous sodium hydrogen acetate solution to the residue. The insoluble crystals were collected by filtration, washed with water, and dried to obtain 4.93 g of 4. 1 〇 4 1: NMR (d6-DMS 0 (syn / anti mixture)) 5: 3. 9 5/4. 13: 6.4 / l (3H, 2xs) 6.81 (lH, bs), 7.12 (lH, s), 7.3 to 7.5 (1 〇H M), 8. 0 6 (2H, d J = 6 Hz), 8. 1 9 (1 Η, bs), 8. 7 l (2H, d, J = 6 Hz). IR (Nujol) y cnr1: 3104, 2606, 1742, 1630, 1600 (7) 0.82g &lt; 2i »mol) of hydrazone is dissolved in 5nl of dichloromethane, methoxybenzene 1.1 is added, and the solution is cooled under ice Add trifluorosugar 6b1 and stir for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by M-tube chromatography (water-methanol) to obtain 0.65 g of raw _2_. 4 2: NMR (d6-DMS〇) &lt; 5: 3. 9 l (3H, s), 6. 9 4 (lH, bs), 7.42 (lH, bs), 7.9 (3H, m), 8.55 ( 2H, bs). (8) Dissolve 0.65 g (2.65 niiol) of _2L in DMF10ul, add 0.65 g of carbonyldioxazole <4MOU under ice cooling, and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water and dried, and concentrated under reduced pressure to obtain 586 mg of a crude product with a yield of 78.1!?:. 4 3: NMR (de —DMSO (syn / anti. Mixture)) d: 3. 9 4/4. 2 5 = 2.5 / l (3H, sx2), IsomerA, 3. 9 4 (3H, s ), 6. 6 5 (1 Η, bs), 7.13C1H s), 7.17 (lH, bs), 7.35 (2H, d, J = 6Mz),: 7.53 (lH, s), 8.02 (lH, s) , 8.52 (2HdJ = 6H2), lsomer B, 4.25 (3H, s), 7.30 (lH, bs), 7.41 (lH, s), 7.42 (2 H, d, J = 6Hz), 7.71 (lH, bs) , 7.73 (lH s) 8.35C1H This paper size is applicable to China National Standard (CNS) A4 size (210X25 * 7mm) 50 (Please read the note on the back before filling this page)-· ιι 1 ^ 1 &quot;. 装. Order a A7 _____B7__ V. Description of the invention (47) s) 8. 5 7 (2 H d J = 6 Hz) (9) Dissolve 586g (2 · IhboI) of _2_ • in DMF4al; First, 174 mg of cyanamide (4.UBOl>) was dissolved in DMF2il, and sodium hydride (6 (U) 164eg (4.UBOl>) was stirred for 30 minutes, and the solution thus formed was added to the above. Stir in the solution for 1 hour at room temperature; add 0.5 · 1 of acid to the reaction solution * concentrate under reduced pressure * residue M tube chromatography (20Z formazan-water) »dissolution, the residue of the dissolution solution is different Washed with propanol to obtain 275ng of crystalline powder, yield 48.6 X. 4 4: NMR (d6-DMSO —)) &lt; 5: 3. 8 2 (3 H, s), 6.88 (lH, bs), 7.98 (lH, bs), 8.12 (2H, d, J = 6H z), 8. 6 0 (2H, d, J = 6Hz). IR (Nujol) vcnr1: 340 0,218 0,167 5,164 0,1620 .-- I HI-I-j-II— 11-. '1.-I (Please read the notes on the back before filling out this page)

， 1T Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives. This paper is printed according to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -51- 51 A7 B7 V. Description of the invention (48) 〇, Ν rxΆοοοη, Ν, ΗΝ ^ ΝΗ2 45 POM5;

Ο

vV N-CN χ ΝΗ ΝΗ2 (Please read the precautions on the back before filling in this page) -0. 11 47 (1) Add 3.078 (10 ·· 〇〇 之 5_1_check Yi to DMF30 · !, add 1- 2.03 g (15 «ol) of hydroxybenzotriazole, followed by addition of 2.88 g (15 MO) of water-soluble trihalide, and stirred at room temperature for 1 hour. To the reaction solution was added 4_5_ 2.2 g (15 MO) And DM FlOil solution of diisopropylethylamine 2.6 · 1 &lt; 15 ·· 〇υ, stirred for 1 hour under room rent. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and dried. Then, it was crimped under reduced pressure. The residue was filtered by ethyl crystallization * to obtain 3.23 g of raw _6_ with a yield of 81.9X. 4 6: NMR (CDCls) 5: 1. 4 8 (9 H, s) . 6. 4 4 (2 H, s), 6.51 (lH, bs), 7.43 (2H, d, J = 6.2Hz), 7.50 (lH, d, J = 2Hz), 7.58 (lH, d, J = 2Hz), 7.76 (lH, bs), 8.56 (2 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) α Printing policy of the Zhengong Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs 52 A7 _____ Β7__ V. Description of the invention (49) H, d, J = 6. 2H), 8. 6 0 (lH, bs). IR CNujoDi ^ cm-1: 357 4, 339 8, 173 5, 163 1, 159 5 (2) Dissolve ammonium 21 BS (5mB0l) in DMF5nl, add sodium hydride (603; U20ig &lt; 3Baol), stir at room temperature for 30 minutes, and then add 394 g &lt; 1M〇l &gt;; Shengsheng _, stir for 7 hours at room temperature. Add acetic acid 0.5β1 to the reaction solution, concentrate under pressure, add ice water to the residue, filter out insolubles, wash with water, and then wash with ethyl acetate After drying, 218 g was obtained in a yield of 85.7Z. 4J_: NMR Cde-DMSO) &lt; 5: 7. 5 5 (2H, d, J = 6 Hz). 7. 8 l (lH, s), 7.93 ( lH, s), 8.50 (2H.d, J = 6Hz), 8.64 (1 H, bs), 9. 1 2 (lH, bs). IR (Nujol) vcm'1: 3420,3360,2240,1690, 165 0, 16 1 100% analysis (Ci2Hi〇Ne〇. 0.4H2O) Calculated 値: C, 55.13; H, 4.16; N, 32.14 Measured 値: C, 55.22; H, 4.24; N, 31.82- ---I-1 installed! (Please read the note on the back before filling in this page), π Printed on the paper printed by the Pioneer Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 53-Α7 Β7 5. Description of the invention (50)

N

CHO 48

Boc

CH = NOMe 49

Boc

------ 装 — (Please read the notes on the back before filling this page)

Me ^ 'NHCONHCN NH 52 Order Du Yinyang (1 &gt; The solution of 5.61g (30.Unol) in THF140b1, add (Βο &lt; 〇, 0 (8.3 · 1 , 36.1 · 〇1> and DMAP50 (Ug, stirred at room temperature for 30 minutes. Shovel. The reaction solution was decanted under reduced pressure, ether and hexane were added to the residue, and the precipitated crystals were collected by filtration to obtain raw white crystals. 8.07 g, yield 95%: up 105 ~ 107 ° C 〇 4 8: NMR (CDC13) 5: 1. 6 6 (9H, s), 2. 4 8 (3H, s), 7.30 (2H, d, J = 6.2Hz), 7.52 (lH, s), 8.65 (2H, d, J = 6.2Hz), 10.4 7 (lH, s) 〇IR (CHC13) v cm-1: 1745,1660, 1604. (2) The solution of 8.06g (28.2 «ol &gt;) in methanol 120 · 1 was applied to the paper size of China National Standard (CNS) A4 (2 丨 0 X 297 mm) 54 / it \ Economy Printed by A7 _B7_ of the Central Laboratories and Consumers Cooperatives of the Ministry of Foreign Affairs of the People's Republic of China 5. Description of the Invention (si) Pyridine 2.73 · 1 was added, followed by MeONHa · HC1 2.47g (29.6 &quot; ol &gt;), and stirred at room temperature for 80 minutes. Remove the reaction solution under reduced pressure, add ethyl acetate 10 (U1 and water 100 |), and separate the ethyl acetate layer to The ethyl gluconate layer was washed with water and saturated brine, and then dried over magnesium sulfate, and then distilled under reduced pressure to obtain 8.08 g of white crystals with a yield of 91X. Yield: 104 ~ 106 ° C. 4 9: NMR (CDC13) &lt; 5: 1. 6 1 (9H, s), 2. 3 4 (3H, s), 3.97 (3H, s), 7.32 (2H, d, J = 6.2 Hz), 7.44 (lH, s), 8. 6 1 (lH, s), 8. 6 1 (2H, d, J = 6.2 Hz). IR (CHC13) van · 1: 1740,1604. (3) The zinc powder 6.0 g of turbidity was added to 20 nl of acetic acid and 10 ml of acetic acid, and a solution of 3.0 g (9.5 UinOl) of acetic acid 15 · 1 was added, and stirred at room temperature for 30 minutes, and then stirred at 35 ° C. 30 minutes. After filtering off the zinc powder and removing the mother liquor, inject the gaseous methane and water into the residue, adjust the pH to 9 with ammonia water and sodium hydrogen sulfonate; take out the gaseous methane layer and wash it with water. After drying over magnesium sulfate, it was evaporated under reduced pressure to obtain a crude product 5_0_. Dissolve 5- £ L in T90 F90nl, add 1.54 g (9.50 mol) of carbonyl dibenzyl, stir in the room for 81 minutes and stir. The resulting reaction solution is poured into water, and extracted with ethyl acetate Then, the ethyl acetate layer was washed with water and saturated brine, and then dried over magnesium sulfate, and then evaporated under reduced pressure, and the residue was washed with ether to obtain white powder 5 1 &gt; 2.65 g in total »Yield 732. 5 1: NMR (de-DMSO) 5: 1. 5 3 (9H, s), 2. 2 0 (3H, s), 4.65 (2H, bs), 7.01 (lH, s), 7.49 (2H, d, J = 6.4 Hz), 7.70 (lH, s), 7.73 (lH, s), 8.27 (lH, s), 8.5 7 (2H, d, J = 6.4Hz). This paper size applies to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) -55-(Please read the precautions on the back before filling this page) -Packing ·

* tT A7 B7 5. Description of the invention (52) (4) Dissolve 2.65g (6.95niol) in DMF30ml. Separately, amine (HeNCN) (321ag, 7.63 ·· 〇Π was dissolved in DMF20b1, NaH306g (7.63i »B〇l) was added, and the mixture was stirred at room temperature for 10 minutes, and then added under ice-cooling. 1_ solution, after stirring at room temperature for 30 minutes, add acetic acid 0.88β1 (15 · 4 · βο1), evaporate under reduced pressure; pour water into the residue and add 2N-HC1 3.48 «1, and stir under ice cooling The precipitated insoluble matter was filtered, washed 2 times with M isozyme, and then washed 2 times with M ether to obtain a yellow powder 5 2 965 ^ g, yield 5U. 5 2: NMR (de-DMSO) &lt; 5 : 2.17 (3H, s), 4.20 (2Η, bs), 7.20 (lH, bs), 7.37 (lH, bs), 7.44 (2H, d, J = 6. 4Hz), 8.4 5 (2H, d, J = 6.4Hz), 10.95 (lH, bs) 〇 (Please read the precautions on the back before filling this page) 1H IJ ^ i.

, 1T

Li Li 1 5 IS

35 '、 POM 2) NaOHaq. Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

IS

H2NCN / NaH

H pOOH H

N

(1) The solution of 4.30g (15.0M〇l) in THF120nl, plus the paper size is applicable to China National Standards (CNS) A4 specifications (210X297 mm) -56 _ 56 V. Description of the invention (53) A7 B7 The Ministry of Economic Affairs of the Central Bureau of the Central Bureau of Work and Consumer Cooperatives printed ^ £ _ £ _1_6_028 &lt; 180.0 | «111〇1) and returned for 2 hours and 20 minutes. Reduce reaction «Reaction solution * Dissolve the residue in formazan 80 · 1, add 2N-NaOH 37.5 * 1, and stir at 50 ° C for 1 hour. Add 2N-HC1 37 · 5β1 to the resulting solution. Adjust it to about 3 and concentrate under reduced pressure so that it does not contain formazan; add ethyl acetate vinegar 200 · 1 and water 50 · 1 to the seawater after the shrinkage, and filter the insolubles to obtain 2.82 g of pale yellow crystals. Yield: 88 ×. up 272 ~ 27 4 ° C 〇3: NMR (de-DMSO) 6: 6.22 (lH, d, J = 16. OHz), 7.11 (lH, bs), 7.41 (lH, d, J = 16.0 Hz), 7.58 · (2Η, d, J = 5.6 Hz), 7.79 (lH, bs), 8.47 (2H, bs), 11.91 (1 H, bs), 12.1 (lH, bs). IR (KB r) vein-1: 3431,1670,1609〇 (2) Put 2.82g (13.2uol &gt; of DMF50b1 in DMF50b1, add 3.03g of fluorenyldioxazole (15.8MOL &gt;), and prepare in room Stir for 45 minutes. Remove the reaction solution under reduced pressure. Wash the residue with water to obtain 3.19 g of yellow crystals. Yield 923: · ρ 213 ~ 215eC. 54: NMR (d6-DMS0) 5: 7. 1 7 (lH, bs), 7. 3 3 (lH, d, J = 15.6Hz), 7.43 (lH, bs), 7.59 (2H, d, J = 4.8Hz), 7.81 (lH, bs), 7.84 (lH , D, J = 15.6 Hz), 8.00 (1H, bs), 8.5 1 (lH, bs), 8.5 2 (2H, d, J = 4. 8 Hz), 12.13, 1 H, bs) IR (KB r ) v cm-1: 1708. 1692, 1618, 1602 (3) 1.90 g (7.19 aaol &gt;) was dissolved in DMF50! &gt; 1. In addition, HaNCN 332ng (7.9〇BB〇l) was dissolved in DMF30nl. Add NaH 316g (7.90 «ol &gt;), stir for 10 minutes at room temperature. Under ice cold, read this (please read the precautions on the back before filling this page) -pack-, ys This paper size applies to China Standard (CNS &gt; A4 size (210X297 mm) 57 Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7, B7 V. Description of the invention (54) The solution was stirred at room temperature for 20 minutes. To the obtained reaction solution was added 0.9111 acetic acid (15.8 «11〇1>, and distilled under reduced pressure; water was poured into the residue, 2N-HC1 3.60β1 was added, and the precipitate was collected by filtration. Insoluble matter, 1.74 g of yellow crystals were obtained, yield 100¾. Melting point was greater than 300eC. 5 5: NMR (de-DMSO) (5: 6.30 (lH.d. J = 15. 6 Hz). 7.18 (lH, bs) , 7.46 (lH, d, J = 15.6Hz), 7.69 (2H, d, J = 6.4Hz), 7.89 (lH, bs), 8.51 (2H, d, J = 6.4Hz) IR (Nujol) ycm- 1: 2 1 6 4, 1 6 2 6〇

56 H CONHCN

(4) 3.19 g (12.1 μοΙ) was poured into DMF50W, and Bocao &lt; 3.33 il, 14.5 ·· 1) and 4-dimethylaminopyridine 147 g (1.20 〇1 &gt;) were added at room temperature. It was stirred for 30 minutes. The resulting solution was distilled under reduced pressure, and the residue was washed with ethyl acetate to obtain 5_ £ 3.98 g of light yellow crystals, yield 90 ×; melting point 172 ~ 175.05_6 .: NMR (d6-DMSO) 5: 1. 65 (9H, s). 7. 1 7 (lH, bs), 7.54 (lH, d, J = 15.2Hz), 7.72 (2H, d, J = 6.2Hz), 7. This paper scale applies to National Standard (CNS) A4 Specification (210X 297 mm) 58 Please read the notes on the back 1¾ Write this page-pack-, 11 A7 B7 V. Invention Description (55) 91 (lH, bs), 7.97 ( lH, bs), 8.28 (lH, bs), 8.57 (lH, d, J = 15.2Hz), 8.61 (2H, d, J = 6.2Hz), 8.68 (lH, bs) IR (KBr) vcnr1: 1748 (1), 1696, 1602. (5) Dissolve 3.98 g (10.9 minol) in DMF80b1 and cool to -20eC. In addition, dissolve HaNCN551mg (13.1i> aol>) in DMF30b1 and add NaH439ng (10.9BB. l &gt; Stir for 10 minutes at room temperature. This solution was ice-cooled and added to the _51 solution and stirred at -20 ° C for 1 hour. 2N-HC1 10.9 · 1 was added to the resulting solution, and the mixture was distilled under reduced pressure; water was added to the residue, and sodium sulfonate 917ag (10.9M0l) was added. The insoluble matter was filtered and washed with ethyl acetate. Yellow crystal 3.3U, yield 933: melting point 230 ~ 235 ° 0 5 7: NMR (de-DMSO) &lt; 5: 1. 6 2 (9 H, s). 6. 4.6 (1 H, d, J = 16.2Hz), 7.59 (lH, bs), 7.85 (2H, bs), 8.21C1H, d, J = 16.2Hz), 8.2 4 (lH, bs), 8.60 (2H, bs). IR (Nujol) vcm -1 ： 2 1 4 8, 1 7 4 6, 1 6 3 1 〇—HI— n 14— 11 In 1 c (Please read the notes on the back before filling this page) Central Standards Bureau, Ministry of Economic Affairs, Shellfish Consumer Cooperative The paper size for printing is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of invention (56) 靱 谄 锎 1ft

o &lt; CN +

NH 60 59

COOMe NH 61

COONa NH

^ CONHCN NH 62 63 ~~ (1) Dissolve 20.90g (76.8M〇l) in acetic acid 360 · 1, and add NaBH «2.91g (76.8M〇l) at -25eC. Stir at the same temperature. After 1 hour, the pH of M IN-HC1 was adjusted to 7. The reverse dipping solution was poured into 500 · 1 of water, and extracted with ethyl acetate twice, and then the ethyl acetate layer was washed with M water and saturated brine, and then M After the magnesium sulfate was dried, the ether was reduced to steam. The residue Mb_ was washed to obtain 18.3 g of 5 ft white crystals with a yield of 87¾. Melting point 125 ~ 128 lit HJ— Γ (Please read the note on the back before filling (This page)-Ordered by the Central Bureau of Quasi-Ministry of Economic Affairs, Shellfish Consumer Cooperative, 5 8: NMR Cd6-DMSO) 5: 1. 5 9 (9 H, s), 4. 6 5 (2H, d, J = 5.6 Hz), 5.15 (lH, t, J = 5.6Hz), 6.75 (lH, d, J = 2.0Hz). 7.63 (2H, d, J = 6. 0Hz), 7.9 1 (lH, d, J = 2 0Hz), 8. 5 0 (2H, d, J = 6.0 Hz). IR (CHC13) p cm · 1: 3532, 1731, 1605 (2) 18.30 «(66.7111 通 〇1 &gt; 之 丘 _2 ^ is suspended in 〇« 卩 9〇1 | 1, applicable to this paper scale China National Standard (CNS) A4 specification (210X297 mm) 60 Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperatives A7 B7 V. Description of the invention (57) Add S0C1, 7.26 · 1 (100 · ιβο1) under cold conditions, and then Stir at room temperature for 1 hour and 30 minutes. Dilute the obtained solution with diethyl ether and filter the insolubles, dissolve the insolubles in DMF180b1, and add 36.9 g (26 7 mmol) of potassium sulfonate and water (30 ml) under ice cooling. 8.7 g of potassium cyanide (133 Bmol &gt; water (15 · Π solution, tetrabutylammonium bromide 2.158 (6.7 «1 * 〇1 &gt;), and carry it for 24 hours under the same lease. Inject the reaction solution into water (600 In 1), the MSI ethyl acetate was extracted twice, and then the ethyl gluconate layer was washed with water and saturated brine, and then dried over magnesium sulfate, and then distilled under reduced pressure. The obtained residue was subjected to silica gel tube chromatography (toluene 82 / lt; 24.07 / ethyl glyconate = 2/1 ~ 1/3 &gt; treated to obtain white crystals 5_8_6.83g, yield 36¾; and white crystals 3 · 36, yield 27%. Combined the aforementioned product 6. 82 &lt; 24.07 &gt; and £ _ 〇_2.59 笤 (14.131111〇1), dissolved in 2.961 &lt; -11 {: 1 / formic acid 170il, refluxed for 24 hours. The resulting solution was depressurized, and water (200 · 1) and sodium bisulfate were added. The pH was adjusted to about 8 and extracted twice with ethyl acetate. The ethyl acetate layer was washed with K water and saturated brine, dried over magnesium acetate, and evaporated under reduced pressure. The resulting residue was washed with ethyl ester. The obtained white powder was 6.33 g, and the yield was 77 Z. 5 9 mp 1 2 6 to 1 2 9 t0 NMR (d6-DMSO) 5: 1. 6 2 (9H, s), 4. 2 1 (2H, s), 6 87 (lH, d, J = 2.0Hz), 7.65 (2H, d, J = 6.2Hz), 8.03 (lH, d, J = 2. 0 Hz), 8. 5 2 (2H, d, J = 6. 2Hz). IR (KB r) ycm · 1: 2 2 5 5, 2 2 0 3, 1 7 3 9, 1 6 0 3〇6 0 mp 1 6 8 ~ 1 7 2 ° C〇NMR (drDMSO ) d: 3. 9 8 (2H, s), 6. 5 2 (lH.bs), 7.47 (lH, s), 7.48 (2H, d, J = 6.2Hz), 8.41 (2H, d, J = 6. 2Hz) 〇 This paper size uses Chinese National Standard (CNS) A4 specification (210 X 297 mm) 61 1 ·· I —y 1 I n.! Γ (Please read the notes on the back before filling (This page), ΤΓ A7 __B7_ V. Description of the invention (58) IR (KB r) pcnr1: 2 2 5 8, 1 6 0 4〇6 1 mp 1 4 7 ~ 1 5 0Co NMR (d6-DMSO) ο: 3. 64 (3H, s). 3. 66 (2H, s) N 6. 41 (lH, bs) , 7.40 (lH, bs), 7.46 (2H, d, J = 6.0 Hz), 8.3 9 (2H, d, J = 6.0 Hz), 11.13 (lH, bs). I R (KB r) vcm.1: 3446, 1731, 1602. (3) Put 6.33 (29.271 «1« 〇1) stone _ 浊 turbid in methanol 60 agricultural 1, add 2N-N & 0Η17 · 6 · 1, stir under the chamber for 30 minutes, and filter out the insoluble matter 5.59 g of white powder was obtained, yield 85: ί. Melting point is greater than 300 ° C. 6 2: NMR (D2〇) 5: 3.54 (2H, s), 6. 4 6 (1 H, bs), 7.38 (lH, bs), 7.55 (2H, d, J = 4.6 Hz), 8.36 (2H , d, J = 4.6 Hz). I R (KB r) vcnr1: 1638,1609.1 5 71. Printed by the Central Working Group of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (please read the precautions on the back before filling this page) (4) Put 1.0g (4.46 «ol) of the hill_2JS in the water &lt; 20al &gt; IN-ΗΠ (4.46 · 1 &gt; neutralize it, evaporate it under reduced pressure. Suspend the obtained residue in DMF 20al, and add oxydioxazole 868ag (5.35BB〇U) under ice cooling, then stir at room temperature. 1 hour. In addition, HaNCN 206 ag (4.91 «〇1>) was dissolved in DMF15al, NaH196ng (4.91 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After the aforementioned solution was added under ice-cooling, the mixture was stirred at room temperature. 1 hour, add 1N-HC1 4.9U1 to the obtained reaction solution, adjust the pH to about 7 in M acetic acid, and reduce the pressure in the steam box. Add water to the residue and filter out the insoluble matter that precipitates. 663 g Yield: 663: Melting point: 228 ~ 230eC. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) Cutting example 17

16

N

A7 B7 V. Description of the invention (59) H: NMR (de-DMSO) 5: 3. 4 9 (2H, s), 7. 4 6 (1H, bs), 7.60 (lH, bs), 7.71 (2H, d, J = 6.0 Hz), 8.47 (2 H, d, J = 6.0 Hz), IR (Nujol) i; cnr1: 2138,1631. (Please read the notes on the back before filling out this page)-装-

IN

CONHCN 67 J3. / I * v

Du printed by the Ministry of Economic Affairs of the Central Bureau of Standardization of the People's Republic of China (1) Add 60Z sodium hydride (0.86g, l.leq) to 丄 fi_ (3.32g, 19.5mo1) / DMF (33h1 &gt;), under the chamber Stir for 20 minutes. Cool to -30 ° C, add Π-(: Η30 (: 0ΒιΜ3.0β1, 1.06q>), and stir at -10 ~ 0. (: For 1 hour. Pour into ice water, extract with ethyl acetate, It was then washed with water and saturated saline, and the residue was purified by silica gel chromatography to obtain (oily; 5.96g, 21.9 ·· ο1>, yield 112¾.

H: NMR (CDCla) 5: 1. 19 6 (9H, s). 5.10 (lH, dd, J) This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 63 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives A7 ______B7_ V. Invention (60) = 1.8, 10.8 Hz), 5. 4 5 (lH, dd, J = 1.8.6 Hz), 5. 7 8 (2H, s), 6.64 (lH, dd, J = 10.8, 17.6 Hz), 5.78 (2H, s), 6.64 (lH, dd, J = 10.8, 17.6 Hz), 7.〇〇 (2H, bs), 7. 31 (2H, dd, J = 1.6, 4. 6 Hz), 8.55 (2H, dd, J = i. 6, 4. 6 Hz). I R (CHC13) vcnr1: 1 7 3 3, 1 6 0 2. (2) At -20eC, add POC13 to DMF (20 * 1 &gt;, stir at 0-c for 20 minutes, and add 丄 ZJ5.90g &gt; / DMF30il, heat at 55eC for 1.5 hours, and then It was poured into ice water, neutralized with potassium osmate, and extracted with ethyl gluconate. The shrinkage residue was crystallized from toluene to obtain a fi 4 of 4.57a, and the yield was calculated as 782 from JL_S_. Melting point 148 ~ 152.0 ^ _4: NMR (de-DMSO) &lt; 5: 1. 1 5 (9 H, s) N 5.94 (2H, s) &gt; 6.45 (lH, dd, J = 7.8, 15.6 Hz), 7.40 (2H, dd , J = 1.6, 4.6 Hz), 7.43 (lH, d, J = 2.2 Hz), 7.65 (lH, d, J = 15. 6), 7.81 (lH, d, J = 2.2 Hz), 8.58 (2H, dd, J = 1.6, 4.6 Hz), 9. 54 (lH, d, J = 7.8 Hz). IR (Nujol) ^ 0 111 ^: 3020, 1717, 1649,1598, 151 9,141 3, 1283, 1208,1131,960 (3) NaC10a (l_49g) / NHaS0aH (1.60g) / Ha0 (35 * l &gt; solution was added with 6 4 (2.24g) / formase (22.1 &gt;), at 5 ~ 10eC Stir for 40 minutes. Add Na, S03 ($ &14; 14g) / Ha0 (25al &gt;), and stir at 100 ° C for 20 minutes, then depressurize and remove formate, then extract with ethyl acetate, wash with water, After concentration, the residue was crystallized from dihelium methane / toluene to obtain <1.17 g. Read the notes on the reverse side and fill in this page again)-Binding. Order d This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 64 Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (61) Rate 49.6J :); melting point 205 ~ 207eC. 65: NMR (de-DMSO) 5: 1. 15 (9H, s), 5. 9 l (2H, s), 6. 14 (lH, d, J = 15. 6Hz). 7. 2 7- 7. 4 0 (3H, m), 7.51 (1 H, d, J = 15.6Hz), 7.67 (lH, d, J = 2Hz), 8.57 ( 2H, s, J = 5.8 Hz). IR (Nujol) y cmM: 3100.2446, 1746, 1686, 160 4,1399, 1279, 1267, 1109.972 (4) at room temperature in fi_S_ (l.〇 〇g &gt; / DMP was added with carbonyldioxazole (〇.67g &gt;, and stirred at room temperature for 1 hour; HaNCN (212ng &gt; / 60XNah (177ig &gt; / DMF (15nl &gt;) solution was added in Stir for 2 hours, then stir at 40 ° C for 1 hour. After adding sugar acid (.29 «1>), it was shrunk to about 5al under reduced pressure. Dissolved in water (50ffll), added ethyl acetate (10.1), hexane (10ml), and then added heteroacid, The aqueous layer was neutralized to precipitate crystals; the crystals were collected, washed with water and ethyl acetate to obtain crude crystals (0.91 g, 84.72). Melting point 192-193-C. 6 6: NMR (d6-DMS0) 5: 1. 1 4 (9H, s), 5. 9 4 (2H, s), 6. 2 3 (1 H, d, J = 1 5. 6 Hz) n 7. 3 2 — 7. 4 δ (3 H, m) N 7.6 1 (1 H, d, J = 15.6Hz), 7-68 (lH, d, J = 1.8Hz), 8.61 (lH, bs) 〇IR (Nujol) y cm'1 : 3108, 2224, 1742, 1687, 137 3, 1174, 1120, 978 (5) Put 83.8 (2.35 · · 〇1) turbidity in methanol 20.1, add 2N to it at room temperature After NaOHaq 6. · 1 (12 ·· ο1), stir under room overflow for 3 hours; after tomorrow, add 2N HCL 6b1 under ice cooling, decompress and remove the paper. This paper applies the Chinese National Standard (CNS) A4 specification (210X297). Li) (Please read the notes on the back before filling in this page)

65 V. Description of the invention (62) A7 B7 formazan, filter out the precipitated solids, and then wash them with water and ethyl alcohol in order. The solid collected by filtration was dried to obtain 530ag (952>) as a yellow powder. 6 7: NMR (de-DMS0) 5: 1 1. 79 (lH, m), 8.58 (2H, m), 7.69 (lH, d, J = 15.6 Hz), 7.54 (lH, s), 7.40 (2H, d, J = 5.7 Hz), 7.27 (lH, s), 6.21 (2H, d, J = 15.6 Hz). IR (Nujol) i; cm-1: 3 3 5 0, 3 1 9 2, 2 1 7 0, 1 6 2 6, 1 5 2 8, 1 3 4 9, 1 0 6 6〇

j6

1) NaH 2) Bu’CC ^ CHgCL

~ POM (Please read the precautions on the back before filling out this page) —vf. 'Γ Pack-6;

POCI3 DMF N

CHO Na〇lo2 H2NSO3H POM 75

76 · Order

1) CO (Im) 2 2) H2NCN / NaH

78 -►

Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

.CONHCN 71 CHa〇Na) N //

68

(1) Put 50 »g (346.8M〇l) of fijD into anhydrous DMF 500 · 丨 to make it thin. Under ice cold, add M while flowing nitrogen gas, and add 6 (UNaH This paper standard is applicable to China) Standard (CNS) A4 specification (210 × 297 mm) 66-66 Printed on the consumer work cooperative of the Central Bureau of the Ministry of Economic Affairs A7 __________B7 V. Invention ^ Ming (63) 15.2g (381.5i «mol &gt;, under room irrigation Stir for 20 minutes. Then, cool to -30 ° C, and slowly drop Butc0, CHaCl 53 · 1 (36 7 · 6 ·· 〇1>) at the time of M30 minutes, at -100 Stir for 2 hours. Then, pour the reaction mixture into 2 • 4 L of ice water and extract with 2 L of ethyl acetate. The organic layer is washed with water and water in order, dried over magnesium sulfate, concentrated under reduced pressure, and filtered. Precipitated crystals. The crystals were washed and dried with cyclohexane to obtain white crystals. 83.24 g (931. Pei 96 ~ 99. {:. 6. ': NMR (CDC13) &lt; 5: 8. 5 l (2H, dd, J = 4. 6, 1. 6 Hz), 7. 37 (2H, dd, J = 4.6, 1.6 Hz), 7.28 (lH, m), 6.89 (lH, dd, J = 2.8 , 2.2Hz), 6.55 (lH, dd, J = 2.8, 1.8Hz), 5.82 (2 H, s), 1. 1 (9H, s) IR (Nujol) vein-1: 172 3, 159 7,1132 (2) Anhydrous DMF372nl (4.8mol) is cooled to -20eC under helium flow, and 120ml (1.282B0U) of POC13 is added dropwise over a period of 40 minutes, and then 6 '82.8g (320.5nol) of raw material is added, Warm at 60 ° C for 3 hours. Then, cool to room temperature, pour into 2L of ice water, add 266g of potassium osmate (1.923 »〇U, make it pH 8 while stirring, and filter out the precipitate. The solid material was dissolved in 2.2L of methyl ethyl hydrazone, M was dried with magnesium acid, concentrated under reduced pressure, and then recrystallized from toluene to obtain a crystal with a color of 65.69 g (725>. Melting point 183 ~ 186eC. 7_5 .: NMR (CD Cl3) (5: 9.69 (lH, d, J = 1.0 Hz) N 8.5 9 (2 H, dd, J = 4.5, 1.7 Hz), 7.60 (lH, m), 7.40 (2H , dd, J = 4. 6Ηζ, 1.6Ηζ), 7.3 2 (lH, d, J = 2.0Hz), 6.28 (2H, s), 1. 1 7 (9H.s) This paper standard applies to Chinese national standards隼 (CNS) A4 size (210X297 mm) -67----------- ΐ Equipment-^ Γ (Please read the precautions on the back before filling this page)

, tT A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (64) IR (Nujol) vcm · 1: 1 7 1 8, 1 6 5 5. 1 6 0 0, 1 4 2 6, 1 1 4 1 (3) Dissolve Hua (: 10,18.168 (200.8 | 〇111〇1) and 1 ^ 5031119.50 volume (200 • 8 acid · ο1) in 1636ml of water, and dropwise add 23g (80.3 34 · Ο1) 400 ml of methanol solution, and stir for 3 hours under ice-cooling; Then, add NaaS0a50.62g (401.6naol) aqueous solution 250 drops 1 under ice-cooling, and stir for 30 minutes. Then, remove the methanol by depressurizing, The precipitated solid was collected by filtration, and dried to obtain a margin powder 7 6 / 21. 14 g (87¾). Melting point 241.5 5 to 243-C ° 76: NMR (d6-DMSO) 5: 12.7 9 (lH, bs) s 8. 5 0 (2 Η, dd, J = 4.6, 1.5 Hz), 7.99 (lH, d, J = 2 Hz), 7.61 (2H, dd, J = 4.6, 1.6 Hz), 7.47 (lH, d, J = 2.0Hz), 6.21 (2H, s), 1. 1 l (9H, s) IR (Nujol) y cur1: 1734, 1686, 1610, 1195, 1129 (4) NH8CN 12.965g (308M. l) Dissolved in DMF130 «1, add NaHl l_719g (292.98M0l) under ice cooling, and then add it back to the chamber # * until the hydrogen generation stops. 46.628 (154.2 Pass 11〇1 &gt; 2 ^ 6_1_ Dissolved in 〇 {&lt; 卩 470 卩 1, add 32.51g (200 «ol) of carbonyldioxazole in the chamber, stir it for 1 hour, cool it with ice, dropwise add the previously produced Na * [NH-CN] / DMF solution, stir it for 1 hour at room temperature, add 5N-HC1 under ice cooling, adjust the pH to about 7, and concentrate the DMF under reduced pressure. Add ice water to the obtained residue 900 »1, destroy the precipitated solids, wash them with water and K in sequence, dry the filtered solids, and transfer the colored powder 7 8 50g (99U. 瑢 point 253 ~ 256β -----:- -«---- install-(Please read the precautions on the back before filling this page), ιτ

This paper size applies the Chinese National Standard (CNS) A4 specification (2! 0 × 297 mm) 68-68 V. Description of the invention (65) A7 B7 Seal 7_8: NMR (d6-DMSO) ) (5: 8. 6 4 (2H, d, J = 6.6Hz). 8.09 (lH, d, J = 1.8Hz), 7.96 (2H, d, J = 6.6Hz), 7.43 (1 H , d, J = 1.8Hz), 6.32 (2H, s), l.ll (9H, s) IR (Nujol) y cm · 1: 218 4,214 2,171 1,163 4,156 5, 122 6,1155 (5 &gt; set 50.2 g (154naol &gt;): Z_8JW was put into 1L of methanol, and 2N-NaOH 385β1 (770 ·· 〇1) was dropped at room temperature, and after stirring for 1 hour in the chamber group, 2N HC1 385ml was added under ice cooling, and the pH was adjusted. To 7, the methanol was decanted, and then the precipitated solid was filtered, washed with water, isopropanol, and ether in order, and then dried to obtain 7 1 32 g (100: 0) as a white powder. The melting point was 268 to 270. 〇7J ,: NMR (d6-DMSO) (5: 1 2.2 (1 Η, i). 8. 5 8 (2 H, d, J = 6.2 Hz), 7.96 (2H, d, J = 6.8) Hz), 7.88 (lH, m), 7.29 (lH, s) IR (Nujol) vcm-1: 3320,3186,3066,2624,2144, 163 3, 157 0,152 7, 140 7, 133 6, 121 5 , 1 2 1 00 (6) will be 32g (150uol &gt; of: LJ JB was thirsty in anhydrous formazan 60 · 1. Under ice-cooling, 1.14M CH, 0Na / methanol solution 135.1 (1 50 ·· 〇1 &gt;) was added dropwise in an airless roll, and then stirred for 10 minutes under ice-cooling. Then, add isopropion 350 · 1, remove the formazan under reduced pressure, and filter out the praying solids; wash the filtered solids with isopropanol and ether in order, and dry to obtain £ L_a_ 35.6g of light yellow powder (992 &gt;. 6 8: NMR (de-DMSO) 5: 1 1. 4 4 (1 Hm). 8. 3 9 (2H, d, J = 5.8Hz), 7.53 (2H, d, J = 6.0 Hz), 7.39 (lH, m), 6. Please read the note above SC SC bound booklet paper size applicable to national standards (CNS) A4 specifications (210X 297 mm) 69 A7 B7

76 '

tC02H 76 V. Description of the invention (66) 9 ΚΙΗ, η) IR (Nujol) i.cni-1: 332 4,271 4,215 4, 160 9, 157 6, 1 5 0 7,1 2 1.9,1 1 4 6,1 1 3 1, co2h

* POM (Please read the notes on the back before filling this page).

N

, ^ 1 CO (Im) 2

(Boc) aO -► 77 Shellfish Consumer Cooperative Du Yinzhuang (1) of the Central Standards Bureau of the Ministry of Economic Affairs (1) Put 5.5g (18.19naol) into the formazan 11 channel 1 and dropwise add 2N Na0Haq45nl ( 90i &gt; mol), after stirring at room temperature for 90 minutes, 2N HC1 45ml (90mmol &gt;) was added under ice-cooling, and the formate was removed under reduced pressure. The precipitated solid was filtered, washed with water and ethyl acetate sequentially, and dried. To obtain a light recording powder 7 6 3.26 g (95: U. Melting point on 300 eCK. 7 6: NMR (d6-DMSO) &lt; 5: 12. 1 5 (lH, bs) N 8. 4 5 (2 H , m), 7.72 (lH, m), 7.62 (2H, d, J = 5.70Hz), 7.29 (1Η, π〇, I RCNujoDvcm'1: 162 9,156 1,152 9,1210 (2 &gt; will hire 3.258 (17.28 鼸〇1) of: 1_ £ _ added to anhydrous 01 ^ 40, wish 1. At room temperature, add 5.60g (34.56an «) of stilbodiimidazole in a nitrogen roll at room temperature. This paper is applicable to national standards (CNS). A4 specifications (210X297 mm) 70 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 ___B7_ V. Description of the invention (67) 1 &gt;, «Mix for 2.5 hours; then, decompress and remove DMP in the residue Add ΙΟΟηΓ ice water to precipitate solids. Filter the solids, It was washed with water, isopropion, and ether, and dried to obtain a light yellow powder: ZJZ_3.7g (90 X). Melting point on 300eCM. 7 7: NMR (de-DMSO) 5: 1 2. 8 lHz (lH, bs), 8. 4 9 to 8. 54 (3H, m), 8.08 (lH, s), 7.89 (lH, s), 7.75 to 7.78 (3 H, m) v 7. 1 8 (lH, s) IR (Nujol) vcm-1: 166 2,159 9,1219 (3) 3.65g (15_32aB〇l) of 2_2_ was added to anhydrous DMF70 »1, and <Boc) aO was added dropwise in a Hi gas stream at room temperature. 7β1 (30.64 · «ο1 &gt;, further added a small amount of 4-dimethylaminopyridine, and stirred at room temperature for 70 minutes; then, the reaction solution was concentrated under reduced pressure and added to the obtained residue. Diethyl ether of 200 · 1, the precipitate precipitated was filtered, washed with dimethyl ether, and dried to obtain a light yellow powder 7 9 4.48 g &lt; 86X). Melting point 300 eCM. 7 9: NMR (d6 — DMSO) 5: 8. 5 7 (2H, d, J = 5. 8Hz), 8.37 (2H, m), 7.78 (3H, m), 7.67 (lH, s), 7.19 (lH, s), I. 43 (9H, s ) IR (Nujol) vcm-1: 174 9,172 6,160 3,1239 (4) Add NheCN1.557g (37.04ni &gt; ol) to anhydrous DMF30b1, add 60UaH 1.235g (30.87niiol) to the radon stream under ice cooling In the room Let stand for 15 minutes. In addition, 10.445 g (30.87mnol) of ZJ2JHI was placed in anhydrous DMF140 1 and cooled to -45 ° C. Under a nitrogen flow, W [NH-CN]- / DMF, then mix at 9-30C (please read the precautions on the back before filling this page)

-、 1T This paper is again applicable to the Chinese National Standard (CNS) A4 specification (2Ι0 × 297 mm) 71-71 V. Description of the invention (68) A7 B7 0 minutes, then add IN HC1 62 · 1 &lt; 62 · under ice cold · Ο1), concentrated under reduced pressure. To the obtained residue was added ice water 400 · 1 * and then 2.59 g of sodium hydrogen sulfonate (30.87 MOL), and the pH was adjusted to about 7. Subsequently, the precipitated solid matter was filtered off, followed by M water and isopropanol. After washing with ether, it was dried and dried to obtain a light yellow powder 6 9 8.97 g (93: U. Melting point 257 to 260 eC. 6 9: NMR (d6-DMSO) &lt; 5: 8. 6 7 (2 H, d, J = 6. 0 Hz). 8. 28 (lH, d, J = 1. 6Hz). 8. 0 2 (2 H, d, J = 6. 2 Hz). 7.33 (1 H, d, J = 1 6Hz), 1.5 5 (9H, s) IR (Nujol) ycm * 1: 215 0.174 1,167 5,1523

2ft N

NaCIO, nh2so3h-* »

1) CO (Im) 2 2) H2NCN / NaH

CONHCN

NaOHaq

Printed by POM, Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs,

82

(1) Under ice-cooling, 8 0 15.0 g (50 «nio 1 &gt; of formazan 150b1) was added dropwise to a 250b1 solution of NaCl〇a 9.95g (U〇mol) and NHaS〇3H 10.68g (110mnol). After stirring the solution under ice-cooling for 40 minutes, add NaaS0 dropwise (please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention (of) A7 B7 327.7g (22〇BB〇l &gt; water 150ml) printed by the Shellfish Consumer Cooperative of the Central Bureau of Standardization of the Ministry of Economic Affairs The solution was further stirred in ice-cold for 20 minutes, and the precipitated solid matter was washed with water, dissolved in methanol 400b1 / 300 ml of ethyl acetate, and then added with 200al of toluene, and concentrated under reduced pressure, and the precipitated solid matter was filtered to obtain a white powder_ &amp; 1 10.57s (66.8Z). Melt 211 ~ 214eC. 8 1: NMR (de-DMSO) 5: 12. 8 3 (lH, bs) N 8. 5 6 (2 H, dd, J = 4.5 Hz, 1.5Hz), 7.62 (lH, s), 7,42 (2H, m), 6.18 (2H, s), 2.42 (3H, s), l.ll (9H, s) I RCNujoDvcin-1: 3 1 3 6, 2 3 7 2, 1 7 2 5, 1 6 7 7, 1 6 0 6, 1420, 1260, 124 2, 1130, 111 2, 102 0, 963 (2) In NH, CN 723 8 (17 · 2 · βο〇 in anhydrous DMF40nl solution was added 60:!; Heart 1167〇1 ^ (16.63 »1« 〇1 &gt;, stirred for about 1 hour under the chamber group until the generation of hydrogen stopped humiliating. Also, Under a stream of «, 2.23 g (13.76m« 〇l) of carbonyldioxazole was added to a solution of raw material U_3.63g (11.47mB0l) in anhydrous DMF50b1, at room temperature After stirring for 1 hour, it was ice-cold, and the previously generated Na * [NH-CN] • / DMP solution was added dropwise, and stirred under the chamber for 5 hours, and then, 2N HC1 was added under ice-cold, and the pH was adjusted to about 7, reducing Κ »DMF, add 300nl of ice water to the residue, filter out the solids, wash the bran in sequence with M water and ether, and dry to obtain 8 2 3.9g (995). Melting point 209 ~ 211 8 2 : NMRCde-DMSO) (5: 8. 6 9 (2 H, d, J = 6. 2 Hz). 7. 88 (2H, d, jF6.8 Hz), 7.78 (lH, s), 6.26 (2H, s), 2.50 (3H, s), 1.1 l (9H, s) IR (Nujol) vein · 1: 271 2, 214 4, 171 0,157 9, 152 6, This paper standard is applicable to the national standard of country t ( CNS) A4 size (210X297mm) 73 (Please read the precautions on the back before filling this page)-Pack.

* tT »· ϋ · ---- 11 V. Description of the invention (7〇A7 B7 Printed by the Bayer Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs 1459, 1336, 1281, 1255, 1151 (3) 3.98 &lt; 11.46 fiber Let 〇1 &gt; 五 _2 ^ be cloudy in formazan 2〇1 »1, drip 2N NaOHaq3〇Bl (15i» B〇l) at room temperature to completely dissolve, and stir at room temperature for 1 hour. Add 130ml of 2N HC1 under ice cooling, adjust the pH to about 7, depressurize and remove the methanol, filter out the solids, wash them in order with K water and ether, and dry them to obtain yellow powder 2_2__2.19g (84S: 〉. Melting point 226 ~ 230eC 〇7 2: NMR (d6-DMSO) 5: 1 1. 7 6 (1 H. m). 8. 6 2 (2 H, d, J = 5.7 Hz), 7.93 (2H, d, J = 6.0 Hz), 7.60 (lH, d, J = 2.4 Hz), 2. 5 9 (3H, s) I RCNujoDycm-1: 3 1 6 2, 2 6 0 6, 2 1 4 4, 1 6 3 1,1 5 5 8, 151 5, 145 4, 133 3, 121 3, 115 3 (4) Add 72.638 &lt; 55.81 »1» 〇1) and suspend in anhydrous methanase 335 * In 1, under ice-cooling, a 1M CH30Na / methanol solution 51.3b1 (53.0mo1 &gt;) was added dropwise in a thoron roll, and the mixture was stirred at room temperature for 10 minutes. Subsequently, isopropylamidine 335βΠ was added, and then isopropanol 100 was added. 1 with ether 100 Mixture of 1 * Stir for a while in the room, and filter out the solids * Methyl ether was washed and dried to obtain a light yellow powder: Z_Q_ 13.61g &lt; 99X &gt;. 7 0: NMR (d6-DMS0) 5: 1 1. 〇8 (lH, bs), 8. 4 4 (2H, dd, J = 4.5 Hz, 1.5 Hz), 7. 3 9 (2H, dd, J = 4. 3 5 Hz, 1. 6 5H z), 7.03 (lH, d, J = 3.3Hz), 2.48 (3H, s) IR (KBr) u cnr1: 3434, 3375,215 3, 1606,1563, 1473,1426,1413,1339 , 1229,1145,835,8 11 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) -74-74 Please read the note Iioi page first. 5. Description of the invention (? 1 CH,

(Boc) 20 A7 B7 CH,

8.0s (35.4aaol &gt; 2_2Jw was added to DMF190H1, and (Boc) a〇34.8g (159_3Bi »ol) was added dropwise at room temperature, and 4-dimethylaminopyridine 0_86g &lt; 7.08a * ol) was added dropwise. And stirred at room temperature for 45 minutes. Subsequently, a mixed solution of ethyl acetate 400b1 and 100bI of water was poured into the reaction solution under ice cooling, and the aqueous layer was separated and concentrated under reduced pressure. The resulting residue was diluted with dilute hydrochloric acid, and the precipitated insoluble matter was filtered. (S_2_ 4.08g &lt; 352). 8 3: NMR (de-DMS0) 5: 8. 6 5 (2H, m), 7. 8 6 (lH, s), 7.70 (2H, d, J = 5.2 Hz), 2.23 (3H, s), 1.54 (9H, s) IR (KBr) vcm-1: 3104, 2174, 1754, 1639 (Please read the precautions on the back before filling out this page) • —1 n —J ·. Packing. Order Central Standards Bureau of the Ministry of Economic Affairs The paper size printed by Beigong Consumer Cooperative is applicable to the Chinese National Standard (CMS) A4 specification (2 丨 0X297 mm) -75-75 A7 B7 V. Description of the invention (72) Tong Li 22

&quot; CI 84

85

NaOHaj 1) CO (Im) 2 ^ «-ΝΗ Cl 2) H2NCN / NaH

86 N

(Please read the notes on the back before filling this page) Γ -4— n. 装-

, * T Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs (1) Dissolve 2_86g (10M〇l) of i_5_ in anhydrous toluene 50kg1, add _8_4_4.97 «(13« ^ 〇1 &gt;, 120. (: oil bath heating and rolling back for 3.5 hours, M after cooling to the chamber #, because there is crystal precipitation, it was filtered, washed with hexane to obtain B_5_ 3.9g. Second, ^ _5JW Put in formazan 80 · 1 and suspend it, add 2N NaOH 24 · 1 &lt; 48 ·· ο1 &gt; at room temperature, and stir for 90 minutes. Then, reduce «demethylase, and the residue in toluene 100 · 1 × 2 After the second wash, the water layer was separated, and 1NΗΠ48 · 1 was added under ice cooling, the pH was adjusted to 7, and the precipitated solid matter was filtered, washed with water and ether in order, and dried to obtain a yellow powder 1 • 20g (closed) 50¾). Melt 300. [above.

8 6: NMR (d6-DMSO) 5: 1 1. 9 3 (lH, bs). 8. 4 8 (2H, d, J = 5.4Hz), 7.88 (lH, m), 7.85 (lH, s) , 7.63 (2H, d, J This paper size applies to the Chinese National Standard (CMS) A4 specification (2 丨 0X297 mm) 76 A7 B7 V. Description of the invention (73) = 5. 8Hz), 7. 5 3 (1H, s) IR (Nujol) vcm-1 ^ 7 14, 1619, 1530, 1374, 1203, 9 2 7 (2) Dissolve 302 μ (7.17 ·· 〇Π of NHaCN in DMP6 «1, under ice-cooling, under nitrogen After adding 60ZNaH268ag (6.69MOL) to the roll, stir at room temperature for 2.5 hours to prepare a solution of ^ [α41 &lt;] _ / 0 »^. Next, 1.198 (4_78« 〇1 &gt; reach _ £ " ) 11 into anhydrous 1) &gt; ^ 158 | 1 and suspend it, add carbonyldioxazole 1.〇8 &lt; 6_21ββο1) at room temperature, stir for 3 hours, and then, under ice-cooling, in the reaction solution The previously generated Na * [NH-CN]-/ DMF solution was dropped and stirred at room temperature for 90 minutes. Subsequently, sugar acid was added under ice cooling, the pH was adjusted to 7, and concentrated under reduced pressure. 200 ml of ice water was added to the obtained residue, and the precipitated solid matter was collected by filtration, and washed sequentially with M water, isopropyl alcohol, and ether. Dry it to get yellow edge powder 2_2_928Bg (73Z &gt; .melt & \ 300. (: To. 73: NMR (de-DMS0) &lt; 5: 12. 1 0 (lH, bs). 8. 6 4 ( 2H, d, J = 6.4Hz), 8.11 (2H, d, J = 7Hz), 8.09 (lH, s), 7.75 (lH, s), 7.52 (lH, s) Consumption cooperation Du printed (Please read the precautions on the back before filling this page) IR (Nujol) vcm-1: 271 8, 215 2, 162 7, 157 2, 152 6, 137 4, 1206 This paper size applies to China National Standard (CNS) A4 Specification (210X297 mm) 77 A7 B7 V. Description of Invention (74)

鯆 _ 俐 23 N

88

NaOHaq, co2h NH * CH3 89

H (Please read the precautions on the back before filling out this page): Packing1) CO (Im) 2

2) H2NCN / NaH nO ~ 〇 ^ conhcn Order 74 (1) 2.86 g (10 Bi »ol) of: Z_5JK Pan in a mixture of toluene 120 · 1 and THF 30 · 1, at room temperature under nitrogen 25 ·· ο1 was added to the stream, and it was heated and rolled at 10 ° C. for 8 hours. Then, it was cooled to room temperature and reduced to a concentration of K, to obtain £ L8_3.7g. Next, S_SJjd was put into formazan 80 · 1, and 2N NaOH 25 · 1 (50 ·· 〇1 &gt; was added under the chamber plaque, and stirred for 3 hours. "Then, the formate was decompressed under reduced pressure, and the residue was 100 toluene. * Wash it 1 × 3 times, and neutralize the water layer with M 2N HC1 under ice-cooling to make the pH 7 and filter out the solids. After washing it with water and ether in order, it is dried to obtain a yellow powder. ^ 11.8g (52: 0. Melting point at 300 ° CM. 8 9: NMR (d6-DMSO) 5: 8. 6 8 (2H.dt J = 6. 4Hz). Industrial and consumer cooperatives printed on this paper are applicable to the national standard of the country (0 milk) 8 4 specifications (2 丨 0 '乂 297 mm) 78 A7 B7 V. Description of the invention (75) 26 (2H, d, J = 6.8Hz ), 8.17 (lH, s), 7.51 (lH, s), 7.29 (lH, s), 2. 1 (3H, s) IR (Nujol) vcm'1: 1681,1620,1571,1375,1313 , 119 8,116 2,1013 (2 &gt; Dissolve 266μ (6_33 ·· 〇1 &gt;) of NNaCN in anhydrous DMF 1〇ΐ, add 603 under ice-cooling; NaH236g (5.9U * ol), at room temperature Stir for 50 minutes to prepare a Na * [NH-CN]-/ DMF solution. Secondly, put 96 3 g (4.22 MOL) into anhydrous DMP15 ^ 1, and place it in the chamber. Then, the carbonyl dioxazole 889 (5.49 · β〇Π was stirred for 1 hour in a helium roll, and then, under ice cooling, the previously prepared Na * [NH-CN]-/ DMP solution was added dropwise. Stir for 2.5 hours at room temperature, then add acetic acid 0.72 · 1 (12.66 ·· ο1 &gt;) under ice-cooling and concentrate under reduced pressure. Add ice water 200 · 1 to the resulting residue to precipitate out, and filter out the precipitated solids. It was washed sequentially with water, isopropylase, and ether, and then dried to obtain a yellow powder: H 1.05g (99X). 7 4: NMR (de-DMSO) 5: 1 2. 4 4 (lH, bs), 8 7 3 (2H, d, J = 6.2Hz), 8.29 (2H, d, J = 6.8Hz), 8.25 (1Η, π〇, 7.40 (2H, s), 2. 1 7 (3H, s ) (Please read the precautions on the back before filling out this page): 装 ·-泉 'Employees' Cooperative Cooperative Seal of the Central Bureau of Standards, Ministry of Economic Affairs 2 2 721 2 4 3 7: 3 7 1 W, S3) 2 015 UJ1 ( Nco R 9 I 5 4 IX 2 ο 4 2 2, ο 8 1 This paper size applies to Chinese National Standard (CNS) A4 specifications (21 OX 297 mm) A7 B7 V. Description of the invention (76)

Lili 24 IS

(Boc) 20

N

N

NaH (Et0) 2P (0) CH2C02Et

CH, IS

In ^^ 1 · a ^ i— mw nil— m HI ^ Iv- (Please read the precautions on the back before filling out this page) E body: Z body = 3: 7 (1) Put 2 · 2§ (7 · 32β · ο1 &gt; Nothing was cloudy in methanol 40 · 1, and 2N NaOHaql8 * l (36M〇l &gt;) was added under the chamber, and the mixture was stirred for 1 hour, and then 2N HC1 18β1 (36 · βο1 ), Remove the methanol under reduced pressure, extract the residue with ethyl gluconate 50 · 1 × 3 times, combine the organic hydrazone, dry it with magnesium acetate, and then remove the magnesium sulfate by filtration. The filtrate is condensed under reduced pressure, and the precipitate is collected by filtration. The crystals were washed with diethyl ether and dried to obtain 1.08 g of white crystals (79Z &gt;. 179 ~ 181eC. 1_2: NMR (CDC13) 5: 9.60 (lH, bs), 8.5 8 (2H, d. J = 5. 4 Hz), 7. 4 5 (1 H, dd, J = 3.15, 1.65 Hz), 7. 4 1 (2 H, dd, J = 6. 3, 3. 0 Hz), 7. 2 3 (1 H, dd, J = 2. 5 5, 1. 6 5 Hz), 2. 5 l (3H, s) This paper size applies to China National Standard (CNS) Α4 specification (210X 297 mm) ）, Ιτ &gt; Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 80 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy A7 B7 V. Description of the invention (77) IR (CHC l3) y cm-1: 3438,3002,1650, 1602,13 9 1,131 3,127 3,943 (2) Suspend 1.08g (5.8〇BB〇l) in anhydrous THF20d, and drop drop under nitrogen rolling &lt;; Boc) e〇3_3β1 (14 · 5 · βιο1), further, 4-dimethylaminopyridine 71 μ &lt; 〇_58 ·· ο1 &gt; was added, and the mixture was stirred under room rent for 80 minutes, and then the pressure entanglement was eliminated. , N-hexane 60 · 1 was added to the residue, and the mixture was slowly mixed at room temperature, and the precipitated crystals were filtered and dried to obtain white peach crystals 9 3 1. 39 g (84: 0. melting point 113 ~ 115. 0. 93: NMR (CDCl3) d: 8. 6 0 (2 H, d, J = 6. 0 Hz). 7. 7 1 (1 H, d, J = 1.8 Hz), 7.39 (2H, dd, J = 4.6, 1.6Hz), 7.15 (1 H, d, J = 1.8Hz), 2.52 (3H, s), 1.61 (9H, s) IR (CH: 2982,1752,167 7, 160 4, 139 2,1 2 8 1,1 2 3 7,1 1 4 8 (3) Add 1.128g (28.20aaol) of NaH to anhydrous THP30 · 1, dropwise (Et0 &gt; aP (0) CHaC0aEt 5.73) at 25 ° C. 1 (28.92m0U, after stirring at room temperature for 20 minutes, _2_2_ 1.38g (4.82anol &gt;) of anhydrous THF 13.1 solution was added dropwise under ice-cold time for 10 minutes, and stirred at room temperature 100 minutes. Subsequently, IN HC1 28 · 1 was added under ice-cooling, and extracted with ethyl acetate 50β1 × 3 times; the organic layers were combined, washed with M saline twice, dried, and the residue was concentrated and purified by M silica gel tube chromatography. To obtain white crystals h (e) &gt; 433 »g and orange oil g 9 4 (zani. Olg &gt; 1.444 g, total yield 842. Form E: mp 9 1-9 3T. NMR (CDC13) &lt; 5: 8.57 (2H, d, J = 5. 4 Hz), 7. 6 8 (lH, d) This paper uses China National Standard (CNS) A4 (210X 297 mm) 81 (Please read first Note on the back, please fill in this page again) -Installation · -Order A7 B7 V. Description of the invention (78) d'J-1.7'l.lHz), 7.38 (2H, dd, J = 4.8Hz, 1.2Hz), 6 5l (lH, dd, J = i.9, 0.9 Hz), 5 9 9 (1h.s), 4 2 2 (2h & J = 7.1Hz), 2.42 (3H, s), 1.60 (9H , s), 1.32 (3H, t, J = 7.2 Hz) I RCCHC 13) ^ 00-1: 2980.1747,1705,1604,135 5, 1 2 8 7, 1 1 5 5, 1 1 4 0 Z Waist: NMR (CDC13) &lt; 5: 8. 5 4 (2H, d, J = 6.2 Hz), 7. 7 1 (1 H, dd, J = 2.0, 0.8 Hz), 7.38 (2H, dd, J = 4.5, 1.7 Hz), 6. 3 8 (lH, dd, J = 1. 9, 0.7 Hz), 5.98 (lH, dd, J = 1.4, 0.8 Hz), 4. 01 (2H, ci, J = 6.4Hz), 2.21 (3H, s), 1.57 (9H, s), 1. 1 2 (3H, t, J = 7Hz) IR (CHC13) vcm-1: 2976,1743 , 1710,1604,13 7 0, 1 2 7 7, 1 2 2 0 (Please read the precautions on the back before filling this page) CH?

NaOHaq

C02H §5 (E)

CH 3 Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 1) CO (Im) 2

2) H2NCN / NaH

-nD ^ vVC0NHCN 96 (E) (4) Dissolve 334g (0.94nn〇U in formazan 7 * 丨, add IN Na0Haq4.7 «1 (4.7i * ol) dropwise under the chamber, at 60 ° c Stir down 2 This paper size is in accordance with Chinese National Standard (CNS) A4 (2 丨 0X297 mm) Printed on the A7 _B7_ by the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (79) hours; After adding IN HC1 4.7 · 1, remove the formazan, and then filter out the solids, wash them sequentially with water and ether, and dry them to obtain a light yellow powder S "5_ (E &gt; 180« g &lt; 8U) .Melting 243 ~ 245. (: 9 5 (E): NMR (de-DMS0 + D20 + DCl) 5: 1 2. 3 5 (1 Η, bs), 8.66 (2H, d, J = 6.9Hz ), 8.20 (2H, d, J = 7.2 Hz), 8.12 (lH, d, J = 0.9 Hz), 7.40 (lH, s), 6.26 (lH, s), 2. 4 8 (3H, s) (I RCNujol) vcm-1: 324 2,167 0,161 0,157 0,131 2, 121 6,116 0,101 0,799 (5) NH, CN 249ng (5.92MOL) was dissolved in anhydrous DMF8 !, and 602NaH 304ag (7.6Biol>) was added under ice cooling. , Stir in the room for 40 minutes to prepare a Na * [NH-CN]-/ DMF solution. Next, add 169 · «(0.74 ·· 〇1 &gt; of 9 5 (E &gt;) Suspend it in anhydrous DMF 7.1, add carbonylditriazole 156 (0.96 ·· ο1 &gt; under nitrogen flow, and stir for 1 hour in the room. After that, add the above W [NH-CN] dropwise under ice cooling. / DMF solution, stirred at room temperature for 6 hours, and then added etheric acid 0.97 ^ 1 &lt; 22.8 »〇1) dropwise under ice-cooling, and concentrated under reduced pressure * After adding ice water 80 · 1 to the residual solution and stirring, The solid was collected by filtration, washed sequentially with water, isopropion, and ether, and then dried to obtain a yellow powder 2_β_ (Ε &gt; 128M &lt; 66 ×). Melting point 217 ~ 220 ° C. 9 6 (E): NMR (d6- DMSO + DCl, D2〇) (5: 1 2. 5 7 (1 Η, bs), 8.70 (2H, d, J = 6.8Hz), 8.23 (2H, d, J = 6.8Hz), 8.20 (lH, s), 7.49 (lH, d, J = 0.4H2), 6.28 (lH, s), 2. 52 (3H, s) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 83 I --------- 1 Install ------ &quot; Order ------ ▲ ^ f \. (Please read the precautions on the back before filling this page) A7 B7 V. Description of the invention (80) IR (Nujol) vcm-1: 2 1 4 2, 1 6 2 9. 1 5 3 7, 1 3 0 0. 1 2 5 5, 1 2 0 2, 9 3 0 ch3Boc

NaOHaq CH3 S? (Z) 9§ (Z) 1) CO (Im) 2

2) H2NCN / NaH

NH CONHCN 96 (2) (Please read the precautions on the back before filling out this page). Pack. (6) Add 517g (1.45 »ol &gt; of 9 4 &lt; Z) in diluent 1U1 and dissolve it. IN Na0Haq7.25 »l (7.25MOL) was added dropwise thereto at room temperature, warmed at 60 ° C and stirred for 45 minutes, then, 7.25ml of IN HC1 was added under ice-cooling, and ethanol was decanted under reduced pressure. The precipitated solids were collected by filtration, washed with water and ethyl K sequentially, and dried to obtain a light yellow powder 3_5_ (叾) 25 (^ 8 (76:!; &Gt;. Melting point 1 5 3 ~ 156 ° C. 9_5 ( Z): NMR (de-DMSO) 5: 1 3. 2 3 (lH, s). 8.52 (2 H, d, J = 4.6 Hz), 7.91 (lH, d, J = 1.6 Hz), 7, 73 (2H, d, J = 5.8Hz), 7.27 (lH, s), 5.69 (lH, d, J = 0.8Hz), 2. 2 9 (3H, s) IR (Nujol) i / cm-1: 3368,2156,1630,1558,1507, 1 2 0 8,1 1 5 4.92 9 (7) Add 605; NaH 76 »g (1.887 * B〇l &gt;) to anhydrous DMF2W, under ice-cooling, under nitrogen NheCN 86μ (2 · 04 · βο1) was added to the roll, and stirred at room temperature for 90 minutes, and adjusted to a Na * [NH-CN] / DMF solution. This paper is based on the Chinese National Standard (CNS) A4 specification ( 210X297 mm) Booking ---- Central Ministry of Economic Affairs A7 __ B7 printed by the Bureau ’s Consumer Cooperative Fifth, the description of the invention Ui) Second, add 3_ΚZ) 233μ (1 · 02 ·· 〇1 &gt; to anhydrous DMF5d, add Xiangji dioxazole 255 at room temperature »G (1.632enol), after stirring at room temperature for 105 minutes, add the previously generated Na * [N H-CNL / DMF solution dropwise under ice cooling, and stir for 2 hours at room temperature. After sugar, cool under ice IN HC1 3.6β1 (3 · 6 ·· ο1) was added dropwise, DMF was removed under reduced pressure, ice water 100 · 1 was added to the residue and stirred, and the precipitated solid matter was filtered, followed by water, isopropylase And B. "Washing, drying, drying, brown powder J2_6JZ) 174es (6 830. Melt sticking 219 ~ 221 ° C 〇9_6 (Z): NMR (d6-DMSO) 5: 1 2, 2 9 (lH, bs ) N 8. 5 8 (2 H, d, J = 6.2 Hz), 7.99 (lH, s), 7.96 (2H, d, J = 6.2 Hz), 7.19 (lH, s), 5.67 (lH, d, J = 〇.4Hz), 2.21 (3H, s) IR (Nujol) vein-1: 271 8, 215 0, 160 7, 156 2, 150 3, 128 3,119 9,1153 (Please read the precautions on the back first (Fill in this page again.) The printed paper size of the China Industrial Standards Bureau of China ’s Quasi-Bureau Consumer Cooperative is applicable to China National Standard (CNS) A4 (210X297 mm_) A7 B7 V. Description of the invention (82) &lt; y c〇ch3

LiN (TMS) 2 (C02Et) 2 C0CH2C0C02Et 99

CH30 ®

103 (Please read the note on the back before filling this page). Packing. Τ-Order printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (1) Add 23.72g (214.4 «ol) of _ to anhydrous THF215 * i, cooling at -72 ° C, adding (CoeEt &gt; a 29 · 12 · 1 (21 4.4 ·· 〇1 &gt;) under air pressure, and then adding LiN (TMS) 8 / THF solution &lt; 1 · ο1) 214 · 1, while slowly heating the ridge chamber fi and stirring for 1 hour, and then cooled to -65 ° C again, 5N HC1 64al was added dropwise, and stirred at room temperature for 30 minutes. Subsequently, the reaction was The solution was concentrated and reduced. IN NaOH 128.7 »1 was added to the residue, and the precipitated crystals were filtered, washed with water and ether in order, and dried to give a yellow knot a 9 9 64¾. Second, after cooling to -30 ° c, It was dissolved in the port HC1 2 6 · 1 and water 51 · 5ι1, and then AHaNNHe was added. Η * 0 9.0 · 1 (185 · βο1 &gt;), stirred at 85 ° C for 40 minutes, and then added IN NaOH under ice cooling 13 Λ This paper size is applicable to the national standard (CNS) A4 specification (210 X 297 mm) -86-Printed A7 B7 by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (83) 〇 · 1, filter The precipitated crystals were sequentially washed with water, isopropion and ether, and dried to obtain yellow powder 丄 J3jQ_ 27.9g (705;). Melting point 215 ~ 217. C 〇-1 〇Q: NMR (de_DMS 0) 5: 1 4. 4 (bs, 1 H), 8. 6 7 (2 H, d, J = 6 Hz), 7.95 (2H, d, J = 6 Hz), 7.56 (lH, m), 4.35 (2 H, q , J = 7 Hz), 1. 3 3 (3 H, t, J = 7 · 1 Hz) I RCNujoDi ^ cm-1: 1726,1609,1572,1248,1 204 (2) will be 2. 17g (10nii 〇l) of 100 was added to acetic acid 40 · 1 and suspended, and IN NaOH 50 · 1 was added dropwise at room temperature, stirred at 60eC for 2 hours, and then 50 ml of IN HC1 was added under ice-cooling. The methanol was decanted, and the precipitated solid matter was collected by filtration, washed sequentially with M water, THF, and diethyl ether, and dried to obtain & color powder 1 0 1 1.47 g (78Z). Melting point 300-C or more. 10 1: NMR ( de-DMSO + DC Γ) &lt; 5: 8. 9 l (2H, m). 8.5 0 (2H, d, J = 5.8Hz), 7.80 (lH, s) IR (Nujol) vcm-1: 3 1 4 4, 2 4 5 4, 2 0 6 8, 1 6 3 7, 1 5 9 8, 1552,1403,137 5,1202,831.807 (3) 625 shirts (14.86 spiritual articles 〇1 &gt; ? &lt; dissolved in anhydrous 0 &gt; ^ 17 «1, add 6tUNaH565» g (1 4.12i «i« ol), stirred at room temperature for 1 hour to prepare a Na * [NH-CNr / DMF solution; secondly, 1.406g (7.432 ** 〇n of JLJJS) was turbid in anhydrous DMF 50 · 1 Under room rent, add 2.049 g of carbonyldioxazole (12.63 tentacles>) to the radon roll, stir for 2 hours, and dropwise add the above Na * [NH-CN] _ / D MF solution under ice cooling. <1 hour at room temperature. Then, add IN under ice cold. This paper size is in use ® National Standard (CNS) Α4 size (210X297 mm) ------- 1 --- pack-Γ (Please read the note on the back first) (Please fill this page again)

, 1T A7 _B7_ V. Description of the invention (84) After C1 20 · 1, depressurize and remove DMF * Add ice water 200 · 1 to the residue, filter out the solids, and sequentially remove M water, isopropyl yeast, and ether Wash the sickle and dry to obtain white powder JLQ_2_ 1.225 &lt; 77Ό. Melting point 30 (on TCM. 10 2: NMR (de-DMSO, DCl) g: 8. 9 8 (2 H, d., J = 6 Hz), 8.52 (2H, d., J = 6.2 Hz), 7.95 (lH, s), I RCNujoDi ^ cm-1: 2170,1635,1573,1541,1 3 45, 9 5 7 (4) 479g (2 · ol &gt; 丄 _Q "2JW in anhydrous formase 5 • 1 medium and suspended, and under ice-cooling, a MeONa / formase solution (1.1M, 1.75 · 1 &gt;) was added dropwise under a nitrogen roll; * so * stirred at 0eC for 20 minutes; then, the reaction solution was poured into In propanol 50 · 1, the solution was concentrated under reduced pressure until it was free of methanol, and the solid matter was collected by filtration, washed sequentially with isopropylase and ether, and dried to obtain white powder l.Q_a. 420 g (89X). 10 3: NMR (D20) 5: 8. 5 2 (2Η, πm), 7. 6 7 (2H, m), 7. 0 6 (1H, s) I RCNujoDycm-1: 309 0,215 0,161 1,158 1,156 2, 141 3.137 5,134 0,988 {Please read the precautions on the back before filling this page) Binding of printed paper sizes of the Central Standards Bureau Industrial and Consumer Cooperatives of the Ministry of Economics, Chinese National Standard (CNS) A4 (210 X 297 mm) 88-V. Description of the invention (85) 丨 ./

HCI.N) -CH2C02H 104 HC02Et

NaH

N

106 A7 B7

SOCI2 / EtOH CH2C02Et 105

P〇2Et 1) MsCI CH ^ .〇0Na®

2) HSCH2C02Et Et3N (Please read the precautions on the back before filling this page).

C02Et OH H CH2C02Et 107

C02Et

LiCI (n-Bu) aSnH Pd (PPh3) 4

-IT Λ Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs O- &lt; y C02Et NaOHaq

&lt; &gt; {yc〇2H 110 111 M ^ V- ^ s ^ C0NHCN 1) CO (Im) 2 — 2) NaH / NH2CN ^ 112 This paper size applies to China National Standard (CNS) A4 (210 X 297) (89%) -89 89 Α7 Β7 Printed by the shellfish consumer cooperation department of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (86) (1) 48g (276_5M〇l) of JLQ_ "JBS turbid in anhydrous acetic acid 500 · 1 Under ice cooling, add SOCU 40 · 34 · 1 (553 ·· 〇1>) dropwise in a helium stream for 20 minutes. At 50 ° C, add fi and one side »mix for 70 minutes, and concentrate under reduced pressure. To the obtained residue, add acetic acid 500 · 1 and water 100 1 and sodium methoxide to neutralize, adjust the pH to about 7, and separate the ethyl vinegar layer of acid and acid. And box, it is 1 〇 5 44.96g (98Z) 〇 10 5: NMR (CDC13) &lt;?: 8. 5 7 (2H, dd, J = 6. 0, 1. 5Hz), 7.25 (2H, d, J = 6.0 Hz), 4.18 (2H, q, J = 7.2 Hz), 3.6 2 (2H, s), 1.27 (3H, t, J = 7.2 Hz) (2) 1 of 44_83g (271.4naol) 0 5 Add to anhydrous THF450 spirit 1, add 11 (: 01 ^ 165.77 | «1 (814,11〇1)) to radon roller, and then add 605: NaH 13.30g (325.68uol), stir at room temperature After 3 hours, add B »720ib1, and filter out the precipitated precipitate, 59.39 g of powder 106. 10 6: NMR (D2Q) g: 8.94 (lH, s), 8.36 (2H, d, J = 6. 2Hz), 7.43 (2H, d, J = 6.2Hz), 4.16 (2H, q, J = 7.0Hz), 1. 2 5 (3H, t, J = 7. 3Hz) (3) will be 59.39 g (276uol &gt; «into anhydrous THF 480 * 1, add MsCl 21.36ϋ1 (276 ·· ο1) in a rabbit air roller under ice cooling, stir for 35 minutes, and then add HSCH» C0 * in order. Et 30.26 · 1 (276 〇1> and {1 "42.32 321 (303.6 鼸 〇1>), and stirred under ice-cooling for 20 minutes. Subsequently, the reaction solution was added with ethyl acetate 600 · 1 and water 600 · 1. Separate the BII acid layer, wash in sequence with M water and saturated brine, and then dry with magnesium sulfate (please read the precautions on the back before filling this page) • ΙΗ n IJ Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 90 A7 B7 Printed by the Central Government Bureau of the Ministry of Economic Affairs, Printed by Shellfish Consumer Cooperative, V. Description of the invention (87) Drying; After filtering out the broken magnesium acid, the filtrate is depressurized Concentrated, the resulting residue was treated with silica gel tube chromatography, and toluene / ethyl acetate = 2/1 The eluted fraction was concentrated under reduced pressure to obtain an oily substance 107.11g (87X &gt;). 10 7: NMR (CDC13) 5: 8. 6 4 (2H, dd, J = 6. 0, 1. 6 Hz), 7.98 (lH, s), 7.25 (2H, dd, J = 6.0, 1.8Hz) , 4.24 (4H, q, J = 7.0), 3.53 (2H, s), 1.31 (3H, t, J = 7.0Hz), 1. 2 9 (3H, t, J = 7. 1Hz) IR (CHC13) vcm'1: 2980,1737,1700,1600,15 7 5,13 6 5,129 5,124 0,1180

(4) 71.11g (240.8aaol) of 丄 _QJL was added to anhydrous THF 700 1, cooled to 50 ° C, and LiN (TMS) * / THF Uol solution 265 «1 (265 ··) was added dropwise in a nitrogen stream. 〇1), stirred at room temperature for 1 hour, then, SI acid 30.33 · 1 (529β · 〇1>) was added, and concentrated under reduced pressure, to the resulting residue was added 1L ethyl acetate and water 500 · 1, The ethyl acetate layer was separated, washed sequentially with water and saturated brine, and then dried over magnesium sulfate. After filtering off the broken magnesium acid, the filtrate was concentrated under reduced pressure, and CHaCla300il was added to the residue. After the insoluble matter was filtered off, The filtrate was concentrated under reduced pressure to obtain 10 7 56.82 g (95Z &gt;. Melting point 123 ~ 125 ° C 10 8: NMR (CDCls) &lt; 5: 1 0. 2 8 (1 H, bs), 8. 6 5 (2H, dd. J = 6.2, 1.8 Hz), 7.68 (lH, s), 7.67 (2H, dd, J = 6.4, 1.6 Hz), 4.42 (2H, q, J = 7.0 Hz), 1.41 (3H , T, J = 7.2Hz) IR (CHC13) vcnr1: 2980, 1658, 1605, 1570, 14 4 0,1 3 7 7.1 3 2 8,1 1 9 0 (5) 56.828 &lt; 228 «〇1 &gt; Zhi 丄 _〇_ £ _ Dissolved in anhydrous (: 11 丨 0 ^ 100 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 91 I— IT —I— n I-., Vr II —— Order one —I —— 111 ^ (Please read the notes on the back before filling in this page) A7 B7 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs V. Invention Description (88) Oal, cool at -30 ° C, 51.50 g (25 Unol) of (2,6-di-third-butyl-4-methyl Iftidine) was added dropwise under nitrogen, and further (CF3SOa), 0 47.95 · 1 (285 · π «ο1 &gt;, After stirring under ice-cooling for 50 minutes, the reaction solution was concentrated under reduced pressure. To the obtained residue were added ethyl acetate 1000B1 and saturated sodium iodate 550-1, and then ethyl acetate was separated and washed with water and saturated brine in this order. After that, the magnesium was dried over magnesium, and then the magnesium sulfate was filtered off. The filtrate was concentrated under reduced pressure. After silica gel chromatography, the toluene / ethyl acetate = 4/1 was eluted and concentrated under reduced pressure. 9 67_32g (775 &gt;. Melting point 100 ~ 101eC. 10 9: NMR (CDC13) 5: 8. 72 (2H, dd, J = 6. 0. 1. 4Hz). 7.64 (lH, s), 7.39 (2H, dd, J = 6.2, 1.6 Hz), 4.46 (2H, q, J = 6.8 Hz), 1.43 (3H, t, J = 7.0 Hz) IR (CHC13) vcm-1: 2970,1715,1600,1430,13 7 5,129 0,126 5,124 0,1220 (6) Add Pd &lt; PPh3) * 4.09g (3.54 «B〇l &gt; and LICl 22.51g (531 mol) In anhydrous THF 700 · 1, 丄 _Q_Q_ 67.32g (177 ·· ο1 &gt; and (n-Bu) 3SnH 114 · 3 · 1 (425 ·· ο1 &gt;) were further added, and heated under reflux at 85-C for 2 hours; Then, reduce the pressure and reduce the pressure, add diethyl ether, filter off the insoluble matter, add IN HC1 to the mother liquor, adjust the pH to 1, and separate the aqueous layer. * Add hydrazone and sulfonic acid, and adjust the pH to 9. M ethyl acetate extraction; combined with ethyl gluconate layers, washed with M saturated brine, and then dried with magnesium sulfate; filtered to remove magnesium sulfate, concentrated the mash solution under reduced pressure, and obtained the residue M silica gel tube chromatography It was purified by the method, and the toluene / ethyl etherate = 1/1 eluted portion gave 丄 _〇_ 39.2 6g (95Z>). Melting point 79 ~ 80. (: .110: NMR (CDC13) 5: 8. 6 (2H, d, J = 6. 2 Hz). 8. 1 (Please read the precautions on the back before filling out this page) -Packing-、 11-^ This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 92-92 鳑 ^ Central Central Soap and Co-worker Twist ^ A7 B7 5. Description of Invention (89), Original Supplement 2 (lH, s), 7.85 (lH, s), 7.50 (2H, dd, j = '6.4, 1.8Hz), 4.41 (2H, q, J = 7.4Hz), 1.42 (3H, t, J = 7.2Hz ) IR (CHC13) van-1: 2970,1700,1600,1430,14 1 8,128 0,125 0,1080 (7) Add 2.33 g (10 nmol) of 1 10 to 50 ml of methanol and suspend it. Add IN NaOH 20nl (20ininol) at room temperature, stir at 50 ° C for 25 minutes, and then add IN HC1 20sil under ice-cooling. Then remove the formate under reduced pressure, filter out the precipitated solids, and sequentially isolate isopropyl. Wash with alcohol and ether, and dry it to obtain 1 1 1 2.028 (985 :). Melting point 300. (: above. 111: NMR (d6-DMSO) o: 8. 6 l (2H.d. J = 6Hz) 8. 5 l (lH, s), 8.27 (lH, s), 7.77 (2H, d, J = 6Hz) I RCNujoDi / cin-1: 3336,3080.1699.1611.1296, 1211,106 5,1026 (8 ) HSNCN 246mg (5.84ffimol) Dissolved in 15 ml of anhydrous DMF, 214 mg (5.36 mmol) of 602NaH was added thereto, and stirred at room temperature for 20 minutes to prepare a Na * [NH-CN]-/ DMF solution. Next, 1.0 g (4.87 m «i 01) I_LJJra was added to 20 ml of anhydrous DMF, 1.03 g (5.36 mm) of carbonyldiimidazole was added, and after stirring at room temperature for 95 minutes, 逑 Na * [NH-CN]-/ DMF was added dropwise under ice cooling The solution was then stirred under ice-cooling for 1 hour, and 14.6 ml of IN HC1 was added. DMF was distilled off under reduced pressure, 30 ml of water was added to the obtained residue, and the precipitated solid matter was collected by filtration, and sequentially washed with isopropyl alcohol and ethyl acetate. Drying gives white powder 1 1 2 921ng (82 X). Melting point 249 ~ 2 51 ° c. 112: NMR (d6-DMSO) (5: 8. 8 2 (2 H, d, J = 6. 0: Hz ). 8. This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (2IOX297mm>-^ 袈 — (Please read the note f on the back before filling this page)-* A7 B7 V. Description of the invention (90) 6 3 (lH, s), 8. 2 8 (2H, d, J = 6.0 Hz), 8. 2 l (lH, s) I RCKBrhcm · 1: 3044, 2152, 1638, 1 594, 1539, 143 6,133 2,124 1,121 0,816 Manufacturing 27

117 — ^ 1 '—4— · 11 ΙΛ · 11 nn mn Γ (Please read the precautions on the back before filling out this page), -ιττιτική printed by the Zhengong Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs (1) will be 19.26g (82.56 · Xinjiang ol) Add 1 1 0 to _ Shuijiaben 500 1 and cool to -70. 0, add DIBAH / toluene solution 165 · 12 · 1 (248 ·· ο 1, 1.5M), stirred at -70 ° C for 35 minutes, and then added formazan 30.ini (744bbo1) and water 13.4.1 (744 ·· ο υ) under ice cooling, heated at 50 ° C, filtered Remove the insoluble matter. Reduce the concentration of the mother liquor by K and condense to obtain the target product JL_LJ3_ 14. llg &lt; 89! 〇. Melt 138 ~ 139eC. 113: NMR (d6-DMSO) 5: 8. 5 6 (2 H, dd, J = 6. 2, 1. 8 Hz), 8.09 (lH, d, J = 1.6Hz), 7.68 (2H, dd, J = 6.2, l. 6Hz), 7.51 (lH, s), 5.59 (lH, t ， J = 5.7Hz), 4.67 (2 H, d, J = 6. 0Hz) -ϋ— —If · This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 94 A7 _B7_ V. Description of the invention (9l) IR (Nujol) i; cin-1: 160 0,141 5,132 0,114 4,102 0, 1 0 0 1,8 0 1 &lt; 2 &gt; 1_g_2_ of 1.913g &lt; 10ai «〇l &gt; was dissolved in Anhydrous CHaCla In 250 1, at room temperature, Mη0 »(Activation &gt; 6.955g &lt; 80% 〇〇1 &gt;) was added to the gas-roller and stirred for 20 hours; then, Mn0a was filtered off and decompressed under reduced pressure. After CH2C13, MCHaCU / n-hexane recrystallized the obtained residue to obtain 1.42 g (75X) of white powder 1 14. Melting point 95 to 96 ° C. 114: NMR (CDC13) &lt; 5: 10.0. 〇〇 (lH, s), 8. 6 9 (2H, d, J = 6Hz), 8.09 (lH, s), 8.05 (lH, s), 7.49 (2H, d, J = 6. 3 Hz) IR (CHC13) vcm- 1: 2962,2820.1676.1601,14 1 8,117 4,820 (3) Dissolve 669μ &lt; 3.535ββο1) in anhydrous THF7b1, and add Ph3P = CHC〇aMe 1.30g ( 3.89n »〇1 &gt;, heated to reflux at 77eC for 1 hour. Subsequently, the decompression box went to THP, and 1ΊR was obtained. The staff consumer cooperative of the Central Bureau of Procurement of the Ministry of Economic Affairs secondly instigated the solution in methanol 18 · 1, added IN NaOHaql 8 · 1, and then mixed at 60 ° C. 1 hour, followed by decompression® forenzyme, the obtained aqueous layer M toluene 100 · 1 × 3 times cleaned, the aqueous layer was separated, 1NΗΠ18 · 1 was added under ice cooling, the pH was adjusted to about 7, and the precipitated solid matter was filtered, It was washed sequentially with M water and diethyl ether; the dried powder yielded white powder 丄 _L_a 517M (63: ϋ &gt;. Melting point 297 ~ 300. (: (Decomposition>).

116: NMR (de-DMSO) 5: 12.5 KlH.bs). 8. 6 2 (2 Η, d, J = 5 Hz), 8.37 (lH, s), 8.12 (lH, s), 7.75 (lH, d) , J 95 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (92) = 15. 〇Hz) s 7. 7 3 (2H, d, J = 6Hz), 6.31 (lH, d, J = 15.8 Hz) IR (Nuj〇l) vCm-i: 30%, i69 8, 163 1,161 0,1316, 118 7 (4) will be 182β8 (4_32 ... ο1 &gt; NNaCN is dissolved in anhydrous DMP5al, and 60ZNaH 156μ (3.89 ·· 〇1) is added to the nitrogen stream under ice cooling, and stirred for 1 hour under room rent to prepare Na * [NH-CN]-/ DMF Solution. Secondly, add 500 轺 (2.16 &quot; 〇1) of 丄 _1_6_ »to anhydrous 0} ^ 15, and add carbonyldioxazole 456ig (2.81« ol ), Stand for 2 hours; then, cool to ice, add the above Na * [NH-CN]-/ DMF solution dropwise, and stand for 70 minutes at room temperature; after sugar, add IN HC1 7 under ice · 1, adjust the pH to about 7, broadcast the DMF under reduced pressure, add ice water 100 · 1 to the residue, filter out the precipitated solids, and wash them with water, isopropanol, and ethyl K in order. Got white Powder 1 1 7 471ag (86; i :). Melt 248 ~ 250. (: 〇117: NMRCd6-DMS 0) (5: 8.66 (2H, d, J = 6.7 5 Hz). 8.43 (lH, s) , 8.15 (lH, s), 7.87 (2H, d, J = 15.3Hz), 7. 7 8 (2H, d, J = 6.0 Hz), 6. 3 9 (lH, d, J = 1 5 · 6Hz), IR (Nujol) v cnr1: 2154,1612,1503,1326,1183, 9 5 9, 8 2 0 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) y--j- --Η 装-^ -ν · (Please read the notes on the back before filling out this page, 1T-Tourism-Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives-96 A7 B7 V. Description of the invention (93

BocNH BocNH

Ο

Boc 29

COOPMB

NHCONHCN nh2— &lt; (ch2f 0Θ I v NHC = NCN Boc I- 丄 l ^ CONH s &gt; 0 Ιθ W (into ch2f h

NHCONHCN lV (Please read the precautions on the back before filling out this page)-Install _, 1T (1) and solve 1.37 (4) in Ι) Μ50 &lt; 15 · υ, add V- 丄 3.66g (4.8 ·· 〇υ the solution of 1 guess 15.1, after stirring at room temperature for 2 hours, and then forced to add 0.92g &lt; 1.2M〇l &gt;, »for 2 hours. The reaction solution was poured into the BK-water mixture The insolubles were filtered, washed with water, washed with B, and dried to obtain 16.038 (yield; Ding Dong's). I-1: NMRCCDC 1 3-CD30D) 5: 1.5 6 (9 Η. s), 1.6 7 (9H, s), 3.81 (3H, s), 4.59 (2H, bs), 5.1 to 5.6 (5H, m), 5. 7 7 (2H, d, J = 5 5Hz), 5 9 8 Cl H, d, J = 5 Hz), 6.77 (1 H, bs), 6.91 (2H, d, J = 8 Hz), 7.33 (2H, d, J = 8 Hz), 8. This paper is applicable to the standard China National Standard (CNS) A4 specification (210x297 male *)-, β ---- · Printed by the Shellfish Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs 97 Printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention (94) 0 3 (2H, d, J = 6Hz), 8. 8 7 (2H, d, J = 6Hz). (2) Dissolve 6.03g (5.5unol) of 1- 丄-in digas methane 40 · 1, cool at -30 ° C, and add 6.6g (49inol) of methoxybenzene 30 · 1 of vaporized aluminum After the solution, stir for 40 minutes at the same temperature; pour the reaction solution into a dilute hydrochloric acid-ethanol (1: 1) mixture; wash the aqueous solution under reduced pressure, and remove the organic solvent in the dehydrated layer. Then, it was processed by tube chromatography, and was dissolved by 5J: acetamidine-0. 05N sodium hydrogen iodate aqueous solution. The eluate was concentrated under reduced pressure, neutralized with diluted hydrochloric acid, and insoluble matter was filtered and dried. 1-1 '0.46 g (yield: 12.82). I-Γ: NMR Cd6-DMS0 + D20) 5: 2. 9 7, 3. 5 4 (2Η, ABq, J = 2 1. 0 Hz), 4.13 , 4.40 (2H, ABq, J = 16. 5Hz), 4.67, 5.22 (2H, ABq, J = 15. 0Hz), 5.10 (lH, d, J = 5 Hz), 5.70 (2H, d, J = 5 6Hz), 5.74 (lH, d, J = 5Hz), 6.61 (lH, s), 7.74 (2H, d, J = 7Hz), 7.79 (lH, s), 8.67 (2 H, d. J = 7Hz) 〇IR (KBr) read -1: 2252,2151,1773,1671,1636. Also, in the middle «Ι-JL ·, depending on the conditions of isolation or box, pyridine anchor ions can also be obtained The salt neutralized by 1- and other inorganic furnace, at this time, it can be the same as The above-mentioned deprotection reaction is transformed into compound I-JL1_ ° (Please read the note on the back before filling this page) "Binding · Bookbinding-Traveling. This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 98 A7 -________ B7 V. Description of the invention (95)

1-2 '(Please read the precautions on the back before filling this page), J—I —J. · -Pack. Order (1) V-2_ 0.91g &lt; 1.2 鼸 鼸 〇1 &gt; and 3 4 · 254Μ (1 · ϋ〇1 &gt; Dissolved in DMS0 &lt; 5i «l), stirred for 2 hours under room S; pour the reaction 掖 into B_ to make insoluble matter precipitate, remove by decanting the ether layer, and use water and ether again The insoluble matter was washed and dried to obtain 1.11 g (yield: 89.X). I_1: NMR (d6 —DMSO) &lt; 5: 1.2 4 (3H, t, J = 7Hz), 1.51 (9H.s), 3.5 5,3.7 0 (2H, ABq, J = 10Hz), 3.71 (3 H, s), 4.17 (2H, q, J = 7Hz), 5.18 ~ 5.31 (3H, m), 5.4 This paper size is applicable to China National Standard (CNS) A4 (2l0X 297mm)

|: Gray--H Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed A7 __B7 , J = 5Hz), 6.91 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 8.06 (lH, s), 8.15 (2H, d, J = 6 Hz), 8.40 (lH , s), 8.76 (2H, d, J = 6Hz). (2) Dissolve 0.91g (0.9ai «ol) of 1-2_ in digas methane 10» l-nitromethane 6 * 1 mixture, and add 0.72 g of gasified aluminum at -20 ° C ; 5.4ai «o 1 &gt; of methoxybenzene 6.1 solution, stir for 1 hour at the same temperature; pour the reaction solution into a dilute hydrochloric acid-acetic acid mixture, and wash it with MG and reduce it. Organic solvent in the water layer. The water layer was processed by tube chromatography. The solution was dissolved by 12% acetonitrile-0.0 5N aqueous solution of argon sodium. The concentrated eluate was neutralized with M diluted hydrochloric acid to obtain I-2_L_ 223 «g. (Yield: 38.7 ×). I -2_1: NMR (de-DMSO-DzO) &lt; 5: 1.21 (3H, t, J = 7 Hz), 3_ 1 7, 3. 5 7 ('2H, ABq, J = 1 0.8 Hz) 5.08, 5.5.2 (2 H, ABq, J = 18.0 Hz), 5.10 (lH, d, J = 5Hz), 5.74 (1Η, d, J = 5Hz), 8.17 (lH, s) , 8.21 (2H, d, J = 7Hz), 8.36 (1 H, s), 9.13 (2H, d, J = 7Hz). IR CKB r) vca1: 2177,1772.1636〇 (Please read the notes on the back before filling out this page) • n si This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 100 A7 B7 V. Invention k Ming (97) Dou Shi Ji

BocNH

V-2

44 CH3 (Please read the notes on the back before filling this page) • —1--r.

CH3 __j 〇㊀

OE Canton I &quot; ll JL ^ C = NCN COOPMB, • ba 1-3, \ -a Printed by the Bayer Consumer Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs

) ° ch3 1 ^; This paper size applies to Chinese National Standard (CNS) A4 specification (210XZ97 mm) 101 A7 B7 V. Description of the invention (98) (1) MV-2_ 910 shirt (1.2 Tengdao 〇1) and 4 · 4 · 240 · 8 (〇.9 ·· 〇1) as raw materials, and the reaction was carried out according to the method of Example 1 to obtain _2_〇.79g (yield: 85.4¾) 〇 (2) in CHaCla-CH3NOa In the experiment, MA1C1 acts on _2 ″ of 783.8 (0.76ββο1) to obtain I-_2 ″ _ 30ag (yield: 5.6 ×). I -l ': NMR (de-DMSO) δ: 1.2 1 (3 H, t, J = 7Hz). 3. 37, 3.52 (2H, ABq, J = 18.0Hz), 3.82 (3H, s), 4.14 (2 H, q J = 7Hz), 5.19 (lH, d, J = 5Hz), 5.17, 5.38 (2H, ABq, J = i5.0 Hz), 5.88 (lH, dd, J = 5Hz, 8Hz), 6.92 (1 H, s), 8.05 (lH, s ), 8.15 (2H, bs) 8.28 (2H, d, J = 7Hz), 8.73 (2H, d, J = 7Hz), 9-60 (2H, d, J = 8Hz), 12.12 (1 H, bs) IR (KB r) vcm · 1: 2257, 2164, 1780, 1671.16 36〇 ---- 11 --- 1 Packing ------ Order ------_ Λ (Please read the note on the back first Please fill in this page again) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, this paper is printed in accordance with Chinese national standards (CNS &gt; A4 specifications (210X297 Public holiday

J 102 A7 B7 V. Description of Invention (99) Example 4

&gt; NCN nh2 +

1-4 --Installation-Γ (Please read the precautions on the back before filling out this page) Order 31

, NCN

NH 丨 2 -1-: —II-· 1-4 'This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) — 111 ^ — 103 Printed by the Industrial and Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs B7 V. Description of the invention (100) (1) Dissolve 203ng (0.8M〇l &gt; of life_2_ in DMS0 (10 «1 &gt;), add V-2_ 789m (1 / 03bbo1), and stir for 45 minutes; one side While stirring, the obtained solution was added dropwise to B &lt; 500 * 1>, and the mother liquor was decanted to obtain an oily insoluble matter; the insoluble matter M was washed with water and filtered, and the filtered insoluble matter was dissolved in three gases In a mixed solution of methane and acetonitrile, dried with magnesium methanoate to obtain I-4 830ig °

I ~ ±: NMR (d6-DMSO) 5: 1.24 (3H, t, J = 7.0 Hz) N 1.51 (9H, s), 3.53 (2H, bs), 3.73 (3H, s), 4.21 (2 H, q, J = 7.0Hz), 5.22 (2H, bs), 5.22 (lH, d, J = 5.2H z), 5.4 3 (2H, bs), 6.0 0 (lH, dd, J = 5.2, 8.6Hz) , 6.93 (2H, d, J = 8.6Hz), 7.37 (2H, d, J = 8.6Hz), 8.08 (1 H, bs), 8.15 (2H, d, J = 6.6Hz), 8.3 3 (lH .bs), 8.7 7 (2H, d, J = 6.6 Hz), 9.0 4 (lH, bs), 9.69 (lH, d, J = 8. 6 Hz), 11.18 (lH, bs), 12.61 (lH, bs), 12.96 (1H, bs) 0 IR (KB r) ycm-1: 2182,1784,1713,1679,1634〇 (2) Dissolve Ii 820 «^ (0 · 81μο1) in methane gas 30 · 1 And CH 3N0a 30 and 1, methylbenzene 1.06 · 1 (9.75ββο1) was added. At -20. (: Next, to this solution was added Liu 1 (: 13 of (: 1 ^ 〇8 solution (1 »〇7.29 * 1, sowing at the same temperature for 30 minutes). Under ice cooling, water (100ml) and Ethanol (100 nl) and 3.4 g of sodium tartrate (14.8anol &gt; were stirred and prepared, and then poured into the aforementioned reaction solution; the resulting suspension was washed with ethyl acetate, and the aqueous layer was concentrated under reduced pressure and subjected to tube chromatography (405; Yi Jian / water) treatment; concentration of the eluate under reduced pressure, filtration of the insoluble matter precipitated, to obtain bu sheng "_ 11US (the yield of this paper applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 104 ^^ 1 I Jrf In i ^ nn ^ i nn nn Γ (Please read the precautions on the back before filling this page) Order

JA 7 B7 V. Description of the invention (101) I -4;: NMR (d6-DMS0 (+ D20)) 5: 1.2 0 (3H, t, J = 7. 0Hz), 3.0 9,3.5 2 (2H, ABq , J = 19.0Hz), 4.12 (2H, q, J = 7.0Hz), 4.9 6,5.5 4 (2H, ABq, J = 13.8Hz), 5. 06 (lH, d, J = 5.0Hz), 5.70 (lH, d, J = 5.0Hz), 8.10 (lH, bs), 7.20 (2H, d, J = 7.0Hz), 8.26 (lH, bs), 9.20 (2H, d, J = 7.0Hz) . I R (KB r) vcnr1: 2182,1768,1635. (Please read the notes on the back before filling in this page) • Binding and Binding of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Co-operation, Du Printed This paper is sized according to National Standard (CNS) A4 (210 X 297 mm) 105 A7 B7 V. Description of the Invention (102) Examiner Li BMe

A COOPMBV-2

1-5 (Please read the precautions on the back before filling out this page) -ΙΊ I IJ .. 装 装 Order printed by the Central Laboratories of the Ministry of Economic Affairs

1-5 'This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 厘 297mm) -106-106 A7 B7 (1) Dissolve 5_2_ of 95lBg (3.73BB0l) in DMSO 40 · 1, add V-2_ 4.24g (5.59aB0l), and stir at room temperature for 30 minutes; the resulting reaction is stirred while stirring The liquid was added dropwise to diethyl ether 200 · 1, and the mother liquid was decanted to obtain an oily insoluble matter. 400 ml of water was added to the insoluble matter, and after washing, the precipitated insoluble matter was collected by filtration; the obtained insoluble matter was dissolved in a mixed solution of three gaseous methane and acetonitrile, ethyl acetate 100 bI and ether 400 b 1 were added, and the precipitate was filtered out Insoluble matter, I-5_ 3. 14 g (yield: 83¾) was obtained. 1-5 .: NMR (d6-DMSO) 5: 1.23 (3H, t, J = 7.0 Hz), 1.50 (9H, s), 2.26 (3H, s), 3.44 ~ 3.64 (2H, m), 3. 72 (3H, s), 4.20 (2H, q, J = 7.0Hz), 4.20 (2H, bs), 5.22 (2H, bs), 5.23. (LH, d, J = 5.4Hz), 5.25 ~ 5.43 (2H, m), 5.99 (lH, dd, J = 5.4,8.2Hz), 6.92 (2H, d, J = 8.6Hz), 7.21 (lH, bs), 7.36 (2H, d, J = 8.6 Hz), 7.7 8 (lH.bs), 8.0 5 (2H, d, J = 7.2Hz), 8.5 8 (2H, d, J = 7.2Hz), 9.69 (lH, d, J = 8.2Hz), 11.56 (lH, s), 1 2. 6 0 (lH, bs). IR (KB r) vcm-1: 2244, 2146, 1786, 1714, 1 6 3 4〇 (2) Solve 3.13g (3.09 «ol) of 5JS in two gas methane 30 · 1 and C Η, Ν0, In 20 · 1, methoxybenzene 4.03 · 1 (37.08 · 1) was added and cooled to -20 ° C. After adding A1C132CH3N0, solution (1M) 4.03 · 1, it was stirred at the same temperature for 40 minutes. Under ice-cooling, the acetic acid 100 · 1 and 0.1N-HC1 100 · 1 were stirred and prepared, and the reaction solution was poured; the obtained suspension liquid M ether was washed, the aqueous layer was concentrated under reduced pressure, and then subjected to tube chromatography. (B please / 〇.5N-NaHC〇3 10 ： 〇 treatment. M IN Η This paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) 107 (Please read the precautions on the back before filling in this page)) -Packing A7 B7 V. Description of the invention (104) C1 adjusts the pH of the eluate to 7, after concentrating under reduced pressure, further adding 1N-HC1, and filtering out 515mg of 1-5-22 (yield: 27X0). I -5;: NMR (d6-DMSO) δ: 1.16 (3H, t, J = 7. 2Hz), 2.21 (3H, s), 3.0 0,3.5 6 (2H, ABq, J = 18.6Hz), 3 .09 (2H, q, J = 7.2Hz), 4.09 to 4_33 (2H, m), 4.70, 5.24 (2H, ABq, J = 13.8Hz), 5.08 (lH, d, J = 4.6Hz), 5.75 (lH, dd J = 4.6,7.8Hz), 7.74 (2H, d, J = 7.0), 7.75 (lH, bs), 7.66 (2H, d, J = 7.0), 7.46 (lH, d, J = 7. 8Hz), 1 1. 8 0 (lH, bs) 0 IR (KB r) cm'1: 2244, 2160, 1769, 1676, 1633〇 (Please read the precautions on the back before filling in this page) Printed by the Bureau of Standards, Consumer Cooperatives, the paper size is applicable to the Chinese National Standard (CNS) M specifications (210X297 mm) A7 B7 V. Description of the invention (105) Fend you I ft

55

!-£

Please read the precautions ¥ Printed on this page by the Ministry of Economic Affairs of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (1 &gt; Will be 477g (2M〇l &gt; thirst for DMS025), add YA-2L 2.73g (3.6〇M 〇l), stirring at room temperature for 7 hours; while stirring, the reaction solution obtained was added dropwise to 500 «1 in acetic acid * decanting the mother liquor to obtain oily insoluble matter; insoluble matter M was washed with water * filtered Precipitated insoluble matter; the obtained insoluble matter was dissolved in a mixed solution of chloroform and acetonitrile, and the magnesium sulfate was dried, and then dropped into ethyl acetate 100bI while stirring. Further, 500 ml of ether was added, and the precipitated insoluble matter was filtered off. I-_6_ 1.31s "yield: 663;). I -6 .: NMR (de-DMSO) 5: 1.23 (3H, t, J = 7.0 Hz). • 50 (9H, s) , 3.52 (2H, bs), 3.73 (3H, s), 4.20 (2H, q, this paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) System A7 ______B7 _ V. Description of the invention (106) J = 7.0 Hz), 5.23 (lH, d, J = 5.0Hz), 5.24 (2H, bs), 5.39 (2H, bs), 5.99 (lH , Q, J = 5.0, 8.2 Hz), 6.38 (lH, d, J = 15.2 Hz), 6.93 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.36 (lH, bs), 7.47 (lH, d, J = 15.2 Hz), 8.2 1 (2H, d, J = 7.0 Hz), 8.25 (lH, bs), 8.68 (2H, d, J = 7.0 Hz), 9.69 (lH, d. J = 8.2 Hz), 12.61 (lH, s) IR (KB r) vcnr1: 2230, 215 0, 178 5, 1712,169 0,1616. (2) 1.30 g (1.30 MOL) of I__6_ was dissolved in diaminomethane 20 · 1 and CH, N0S20 fiber 1, and methoxybenzene 1.70 · 1 was added. 14 · 9ϋΐΒ〇υ; cool at -20 ° C, add A1CU's CH3N0 * solution (1M) 11.7 · 1, and stir for 30 minutes at the same temperature; stir under ice-cold preparation to prepare acetic acid 100 · 1 and 0.1 N-HC1 100 · 1, added to the reaction solution; M ethyl «wash the obtained suspension liquid, the aqueous layer was concentrated under pressure * M tube chromatography (102 acetonitrile / 0.05N-hydrogen iodate Na) treatment; after concentrating the eluate under reduced pressure, the pH of M1N-HC1 was adjusted to about 2, and the precipitated insoluble matter was filtered, washed with M isozyme and ether to obtain IS, 131 * g (yield: 16¾). I — 6 ': NMR (de-DMSO) 5 ·· 1. 2 1 (3H, t, J = 7.0 Hz), 3.3 3,3.5 4 (2H, ABq, J = 18.4 Hz), 4.14 (2H, q, J = 7.0Hz), 5.17 (lH, d, J = 5.0Hz), 5.21, 5.41 (2H, A Bq, J = 14.6Hz), 5.86 (lH, dd, J = 5.0, 8.2Hz), 6.33 (lH, d, J = 16.0 Hz), 7.18 (lH, bs), 7.24 (lH, d, J = 16.0 Hz), 8.14 (2H, bs), 8.16 (lH, bs), 8.19 (2H, d, J = 6. 2Hz), 8.81 (2H, d, J = 6.2Hz), 9.57 (lH, d, J = Please read the precautions for the first page, binding and binding, the paper size of this paper applies to the Chinese National Standard (CNS)) Α4 Specifications (210X297 mm) 110 A7 ____'__ B7___ V. Inventory (107) 8. 2Hz), 1 2. 3 3 (lH.bs). I R (KB r) ucnr1 ： 2232,2148,177 2, 1673,16 l9〇 Fu Lili 7

1-7; (Please read the precautions on the back before filling this page). Packing. Order printed by the Central Ministry of Economic Affairs of the Central Bureau of Zhuhai Bureau Cooperative Consumer Cooperative (1) 508ng (150n lotus οΠ 5 7 hanging on DMS0 1 〇β1, add Ν, Ο-bis (trimethylsilyl> acetamide 403 w 1 (1.63 · βο1) and stir, then add V-JL 1.24 (1.63), and search for 95 minutes at room temperature; The obtained reaction solution was added dropwise to a 5: UaCl aqueous solution, and the precipitated insoluble matter was collected by filtration; the insoluble matter was dissolved in Etto 50 «1, 50 nl of ethyl acetate was added, and concentrated under reduced pressure, and then ethyl acetate 50 b 1 was further added. Pressure concentration; add diethyl ether 100 · 1 to the concentrate, and filter out the insolubles to obtain I-: Z_ 1.45g (yield: 982 &gt;. This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) 111 -Ill Printed by A11 B7, Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention (108) I -1_: NMR (de-DMSO) 5: 1. δ 1 (9 H , s), 1. 6 4 (9 Η, s), 3.54 (2H, bs), 3.73 (3H, s), 5.17 ~ 5.31 (2H, m), 5.25 (lH, d, J = 4. 6Ηζ) , δ. 4 7 (2H, bs). 5.8 1 (2H, d, J = 55.4Hz), 6.00 (lH, dd, J = 4.6Hz, 8.2Hz), 6.45 (lH, d, J = 15.4Hz), 6-91 (2H, d, J = 8.4Hz), 7.35 (2 H, d, J = 8.4Hz), 7.65 (lH , Bs), 8.01 (lH, d, J = 15.4 Hz), 8. 4 4 (2H, d, J = 6. 4 Hz), 8. 5 6 (lH.bs), 8. 8 2 (2 H, d, J = 6.4 Hz), 9 · 8 9 (lH, d), 1 2 · 6 7 (lH, bs).

IR (KB r) ycm-1: 2234, 2150, 1770, 1715, 161 5C (2) Dissolve 1-2 of 473M (0.49 · 〇1 &gt;) in digas methane 8.1 and CH, Ν0 · In 3.1, add methoxybenzene 640w 1 (5.89mo1 &gt;; place this solution in 4. (: cool down, add 11 丨 (: 1 «of (: 11! 1 (: 1111 Section Solution 4.41»)丨 Shake for 30 minutes under ice cold; first prepare 1N-HC150b1 and ether 50 · 1 under ice cold and inject the above reaction solution; filter insoluble matter from the suspension obtained and dissolve it in hydrogen sulfonic acid aqueous solution After filtering the insoluble matter in the filter, the MW HP-20SS tube analyzer (2 ~ 4¾acetonitrile / water) was used to separate the sugar. M1N-HC1 adjusted the pH of the eluate to 3.05, concentrated under reduced pressure, and filtered. The precipitated insoluble matter * M was washed with isopropane and diethyl ether to obtain di-2-137137 g (yield: 36Z). I-Γ: NMR (de-DMSO) (5: 3.2 9, 3.5 6 (2H, ABq, J = 18.0Hz), 5.18, 5.43 (2H, ABq, J = 14.6Hz), 5.19 (lH, d, J = 5.〇Hz), 5.75 (2H, d, J = 54.0Hz), 5.8 5 (1 H.dd, J = 5. 0, 8. 2 Hz) n 6.3 4 (1 H, d, J = 1 5. 6 Hz) N 7.20 (lH, bs), 7.28 (lH, d, J = 15.6Hz), 8.12 (1H, bs), 8.19 (2H, d, J = 6.6Hz), 8.81 ( 2H, d, J = 6.6Hz), (Please read the precautions on the back before filling this page)

, 1T This paper uses the Chinese National Standard (CNS) A4 size (210X297 mm) 112 -1 1 o _ A7 B7 V. Description of the invention (109) 8. 8 1 (lH, d, J = 8. 2Hz). I R (KB r) vcnr1: 2228, 2146, 1772, 1680, 1620. Review

CONHCN

HaN_CONH s 9®Na® (Please read the precautions on the back before filling out this page) -Packing _ ·· ** Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 0Et coo © 1-8; (1) 100Bg ( 0.44anol) was dissolved in DMSO lOal, V-_2_ 402Bg (0.53mnol) was added, and the mixture was stirred at room temperature for 30 minutes. With stirring, the reaction solution was added dropwise to 200 K of ethyl K and the mother liquid was decanted to obtain Oily insoluble matter; the insoluble matter was dissolved in digas methane 10 1 and further added dropwise to 200 · 1 ether with stirring, and the precipitated mercury dissolved matter was filtered to obtain I-S_ 374 ^ g ( Rate: 86X &gt;. I-8 .: NMR (de-DMS 0) 5: 1. 2 4 (3 H, t, J = 7. 0 Hz), 1. 51 (9H, s), 3.44 ~ 3.62 ( 2H, m), 3.70 (2H, s), 3.74 (3 H, s), 4.20 (2H, q, J = 7.0Hz), 5.24 (lH, d, J = 5.2Hz) This paper standard applies to Chinese national standards (CNS) A4 specification (21 × X 297 public holidays) -113-Printed by A7 B7, Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs 5. Description of invention (110), 5.25 (2H, bs), 5.36 (2H, bs) , 5.99 (lH, dd, J = 5.2, 8.8Hz), 6.68 (lH, bs), 6.93 (2H, d, J = 8.6Hz), 7.37 (2H, d, J = 8.6Hz), 7.97 (lH , bs), 8.10 (2H.d, J = 7.0 Hz), 8.58 (2H, d, J = 7.0 Hz), 9.71 (lH, d, J = 8. 8 Hz), 1 1. 6 2 (lH, bs), 1 1. 7 8 (lH, bs), 1 2. 6 1 (lH, bs) 〇IR (KBr) vcm-1: 2250, 2156, 1784, 1715. (2) 370ig (0.38aaol &gt; I-_a_ was dissolved in dihelium methane 6il and CH sNOa6 ^ 1, methoxybenzene 490 · 1 (4 · 5 · 〇1 &gt; was added, and AlCla2CH3NOe solution (1M & gt) was added at -2 (TC). 3.38 · 1; Stir the leaves for 30 minutes under the same rent. In addition, firstly, in a solution of CH3C00Na863mg (10.5BB〇l &gt;) in water (100b 1), add ethyl 100 * 1 and ethyl 200 · 1; Inject the anti-sacrifice solution. Filter the insoluble matter hired by water, and dissolve the insoluble matter in the aqueous sodium hydrogen iodate solution. If a small amount of insoluble matter is filtered, the mother liquor M tube chromatography (10¾ formazan / 0.05N sulfonic acid) Isolation and refining; reducing the solution by K, reducing the pH to 6.9 with 1N-HC, and desalting to obtain I-J8_1-70mg (yield: 28X). I -8. *: NMR (d6-DMSO) 5: 1.20 (3H, t, J = 7. 2 Hz). 3.0 5,3.4 9 (2H, ABq, J = 18.3 Hz), 4.11 (2H, q, J = 7.2Hz), 4.8 4,5.4 3 (2H, ABq, J = 14.0Hz), 5.06 (1 H, d, J = 5. 0Hz) s 5.67 (1 H, dd, J = 5. 0, 8 4 Hz). 6.50 (lH, bs), 7.78 (lH, bs), 8.05 (2H, d, J = 7.0 Hz), 9.0 l (2H, d, J = 7.0 Hz), 9.47 (lH, d, J = 8.4Hz), 9.87 (1 H, s), 1 1. 5 4 (iH, bs). IR CKB r) vcr1: 2156.1764, 1681, 1634. The paper size is applicable to the National Standard of China (CNS) 8-4 (2 丨 OX 297 mm) I. HI —dr--nf ^^^ 1 nn n (Please Read the notes on the back before filling in this page) Order a-114 V. Description of the invention (m) In the example of sinus under M, a TD ZO table BocNH-4 and

Boc N jTD2L ^ CONH Boc 〇Θ Na® + o ^ _ ph2c co2pmb 68 V-1 Today TDZ ... c〇NH Boc .CONH s ΘΘ: / o 〇K ^ nQ ^ ncn co2pmb

H2N

Printed by the Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs I-9

-l ^ CONH 1-9 '(1) Dissolve 234 mg (lBnol) of tritium in DMSO (7 bond 1 &gt; and add 83 ° Bg (l_09BB〇l &gt; -I_, stirred for 1 hour; then, the reaction solution was poured into 5¾ saline of 70b1, and the precipitated solid was filtered out; dissolved in a mixed solution of acetonitrile 40ml / three gas methane 20 · 1, and dried over magnesium sulfate * After concentrating under reduced pressure, the obtained residue was added to 50 nl of ethyl acetate, and the precipitate was filtered and dried to obtain a yellow powder. The size of the paper was applicable to the Chinese National Standard (CMS) A4 specification (210X 297 mm). 115 Ministry of Economic Affairs Printed by the Central Bureau of Standards Shellfish Consumer Cooperative A7 ___B7_ V. Invention (明) l-s_ 739ig (872) »1-9 .: NMR (de-DMSO) d: 1 2. 6 7 (lH, bs ). 1 2. 12 (1 H, bs), 9.90 (lH, d, J = 8.7Hz), 8.58 (2H, d, J = 7.2Hz), 8.19 (2H, d, 6.9Hz), 7.92 (lH , bs), 7.35 (2H, d, J = 8.4 Hz), 7.22 (lH, s), 6.92 (2H, d, J = 8.4Hz), 5.99 (1 H, dd, J = li. 5Hz, 7.3 Hz), 5.90 (lH, s), 5.72 (lH, s), 5. 2 1-5. 3 4 (5H, m) N 3.73 (3H, s) N 3. 4 3, 3. 5 8 (2 H, A Bq, J = 1 9Hz), 1. 5 l (9H, s) I RCKBOi / cm'1 2970, 2148, 178 4, 1711, 1635, 1548 (2) I-_Q_ of 729β8 &lt; 0.886ββ〇Π was added and suspended in 20ml of anhydrous digas methane and anhydrous CH3N0 * 50b1, at -3 ° C Under cooling, methoxybenzene 1.1 »| 1 (10.32 Li 1« 〇1> was added dropwise in a nitrogen roll, and then liol TiCU / digas methane solution 5-16 · 1 (5.16ϋ · was added dropwise over a period of 10 minutes. 〇υ, after stirring, stir at 0 ° C for 1 hour; then, drop the reaction solution in a mixture of IN HCL 10 dish 1 and 5X saline 10 · 1 under ice cooling, add ether 80 · 1, and filter Take out the precipitated solids; wash them with M IN HC1 and water, dissolve them in sodium iodate, and crack them with M tube chromatography; dissolve 7Z acetonitrile / 0.05N sodium hydrogen acetate to dissolve the pH Adjust to 2.9, concentrate under reduced pressure, and filter out the precipitated solids * M water, isopropylase, and diethyl ether, and wash them to obtain a yellow powder If 266mg (49.42) ®. If 1 mol AlCl3 / CH3NOe solution is used as Louis The same result can be obtained with acetic acid. "I": NMR (d6 —DMSO) 5: 1 2. 1 l (lH, bs), 8. 7 (2 H, d, J = 6.9Hz), 8.22 (2H, d, J = 7.2 Hz), 8.20 (2H, s), this paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 116 ~ Π6 (Please read the precautions on the back before filling this page) • Ikr— · • equipment · Order A7 B7 V. Description of the invention (113) 7.90 (lH, s), 7.21 (lH, s), 5.90 (lH, dd, J = 8.4, 4.8 Hz), 5.85 (lH, s), 5.66 (lH, s), 5.3 8,5.2 2 (2H, ABq, J = 18Hz), 5.21 (lH, d, J = 5.1Hz), 3.5 6,3.3 6 (2H, ABq, J = 1 8Hz), IR (KBr) vcm-1: 3412,2256,2156,1777,167 7, 163 6,156 9,121 9.1149 fTDZ, / CONH Soc

FH2C + co2pmb (Please read the precautions on the back before filling out this page)-Install · V-1 69 fTDZ, / C〇NH Boc

, 1T Sealed I-9 *, Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (3) As above, it was made by 7- 丄 _4.118 people &lt; 9.92 Tengzhong 01 &gt; and £ _ ^ 2.811 (9 articles) I-_a_, 7.35 g (765i) 〇 -9. '3.: NMR (d6-DMSO) 5: 12. 6 8 (lH, bs). 9.9 5 (1 H, d, J = 10.3 Hz ), 8.76 (2H, d, J = 7.90Hz), 8.43C1H, s), 8.37 (2H, d, J = 7.50Hz), 7.37 (3H, d, J = 7.90Hz), 6.91 (2H, d, J = 8. 6 9 Hz). 6.00 (lH, dd, J = 8.77,6.3 2Hz), 5.90 (lH, bs), 5.71 (lH.bs), 5.15 ~ 5.50 (5H, m), 3.72 (3H, s), 3.4 9, 3.5 9 (2H, ABq, J = 19.7 Hz), 1. 5 6 (9H, s), 1.5 l (9H, s) IR (KBr) vcm-1: 2970, 2150, 1788,1714,1634, This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297mm) -117 117 A7 B7 V. Description of the invention (114) 124 6,1149 Window window 10 tdz, ^ conhb. cX v

co2pmb f702. XONH

CH3 〇Θ Na © O ^ NCN 70

〇Θ NCN C02PMB 1-10 (Please read the precautions on the back before filling this page)

AT〇Z r〇NH

〇 ^ N ^ c〇NHCN order 1-10 · (1) As above, a yellow powder I-i_Q_4 was prepared from 7 0 1.24g (5.0aiH0l) and V-J_ 4. 14 (5.0 · following 0l>). 75g. Furthermore, M is the same as the above method, and Φ I- 1 0 4.75 «(5 ·· ο1) was prepared as a light yellow powder 1-1 1.3 g (41Z &gt;). I -IQ: NMR (de-DMS 0) 5: 12.67 (1 H, bs). 11.84 (1 H, bs), 9.90 (lH, d, J = 8-l Hz), 8.60 (2H, d, J = 4.9 Hz), 8. 0 9 (2H, d , J = 6. 9Hz). 7. 6 9 (1 H, d, J = 3.3 Hz). 7.3 6 (2H, d, J = 8.4Hz), 6.91 (2H, d, J = 8.7Hz) , 6.04 (1 H, dd, J = 8.4, 4.8 Hz), 5.90 (lH, bs), 5.72 (lH, bs), 5. 2 0 to 5.44 (5H, m), 3.72 (3H, s), 2.63 (3H, s), 1.51 (9 This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 public holidays) H — -------: ··-* Employee Consumer Cooperatives, Central Procurement Bureau, Ministry of Economic Affairs Seal 袈 118 A7 B7 V. Description of the invention (115) H, s) I RCKBrhcnr1: 297 0, 2150, 1784, 1711, 1633 I -1 0,?: NMR (dfi-DMSO) 5: l 1. 8 3 ( 1 H.bs), 9.8 (1 H, d, J = 8.2 Hz), 8.70 (2H, d, J = 6.60 Hz), 8.20 (2H.s), 8, 13 (2H, d, J = 6.60 Hz), 7.68 (lH, d, J = 3.40 Hz), 5.89 (2H, m), 5.62 ( lH, s), 5.43, 5.23 (2H, ABq, J = 14Hz). 5. 2 0 (lH, d, J ==, 5. 0Hz), 5. 5 9. δ. 3 7 (2 H, A Bq, J = 18.5 Hz), 2. 6 4 (3H, s) IR (Nujol) y cm · 1: 3184, 2144, 1773, 1675, 1633, 12 15

Boc—ATDZ JZ, ^ CONH ^ 5. Red Seven P ^ NCN CO2PMB Boc 1-10 '(Please read the notes on the back before filling out this page) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (2 &gt; Ibid., Guaranteed by Boc No. 7 0 150 «^ (0.43« 〇1>) and \ ^ 1_ 328 · 8 (0.43 ·· 〇1) to obtain a yellow-brown powder 1_cl '451llg0 I -10': NMR (CDC13) &lt; 5: 9. 0 4 ( lH, d, J = 7.0 Hz), 8..0 5 (2H, d, J = 6.4 Hz), 7.91 (lH, s), 7.34 (2H, d, J = 1.0 Hz), 6.90 ( 2H, d, J = 8.6 Hz), 6.0 (lH, d, J = 5.0 Hz), 5.93 (lH, m), 5.64 (lH, m), 5.20 to 5.30 (5H, m), 3.8 l ( 3H, s), 3.4 2, 3.5 9 (2H, ABq, J = 19Hz), 2.36 (3H, s), 1. 6 l (9H, s), 1. 5 7 (9H, s) This paper size applies China National Standard (CNS) A4 specification (210X297 mm) 119 5. Description of invention (116)

I RCCHCla) ^^-1: 2980,225 0,215 4,176 9,171 6, 163 4, 154 3, 124 5, 1149 Example 11 ATDZ XONH tT co2pmb

CONHCN V-2

M1

CONH &lt; Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1-1V (1) Put 50〇8 (2.36 ·· 〇1): L_U〇 into anhydrous DMSO In 20 · 1, under the room », add 2.324 g (3.06nnol &gt;) to the« air roll and stir for 2 hours; then, drop the reaction solution into 500 · 1 diethyl ether to obtain the precipitated oil, and then Dissolved in diaminomethane 8.1, and slowly dripped this dichloromethane solution in agitated diethyl ether 500 · 1. The precipitate was filtered and dried to obtain 2.5 g of yellow powder I-I. I —: NMR (d6 — DMS〇) &lt; 5: 1 2. 6 5 (1 H, bs), 1 2. 6 0 (1 H, bs), 9.70 (lH, d, J = 8 Hz), 8.68 (2H, d , J = 6Hz), 8. 18 (2H, d, J = 7.5Hz), 8.15 (lH, bs), 7.45 (iH, bs), 7. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -120-A7 __B7_ V. Description of the invention (117) 3 7C2Hfdf J = 8. δΗζχ 6. 8 4 (2 H, d, J = 8. 5 Hz), 5.98 (1 H, dd, J = 10, 5 Hz), 5.12 to 5.43 (5H, m), 4.20 (2H, q, J = 7.25 Hz), 3.73 (3H, s), 3.4 to 3.7 (2H, m), 1.5CK9H, s), 1. 2 3 (3H, t, J = 7. 5 Hz), IR (CHC13) vcm-1: 2986, 2250, 2150, 1772, 171 5, 1 63 3 (2) Same as i, by I- 丄 1 290 shirts &lt; 0,3 «1« 〇 1 &gt; A pale yellow powder 1-.11 ·, 68 ng (375!) Was obtained. I -11: NMR (d «-DMSO) d: 12.1 KlH.bs). 9.60 (1 H, d, J = 8.1 Hz), 8.67 (2H, d, J = 6.9 Hz), 8.23 (2H, d , J = 6.9Hz), 8.14 (2H, s), 7.90 (lH, s), 7.21 (lH, s), 5. 9 0 (lH, dd, J = 9, 5. 2 Hz), 5.3 8, 5. 2 1 (2H, ABq, J = 15.8Hz), 5.19 (lH, d, J = 5.1Hz), 4.14 (2H, q, J = 6.9Hz), 3.5 2, 3.3 8 (2H, ABq, J = 19.5 Hz), 1.21 (3H, t, J = 7. 0 5Hz) IR (KBr) van.1: 2989, 2257, 2155, 1775, 1674, 163 6, 156 9, 133 5, 1162 ( Please read the notes on the back before filling out this page) = Packing. Order-East. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This paper is sized for China National Standards (CNS) A4 (210 X 297 mm) 121 A7 B7 V. Description of Invention (lis)

+ N

CONHCN 71

CONH f (ch4 (Please read the precautions on the back before filling this page) Η2ΝΪ ^ Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy m 1-12 '(1) Ibid., By V-_2L 777 «g (lBmoI) 7S 7 T 212ag (laaol) gives yellow powder I- 丄 _2_ 937 «g (95X). I -12: NMR (d6-DMSO) &lt; 5: 1 2. 8 6 (lH, m). 12. 6 4 (1 H, m), 9.76 (lH, d, J = 7.5Hz), 8.70 (2H, d, J = 7.5Hz), 8.21 (1Η, π〇, 8.19 (2H, d, J = 6Hz), 7.56 (lH, s), 7.38 (2H, d, J = 9Hz) &gt; 6.92 (2H, d, J = 9Hz) n 6.00 (lH, dd, J = 9,5Hz), 5.10 ~ 5.50 (5H, m), 4.78 (lH, m), 4.54 (2 H, m), 4.32 (lH, m), 3.72 (3H, s), 1.50 (9H, s) IR (CHCla) ^^- 1: 3012, 2400, 2250, 1771, 171 5,168 6,154 9,124 6,1151 This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 122-A7 B7 V. Description of the invention (119) (2) Same as above, light yellow powder I-1 2, 117Bg (19%) 〇I-丄 1,: NMR (d6_DMSO) 5: 1 2 · from raw material 1- 丄 _ £ _ 93〇M (〇 · 94ϋ · ο1). 1 l (lH, bs), 9. 6 7 (1 H, d, J = 9Hz), 8.68 (2H, d, J = 6.6Hz), 8.23 (2H, d, J = 6.8Hz), 8.16 ( 2H, s), 7.90 (lH, s), 7.21 (lH, s s), 5. 9 0 (lH, dd, J = 9, 5 Hz), 5.38, 5.20 (2H, ABq, J = 14.5 Hz), 5.19 (lH, d, J = 5.0 Hz), 4.75 (lH, m), 4.51C1H, m), 4.42 (lH, m), 4.27 (lH, m), 3.5 5,3.2 6 (2H, ABq, J = 19.5 Hz) IR (KBr) r; ci-1 : 2256, 2154, 1776, 1676, 1636. 156 9,133 4,1161 (Please read the precautions on the back before filling out this page) 'L— ϋ IL · .Equipment., Tr Examination Example 1: ¾

V-2 ATDZ ^ x〇nH Boc

+ IS

Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 丨? s CH3〇0 Η2N ~ &lt; δνΝ 'Ν_ί CONH j C02PMB 1-13 in gh μΐ3 · The paper scale is applicable to China National Standard (CNS) A4 (2! 〇X 297 mm) -123 123 —-I g — Hr Printed by A7 B7, Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (120) (1) Ibid., V-_2L 910ng (1.2niol) and 7 2 226ag (lano 1) were used to obtain yellow powder 1-1 3 1.57. I -1_3: NMR (d6-DMSO) &lt; 5: 12.61 (lH, m) N 11.96 (1H, m), 9.7 1 (lH, d, J = 9Hz), 8.60 (2H, d, J = 6.5Hz), 8. 2 0 (lH, m), 8'll (2H, d, J = 7Hz), 7.78 (lH, s), 7.38 (2 H, d, J = 9.0Hz), 6.96 (2H , d, J = 9.0Hz), 5.99 (lH, m), 5.10 ~ 5.56 (5H, m), 4.20 (2H, q, J = 6.0Hz), 3:73 (3 H, s), 2.5 5 ( 3H, s), 3.4 0 to 3.6 2 (2H, in), 1.5 1 (9H, s), I. 2 3 (3H, t, J = 7Hz) IR (CHC13) vcnr1: 2988, 2154, 1772, 1715 1,154 0, 1 2 4 5, 1 2 2 0 (2) Same as above, and the light yellow powder I-13, 2 Ug (3.3: S) was obtained from 1- 1 3 985ag (UBOl). I-U ': NMR (de-DMSO) &lt; 5: 1 1. 8 3 (lH, bs), 9. 5 9 (1 H, d, J = 9Hz), 8.71 (2H, dJ = 6.5Hz) , 8.14 (4H, m), 7.69 (lH, d, J = 3.0Hz), 5.88 (lH, dd, J = 8.2,5.1Hz), 5. 4 3, 5. 1 9 (2H, ABq, J = 13.6 Hz), 5.18 (lH, d, J = 5.0 Hz), 4.15 (2H, q, J = 6.3 Hz), 3.57, 3.29 (2H, ABq, J = 19 Hz), 2.64 (3H, s ), 1.21 (3H, t, J = 6.9Hz) IR (KBr) vcm-1: 2253.2155, 1779, 1634, 1563, 1391, 1156 This paper size applies to China National Standard (CNS) A4 specification (210X29 ·; mm ) ---- 1 --'---! Install-Γ (Please read the precautions on the back before filling this page)

, 1T 124 ΙύΗ 1 B7 5. Invention Description (ui)

Chong Lili 1A

fTDZ, ^ CONH Boc T

V-2 co2pmb

n- ^ L ^ conh H2N- &lt; S &gt; (Please read the notes on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives i 1-14 '(1 &gt; Ibid., by ν- 2_ 1.898 &lt; 2.48 hurricane surface 〇1 &gt; and £ _ ^ _ 506 ^ g &lt; 2.0 7 ·· ο1) gave 2.27g of yellow powder. I _l_i: NMR (d6-DMSO) &lt; 5: 12.61 (1H, s), 12.27 (1 H, s), 9.7 1 (lH, d, J = 9Hz), 8.7 8 (2H, d, J = 6.9 Hz), 8.05 (2H, d, J = 6.9Hz), 7.83 (lH, s), 7.79 (lH.s), 7.7 l (lH, d, J = 1 6. 5Hz), 7. 3 6 (2H, d, J = 9Hz), 6. 9 2 (2H, d, J = 8.4Hz), 6.38 (lH, d, J = 15Hz), 5-99 (lH, dd, J = 9.8, 5Hz) , 5.43 (2H, ABq, J = 15.8Hz), 5.24 (3H, d, J = 5.1Hz), 4.20 (2H, q, J = 7.2Hz), 3.73 (3H, s), 3. 3 8, 3.5 8 (2H, ABq, J = 9.8Hz), 1.50 (9H, s), 1.24 (3 Ht J = 7. 0 5 Hz) IR (CHC13) v cm · 1: 2988,2362,1774,1716,160 copies Paper size applies Chinese National Standard (CNS) A4 specification (210: &lt; 297 mm) -125 ~ A 7 B7 V. Description of the invention (122) 1,154 0,1243 (2) Same as above, made of raw materials I- 丄 _4_ 2.256g (2_07 «na〇l >> light yellow powder 1-14 '536 (40: 0. I-14': NMR (d6-DMSO) (5: 12.06 (lH, bs). 9. 6 0C1 H, d, J = 9Hz), 8.89 (2H, d, J = 6.6H?), 8.03 (2H, d, J = 6.9Hz), 7.71 (lH, s), 7.57 (lH, d, J = 15.3Hz), 7.48 (lH, s), 6.25 (lH, d, J = 15.6Hz), 5.83 (lH, dd, J = 8. 3,6Hz), 5.4 4,5.2 3 (2H, ABq, J = 15Hz), 5.18 (lH, d, J = 6Hz), 4.1 4 (2H, q, J = 6.9Hz), 3.60, 3.3 7 (2H, A Bq, J = 18Hz), 1.22 (3H, d, J = 7.05Hz) I RCKBOvcar1: 2980,2242,2156,177 4, 16 71, 163 4, 153 9, 139 1, 1169 Shen Lili is LDVC0 ws H 000 + Et co2pmb V-2 73 λ · &lt; &quot; · *

V-2 tdz ^ CONH Boc T (Please read the notes on the back before filling this page)

, 1T Printed by Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs

COsPMB

〇Θ C = NCN μΐ5 ατο ^ οονη M5_ (1) Same as above, composed of VL 91lBg (1.2aaol) and 2 ^ 2- 273ag (Ua〇 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) ) 126 Printed by Shelley Consumer Cooperative of Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (123) 1> Obtained yellow powder I-1 5 1. 12g ° I -15: NMR (de-DMSO) d: 12.60 (lH , m), 12.31 (1 H, m), 9.70 (lH, d, J = 9Hz), 8.66 (2H, d, J = 7.0Hz), 8.29 (lH, s), 8.22 (2H, d, J = 8-5Hz), 7.79 (lH, s), 7.6 1 (1H, s), 7.38 (2H, d, J = 9Hz), 6.95 (2H, d, J = 9.1Hz), 5.99 (lH, dd, J = 9.5Hz), 5.40 (2H, m), 5.24 (3H, m), 4.20 (2H, q, J = 7.5Hz), 3.73 (3H, s), 3.30 ~ 3.60 (2 H, m) , 1.50 (9H, s), 1.23 (3H, t, J = 7.5Hz) I RCNujoDvcm-1 2 3: 297 8, 215 8, 177 2, 171 6, 154 2, 1 3 69, 1 2 4 5 — (2) Same as above, I. lg (1.000 to get yellow powder I 282ig (41: 0) (Please read the precautions on the back before filling out this page)-Loading ·,? Τ This paper size applies to Chinese national standards (CNS) Α4 specification (210 × 297 mm) -127-127 1 -15 ·: NMR (d6-DMSO) 5: 1 2 · 2 2 (lH, bs), 9. 6 0 (1 H, d, J = 9.0Hz), 8.79 (2H, d, J = 6.8Hz), 8.14 (3H, s), 7.74 (lH, s), 7.55 (lH, s), 5.87 (lH, dd, J = 8.5, 5Hz), .5. 4 1, 5. 2 3 (2H, ABq, J = 1 5Hz), 5.18 (lH, d, J = 5.0 Hz), 4.14 (2H, q, J = 7.0Hz) , 3.36 to 3.60 (2H, m), 1.2 1 (3H, t, J = 7. 1Hz) 3 IR (KBr) vcm-1: 298 4, 225 7, 2157.1775, 1671, 4 162 3, 156 4 , 134 8, 1155 A7 B7 V. Explanation of the invention () 24) Examination period I 1ft fDZ, ^ CONHB〇c &gt; »+ nD ^ vV '

CONHCN

C02PMB V-2 74 Xi Ding dz, ^ CONH Boc j!

Et co2pmb 1-16

ATDZ, / CONH (please read the notes on the back before filling out this page) Du Yin 袈, 1-16. (1) Ibid., By vi 1.82g (2.4iBB〇 &quot; and 7 4 5.05ng (2nn 〇l) to obtain yellow powder JL_6_ 2.26g. I -16: NMR (d6-DMSO) 5: 12.61 (1 H, s), 12.30 (1 H, s), 9.70 (lH , D, J = 9Hz), 8.68 (2H, d, J = 6.6Hz), 8.29 (2H, d, J = 6.9Hz), 8.13 (lH, s), 7.37 (2H, d, J = 8 7Hz), 7. 3 l (lH, s), 6. 9 2 (2H, d, J = 8. 4Hz), 5. 9 9 (1 H, dd, J = 9.5Hz), 5.39 (2H, brs), 5.24 (3H, m), 4.20 (2 H, q, J = 7.2Hz), 3.73 (3H, s), 3.51 (2H, ABq, J = 19. 5Hz), 2.15 (3H, s), 1.50 (9H, s), 1.23 (3H, t, J = 7.2 Hz), IR (CHCl3) ^ cm-1: 2990,2234.2144,1771,171 6,168 2,162 9,124 5,1543 This paper standard applies to the Chinese National Standard (CNS ) A4 specification (210X297 mm) 128 -1 OO-V. Description of the invention (l25) atdz, / C〇nh

A7 B7 co2㊀

CONHCN 1-16 '(2) Ibid., From 1- 丄 _ £ _ 2.02g (2aB0l), a yellow powder 1- 丄 _2_, 476ig (36X) β 1-16. *: NMR (d6-DMSO) d: 12. 10 (lH, bs), 9. 62C1 H, d, J = 9Hz), 8.73 (2H, d, J = 6.9Hz), 8.24 (2H, d, J = 7.2Hz), 8.12 (2H , s), 8.08 (lH, d, J = 1.2 Hz), 7.36 (1 H, s), 7.11 (lH, s), 5.86 (lH, dd, J = 9.8, 5.1 Hz), 5.4 1, 5. 2 0 (2H, ABq, J = 1 4Hz), 5.18 (lH, d, J = 4.8 Hz), 4. 15 (2H, q, J = 6.9 Hz), 3.58, 3.33 (2H, ABq, J = 18 Hz), 2.0 9 (3H, s), 1.2 2 (3H, t, J = 7.2Hz) IR (KBr) y cm · 1: 2987,2243,2150,1775,1672, 163 1,153 0,135 5,1152 ( (Please read the notes on the back before filling out this page) -install.

, 1T Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -1? .Q-129 A7 B7 V. Description of the Invention (126) Example 17

Tdz, ^ CONH Boc T fh2c + o ~ iy

CONHCN

C02PMB V-i 112 TDZ, &gt; c〇nh Boc: FH &gt; co2pmb 1-17

ATDZ, / CONH

FH2C ^^ n〇- ^ vconhcn (Please read the precautions on the back before filling in this page) 0 meL · — a ^ n HBl · -Pack- 1-17 '(1) Will be 229g (lM〇U 的 丄 _I_2J 〇Into DMS07W and suspend it, add V-JL 957 «g (1.2« mol &gt;) to the air sacrifice under room temperature, and stir at room temperature for 100 minutes; then, after the insoluble matter is filtered off, The filtrate was dropped into 5Z saline solution, and the precipitated solid matter was collected by filtration and washed with 5ϋί saturated saline solution. Then, this solid matter was dissolved in a solution of acetamidine / three gas methane = 3/1, and the organic layer was separated. After drying with magnesium sulfate, the magnesium sulfate was filtered off. The filtrate was decompressed and concentrated. The residue was poured into ethyl sugar 100 · 1, and the precipitated solid matter was filtered and dried to obtain a yellow powder. 2_ 344 »g (4 (U). I -17: NMR (de-DMSO) (5: 12.6 9 (lH, bs). 9.90 (1 H, d, J = 8.2Hz), 8.85 (2H, d, J = 7Hz), 8.71 (lH, s), 8.49 (2H, d, J = 7Hz), 8.24 (3H.s), 7.37 (2H, d, J = 8Hz), 6.90 (2H, d, J = 8Hz), 5.99 (lH, dd, J = 8.2,4.8Hz), 5.94 (lH, s), 5.67 (lH, bs), 5.47 (2H, bs), 5.14 — 5.26 This paper size is applicable to China Standard (CNS) A4 size (210 X 2 97 mm)

Printed 130 A7 B7 by the Shell Specimen Consumer Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs. ) IR (KBr) vcm-1: 2970, 2166, 1787, 1712, 1632. 153 9,124 5,115 1,855 (2) Same as above, from 1- 1 7 335ng &lt; 0.388M〇l &gt; yellow-white powder I ~ 1 7 ' 25 ^ g (10X &gt;.

1 ~ 1_I ,: NMR (de-DMSO) 5: 9.79 (lH, d, J = 8.1H z), 8.98 (2H, d, J = 6.6Hz), 8.66 (lH, d, J = 1.8Hz), 8.5 3 (2H, d, J = 6.9Hz), 8.19 (3H, s), 5.89 (lH, dd, J = 8.0, 5.3Hz), 5.84 (lH, s), 5.66 (lH, s), 5.51 , 5.32 (2H, ABq, J = 14.6Hz), 5.20 (lH.d, J = 5.1Hz), 3.5 6, 3.3 7 (2H, ABq, J = 1 8. 3Hz) IR (KBr) vcm'1: 2170,1777,1675,1633,15 3 8, 134 9, 115 4, 106 2, 989 (Please read the precautions on the back before filling out this page) &quot; installation--'V6 shellfish consumption by the Central Standards Bureau of the Ministry of Economy The paper size of the printed form of the cooperative is applicable to the Chinese National Standard (CNS) A4 (210 x 297 cm) 131 A7 B7 V. Description of the invention (128) Support 18

V-2

NCN

ATDZ, / CONH 1-18, S (Please read the notes on the back before filling this page) -►

CONHCN 1-18 'Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (1) Same as before. V-2_ 1.749g (1.844M〇l &gt;) and UiU-413ag (1.756 ·· ο1) were used to obtain the black powder 1-1. ft 1.462g (962). I -18: NMR (de-DMS0) 5: 1 4.1 KlH.bs). 12.60 (1 H, bs), 9.70 (lH, d, J = 8.4 Hz), 8.85 ( 2H, d, J = 6.8 Hz), 8. 47 (2H, d, J = 6.8 Hz). 7.49 (lH, s). 7.35 (2H, d, J = 8.6 Hz), 6.91 (2H, d, J = 8.6Hz), 5.99 (lH, dd, J = 8.6, 5.0Hz), 5.43, 5.51 (2H, ABq, J = 16.5Hz), 5.16-5. 33 (3H, m), 4.19 (2H, q , J = 7.〇Hz), 3.72 (3H, s), 3.6 0, 3.47 (2H, ABq, J = 19Hz), 1.50 (9H, s), 1.23 (3H, t, J = 7. 2Hz) IR (KBr) y cm'1: 2970, 215 4, 1789, 1713, 1636, this paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 132 A7 B7

+ N

CONHCN Printed by the Central Ministry of Economic Affairs and only printed by the Consumers' Cooperatives. V. Invention Description (1 5 3 8,134 1,124 5,115 1.1034 (2) Same as before, from 335mg (〇.388iniB〇l &gt; I- 丄) to obtain a yellow-white powder I 1.8 '25eg (10%) 〇I-U': NMR (d6 — DMSO) o: 1 4. 0 9 (lH, bs), 9.6 0 (1 H, d, J = 8.4 Hz) n 8. 9 2 (2H, d, J = 6. 9Hz). 8. 5 1 (2H.d, J = 6. 9Hz), 8.12 (2H, s), 7.47 (lH, s), 5.91 (lH, dd, J = 8. 4, 4'8Hz), 5.5 2,5.3 8 (2H, ABq, J = 14.9Hz), 5..19 (1 H, d, J = 5. 1Hz), 4. 1 4 (2H, q, J = 7. 2Hz). 3.56, 3.4 1 (2H, ABq, J = 15.5Hz), 1.2 l (3H, tf J = 7. 0 5Hz) I RCKBOi / cm-1 : 2 9 7 0, 2 1 5 8, 1 7 7 4.1 6 7 1, 1 6 3 6, 152 6,140 3,134 5,115 4,1036

V- £

1-19 'This paper size applies Chinese National Standard (CNS) A4 (210X 297mm) -133 (Please read the precautions on the back before filling this page)

B7 V. Description of the invention (l30) (Please read the precautions on the back before filling in this page) (1) Put 306μ &lt; 1.2 ·· ο1 &gt; of the "LJZJBI" into DMSO 6. · 1, While stirring, add Ν, Ο-bis (trimethylsilyl) acetamidine 292 «1 (1.2 ·· ο1 &gt;, and then add V-2_ 1.195β (1 · 26 ·· ο1) in the room while stirring. Stir at room temperature for 85 minutes; then, add the anti-droplet to 55; saturated saline 65.1, filter out the precipitated solids, and wash with water; then, dissolve this yellow solid in Otsuki / Three gas methane (80 · 1 / 30β1 &gt; solution, dried magnesium sulphate, dehydrated magnesium sulfate, concentrated the filtrate under reduced pressure, and added the residue to ethyl succinate 50 · 1, and then added ether 100 · 1, the precipitated crystals were collected by filtration, and dried to obtain a yellow powder I-1_9_ 840 μ (79 × &gt;. I -19 .: NMR (d6-DMSO) d: 12.60 (lH, bs), 9.6 9 (1 H, d, J = 8.4Hz), 8.91 (2H, d, J = 7.2Hz), 8.78 (lH, s), 8.44 (2H, d, J = 6.9Hz), 8.19 (lH, s) , 7.63 (lH, d, J = 15.6Hz), 7.35 (2H, d, J = 8.7Hz), 6.91 (2H, d, J = 8.7Hz), 6.39 (lH, d, J = 15.6Hz), 5. 99 (lH, dd, J = 8.6 Hz, 5.0 Hz), 5.5 3, 5.46 (2H, ABq, J = 13.5 Hz), 5.17-5.26 (3H, m), 4.20 (2H, q, J = 7.2 Hz ), 3.72 (3H, s), 3.5 4, 3.5 9 (2H, ABq, J = 17.3Hz), 1.50 (9H, s), 1.2 3 (3H, t, J = 7Hz) IR (KBr) i / cm · 1 printed by consumer cooperatives: 2970, 2228, 2148, 1788, 1713, 1630, 153 7. 151 4, 1 369, 124 5, 1 153. 1033 (2) Same as above, by 83Us (0.94mo1 &gt; yellow-white powder 1-J_9_i232ig (37Z) 〇1 ~ 19 ': NMR (de-DMS0, D20) 5: 9.62 (lH, d, J = 7.5 Hz), 9.00 (2H, d , J = 6.0 Hz), 8.70 (lH, s), 8.44 (2H, 134) The paper size is applicable to the national standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (1M) d, J = 4.8Hz), 8.12 (lH, s), 7.58 (lH, d, J = 15.3Hz), 6.35 (lH, d, J = 15.2Hz), 5.87 (lH, d, J = 6Hz), 5,54, 5.33 (2H, ABq, J = 15Hz), 5.17 (lH, d, J = 6Hz), 4.13 (2H, q, J = 7. 5Hz), 3. 77, 3.37 (2H, ABq, J = 18Hz) , 1.22 (3H, t, J = 6.8Hz) IR (KBr) v cut1: 2257,2158,1776,1674,1623, 153 6, 135 7, 115 6, 1038

V-2

(Please read the notes on the back before filling this page).

、 1T Λ Printed by the Consumers' Cooperative of Zhongli Standards Bureau of the Ministry of Economic Affairs

(1) Same as before, S_fi_ (E) 123i «g (0_488Bii〇l &gt; and V-2_ 458mg (this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -135-A7 _____ B7_5 Description of the invention (l32) 0.58β · ο1 &gt; Obtained yellow powder 1-2 Ο 393 · 8 (quantitative). I-and · NMR (de-DMS0) 5: 1 2. 6 0 (lH, bs), 1 2. 4 9 (1 H, bs), 9.69 (lH, d, J = 8.1 Hz), 8.68 (2H, d, J = 6.9 Hz), 8.24 (2H, d, J = 6.6 Hz), 8.22 ( lH, s), 7.41 (lH, s), 7.35 (2H, d, J = 8.7Hz), 6.92 (2H, d, J = 8.7Hz), 6.27 (1H, d, J = 0.6Hz ), 5.99 (lH, dd, J = 8.2 5,4.9 5Hz), 5.4 1, 5.38 (2H, ABq, J = 9Hz), 5. 1 6 — 5. 25 (3H, m), .4. 2 0 (2H, q, J = 7. 2Hz). 3.73 (3H, s) n 3. 5 7, 3. 4 9 (2 H, A Bq, J = 17.3Hz), 1.50 (9H, s), 1.24 (3H, t, J = 7.05H z) I RCKBr) vcm'1: 2 9 7 2, 2 2 3 0, 2 1 4 4, 1 7 8 6, 1 7 1 1, 1633, 1610, 1543, 1245,1153,1033,931 (2) Same as before, yellow color powder 20, 75ig (26X) «I-2 0,: NMR (d from 1-2 Q 382 · 8 (0.43 ·· 〇1) "DMSO) 5: 1 2. 2 6 (lH, bs), 9. 5 5 (1 H, d, J = 7.8Hz), 8.84 (2H, d, J = 6Hz), 8.21 (2H, d, J= 6Hz), 8.13 (2H, s), 8.08 (lH, s), 7.25 (lH, s), 6.31 (1H, s), 5.84 (lH, dd, J = 9,5.4Hz), 5.39,5 · 16 (2Η, ABq, J = 14Hz), 5.14 (lH, d, J = 5.4Hz), 4.14 (2H, q, J = 6.3Hz)% 3. 5 8, 3. 2 6 (2H, ABq, J = 2 0Hz) n 2.50 (3 H, s), 1.2 l (3H, t, J = 6.9Hz) I RCKBOi / cm-1: 2238,2147,1775,1676,1635, 1605,15 2 5,1353,1154,1037,933 (Please read the notes on the back before filling out this page) --9 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -13〇 ~ A7 B7 5 2. Description of the invention (B3)

V-2

Same as before, the yellow-brown powder 485m (99Z) was obtained from 9 ft (Z) 162m (0.642m〇U and V-2_ 552ig (〇.706βιο1). (Please read the precautions on the back before filling this page). · Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative I-2 1: NMR (d6-DMSO) 5: 1 2. 6 0 (1 H, bs). 12.42 (1 H, bs), 9.69 (lH, d, J = 8.1 Hz), 8.6 5 (2H, d, J = 6. 6 Hz), 8. 2 2 (2H, dd, J = 6. 6, 0.6 Hz), 8. 1 6 (lH, d , J = 3. OHz), 7.36 (2H, d, J = 8.4Hz), 7.33 (lH, d, J = 3.0Hz), 6.9 2 (2H, d, J = 8. 4Hz), 5. 9 8 (lH, dd, J = 8. 9, 4.5 Hz), 5. 71 (lH, s), 5.39, 5.37 (2H, ABq, J = 8 Hz), 5.13-5. 26 (3H, m), 4.20 (2H, q, J = 6.9Hz), 3.73 (3H, s), 3.4 8, 3. 5 6 (2H, ABq, J = 1 8.8Hz). 2.24 (3H, s). 1.50 (9 H, s), 1. 2 3 (3H, t, J = 7. 2Hz) IR (KBr) y cm · 1: 2970,224 0, 214 4, 1787,171 2, IΛ I—: I 1-· This paper Standards: Chinese National Standard (CNS) A4 specifications (210X 297 mm) 137 A7 B7 V. Description of the invention (134) 1632,1546,1514,1246,1154,1033,93 2 ΐ · (Please read the note on the back first (Please fill in this page again) Inhibition concentration (MIC). Dilute the test compounds in sequence, inject 1.0 · 1 each into a petri dish, and then inject tryptone 臃 亘 amaranth culture base 9.0 丨 1 and mix; on this mixed agar plate Apply the suspension of the test bacteria, and after eating overnight at 37-C, the lowest irrigation degree of the test compound that can completely inhibit the proliferation of the test bacteria is the MICo test bacteria-Gram-exposed bacteria: S. pyogenes C-203 S. agalactiae ATCC13813, S. pn eumoniae Type I, S. pneumoniae SR16675 (PC-R), S.mitis ATCC9811; Gram-negative bacteria: 5. pneumoniae SB1, P. mirabilis PK-4, P. vulgaris CN -329 Results: _MIC (^ g / ml) __ inoculation amount 10 eCFU / ml test compound I-! Of the compound control compound of the present invention, If ⑴ (2) ___ (^ &amp; 1) (Exemplary Example 9) Lange-positive bacteria ^ ~ &quot; Printed by S.pyogenes C-203 0.006 0.006 0.013 0.006 S. agalactiae ATCC13813 0.025 0.013 0.1 0.025 S. pneumoniae Type I 0.013 0.006 0.05 0.006 S. pneuioniae SB16675CPC-B) 0.2 0.2 0.78 0.39 S. mitis ATCC9811 Gram-negative 豳 0.05 0.025 0.1 0.025 K. pneumoniae SB1 0.006 0.006 0.05 0.013 P.mirabilis PE-4 0.013 0.013 0.1 0.05 P. vulgaris CN-329 0.013 0.013 0.1 0.025 138 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 389 * 768 A7 ____B7 V. Description of the Invention (l35) (Control Compound)

(Please read the note on the back before filling in this page.) Printed by the Central Samples Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. It can be clearly seen from Table 1 that the compounds of the present invention are representative of pathogenic bacteria that are valued clinically. Sexual strains, have a fairly balanced excellent antibacterial effect. aChi Li 2 The half-life in blood and the therapeutic effect on mouse infections are the same as in Test Example 1 above, using compound BU3_ '' and the control compound (1>). Table 2 Half-life in blood (h) 1 -_2_ Control compound rat 0_96 0.39 Monkey 2_48 1.28 To produce antibacterial effect on pus, it is necessary to make long-term contact with tincture. Therefore, the half blood stage (T 1/2) in the M blood is more favorable for the elderly. The above results show that 》 The compound of the present invention is also effective in the treatment of Epiderma infection. 、 Τ.?. This paper size applies the Chinese National Standard (CNS) A4 specification (21 × X 297 mm) -139-389766 A7 B7 V. Description of the invention (136) Table i Effect of mouse infection treatment EDeD (mg / kg) 1-9 &quot; Sealed compound ⑴ S. aureus Smith 0.41 0. 76 S. pneumoniae Type I 0. 042 0.69 P. vulgaris GN-329 0.009 0.61 P. aeruginosa SR24 0.38 1.52 P. aeruginosa E-2 0.79 4. 73 The results listed above show that the compounds of the present invention have therapeutic effects in vivo. -10¾ (Please read the precautions on the back before filling this page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs Consumption Cooperatives Printed on Paper Available in China Home Standard (CNS) Α4 Specifications (210 X 297 mm) - 140

Claims (1)

Announcement VI. The scope of patent application A8 B8 C8 D8 383 *? Βδ No. 861 〇42 5 8 Patent application is specifically for-Fan-im Date of amendment: October 1988 1. A cephalosporin of formula I Compounds or their salts (esters) or their hydrates: ίοο ©, (In the formula, Acyl means fluorenyl; Het is a group selected from the group consisting of furyl, cetyl, tetrazolyl, and Base, carbazolyl, imidazolyl, oxazolyl, oxazolyl, pyridyl, oxazinyl, triazinyl, pyrrolidinyl, thiazolyl, oxazinyl, imidazolyl, oxazoline , Oxalinyl, michelinyl, β-base, D-base, morphinyl, thiomorpholinyl, oxadiazolinyl and dioxanyl; Ri is hydrogen, C16 alkyl or Cw alkenyl; a is C6 alkenyl, optionally amine, halogen, or C2-6 alkenyl or single bond substituted by C6 alkenyl; B is imine or single bond; D is single bond Or the following chemical formula-Het-AB-CO-D-NHCN 2. A compound or a hydrazine (ester) thereof or a hydrate thereof according to item 1 of the scope of patent application, wherein in the compound, the Acyl is a group represented by formula III: Dimensions applicable in this paper ® Grid G &quot; x297 public love) Announcement VI. Scope of patent application A8 B8 C8 D8 383 *? Βδ No. 861 〇42 5 No. 8 patent application application is specifically-fan—im Date of amendment: 88 October 10. 1. A cephalosporin compound or a salt (ester) thereof, or a hydrate thereof, of the following formula I: ίοο © (wherein, Acyl means amidino; Het is a group selected from the following group : Furyl, cetyl, tetrazolyl, rockyl, carbazolyl, imidazolyl, oxazolyl, oxazolyl, pyridyl, oxazinyl, triazinyl, pyrrolidinyl, thiazolyl, Oxazinyl, imidazolidinyl, oxazolinyl, oxazolinyl, mironyl, β-base, D-base, morpholinyl, thiomorpholinyl, oxadiazolinyl and Dioxane; Ri is hydrogen, C16 alkyl or Cw alkenyl; a is Cl 6 alkylene, optionally amine, halogen or C6-6 alkylene substituted by a C6 alkyl group or a single bond; B is an imine group or a single bond; D is a single bond or the following chemical formula -Het-AB-CO-D-NHCN 2. A compound or a hydrazine (ester) thereof or a hydrate thereof according to item 1 of the scope of patent application, wherein in the compound, the Acyl is a group represented by formula III: The standard of this paper is applicable to G® G &quot; x297 public love) 38976S is the scope of patent application. (Where X means CH or N; Y means protected or unprotected amine group; Z means hydrogen or optional Is a 6-alkyl group substituted with a halogen atom). 3. The compound or its salt (ester) or its hydrate according to item 1 of the scope of patent application, wherein the above Het refers to the group represented by formula IV: 4. The compound or the salt thereof according to item 1 of scope of patent application ( Esters), or hydrates thereof, in which the above-mentioned A-based single bond or vinyl group, b-based single bond, and D are also single bonds "5. If the compound or the salt (ester) of item 1 of the scope of patent application, or Its hydrate, wherein the above Acyl is of formula III: (In the formula, X means CH or N; Y means protected or unprotected amine group; Z means a group substituted by a gas or optionally a functional atom) A shown by the group; A is a single bond Or vinyl; B is a single bond; d is also a single bond ------------ Q --------. Order, -------- line (please first Read the notes on the back and fill in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. — A kind of antibacterial pharmaceutical composition, which contains the compound or its salt (Xue) as described in the first patent application park , Or its hydrate β 7. —A pyridine derivative or its salt of the following formula VI, Het-AB-CO-D-NHCN απβΐ-fl v -2. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A8 38376S 1 6. Scope of patent application (where 'Het is selected from the group in the following groups: singyl group, thienyl group, four-zero seat group, 0tb rock group, and tack group) , Miso group, "salyl group", oxalyl group, ° tb bityl group, noisy "qinyl group", "three" qinyl group, raffinyl group, βxanthenyl group, oxazinyl group, imidazolyl group, Thiazolinyl, oxazinyl, imidazolinyl, piperidinyl, piperidine Group, morpholinyl group, thiomorpholinyl group, oxadiazolinyl group and one. Axanyl group, R1 is argon, Ct-6 alkyl group or 0 · 6 dilute group; a is Ck alkylene group, optional C26 is an alkenyl group or a single bond substituted with amine, halogen or Ck alkyl; B is an imino group or a single bond; D is a single bond or the following chemical formula ----------II ι \ ί ^. II (Please read the notes on the back before filling this page) -Ordered ‘1 ·; Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 mm)