TW533206B - A novel cryptophycin compound and its pharmaceutical composition - Google Patents

Abstract

The invention provides novel cryptophycin compounds which can be useful for disrupting the microtubulin system, as antineoplastic agents, and for the treatment of cancer. The invention further provides a formulation for administering the novel cryptophycin compounds.

Description

Γ33206 Α7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs B7 ---! — ..... '' —.........—— V. Description of the invention (1) The present invention relates to medicine and In the field of organic chemistry, we provide novel cryptophycin compounds for use as anti-microtubule agents. Cell tumor disease is characterized by cell proliferation that is not normally controlled by cell growth, and is the leading cause of death in humans and other mammals. Clinical experience with cancer chemotherapy has proven that new and more effective drugs are needed to treat these diseases. The microtubule system of nucleus cells is the main component of the cytoskeleton, which is a kind of dynamic assembly and decomposition body; it is formed by the aggregation of the heteroduplexes of tubulin to form microtubules. Microtubules play an important role in regulating cell structure, metabolism, and division. The dynamic state of the microtubules is important for their normal function. With regard to cell division, tubulin aggregates into microtubules, which form mitotic spindles. When the use of the mitotic spinning bell is complete, the microtubules are deagglomerated. Therefore, agents that disrupt the polymerization or depolymerization of microtubules to inhibit mitosis include some of the most effective cancer chemotherapeutics in clinical use. In addition, the compounds described herein also have fungicidal properties. Moreover, such agents that can disrupt the microtubule system can be used for research purposes. β Certain cryptocryptin compounds are known in the literature. However, cryptocryptin compounds with greater solubility and footing are required for most medical applications. In addition, a wider range of cryptocryptin compounds may provide alternative treatment options for patients with cancer. Applicants have now discovered novel compounds that provide greater water solubility and compounds that can disrupt microtubule systems.本 烟 日 日 # 人 仏 _ + The compound of the invention can be used to treat neoplasms. These compounds can be prepared using synthetic formulas _., ^., 々, and are suitable for the development of useful drugs. The present invention provides a novel cryptocryptin compound of the following formula I The paper is applicable to the Chinese National Standard (CNS) A4 specification (^ 0X291 ^^ • is--i — -1 · (Read the precautions on the back before filling this page)

, 1T

533206 A7 B7 V. Description of the invention (2

Ar is selected from phenyl, simple unsubstituted aryl, simple substituted aryl, substituted heteroaryl, unsubstituted heteroaryl, heterocyclyl, Cl_alkyl, C2_C12 alkenyl, c2 -C12 alkynyl, NR51R52, COR52, OR53, formula Ar 'C12 and (Please read the precautions on the back before filling this page}

, 1T > 56

Ar1 R51 is selected from hydrogen and CKC3 alkyl; R52 is selected from hydrogen and CVC3 alkyl; R53 is selected from CVCu alkyl; R54 is selected from hydrogen, CVC6 alkyl and CVC6 alkyl (R57'R57nR57 '"), Simple unsubstituted aryl, simple substituted aryl, heterocyclyl, phenyl, halogen, 4- (third butyldimethylsilyloxy) -benzyltriphenyl rust, COOR57, P03H , S03H, S02R58, N (R59) R60, NHOR61, NHCHR61 ,, CN, N02, halogen, 〇62, CH2 (0) R62 ,, -CH20C (0) R95, -5- This paper standard applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 0. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

101 ^, 102ϋ 103> 533206 A7 B7 V. Description of the invention (3 CH2N (R96) R96 ', COR1 ..., (CKC6 alkyl) OR1 () ..., ^, and SR63; R95 is selected from -R98NH3; R96 and R96, each independently selected from hydrogen and (^ -〇6alkyl, -R97NH3, and -R99NR99 ^ R99n; R97 is selected from CKC6 alkyl; R98 is selected from CVC6 alkyl; alkyl; RW and R99 " each independently Selected from hydrogen and CVC6 alkyl;

R1 () () is selected from hydrogen, and Si (R1UiRiU2R 111 () 2 is (: 1-0: 6 alkyl (Please read the precautions on the back before filling in this page)

R 103 &amp; Ci_C6 antibody R104 is selected from C (0) CKC6 alkyl N (R1C) 6) (R59) R6 °, CCCOCkCg alkyl N +, fused bicyclic ring, and nhr1Q5n (r1G6) (r59) r6 (); R1U5 is selected from <3 (0) (^ · (36 alkyl, CVC6 alkyl R1G6 is selected from hydrogen, CVC6 alkyl, C (0) 0Rli) 7 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed R1U / is selected from hydrogen, CVC6 alkyl, CR1G8R1G9R11 () R1G8 is selected from hydrogen and CVC6 alkyl; R1G9 is selected from hydrogen and CVC6 alkyl; R11G is selected from hydrogen and cvc6 alkyl;

R111 is selected from hydrogen, CVC6 alkyl, and C (0) OR R55 is selected from hydrogen, (^-(^ alkyl107C (R57, R57 &quot; R57 '"), a simple unsubstituted 57 aryl group, Simple substituted aryl, phenyl, COOR57, P03H, S03H, -6-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (4) S02R58, NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63; R56 is selected from hydrogen, CVCe alkyl, C (R57'R57nR57m), simple unsubstituted aryl, simple substituted aryl, phenyl COOR57, P03H, S03H, S02R58, NR59R6., NHOR61, NHCHR61 ', (Ci-Ce) alkyl_NR59R60, CN, N02, halogen, OR104, CR104, OR62, and SR63; R57 is selected from hydrogen and CVCu alkane R57 'is selected from hydrogen, halogen, and CVC12 alkyl; R57 "is selected from hydrogen, halogen, and CVC12 alkyl; R57" "is selected from hydrogen, halogen, and (VCn alkyl; R58 is selected from Hydrogen and CVCn alkyl; R59 is selected from hydrogen, (CkCs) alkyl, third butoxycarbonyl, carbonyl · thirdbutoxy (t_BOC), and fluorenylmethoxycarbonyl (FMOC ); R0G is selected from hydrogen and (CKC6) alkyl; R61 is selected from hydrogen, OR64, CH2NHR65, NHR65 ', and fluorenylmethoxycarbonyl (FMOC); R61' is selected from hydrogen, OR64, CH2NHR65, NHR65 ', And fluorenylmethoxycarbonyl (FMOC); printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) R62 is selected from hydrogen and C! -C6 alkyl; R62 'is selected from hydrogen, OH, OR62, and CVC6 alkyl; R63 is selected from hydrogen and CVC6 alkyl; R64 is selected from hydrogen, (CrC6) alkyl, CH2NR66R67; R65 is selected from hydrogen, alkyl, NH2 , And fluorenylmethoxycarbonyl (FMOC); R65 'is selected from hydrogen, CVC6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC); This paper size applies Chinese National Standard (CNS) A4 specifications (21 〇 × 297mm) 533206 Kl B7 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (5) R66 is selected from hydrogen, CVC6 alkyl, and fluorenylmethoxycarbonyl (FMOC); R is selected from Hydrogen and CVC6 alkyl; R and R2 are each independently selected from the group consisting of sulfonium, amine, diamine, trialkyl, sulfur, dialkylsulfonium, sulfate Phosphate group, OR31, sr31, NR31, OH, SH, NR92, R93, NR94, and NH2; R92, R93, and R94 are each independently selected from CVC6 alkyl; but one of R1 and R2 is selected from OR31, SR31, R31, OH, and SH; or R1 and R2 together with C-18 and C-19 can form an epoxy ring, aziridine ring, episulfide ring, sulfuric acid ring, cyclopropyl ring, or mono (CrCO alkyl phosphate Ring, or R1 and R2 together can form a second bond between C-18 and C-19; R3 is a lower alkyl group; R4 is H or 0H; R5 is Η or 0Η; R4 and R5 can form a second together Bonded between C13 and C14; R6 is a substituent selected from benzamyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, di-hydroxymethyl, S alkoxybenzyl , Or two from alkoxybenzyl, B-ring heteroaryl, substituted heteroaryl, B-ring (Cl_c6) alkyl, (C3_CS) cycloalkyl, substituted CrCs cycloalkyl, Substituted (CVC6) alkyl, a group of the following formula

And the basis of the formula III &quot;: -8-This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm1 (please read the precautions on the back before filling this page), 11 533206 Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau ΑΊ Β7 V. Description of Invention (6) R16

R7 is selected from NR51R52, R53NR51R52, OR53, fluorene and lower alkyl; and 51 and 52 are independently selected from CVC3 alkyl; 1153 is (VC3 alkyl; R8 is fluorene or lower alkyl; or R7 and R8 can form a ring Propyl ring; R9 is selected from the group consisting of fluorene, low-carbon, unsaturated low-carbon, low-carbon ring, and benzyl; R1Q is fluorene or low-alkyl; R11 is selected from hydrogen, 0Η, low-alkyl , Substituted phenyl, benzyl 'substituted benzyl, and phenyl; R14 is selected from hydrogen and lower alkyl; R15, R16, and R17 are each independently selected from hydrogen, OR18, halogen, NR18' R19 ', NO2, OP03Η2, OR19 phenyl, sch2 phenyl, conh2, co2h, ρο3η2, S02R23, and zz; R18 is selected from hydrogen, aryl, CVC6 alkyl, C (0) R9G, and fluorenyl Methoxycarbonyl (FMOC); R18 'is selected from hydrogen, (CVC6) alkyl, and C (0) R90'; R19 is selected from CVC6 alkyl, C (0) R90 ", and fluorenylmethoxycarbonyl (FMOC); R19 'is selected from hydrogen, (CVCd alkyl, and C (0) R90' ''; R90, R9Q ', R9G &quot;, and each is independently selected from hydrogen, (Cl_C6) alkyl, OR9i, And ___ -9- ___ This paper size applies to Chinese National Standard (CNS) A 4 specifications (210 X 297 male f) (Please read the precautions on the back before filling this page) # 西 、 11 533206 A7 B7 5. Description of the invention (7), aryl; R9r is selected from (Ci-C6) alkane R23 is selected from hydrogen and (CVC6) alkyl; R3G is hydrogen or (CVC6) alkyl; or R30 may form a three- to seven-membered ring together with N of C-11; R31 is Selected from P, S, (CkCu) alkyl, B, R32, and Si; R32 is selected from amino acids, sugars, amino sugars, (sugar) q, C (0) R33, and

R33 is selected from R37R38, R38, R37N (R20,) R38, R ^ IsKR ^ XCkC ^) alkyl-C (0) R38, R37N (R2 (V) C (0) R38, R ^ OCCVC ^) alkyl 0 ((ν €: 6) alkyl-CKCkC ^) alkyl0 ((^-(36) alkyl, and r37 (nr18'r2G ') r38; R20 · is selected from hydrogen, CkG alkyl, and- C02R21 '; R2r is selected from hydrogen and (CVC6) alkyl; R34 is (CVC4) alkyl; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) R35 is hydrogen or (CVC3) alkyl group; R36 is hydrogen, OH, letter, (CVC3) alkyl group, OR34, N02, NH2, and heteroaryl group; R37 is (CVC6) alkyl group; -10- This paper size applies to Chinese national standards ( CNS) A4 specification (210X297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _ B7 V. Description of the invention (8)

(NR18, R2.,), Heterocyclyl, heteroaryl, 0H, (Ci_C6) alkyl, and amino acid R39 is fluorene or (CVCe) alkyl; R40, R41, and R42 are each independently selected from hydrogen OR43, halogen 'NΗ2' NO2 OPOCOR4%, -OR44 phenyl, and R45; alkyl; alkyl; R45 is selected from unsubstituted simple aryl and substituted simple aryl; R46 is selected from Η, Na, ((VQ) alkyl, and -C (CH3) 3; r5 () is hydrogen or ^. Η is 0, 1, or 2 m is 0, 1, or 2; p is 0, 1, Or 2; q is 2, 3, or 4; X is selected from 0, C, S, NH and alkylamino; Y) is selected from C, 0, NH, S, SO, SO2, and alkylamino; Z is selected from-(CH2) n-,-(CH2) p-〇- (CH2) m, and (C3-C5) cycloalkyl; ZZ is selected from simple unsubstituted aryl, and simple substituted Aryl group; or its pharmaceutically acceptable salt or solvate; -11-This paper is suitable for financial and family care (CNS) 210X297 public ------ (谙 Please read the precautions on the back before filling this page) Order f «3206 A7 B7, description of the invention (9 but if R1 is selected from halogen, OH, OR31, SH, amine group, amine group, ~ &amp; amine group's bisamine group, trialkyl group , Alkylthio, dialkyl mirror, sulfate, and phosphate, R2 is selected from OH, NH2, NR31 and SH, or R1 &amp; R2 together to form an epoxy ring, aziridine ring, episulfide ring, sulfate ring , A cyclopropyl ring, or an alkyl phosphate ring, or Ri &amp; R2 together to form a second bond; R3 is a lower alkyl group, R and R5 are fluorene, or R4 and r5 together form a double bond between c13 and c14; r6 is benzyl'hydroxybenzyl, alkoxybenzyl, fluorenylbenzyl, diylbenzyl, fluorenylbenzyl, or dihydroxybenzyl; R7, R8 'R9, And R1G are each independently H or lower alkyl; X and γ are each independently 0, nh Λ printed or alkylamine group by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, R50 and R11 are hydrogen; then Ar is not selected from Ci -Ci2 alkyl, Ci_Ci2 alkynyl, phenyl, simple unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl; or if Ar is selected from Cl_Cl2 alkyl , D-Cp alkynyl, phenyl, simple unsubstituted aryl 'substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl; R50 and R11 are hydrogen; then R is selected Sulfonium, amine, monoalkylamino, dialkylamino, trialkylammonium, sulfanyl, dialkylphosphonium, sulfate, phosphate, OR31 and SR31; or if R1 is selected from halogen, OH OR31, SH, amine, monoalkylamino, digeramine, trialkylamine, trialkylammonium, alkylthio, dialkylphosphonium, sulfate'phosphonate, and r2 are selected from 〇H, · 2, NR31 and SH, or rW_ to form an epoxy ring 'p propylene ring, episulfide ring, sulfuric acid ring, cyclopropyl 12 This paper is applicable to China Standard (CNS) A4 specifications ( 2iGx29? ^ Y (Please read the notes on the back before filling this page)

533206 Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs -13 A7 B7 V. Description of the invention (10) ^ 'or a monobasic phosphonic acid ring, or R1 and R2 together form a second bond' R3 is a low-burning group, R4 Is Η, R5 is Η, R50 is hydrogen, and R11 is hydrogen; then Ar is not selected from Ci-Cu alkyl, CrCu alkynyl, phenyl, simple unsubstituted aryl, substituted aryl, and hetero Aryl; or if R1 is selected from halogen, OH, OR31, SH, amine, monoalkylamino, dibasic amine'triolamine, triolamine, sulfanyl, dipitylsulfur, Sulfate group's phosphate group and R2 are selected from OH, NH2, NR31 and SH, or R1 and R2- to form an epoxy ring, aziridine ring, episulfide ring, sulfate ring, cyclopropyl ring, or monoalkane A phosphoric acid ring, or R1 and R2 together to form a second bond, R3 is a lower alkyl group, R4 is Η, R5 is Η, R50 is hydrogen, and R11 is hydrogen; or R50 is selected from the group consisting of ^ and hydrogen; and R11 Is selected from 0Η, lower alkyl, substituted phenyl, benzyl, substituted benzyl, and phenyl; then 1 * is not selected from Ci-C ^ 2 alkyl, CVCu bulk, benzene , Simple unsubstituted aryl 'substituted aryl , Substituted heteroaryl, and unsubstituted heteroaryl; or if R3 is lower alkyl; R4 and R5 are fluorene, or R4 and R5 together form a double bond between Cl3 and &lt; ^ 4; R6 is benzyl, hydroxybenzyl, alkoxybenzyl, halobenzyl, diphenylhydroxybenzyl, halohydroxybenzyl, or dibenzylbenzyl; R7, R8 , R9, and Ri0 are each independently H or lower alkyl; χ &amp; γ are each independently 0, NH, or alkylamino; Ar is formula Ar, and one of R 4 'R55, R56 is selected from alkyl or Element; and R1 and R2 can form an epoxy ring, aziridine ring, episulfide ring, sulfuric acid ring, cyclopropyl ring, or a phosphoric acid phosphate ring, or R1 and R2 can form the first paper standard. China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page}, 11 533206 A7 B7 V. Description of the invention (11 The second key is between C18 &amp;C19; or R2 is optional From OH and SH; then at least two of R54, R55, and R56 must be selected from CkC6 alkyl, simple aryl, phenyl, COOR57, P03, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ,, CN, N02, Halogen, OR62, and SR63; or if R3 is lower alkyl; R4 and R5 are H, or R4 and R5 together form a double bond between C13 and C14; R6 is B-ring heteroaryl, which is substituted Heteroaryl, B-ring (CrCO alkyl, (C3-C8) cycloalkyl, substituted C3-C8 cycloalkyl, substituted (CrCd alkyl, group of the following formula III),

315 R1

R 16 III1 (Please read the precautions on the back before filling out this page}-Order and base of formula III &quot; R 16

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China ▼▼; and X and Y are each independently 0, NH or alkylamine; then Ar is not selected from phenyl or any simple unsubstituted or substituted aryl Or heteroaryl, CVCu alkyl, and CVCu alkynyl. The present invention provides pharmaceutical formulations; a method for disrupting the tubulin system using an effective amount of a compound of formula I; a method for inhibiting mammalian cell proliferation, comprising administering an effective amount of a compound of formula I; and a method for treating mammalian neoplasms Applicable to China National Standard (CNS) A4 specification (210X297 mm) 533206 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (12) The method of forming includes applying an effective amount of the compound. Also provided is a method for controlling M. bacterium infections, comprising administering an effective amount of a compound of formula I to a bacterium that is resistant to or susceptible to bacterium. The term "simple alkyl" as used herein refers to Ci_c7 alkyl, where alkyl is saturated, unsaturated, branched, or straight chain. Examples include, but are not limited to, methyl'ethyl, n-propyl, isopropyl, n-butyl, propenyl, vinyl, second butyl, n-pentyl, isobutyl, third butyl, and Dibutyl, methylated butyl, pentyl, third pentyl, second pentyl, methylated pentyl, etc. The term "fluorenyl" refers to an alkyl group as defined above having one to three double bonds. The term "alkynyl" refers to an alkyl group as defined above having at least one triple bond. Bulk Kitty has only one double bond. The term '' Ci-Cn, alkyl ", where n is an integer from 2 to 12, meaning an alkyl group having one to the above number of carbon atoms, and d-Cn, the alkyl group may be straight or branched. As used herein, the term "; 8-ring (: 1-(: 6-alkyl)" refers to saturated, unsaturated, branched, and straight-chain alkyl groups, where cycloalkyl groups can include up to three non-carbon substituents The non-carbon substituent is preferably selected from 0H, SCH2 phenyl, NH2, CO, CONH2, CO2H, P03H2, S02R21, wherein R21 is selected from hydrogen and Q-C3 alkyl. The term "amino acid" as used herein "Means an organic acid containing an amino group. This term includes naturally occurring and synthetic amino acids, so the amino group can (but need not) be attached to the carbon adjacent to the acid. The amino acid substituents are functional with organic acids The radical is connected to the parent molecule. The term "sugar" as used herein refers to a substituent composed of carbon, hydrogen, and oxygen, wherein hydrogen and oxygen are the same as or close to the proportion of water. -15- __ This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) Order 533206 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The term "carbohydrates" &quot; separate aldehydes, or alcohols or hydrolysis can produce Compounds of aldehydes or ketones. The term "sugars" is generally understood by those familiar with A and B. For example, this glossary, but not limited to, c12h22〇11 &amp; C6Hi () 05. This article The term used in the formula "Amino sugars" is transcribed from A to ^^ I. Sugar-coated sugars contain one to three amine groups to replace any possible position based on cool molecules. The term &quot; sugar &quot; as used herein Subunits form disaccharides or polysaccharides. This term, such as, but not limited to, lactose, maltose, sucrose, fructose, starch, etc. As used herein, a substituted phenyl "epiphenyl group has one to three Non-hydrogen substituents, which may be independently selected from simple alkyl, cl, Br, F, and alkene. As used herein, the term "substituted benzyl" has one to three non-hydrogen substituents , Which can be independently selected from simple alkyl, C1, Br, F, and I 'wherein these substituents can be attached to any possible carbon atom. Some preferred substituted benzyl groups have been mentioned. Terms used herein ,, alkoxybenzyl, The radical is based on any possible position on the benzyl ring. The alkoxy group is preferably (Cl_C3) alkoxy. The methoxy group is particularly preferred. The term &quot; haloalkoxybenzyl &quot; In addition to the substituents, there are _ substituents. Each halo or alkoxy group is substituted on any possible carbon. Similarly, the benzyl group substituted by the "from hydroxybenzyl" epiprotective group also has a single substitution based on benzene On any possible carbon of the methyl ring. Finally, the term "di-alkoxybenzyl &quot; epialkyloxy-substituted benzyl also has two fluorene substituents each independently substituted on any of the benzyl ring May be on carbon. "B-ring heteroaryl" as used herein. The epiaryl ring contains one or more non-carbon substituents selected from oxygen, nitrogen, and sulfur. The best B ring heterocyclic group is selected from, but not -16- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page} I; Clothes · Order 533206 A7 B7 V. Description of the invention (14 Limited to the following basis:

S

N

S OR20 R2G is selected from hydrogen or CVC6 alkyl. • “B-Cycloaryl” is best selected from the following substituents: printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-17- (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (15) • 'Substituted Aromatics' Tables 1 to 3 The substituent is selected from a simple alkyl group and a substituted _ group. As used herein, a π ring alkyl group, 'Table saturated (1: 3-08 ring alkyl group, which may include 0 to 3 substituents selected from CVC3 alkyl group, Halogen, and OR22, where R22 is selected from hydrogen and CrC3 alkyl. This substituent can be attached to any possible carbon atom. Particularly preferred cycloalkyl is substituted or unsubstituted cyclohexyl. As used herein, "low "Alkoxy" means an alkyl group of one to five carbon atoms bonded to an oxygen atom. As used herein, "low alkyl" means an alkyl group of one to six carbon atoms, including linear and non-linear hydrocarbon chains, including, but Not limited to, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, third butyl, second butyl, methylated butyl, pentyl, third pentyl, second Amyl, methylated pentyl, etc. The term "unsaturated lower alkyl" as used herein, and "Saturated low alkyl" has the meaning commonly used by those skilled in the art for unsaturated and saturated terms. The term "low alkyl" refers to saturated and unsaturated low alkyl. (For example, a saturated group does not have a double or triple bond.) This article As used herein, "allyl-substituted hydrazone" means an olefin having two to seven carbon atoms, which contains an alkyl substituent. The "epoxy ring" as used herein means a three-membered ring whose backbone includes two Carbon atom and one oxygen atom. "Acridine ring" as used herein means a three-membered ring, and its backbone includes two carbon atoms and one nitrogen atom. "Sulfur ring" as used herein means a three-membered ring, Its backbone includes two carbon atoms and a sulfur atom. As used herein, an "episulfide ring" means a three-membered ring, and its backbone includes two carbon atoms and a sulfur atom. As used herein, "sulfate group" means The five-membered ring includes a carbon-carbon-oxygen-sulfur oxygen backbone and another two oxygen atoms connected to the sulfur atom. As used herein, `` a tiger-based phosphate ring '' means that the five-membered ring includes carbon_carbon-oxygen _Phosphorus-Oxygen Trunk and Other ________- 18 -__________ Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) Clothing · Order 533206 A7, Description of the invention (two oxygen atoms 'of which-one has-low burning group' Connected to the scale atom. The "simple unsubstituted aryl group" used in this and the "form ring or bicyclic common car system, for example, but not limited to two ': South base" "base", "sedenyl" Biyodo Radicals, etc., or digass such as, but not limited to, indolyl or naphthyl. ... Deadly used in this text &quot; simple substituted aryl &quot; means that a simple aromatic ring has a halogen and lower alkyl group As used herein, &quot; heteroaryl &quot; an epicyclic ring contains—or a plurality of non-carbon atoms selected from the group consisting of oxygen 'nitrogen, and sulfur. The best heteroaromatic ring has three to eight members in the ring. Heteroaryl rings have three to six members in the ring. Particularly preferred heteroaryl groups have one to three non-carbon atoms in the ring. A five-membered ring containing one oxygen atom is a preferred heteroaryl group; however, the term is not limited to this group. As used herein, a "heterocyclyl" watch ring contains one or more non-carbon atoms selected from oxygen, nitrogen, and sulfur. Heterocyclic rings can be saturated or unsaturated. In addition, heterocyclic rings can be fused to each other to form a bicyclic or tricyclic ring. Ring system. For example, but not limited to, a five-membered ring with two double bonds or a five-membered ring with one double bond. The heterocyclic ring may be unsubstituted or may have one to three substituents selected from Cl-C6 alkyl , Carbonyl, halogen, and OR. The best heterocyclic ring has two to eight members in the ring. The particularly preferred heterocyclic ring has three to six members in the ring. The particularly preferred heterocyclic group has one to three non-carbon atoms in the ring. A heterocyclic ring is a five-membered ring having one nitrogen, one sulfur, one methyl substituent, and two double bonds. Preferred heterocyclic groups include, but are not limited to:

-19- This paper size applies to Chinese National Standard (CNS) A4 (210X'297 mm) (Please read the notes on the back before filling out this page) Order printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 533206 A7 B7 5 (17) Description of the invention (17) The "substituted heteroaryl" table is substituted by one to three substituents selected from simple alkyl and halogen substituted groups. The "halogen ••" or "halogen" used in this table in the history of the periodic table Called a member of the halogen. Halogenation methods include, but are not limited to, the addition of hydrogen halides, substitution at high temperatures, photochemical, etc. These methods are known to those skilled in the art. Particularly good halogens include, but are not limited to: chlorine, chaos, and indifference. The term "aryl" as used herein has the meaning of this term by a person of ordinary skill in the art. Therefore, this term means an organic group derived from the removal of a hydrogen atom from an aromatic hydrocarbon. For example, but not limited to, phenyl, tolyl, salicyl, and the like. The term "mammal" as used herein refers to mammals of higher vertebrates. The term "animal" includes, but is not limited to, mammals, reptiles, amphibians, and fish. The term &quot; mammalian π includes, but is not limited to, humans. The term &quot; treatment &quot; as used herein includes preventing the symptoms described, or ameliorating or eliminating the symptoms that arise. The cryptocryptin compounds described herein are useful for veterinary health purposes and for treating patients. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page). When the desired R6 substituent in the compound contains an amine, the amine substituent of R6 must be protected by an amine protecting group. Standard works can be used by those skilled in the art, including examples of "Protective Groups in Organic Chemistry", Plenum Press, (London and New York, 1973); Greene, TW &quot; Protecting Groups in Organic Synthesis ", Wiley (New York, 1981) ) Guide to easily select a suitable amine protecting group. The term "derivative" as used herein refers to standard chemical transformations known to those skilled in the art, which can produce the desired compounds of the present invention. -20- This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (18) The method of the present invention provides a method for preparing a fully synthesized cryptocryptin compound. Conveniently, commercially available amino acids can be cyclized into Cryptocin molecules. Many known cryptocin compounds have antitumor activity; however, their poor water solubility may cause problems during intravenous administration of the drug. This problem is related to the use of solubilizing surfactants, such as Cremophor, which may It has original toxicity. The invention provides a novel cryptocryptin compound with antitumor activity and greater water solubility. The compound has the desired solubility and acceptable efficacy. The method for preparing the compound of the present invention is best completed in the presence of a solvent. Those skilled in the art can use standard methods to select a suitable solvent. Suitable inert organic solvents include known to those skilled in the art For example, but not limited to, tetrahydrofuran (THF) and dimethylformamide (DMF). DMF is particularly preferred. Water-based solvents are suitable for some methods used herein. The pH of the aqueous solvent can be as desired Adjusted to facilitate the method. Some typical compounds of the present invention are provided in table form; however, the compounds are not intended to limit the scope of the present invention. (Please read the notes on the back before filling this page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs The paper size printed by the consumer cooperative is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7B7 V. Description of the invention (19 Table 1

CI compounds

R 〇Ρ (〇) (α-Βυ) 2

0Ρ (0) (0Ν 佘

►HCI compounds

R 13 NHo

NHCQ2 / -BU

NH2 · HCI (Please read the notes on the back before filling out this page} 15 16 17 18 • NHC〇2i-Bu

, NH2 «HCI NHC〇2〗-印 u Printed by the Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs 10 12

Μθ •, 〇CΛ 'XXA OAc NHC〇2f-Bu Cl nh2 * hci · Cl OMa NHC〇2i- 巳 u

NH2 · HCI 22- 19 20 21 22 25 26 This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

ιϊίΛ ^ ΝΗ2.Λ Λ X

HCI ΝΗΟ〇2ί-Βυ

NH2 * HCI NHC〇2 / -Bu ^^ NHC〇2i * Bu

• NH2.HCI

, NH2 * HCI

RO

OR -OR OR HO '

OH

OH OH

533206 A7 B7 V. Description of the invention (20)

CI ΟΜθ Compound 27

ΝΗ2 · HCI 28

NH2 * HCI C02H 29

VC〇2H

HCI 30

Λ ^ / ν ^ 〇2Η NH2 * HCI 31 32 Ν Α ^ νη2 · NH2 * HCI ‘^^ &gt; ΝΗ2 · Ηα

Other preferred compounds of HCI NH2 * HCI are, for example, but not limited to, the position exchange of adjacent Cl and OR groups in Table 1 above. For example, the same R substituent is as described above, and its basic structure is as follows: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Other advantageous compounds are described in Table 1. However, Ar is Ar ', instead of phenyl, -23- (Please read the precautions on the back before filling this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (21) R54 is the opposite position of OCH3 to Af, and R55 and R56 are each hydrogen. Other advantageous compounds are described in Table 1, however, NH replaces 0 of the Y position of the molecule. For example, a compound in this series is

(Read the precautions on the back before filling this page)

$ V; x: 〇C Other preferred compounds are, for example, but not limited to, those described in Table 1 and the compounds adjacent to the C1 and OR exchange positions, wherein each of the compounds has a methyl group in place of cymene in Cryptophyta The sixth position of the prime ring. See, for example, the following 23. A particularly preferred compound of the present invention has a dimethyl group at the sixth position of the cryptocryptin ring. The preferred compounds of the present invention are shown in Table 1, wherein Ar is Ar '; only one of R54, R55, and R56 is OCH3; R9 and R1G are each methyl. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics A commonly known silylating agent is used in the method of making the compounds of the present invention. See, for example, Calvin, E.W. &quot; Silicon Reagents in Organic Synthesis &apos; 'Academic Press, (London, 1988). Particularly useful dream firing agents include "tri-lower alkyl silyl" agents, which term includes triisopropylsilyl, trimethylsilyl, and triethylsilyl, trimethylsilylpyrene, silyl Urea such as bis (trimethylsilyl) urea (BSU), and silane alkylamines such as N, 0-bis (trimethylsilyl) acetamide (BSA). Among them, BSA is better. Some preferred features of the invention are described in the following table, where each feature can be independently selected to provide a preferred embodiment of the invention. The present invention is not limited to the following features: A) R8 is ethyl, propyl, isopropyl, butyl, isobutyl, or isoamyl-24- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Explanation of the invention (22); B) R7 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl; c) R7 is Η , R8 is methyl, R3 is methyl, X and Y are not both 0; D) R3 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl; E) R9 is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl; F) R1G is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or Isoamyl; G) Cryptocin compounds are at least selected from the group consisting of 0-3, (: -6, (: -7, (^ 10, (: -16, (: -17, and C-18) One base has R stereochemistry (numbering is as described in Formula I above); H) Cryptocin compounds are selected from (3-3, (: -6, (: -7, (: _10, (: _16, (: At least one of the bases of-17 and C-18 has S stereochemistry (the number is as described in the formula I above); I) A r · is a phenyl group having a substituent selected from NR59R6G, NHOR61 and NHCHR61 '; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) J) Y in the compound is selected from alkane Amine, NH, and 0; K) Y in the compound is 0, R7 and R10 are each hydrogen, R9 is a lower alkyl group; R1 is a halogen; L) R7, R8 are each a methyl group; M) R7 is hydrogen; N) R2 is glycine group; -25- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (23) O) R2 is fluorenyl group; (Please read first Note on the back, please fill in this page again) P) R1 and R2 form an epoxy ring; Q) R6 is selected from benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, and di_ Hydroxybenzyl; R) R4 and R5 form a double bond; S) η is 0; R6 is a substituted benzyl, wherein one of the substituents is halogen, ne is an OR12 group, where R12 is a lower alkyl group; T ) Compounds of formula I are used to disrupt the tubulin system; U) Compounds of formula I are used as anti-neoplastic agents; V) Compounds of formula I are used to treat mammalian cancers; W) Compounds of formula I are used as anti-thorium Bactericide; X) R6 is III1, substituted by para-hydroxyl; Y) R6 is selected from the following

0H Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

-26 The size of this paper applies to Chinese National Standard (CNS) A4 specification (210 '乂 297 mm) 533206 A7 B7 V. Description of invention (24)

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

and

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Z) Z is-(CH2) n-, where η is 0 ΑΑ) Z is-(CH2) n-, where η is 2 ΒΒ) Z is _ (CH2) n- Where η is 1 CC) at least one of RD, R1G, and R17 is selected from SCH2 phenyl, ΝΗ2, CO, CONH2, C02H, P03Η2, and S02R21; wherein R21 is selected from gas and Ci_C3 alkyl; -27 Paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 V. Description of the invention (25) DD) Ar is phenyl; EE) Ar is phenyl via one or two OH, OCH3, halogen, And methyl substitution; FF) R2 is selected from halogen, amine, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylphosphonium, sulfate, phosphate, OR31R32, and SR32R32 GG) R6 has Z, where the first carbon of Z is

For the junction of cryptocryptin molecules; HH) Compounds of formula I are used for the treatment of pinworm infections;

(Please read the notes on the back before filling in this page) II) R50 is JJ) R11 is hydrogen; KK) R4 and R5 are each hydrogen; LL) Ar is para-ethyl substituted phenyl; MM) Ar is para Methyl substituted phenyl; NN) Y is HN; 00) R3 is methyl; PP) R6 is selected from the following: Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics -28- This paper size applies to Chinese national standards ( CNS) A4 specification (210X 297 mm) A7 V. Description of invention (26) A7 B7

0H 0H

(Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, this invention provides a method for reducing, including the veterinary composition of pathological symptoms caused by hyperplasia of individuals. Inhibition fine = of = effective amount In the medicine or example disclosed in this article, this method also envelops and proliferates. In the preferred embodiment of the present invention, a symptomatic therapy is performed. At least one of the other treatments is used to reduce the pathogenesis of the disease, which is characterized by the formation of neoplasms. In the pathological condition, the neoplasms are selected from breasts (in addition-preferred embodiments ^ 1. ,, Small cell lung, non-small cell lung, colon orthopedic disease ..., chromosome, pancreatic cancer, central nervous system (CNS), epicardial epithelium, Kuman tissue or bone, sarcoma of head and neck, stomach ( Including skin and food), beta myeloma, bladder, kidney, neuroendocrine (including thyroid), and non-Hodgkin's disease and! 10 deduction 1 ^ 11 disease neoplasms. As used in this article &quot; Normally growing neoplasms, the growth occurs because cell proliferation is not generally limited by growth. As used in this article, "antineoplastic agents" are any neoplasms that can inhibit, remove, obstruct, or reverse cells. Table-29 This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 533206 A7 B7 V. Description of invention (27) type compounds, compositions, mixtures, blends, or blends. Anti-mitotic agents are based on The molecular mechanism of action can be divided into three The first type includes colchicine and colcemid, which inhibit the formation of microtubules by chelating tubulin. The second type includes vinblastine and vincristine, which Causes the formation of agglomerates of tubulin. Vinblastine and vinblastine are well-known anticancer drugs: their role in destroying mitotic spindle microtubules preferentially inhibits hyperproliferative cells. The third category includes taxol, It promotes tubulin polymerization and stabilizes microtubules. Many tumor cells show drug resistance and multiple drug resistance phenotypes, and clinically proven modes of action of antitubulins against neoplastic cells, it is necessary to develop resistance to non-drug resistance Cytotoxic anti-microtubule agents with neoplastic cells and drug-resistant phenotypes. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (read the precautions on the back before filling out this page) Chemotherapy, surgery , Radiation therapy, biological response modifiers, and immunotherapy are currently used to treat cancer. Each treatment has specific indications, and is a skilled artist It is known that one or all of them can be used to achieve complete destruction of neoplastic cells. In addition, the present invention also provides combined chemotherapy, which uses a compound of formula I combined with other anti-neoplastic agents, because combined therapy is generally better than using a single anti-cell Tumor agents are effective. Therefore, another aspect of the present invention provides a composition containing a therapeutically effective amount of at least one compound of formula I (including its non-toxic addition salt) to provide the above benefits. The composition can also be used in conjunction with physiologically Acceptable liquid, gel or solid carriers, diluents, adjuvants and excipients are provided together. These carriers, adjuvants and excipients can be found in US Pharmacopoeia: Vol. XXII and National Formulary Vol. XVII , US ^ Pharmacopoeia Convention. Inc .. Rockville. MD (1989) 0 -30 »^^ The scale is applicable to China's national standard (CNS) A4 specification (210X297 ^^ 533206 A7 B7 V. Description of the invention (28) Other treatment methods Provided at AHFS Drug Information 1993 e. The American Hospital Formulary Service, ρρ 522-660. The reference materials are well known and easily accessible to those skilled in the art. The present invention also provides a pharmaceutical composition for treating neoplastic disease, comprising at least one compound of formula I and at least one other anti-neoplastic agent. Antitumor agents that can be used in combination with compounds of formula I include those provided in Merck Index 11, pp 16-17. Merck &amp; Co., Inc. (1989). The Merck Index is well known and easily available to those skilled in the art. Printed by the Consumers ’Cooperative Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) In another specific embodiment of the present invention, the anti-tumor agent may be an anti-metabolite, which may include, It is not limited to 'selected from methotrexate, 5-fluorouracil, 6-guanosine, cytosine, arabinose, hydroxyurea, and 2-chlorodeoxyadenosine. In another specific embodiment of the present invention, the anti-neoplastic agent is an alkylating agent, which may include, but is not limited to, selected from cyclophosphamide, mephalan, busulfan, paraplatin, phenylbutyric acid Nitrogen mustard (chlorambucil), and nitrogen mustard. In another specific embodiment, the anti-neoplastic agent is phytoalkali, which may include, but is not limited to, selected from vinblastine, vinblastine, paclitaxel, and etoposide. In another specific embodiment, the anti-neoplastic agent is an antibiotic, which may include, but is not limited to, selected from doxorubicin, daunorubicin, mitomycin C, Bole Bleomycin. In another specific embodiment, the anti-neoplastic agent is a hormone, which may include, but is not limited to, selected from 7 / ?, 17α-calusterone, diomostavolone, propionate, epitiostanol, mepitiostane, intrathalamic Testolactone, Tamoxifen, Polyestradiol Phosphate, Megesterol Acetate, Flunidine-31-This paper is sized to the Chinese National Standard (CNS) A4 Specifications (210X 297 mm) 533206 A7 B7 _ 5. Description of the invention (29) Flutamide, nilutamide, and trilotane 〇 In another specific embodiment, the anti-neoplastic agent includes an enzyme, which may include, but not Limited to, selected from L-asparaginase, and aminoacridine derivatives, such as, but not limited to, amsacrine. Other anti-tumor agents include Skeel, Roland T., "Antineoplastic Druge and Biologic Response Modifier ·· Classification, Use and Toxicity of Clinically Useful Agents' Handbook of Cancer Chemotherapy (3rd ed ·), Little Brown &amp; Co. (1991) Provided by: These compounds and compositions can be administered to mammals for veterinary use. For example, breeding animals can be treated in the same way as human clinical patients. Generally, the dosage required for treatment depends on the type used, the mode of administration, and the specific needs of the individual The typical dosage range is about 0.001 to 1000 mg / kg, generally 0.01 to 10 mg / kg of the individual's body weight. Alternatively, the doses in these ranges can be administered in strange quantitative injections over an extended period, generally exceeding 2 4 Hours until the desired therapeutic effect is obtained. In fact, the dosage and route of administration of the drug must be based on relative effects, relative toxicity, tumor growth characteristics, and the effect of the compound of formula I on the cell cycle, pharmacokinetics, patient age, gender, body Condition selection, determined by skilled artisans before treatment Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The compound of formula I, with or without other anti-tumor agents, can be formulated into natural or salt therapeutic compositions. Pharmaceutically acceptable non-toxic salts include addition salts, which can be derived from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or iron hydroxide, and organic bases such as isopropylamine, Trimethylamine, 2-ethylaminoethanol, histidine, procaine, etc. This salt can also be an acid addition salt formed by any free cationic group, generally with -32-this paper Standards are applicable to China National Standard (CNS) A4 specifications (2) 0X297 mm. 533206 A7 _____________ 5. Description of the invention (30) Inorganic acids, such as hydrochloric acid or phosphoric acid, or organic acids, such as acetic acid, oxalic acid, tartaric acid, phenylglycolic acid Etc. Other excipients provided by the skilled artisan of the present invention are, for example, those described in U. SI Pharmacopoeia. The solubility of a particular carrier contained in a particular therapeutic composition depends on the preferred route of administration. For example, anti-redundant tumor The composition can be formulated for oral administration. The composition is typically prepared as a liquid solution or suspension or a solid form. Oral formulations generally include additives such as binders, fillers, carriers, preservatives, stabilizers, emulsifiers, soothing agents Granules, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. These compositions can be in solution, suspension, tablet, pill, capsule, sustained release formulation, or powder, Typically contains 1% to 95% active ingredients. The composition preferably contains from about 2% to about 70% active ingredient. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The composition of the present invention can be prepared as a liquid solution, suspension or emulsion for injection; suitable for dissolution or suspension before injection Solid form in liquid. This injection can be administered subcutaneously, intravenously, intraperitoneally, intramuscularly, intraspinally, or intrapleurally. The active ingredient is usually mixed with a diluent &apos; vehicle &apos; or excipient that is physiologically tolerable and in contrast to the active ingredient. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, etc., and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as a wetting or emulsifying agent &apos; stable or pΗ buffer. The present invention also provides a method for inhibiting the proliferation of mammalian cells by using a compound of the formula I, by contacting these cells with a compound of the formula I in an amount sufficient to inhibit the proliferation of mammalian cells. A preferred embodiment is a method for inhibiting hyperplasia of mammalian cells. For the purpose of the present invention, "hyperproliferative mammalian cells ___-33 _ Zhang Zhi Gu Zhong 0 H family standard (CNS) A4 specification (21〇 × 297 mm) ~ '— —-533206 kl ---- --- B7 V. Description of the invention (31) ~ '~ (Please read the notes on the back before filling out this page) Another preferred specific implementation for mammalian cells that are not restricted by growth characteristics (such as planning cell death) In the example, the mammalian cells are human cells. The present invention further provides that the mammalian cells are in contact with at least one compound of formula I and at least one anti-neoplastic agent. The types of anti-neoplastic agents included are as described above. A method for inhibiting the proliferation of hyperproliferative cells with a drug-resistant phenotype (including hyperproliferative cells with multiple drug-resistant phenotypes) by contacting the cells with a mammalian cell in an amount sufficient to inhibit the proliferation of hyperproliferative cells with a compound. In a preferred embodiment, the mammalian cells are human cells. The present invention further provides contact with a compound of formula and at least one other anti-neoplastic agent as described above. The present invention provides a method for reducing mammalian cell excess. The pathological symptoms (such as neoplasia) caused by hyperplasia are achieved by administering to a subject an effective amount of a pharmaceutical composition containing a formula compound to inhibit the proliferation of hyperproliferative cells. As used herein, "pathological symptoms" refers to any disease Pathology due to proliferation of cells that are not restricted by normal growth. The proliferation of the cells may be caused by the above-mentioned neoplasm. '' Printed in another preferred embodiment by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the neoplasm is Human cells. The present invention provides methods of using compounds of Formula I in combination with other therapies and other anti-neoplastic agents to reduce the pathological symptoms. The efficacy of the compounds of the present invention can be evaluated using standard methods known to those skilled in the art. 5 'This method Examples are as follows: The compounds of the present invention have been found to be useful in combating pathogenic Pseudomonas. For example, the effectiveness of the treatment of new Cryptococcus neoformans can use yeast -34- This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 533206 A7 B7 V. Description of the invention (32) Mother nitrogen-based grapes The test results of agar medium against Cryptococcus neoformans are exemplified. In this analysis, the compound of the present invention was dissolved in Dimethicone supplement Tween 20. A double dilution was made with sterilized distilled water / 10% DMSO to obtain agar. The final drug concentration in the plate for dilution analysis ranges from 0.008 μg / ml to 16.0 μg / ml, which is an extension panel against 84 new Cryptococcus strains. The minimum resistance to 8 4 new Cryptococcus isolates was determined. Inhibition concentration to exemplify the desired antibacterial activity. The minimum inhibitory concentration of KB, human nasopharyngeal carcinoma cell line, LoVo, human colorectal cancer cell line using Corbett analysis screening compounds, see Corbett, T · Η · et al., Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development. pp 35-87, Kluwer Academic Publishers: Norwell, 1992. See also Valeriote, et al., Discovery and Development of Anticancer Agents: Kluwer Academic Publisher, Norwell, 1993. Used to evaluate compounds. Corbett analysis was used to further evaluate the cytotoxicity of the most potent compounds against four different cells, such as murine leukemia, murine solid tumors, human solid tumors, and low malignant fibroblasts. Printed by the Ministry of Economic Affairs of the Central Government Bureau of Consumer Affairs (please read the notes on the back before filling out this page) to further evaluate the compounds against a wide range of mouse and human tumors implanted in the mouse, including drug-resistant tumors. Tumor burden (T / C) (average tumor burden of treated animals versus average tumor burden of untreated animals) was used for further evaluation. Less than 42% of T / C 被 is considered effective by National Cancer Institute Standards; less than 10% of T / C 値 is considered by the National Cancer Institute Standards to be polar active and potentially _-35 -___ This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 533206 B7 5. Description of the invention (33) Clinical activity. Materials Changchun test, cytochalasin B, tetramethylrhodamine (TRITC) -phalloidin, sulforhodamine B (SRB) , And antibodies against y3 · tubulin and vimentin are commercially available from recognized commercial vendors. Eagle (BME) and fetal bovine serum (FBS), a basic medium containing Earle salts, are also commercially available. Cell line

Jurkat T-cell leukemia strains and A-10 mouse aortic smooth muscle cell lines were obtained from the American Type Culture Collection and cultured in BME containing 10% FBS and 50 μg / ml gentamicin sulfate. Human ovarian cancer cells (SKOV3) and a vinblastine-resistant substrain (SKVLB1) were generously donated by Dr. Victor Ling of the Ontario Cancer Institute. Two cell lines were maintained in BME containing 10% FBS and 50 μg / ml gentamicin sulfate. 24 hours after subculture, vinblastine was added to SKKVL1 cells to a final concentration of 1 g / ml to maintain the selection pressure of P-glycoprotein overexpressing cells. Cell proliferation and cycle stop analysis Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (Please read the precautions on the back before filling out this page) Cell proliferation analysis was performed as described by Skehan et al. For Jurkat cells, the cultures were treated with the drug described by Skehan, and the total number of cells was determined by counting cells in a hemocytometer. The percentage of mitotic cells was determined by staining with 0.4% Giemsa in PBS and then quickly washing with PBS. Mitosis was evaluated for at least 1000 cells per treatment, and the mitotic index was calculated as the ratio of cells with mitosis to the total number of calculated cells. ____- 36- _ This paper size applies to Chinese National Standard (CNS) A4 (210X29? Mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (34) Immunofluorescence analysis A-10 Cells were grown on coverslips to near confluence in BME / 10% FBS. Compounds were added to the final concentrations shown in PBS and cells were incubated for 24 hours. To stain microtubules and intermediate filaments, cells were fixed with cold methanol and incubated with PBS containing 10% calf serum to block non-specific binding sites. Cells were then incubated at 37 ° C for 60 minutes with monoclonal antibody-/?-Tubulin or monoclonal antibody-vimentin at the dilution recommended by the manufacturer. Then it was incubated with luciferin-conjugated rabbit anti-mouse IgG for 45 minutes to show bound primary antibodies. The coverslip was placed on a microscope slide, and the fluorescence pattern was detected and photographed using a Zeiss Photomicroscope II1 equipped with an epifluorescence lens equipped with leukin. To stain the microfilaments, cells were fixed with 3% paraformaldehyde, permeated with 0.2% Triton X-100, and chemically reduced with sodium borohydride (1 mg / ml). Then PBS containing 100 nM TRITC-muscarinic acid was added and the mixture was incubated at 37 ° C for 45 minutes. Cells were quickly washed with PBS, then placed on coverslips and photographed immediately, as described above. Effects of Cryptocyanin and Vinpocetine Test on Jurkat Cell Proliferation and Cell Cycle Dose-response curves for the effects of cryptocryptin compounds and vinblastine on the percentage of cell proliferation and mitotic cells were measured. Effects of Cytochalasin B, Vinblastine, and Crytodin on Cell Structure Aortic smooth muscle (A-10) cells were grown on coverslips with PBS, 2 &quot; Μ Cytochalasin B, 100ηΜ vinblastine, or 10ηΜ Alginate compound treatment. After 24 hours, the microtubules and vimentin intermediate filaments were presented by indirect immune glory, and the microfilaments were stained with TRITC-muscarinic acid. Detection of morphological effects of each drug. Untreated cells showed integration of the vast microtubule network with the microtubule tissue center around the nucleus. _-37-_ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

1T 533206 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (35)

Vitmentin intermediate filaments are evenly distributed in the cytoplasm, while microfilament bundles are concentrated on the major axis of the cell. Cytochalasin B causes complete disaggregation of microfilaments and accumulation of crystalline residue. The compound does not affect the distribution of microtubules or intermediate filaments. Observe the microtubules and vimentin intermediates treated with cryptocin, depletion of microtubules and disintegration of vimentin intermediate filaments. Effects of phycocyanin and vinblastine on microtubules stabilized by paclitaxel. A.10 cells were treated with 0 or 10 &quot; μ paclitaxel for 3 hours, and then pbs, 100 nM vinca test or 10 nM Cryptococcus素 化合物。 Compounds. After 24 hours, the microtubules were organized for immunofluorescence detection as described above. Compared to control cells, microtubules are extensively bundled in paclitaxel-treated cells, especially in the polar regions of the cells. As mentioned above, vinblastine causes complete disaggregation of microtubules in unpretreated cells. However, pretreatment with paclitaxel prevents microtubule depolymerization caused by vinblastine. Similarly, microtubules previously treated with paclitaxel were observed treated with cryptocryptin. Susceptibility of microtubules to vinorelin and cryptolin depolymerization A-10 cells were treated with 100 nM vinblastine or 100 nM cryptocryptin for 24 hours, resulting in complete depolymerization of the microtubules. Cells were then washed and incubated in drug-free medium for 1 or 24 hours. After the vinblastine was removed, the microtubules quickly repolymerized, showing a significant amount of microtubules after 1 hour, and a complete recovery of morphology at 24 hours. After treatment with the cryptocryptin compound of the present invention, the cells showed a microtubule state 1 hour or 24 hours after the cryptocryptin compound was removed. Effect of combination of vinpocetine and cryptocryptin on cell proliferation SK0V3 cells were treated with the combination of cryptoxin and vinpocetine for 48 hours. The percentage of viable cells was then measured to calculate the C50 of each composition. Toxicity of vegan, vinblastine, and paclitaxel on SK0V3 and SKVLB1 cells -38- This paper size applies Chinese National Standard (CNS) M specification (21〇 &gt; &lt; 297 public attack) (Please read the precautions on the back before reading) (Fill in this page)

533206 A7 B7 V. Description of the invention (36) SKVLB1 cells are resistant to natural anticancer drugs because of their excessive surface P-glycoprotein. Observe the ability of paclitaxel, vinblastine, and cryptocryptin to inhibit the growth of SKOV3 and SKVLB1 cells. The IC5G dose-dependent inhibitory effects of paclitaxel on SKOV3 and SKVLB1 cell proliferation were 1 and 8000 nM, respectively. Vinblastine also inhibits the growth of two cell lines, 1 (: 50 to 0.35 and 42.011) for SKOV3 and SKVLB1 cells. The cryptocryptin compound of the present invention shows an IV50 that is active on SKOV3 and SKVLB1 cells From about 1 to about 100 pM0, respectively, the new cryptocryptin compounds provided by the present invention prove to be effective cell proliferation inhibitors, which have the effect of destroying the microtubule network and inhibiting mitosis. These studies can show that cryptocryptin compounds damage microtubules Tissue and normal cell functions, including mitosis. Typical anti-microtubule agents, such as colchicine and vinca alkaloids, prevent cell division during mitosis. Appropriately compare the effects of one of these agents and the cryptocryptin compound on cell proliferation. To this end Objective To select vinca alkaloid vinblastine as a representative anti-microtubule agent. Therefore, compare the effects of cryptocryptin compounds and vinblastine on the proliferation and cell cycle progression of Jurkat T-cell leukemia cell line. Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives (please read the precautions on the back before filling this page) because of anti-mitotic effect It is generally achieved by destroying the microtubules in the mitotic spindle, and the effects of cryptocryptin compounds on the cell structure are characterized by fluorescence microscopy. Immunofluorescent staining of cells with cryptocryptin or vinblastine shows that two compounds cause microtubules Complete loss. Similar studies with SKOV3 cells can show that the anti-microtubule effect of cryptocystin is not only for smooth muscle cell lines. -39-This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) Central Ministry of Economic Affairs Standard Bureau of Work and Consumer Cooperatives, India 533206 A7 B7 V. Description of the invention (37) GC3 human colon cancer recording 96 well plate selection wells were inoculated 24 hours before test compound addition (JC3 human colon cancer cells (1 X 10 cells In 100 μl analysis medium i well). Cell-free analysis medium was added to other wells of a 96-well plate. Analysis medium (using RPMI-1640 medium; however, any medium that allows cells to survive) was supplemented with 10% dialysis Fetal bovine serum and 25 mM HEPES buffer. Test compounds were stored in amber bottles before the test to prepare fresh dimethyline飒 stock solution (200 μg / ml), and then immediately prepare a dilution of the test sample in phosphate buffered saline (PBS). Prepare a 1:20 dilution of dimethylarsine solution in pBS to a final concentration of 1.0. Μg / ml. Prepare a series of 1: 3 dilutions (0.5 ml of previous samples in i ml of PBS) using PBs. Use Falcon 2054 tube for analysis. Ten microliter samples of each dilution of test compound are added to each of the GC3 plates. In a well. The plate was incubated at about 37 ° C for 72 hours. 10 μl sample of 3_ [4,5_dimethyl_2_methyl] -2,5-diphenyltetramethylene bromide ("MTT &quot; 5 Μg / ml in pbs) was added to each well. The plate was incubated at 37 ° C for about 1 hour. The plate was centrifuged, the medium was decanted from each well, and 100 microliters of acid-isopropanol (0 04 NHC1 in isopropanol) was added to each well. The plate was read within 1 hour using a test wavelength of 570 nm (SpectraMax reader). Evaluation of the compounds of formula I shows that the compounds are useful in the therapeutic methods described herein. In addition, compounds can be used to disrupt microtubule systems. The preparation of the compounds of the invention can be accomplished using several methods involving activated esters and then chromatography and acid-triggered deblocking (if required). -40- Exhaust,-Zhang Zhang standard L used Zhongguanjia standard (CNS) A4 specifications (2 丨 GX297), (please read the precautions on the back before filling this page)

Consumers' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India 533206 A7 ------- V. Description of Invention (38)

27 R47 = Me For example, '1 (the number of the compound shown in the example of this number table) is treated with acetic anhydride in the presence of triethylamine and 4-dimethylaminopyridine. After flash chromatography, a 3' yield is obtained. 89 %. Similarly, Series 4 was prepared from 1 treated with succinic anhydride and then purified by reverse phase HPLC. The pyridine solution of 1 was exposed to a commercially available smoke test hydrazone gas hydrochloride in the presence of triethylamine and 4 · dimethylaminopyridine, and then subjected to chromatography and treatment with hydrogen gas to obtain 7, high yield rate. Pyridinium salt 8 was prepared according to the method of &gt; Jicolaou, Angew. Chem Int · Ed · EagU 1994, 33 with a yield of 47%. Treatment with 1-methylpyridine, followed by reverse phase jjPLC purification and anion exchange (acetate vs. p-toluenesulfonate) and freeze drying. Esters 5, 9, 11, 13, 15, 17, 19, and 21 are prepared in medium to high yields from 1 and commercially available (except 5 and 9) Nt-boc protected amino acids to 1,3-Dicyclohexylcarbodiimide is activated in the presence of 4-dimethylamino p ratio. Salt _ -41-This paper is suitable for (CNS) A4 size (210X297mm) ~ &quot; &quot; (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (39) Acid salts 10, 12, 14, 16, 18, 20, and 22 are produced in high yields from 9, 11, 13 '15, 17, 19, and 21 respectively with hydrogen chloride in dioxygen. Prepared by treating 4.0 M solution in Lupin and removing the solvent in the air. Disodium salt 6 is derived from 5 after the third butyl ester is cleaved by hydrochloric acid and treated with sodium hydroxide. The acid 24 required for the preparation of 5 was synthesized in 63% yield, and was added through the 5 step sequence of the method of Johns, Synthesis. 1988, 142 to add a phosphate functional group. ηΛχ) 0P (0) (0 f-Bu) 2 24 To evaluate the in vitro cytotoxicity of several novel conjugates in the GC3 tumor cell model. The results shown in Table 2 show that the compounds of this series have good to excellent activity relative to cryptocryptin 55 (1). The preparation of any of the esters of 2 (R1 or R2 is derived from a carboxylic acid) includes various techniques using fluorenyl chloride, anhydride, and general activating reagents such as carbodiimide. Any non-alcoholic solvent can be used. Any mild base and / or catalyst (amine, carbonate) can be used to assist in the esterification. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs—Consumer Cooperatives (please read the precautions on the back before filling out this page) f Urethane 9, 11, 13, 15, 17, 19, and 21 can be converted into corresponding salts by any Strong acids, i.e. inorganic acids, include autogenated hydrogen, hydrogen sulfate, hydrogen sulfate, hydrogen nitrate, peroxyacid argon, or strong organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid ,get on. The salt of 7 can be produced from the corresponding free test using the same acid. Various counter ions (cations) can form salts of 6, including any alkali and alkaline earth metals. Various counterions (anions) can form salts of 8, which are any conjugate bases of acids (organic or inorganic.). -42- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 V. Description of the invention (40) Table 2 · Cryptocin derivatives use the above analysis of in vitro cytotoxicity data. Compound GC3 IC50 (nM) 1 0.065 3 83 4 31 6 3.7 7 116 8 2.2 10 — 12 0.10 14 21 16 230 18 2. 6 20 — 22 7.2 26 — (Please read the notes on the back before filling this page) The analysis results of other compounds of the present invention and GC3 are as follows: Structure IC50 (uM) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

0.7950 Cryptophyllin-141 -43- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (41

0H

C1 OCH 3 Cryptocin-138 structure 0.0308IC50 (uM) (Please read the precautions on the back before filling in this page 〇

Cl 〇ch3 0 · 0034

------- IT Cryptophyllin-139 m n HI ϋ m m l Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Cl 〇CH3 Cryptophyll-140 0.863 -44- The paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (42)

3 Η I-1C c 〇 Cryptocin-143 structure 0.8500 IC50 (uM &gt; (Please read the precautions on the back before filling this page)

OH

Cl OCH3 0.0011 Cryptophyllin-142 Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs, India

3 Η 1 C C 〇 Cryptocin-145 0.000015 • 45- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 533206 A7 i. Description of the invention (43

PH

Cl OCH, Cryptocin-129 Other compounds of the present invention have been tested in GC3 analysis and have a range of ic50 ° from less than 1 to about 700 nM; however, the most typical radon is less than 100 nM. The results of the preliminary solubility comparison studies of 27, 1, and 12 are shown in Table 3. These results show that 12 has a strong solubility. (Please read the precautions on the back before filling out this page) Printed excipient volume adjustment by the Ministry of Economic Affairs Central Consumer Bureau Cooperative Co., Ltd. 0.05M acetate buffer volume / vol% 27 (mg / ml) 1 ( Mg / ml) 12 (mg / ml) 1 propylene glycol ethanol 15 10 BQL BQL &gt; 2.0 2 propylene glycol polyethylene glycol 3000 15 20 BQL 0.0026 &gt; 2.0 3 polysorbate 80 1 (w / v) BQL 0.3113 1- 2 4 Emulphor EL719 1 (w / v) 0.0272 0.3611 1. 5 5 0 · 05M acetate buffer pH 4.0 100 &lt; 0.001 &lt; 0.001 0.03 (BQL = below the limit of quantification, about o.ooi mg / ml) Order .% 1 -46 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297mm) 533206 A7 B7 V. Description of the invention (44 1 to 12 in the aqueous solution pH range 4_8 Comparison of stability characteristics Measured at room temperature for 6 hours. The results of these studies clearly show the excellent water solubility of 12 and: qualitative. For example, at pH 8, cryptofuxin 55 has solubility at room temperature 値 10 g / ml, under substantially the same conditions In comparison, the solubility of 12 is 30 mg / ml. At pH 4, cryptocryptin 55 It has a water solubility of about 50 mg / ml; however, when the pH becomes alkaline, the water solubility of Cryptophyll 55 decreases, while the water solubility of 12 remains substantially stable within the ipH range studied. Based on the degree of hydrolysis The results of the research on the safety and footing are selected to suit parenteral carriers to determine the absolute solubility / stability characteristics of 12. Table 4 illustrates the proteolysis profile of i 2 in these carriers. Preliminary results show that i 2 is in the formulation The acceptable stability in Object 6 is up to 3 weeks. (Please read the notes on the back before writing this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-47- 533206 A7 B7 V. Description of Invention (45 HJI Alginin glycinate 1 2 St. _ .. non-excipients volume / vol% ethanol propylene glycol 0.05 M citrate buffer pH 4.0

2 ethanol propylene glycol 0.05 Μ citrate buffer pH 4.0 10 10 appropriate amount 1.99 (please read the precautions on the back before filling this page) ethanol 0.05 Μ citrate buffer pH 4.0 10 appropriate amount 1.29 4 propylene glycol 0.05 Μ citrate buffer Washing solution pH 4.0 5 Polysorbate 80 0.05 M citrate buffer pH 4.0 10 Right amount 1.58 0.5 (; weight / volume) Right amount 2.21 Printed 6 ethanol propylene glycol 0.05 M citrate buffer by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs pH 4.0 7 ethanol propylene glycol 0.05 Μ citrate buffer pH 4.0 Therefore ο 5 deniers 1 2. Pass 10.27 ο 5 The amount of the compound of the present invention is suitable without surfactant or lactone--48 This paper is applicable to China National Standard (CNS) A4 specification (210X29? Mm) 2 3 4 in the carrier 533206 A7 B7 46 5. Description of the invention (up to high concentrations, which can facilitate the toxicology and clinical evaluation of these compounds. Glycine (12) It has better stability in the physiological pH range in an aqueous environment. In a longer period, it shows an increased shelf life under normal conditions. Although the concentrates 1 and 27 need to be prepared for storage And then diluted before application, but the compounds of the invention can be prepared as ready-to-use solutions. Compounds of formula I can be prepared using compounds of formula II

Among them, Ar, Rl, R2, R3 ,, R5, R7, R8, R9, R10 have the meanings printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs as described in Formula J, and R13 is selected from the third butylaminomethyl (BOC); R24 is selected from the group consisting of M. (N-hydroxysuccinimide, &amp; &quot; NHS &quot; used herein), hydroxysulfosuccinimide and its salts, 2-nitrophenyl, 4—49- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 533206 ΑΊ Β7 5. Description of the invention (47 nitrophenyl, and 2,4-dichlorophenyl; X is 0, NH or alkylamino; Y is 0, NH or alkylamino. Compound of formula III

III wherein the R group and each substituent are as defined above and in the specification, and can be represented by the compound of formula IV

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

IV R25 is the acid of the following formula ψιyR6 co2r27 -50- (Please read the precautions on the back before filling this page)

This paper size applies Chinese National Standard (CNS) A4 specification (2) 0X297 mm 533206 A7 B7 V. Description of the invention (48) R27 is selected from the group consisting of osmium, CKC12 alkyl, and aryl; and contact with silylating agent to prepare . Bis-N, 0-trimethylsilylacetamide (BSA) is a particularly good silanizing agent. The term &quot; active ester substituent &quot; as used herein means that the indicated substituents can be substituted for good leaving groups. Suitable substituents can be selected according to the guidance of standard reference materials, such as 丨 丨 Protective Groups in Organic Chemistry ”, Plenum Press, (London and New York, 1973); Greene, TW 丨 Protecting Groups in Organic Synthesis 丨 丨, Wiley (New York , 1981). See especially Greene, pp. 180-184. A particularly preferred active ester substituent is N-Cytosphine (NHS). Other preferred groups include, but are not limited to

(Please read the notes on the back before filling this page) (0-N_, succinimide), 0-N_hydroxysulfosuccinimide and its salt, 0-2-nitrophenyl, 0 4-nitrophenyl, and 0.2,4-dichlorophenyl, where "0" represents the oxy group required to form an ester functional group. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The term n g as used herein refers to the amidine functional group that can be cleaved under experimental conditions. For example, this glossary is, but is not limited to, -NMe2. For other guidance 'see, for example, Greene, TW &quot; Protecting Groups in Organic Synthesis, Wiley (New York, 1981). O The term "active ester substituent" table used herein can make OR24 substituents a good leaving group. Of substituents. Suitable substituents can be selected by the guidance of standard reference materials, such as &quot; Protective Groups in Organic Chemistry ,,, Plenum Press, (London and New York, 1973); Greene, TW _ -51-This paper standard applies to Chinese national standards ( CNS) A4 specification (210X297 mm.) 533206 A7 B7 V. Description of the invention (49) &quot; Protecting Groups in Organic Synthesis &quot;, Wiley (New York, 1981). A particularly preferred R25 group is N-hydroxysuccinimide (NHS). The methods described herein are best performed in the presence of a solvent. Those skilled in the art can choose a suitable solvent for the above method. Inert organic solvents are particularly preferred; however, aqueous solvents are suitable under certain conditions. For example, if R27 is hydrogen and R13 is BOC, an alkaline aqueous solution can be used as a solvent. When the desired R6 substituent in the compound of formula I contains an amine, the amine substituent of the R6 group must be protected with an amine protecting group. Skilled artisans can easily use standard reference materials to guide the selection of suitable amine-based protective groups, including, for example, &quot; Protective Groups in Organic Chemistry ', Plenum Press, (London and New York, 1973); Greene, TW &quot; Protecting Groups in Organic Synthesis ,, Wiley (New York, 1981). R27 should be such that the -C02R27 substituent can be removed using acidic, neutral, or mildly basic conditions. Preferred R27 groups include, but are not limited to, hydrogen, (^-(^ alkyl, trichloromethyl, trichloroethyl, and methylthiomethyl. R27 is particularly preferably hydrogen. To provide further guidance for those skilled in the art Provide the following 0: Compounds of formula I can be prepared using compounds of formula II (please read the precautions on the back before filling this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Consumption Cooperative

-52- This paper size applies Chinese National Standard (CNS) A4 specification (210X29? Mm) 533206 A7 —_ __67 _ V. Description of invention (50)

Ar, R1, r2, R3, r4, R5, r7, r8, R9, R10 have the meanings described in the formula; R11 'is as defined above for R11; r13 is selected from the amino protecting group; R24 is selected from the active ester Substituents, fluorenylamine substituents, 0_2 · nitrophenyl, 0_4-nitrophenyl, and 0_2,4-dichlorophenyl; X is 0, NH or alkylamino; Y is C ,. , NH, S, SO, S02, or alkylamino. (Compounds of formula III (please read the precautions on the back of itff before filling out this page)

Compound of formula IV

This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 51 V. Description of the invention (R25 is the first note of τδ, and then the acid of the following formula y «6 c〇2r27 · / R27 is selected from the group consisting of fluorene, CVCu alkyl, and aryl; and contacted with a silylating agent. Bis-N, 0-trimethylsilylacetamide (BSA) is a particularly good silylating agent. The term "active ester substituent" of R25 makes OR24 substituents a good leaving substituent. Suitable substituents can be selected according to the guidance of standard references, such as &quot; Protective Groups in Organic Chemistry &quot;, Plenum Press, (London and New York, 1973); Greene, TW &quot; Protecting Groups in Organic Synthesis &quot;, Wiley (New York, 1981). The best R25 group is N-hydroxysuccinimide (NHS) Cooperative printing methods described in this article are best performed in the presence of solvents. Those skilled in the art can choose suitable solvents for the above methods. Inert organic solvents are particularly good; however, under certain conditions water The solvent is suitable. For example, if R27 is hydrogen and R13 is BOC, the test solution can be used as a solvent. When the desired R6 substituent in the compound of formula I contains an amine, the amine substituent of the R6 group must be protected by an amine protecting group. Artists can easily use standard reference materials to guide the selection of suitable amine-protecting groups, including, for example, Protective Groups in Organic Chemistry &quot;, Plenum Press, (London and New York, 1973); Greene, T.W. `` Protecting Groups in- 54 This paper size applies the Chinese National Standard (CNS) A4 specification (210'〆297 mm) 533206-Μ 5. Description of the invention (52

Organic Synthesis' Wiley (New York, 1981). R27 should be a group that allows the -C02R27 substituent to be removed using acidic, neutral 9 or mild alkaline conditions. Preferred R27 groups include, but are not limited to, hydrogen, Ci-G alkyl, trichloromethyl, trichloroethyl, and methylthiomethyl. R27 is particularly preferably hydrogen. To provide further guidance for m learners, provide the following picture ...

Figure I (Please read the notes on the back before filling in this hundred.

0 50% aqueous HF ^ = — 〆 ch3cn

1T

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

Ar

-55-

OR26

This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 533206 Μ B7 V. Description of the invention (53) The halogens, SH, amines, monoalkylamines, and diamines are used in Figure Γ and in the description. Burned amine group, burned thio group, burned thio group, dialkylphosphonium group, sulfate group, phosphate group, or protected OH or, protected SH group; R2 is OH or SH; R20 is a part of synthesis An alcohol protecting group is added during the method to protect alcohol groups that may react during chemical operations, and then removed later in the synthesis. Many reactions to the formation and removal of these protecting groups are described in many standard references, including, for example, &quot; Protective Groups in Organic Chemistry &quot;, Plenum Press, (London and New York, 1973); Greene, T.W. &quot; Protecting Groups in Organic Synthesis '', Wiley (New York, 1981). Those skilled in the art can use the guidance provided in these references to choose a suitable alcohol protecting group. A particularly useful alcohol protecting group is tert-butyldimethylsilyl (TBS). The products of this figure can be derivatized using standard methods to provide other cryptocin compounds. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs __- 56- I Paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 public ^ 206206 A7 B7 54 invention Description (CH3

NHBoc a

(Please read the notes on the back before filling this page) (vi-vii) CH3

O Generally speaking, the method of the present invention is as follows: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 57 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (55)

(Read the precautions on the back before you fill in this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -58- This paper size applies to Chinese National Standards (CNS) A4 specifications (2) 0X297 mm 533206 A7 B7 Description of the invention (56) CH3 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

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

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, COgMe

A7 B7 5. Description of the invention (57 R6 and R11 are as defined in this specification. The products of the figures provided herein can be further derivatized using standard methods to provide other cryptocryptin compounds. Those skilled in the art can use suitable starting materials And reagents, using the instructions in the figure above and the following examples to prepare the desired compound. Ester starting materials can be prepared as follows:

CHO

Step 1 HEW TMG

Step 5 Bu2Sn = 0 TsCi, TEA -60- This paper size is applicable to China National Standards (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back and fill in this -ro

533206 A7 B7 V. Description of the invention (58

OTs OH

Step 6 TBS-OTf EtaN

OTs OTBS

Step 7 NBS / AIBN

OTs OTBS

Step 8 DBU / ACN

OTs OTBS

Step 9 Printed by the Consumer Cooperative of the KCN Central Bureau of Standards

OTBS

Step 10 DIBAL; HEW

OTBS ΟΜθ -61 (Please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (59) R6 has the above definition. For further guidance, the figure below is provided. Some abbreviations are used in the drawings, preparations, and examples, and they are generally known in the art. For convenience, these abbreviations include: DMAP 4-dimethylaminopyridine BOC tert-butoxycarbonyl mcpba m-p-perbenzoic acid TMSC1 chlorotrimethylsilane HEW Horner-Emmons-Wadsworth reaction (aldehydes use phosphates and bases Standard reaction for alkylation) TMG 1,1,3,3-tetramethylguanidine (standard base for HEW reaction) DIBAL diisobutylaluminum hydride (standard reagent for reduction of unsaturated esters to propylpropanol) SEA Sharpless Asymmetric epoxidation (enantiomerically selective epoxidation of allyl alcohol) TBS tertiary butyldimethylsilyl TBS-Otf TBS trifluoromethanesulfonium salt (third butyl alcohol Standard reagent for dimethylsilylation) AIBN 2,2M azobis (isobutyronitrile) (standard group initiator) ACN Acetonitrile DBU 1,8-diazabicyclo [5 · 4 · 0] 11 -7-ene (standard amine base) EDCI 1-ethyl-3 · (3-dimethylaminopropyl) carbodiimide to prepare esters is further illustrated by the preparation section described in this article, this section Provide specific applications of maps for those skilled in the art. -62- This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (60)

Figure I

〇Me 1) 03, Sudan Red-P Bidian, CH2C12 2) Zn, AcOH (88%)

〇HC x- PPh. AR '

Alkali

OTBS OMe

OTBS 3 OMe ----------- Aw .---, i ^ ------ 'Ψ (Please read the notes on the back before filling out this page) Staff Consumption of the Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative 63 The size of this paper applies to the Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (61 Figure 1 continued

KOH

+ TFA- THF, 65 ° C

7 Consumers' Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, Yinfan -64 (Please read the precautions on the back before filling this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (62 Figure 1 Result ^ γ ° 〇 8

Js.〇JLnHBoc DCC, DMAP CH2C12 (75-85%)

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

1T t Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy

Employees' Cooperatives Yinle -66- (Please read the notes on the back before filling this page)

This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of invention (64)

Ar substituents are as described herein. The illustrations are not intended to limit the synthetic illustrations to the phenyl groups exemplified. This method can be widely used by those skilled in the art to provide the desired starting materials for the preparation of the compounds described herein. The required reaction time depends on the starting material and the operating temperature. The optimal reaction time for a particular method is determined by considering the completion goal of the throughput of the material (short reaction time is advantageous) and the maximum yield (long reaction time is advantageous). Certain compounds of the invention can be prepared using biosynthetic pathways. For example, a solution of cryptocryptin 3 (about 0.24 mmol) in DME-H20 (2: 1, 15.0 ml) is treated with bromosuccinimide (about 65 mg) at about 0 ° C and heated to room temperature. temperature. After about 24 hours, the 'solvent removal' residue is dissolved in a solvent (such as cjj3CN) and subjected to reverse-phase HPLC (65:35 CH3CN / H2O, preferably 6 ml / min) to obtain a mixture of cryptocryptin. The mixture was re-chromatographed using normal phase HPLC (1: 1 Hexo / Ethyl Acetate, preferably 3 ml / min) to obtain the desired cryptocin. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) f Similarly, Crytodin 3 (approximately 40 mg, 0.063 mmol) is added to 2: 1 DME / HbCK approximately 6 Ml), N-chlorosuccinimide (0.075 mmol) was added and heated at about 60-70 ° C for about 24 hours. NCS (8 mg) was added and heating was continued for about 24 hours. The solvent was removed and the residue was subjected to HPLC (35% H20 / CH3CH, 6 ml / min) to obtain the desired cryptocin compound. The resulting mixture was purified by HPLC using methanol / water (approximately 4: 1) to obtain the desired purified cryptocryptin compound. To further illustrate the invention, the following examples are provided. The scope of the invention is not limited to the following examples. Preparation 1 Step 1. 5-Phenylpentanyl (E) -enoic acid methyl ester · phosphoranyl acetate (376 g, -67-) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) Consumption cooperation seal of employees of the Central Bureau of Standards of the Ministry of Economic Affairs «533206 A7 B7 V. Description of the invention (65) 417 ml, 2.07 mmoles in THF (750 ml) at 0 ° C with a mechanical stirrer And a 3 liter three-necked round bottom flask with an N2 inlet tube. In the cooled solution, pure tetramethylguanidine (239 g, 260 ml, 2.07 mol) was added dropwise via an addition funnel. The cooled transparent light yellow solution was stirred at 0 ° C for 25 minutes. A solution of dihydrocinnamaldehyde (90%, 253 g, 248 ml, 1.9 mol) in THF (125 ml) was slowly added dropwise to the reaction solution. When the addition was complete, the reaction mixture was stirred for 10 hours and the temperature was raised to room temperature. GC showed that the ratio of the product to the starting material was 95: 5. 500 ml of water was added to the reactor, and the reaction mixture was stirred overnight and separated into two layers. The organic layer was separated and the aqueous layer was extracted with t_BuOMe. The organic layers were combined, dried over MgS04, and then concentrated in the air to obtain a light oil. The crude product was distilled at 129 ° C / 0.3 mm Hg to obtain 360.5 g, 91.7% yield, transparent pale yellow oil. EIMS m / z 190 (13; M +), 159 (410, 158 (39), 131 (90), 130 (62), 117 (22) 104 (12), 95 (57), 91 (100), 77 (21), 65 (59); HREIMS m / z 190.0998 (Ci2Hi4〇2 D-0.4 mnu); UV lmax (e) 210 (8400), 260 (230) nm; IR nmax 3027, 2949, 1723, 1658, 1454, 1319, 1203, 978, 700 cm1; lR NMR d (CDC13) 7.15-7.3 (Ph-H5; bm) 9 7.00 (3-H; dt 15.6 / 6.6), 5.84 (2-H; dt, 15.6 / 1.2), 3.70 (OMe; s), 2.76 (5 · Η2; t, 7.2), 2.51 (4-H2; bdt, 6.6 / 7.2); 13C NMR d (CDC13) 166.9 (1), 148.3 (3 ), 140.6 (Ph-1,), 128.4 / 128.2 (ph27 3 '/ 5 · 6 ·), 126.1 (Ph 4'), 121.4 (2), 51.3 (OMe), 34.2 / 33.8 (4/5). Step 2. 5-Phenylpent-2-en-1-ol. In a 12 liter four-necked round bottom flask equipped with a thermocouple, a mechanical stirrer, and an N2 inlet tube, the enoate (3 10.5 g, 1.5 Mol) was added to the solution in THF (1.5 liters), and cooled to -68 by i-PrOH / C02 bath-This paper size is applicable to China National Standard (Cns) A4 size (210X297), (please read the note on the back first) (Fill in this page again)

533206 A7 B7 V. Description of the invention (66) -71X :. In the reactor, DIBAL (2.5 liters, 1.5 M in toluene, 3.75 moles) was added dropwise at a rate to maintain the reaction temperature &lt; -50 ° C. When the addition was complete, the reaction mixture was stirred overnight and the reaction temperature was &lt; -50 ° C. TLC (3: 1 hexane: EtOAc, SiO2) showed no starting material was present after 16 hours. Increase the reaction temperature to -15 ° C. The reaction was slowly quenched with IN HC1 (150 mL). At this time, the reaction mixture formed a gelatinous solid. A spoon-shaped plate was used to destroy the semi-solids, and 1NHC1 (200 ml) was added to make the mixture liquid. Concentrated HC1 (625 mL) was added to form a two-phase system. The layers were separated and the product was extracted with t-BuOMe. The organic layer was dried over MgS04 and concentrated in the air to obtain a clear pale yellow oil, 247.8 g. The crude product was distilled at 145X: /0.25mm Hg to obtain 209.7 g, 86.2%. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) EIMS m / z 162 (1: M +) 144 (16), 129 (7), 117 (9) 108 (6 ), 92 (17), 91 (100), 75 (5), 65 (12), HREIMS m / z 162, 1049 (CnH140, D_0.4 mmu); UV Imax (e) 206 (9900), 260 ( 360); IR nmax 3356, 2924, 1603, 1496, 1454, 970, 746, 700 cm1; lU NMR d 7.15-7.3 (Ph-H5; m), 5.70 (3-H; dt, 15.6 / 6.0), 5.61 (2-H; dt, 15.6 / 4.8), 4.02 (1-H2; d 4 · 8), 2.68 (5-Η2; t, 7.2), 2.40 (0Η; bs), 2.36 (4- H2; dt, 6.0 / 7.2); 13C NMR dl41.6 (Ph Γ), 131.8 (3), 129.5 (2), 128 · 3/128 · 2 (PΗ 27375, / 6,), 125.7 (Ph 41) , 63 · 3 (1), 35,4 / 33.8 (4/5) 〇 Step 3 · (2S, 3S) -2,3-epoxy-5-phenyl-2-pentanol · In the thermoelectric Into a 1-liter three-necked round bottom flask with a mechanical stirrer and a nitrogen inlet tube, add CH2C12 (350 ml), dried 4A molecular sieve (30 g), and L-(+) diethyl tartrate (7.62 g, 0 · 037 Mol). The resulting mixture was cooled to -20. C, treated with Ti (0 small pr) 4 (9.2 ml, 0.031 mol), and then added the third di-69- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (67) -based hydroperoxide (4.0 M in CH2C12, 182 ml, 0.78 mol) was maintained at a rate of -20 ° C at a temperature. When the addition was complete, the reaction mixture was allowed to stir for an additional 30 minutes, and then treated with a solution of allyl alcohol (50 g, 0.31 mol) in CH2C12 (30 ml), maintaining the temperature at a rate of -20 ° C . The reaction mixture was stirred at the same temperature for 5 hours, and then filtered to add a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 ml) at 0 ° C. The mixture was stirred for 20 minutes, then transferred to a separatory funnel and extracted with t_Bu0Me (2 x 200 mL). The combined organic phases were stirred with a 30% NaOH solution containing NaCl at 0 ° C for 1 hour. The layers were separated and the aqueous phase was extracted with t_BuOMe. The combined organic phases were washed with brine, dried over MgS04, and concentrated to give 52.8 g of an amber oil. Step 4 · (2R, 3R) -2-hydroxy-3_methyl · 5-phenylpentan-1-ol · In a 5 liter three-necked round bottom flask equipped with a thermocouple, a mechanical stirrer, and a nitrogen inlet tube Hexane (1 liter) was added and cooled to 0 ° C. Me3Al in 2.0M solution (800ml, 1.6 moles) in hexane was added, and then a solution of epoxide (120g, 0.677 moles) in hexane (250ml) / CH2Cl2 (50ml) was added , The temperature remains below 20 ° C. When the addition was complete, the turbid reaction mixture was stirred at 5 ° C for 3 5 minutes. A 10% HC1 solution (300 ml) was added dropwise, and then concentrated HC1 (350 ml) was added. The layers were separated and the organic phase was washed with brine and dried over MgS04. After the volatiles were removed in the air, 122.1 g of an oil was obtained. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Step 5. (2R, 3R) -2-hydroxy-3-methyl-5_phenylpent-1-yl Tosylate. Into a 2-liter three-necked round-bottomed flask equipped with a mechanical stirrer and a nitrogen inlet tube, add diol (58 g, 0.30 mol) and dibutyltin oxide (1.5 g, 0.006 mol, 2 mol). %), Tosylsulfonyl chloride (57.5 g, 0.30 mole), CH2C12 (580 ml) and triethylamine (42.0 ml, 0.30 mole). The resulting mixture is stirred at room temperature -70- This paper size applies to Chinese National Standard (CNS) A4 (2i0x297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 --------__ B7 5 2. Description of the invention (68) ^ 2 hours (although the reaction is completed within j hours), filtered, washed with water, and dried with MgS04. The volatiles were concentrated in the air to obtain 1041 g of a light amber oil. Step 6 · (2R, 3R) -2-[(Third-butyldimethylsilyl) oxy] -3 • methyl_ 5-phenylpent-1-yltosylate tosylate ( A solution of 100 g, 029 mol) and diethylamine (810 liters, 0.58 mol) in CH2C12 (1200 ml) was added dropwise with pure TBS-OTf (99 liters, 043 mol). Work up and continue stirring for 20 minutes. The reaction mixture was washed twice with brine, dried over MgS04, and concentrated to dryness. The oil was dissolved in a minimum amount of hexane, filtered through a pad of silica, and dissolved with hexane: EtOAc (9 ·· 1) to give a light amber oil, 34 g. Step 7. (2R, 3R, 5RS) -2-[(Third-butyldimethylsilyl) oxy] small methyl-5-bromo-5-phenylpent-1-yltoluenesulfonate in A 5-liter three-necked round bottom flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen inlet tube was charged with CC14 (1680 liters), TBS Ts (140 g, 0.30 mol), NBS (65 g, 0.365 mol) ), And AIBN (16.5 g, mol). The mixture was evacuated and degassed with complete evacuation, stirred, and backfilled with nitrogen (3x). The reaction mixture was then heated to reflux and turned dark brown. After 15 minutes under vigorous reflux, the reaction mixture turned pale yellow, and chromatographic analysis showed that the reaction was complete. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was redissolved in hexane, filtered, and concentrated to dryness to obtain 170.3 g of a white oil. Step 8 · (2R, 3R) -2-[(Third-butyldimethylsilyl) oxy] -3-methyl-5-phenylpent-4 (E) -en-1-yltoluenesulfonate Ester. A 2 liter three-necked round bottom flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen inlet tube was charged with a solution of bromine (100 g, 0.186 mol) in acetonitrile (700 ml). DBU (83.6 ml, 0.557 mol) was added and the resulting dark brown solution was stirred at reflux for 15 minutes. -71-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling out this page) Order f 533206 Α7 Β7 V. Description of the invention (69) After cooling to high temperature After that, the solvent was removed in the air, and the residue was digested in CHzCh (200¾ liters) and filtered through a silica pad. The volatiles were re-evaporated and the residue was taken up in EtOAc ', washed with water, brine, dried over MgS04, and concentrated to dryness. By preparative mPlc (Prep 500) chromatography, the desired unsaturated compound was obtained (50.3 g, 60% yield, in 4 steps). Step 9 · (3S, 4R) _3-[(Third-butyldimethylsilyl) oxy] 'methyl_ 6-Mulylhex-5 (E) · ^ _1-nitrile benzoate (5 〇g, 〇011 mol) was dissolved in DMSO (1 liter), treated with KCN (14.2 g, 0.22 mol) and water (25 ml), the resulting mixture was stirred at 60 ° C under nitrogen for 18 hours . After cooling to room temperature, the reaction mixture was partitioned between EtOAc (1 liter) and water (1 liter). The aqueous phase was extracted like EtOAc (500 ml). The combined organic phases were washed with brine and

NaJO4 is dry. CHWh flash chromatography on silica to obtain the desired nitrile, yield 92% 〇 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) Step 10 · (5S, 6R ) -5 _ [(Third butyl dimethyl sulfenyl) oxymethylmethyl_ 8-phenyloctyl-2 (E), 7 (E) · dienoic acid methyl ester · nitrile (14.67 g, 46.5 mmol Ear) Dissolved in toluene (200 ml) and cooled to -78 under nitrogen. (:. 1.5M solution of DIBAL in toluene (37.2 ml, 55.8 mmol) was added dropwise and stirred vigorously. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully poured into IN HC1, and the mixture was dropped at room temperature for 30 minutes. The layers were separated, and the organic phase was washed with a saturated sodium tartrate aqueous solution (2x), washed with brine, and dried over NajO4. The volatiles were removed in the air, and the crude The light yellow oil was used directly in the next condensation. The above crude aldehyde was dissolved in THF (90 ml), and trimethyl phosphine acetate (903 ml, 55.8 mmol) and tetramethylguanidine ( 7.0 ml, 55.8 mol) at room temperature -72- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 533206 A7 B7 V. Description of the invention (7〇) Processed under nitrogen. Reaction mixture Stir for 6 hours, then partition between EtOAc (200 ¾ liters) and water (100 mL). Aqueous phase # Et〇Ac (100 mL) was back-extracted, and the combined organic phases were washed with water, brine , Dried over Na 2 SO 4. The volatiles were removed from Coix sylvestris' crude yellow oil (170 g) Chromatography on silica gel with CH2C12: cyclohexan (1: 1: 2: 1) gave 13 67 g of the desired ester 9 78 50 / 〇.

(Please read the precautions on the back before filling this page.) Methyl vinegar (2.667 mmol) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is dissolved in acetone, and then the iNLiOH aqueous solution (26 liters) is at room temperature. Join. The turbid mixture was then diluted with acetone (20 ml) and the resulting more coloured mixture was stirred at room temperature; stirred for 23.5 hours. The reaction mixture was diluted with diethyl ether (400 mL), and the organic phase was washed with 1NHC1 (120 mL), brine (200 mL) and H20 (160 mL). The organic phase was dried and concentrated in the air to obtain a yellow oil, which was purified by column chromatography (concentration gradient ·· 5% AcOH + 20% -40% EtO Ac / Hex: fe) ' 960 mg, 100%). ! Η NMR (CDC13) d 7.38-7.19 (m? PhH5), 7.09 (ddd? J = 15.2? 7.6 and 7.9 Hz, 3-H), 6.38 (d, J = 16 Hz, 8-H), 6.16 (dd, J = 16 and 8Hz, 7-H), 5.85 (d, J = 15.8Hz, 2-H), 3.81-3.75 (m, 5-H), 2.49-2.37 (m, 6-H, 4-CH2), 1.12 (d, J = 6.7Hz, 6-Me), 0.91 (s, SiCMe3), 0.065 (s, SiMe), 0.068 (s, SiMe) ppm; IR u (CHC13) 2957, 2930, 2858, 1697, 1258, 1098, 838 cm · 1; MS (FD) 360.2 (M +, 100); '-73- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 V. Description of the invention (71) [a] D + 87.6 (c 10.5, CHC13); Analysis and calculation of C21H3203 値: C, 69.95; Η, 8.95%. Found 値: C, 69.19;;, 8.39%. Preparation 3

Consumption by employees of the Central Bureau of Standards of the Ministry of Economic Affairs. Printed by the cooperative (please read the precautions on the back before filling this page) in a stirred solution of carboxylic acid (2 亳 mol) in anhydrous dimethylformamide (5.50ml) Add 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.4 mmol) and N-hydroxysuccinimide (2.6 mmol) at room temperature. The mixture was stirred for 28 hours, then diluted with EtOAc (100 mL), washed with 1 NHC1 aqueous solution (2 X 50 mL), H20 (75 mL), dried, and concentrated in the air to give an oil. The crude product was purified by column chromatography (concentration gradient: 5-30% EtOAc / hexane) to obtain the active ester as a pale yellow oil (724 mg, 80%). lR NMR (CDCI3) d 7.36-7.20 (m, PhH5? 3-H), 6.38 (d? J = 16Hz, 8-H), 6.14 (dd, J = 16.1 and 8.0 Hz, 7-H), 6.03 ( d, J = 16Hz, 2-H), 3.79 (q, J = 4.3Hz, 5-H), 2.94 (brs, CH2CH2), 2.58 · 2 · 42〇, 6-H, 4-CH2), 1.10 ( d, J = 6.8Hz, 6-Me), 0.90 (s, SiCMe3), 0.05 (s, SiMe2) ppm; IR u (CHCI3) 2957, 2931, 2858, 1772, 1741, 1648, 1364, 1254, 1092, 1069, 83 8 cm1; MS (FD) 457 (M +, 100); -74- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Μ B7 V. Description of the invention (72) [a] D + 71.3. (C 10.1, CHC13); Analysis and calculation of C25H35N05: C, 65 61; h, 7_7; N, 3.06%. Measured 値: C, 65.51; Η, 7.56; N, 3.02%. Preparation 4

48% HF aqueous solution (15 ml) was added to a stirred solution of stilbene alkyl ether (2.50 g, 5.47 mmol) in CH3CN (130 ml) at 0 ° C. The solution is at 0. (: Stir for 0.75 hours and then at room temperature for 4 hours. Dilute the reaction mixture with diethyl ether (300 ml) and wash with HW until the washing solution reaches about pH 7. The organic phase is dried (MgSCU) and concentrated in the air to obtain Yellow residue, which was recrystallized from Et20 to obtain alcohol as white crystals (1.46 g, 78%). NMR (CDC13) d 7.41-7.20 (m, PhH5, 3-H), 6.48 (d, J = 16Hz, 8-H), 6.15 · 6.07 (η, 7-H, 2_H), 3.71-3.65 (m, 5-H), 2.83 (brs, CH2CH2), 2.60-2.33 (m, 6-H , 4-CH2), 1.95 (brs, 5-OH), 1.14 (d, J = 6.8Hz, 6, Me), ppm; IR u (KBr) 3457, 1804, 1773, 1735, 1724, 1209, 1099, 1067, 1049, 975, 744, 694 cm · 1; UV (EtOH) lmax 250 (e = 20535) nm; MS (FD) 343.2 (M +, 100); [a] D -57.8 0 (c 10.56, CHC13) ; -75- This paper size applies to Chinese National Standard (CNS) A4 (21〇X 297mm) (Please read the precautions on the back before filling this page)

T 533206 A7 ~ ---- ---- B7 V. Explanation of the invention (73) Analysis and calculation of C19H21N05S 値: C 66 46; Η6 · 16; Ν, 4.08%. Measured 値: C, 66.49; Η, 6.16; N, 4.07%.

Cryptocin-5 5 Example 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling out this page) Feng Feng's system for the production of Cryptocin 55 acetate (3). Triethylamine (55 mL, 0.40 mol), 4-dimethylaminopyridine (1.6 Mg, 0.013 mmol), and liver acetate (19 ml, 0.20 mmol). After stirring for 1 hour, the reaction was quenched with 19 ml of methanol, concentrated to a volume of 0.5, and added directly to a flash chromatography column (19 g of flash silica gel). Ethyl acetate-hexane (3: J) was used to dissociate to obtain 88 mg (89%) of the title compound as a white foam. 500 MHz 4 NMR (CDC13) d 7.38-7.31 (m, 5H), 7.24 ( d, 1H, J = 2.1 Hz), 7.22-7.18 (m, 1H), 7.10 (dd, 1H, J = 8.5, 2.1 Hz), 6.88 (d, 1H, J = 8.5 Hz), 6.75 (ddd, 1H, J = 15, 13, 4.6 Hz), 5.78 (dd, 1H, J = 15, 1.0 Hz), 5.55 (d, 1H, J = 7.9 Hz), 5.46 (dd, 1H, J = 9.8, 1.2 Hz), 4.95 (dd, 1H, J = 11, 2.9 Hz), 4.89 (ddd, 1H, J = 9.9, 9.9, 1.7 Hz), 4.81 (d, 1H, J = 9.8 Hz), 4.79- 4.74 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8.1 Hz), 3.22 (dd, 1H, J = 13, 4.1 Hz), 3.16 (dd, 1H, J = 14, -76- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 533206 74

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs IL A7 B7 V. Description of the invention (5.1Hz), 3.07 (dd, lH, J = i4, 7.6Hz), 2.65-2.55 (m, 2H), 2.47-2.39 (m, 1H), 1.95 (ddd, 1H, J = 14, 13, 4.6 Hz), 1.86-1.77 (m, 1H), 1.73-1.66 (m, 1H), 1.68 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H), 1.09 (d, 3H, J = 7.1 Hz), 1.03 (d, 3H, J = 6.7 Hz), 0.97 (d, 3H, J = 6.6 Hz) 0 Example 2 Cryptophyta Preparation of pigment 55 succinate (4). To a solution of (27 mg, 0.038 mmol) and succinic anhydride (5,7 mg, 0.057 mmol) in 383 ml of dichloromethane was added triethylamine (16 L, 0.08 mmol) at room temperature. Ϊ́ΐ5 mmol) and 4-dimethylaminopyridine (4.7 mg, 0.038 mmol). After stirring for 19 hours, 5.7 mg (0.057 mmol) of succinic anhydride and 4.7 mg (0.03 8 mmol) of dimethylaminopyridine were added again, followed by stirring for another 29 hours. The reaction mixture was treated with 0.5 ml of a 1N aqueous solution of hydrochloric acid and washed with methane (3 X 0.5 ml). The combined organic extracts were dried (Na2S04), filtered, and concentrated in the air to a white foam. Purification by reverse phase HPLC gave 10 mg (32%) of the title compound as a white foam: 500 MHz NMR (CDC13) d 7.36-7.31 (m, 6H), 7.22 (br s, 1H), 7.08 (d, 1H , J = 8.4 Hz), 7.02 (br s, 1H), 6.87 (d, 1H, J = 8.4 Hz), 6.61 (m, 1H), 5.94-5.87 (m, 2H), 5.51 (d, 1H, J = 9.8 Hz), 4.95 (dd, 1H, J = 10, 2.8 Hz), 4.87-4.76 (m, 3H), 3.90 (s, 3H), 3.39 (dd, 1H, J = 16, 5.6 Hz) , 3.28 (dd, 1H, J = 16, 8.2 Hz), 3.17 (dd, 1H, J = 16, 5.6 Hz), 3.05 (dd, 1H, J = 16, 8.2 Hz), 2 „68-2.62 (m, 1H), 2.60-2.46 (m, 2H), 2.45 · 2 · 28 (ιη, 3H), 2.01-1.93 (m, 2H), 1.88_1.70 (m, 2H), 1.26 (s , 3H), 1.18 (s, 3H), 1.12 (d, 3H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.6 Hz), 1.0. (D, 3H, 77- This paper size applies China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (%) J = 6.5 Hz). Example 3 Preparation of Cryptocin 55 (2-mono-di-dibutyl phosphatidyl) phenyl acetate S (5) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first) Fill out this page again) at 1 (0.102 mmol), 24 (46 mg, 0 "34 mmol), and 4-dimethylformine (12 mg, 0.102 mmol) in 250 ml of anhydrous digas To the solution in methane was added at room temperature a solution of 1,3-dicyclohexylcarbodiimide (27 mg, 0.134 mmol) in 50 ml of digas. After stirring at room temperature for 6 hours, the reaction mixture was diluted with 1 ml of ethyl acetate · hexane (3: 1), filtered through a ceiite plug, and washed with ethyl acetate-hexane (3: 1). The filtrate and washings were concentrated in the air to a purple foam. Chromatography (15 g of flash silica) and dissolution with ethyl acetate-hexane (4 ·· 1) gave 86 mg (82%) of the title compound as a white foam: 500 MHz! H NMR (CDCla) d 7.35 ( d9 1H? J = 8.3 Hz)? 7.30-7.19 (m? 8H), 7 ″ l (dd, 1H, J = 8.4, 2.0 Hz), 7.02 (t, 1H, J = 7.5 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.84 (d, 1H, J = 7.5 Hz), 6.73 (ddd, 1H, J = 15, 13, 4.7 Hz), 5.92 (d, 1H, J = 7.9 Hz), 5.79 ( dd, 1H, J = 15, 1.0 Hz), 5.43 (dd, 1H, J = 9.4, 1.8 Hz), 4.98 (dd, 1H, J = 12, 3.1 Hz), 4.81 (ddd, 1H, J = 9.9, 9.9, 1.8 Hz), 4.75 (d, 1H, J = 9.4 Hz), 4.73-4.67 (m, lH), 3.90 (s, 3H), 3.49 (d, lH, J = 16Hz), 3.44-3.38 (m , 1H), 3.38 (d, 1H, J = 16 Hz), 3.27-3.17 (m, 2H), 3.10 (dd, 1H, J = 14, 8.2 Hz), 2.55-2.46 (m, 2H), 2.37- 2.27 (m, 1H), 1.95 (ddd, 1H, J = 14, 12, 4 · 5 Hz), 1.83 · 1 · 70 (ιη, 2H), 1.49 (s, 18H), 1.27 (s, 3H ), 1.20 (s, 3H), 1.03 (d, 3H, J = 6.5 Hz), 0.97 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 7.0 Hz). This paper size applies to Chinese National Standard (CNS) A4 specification (21 × 297 mm) _ -78- _ 533206 A7 B7 V. Description of the invention (76) 贲 Example 4 Cryptocin 55 (2 · -phosphate) phenyl Preparation of Disodium Acetate (6) in 5 ^ 84 mg, 0.081 mmol) in 400 ml of dichloromethane at a temperature of 1:50. Hydrogen chloride was added to 40 plex solution (81 亳 =, 0.33 mmol). The light yellow solution was stirred at room temperature for 2 hours. After concentrating in the air to form an off-white foam, the crude dihydrogen phosphate was dissolved in 614 ml of tetrahydrofuran and treated with a 5.00 N aqueous solution of sodium hydroxide (33 ml, 0 163 mmol). After stirring for 10 minutes, the mixture was concentrated in the air to a yellow-brown bubble. The crude salt was absorbed into 1 ml of hot acetonitrile and 0 ;! ml of hot water. The insoluble matter was filtered off, and the filtrate was concentrated in the air to obtain 69 g (87%) of the title compound as a white solid: 500 MHz 4 NMR (MeOH-d4) d 7.58 (d, 1Η, J = 8.2 Hz), 7.38- 7.32 (m, 2H), 7.32-7.28 (m, 3H), 7.28 (d, 1H, J = 2.1 Hz), 7.17 (dd, 1H, J = 8.5, 2.1 Hz), 7.09 (ddd, 1H, J = 7.8, 7.8, 1.7 Hz), 6.98 (d, 1H, J = 8.5 Hz), 6.79-6.70 (m, 2H), 6.67 (d, 1H, J = 7.4 Hz), 5.91 (dd, 1H , J = 15, 1.7 Hz), 5.45 (dd, 1H, J = 9.4, 1.6 Hz), 5.06 (dd, 1H, J = 10, 2.7 Hz), 5.01 (d, lHJ = 9.4 Hz), 4.89- 4.80 (m, 1H), 4.47 (dd, 1H, J = ll, 3.8 Hz), 3.84 (s, 3H), 3.67 (d, 1H, J = 16 Hz), 3.45 (d, 1H, J = 14 Hz ), 3.42 (d, 1H, J = 16 Hz), 3,18 (dd, 1H, J = 14, 3.8 Hz), 3.12 (d, 1H, J = 14 Hz), 2.77 (dd, 1H, J = 14,11 Hz), 2.67-2.60 (m, 1H), 2.56-2.48 (m, 1H), 2.31-2.22 (m, 1H) 1.96-1.88 (m, 1H), 1.85-1.77 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 1.03 (d, 3H, J = 6.2 Hz), 0.98 (d, 3H, J = 6.1 Hz), 0.93 (d, 3H, J = 7.1 Hz). Example 5 -79- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) (Please read the precautions on the back before filling this page) Order _ Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and Consumer Cooperatives Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 _____ B7 V. Description of the Invention (77) ~ ^ s — Cryptocin 5 5 Nicotinate Hydrochloride (7) ## 1 (50 mg, 0.071 mmol) in a solution of 354 ml of pyridine at room temperature was added nicotinyl fluorenyl chloride hydrochloride (15 mg, 0.085 mmol) triethylamine (23 ml, 0.170 mmol) Ear). After stirring for an hour), dimethylaminopyridine (8.6 mg, 0.07! Mmol) was added. After stirring for 5 hours, triethylamine (23 ml, 0J70 mmol), 'dimethylaminopyridine (86 mg, 0.071 mmol), and nicotinylfluorenyl chloride hydrochloride (15 g, 0.5 g). (0 85 mmol) and rinse with 50 ml of pyridine. After stirring for 18 hours, the reaction mixture was treated with 0.5 ml of a saturated aqueous sodium hydrogen carbonate solution, and washed with dichloromethane (4 x 1 ml). The combined organic extracts were dried (NajO4), filtered, and concentrated in a vacuum to a light brown oil. Chromatography (14 g of quick-crush gel) was dissolved with ethyl acetate-hexane (10: 1) to obtain 49 mg (85%) of free base in a white foam. The test acid ester was dissolved in 1¾ liters of dichloromethane 'and treated with a 1.0 M solution of hydrogen chloride in acetic acid (90 ml, 0.090 mmol). The clear, colorless solution was left at room temperature for 5 minutes. The solvent was removed in the air, and 51 mg of the title compound was produced as a white foam: 500 MHz 4 NMR (CDC13) d 8.94 (s, 1Η), 8.78 (br s, 1H), 8.29 (d, 1H, J = 7.0 Hz ), 7.57 (br s, 1H), 7.38 (d, 2H, J = 7.1 Hz), 7.30-7.16 (m, 5H), 7.10 (dd, 1H, J = 8.4, 1.7 Hz), 6.88 (d, 1H , J = 8e4 Hz), 6.71 (m, 1H), 5.80 (d, 1H, J = 15 Hz), 5.74 (d, 1H, J = 9.6 Hz), 5.56 (br s, 1H), 5.00 (d, 1H, J = 9.6 Hz), 4.95 (t, 1H, J = 8.9 Hz), 4.84 (d, 1H, J = 9.8 Hz), 4.77-4.72 (m, 1H), 3.91 (s, 3H), 3.39 ( dd, 1H, J = 13, 8 · 2 Hz), 3.23_3.14 (m, 2H), 3.06 (dd, 1H, J = 14, 7.6 Hz), 2.8, 2.74 (m, 1H), 2.62, 2.45 (m, 2H), 1.93 (ddd, 1H, J = 14, 12, 4.8 Hz), 1.78-1.70 (m, _-80- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ( Please read the precautions on the back before filling out this page) Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 '~~ ---------- B7 V. Invention Description (78)-1H) , l.66-1.59 (m, 1H), 1.25 (s 3H), 1.20 (d, 3H, J = 7.0 Hz),! 19 (S, 3H), 0.98 (d, 3H, J = 6. 7 Hz), 0.84 (d, 3H J = 6.5 Hz) 〇 Example 6 Preparation of Cryptocin 55 N-methylpyridine acetate (8) in U53 mg, 0.075 millimolar) in 751 ml of dichloride Triethylamine (13 ml, 0 090 mol) was added to the solution in methane at 0 ° C, and then 2-fluoro · 1-methylpyridine p-toluenesulfonate (23 mg, 0.0083 mmol) was added. ear). The heterogeneous reaction mixture was warmed to room temperature and stirred for 35 hours, at which time n milligrams (0039 mol) of 2-fluoro-1-methylpyridine p-toluenesulfonate was added. After stirring for 14 5 hours, 11 mg (0.039 mmol) ... fluoromethylpyridine p-toluenesulfonate was added 'and then after 2.5 hours 11 mg (0.039 mmol) 2-fluoro-1 -Methylpyridine p-toluenesulfonate and 13 ml (0.90 mmol) triethylamine were added. After stirring for 1 hour, the reaction mixture was concentrated in the air to an orange foam. Purified by reverse-phase HPLC with simultaneous anion exchange (acetate vs. p-toluenesulfonic acid), then freeze-dried to obtain 30 mg (47%) of the title compound as a white solid: 500 MHz 4 NMR (DMSO-d6) d 8.65-8.58 (m, 2Η), 8.36 (t, 1H, J = 7.8 Hz), 7.68 (d, 1H, J = 8.9 Hz), 7.60 (d, 1Η, J = 6.6 Hz), 7.48 (t, 1H , J = 6.6 Hz), 7.35_7.21 (m, 6H), 7.19 (dd, 1H, J = 8.5, 1.9 Hz), 7.05 (d, 1H, J = 8.5 Hz), 6.49 (ddd, 1H , J = 16, 13, 4.0 Hz), 5.91 (d, 1H, J = 16 Hz), 5.72 (d, 1H, J = 8.0 Hz), 5.66 (dd, 1H, J = 8.0, 1.9 Hz), 5.32 -5.27 (m, 1H), 4.73 (dd, 1H, J = 9.7, 4.3 Hz), 4.24 (ddd, 1H, J = ll, 9.8, 3.7 Hz), 3.93 (s, 3H), 3.81 (s , 3H), 3.32 (dd, 1H, J = 13, 9.3 Hz), 3.05-2.97 (m, 2H), 2.77-2.57 (m, 3H), 2.54-2.47 (m, 1H), 1.76 (s, 3H ), 1.68- The paper size of the table applies the Chinese National Standard (CNS) A4 specification (2! 〇X 297 mm) (Please read the precautions on the back before filling this page). 533206 A7 I_ ___ B7 V. Description of the invention (79) 1.62 (m, 1Η), 1.55 · 1 · 46 (η, 1H), 1.37-1.30 (m 1H), 1.15 (d, 3H, J = 7.0 Hz), 13 (s, 3H), 1.00 (s, 3H), 0.88 (d, 3H, J = 6.7 Hz), 0.73 (d , 3H, J = 6.5 Hz). Example 7 Preparation of Cryptocin 55 Nt-Boc-3- (3-chloro-4 · methoxyphenyl)-(d) -alanine (9) Central Ministry of Economic Affairs Printed by the Consumer Bureau of the Standards Bureau (please read the precautions on the back before filling this page) at 1 (23 mg, 0.033 mmol), Nt-Boc-3- (3 · chloro-4-methoxyphenyl ) _ (D) _Alanine (16 mg, 0.049 mmol), and a solution of dimethylaminotitanium (a few crystals) in 143 ml of anhydrous digas methane. A solution of cyclohexylcarbodiimide (10¾ g, 0.049 mmol) in 20 ml of digas methane. After stirring for 2 hours, the cloudy white reaction mixture was diluted with ethyl acetate hexane (2: 1, 1 ml). , Stirred for 10 minutes, filtered through a celite plug, and washed with ethyl acetate · hexane (2: 1). The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (14 g of flash silica gel, 2: 1 ethyl acetate hexane) gave 29 mg (88%) of the title compound as a white foam: 500 MHz χ MHz NMR (CDC13) d 7.42-7.27 (m, 5H)? 7.24 (d? 1H? J = 2.0 Hz), 7.25-7.18 (m, 1H), 7.09 (dd, 1H, J = 8.4, 1.9 Hz), 6.91-6.86 (m, 2H), 6.84-6.70 (m, 3H), 5.75 (d, 1H, J = 15 Hz), 5.53 (d, 1H, J = 9.6 Hz), 5.47 (d, 1H, J = 7.6 Hz), 5.00 (dd, 1H, J = 10, 2.9 Hz), 4.90-4 · 80 (ιη, 2H), 4.78-4.71 (m, 1H), 4.63 (d, 1H, J = 8.3 Hz), 4.19-4 · 12 (ηι, 1H) , 3.91 (s, 3H), 3.88 (s, 3H), 3.40 (dd, 1H, J = 13, 8.1Hz), 3.25-3.12 (m, 2H), 3.07 (dd, lH, J = 14,7.6Hz ), 2.67 · 2.57 (m, 2H), 2.39-2.27 (m, 2H), 2.15 (dd, 1H, J = 14, 8.0 Hz), 2.01 (ddd, 1H, J = 14, 12, 4.2 Hz), 1.87-1.76 (m, 2H), 1.39 (s, -82- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 _ B7 V. Invention Explanation (8〇) 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.09_1.04 (m, Η), 1.01 (d, 3H, J = 6e3 Hz) 0 Example 8 Cryptocin 55 3- (3-chloro-4-methoxyphenyl) _ (D) _ alanine hydrochloride (10) was prepared at 9 (27 mg, 0.027 mmol) at 265 A solution of 4.0 M of hydrogen chloride in 1,4-dioxolane (33 ml, 0.133 mmol) was added to the solution in ml of digas methane at room temperature. After stirring for 3 hours, the transparent, colorless reaction mixture was concentrated in the air to 26 mg (96%, corrected for 5% dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH_d4) d 7_79 (d, 1H, J = 7.3 Hz), 7.49-7.45 (m, 2H), 7.43 · 7 · 48 (ιη, 3H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.13 (d, 1H, J = 2.2 Hz), 7.07-6.95 (m, 3H), 6.71 (ddd, 1H, 15 13, 3.8 Hz), 5.98 (dd, 1H, J = 15, 1.8 Hz), 5.69 (d, 1H, J = 10 Hz), 5.22 (d, 1H, J = 10 Hz), 5.18 (dd, 1H, J = 10, 2.5 Hz), 4.89-4.80 (m, 1H), 4.53 (dd, 1H, J = ll, 3.7 Hz), 4.16 (dd, 1H, J = 10, 4.4 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.51 (dd, 1H , J = 13, 9 · 9 Hz), 3.20 (dd, 1H, J = 14, 3.7 Hz), 3 ″ 4 (dd, 1H J = 13, 2 · 3 Hz), 2.82-2.75 (m, 3H) , 2.45 (dd, lH, J = 15, 4.5Hz), 2.42-2.34 (m, lH), 2.08-2.00 (m, lH), 1.97-1.86 (m, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.16 (d, 3H, J = 7.1 Hz), 1.10 (d, 3H, J = 6.1 Hz), 1.06 (d, 3H, J = 6.0 Hz). Example 9 Preparation of Cryptocin 55 N-t_Boc-Glycine (11) at 1 (118 mg, 0.167 mmol), Nt-Boc-glycine (44 mg, -83-This paper is scaled to China National Standard (CNS) A4 Specification (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 Α7 Β7 V. Description of the Invention (81) 0.251 mmoles and 4-dimethylaminopyridine (2.0 mg, 0.0167 mmoles) in 490 ml of anhydrous dichloromethane To the solution at room temperature was added a solution of ι, 3 · dicyclohexylcarbodiimide (52 mg, 0.251 mmol) in 67 ml of digas methylbenzene at room temperature. After stirring for 50 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 1 ml), stirred for 10 minutes, filtered through a ceiite plug, and ethyl acetate-hexane (3: 1) wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (19 g of flash silica, 3: 1 ethyl acetate hexane) gave U8 mg (96%) of the title compound as a white foam: 500 MHz Tun NMR (CDC13) d 7.34 (s, 5H), 7.24 (d , 1H, J = 2.0 Hz), 7.23-7.19 (m, 1H), 7.10 (dd, 1H, J = 8.4, 2.0 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.79 · 6 · 70 (η, 1H), 5.77 (d, 1H, J = 13 Hz), 5.50 (d, 1H, J = 8.0 Hz), 5.47 (d, 1H, J = 9.8 Hz &gt;), 4.97 (dd, 1H, J = ll, 2.7 Hz), 4.89 (t, 1H, J = 10 Hz), 4.83 (d, 1H J = 9.8 Hz), 4.79-4.72 (m, 1H), 4.68 (br s, 1H), 3.91 (s , 3H), 3.66 (dd, 1H, J = 18, 5.3 Hz), 3.42-3.35 (m, 2H), 3.21 (dd, 1H, J = 13, 4.0 Hz), 3.17 (dd, 1H, J = 15 , 5.1 Hz), 3.08 (dd, 1H, J = 15, 7.6 Hz), 2.66-2.57 (m, 2H), 2.47-2.38 (m, 1H), 1.95 (ddd, 1H, J = 14, 12, 4.7 Hz), 1.85-1.77 (m, 1H), 1.75-1.67 (m, 1H), 1.43 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.08 (d, 3H, J = 7.0 Hz), 1.03 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.5

Hz). Example 9 Preparation of Cryptocin 55 Glycolate Hydrochloride (12) In a solution of 11 (122 mg, 0.141 mmol) in 471 ml of digas methane, hydrogen chloride was added at room temperature to 1,4-dioxygen. Lu Yingzhong's 4.0 Μ solution (178 -84 _ This paper size applies to the Chinese National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)) Printed by Employee Consumer Cooperative 533206 A7 "----- B7 V. Description of Invention (82)

Pen-liter, 0.707¾ Moore). After stirring for 1 hour and 20 minutes, the transparent colorless reaction mixture was concentrated in the air to obtain 120 mg (99%, corrected for 7% by weight of dioxolane) of the title compound as a white foam: 5000 mHz 4 NMR ( MeOH-d4) d 7.81 (dd, 1H, J = 8.5 Hz, 2.2 Hz), 7.46-7.41 (m, 2H), 7.40 · 7 · 36〇, 3H), 7.31 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.70 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.97 (dd, 1H , J = 15, 1.7 Hz), 5.55 (d, 1H, J = 9.9 Hz), 5.18 (d, 1H, J = 9.9 Hz), 5.14 (dd, 1H, J = 10, 2.8 Hz), 4.84 (t , 1H, J = 10 Hz) 4.52 (dd, 1H, J = ll, 3.7 Hz), 3.87 (s, 3H), 3.78 (d, 1H), J = 18 Hz), 3.50 (dd, 1H, J = 13, 9 · 8 Hz), 3.23 (d, 1H, J = 18 Hz), 3.20 (dd, lH, J = 14, 3.6Hz), 3.13 (dd, lH, J = 13, 2.4Hz), 2.80- 2.69 (m, 3H), 2.41-2.32 (m, 1H), 1.99-1.92 (m, 1H), 1.91-1.81 (m, 2H), 1.25 (s, 3H), 1.20 (s, 3H), 1.12 ( d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.04 (d, 3H, 6.2 Hz). Example 1 Preparation of Cryptocin 55 Nt-Boc-b-alanine (13) at 1 (102¾ g '0.145¾ mole)' N_t_Boc-b_ alanine (41¾ g, 0.217 mmol), and 4 -Dimethylaminopyridine (18 mg, 0.145 mmol) in a solution of 400 ml of anhydrous dichloromethane at room temperature was added with ι, 3. Dicyclohexylcarbodiimide (45 mg, 0.217 mmol) 82 ml of a solution in dichloromethane. After 3.5 hours, the 'turbid white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 1 ml), and it was good; dropped for 10 minutes, filtered through a celite plug, and ethyl acetate-hexane (3: 1) )wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (21 grams of rapid silicone, 2: 1, then 4: 1 ethyl acetate · -85- The paper size applies to Chinese National Standard (CNS) A4 specifications ^ 21〇 ^ 297 mm) ~ (Please read the back (Please fill in this page again)

533206 A7 B7 V. Description of the invention (83) Hexane), 121 mg (95%) of the title compound was obtained as a white foam: 500 MHz 'Η NMR (CDC13) d 7.44-7.39 (m, 2H)? 7.37-7.31 ( m9 3H)? 7.32 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.72 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.96 (dd, 1H, J = 15, 1.6 Hz), 5.51 (d, 1H, J = 9.8 Hz), 5.11-5.06 (m, 1H) 5.08 (d, 1H, J = 9.8 Hz), 4.90-4.83 (m, 1H), 4.50 (dd, 1H, J = ll, 3.6 Hz), 3.86 (s, 3H), 3.52-3.46 (m, 1H), 3.20 (dd , 1H, J = 14, 3.6 Hz), 3.13 (br d, 1H, J = 14 Hz), 3.05-2.92 (m, 2H), 2.79_2.63 (m, 3H), 2.45_2.37 (m, 1H), 2.24 (dt, 1H, J = 16, 7.0 Hz), 2.08-1.99 (m, 1H), 1.96-1.79 (m, 3H), 1.43 (s, 9H), 1.25 (s, 3H) , 1.21 (s, 3H), 1.12 (d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.02 (d, 3H, J = 6.1 Hz). Example 1 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling in this hundred ()

Preparation of Cryptocin 55 b-alanine hydrochloride (14) In a solution of 13 (119 mg, 0.136 mmol) in 452 ml of dichloromethane, hydrogenated gas was added at room temperature to 1, 4 -A 4.0 M solution in dioxan (170 ml, 0.679 mmol). After stirring for 2 hours and 5 minutes, the cloudy white reaction mixture was concentrated in the air to obtain 110 mg (96%, corrected for 4% by weight of dioxolane) of the title compound as a white foam: 500 mHz 4 NMR (MeOH -d4) d 7.80 (dd, 1H, J = 9.7, 2.3 Hz), 7.45-7.40 (m, 2H), 7.39_7.32 (m, 3H), 7.20 (dd, 1H, J = 8.4, 2.1 Hz) , 7.01 (d, 1H, J-8.4 Hz), 6.68 (ddd, 1H, J = 15, 13, 3 · 8 Hz), 5,98 (dd, 1H, J = 15, 1 · 7 Hz), 5.48 (dd, 1H, J = 9.4 1.0 Hz), 5.15-5.11 (m, 1H), 5.13 (d, 1H, J = 9.4 Hz), 4.82 (t, 1H, J = 10 Hz), 4.51 (dd, m, J = u, 3 7 -86-This paper size applies to Chinese National Standard (CNS) A4 (2IOX297 public director) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of Invention (84)

Hz), 3.90 (s, 3H), 3.50 (dd, 1H, J = 14, 9.8 Hz), 3.20 (dd, 1H, J = 14, 3.7 Hz), 3.14 (dd, 1H, J = 14, 2 ·· 4 Hz), 2.85 (t, 2H, J = 7.0 Hz), 2.80-2.65 (m, 5H), 2.54 (dt, 1H, J = 17, 7 4 Hz), 2.42-2.33 (m, 1H), 2.22 (dt, 1H, J = 17, 6.7 Hz), 1.90-1 81 (m, 3H), 125 (s, 3H), 1.20 (s, 3H), 1.13 (d, 3H, J = 7.1 Hz), 108 (d, 3H, J = 63 Hz), 1.04 (d, 3H, J = 6.2 Hz). Example 11 Cryptocin 55 Nt-Boc_g_aminobutyric acid Purpose (15) Preparation at 1 (48 mg, 0.068 mmol), Nt-Boc_4_aminobutyric acid (18 mg '0.088¾ mole) 'And a solution of 4 · dimethylaminoethyl dianlide (8 mg, 0068 mmol) in 150 ml of anhydrous dichloromethane was added i, 3-dicyclohexylcarbodiimide (18 mg, 0.088 mmol) at room temperature. Mol) in 50 ml of dichloromethane. After stirring for 45 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 0.5 ml), stirred for 5 minutes, filtered through a celite plug, and ethyl acetate-hexane (3: 1) wash. The filtrate and washings were concentrated to a colorless oil in the air. Chromatography (15 g of flash silica gel, 3: 1 ethyl acetate hexane) gave 55 mg (90%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) d 7.38_7.32 (m, 5H ), 7.24 (d, 1H, J = 1.9 Ηζ), 7.22_ 7 · 19 (η, 1H), 7.10 (dd, 1H, J = 8.4, 1.9 Hz), 6.88 (d, 1H, J = 8.4 Hz ), 6.75 (ddd, 1H, J = 15, 13, 3.9 Hz), 5.78 (d, 1H, J = 15 Hz), 5.60-5.55 (m, 1H), 5.49 (dd, 1H, J = 9.8, 1.4 Hz), 4.96 (dd, 1H, J = ll, 3.0 Hz), 4.89 (t, 1H, J = 9.2 Hz), 4.81 (d, 1H, J = 9.8 Hz), 4.78-4.70 (m, 1H), 4.44 (br s, 1H), 3.91 (s, 3H), 3.40 (dd, 1H, J = 14, 8.1 Hz), 3.22 (dd, 1H, J = 14, 4.1 Hz), 3.22-3.15 (m, 1H ), -87- This paper size applies to Chinese National Standard (CNS) A4 (21 OX 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (85) 3.〇8 (dd, 1H, J = 14, 7.8 Hz), 2.89-2.82 (m, 2H), 2.67-2.56 (m, 2H), 2.47-2.38 (m , 1H), 2.11-2.04 (m, 1H), 2.0 (M.77 (m, 3H), 1.75_1.67 (m, 1H), 1.45 (s, 9H), 1.50_1 · 40〇η, 2H ), 1.27 (s, 3H), 1.20 (s, 3H), 1.09 (d, 3H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H , J = 6.6 Hz). Example 1 3 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Cryptocin 55 g-aminobutyrate hydrochloride (16) was prepared at 15 (53 mg , 0.059 mmol) into a solution of 297 ml of digas methane at room temperature was added a 1.0 M solution of hydrogenated hydrogen in ether (297 ml, 0.297 mmol). The starting material precipitated as a white paste, which was redissolved by adding 150 ml of dichloromethane. After stirring for 4 hours, 59 ml (0.059 mmol) of a hydrogen chloride solution was added. The stirring was continued for 14 hours, and the reaction mixture was concentrated in the air to obtain 49 mg (100%) of the title compound as a white foam: 500 mHz NMR (DMSO-d6) d 8.49 (d, 1H, J = 8.0 Hz), 7.72 (br s, 3H), 7.44-7.33 (m, 5H), 7.32 (d, 1H, J = 1.9 Hz), 7.29 (dd, 1H, J = 9.4, 2.6 Hz), 7.20 (dd, 1H, J = 8.5, 1.9 Hz), 7.06 (d, 1H, J = 8.5 Hz), 6.48 (ddd, 1H, J = 15, 13, 3.9 Hz), 5.87 (d, 1H, J = 15 Hz), 5.37 (d , 1H? J = 9.7 Hz) 9 5.33 (d, 1H, J = 9.7 Hz), 5.04 · 5.01〇, 1H), 4.73 (t, 1H, J = ll Hz), 4_25 (ddd, 1H , J = 12, 9.8, 3.5 Hz), 3.82 (s, 3H), 3.40-3.30 (m, 1H), 3.07-3.01 (m, 2H), 2.72 (dd, 1H, J = 14, 12 Hz), 2.65-2.47 (m, 4H), 2.38-2.28 (m, 1H), 2.21 (dt, 1H, J = 17, 7.5 Hz), 1.97 (dt, 1H, J = 17, 7.5 Hz), 1.8 (M. 70 (m, 3H), 1.54-1.46 (m, 2H), 1.17 (s, 3H), 1.03 (s, 3H), 1.01 (d, 3H, J = 7.0 Hz), 0.99 (d, 3H, J = 5.8 Hz), 0.95 (d, 3H, J = 5.8 Hz). _________-88 -___ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (86 ) Example 1 4 (Read the precautions on the back of the page before filling in this page) Cryptophyll 55 N-t_Boc_ (L) -alanine (I7) was prepared at 1 (103¾ g, 0.146¾ mol), N + B Solution of 〇C- (L) -alanine (41 mg '0.219 mol) and 4-dimethylamino p ratio bite (丨 8 mg, 〇146 mmol) in 400 ml of anhydrous dichloromethane Added at room temperature, a solution of 3-dicyclohexyl post-imide (45 mg, 0.219 mmol) in 87 ml of dichloromethane. After stirring for 5 hours and 50 minutes, the cloudy white reaction mixture With 5.5¾ g (0.029¾ mole) of Nt-Boc- (L) -alanine, 6.0 mg (0.029 mmol) of 1,3-dicyclohexyl-degraded diimine, and some 4-dimethylamine groups ρ ratio lake crystallization treatment. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate-Yiyuan (3: 1.1 ml printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs), stirred for 10 minutes, filtered through a celite plug, and ethyl acetate -Hexane (3: 1) wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (22 g of flash silica, 1.5: 1, then 2: 1, and then 4 · 1 ethyl acetate-hexane) gave 96 mg (75%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) d 7.35-7.30 (m, 5H), 7.26-7.21 (m, 2H), 7.10 (dd, 1H, J = 8.4, 1.9 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.76 (ddd, 1H J = 15, 13, 4.2 Hz), 5.77 (d, 1H, J = 15 Hz), 5.52 (d, 1H, 7.6 Hz), 5.44 (d, 1H, J = 9.7Hz), 4.98 (dd, lH, J = ll, 2.5Hz), 4.85-4.81 (m, 2H), 4.75 (q, 1H, J = 6.8 Hz), 4.56 (d, 1H, J = 7.8 Hz), 4.01- 3.96 (1H), 3.91 (s, 3H), 3.41 (dd, 1H, J = 13, 8.3 Hz), 3.20 (dd, 1H, J = 13, 4.0 Hz), 3.16 (dd, 1H, J = 15, 5.9 Hz), 3.08 (dd, 1H, J = 15, 7.6 Hz), 2.65-2.57 (m, 2H), 2.40-2.31 (m, 1H), 2.02-1.96 (m, 1H), 1 · 87-1 · 73〇, 2H), 1.43 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.1-1.02 (m, 9H), 0.99 (d, 3H, J = 6.3 Hz). -89- __ This paper size applies to Chinese National Standard (CNS) A4 (21 × 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 533206 A7 ---- B7 __ V. Description of the Invention (87) ~~ Example 1 5 Preparation of Cryptocin 55 (L) -alanine hydrochloride (18) In a solution of 17 (95 mg, 0.108 mmol) in 361 ml of dichloromethane was added hydrogenated hydrogen at room temperature. A 4.0 M solution of 1,4 · dioxolane (135 L, 0.542 mmol). After stirring for 2.5 hours, the cloudy white reaction mixture was concentrated in the air to obtain 90 mg (96%, corrected for 6% by weight of dioxolane) of the title compound as a white foam: 500 MHz NMR (MeOH-d4) d 8.54 (d, 1H, 7.6 Hz), 7.81 (br d, 1H, J = 9.7 Hz), 7.46-7.44 (m, 2H), 7.39_7.37 (m, 3H), 7.32 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.0 Hz), 7.01 (d, 1H, J = 2.0 Hz), 6.69 (ddd, 1H, J = 15, 11, 3 · 7 Hz), 5.99 (d , 1H, 15 Hz), 5.55 (d, 1H, J = 9.8 Hz), 5.20 (d, 1H, J = 9.8 Hz), 5.15 (dd, 1H, J = ll, 2.7 Hz), 4.78 (t, 1H , J = ll Hz), 4.53_4 · 50 (ιη, 1H), 3.87 (s, 3H), 3.65 (q, 1H, J = 7.3 Hz), 3.50 (dd, 1H, J = 13, 9.8 Hz) , 3.20 (dd, 1H, J = 14, 3.5 Hz), 3.14 (br d, 1H, J = 13 Hz), 2.81 · 2 · 71 (η, 3H), 2.41 · 2 · 34 (ηχ , 1H), 1.98-1.93 (m, 1H), 1.88-1.82 (m, 2H), 1.41 (d, 3H, J = 7.3 Hz), 1.25 (s, 3H), 1.20 (s, 3H), 1.13 ( d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.04 (d, 3H, 6.0 Hz). Example 1 6 Preparation of Cryptocin 55 Nt-Boc- (D) -alanine (19) At 1 (25 mg, 0.035 mmol), Nt-Boc- (D) -glycine (10 mg, 0.053 mmol) and 4-dimethylaminopyridine (0.4 g, 0.0035 mmol) in a solution of 130 ml of anhydrous digas methylbenzene at room temperature were added with ι, 3-dicyclohexylcarbodicarbonate Imine (11 mg, 0.053 mmol) in 47 ml of Digas-90- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 __________B7 V. Description of the Invention (88) Solution in alkane. After stirring for 5.5 hours, the cloudy white reaction mixture was diluted with ethyl acetate and hexane (3: 1, 0.5 ml), stirred for 10 minutes, filtered through a ceiite plug, and filtered with ethyl acetate-hexane (3: 1). )wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (15 g of flash gel, 2 ·· 1 ethyl acetate-hexane) gave 26 mg (83%) of the title compound as a white foam: 500 MHz ι500 NMR (CDC13) d 7.49-7.29 (m, 5H ), 7.24 (d? 1H, J = 2.0 Hz), 7.22-7 · 18〇, 1H), 7.09 (dd, 1H, 8.4, 2.0 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.76 (ddd, 1H, J = 15, 13, 4.4 Hz), 5.77 (d, 1H, 15 Hz), 5.56 (d, 1H, J = 9.9 Hz), 5.48 (d, 1H, J = 7.7 Hz), 5.01 (dd, 1H, J = 10, 2.6 Hz), 4.91 (t, 1H, J = 9.4 Hz), 4,84 (d, 1H, J = 9.9 Hz), (81-4.73 (m, 2H), 3 · 99 · 3 · 93 (ιη, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8.0 Hz), 3.22 (dd, 1H, J = 13, 3.6 Hz), 3.17 (dd, 1H, J = 14, 5.0Hz) 53.08 (dd, 1H, J = 14Hz), 2.68-2.58 (m, 2H), 2.42-2.35 (m, 1H), 2.04_1.94 (m, 1H ), 1.87-1.50 (m, 2H), 1.42 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.09 (d, 3H, J = 7.1 Hz), 1. 4 (d, 3H J = 6.4 Hz), 0.99 (d, 3H, J = 6.3 Hz), 0.65 (d, 3H, J = 6.8 Hz). Example 1 7 Cryptocin 55 (D) -alanine salt (20) was prepared in 18 (24 mg, 0.027 mmol) in 274 ml digastric acid. To the solution at room temperature was added a solution of hydrogenated gas in 40-dioxane (34 ml, 0.137 mmol) in 14-dioxolane at room temperature. After stirring for 35 hours, the transparent colorless reaction mixture was concentrated in the air to obtain 24 Mg (100% to 8% by weight of dioxolane) The title compound was white d4) d 7.79 (d? 1H? J = 9.5 Hz)? 7.47-7.40 (m? 2H)? 7.40-7.36 (m9 _____ -91-This paper size is suitable for household standard (CNS) M specifications (public (please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of Invention (89) 3H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.0 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.71 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.98 (dd, 1H, J = 15, 1.6 Hz), 5.65 (d, 1H, J = 10 Hz), 5.20 (d, 1H, J = 10 Hz), 5.17 (dd, 1H, J = ll, 2.5 Hz), 4.88-4.78 (m, 1H), 4.53 (dd, 1H, J = li, 3.7 Hz ), 3.95 (q, 1H, J = 7.2 Hz), 3.87 (s, 3H), 3.51 (dd, 1H, J = 13, 9.8 Hz), 3.20 (dd, 1H, J = 14, 3.6 Hz), 3.14 (dd, 1H, J = 13, 2.3 Hz), 2.81-2.74 (m, 3H), 2.41 · 2 · 34〇, 1H), 2.07-1.99 (m, 1H), 1.96-1.84 (m, 2H ), 1.26 (s, 3H), 1.21 (s, 3H), 1.15 (d, 3H, J = 7.1 Hz), 1.09 (d, 3H, J = 6.0 Hz), 1.05 (d, 3H, J = 6.0 Hz ), 〇.80 (d, 3H, J = 7.4 Hz) 〇 Example 1 8 Cryptocin 55 Na_Ne-di-t-Boc_ (L) -lysinate (21) was prepared at 1 (105 mg, 0.149 Mmol), Na-Ne · di-t-Boc- (L) -lysine (67 mg, 0.193 mmol), and 4-dimethylaminopyridine (18 mg, 0.149 mmol) Moore) in 400 ml anhydrous II The methane was added at room temperature over 1,3-dicyclohexyl carbodiimide (4〇 mg, 0.193 mmol) methane in the second gas 96 ml of solution. After stirring for 4 hours, the cloudy white reaction mixture was mixed with 10 μg (0.030 mmol) of Na-Ne · di-t-Boc_ (L) _ionine and 6.1 mg (0.030 mmol) of 1 A solution of 1,3-dicyclohexylcarbodiimide in 100 ml of digas methane. After stirring for 1 hour, the cloudy white reaction mixture was diluted with ethyl acetate · hexane (3: 1, 1 ml), stirred for 10 minutes, filtered through a celite plug, and washed with ethyl acetate · hexane (3: ”). The filtrate and washings were concentrated into a white foam in the air, and the above conditions were performed again, using 34 mg (0.097 mmol), Na_Ne + B〇c_ (L) lysine, 20 mg (〇97 ________ a 92 The standard of this paper is Chinese National Standard (cNS) --- (Read the precautions on the back before filling in this page)

533206 A7 ______67__ V. Description of the invention (90) (Please read the notes on the back before filling out this page) 亳 Mo Er) 1,3-Dicyclohexylcarbodiimide, and 9.1 mg (0.075 mmol) 4 -Dimethylaminopyridine. After stirring for 1.5 hours, the reaction mixture was treated as described above to obtain a crude white foam. Chromatography (21 grams of flash silica, 1: 1, and then 4 ·· 1 ethyl acetate-hexane) gave 112 mg (73%) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) d 7.42-7.37 (m, 2H), 7.36 · 7 · 29 (ιη, 3H), 7.27 (br s, 1H), 7.16 (br d, 1H, J = 8.5 Hz), 6.97 (d, 1H, J = 8.5 Hz), 6.72 (ddd, 1H, J = 15, 13, 3.5 Hz), 5.92 (d, 1H, J = 15 Hz), 5.50 (d, 1H, J = ll Hz), 5.11-5.04 (m , 2H), 4.84 (t, 1H, J = 10 Hz), 4.48 (dd, 1H, J = ll, 3.6 Hz), 3.84 (s, 3H), 3.75 (br s, 1H), 3.50-3.43 (m , 1H), 3.17 (dd, 1H, J = 14, 3.6 Hz), 3.11 (d, 1H, J = 14Hz), 2.97_2.91 (m, 2H), 2.76, 2.58 (m, 3H), 2.36 2.27 (m, 1H), 1.98-1.80 (m, 3H), 1.48_1.38 (m, 2H), 1.43 (s, 9H), 1.40 (s, 9H), 1.35_1.25 (m, 2H), 1.23 (s, 3H), 1.20 (s, 3H), 1.15-1.09 (m, 2H), 1.07 (d, 3H, J = 6.8 Hz), 1.06 (d, 3H, J = 6.0 Hz), 1.01 (d, 3H, J = 6.1 H. Example 1 9 Cryptophyll 55 (L) · lysine dihydrochloride (22) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was prepared at 21 (107 mg , 0.103 millimoles) at 345 milliseconds A solution of digas in methane was added at room temperature to a 4.0 M solution of hydrogenated hydrogen in 1,4-dioxolane (155 ml '0.621 mmol). After stirring for 4 hours, the cloudy white reaction mixture was filtered. Collected The white solid was washed with methane (2 × 1 mL) and dried in the air at room temperature to obtain 87 mg (93%) of the title compound: 500 MHz 4 NMR (MeOH-d4) d 8.61 (d, 1H, J = 7.7 Hz), 7.81 (d, 1H, J = 7.7 Hz), 7.47-7.44 (m, 2H), 7.40-7.38 (m, 3H), 7.31 (d, 1H, J = 2.2 _____- 93- This paper size Applicable to Chinese National Standards (Specifications (210 &gt; &lt; 297mm) 533206 A7 ___ B7 V. Description of Invention (91)

Hz), 7.20 (dd, 1H, J = 8.4, 2.2 Hz), 7.00 (d, 1H, J = 8.4 Hz), 6.63 (ddd, 1H, J = 15, 13, 4.0 Hz), 6.00 (dd, 1H , J = 15, 1.6 Hz), 5.55 (d, 1H, J = 9.8 Hz), 5.20 (d, 1H, J = 9.8 Hz), 5.15 (dd, 1H, J = 10, 2.9 Hz), 4.68 (t, 1H, J = 11 Hz), 4.55-4.49 (m, 1H), 3.87 (s, 3H), 3,79 (t, 1H, J = 5.6 Hz), 3.52 (dd, 1H, J = 14 , 9.9 Hz), 3.20 (dd, 1H, J = 14, 3.6 Hz), 3.13 (dd, 1H, J = 13, 2.4 Hz), 3.06-2 · 98 (η, 1H), 2.94 2.87 (m, 1H), 2.85-2.74 (η, 3H), 2.45-2.38 (m, 1H), 1.98-1.76 (m, 5H), 1.71-1.6 (m, 2H), 1.39_1. 30 (m, 2H), 1.25 (s 3H), 1.18 (d, 3H, J = 8.2 Hz), 1.17 (s, 3H), 1.08 (d, 3H, J = 6.2 Hz), 1.05 (d, 3H, J = 6.1 Hz). Example 2 Preparation of 0 2 · _ (di-tert-butyl phosphate) phenylacetic acid (24) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) at 2 ' · Light phenethyl alcohol (1.05 g, 7.60 mmol) was added to a solution in 15.2 ml of Ν, Ν-dimethylmethanamine at 0 ° C. Mizo (621 mg, 9.11 mmol) And tert-butyldimethylsilyl chloride (1.26 g, 8.34 mmol). After stirring for 40 minutes at 0 ° C and 45 minutes at room temperature, 155 mg (2.28 mmol) of imidazole and 229 mg (1.52 mmol) and tert-butyldimethylsilyl chloride were added. The reaction mixture was stirred for 15 minutes, at which time 150 ml of tert-butyl methyl ether was added. The mixture was washed with cold 1 aqueous hydrochloric acid (1 X 15 ml) and then with water (1 X 15 ml). The organic layer was dried (NajO4), filtered, and concentrated in the air to a yellow oil. Chromatography (70 g of silica gel) was dissolved in hexane · ethyl acetate (5: 1) to obtain 1.81 g (94%) of a 1 ° silyl ether as an off-white oil. In silane alkyl ether (506 mg, 2.00 mmol) and diethyl tertiary diethylaminoarsonate (93%, 600 ml, 2.00 mmol) in 2 ml of tetrahydrocranium __- 94-i paper size applies Chinese National Standard (CNS) A4 specifications (210 father 297 mm 1 &quot; &quot;-533206 A7 B7 V. Description of invention (92) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please Read the precautions on the back before filling this page} Add 1H-tetrazole (421 mg, 6.01 mmol) to the solution at room temperature. After stirring for 4 5 minutes, the reaction mixture is cooled to _ 丨 ° C, and quickly A solution of m-gas perbenzoic acid (99%, 450 mg, 2.61 mmol) in 3.6 ml of dichloromethane. The cloudy white reaction mixture was heated to room temperature and stirred for 5 minutes. The reaction was carried out in 4 ml of 10% Quenched with sodium bisulfite aqueous solution, stirred vigorously for 10 minutes, diluted with 15 ml of tertiary butyl methyl ether, diluted with 0% aqueous sodium hydrogen sulfite solution (2 X 10 ml), and then with 0.05 N sodium hydroxide Aqueous solution (2 X 100 liters) was washed. The organic layer was dried (NajO4) 'filtered, in the air Condensed to a colorless oil (941¾ g) which was used directly in the next step. The crude phosphate was dissolved in 10 ml of tetrahydrofuran and cooled to 0 ° C to a 1-inverse solution of tetra-n-butylammonium fluoride in tetrahydrofuran. (2.4 ml, 2,4 mmol). After 0. (: stirring for 20 minutes and 1.5 hours at room temperature, the reaction mixture was diluted with 60 ml of tert-butyl methyl ether, and water (1 \ (10 ml), and then washed with brine (1 &gt; &lt; 10 ml). The organic layer was dried (Na2SO4) 'filtered and concentrated in the air to a yellow oil. Chromatography (50 g of snap dream gel) to Ethyl acetate (3: J) was dissolved to obtain 525 mg (79%) 1. Alcohol as an off-white oil. Alcohol (123 mg, 0.372 mmol) in acetonitrile tetragasified carbon (1: 1, 1.49) Water (1.1 ml) was added to the solution in room temperature, followed by sodium periodate (239 mg, 1.12 mmol) and ruthenium (III) chloride hydrate (1.8 mg, 0.0082 mmol). Brown The mixture was stirred rapidly at room temperature for 55 minutes. It was concentrated and chromatographed in the air (8 g of flash silica gel with 10% methanol-ethyl acetate). Dissolution) to obtain 109 mg (85%) of the title compound as a purple oil: 500 MHz 4 NMR (CDC13) d 7.49 (d, 1H, J-7 · 53 Hz), 7.30-7.15 (m, 3H), 3.77 (s, 2H), 1.51 (s, 18H). Example 2 1 _-95- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Explanation of the Invention (93) The compounds of Examples 21-26 were prepared using the method substantially as described above. Spectral properties of Cryptocin-129 EIMS m / z (relative intensity) 654/656 (2.1 / 0.8, M-HBr), 412/414 (9 · 7/3 · 6), 280/282 (10 · 3 / 3.5), 227 (15.2), 195/197 (50.1 / 16.3), 105 (100), 91 (100); high-resolution EIMS m / z 654.2687 (C35H43C1N208, D 2.1 mmu). 4 NMR (CDC13) amino or hydroxy acid unit d (carbon position, multiplicity; J Hz) 7-bromo-5,8-dihydroxy-6-methyl-8-phenyl-2-octanoic acid (A ) 5.76 (2, d; 15.3), 6.68 (3, ddd; 15.3, 9.9 and 5.6, 2.29 (4, ddd; 14.2, 10.6 and 10.4), 2.67 (4, dd; 14.2 and 5.4 ), 4.95 (5, ddd; 10.3,10 · 3 and 1.8), 2.47 (6, m), 1.15 (6-Me, d; 6.5), 4.29 (7, dd; 9.1 and 2.1); 4.84 (8, d; 9.0, 7.34-7.39 (10 / ll / 12/13/14, m); 3-gas-4 · methoxyphenylalanine (B) 4.80 (2, m), 5.73 ( 2-NH, d; 8 · 8), 3.01 (3, dd; 14.6 and 7.6), 3.16 (3, dd; 14.3 and 5.6), 7.23 (5, d; 2.0), 3.87 (7-OMe, s), 6.84 (8, d; 8.4), 7.09 (9, dd; 8.4 and 2.0); 3-amino-2-methylpropionic acid (C) 2.73 (2, m), 1.23 (2-Me, d; 7.2), 3.25 (3, ddd; 13.5, 6.5 and 6.5), 3.53 (3,4 (1 (1; 13.4,5.4 and 3.9), 6.93 (3-; ^ 11,1) 1 ^; 6.1) ; Hydroxylic acid (0) 4.91 (2, dd; 10.5 and 2.8, 1.49 (3, m), 1.80 (3, m), 1.73 (4, m), 0.92 (4-Me, d; 6.5), 0.89 (5, d; 6. · 5). 13C NMR (CDC13) unit d (carbon position) A 165.4 (1), 125.2 (2), 141.3 (3), 36.6 (4), 75.7 (5) , 37.9 (6), 11.8 (6-Me), 60.3 ( 7), 76.7 (8), 141.6 (9), 126.8 (10/14), 128.7 (11/13), 128.8 (12); B 171.0 (1), 53.6 (2), 35.0 (3), 130.0 ( 4), 131.0 (5), 122.4 (6), 153.9 (7), 56.1 (7-OMe), 112.3 (8), 128.4 (9); C 175.4 (1), 38.4 (2), 14.0 (2_Me) , 41.3 (3), D 170.2 (1), 71.3 (2), 39.6 (3), 24.8 (4), 23.2 (4-Me), 21.4 (5). _______- 96-_ This paper size applies to China National Standard (CNS) A4 (21〇X 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (94) Example 2 2 Spectral properties of cryptolin-138 EIMS m / z (relative intensity) 734/736 (0.3 / 0.1), 654/656 (0.6 / 0.2), 412/414 (12.6 / 4.7), 313/315 (20.4 / 12.5) 280 (7.6), 227 (3.5), 195/197 (44.7 / 15.6), 155/157 (35.4 / 13.6), 105 (33.6), 91 (34.2), 80/82 (100/100); High-resolution EIMS m / z 734.1985 (C35H44ClBrN208, D-1.6 mmu), 654.2722 (C35H43C1N208, D-1.4 mmu). 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity *; J Hz) 7-&gt; odor-5,8_ mesyl-6-methyl-8-feng ^ -2 -octyl Acid * (A) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 5.78 (2, d; 15.5), 6.69 (3, ddd; 15.1,9.8 and 5.3), 2.33 (4, m), 2.71 (4, m), 4.97 (5, ddd; 10.4, 10.4, and 1.6), 2.45 (6,111), 1.17 (6 · Me, d; 6.3), 4.40 (7, dd 10.1 and 2 · 2), 5.06 (8, d; 10.1), 7.36-7.42 (10/11/12/13/14, m); 3-Gas-4-methoxyphenylalanine ( B) 4.82 (2, m), 5.69 (2.NΗ, d, 8.7), 3.02 (3, dd; 14.5 and 7.5), 3.17 (3, dd; 14.5 and 5.4), 7.23 (5, d; 2.1), 3.88 (7-OMe, s), 6.85 (8, d; 8.4), 7.09 (9, dd; 8.4 and 1.9); 3-amino-2-methylpropionic acid (C) 2.73 ( 2, m), 1.23 (2-Me, d; 7.3), 3.25 (3, ddd; 13.4, 6.5, and 6.5) 3.54 (3, m), 6.92 (3 · ΝΗ, brt; 5.7 ); Hydroxylic acid (D) 4.91 (2, dd; 10.6 and 2.7), 1.43 (3, m), 1.82 (3, m), 1.75 (4, m), 0.93 (4-Me, d; 6.6) 0.90 (5, d; 6.6). 13C NMR (CDC13) unit d (carbon position) A 165.4 (1), 125.2 (2), 141.2 (3), 36.6 (4), 76.5 (5), 38.2 (6), 11.7 (6-Me), 55.3 (7), 87.4 (8), 137.4 (9), 128.0 (10/14), 128.7 (11/13) 129.3 (12); B 171.0 (1), 53.6 (2), 35.0 (3), 129.9 ( 4), 131.0 (5), 122.4 (6), 153.9 (7), 56.1 (7-OMe), 112.2 (8), 128.4 (9); C 175.5 (1), _ -97- _ this paper Standards are applicable to China National Standard (CNS) A4 specifications (2 丨 OX 297 mm) 533206 A7 B7 V. Description of invention (95) 38 · 4 (2), 14.0 (2_Me), 41.2 (3), D 170.2 (1) , 71.2 (2), 39.6 (3), 24.8 (4), 23.2 (4-Me), 21.4 (5). Example 2 3 Spectral properties of Cryptocin-139 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) EIMS m / z (relative intensity) 732/734 (0.3 / 0.3) , 652/654 (0.9 / 0.5), 533 (13.6), 445 (5.7), 195/197 (9/2/11 · 4), 105 (96.2), 80/82 (100/100); High-resolution EIMS m / z 732.1783 (C35H42ClBrN208, E 3.0 mmu), 652.2573 (C35H41C1N208, E-2.1 mnrn) 〇 NMR (CDC13) amino or hydroxy acid unit d (carbon position, multiplicity; JHz) 7-bromo-8-oxy Methyl-5-hydroxy-6-methyl-8-phenyl-2-octanoic acid (A) 5.75 (2, d; 15.4), 6.68 (3, ddd; 15.2, 10.1 &amp; 5.0), 2.31 (4 , Ddd; 14.2, 10.7 &amp; 10.7), 2.63 (4, dd; 14.4 and 5.1), 5.09 (5, ddd; 9.7, 9.7 and 1.5), 2.46 (6, m), 1.18 (6- Me, d; 6.6), 5.41 (7, d; 3.5), 7.94 (10/14, brd; 8.6), 7.50 (11/13, t; 7.8), 7.63 (12, brt; 7.5); 3-chlorine 4-methoxyphenylalanine (B) 4.80 (2, m), 5.64 (2-ΝΗ, d; 8.3), 3.04 (3, dd; 14.6 and 7.2), 3.14 (3, dd; 14.4 &amp; 5.5), 7.22 (5, d; 2.0), 3.87 (7-OMe, s), 6.84 (8, d; 8.3), 7.08 (9, dd; 8.3 2 · 3); 3-Amino-2-methylpropionic acid (C) 2.76 (2, m), 1.26 (2-sided Me, d; 7.1); 3.31 (3, ddd; 13 · 7,6 · 8 And 6.6) 3.53 (3 m), 6.95 (3 · NΗ, brt; 5.9); leucoic acid (D) 4.93 (2, dd; 10.6 and 3.0), 1.51 (3, m), 1.95 (3, m), 1.80 (4, m), 0.97 (4-Me, d; 6.8), 0.91 (5, d, 6.6), 13C NMR (CD13) unit d (carbon position) A 165.2 (1) , 125.3 (2), 141.0 (3), 36.2 (4), 76.0 (5), 39.3 (6), 13.8 (6-Me), 51.8 (7), 192.3 (8), 134.2 (9), 128.7 (10/14), 129.0 (11/13), 134.0 (12); B 170.9 (1), 53.7 (2), 35.0 (3), 129.8 (4), 131.0 -98-This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (96) (5), 122.4 (6), * (7, not measured), 56.2 (7_0Me), 112.3 (8), 128.4 (9); C 175.6 (1), 38.3 (2), 14.2 (2-Me), 41.1 (3), D 170.2 (1), 71 · 1 (2), 39.8 (3), 24.7, 23.2 (4 -Me), 21.3 (5). Example 24 Spectral properties of Cryptocin-145 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) EIMS m / z (relative intensity) /0.2), 654/656 (1.5 / 1.1), 412/414 (2.2 / 1.0), 313/315 (19.5 / 12.9) 227 (4.1), 195/197 (11.5 / 3.7), 105 (14.6), 91 (25.2), 80/82 (100/100); high resolution EIMS m / z 736.1980 (C35H44ClBrN208, E-3.1 mmu), 654.2714 (C35H43C1N208, E-0.6 mmu). 4 NMR (CDC13) amine or hydrogen amine or hydroxy acid unit d (carbon position, multiplicity; JHz) 7-bromo · 5,8-dihydroxy-6_methyl-8 · phenyl · 2-octanoic acid (A) 5.81 (2, d; 15.7), 6.72 (3, m), 2.31 (4, m), 2.77 (4, m) 5.62 (5, m), 2.42 (6, m), 1.22 (6- Me, d; 7.0), 4.23 (7, dd; 8.0 and 3.2), 4.94 (8, d; 7.9), 7.32-7.28 (10 / 11/12/13/14, m); 3-chloro_ 4-methoxyphenylalanine (B) 4.82 (2, m), 5.72 (2-ΝΗ, brs), 3.05 (3, m), 3.15 (3, m), 7 „23 (5, brs), 3.88 (7-OMe, s), 6.84 (8 brd; 7), 7.09 (9, m), 3-amino-2-methylpropionic acid (C) 2.75 (2, m), 1.25 ( 2-Me, d; 7.0), 3.30 (3, m), 3.53 (3, m), 6.97 (3-N, brs); white hydroxy acid (D) 4.90 (2, dd; 9.7 and 3.6), 1.58 (3, m), 1.82 (3, m), 1.70 (4, m), 0.95 (4-Me, d; 6.6), 0.89 (5, d; 6.6). 13C NMR (CDC13) unit d ( Carbon position) A 165.14 (1), 125.2 (2), 141.3 (3), 35 · 8 (4), 75.8 (5) 41.2 (6) 13 · 4 (6_Me), 60 · 7 (7), 76 · 5 (8), 141.6 (9), 126.8 (10/14), 128.5 (11/13), 128.6 (23); dB 170.5 (1), 53.7 (2), 35.0 (3), 129.9 (4), 131.0 (5), 122.4 (6), 154.0 -99- Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of invention (97) (7), 56.2 (7. OMe), 112.3 (8), 128.5 (9); C 175.4 ( 1), 38.4 (2), 14.1 (2-Me), 41.2 (3), D 170.5 (1), 71.3 (2), 39.7 (3), 24.6 (4), 22.9 (4-e), 21.5 (5) 〇 Example 2 5 Spectral properties of Cryptocin-140 EIMSm / z (relative intensity) 690/692 (2 · 3/1 · 8), 654/656 (3 · 8/2 · 2) , 412/414 (5.4 / 2.1), 280/282 (5.4 / 2.2) 227 (10.2), 195/197 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (27.8 / 10/4), 155/157 (53.7 / 16/4), 105 (81.0), 91 (100); high resolution EIMS m / z 690.2427 (C35H44C12N208, E 4.8 mmu), 654.2760 (C35H43C1N208, Ε_5 · 2 mmu). 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; JHz) 7-Ga-5,8-dihydroxy-6 · methyl-8-phenyl-2-octanoic acid (A) 5.77 (2, d; 15.4), 6.68 (3, ddd; 15.3, 9.8 and 5.6), 2.29 (4, m), 2.67 (4, m), 4.98 (5, ddd; 10.3, 10.3 and 1.7), 2.64 (6, m), 1.15 (6-Me, d; 6.6), 4.19 (7, dd; 9.2 and 2.1), 4.72 (8, d; 9.2), 7.33 · 7 · 3 9 (10 / 11/12/13/14, m); 3-chloro-4-methoxyphenylalanine (B) 4.81 (2, m), 5.69 (2 · ΝΗ, d; 8/8), 3.01 (3, dd; 14.5 and 7.5), 3.16 (3, dd; 14.5 and 5.5), 7.23 (5, d; 2.1) 3.87 (7-OMe, s), 6.84 (8, d; 8.3), 7.09 (9, dd; 8.4 and 2.0); 3-amino-2-methylpropionic acid (C) 2.73 (2, m), 1.22 (2-Me, d; 7.3), 3.24 (3, ddd; 13.5, 6 · 8 and 6.8), 3.53 (3, m), 6.91 (3-ΝΗ, brt; 6.0); leucoic acid (D) 4.89 (2, dd; 10.4 and 2.9), 1.39 ( 3, m), 1.69-1.80 (3/4, m), 0.90 (4-Me, d; 6.4), 0.87 (5, d; 6.6). 13 C NMR (CDC13) unit d (carbon position) A 165.4 (1), 125.2, 141.4 (3), 36.7 (4), 75.5 (5), 38.1 (6), 10.4 (6-Me) , 65.0 (7), 75 · 8 (8), 141.4 (9), 126.8 (10/14), 128.7 (11/13), -100- This paper size applies to China National Standard (CNS) A4 (210X297) (%) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of Invention (98) 128.8 (12); B 171.0 (1), 53.6 (2), 35.0 (3), 129.9 (4), 131.0 ( 5), 122.4 (6), 153.9 (7), 56.1 (7-OMe), 112 · 2 (8), 128.4 (9), C 175.5 (1), 38.4 (2), 14.1 (2-Me ), 41.3 (3), D 170.3 (1), 71.3 (2), 39.5 (c), 24.7 (4), 23.2 (4-Me), 21.4 (5) 〇 Example 2 6 Cryptocin Spectral properties of -141 EIMS m / z (relative intensity) 654/656 (1.8 / .8, M-HC1), 412/414 (7.6 / 3.1), 280/282 (3.2 / 2.0) 227 (8.4), 195 / 197 (35.6 / 11.9), 155/157 (100 / 37.2), 105 (68.1), 91 (88.4); high resolution EIMS m / z 690.2468 (C35H44C12N208, E 0.6 mmu), 654.2706 (C35H43ClN2O8, E 0.2 mmu) . 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position 'multiplicity; JHz) 7 -Ga-5,8_dilyl-6_methyl · 8_phenyl-2 -octanoic acid (A ) 5.69 (2, d; 15.4), 6.62 (3, ddd; 15.1, 9.9 and 5.2), 2.07 (4, m), 2.49 (4, dd, 14.4 &amp; 5.4), 4.96 (5, ddd; 10.5, 10.5 &amp; 1.8), 1.88 (6, m), 1.07 (6-Me, d; 6.8, 4.24 (7, dd; 8.9 and 1.9), 4.73 (8, d; 8.8), 2.80 (8 · ΟΗ, broad peak), 7.32 (10/14, dd; 7.6 and 1.9), 7.36 · 7 · 42 (11/12/13, m); 3-gas-4_methoxyphenylpropylamine Acid (B) 4.78 (2, m), 5.65 (2-NH, d; 8.6), 3.00 (3, dd; 14.4 and 7.2), 3.13 (3, dd; 14.4 and 5.6), 7.20 ( 5, d; 2.3) 3.86 (7_OMe, s), 6.82 (8, d; 8.3), 7.06 (9, dd; 8.3 and 2.2); 3. Amino-2-methylpropionic acid (C) 2.73 (2 ,), 1.23 (2-Me, d; 7.2), 3.27 (3, ddd; 13.5,6.8 and 6.8), 3.51 (3, ddd; 13.5,5.0 and 3.8), 6.91 (3-Ν91, brt; 6.0); hydroxy acid (D) 4.83 (2, dd; 10.4 and 2.9), 1.48 (3, m), 1.70 (3, m), 1.76 (4, m), 0.99 (4-Me D; 6.5), 0.95 (5, d; 6.5). 13C NMR (CDC13) unit d (carbon position) A 165.3 (1), 125.2 (s), -101 -This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before filling this page) Order • 1 533206 A7 _ B7 V. Description of the invention (99) 141.0 (3) , 36.2 (4), 75.5 (5), 39.3 (6), 10.8 (6-Me), 70.0 (7), 76.2 (8), 138.9 (9), 126.7 (10/14), 129.0 (11 / 13), 129.0 (12); B 170.9 (1), 53.6 (2), 35.0 (3), 129.8 (4), 131.0 (5), 122.4 (6), 153.9 (7), 56.1 (7 -) Me), 112.2 (8), 128.4 (9), C 175.5 (1), 38.2 (2), 14.1 (2_Me), 41.1 (3), D 170.2 (1), 71.2 (2), 39.6 (3), 24.8 (4), 23.2 (4-Me), 21.4 (5). Example 2 7

Figure 1 Experiment

OHC

(Please read the notes on the back before filling this page) The solution printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed in ene 1 (1.15 g, 3.52 mmol) in 50 ml of CH2C12 is 78Ί: add pyridine (0.3 ml , 3.9½ mol) and 0.98 ml of 0.1% solution of Sudan Red 7B in CH2C12. Ozone slowly bubbled in until red became yellow. The progress of the reaction was detected by TLC. Upon completion, zinc powder (1.63 g, 2.49 mmol) and 3.4 ml of glacial acetic acid were added. The ice bath was removed and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered through Celite, washed with CuSO4 (3 x 30 ml), then with water (3 x 20 ml), and finally with a saturated aqueous solution of NaHC03 (2 x 20 ml). The organic layer was dried over MgS04, filtered, and concentrated in the air to obtain 0.937 g (88%) of the desired aldehyde, which was used in the next step without further purification: 1HNMR (300 MHz, CDCl3) d9.74- 9.73 (d, 1 H, J = 1.97 Hz), 7.0-6.82 (m, 1 H), 5.91-5.86 (d, 1 H, J = 15.4 Hz), 4.1-4.0 (m, 1 H), 3.73 (s, 3 H ), 2.55_2.4 (m, 3 H), -102- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 V. Description of the invention (1C) C)) l 〇9- 1.07 (d, 3 H, J = 6.8 Hz), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).

A 15 M solution of methyl lithium (9.6 ml, 14.4 mmol) complexed with lithium bromide in ether was added dropwise to a solution of 2,5-dimethylbenzyltriphenylphosphonium chloride in 120 ml of THF- 78 ° C solution. The solution was slowly heated to 0 ° C and cooled down to 78C. Acid 2 was added dropwise to the solution at -7 C in 40 ¾ liters of THF. The mixture was stirred at -78 ° C for 15 minutes, and then slowly warmed to room temperature. After 1 hour at room temperature, saturated NH4C1 (50 ml) was added and the solution was extracted with ether. The ether layer was washed with water (2 X 50 ml), then brine, dried over MgS04, filtered, and concentrated in vacuo. A mixture of E: Z isomers of crude styrene was purified on silica gel using .2% EtOAc / hexanes to obtain 2.32 g (58%) of a clear oil. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling in this page) E: Z mixture in 120 ml of benzene in thiophenol (0.3 ml) and 1,1, -azobis (cyclo Hexacarbonitrile (VAZO) (0.16 g) was refluxed for 8 hours. Then the solution was cooled to ambient temperature, concentrated under vacuum, and purified by column chromatography (silica gel, 2-5% EtOAc / hexane). 2.2 g (95%) of the pure E isomer was obtained as a clear oil: [a] 2 () D + 34.6. (Cl.O, MeOH); 4 NMR (300 MHz, CDC13) d 7.3-7. 0 ( m, 4 H), 6.62-6.57 (d, 1 H, J = 15.8 Hz), 6.11-6.03 (dd, 1 H? J = 15.8, 8.1 Hz), 5.93-5.88 (d, 1 H, J = 15.5 Hz), 3.82-3.78 (m, 1 H), 3.78 (s, 3 H), 2 · 6_2 · 34 (η, 3 H), 2.37 (s, 3 H), -103- This paper scale applies to China Standard (CNS) A4 specification (21 × 297 mm) 533206 A7 B7 V. Description of the invention (101) 2.34 (s, 3 H), 1.18-1.16 (d, 3 H, J = 6.8 Hz), 0.96 (s, 9 H), 0.13 (s, 3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDC13) d 167.2, 146.9, 136.9, 135.7, 133.3, 132.4, 130.5 128.8, 128.1, 126.5, 123.2, 75.5, 51.8, 43.4, 37.9, 26.2, 21.4, 19.7, 18.5, 16.7,-4.0,-4.2; IR (CHC13) 2955, 2930, 2858, 1718, 1658, 1603, 1496, 1472, 1438, 1362, 1325, 1280, 1258, 1097, 1040 cm.1; Analysis and calculation of C24H3803Si 値: C, 71.59; H, 9.51. Measured 値: C, 7L38; Η, 9.30. (Please read the precautions on the back before filling this page)

The Consumer Cooperative Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs added 11 ml of a 2MKOH solution to a solution of ester 3 (2.2 g, 5_46 mmol) in 10 ml of THF. Stir vigorously and heat the resulting mixture at 65 ° C for 24 hours. After cooling to ambient temperature, 11 ml of a 2M solution of HC1 was added, and the resulting mixture was stirred vigorously for 30 minutes. Ethyl acetate (50 ml) was added to the mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with 50% brine (3 X 30 mL), dried over Na2S04, filtered, and concentrated in the air to obtain 2.12 g (100%) of the desired acid as a thick yellow *: 1HNMR (300 MHz, CDCl3) d7.26-6.95 (m, 4H), 6.62-6.57 (d, 1 H, J = 15.8 Hz), 6.1-6.02 (dd, 1H, J = 15.8, 8.0 Hz), 5.92-5.87 ((1 , 1 H, J = 15.7 Hz), 3 · 9-3 · 8 (η, 1 H), 2.6-2.2 (m, 3 H), 2.36 (S, 3 H), 2.34 (s, 3 H), 1.18-1.15 (d, 3H, J = 6.8 Hz),: 104-This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 533206 Printed by A7, Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs _______B7 5 Description of the invention (102) 0.994, 9H), 0.12 (s, 3 H), 0.11 (s, 3 H) 0

To a solution of acid 4 (2.12 g, 5.46 mmol) and diisopropylethylamine (2.9 ml, 16.4 Φmol) in 7 ml of DMF at 0 ° C was added dropwise diphenylphosphine sulfonium chloride (1.1 Ml, 6.01 mmol). After stirring at 0 ° C for 5 minutes and at room temperature for 30 minutes, the 3- (3-chloro-4-methoxyphenyl) -D-alanine_2,2,2-trichloroethyl ester TFA salt 5 was added dropwise in 7 ml of DMF. The resulting mixture was expanded at room temperature: dropped for 2 hours, poured into 100 ml of water, and washed with ether (3 x 50 ml). The combined organic layers were washed with brine, dried over MgS04, filtered through Celite, and concentrated in the air. Purify by column chromatography (silica gel, 10-30% EtOAc / hexane) to obtain 2.86 g (72%) amidine 6 as a white foam: [a] 20D + 44.8. (Cl.O, MeOH); NMR (300 MHz, CDC13) d 7.25 (s, 1 H), 7.22 (s, 1 H), 7.1-6.83 (m, 5 H), 6.6-6. $ 5 (d , 1 H, J = 15.7 Hz), 6.11-6.03 (dd, 1 H, J = 15.6, 8.1 Hz), 5.9-5.8 (m, 2 H), 5.18-5.05 (m, 1 H), 4.83-4.75 (q, 2 H, J = 12.0 Hz), 3.9 (s, 3 H), 3.83-3.68 (m, 1 H), 3.3 雠 3.1 (m, 2 H), 2.6-2.36 (m, 3 H), 2.36 (s, 3 H), 2.32 (s, 3 H), 1.16-1.14 (d, 3 H, J = 6.7 Hz), 0.95 (s, 9 H), 0.11 (s, 3 H), 0.05 (s , 3 H); 13C NMR (75 MHz, CDC13) d 170.0, 165.1, 154.2, 143.1, 136.4, 135.3, 133.0, 132.0, 131.0, 130.9, 130.0, 128.4, 128.3, -105- The paper dimensions are applicable to Chinese national standards (CMS) A4 specification (21 OX 297 mm) (Read the precautions on the back before filling in this page)

533206 127.7, 126.1, 124.6, 112.3, 112.1, 94.2, 75.0, 74.7, 56.0, 52.9, 42 · 8, 37 · 5, 36.5, 25 „8, 20.9.9, 19.3, 18.0, 16.4,-4.3,-4 · 7; IR (CHC13) 3428, 2957, 2930, 2857, 1759, 1676, 1645, 1606, 1503, 1464, 1442, 1380, 1349, 1281, 1259, 1173, 1067 cm1. Example 2 7

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (103) Figure 1 Experiment The solution of ene 1 (1.15 g, 3.52 mmol) in 50 ml of CH2C12 contains -78. (: Add pyridine (0.3 ml, 3.9 mmol) and 0.98 ml of 0.1% solution of Sudan Red 7B in CH2C12. Ozone is slowly bubbled in until red turns to yellow. The reaction progresses with TLC Detection. When complete, zinc powder (1.63 g, 2.49 mmol) and 3.4 ml of glacial acetic acid were added. The ice bath was removed and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered through Celite and CuS04 (3 X 30 ml), and then washed with water (3 X 20 ml), and finally saturated NaHC03 aqueous solution (2 X 20 ml). The organic layer was dried over MgS04, filtered, and concentrated in the air to obtain 0.937 g (88%) of the desired Aldehyde, which was used in the next step without further purification: 1HNMR (300 MHz, CDCl3) d9.74-9.73 (d, 1 H, J = 1.97 Ηζ), 7.0 · 6.88, 1 H), 5.91-5.86 (d, 1 H, J = 15 Hz), 4.1 · 4.0 (ιη, 1 Η), 3.73 (s, 3 Η), 2.55-2.4 (m, 3 Η), 1.09-1.07 ( d, 3 Η, J = 6.8 Η ζ), 0.87 (s, 9 Η), 0.08 (s, 3 Η), 0.06 (s, 3 Η). 106- This paper size applies to Chinese National Standard (CNS) Α4 size (210X 297mm) k (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (104)

A 1.5 M solution of methyl lithium (9.6 ml, 14.4 mmol) in lithium ether complexed with lithium bromide was added dropwise to 2,78-dimethylbenzyltriphenyl chloride in 120 ml of THF at -78 ° C solution. The solution was slowly heated to 0 ° C and cooled down to -78t. Aldehyde 2 was added dropwise to the solution at -78 ° C in 40 ml of THF. The mixture was stirred at -78 ° C for 15 minutes and then slowly warmed to room temperature. After 1 hour at room temperature, saturated NH4C1 (50 ml) was added and the solution was extracted with ether. The ether layer was washed with water (2 X 50 ml), then brine, dried over MgS04, filtered, and concentrated in vacuo. A mixture of E: Z isomers of crude styrene was purified on silica gel using 2% EtOAc / hexanes to obtain 2.32 g (58%) of a clear oil. The E: Z mixture was refluxed in 120 ml of benzene for 8 hours in the presence of thiophenol (0.3 ml) and 1, r-azobis (cyclohexanenitrile) (V AZO) (0.16 g). The solution was then cooled to ambient temperature, concentrated under awl, and purified by column chromatography (silica gel, 2-5% EtOAc / hexane) to obtain 2.2 g (95%) of the pure E isomer as a transparent oil: [αρΟίτ ^ Ι ^ Οΐ.Ο, ΐν ^ ΟΗ ^ / ΗΝΜΙΐρΟΟΜΗζ, ΟΟαΟ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) d7.3-7.0 (m, 4H) , 6.62-6.57 (d, lH, J = 15.8Hz), 6.11-6.03 (dd, lH, J = 15.8, 8.1Hz), 5.93-5.88 (d, lH, J = 15.5Hz), 3.82-3 · 78 (m, 1 H), 3.78 (s, 3 H), 2.6-2.34 (m, 3 H), 2.37 (s, 3 H), 2.34 (s, 3 H), 1.18-1.16 (d, 3 H, J = 6.8 Hz), 0.96 (s, 9 H), 0 · 13 (s, 3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDC13) d 167.2, -107- Applicable to this paper standard China National Standard (CNS) A4 specification (210X 297 mm) 533206 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 ____ _B7 V. Invention Description (105) 146 · 9, 136.9, 135.7, 133.3, 132.4, 130.5, 128.8 , 128.1, 126.5, r 123.2, 75.5, 51.8, 43.4, 37.9, 26.2, 21.4, 19.7, 18.5, 16.7, • 4.0 ·-4.2; IR (CHC 13) Analysis and calculation of 2955, 2930, 2858, 1718, 1658, 1603, 1496, 1472, 1438, 1362, 1325, 1280, 1258, 1097, 1040 cnT1; C24H38〇3Si: C, 71.59; H, 9.51. Found 値: C, 71.38; Η, 9.30.

To a solution of ester 3 (2.2 g, 5.46 mmol) in 10 ml of THF was added 11 ml of a 2M KOH solution. With vigorous stirring, the resulting mixture was heated at 65x: for 24 hours. When cooling to ambient temperature, 2 ml of HC1 2M solution was added, and the resulting mixture was vigorously stirred; stirred for 30 minutes. Ethyl acetate (50 ml) was added to the mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with 50% brine (3 X 30 mL), dried over Na2S04, filtered, and concentrated in the air to obtain 2.12 g (100%) of the desired acid as a thick yellow *: 1HNMR (300 MHz, CDCl3) d 7.26-6.95 (m, 4H), 6.62 · 6.57 (d, 1 H, J = 15.8 Hz), 6.1-6.02 (dd, 1H, J = 15.8, 8.0 Hz), 5.92-5.87 (d, 1 H, J = 15.7 Hz), 3 · 9-3 · 8 (ιη, 1 H), 2.6-2.2 (m, 3 H), 2.36 (s, 3 H), 2.34 (s, 3 H), 1.18-1.15 ( d, 3H, J = 6.8 Hz), 0.94 (s, 9H), 0.12 (s, 3 H), 0.11 (s, 3 H). __ -108_ This paper size applies to China National Standard (CNS) A4 (21 OX297 mm) (Please read the precautions on the back before filling this page)

, 1T 533206 A7 B7 V. Description of the invention (106)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) in Acid 4 (2.12 g, 5.46 mmol) and Diisopropylethylamine (2.9 ml, 16.4 mmol) ) Diphenylphosphine hydrazone chloride (1.1 ml, 6.01 mmol) was added dropwise to a 0 ° C solution in 7 ml of DMF. After stirring at 0 ° C for 5 minutes and at room temperature for 30 minutes, '3- (3-chloro-4-methyllactyltolyl) _D-alanine-2,2,2-trichloroethyl TFA Salt 5 was added dropwise in 7 ml of DMF. The resulting mixture was stirred at room temperature for 2 hours, poured into 100 ml of water, and washed with ether (3 x 50 ml). The combined organic layers were washed with brine, dried over MgS04, filtered through Celite, and concentrated in the air. Purify by column chromatography (silica gel, 10-30% EtOAc / hexane) to obtain 2.86 g (72%) amidine 6 as a white foam: [&amp;] 2. 〇 + 44.8. 〇1.0, MeOH); NMR (300 MHz, CDC13) d 7.25 (s, 1 H), 7.22 (s, 1 H), 7.1-6.83 (m, 5H), 6.6-6.55 (d, 1H, J = 15.7 Hz), 6.11-6.03 (dd, 1 H, J = 15.6, 8.1 Hz), 5.9-5.8 (m, 2 H), 5.18-5.05 (m, 1 H), 4.83-4.75 (q, 2 H, J = 12.0 Hz), 3.9 (s, 3 H), 3.83-3.68 (m, 1 H), 3.3-3.1 (m, 2 H), 2.6-2.36 (m, 3 H), 2.36 (s, 3 H ), 2.32 (s, 3 H), 1.16-1.14 (d, 3 H, J = 6.7 Hz), 0.95 (s, 9 H), 0.11 (s, 3 H), 0.05 (s, 3 H); 13C NMR (75 MHz, CDC13) d 170.0, 165.1, 154.2, 143.1, 136.4, 135.3, 133.0, 132 · 0, 131.0, 130.9, 130.0, 128.4, 128.3, 127.7, 126.1, 124.6, 112.3, 112.1, 94.2, 75.0, 74.7, 56.0, _-109- __ This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (107) 52.9, 42.8, 37.5, 36.5, 25.8, 20.9 , 19.3, 18.0, 16.4,-4.3,-4.7; r IR (CHC13) 3428, 2957, 2930, 2857, 1759, 1676, 1645, 1606, 1503, 1464, 1442, 1380, 1349, 1281, 1259, 1173, 1067 cm · 1. Example 2 9

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (read the precautions on the back and then fill out this page). Ester (2.1 g) is gasified from 2.5 g of aldehyde 2 and 5.0 g of 3-methylbenzyltriphenyl scale. Prepared using the above procedure, yield 65%: [a] 20D + 45.55. (C 1.0, MeOH): lH NMR (300 MHz, CDC13) d 7.22-6.88 (m, 5 H), 6.37-6.31 (d, 1 H, J = 16.0 Hz), 6.18-6.10 (dd, 1 H, J = 16.0, 8.0 Hz), 5.86-5.81 (d, 1 H, J = 15.5 Hz), 3.8_3.7 (m, 4 H), 2.5-2.3 (m, 6 H), l.ll-1.08 ( d, 3 H, J = 6.9 Hz), 0.91 (s, 9H), 0.061 (s, 3 H), 0.052 (s, 3 H); 13C NMR (75 MHz, CDC13) d 166.7, 146.4, 137.5, 135.9 , 131.6, 130 · 4, 128,3 127.7, 126 · 7, 123.1, 122.8, 75.0, 51.3, 42.7, 37.4, 33.8, 25.8, 21.9, 21.3, 18.0, 16.0, -4.5, -4.6; IR (CHC13) 2953, 2931, 2859, 1718, 1658, 1604, 1472, 1454, 1438, 1258 cnT1 0 acid (4.93 g) was prepared from 2.0 g of ester using the above procedure, yield 100%: iH NMR (300 MHz, CDC13 ) d 7.22-7.0 (m, 5 H), 6.38-6.33 (d, 1 H, -110-) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ~ '— 533206 A7 B7 V. Invention Explanation (1〇8) J = 16.0 Hz), 6.18-6.1〇 (dd, 1 H, J = 16.〇, 8 〇Hz, &lt; ο, · υ rtz), 5.87-5.82 (d, 1 H, J = 15.7 Hz), 3.8-3.7 (m, 1 H), 2.5-2.35 (m 3 H, i vm? J H), 2.34 (s? 3 H) 1 · 12-1 · 09 ((1, 3 H, J = 6.8 Hz), 0.9 (s, 9 H) 〇068r, ΔU U68 (s, 3 H), 0.061 (s, 3 H). Amidoamine (2.9 g) It was made from 1.93 g of acid using the above procedure to obtain π coat W, yield 72%: ιΗ NMR (300 MHz, CDC13) d 7.22-7.1 (m, 4 H), 7.U7 〇 (m 2 H) 6 „9 -6.8 (m, 2 H), 6.36-6.30 (d, 1 H, J = 16.0 Hz), 6.1.1, 6 ^ (Hj, J = 16.0, 8 · 0 Hz), 5.82-5.77 (m, 2 H), 5.1-5, 0 (% i H), 4 7'8 · 4.71 (q, 2H, J = 12.0 Hz), 3.86 (s, 3H), 3.8-3.7 (m, iH) 3 25 · 3.15 (m, 2 H), 2.5-2.3 (m, 6 H), 11-1.08 (d, 3 H, J == 6 '8 Hz), 0.88 (s, 9 H), 0.056 (s, 3 H), 0.044 (s, 3 H). The alcohol (2.0 g) was prepared from 2.4 g of starting amidine using the above procedure, yield 100%: 'H NMR (300 MHz, CDC13) d 7.25-6.8 (m, 8 Η), 6.46- 6.41 (d, 1 H, J = 15.9 Hz), 6.16-6.07 (dd, 1 H, J = i6.〇, 8 8 Hz), 5.95-5.8 (m, 2 H), 5.1-5.0 (m, 1 H), 4.81- 4.7 (q, 2 H, J = 12.0

Hz), 3.87 (s, 3 H), 3.7-3.6 (m, 1 H), 3.22-3.05 (m, 2 H), 2.5-5.34 (m, 3 H), 2.34 (s, 3 H), 1.8-1.7 (bs, 1 H), 1.15-1 i3 (d, 3 h, J = 6.8 Hz) 〇 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (2.3 g) was prepared from 2.0 g of starting alcohol using the procedure described above, yield 76/0: [a] 20D + 31.6. (c 1.08, MeOH); 4 NMR (300 MHz, CDC13) d 7.2- 7.0 (m, 6 H), 6.84-6.81 (d, 1 H, J = 8.4 Hz), 6.80 · 6 · 73〇, 1 H), 6.53-6.50 (bd, 1 H, J = 7.3 Hz), 6.4-6.35 (d, 1 H, J = 15.8 Hz), 6.03- 5.95 (dd, 1 H, J = 15.8, 8.5 Hz) , 5.9-5.85 (d, 1 H, J = 15.7 Hz), 5.42-5.35 (bt, 1 H, J = 6.38 Hz), 5.1-4.82 (m, 3 H), 4.8- -111-This paper size applies China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Invention Description (109) 4 „67 (q, 2 H? J = 12.0 Hz), 3.85 ( s, 3 H)? 3.28-3.26 (d? 2 H, J = 6.46 Hz), 3.23-3.16 (dd, 1 H, J = 14.3, 5,8 Hz), 3.1-3.03 (dd, 1 H, J = 14.2, 6.7 Hz), 2.7-2.4 (m, 3 H), 2.33 (s, 3 H), 1.8-1.5 (m, 3 H), 1.43 (s, 9 H), 1.2 (s, 3 H) , 1.15 (s, 3 H), 1.12-ll (d, 3 H, J = 6.7 Hz), 0.88-0.86 (d, 3 H, J = 6.2 Hz), 0.84-0.82 (d, 3 H, J = 6.4 Hz); 13C NMR (75 MHz, CDC13) d 170 · 6, 170 · 0, 165.2, 154 · 0, 139.2, 138.0, 136.7, 135.8, 131.8, 131.1 129.7, 128.8, 128.4, 128.2, 126.8, 125.3, 123.3, 122.2 3, 112.1 94.2, 78.9, 74.5, 7L3, 56.0, 53.1, 48.6, 43.9, 41.0, 39.4, 36.5, 33.3, 28.3, 24.7, 22.9, 22.7, 22.3, 21.3, 21.2, 16.5; IR (CHC13 ) 3426, 3383 2967, 2935, 2874, 2841, 1727, 1710, 1680, 1646, 1605, 1504, 1368, 1280, 1259, 1169, 1151 cnT1 styrene (0.86 g) is based on 2.2 g of starting aminomethyl The acid ester was prepared using the above procedure with a yield of 54%: [a] 2 ° D + 33.1. (C 1.03, MeOH); 4 NMR (300 MHz, CDC13) d 7.24-7.0 (m, 7 H), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.82-6.70 (m, 1 H) , 6.39-6.34 (d, 1 H, J = 15.8 Hz), 6,03-5, 95 (dd, 1 H, J = 15.8, 8.7 Hz), 5.78-5.73 (d, 1 H, J = 15.2 Hz ), 5,67-5.64 (d, 1 H, J = 7.8 Hz), 5.1-5.0 (m, 1 H), 4.87-4.83 (dd, 1 H, J = 10.2, 3.5 Hz), 4.8-4.7 ( m, 1 H), 3.9 (s, 3 H), 3.45-3.38 (dd, 1 H, J = 13.4, 8.6 Hz), 3.2-3.0 (m, 3 H), 2 · 6_2 · 3 (ιη , 3 H), 2.32 (s, 3 H), 1.75-1.25 (m, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), l_13-l.ll (d, 3 H9 J = 6.8 Hz), 0.75-0.72 (t? 6 H, J = 5.7 Hz); 13C NMR (75 MHz, CDC13) d 177.9, 170.5, 170.3, 165.1, 154.0, 142.1, 138.0, 136.6, 135.6, 131.8, 130.8 , 129.9, 129.6, 128.4, 128.22, -112- This paper size applies to China National Standard (CNS) A4 (210 'x 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 ________B7 V. Description of the invention (110) 128.17, 126.7, 124.5, 123.3, 122.5, 112.3, 71.4, 56.1, 54.3, ψ 46.4, 42.7, 42.2, 39.4, 36.5, 35.3, 24.5, 22.8, 22.6, 22.5, 21.2 , 21.1, 17.2; IR (CHC13) 3424, 3021, 3017, 2965, 1747, 1711, 1680, 1652, 1528, 1503, 1485, 1259, 1151, 1067 cm1; Analysis and calculation of C37H47C1N207 値: C, 66.60; Η, 7.10; N, 4.20. Measured 値: C, 66.79; Η, 7.03; Ν, 4.25. Example 3 0 (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs f

b Epoxide, the title compound (0.20 g) was prepared from 0.667 g of starting styrene using the above procedure, yield 29%: 4 NMR (300 MHz, CDC13) d 7.3-7.0 (m, 7 H) , 6.90-6.87 (d, 1 H, J = 8.4 Hz), 6.87-6.75 (m, 1 H), 5.79-5.74 (d, 1 H, J = 14.8 Hz), 5.54-5.51 (d, 1 H, J = 7.8 Hz), 5.28-5.22 (m, lH), 4.89-4.85 (dd, lH, J = 10.4, 3.5Hz), 4.2-4.75 (m, lH), 3.92 (s, 3H), 3.69-3.68 (d, lH, J = 1.63), 3.51-3.44 (dd, 1 H, J = 13.4, 8.6 Hz), 3.2-3.1 (m, 2 H), 2.98-2.95 (dd, lH, J = 7.6, 1.6 Hz), 2.65-2.32 (m, 3H), 2.32 (s, 3H), 1.85-1.6 (m, 3H), 1.4-1.25 (m, 1H), 1.27 (s, 3H), 1.21 (S, 3H), 1.21-118 (d, 3 H, J = 7.5 Hz) 0.90-0.86 (t, 6 H, J = 6.13 Hz). Example 31-113- This paper size applies Chinese National Standard (CNS) A4 (210 X MM mm) 533206 A7 B7 V. Description of the invention (111)

(Please read the precautions on the back before filling this page) Add chlorotrimethyl to -60 ° C in b epoxy (0.1 g, 0.147 mol) in six of 5.0 ml of CHci3 Silica (0.093 ml, 〇74 Jiatiji, Mao Maodou). The solution was stirred at -6 (TC for 30 minutes and at room temperature for 1.5 hours, and then concentrated under vacuum. The resulting residue contained a 50:50 mixture of cis (syn) and trans (anti) chlorohydrin. Purified by reverse phase HPLC to obtain 0.028 g (27%) of the desired trans isomer: 4 NMR (300 MHz, CDC13) d 7.2 8-7.2 (m, 5H), 7.13-7.1 (dd, 1H, J = 8.32, 1.95 Hz), 6.91-6.88 (d, 1H, J = 8.5 Hz), 6.88-6.78 (m, 1 H), 5.86-5.81 (d, 1 H, J = 15. 0 Hz), 5 , 73-5.71 (d, lH, J = 7.8Hz), 5.24_5.17 (t, lH, J = 9.4Hz), 50-4.96 (dd, 1 H, J = 9.58, 2.93 Hz), 4.81-4.74 (m, 1 H), 4.67 · 4 · 64 (d, 1 H, J = 9.73 Hz), 4.06-4.03 (dd, 1 H, J = 9.6, 1.1 Hz), 3.92 (s 3 H), 3.47-3.39 (dd, 1 H, J = 13.2, 8.3 Hz), 3.24-3.0 (m, 3 H), 2.8-2.4 (m, 2 H) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (s, 3 H) 1.9-1.4 (m, 4 H), 1.28 (s, 3 H), 1.22 (s, 3 H), 1.09-1.07 (d, 3 H, J = 6.95 Hz) 0.98-0.96 ( d, 6 H, J = 6.4 Hz).. Example 3 2 -114- This paper size applies the Chinese National Standard (CNS) A4 specification (210'〆297 mm) Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau 533206 A7 B7 V. Description of Invention (112)

The ester (2.75 g) was prepared from 3.39 g of aldehyde 2 and 7.7 g of gasified 4-methoxybenzyltriphenyl scale using the above procedure, yield 54%: [a] 2 () D + 71.85. (C 1.03, MeOH): 1U NMR (300 MHz, CDC13) d 7.25-7.21 (m? 2H? J = 9.0

Hz), 7.0-6.85 (m, lH), 6.81-6.78 (d, 2H, J = 8.5Hz), 6.30-6.23 (d, 1 H, J = 16.3 Hz), 6.0-5.9 (dd, 1 H, J = 16.3, 8.2 Hz), 5.81-5.75 (d, 1 H, J = 14.26 Hz), 3.75 (s, 3H), 3.67 (s, 4 H), 2.42-2.22 (m, 3 H), 1.05- 1.02 (d, 3 H, J = 6.8 Hz), 0.86 (s, 9 H), 0.005 (s, 3 H), -0.001 (s, 3 H); 13C NMR (75 MHz, CDC13) d 166.7, 158.8 , 146.4, 130. 4, 129.7, 129.7, 127.0, 122.7, 113.8, 75.0, 55.2, 51.3, 42.7, 37.4, 25.8, 18.0, 16.1, · 4.5, -4.6; IR (CHC13) 3010 , 2955, 2930, 2898, 2857, 1718, 1658, 1607, 1511 cm1 Acid (1.58 g) was prepared from 1.7 g of ester using the above procedure, yield 96/0: iH NMR (300 MHz, CDCI3) d 7.3 -7.27 (d, 2 H, J = 8.7 Hz), 7.13- 7.03 (m, 1 H), 6.86-6.83 (d, 2 H, J = 8.6 Hz), 6.35-6.29 (d, 1 H, J = 16.0 Hz), 6.04-5.96 (dd, 1 H, J = 15.9, 8.0 Hz), 5.87-5.81 (d, 1 H, == 15 · 8 Hz) 3.8 (s, 3H), 3.79-3.7 (m, 1 H), 2.5-5.33 (π, 3 H), 1.1.1.0 (d, 3 H, J = 6.8 Hz), 0.9 (s, 9 H), 0.05 (s, 3 H), 0.055 -115- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (113) (s9 3 Η) 〇 醯 amine (2.09 g) was prepared from 1.58 g of acid using the above procedure, yield 70%: [a] d + 2.0 (c 1.0, CHCI3); H NMR (300 MHz? CDCI3) d 7.28-7.26 (d, 2 H, J = 7.33 Hz), 7.18_7.17 (d, 1 H, J = 1.8 Hz), 7.04-7.0 (dd, 1 H, J = 8.5, 1.8 Hz), 6.90-6.79 (m, 3 H) 6 32-6 27 (d, lH, J = 16.0Hz), 6.05-5.97 (dd, lH, J = 16.0, 8.1 Hz), 5.83-5_76 (m, 3 H), 5.09-5.05 (m, 1 H), 4.82_4.7 (q, 2 H, J = 11.9 Hz), 3.86 (s, 3 H), 3.8 (s , 3 H), 3.77-3.7 (m, 1 H), 3.24-3.17 (dd, 1 H, J = 14.2? 5.7 Hz), 3.13-3.07 (dd, 1 H, J = 14.2? 5.94 Hz), 2.5 -2.3 (m, 3 H), 1.09-1.06 (d, 3 H, J = 6.8 Hz), 0.89 (s, 9 H), 0.048 (s, 3 H), 0.038 (s, 3 H); 13C NMR (75 MHz, CDC13) d 169.9, 165.1, 158.7, 154.2, 143.0, 135.5, 131.0, 130.4, 129.6, 128.4, 127.0, 124.6, 122.5, 113.8, 112.1, 94.2, 75.0, 74.7, 56.0, 55.2, 52.9, 42.5 , 37.4, 36.4, 25.8, 18.0, 16.4, -4.4, -4.7; IR (CHC13) 2957, 2931, 2857, 1757, 1676, 1644, 1607, 1511, 1503 cm'1. Alcohol (1.35g) was prepared from i.63g of starting seamamine using the above procedure, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Productivity and Economy (please read the precautions on the back before filling this page) 98%: [a] 2% + 55.7. (c 1.0, MeOH); 4 NMR (300 MHz, CDC13) d 7.31-7.29 (d, 2 H, J = 7.9 Hz), 7.18 (s, 1 H), 7.05-7.02 (d, 1 H, J = 8.3 Hz), 7.0-6.87 (m, 1 H), 6.86-6.83 (d, 3 H, J = 8.2 Hz), 6.44-6.38 (d, 1 H, J = 15.8 Hz), 6.0-5.82 ( m, 3 H), 5.10-5.0 (m, 1 H), 4.81-4.7 (q, 2 H, J = 11.8 Hz), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.67 -3.60, 1 H), 3.24-3.19 (dd, 1 H, J = 14.1, 6.1 Hz), 3.12-3.07 (dd, 1 H, J = 14.4, 5.9 Hz), 2.5-2.25 (m, 3 H), 1 · 8_1.6 (bs, 1 H), iM-Lad, 3 H, J = 6_6 Hz); 13C NMR (75 MHz, __ 一 -116-) This paper is applicable to national standards (CNS) ) A4 specification (21 × 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (114) CDC13) d 170.1, 165.2, 159.0, 154.2, 142.5, 131.2, 131.0, 129 · 8 , 128 · 7, 128.4, 127.2, 125.0, 122.4, 113.9, 112.2, 94.2, 74.7, 73 · 8, 56.05, 55 · 2, 53.0, 43.2, 37.1, 36. 4, 16.8; IR (CHC13) 3428, 2964 , 2936, 2912, 2874, 2840, 1758, 1677, 1645, 1607, 1512, 1503, 1258, 1175 cm-1 0 The matrix (1.69 g) consists of 1.26 g of starting alcohol was prepared using the procedure described above, yield 89%: [a] 20D + 35.2. (C 1.02, MeOH); 4 NMR (300 MHz, CDC13) d 7.26-7.23 (d, 21 H, J = 8.0 Hz), 7.18-7.17 (d, 1 Η, J = 1.7), 7.07-7.03 (dd , LH, J = 8.4, L6), 6.85-6.7 (m, 4H), 6.53-6.5 (d, 1 H, J = 7.9 Hz), 6.36-6.31 (d, 1 H, J = 15.8 Hz), 5.9-5.81 (m, 2 H), 5 42-5.35 (t, 1 H), 5.1-4.95 (m, 2 H), 4.94-4.90 (dd, 1 H, J = 9.6, 3.4 Hz), 4.81- 4.67 (q, 2 H, J = 11.9 Hz), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.28-3.26 (d, 2 H, J = 6.5 Hz) 3.23-3.16 (dd, 1 H, J = 14.3, 5.8 Hz), 3.09-3.02 (dd, 1 H, J = 14.1, 6.7 Hz), 2.61-2.4 (m, 3 H), 1.8-1.5 (m, 3 H), 1.43 (s , 9 H), 1.20 (s, 3 H), 1.15 (s, 3 H), 1.11-1.09 (d, 3 H, J = 6.7 Hz), 0.87-0.85 (d, 3 H, J = 6.4 Hz), 0.84-0.82 (d, 3 H, J = 6.5 Hz); 13C NMR (75 MHz, CDC13) d 174.9, 170 · 6, 169 · 9, 165.3, 159.0, 154.0, 139.3, 135.4, 131.1, 131.0 , 129.6, 128.8, 128.4, 127.8, 127.2, 125.2, 122.2, 113.9, 112.2, 94.3, 74.5, 71.3, 56.0, 55.2, 53.1, 48.6, 43.9, 41.0, 39.4, 36.5, 28.3, 24.7, 22.9, 22.7, 22.3 , 21.4, 16.6; IR (CHC13) 3426, 3383, 2965, 2936 , 2874, 2840, 1728, 1711, 1680, 1646, 1607, 1512, 1465, 1367, 1254, 1175, 1067 cm · 1. Styrene (0.676 g) is made from 1.43 g of the starting urethane using the above procedure __117- ___ This paper size is suitable for financial and domestic use (CNS) Α4 · ϋχ297 // &gt; Α) ( (Please read the notes on the back before filling out this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 118- 533206 A7 B7 V. Description of the invention (115) Preparation, 65% yield: 4 NMR (300 MHz, CDC13) 7.26-7.23 (mount 3 poor 'J == 8.4 Hz ), 7.20-7.19 (d, 1 H, J = 1.8 Hz), 7.07-7.03 (e.g., 'J = 8.4, 1.9 Hz), 6.84-6.81 (d, 3 H, J = 8e5 Hz), 6 · 8_6 · 7〇 », 1 ^ 6 · 36 · 6 · 31 ((1, 1 H, J = 15.8 Hz), 5.89-5.81 (dd, 1 H, J = 15 · 8, 8 · Hz), 5.78 -5.73 (d, 1 H, J = 13.7 Hz), 5.68'5.66 (d, 1 H, · Hz), 5.05-4.99 (ddd, 1 H, J = 10.6, 6.6, 1.6 Hz), 4.87-4.82 ( dd, H, &gt; 9.7, 3.1 Hz), 4.78_4.7 (m, 1 H), 3.86 (s, 3 H), 3.790, 3 '3 45-3.37 (dd, 1H, J = 13.4, (8 · ό Hz), 3.15-3.0 (m, 3H), 2 · 6_2 · (m, 3 H), 1.7_1.3 (m, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), l · 12 ... (d, 3 H, J = 6.8 Hz), 0.76-0.75 (d, 3 H, J = 2.9 Hz), 0.74′.73 (d '3 H, J = 2.8 Hz). Example 3 3 OMe To a solution of potassium tributoxide (117 g, 0.5 mmol) in 120 ml of THF / p-nitro-benzyltriphenyl rust ( 50 grams, 5 millimoles) 'in small portions, Within 30 minutes. The mixture was stirred for 1 hour. The aldehyde 2 was added dropwise to the resulting mixture in 2. ml of THF. The mixture was stirred for 15 minutes, slowly warmed to room temperature, and stirred overnight. Saturated nh4ci water-soluble paper scale Shicaihan iS 丨 ⑽ 丨 Please first. Please read this rhyme and pay special attention to filling in this education.

533206 A7 ________ B7 V. Description of the invention (116) Liquid (50 ml) was added, and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgS04, filtered, and concentrated in the air. The mixture of E: Z isomers of crude styrene was purified on silica gel using 2% EtOAc / hexane to obtain 0.5 g of Z isomer and 1.1 g of E isomer (42%) as a yellow oil: [a] 2 () D + 63.81. (C 1.05, MeOH); NMR (300 MHz? CDC13) d 8.18-8.15 (d5 2 H, J = 8,6Hz), 7.47-7.44 (d, 2H, J = 8.7Hz), 7.0-6.85 (m, lH), 6.5 · 6.3 (m, 2 H), 5.87-5.82 (d, 1 H, J = 15.6 Hz), 3 · 8-3 · 73 (η, 1 H), 3.73 (s, 3 H), 2 · 55 · 2 · 35〇, 3H), 1.13-1.1.11 (d, 3 H, J = 6.9 Hz), 0.90 (s, 9 H), 0.059 (s, 3 H), 0.047 (s, 3 H); 13C NMR (75 MHz, CDC13) 166.5, 145.5, 143.9, 137.3, 128.7, 126.4, 123.9, 123.1, 74 · 6, 51.3, 42 · 8, 37.8, 33.8, 25.7, 24 · 3, 21.9, 18 0, 16 · 3 -4.4, 4 · 7; IR (CHC13) 2953, 2931, 2859, 1719, 1658, 1596, 1518, 1472, 1438, 1345, 1259, 1110 cm1 Printed (Please read the notes on the back before filling this page) Rhenamine (3.06 g) is prepared from 2.55 g of acid using the above procedure, yield 65%: [a] 20D + 70.67. (C 1.05, MeOH); 4 NMR (300 MHz, CDC13) d 8.15-8.12 (d, 2H, 8.7Hz), 7.45-7.42 (d, 2H, J = 8.7Hz), 7.17 7.16 (d, 1 H , J = 2.0 Hz), 7′4,7.01 (dd, 1 H, J = 8.45, 1.9 Hz), 6.88-6.82 (m, 2H), 6.43-6.3 (m, 2 H), 5.93-5.91 (d , 1 H, J = 7.5 Hz), 5.84-5.79 (d, 1 H, J = 15.3 Hz), 5.1-5.0 (m, 1 H), 4.82 · 4 · 69 (q, 2 H, J = 11.9 Hz), 3.85 (s, 3 H), 3.8-3.7 (m, 1 Η) 3.24-3.18 (dd, 1 H, J = 14.3, 5.7 Hz), 3.13-3.06 (dd, 1 H, J = 14.2 , 6.05 Hz), 2.52_2.3 (m, 3 H), l.ll-1.09 (d, 3 H, J = 6.8 Hz), 0.88 (s, 9 H), 0.041 (s, 3 H), 0.032 (s, 3 H); 13C NMR (75 MHz, CDC13) d 170.0, 165.0, 154.2 146.5, 144.0, 142.2 137.4, 136.0, 131.0, -119- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 F) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (117) 128.7, 128.4, 126.4, 124.9, 123.9, 122.5, 112.1, 94, 1, 74.72, 74.67, 56.0 , 52.9, 42 · 7, 37.8, 36.4, 25.7, 18.0, 16.5, -4.7, · 4.3; IR (CHC13) 3429, 2957, 2931, 2858, 1757, 1677, 1645, 1597, 1517, 1503, 1345, 1259, 1180, 1110, 1067, 1026 cm1. The matrix (3.3 g) was prepared from 2.54 g of starting alcohol using the procedure described above, yield 87%: [a] 20D + 38.2. (C 1.07, MeOH); 4 NMR (300 MHz, CDC13) d 8.23_8.2 (d, 2 H, J = 8.7 Hz), 7.52-7.49 (d, 2 H, J = 8.7 Hz), 7.21 (s, 1 H), 7.12-7.08 (dd, 1 H, J = 8.2, 1.8 Hz), 6.89-6.86 (d, 1 H, J = 8.4 Hz), 6.86-6.75 (m, 1 H), 6.6 -6.58 (d, 1 H, J = 8.0 Hz), 6.55-6.5 (d, 1 H, J = 15.9 Hz), 6.31-6.23 (dd, 1 H, J = 15.8, 8.5Hz), 5.97-5.92 ( d, lH, J = 15.5Hz), 5.4-5.3 (bt, lH), 5.2-5.0 (m, 2 H), 4.98-4.94 (dd, 1 H, J = 9.5, 3.6 Hz), 4.86-4.72 ( q, 2 H, J = 12Hz), 3.9 (s, 3H), 3.33-3.3 (d, 1H, J = 6.6Hz), 3.27-3.22 (dd, 1 H, J = 14.1, 5.7 Hz), 3.14- 3.07 (dd, 2 H, J = 14.0, 6.7 Hz), 2.8-2.5 (m, 3 H), 2.9-1.47 (m, 3 H), 1.47 (s, 9 H), 1.3-1.2 (m , 9H), 0.91-0.89 (d, 3 H, J = 6.4 Hz), 0.87-0.85 (d, 3 H, J = 6.4 Hz); 13C NMR (75 MHz, CDC13) d 176.8, 170.6, 169.9, 165.1 , 156.2, 154.0, 146.8, 143.2, 138.8, 135.8, 135.4, 131.1, 129.7, 128.7, 128.4, 126.7, 126.6, 125.5, 123.9, 122.2, 112 ", 94.2, 79.0, 76.2, 74.5, 71.2, 56.0, 53] , 48.5, 43.9, 41.2, 39.4, 36,5, 33.3, 28.3, 24.7, 22.9, 22.7, 22.3, 21.4, 16.3; IR (CHC13) 3426, 3385, 2967, 2936, 2874, 2841, 1712, 1681, 1646, 1597, 1519, 1500, 1345, 1280, 1259, 1170, 1150, 1067, 1024 cm · 1 〇 The styrene product (0.55 g) is based on 1.77 g of the starting urethane. The above procedure is -120. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back first) (Fill in this page again), 11 1 #, 533206 A7 B7 1. Description of the invention (118) Sequence preparation, yield 42%: 4 NMR (300 MHz, CDC13) 8.23-8.21 (d, r 2 H, J = 8.7 Hz ), 7.52-7.49 (d, 2 H, J = 8.7 Hz), 7.24-7.2 (m, 2 H), 7.11-7.08 (dd, 1 H, J = 8.5, 1.92 Hz), 6.89-6.87 ( d, 1 H, J = 8.4 Hz), 6.86-6.72 (m, 1H), 6.56-6.51 (d, 1H, J = 15.9Hz), 6.33-6.25 (dd, 1 H, J = 15.9, 8.7 Hz) , 5.94-5.91 (d, 1 H, J = 7.8 Hz), 5.83-5.78 (d, 1H, J = 15.2 Hz), 5.17-5.12 (m, 1H), 4.92-4.88 (dd, 1 H, J = 9.7, 3.6 Hz), 4.8-4.75 (m, 1 H), 3.92 (s, 3 H), 3.5-3. 43 (dd, 1 H, J = 13.5, 8.73 Hz), 3.2-3.1 (m, 3 H), 2.7-2.35 (m, 3 H), 1.8-1.6 (m, 2 H), 1.4-1.19 (m, 1H), 1.2 (s, 3 H), 1.16-1.14 (d, 6 H), 0.82-0.81 (d, 3 H, J = 3.73 Hz), 0.80-0.79 (d, 3 H, J = 3.87 Hz). Example 3 4 (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs! H NMR (300 MHz? CDC13) 8.5 (s? 1 H)? 7.76-7.74 (d? 2 H? J = 7.4Hz), 7.58-7.56 (d, 2H, J = 7.4Hz), 7.5-7.1 (m, 8H), 7.03-7.0 (d, 1 H, J = 8.2 Hz), 6.81-6.78 (d, 1 H, J = 8.5 Hz), 6.78-6.65 (m , 1 H), 6.37-6.34 (d, 1 H, J = 7.3 Hz), 5.84-5.81 (t, 1H, J = 5.2 Hz), 5.69-5.64 (d, 1 H, J = 15.0 Hz), 5.18 -5.15 (bd, 1 H, J = 9.0 Hz.), 4.83-4.6 (m, 2H), 4.45-4.43 (d, 2H, J = 6.7Hz), 4.24-4.19 (t, 1H, J = 6.6 Hz ), 3.99 (bs, 2 H), 3.81 (s, 3 H), 3.61 (s, 1 H), this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). 533206 A7 B7 V. Invention Explanation (119) 3.46-3.39 (dd, 1 H, J = 13.4, 8.8 Hz), 3.2-3.8 (m, 5 H), 2.6-2.3 (m, r (Please read the notes on the back before filling this page ) 3 H), 1.8-1.3 (m, 3 H), 1.2 (s, 3 H), 1.14 (s, 3 H), 1.12-ll (d, 3 H, J = 6.8 Hz), 0.86_0.81 (t, 6 H, J = 7.3 Hz). Example 3 5

NMR (300 MHz, CDC13) d 9.5 (bs, 2 H), 7.6-7.57 (d, 2 H, J = 8.1 Hz), 7.24-7.18 (m, 5 H), 7.05-7.03 (d, 1 H , J = 8.3 Hz), 6.84-6.82 (d, 1 H, J = 8.4 Hz) 6.82-6.65 (m, 1 H), 6.02-6.0 (d, 1 H, J = 7.6 Hz), 5.72-5.67 ( d, 1 H, J = 15.3 Hz), 5.19-5.16 (bd, 1 H, J = 10.5 Hz), 4.9-4.6 (m, 2 H), 3.85 (s, 3 H), 3.64 (s, 1 H ), 3.55 · 3.4 (m, 3 H), 3.2-2.95 (m, 3 H), 2.90-2.88 (d, 1 H, 7.11 Hz), 2 · 6 · 2 · 3〇, 3 H), 2.0- 1.3 (m, 3 H), 1.2 (s, 3 H) 1.15 (s, 3 H), 1.13-l.ll (d, 3 H, J = 6.9 Hz), 0.90-0.84 (t, 6 H, J = 7.2 Hz). Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -122- This paper size applies to the Chinese National Standard (CNS) A4 (2lOX 297 mm) 533206 A7 B7 V. Description of the invention (120) Figure 2

HF, CH3CN (94%) (Please read the notes on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

15 -123- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297mm) 533206 A7 B7 V. Description of invention (121) Figure 2 continued

DCC, ΌΜΛΡ CH2C12 (75-85%)

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

1) TFA 2-hydroxypyridine toluene

Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-124- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (122) Printed by a cooperative

mCPBA CH2C12

tmsci, chci3 · 6〇β and 〇ec

-125 (Please read the notes on the back before filling this page

、 1T This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × '297 mm) 533206 A7 B7 one ... one—one ^ _ —- -------—_ _ five. Description of the invention (123) At 晞 17 (0.3 g '0.50 ¾ mole) at _78. 0 in 9.0 ml CH2Cl2 / 1.0 ml

To MeOH was added 2-methylpyridine (0.07 Torr, 0.074 mmol). This solution was subjected to 1,2 equivalents of ozone 'and the odorous oxide was quenched with dimethylsulfide (I ml, 22 mol). The mixture was slowly warmed to room temperature and stirred overnight. The solution was washed with water (2 X 20 mL), dried over NaJO4, filtered, and concentrated in the air to obtain 0.251 g (87%) of aldehyde. 18: 1HNMR (300 MHZ, CDCl3) d9.64-9.63 (d, 1 H , J = 1.05 Hz), 7.25-7.2 (m, 2 H), 7.08-7.05 (d, 1 H, J = 8.2 Hz), 6.86-6.83 (d, 1 H, J = 8.4 Hz), 6.83-6.7 (m, 1 H) 5.81-5.76 (d, 1H, J = 15.1 Hz), 5.75-5.65 (bs, 1 H), 5.38-5.3 (m, 1 H), 4.85-4.81 (dd, 1H, J = 10.2, 3.2 Hz), 4.80-4.7 (m, 1 H), 3.87 (s, 3 H), 3.46-3.39 (dd, 1 H, J = 13.5, 8.7 Hz), 3.2-3.〇 (m, 3H ), 2 · 7-2 · 4 (ιη, 3 H), 1.8-1.6 (m, 2 H), 1.4-1.3 (m, 1 H), 1.23 (s, 3H), 1.18-1.16 (d, 6 H), 0.94-0.92 (d, 3 H, J = 6.5 Hz), 0.88-0 · 86 (d, 3 H, J = 6.4 Hz). (Please read the notes on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs -126- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 V. Description of the invention (124 Figure 3

OHC: [H5I〇6 OMe THF: H20 Cryptocin 53 h2sq4DME: H20 18

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

Printed by the Employees 'Cooperatives of the Central Bureau of Standards of the Ministry of Economics -127 This paper size applies to Chinese National Standards (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of Invention (125) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics system

(Please read the precautions on the back before filling this page) -128- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of Invention (彳 26)

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

、 1T j #, -129- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (127) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

? BUU, THF, -780C 2) VAZP ^ qin / T stick, Δ

1) T = SSP

TIPSP

This paper size applies to Chinese National Standard (CNS) Α4 size (210X 297 mm) (Please read the precautions on the back before filling this page)

、 1T 533206 A7 B7 V. Description of the invention (128) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

33

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

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This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (129) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

-132- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 533206 V. Description of invention (130) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size is applicable to Chinese National Standard (CNS) A4 specification (230X 297 mm) 533206 A7 B7 V. Description of the invention (131)

HPLC

FMOCHN

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

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(Please read the precautions on the back before filling this page) Order 34 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 ------ B7 V. Description of the invention (132) Economy Yin Fan, a consumer cooperative of the Ministry of Standards and Technology, added 5 drops of concentrated H2S04 to a solution of Cryptophytin 53 (0.15 g, 0.23 mmol) in 3 ml of DME and 2.0 ml of H20. The mixture was stirred overnight, 5 drops of H2S04 was added, and continued to stir for 24 hours. Saturated NaHC03 was added slowly until all reactivity disappeared, and the mixture was extracted with CH2C12. The organic layer was washed with brine, dried over Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by column chromatography (crumb, 2% MeOH / CH2Cl2) to obtain 0.13 g of a diol. To a mixture of diol in 4.0 ml of THF and 2.0 ml of H20 was added NaIO4 (0.144 g, 0.675 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in the air, 5 mL of 0 was added, and extracted with CH2C12. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in the air to obtain 0.10 g (77%) of aldehyde 18. In a TIPS-protected vaporized 4-hydroxybenzyltriphenyl scale (0.23 g, 0.04 mmol) in 3.0 ml of THF, 0.25 liter of n-butyl clock 1.6 was added dropwise at _78 ° C. M solution. The mixture was slowly heated to 0 ° C and stirred for 10 minutes. To aldehyde 18 in 4.0 ml of THF at -78 C was added dropwise 2.5 ml of a 13 M lamp color solution. The resulting mixture was stirred at -78 ° C for 2 hours and at room temperature for 30 minutes. Saturated NHUCIGO ml) and ethyl acetate (10 ml) were added to separate the layers. The organic phase was washed with water (3 x 10 ml) and brine. Finally, the residue was dried over MgS04, and the organic phase was filtered 'concentrated in the air' and the resulting residue was purified by column chromatography (gel, 70% EtOAC / hexane) to obtain 0.09 g (62%) of the desired styrene. Example 3 8

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before filling this page) Order J · 533206 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Note (133) 2 M peroxyacid aqueous solution (15 ml, 30 mmol) was added to a solution of cryptocryptin 53 (2.0 g, 2.99 mmol) in 30 L of DME, and the resulting mixture was stirred. Fall for 6 hours. It was carefully neutralized with saturated NaHC03 (50 ml), the mixture was extracted with CH2C12 (4 X 100 ml), and the combined organic layers were dried over NaJO4, filtered, and concentrated in the air. Purification by column chromatography (silica gel, 5% MeOH / CH2C12) gave diol 19 (1.5 g) in 72% yield as a 3: 1 trans / cis mixture. To a solution of diol (1.0 g, 1.46 mmol) in 20 ml of THF and 15 ml of water was added Na104 (1.9 g, 8.9 ml), and the mixture was stirred under nitrogen overnight. After removing THF under reduced pressure, the residue was diluted with water (00 ml) and extracted with CH2C12 (4 × 50 ml). The combined organic extracts were washed with brine (25 mL), dried over NaJO4, filtered, and concentrated under reduced pressure. Residual benzaldehyde was removed, and the solid was dissolved in 100 ml of toluene and then toluene was removed on a rotary evaporator (rc). Secondary evaporation from toluene gave aldehyde 18 as a yellow foam (0.828 g). The yield is 98%. The generated aldehyde is used without further purification. For stability, it is stored in -23X :: [Y] 20d + 23.0. (C 0.565, CHC13); 4 NMR (300 MHz, CDC13) d 9.64-9.63 (d, 1 H, J = 14 Hz), 7.28-7.26 (m, 1 H), 7.21-7.20 (d, 1 H, J = 1.9 Hz)? 7.08-7.05 (dd, 1 H, J = 7.1, 1 · 7 Hz), 6.87-6.84 (d, 1 H, J = 8.5 Hz), 6.82-6.72 (m, 1 H), 5.80-5.75 (d, 1 H, J = 15.0 Hz), 5.54-5.51 ( d, 1 H, J = 7.7 Hz), 5,40-5.33 (m, 1 H), 4.85-4.81 (dd, 1 H, J = 9.7, 3.2 Hz) 4.78-4.71 (m, 1 H), 3.88 (s, 3 H), 3.46-3.39 (dd, 1 H, J = 13.5, 8.6 Hz), 3.15-3.03 (m, 3 H), 2.68-2.35 (m, 3 H), l_82-1.63 (m, 2 H), 1.45-1.37 (m, 1 H), 1.24 (s, 3 H), 1.19-1.16 (d, 3 H, J = 7.1 -136- This paper size applies to China National Standard (CNS) A4 specifications ( 2ϋ97mm) (Please read the notes on the back before filling out this page}-, ^ τ ·· 533206 A7 B7 V. Invention Description (134)

Hz), 1.18 (s, 3 H), 0.94-0.92 (d, 3 H, J = 6.5 Hz), 0.89-0.87 (d, 3 r H, J = 6.5 Hz); 13C NMR (63 MHz, CDC13) d 200.7, 177.8, 170.6, 170.1, 165.1, 153.9, 141.1, 130.7, 129.8, 128.1, 124.9, 122.3, 112.3, 73.4, 71.1, 56.0, 54.6, 49.9, 46.4, 42.7, 39.2, 36.1, 35.2, 24.7, 22.8 , 22.7, 21.3, 10.7; IR (CHC13) 3422, 2964, 2936, 1755, 1730, 1718, 1678, 1529, 1504, 1487, 1474, 1464, 1442, 1320, 1303, 1281, 1259, 1244, 1185, 1151 , 1127, 1067 cm · 1; Analysis (C29H39C1N206): C, H, N. Example 39 (Please read the precautions on the back before filling this page)

, 1T .. Printed on 4- (triisopropylsilyloxymethyl) benzyltriphenyl bromide (76 g, 12.2 mmol) in 100 ml of THF In _5 (TC was added dropwise a 1.5 M solution of n-butyllithium (8.1 ml, 12.2 mmol). The mixture was slowly warmed to room temperature and stirred for 30 minutes. In aldehyde 18 (2.95 G, 5.1 mmol) in 100 ml of THF and added dropwise to the red solution via a double-tipped needle at -78 ° C. The resulting mixture was stirred at -78 ° C for 3 hours and at room temperature for 45 minutes. Saturated NH4C1 (100 ¾ liters) and ethyl acetate (100 ml) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (2 X 50 ml). The combined organic layers were water (3 x 40 ml) and brine. The washes were dried over MgSCU, filtered, and concentrated in the air. The resulting yellow residue was purified using column chromatography (silica gel, 10-20-50 / 50 / Acto / hexane) to obtain 3.6 g ( 84%) Desired styrene, white solid, E: z isomer -137- This paper size applies Chinese National Standard (cns) μ size a 533206 Member of Central Standards Bureau, Ministry of Economic Affairs Kl B7 printed by a consumer cooperative V. Description of the invention (135) &gt; Kun compound. A mixture of isomers (7.3 g, 8, millimolar) was dissolved in 24 ml of benzene, in azobis (cyclohexane Nitrile (VAZO) (0.32 g, 087 mmol) and sulfur (3.7 ml, 4.0 mmol) were heated to reflux. After 5 hours of reflux, the solution was concentrated and the residue was layered on a column. (Silica gel, 5-50% EtOAc / hexane) to obtain 6.7 g (92%) E isomer 20 as a white solid: [^] 2V31.9〇 (c 1.0? CHCls); lR NMR ( 300MHz? CDC13) ^ 7.3.3.22 (ιη, 5 H), 7.20-7.19 (d, 1 H, J = 1.95 Hz), 7.07-7.04 (dd, 1 H, J = 8.4, 2.0 Hz), 6.85-6.82 (d, 1 H, J = 8.5 Hz), 6.8-6.7 (m, 1 H), 6.4-6.38 (d, 1 H, J = 15.8 Hz), 6.02-5.94 (dd, 1 H, J = 15.8, 8.8 Hz), 5.77-5.72 (d, 1 H, J = 14.9 Hz), 5.56-5.54 (d, 1 H, J = 7.9 Hz), 5.1-4-7 (ηι , 5 H), 3.9 (s, 3 H), 3.45-3.37 (dd, 1 H, J = 13.5, 8.5 Hz), 3.2-3.0 (m, 3 H), 2.6-2.3 (m, 3 H ) 1.7-1.5 (m, 2 H), 1.4 · 1 · 〇 (η, 31 H), 0.75-0.71 (t, 6 H, J = 6.1 Hz); 13C NMR (63 MHz, C DC13) ^ 177.8, 170.5, 170.4, 165.2, 153.9, 142.1, 141.1, 135.2, 131.5, 130.8, 129.7, 129.6, 128.1, 125.9, 124.5, 122.4, 112.2, 77.0, 71.4, 64 · 7, 56.0, 54.4 , 46.4, 42.7, 42.2 39.4, 36.5, 35.3, 24.5, 22.8, 22.6, 22.5, 21.2, 17.9, 17.2, 1L9; IR (CHC13) 3423, 2962, 2945, 2867, 1746, 1712, 1681, 1652, 1528, 1503, 1485, 1473, 1464, 1303, 1259 cm1; Analysis (C46H67ClN208Si): C, H, N. Example 4 0

-138- This paper size is applicable to Chinese National Standard (CNS) A4 (2l0X 297mm) (Please read the precautions on the back before filling in this document

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7_______ V. Description of the invention (136) 3-Gas peroxybenzoic acid (0.27 g, 1.59 mmol) Added styrene 20 (1.25 ψ g, L49 mmol ) In 20 ml of 0 ° C solution in CH2C12. The solution was stirred at 0 ° C for 1 hour and overnight at room temperature. Concentration in tritium air, reverse phase HPLC separation of the resulting epoxide, 0.67 g of Θ epoxide 22 (57%) was obtained as a white solid: [Yi] 20D + 20.9. (C 0.765, CHC13); 4 NMR (300 MHz, CDC13) d 7.35-7.33 (d, 2 H, J = 7.8 Hz), 7.26-7.2 (m, 4 H), 7.05- 7.02 (bd, 1 H, J = 8.2 Hz), 6.84-6.81 (d, 1 H, J = 8.4 Hz), 6.81-6.65 (m, lH), 5.8-5.65 (m, 2H), 5.25-5.15 (m, lH), 4.9- 4.7 (m, 4 H), 3.9 (s, 3 H), 3.7 (s, 1 H), 3.46-3.42 (dd, 1 H, J = 13.4, 8.8 Hz), 3.15-3.0 (m, 3 H) , 2.93-2.9 (d, 1 H, J = 7.3 Hz), 2.6- 2.4 (m, 2 H), 1.8-1.6 (η, 3 H), 1.4-1.0 (m, 31 H), 0.83-0.79 (t, 6 H, J = 5.3 Hz); 13C NMR (63 MHz, CDC13) d 177.7, 170.5, 170.4, 165.1, 153.9, 142.1, 141.6, 136.7, 135.1, 130.7, 129.8, 128.1, 125.9, 125.5, 124.6, 122.3, 112.2, 75.9, 71.0, 64.6, 63.0, 58.9, 56.0, 54.6, 46.3, 42.7, 40.5, 39.2, 36.8, 35.2, f 24.2, 22.8, 22.7, 22.6, 18.0, 13.4 , 11.9; IR (CHC13) 3424, 2962, 2945, 2867, 1751, 1712, 1682, 1528, 1503, 1485, 1473, 1464, cm · 1; Analysis (C46H67ClN209Si): C, H, N. Example 4 1

1.0 M solution of tetrabutylammonium oxide (0.14 ml, 0.14 mmol) in THF __ -139- This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) (Please read first Note on the back then fill in this tile. 533206 A7 B7 V. Description of the invention (137) (Please read the notes on the back before filling out this page) Add dropwise &gt; 5 Epoxide 22 (0.1 g, 0.17 mmol) in 3.5 ml of 0 ° C solution in THF. The solution was warmed to room temperature and stirred for 20 minutes, then water (10 ml) and ethyl acetate (20 ml) were added. The layers were separated The aqueous phase was extracted with CH2C12 (3 &gt; &lt; 20 ml). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in the air to obtain free alcohol. Column chromatography (silica gel, 70-100% EtOAc- Hexane) Purified to obtain 0.068 g (84%) of pure alcohol 23 as a white solid: [from] 20d + 26.2. (C 0.435, CHC13); 4 NMR (300 MHz, CDCls) ^ 7.39-7.36 ( d, 2 H, J = 7.8 Ηζ), 7.26-7 · 23 (d, 3 H, J = 9.1 Hz), 7.18 (s, 1 H), 7.05-7.02 (d, 1 H, J = 8.5 Hz), 6.85- 6.82 (d, 1 H, J = 8.2 Hz ), 6.82-6.7 (m, 1 H), 5.72-5.67 (d, 1 H, J = 15.1 Hz), 5.55-5.52 (d, 1 H, J = 7.8 Hz), 5.22-5.17 (m, 1 H ), Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4.85-4.7 (m, 4 H), 3.9 (s, 3 H), 3.7 (s, 1 H), 3.45-3.38 (dd, 1 H, J = 13.4, 9.3 Hz), 3.2-3.0 (m, 3 H), 2.92-2.89 (d, 1 H, J = 7.6 Hz), 2.65-2.4 (m, 2 H), 1.8-1.6 (m, 4 H) , 1.4-1.2 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.16-1.13 (d, 3 H, J = 7.2 Hz), 0.86-0.82 (t, 6 H , J = 6.5 Hz); l3C NMR (63 MHz, CDC13) β 177.8, 171.0, 170.4, 165.5, 153.8, 141.5, 141.4, 135.7, 133.5, 130.6, 130.0, 128.0, 127.1, 125.6, 124.6, 122.2, 112.3, 77.2, 76.5, 76.0, 71.0, 64.2, 63.1, 58.8, 56.0, 54.7, 46.3, 42.7, 40.5, 39.3, 36.9, 35.1, 24.5, 22.7, 22.5, 22.1, 13.4; IR (CHC13) 3422, 2992, 2963, 2936, 2874, 1751, 1713, 1682, 1651, 1504, 1486, 1303, 1259, 1 186, 1165, 1151, 1067 cm1; FAB HRMS [M + H] (C37H48C1N209) calculation: 699.3048, measured値 699 · 3054. _-140- This paper size applies to Chinese National Standard (CNS) A4 specification (210X29? Mm) 533206 A7 ________B7 V. Description of the invention (138) Example 4 2

In alcohol 23 (0.08 g, 0.114 mmol), N- (third butoxycarbonyl) glycine (please read the notes on the back before filling this page) (0.034 g '0.194¾ mol) And 4-dimethylaminopyridine (Dmap) (0.004 g, 0.034 mmol) were added to a 0 ° C solution in 2.0 ml of CH2C12; ι, 3-monocyclohexylcarbodiimide (DCC) (0.040 g, 0.194 mmol). The mixture was stirred at 0 ° C for 10 minutes and at room temperature for 45 minutes, filtered, and concentrated in the air. The resulting residue was purified using column chromatography (silica gel, 70-80% EtOAc / hexane) to obtain 0.07 g (72%) of the ester as a white solid: [middle] 2Od + 18.5. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (c 0.65, CHC13); lR NMR (300 MHz, CDC13); 7.4-7.2 (m, 6 H), 7.11-7.08 (dd, 1 H, J = 8.4, 1.8 Hz), 6.9-6.87 (d, 1 H, J = 8.4 Hz), 6.86-6.7 (m, 1 H), 5.78-5.73 (d, 1 HJ = 15.2 Hz), 5.64-5.62 (d, 1 H, J = 7.4 Hz) 5.3-5.22 (m, 1 H), 5.22 (s, 2 H), 5.1-5.0 (bs, 1 H), 4.9-4.7 (m, 2 H), 4.0-3.99 ( d, 2 H, J = 5.4 Hz), 3.9 (s, 3 H), 3.73-3.72 (d, 1 H, J = 10. H), 3.5-3.43 (dd, 1 H, J = 13.4, 8.6 Hz ), 3 · 2 · 3 · 0 (η, 3 H), 2.95-2.92 (d, 1 H, J = 6.4 Hz), 2.65_2.4 (m, 2 H), 1.8-1.6 (m, 3 H ), 1.5 (s, 9 H), 1.45-1.3 (m, 1 H), 1.26 (s, 3 H), 1.2 (s, 3 H), 1.2-1.17 (d, 3 H, J = 8.7 Hz) , 0.9-0.86 (t, 6 H, J = 6.3 Hz); 13C NMR (63 MHz, CDC13) β 177.7, 170.6, 170.3, 170.2, 165.1, 155.6, 153.8, 141.4, 137.1, 135.6, 130.6, 129.9 , 128.6, 128.0, 125.7, 124.7, 122.2, 112.2, 79.9, 75.8, 70.9, 66 · 4, 63 · 1, 58 · 5, 56 · 0, this paper is again applicable to the Chinese National Standard (CNS) Α4 specification (210X297 Mm) -141- _ 533206 A7 B7 V. Invention (139) 54.7, 48.9, 46.3, 42.7, 42.4, 40.5, 39.3, 36.8, 35.2, 28.2, 24.5, 22.8: 22.7, 22.6, 21.2, 13.5; cm- 丨; analysis (C44H58C1N3〇i2): c, h, n. Example 4 3

Trimethylsilyl gas (0.09 L, 0.75 mmol) was added to 13 epoxide 24 (0.16 g, 0.187 mmol) in 50 ml of CHCl3 * _60x: solution. After stirring at -60 to -40 ° C for 2 hours, 009 ml of TMSC1 was added and stirring was continued for 3 hours. The solution was heated to room temperature, concentrated, and purified by reverse-phase preparative HpLC (55:45) CH3CN: H20, and the two gas alcohols formed were separated. This purification yielded 0.058 g (35%) of the desired alcohol 25: [ar] 2 () D + 50.5. (C 1.075, CHC13); lU NMR (300 MHz, CDC13); 7.42-7.2 (m? 6 H)? 7.13-7.09 (dd, 1 H, J = 8; 4, 1.8 Hz), 6.9-6.87 (d , 1 H, J = 8.4 Hz), 6.85_ 6.7 (m, 1 H), 5.9-5.8 (m, 2 H), 5.2 (s, 3 H), 5.15-5.05 (m, 1 H), Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page) 5.0- 4.9 (m, 1 H), 4.8-4.72 (m, 1 H), 4.71-4.68 (d, 1 H, J = 9.7 Hz), 4.07-4.03 (d, 1 H, J = 9.3 Hz), 3.99-3.97 (d, 2 H, J = 5.5 Hz), 3.9 (s, 3 H), 3.44-3.37 (dd, 1 H, J = 13.6, 8.3 Hz), 3.23-3.14 (m, 2 H), 3.08-3.0 (dd, 1 H, J = 14.5, 8.0 Hz), 2.75-2.4 (m, 3 H), 2.0- 1.7 (m, 3H), 1.5 (s, 10H), 1.26 (s, 3H), 1.21 (s, 3H), 1.08-1.06 (d, 3 H, J = 7.0 Hz), 0.977-0.963 (d, 3 H, J = 4.0 Hz), 0.956-0.942 (d, 3 H, J = 4.1 Hz); 13C NMR (63 MHz, CDC13) 177.5, 170.5, 170.2, 170.1, 165.3, 153.9, 142.2, 139.0, 138.3, 136.1 ， -142- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) 533206 Printed by A7 B7, Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs V. Description of the invention (140) 130.8, 129.9, 128.7, 128.2, 128.1, 124.5, 122.3, 112.2, 80.0, ψ 76.1, 73.9, 71.1, 66.2, 61.7, 56.1, 54.6, 46.4, 42.7, 42.3, 39.6, 38.4, 36.3, 35.1, 28.2, 24.8, 23.0, 22.9, 22.7, 21.5, 8 · 6; IR (CHC13) 3428, 3009, 2966, 2935, 1750, 1714, 1683, 1504, 1486, 1369, 1259, 1193, 1162, 1127, 1067; FAB HRMS [M + 11] ((: 44116. (: 11 ^ 3012) Calculation 値 892.3554, Measured 値 892.3565 〇 Example 44

A 4 μ solution of hydrogenated gas in 1,4-dioxolane (0.08 ml, 0.33 mmol). Glycine 25 (0.058 g, 0.065 mmol) was added to 0.2 The solution in CH2Cl2 was decanted. The resulting mixture was stirred at room temperature for 3 hours, concentrated in the air, and maintained in the air for 3 days to remove 丨, 'dioxolane, to obtain the desired hydrochloride 26, quantitative yield: ㈤' + 26 2 . (C 〇58, Me〇H); ΐβGu Fan (500 MHz, CD3OD) d 7.48-7.42 (q, 4H, J = li.2Hz), 731- 7.3 (d, 1H, · T = 2.0 Hz ), 7.21-7.19 (dd, 1H, J = 8.5, 2 Hz), 7 〇_ 7.0 (d, 1 H, J = 8.4 Hz)? 6.8-6.7 (m9 1 H), 6.0-5.95 (dd? 1 HJ = 15.2, 1.5 Hz), 5.3 (d, 2 H, J = 1 3 Hz), 5 i6 5 "plus '^'

5.09-5.07 (dd, 1 H, J = 1.0, 3.6 Hz), 4.84-4 82 (d, ihj = 9 &amp; Hz), 4.54.4.51 (dd? 1 H? 3.7 Hz)? 4.05.4.03 (dd5 1 HJ = 9.59 1.8 Hz), 3.9 (s? 2 H)? 3.86 (s? 3 H), 3.5-3.47 (^ 1 H3? J = 13.5 Hz), 3.22-3.18 (dd, 1 H, J = 14.5, 3.6 Hz), 3.14.3.11 (d, 1 (Please read the precautions on the back before filling this page)

-143- 533206 A7 _ B7 _ V. Description of the invention (141) H, J = 13.5 Hz), 2.8-2.77 (d, 1 H, J = 14.4 Hz), 2.78-2.75 (m, 2 H), r 2.55 -2.35 (m, 2 H), 1.9-1.55 (m, 4 H), 1.4-1.3 (m, 1 H), 1.24 (s, 3 H), 1.2 (s, 3 H), 1.04-1.03 (d , 3 H, J = 7.0 Hz), 1.02-1.0 (t, 6 H, J = 7.2 Hz); 13C NMR (75 MHz, CDC13) β 178.9, 173.8, 171.9, 168.3, 155.3, 144.2, 141.8, 136.7, 132.3, 131.5, 129.75, 129.7, 129.4, 125.2, 123.3, 113.5, 77.2, 74.7, 72.6, 68.5, 63.5, 57.6, 56 · 7, 47.6, 44.1, 41.1, 40.4, 37.9, 36.5, 26.3, 23.6, 23.5, 22.2, 9.0; IR (KBr) 3412, 2961, 2935, 1752, 1722, 1669, 1504, 1473, 1279, 1259, 1207, 1151, 1126, 1065 cnT1. Example 4 5 (Read the precautions on the back before filling in this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs on chlorohydrin 25 (0.14 g, 0.16 mmol), N- (third butoxycarbonyl) glycine (0.041 g, 0.24 mmol) and 4 -Dimethylaminopyridine (DMAP) (0.002 g, 0.016 mmol) To 0.7 ml of CH2C12 was added 1,3-dicyclohexylcarbodiimide (DCC) (0.049 g, 0.24 mmol). The mixture was stirred at room temperature! Hours, filtered with ethyl acetate, and concentrated in the air. The resulting residue was purified using column chromatography (silica gel, 50-60-70% EtOAc / hexane) to obtain 0.158 g (97%) of diglycinate 27 as a white solid: [from] 20D + 44.0. (C 1.25, CHC13); NMR (300 MHz, CDC13) ^ 7.4-7.2 (m, 7 H)? 7.13, 7.10 (bd, 1 H, J = 9.8 Hz), 6.91-6.88 (d, 1 H, J = 8.4 Hz), 5.8-5.77 (d, 1 H, J = 15.3 Hz), 5.6-5.58 (m, 1 H), 5.49-5.46 (d, 1-144- This paper size applies to the Chinese National Standard (CNS) A4 specifications (210X29 '/ mm) — 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (142) H, J = 9.6 Hz), 5.19 (s, 2 H), 5.1-4.7 ( m, 6 H), 3.98-3.97 (d, 2 H, ψ J = 5.0 Hz), 3.93 (s, 3 H), 3.69-3.62 (dd, 1 H, J = 18.2, 4.0 Hz), 3.5 -3.0 (m, 5 H), 2.7-2.35 (m, 3 H), 2.0-1.7 (m, 3 H), 1.49 (s, 9 H), 1.44 (s, 9 H), 1.28 (s, 3 H), 1.22 (s, 3 H), ll-1.08 (d, 3 H, J = 7.0 Hz), 1.06-1.04 (d, 3 H, J = 6.4 Hz), 1.0-0.98 (d, 3 H, J = 6.2 Hz); 13C NMR (63 MHz, CDC13) β 177.6, 170.4, 169.9, 168.5, 165.0, 155.2, 153.9, 141.6, 138.6, 137.3, 136.3, 130.8, 129.8, 128.2, 128.1 , 124.6, 122.3, 112.2, 79.9, 74.7, 71.1, 66.2, 60.0, 56.0, 54.5, 46.5, 42.8, 42.4, 41.8, 39.5, 38.0, 36.5, 35.2, 28.2, 28.15 24.8, 23.1, 22.8, 22.6, 21.4, 9.9; IR (CHC13) 3431, 2982, 2966, 2935, 2872, 1756, 1713, 1685, 1504, 1369, 1258, 1193, 1161; FAB HRMS [M-BOC + Η] (C46H63C12N4013) calculation 値 949.3769, measured 値 949.3777. Example 4 6

4 M solution of hydrogenated gas in 1,4-dioxolane (oi ml, 042 mmol) solution of diglycinate 27 (0.044 g, 0.042 mmol) in 0.2 ml CH2C12 Inside. The resulting mixture was stirred at room temperature for 3 hours, concentrated in the air, and maintained in the air for 3 days to remove the residual dioxin, and the desired hydrochloride 28 was obtained. Quantitative yield: [(^ ] 20D + 33.1. (C 〇865, MeOH); 4 NMR (500 MHz, CD3OD) (ί 7.77-7,74 (d, 1 H), 7.46-7.41 (q, 4 -145- This paper rule applies China National Standard (CNS) A4 Specification (2ΐϋ_7mm) (Please read the precautions on the back before filling in this page}

533206 A7 B7 _ 丨 _ 丨 · 1 ·. —__.--______________----- _ ----- V. Description of the invention (143) H, J = 20.3, 8.4 Hz), 7.29-7.28 (d, 1 H, J = 2.1 Hz), 7.18-7.16 (dd, r 1 H, J = 8.6, 2.1 Hz), 6.99-6.97 (d, 1 H, J = 8.5 Hz), 6.7-6.6 (m, 1 H ), 5.95-5.92 (d, 1 H, J = 15.3 Hz), 5.54-5.52 (dd, 1 H, J = 9.5, 1.4 Hz), 5.5 (s, 1 H), 5.28 (s, 2 H), 5.21-5.19 (d, 1 H, J = 9.4 Hz), 5.12-5.09 (dd, 1 H, J = 10.5, 3.1 Hz), 4.87-4.85 (d, 1 H, J = 12.4 Hz), 4.5_4. 47 (dd, 1 H, J = 11.3, 3.7 Hz), 3.9 (s, 2 H), 3.84 (s, 3 H), 3.82-3.79 (d, 1 H, J = 17, 8 Hz), 3, 48-3.45 (d, 1 H, J = 13.7 Hz), 3.35-3.3 (m, 1 H), 3.19-3.15 (dd, 1 H, J = 14.5, 3.8 Hz), 3.11_3.09 (d, 1 H, J = 13.8 Hz), 2.77_2.6 (m, 3 H), 2.37-2.3 (m, 1 H), 1.95-1.75 (m, 3 H), 1.22 (s, 3 H), l_17 (s , 3 H), 1.08-1.07 (d, 3 H, J = 7.0 Hz), 1.03-1.02 (d, 3 H, J = 6.4 Hz), 1.0-0.99 (d, 3 H, J = 6.2 Hz); 13C NMR (63 MHz, CDC13) β 178.8, 173.8, 171.9, 168.5, 168.2, 167.8, 155.4, 143.5, 139.3, 137.6, 132.2, 131.4, 129.7, 129.5, 12 9.4, 125.3, 123.3, 113.5, 77.9, 76.2, 72.4, 68.2, 60.8, 57.7, 56.7, 47.5, 44.2, 41.2, 40.5, 39.8, 37.9, 36.5, 26.3, 23.7, 23.4, 22.0, 9.9; IR (KBr) 3417, 3234, 2959, 2873, 2622, 1757, 1724, 1673, 1504, 1473, 1303, 1259, 1221, 1150, 1065 cm-1 o Example 4 7

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Fragment C * Free Acid (0.22 g, 1.02 mmol), DMAP (0.032 g, -146- this paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (144) 0.26 mol) and DCC (0.21 g, 1.02 mmol) at 0 ° C at Stir in 6.5 ml of CH2C12 for 30 minutes. Free alcohol 29 (0.35 g, 0.51 mole) is added dropwise in 6.0 ml of CH2C12. The mixture is stirred at 0 ° C for 10 minutes and at room temperature for 24 hours, and finally at It was heated at reflux for 3 hours and cooled back to room temperature. The reaction mixture was concentrated in the air and filtered through Celite using EtOAc. The resulting residue was purified using column chromatography (silica gel, 60 · 70% EtOAc / hexane) to obtain 0.38 g (85%) of the above ester as a white solid: [戌] 2% + 23 · 2. (C 1.0, CHC13); xH NMR (300 MHz, CDC13) ^ 7.4-7.2 (m, 6 H), 7.12-7.08 (dd, 1 H, J = 8.4, 2.0 Hz), 6.9-6.87 (d, 1 H, J = 8.5 Hz), 6.87-6.75 (m, 1 H), 6.47-6.42 (d, 1 H, J = 15.8 Hz), 6.11 6.03 (dd, 1 H, J = 15.8, 8.8 Hz), 5.82-5.77 (d, 1 H, J = 14.9 Hz), 5.61-5.58 (d, 1 H, J = 7.8 Hz), 5.12 (s, 2 H), 5.12-4.75 (m, 4 H), 3.9 (s, 3 H), 3.49-3.42 (dd, 1 H, J = 13.4, 8.7 Hz), 3.29-3.27 (d, 1 H, J = 6.5 Hz), 3.2-3.1 (m, 3 H), 2.65-2.3 (m, 3 H), 1.8-1.6 (m, 3 H), 1.47 (s, 9 H), 1.45-l, 3 (m, 1 H), 1.3_1.15 (m, 15 H), 0 · 79_0 · 75 (t, 6 H, J = 6.4 Hz); 13C NMR (75 MHz, CDC13) d 177.8, 170.4, 165.1, 153.9, 141.9, 136.7, 135.1, 131.1, 130.8 129.7, 128.3, 128.2, 126.2, 124.6, 122.4, 112.2, 76.9, 71.3, 66 · 0, 56.0, 54. 4, Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the back first) Please fill in this page again) 48.2, 46.4, 43.7, 42.6, 42.2, 39.4, 36.4, 35.2, 28.3, 24.5, 22.8 22 · 6, 21.2, 17.2; IR (CHC13) 3426, 2968, 2935, 2874 , 2841, 1 746, 1713, 1684, 1652, 1504, 1486, 1474, 1368, 1318, 1304, 1259, 1244, 1165, 1151, 1067 cm-1; FAB HRMS [M-BOC + H] (C42H57C1N309) Calculate 値 782.3783, find 値 782.3788. Example 4 8 _ 147- _ This paper size applies to the Chinese National Standard (CNS) A4 (21 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 _ B7 V. Description of the invention (145)

3-chloroperoxybenzoic acid (0.092 g, 0.54 mmol) was added to the starting styrene (0.45 g, 0.51 mmol) in 9.0 ml of CHW12 (in TC solution. The solution was stirred at 0 ° C for 1 It was stirred at room temperature for overnight and overnight. Concentrated in the air, the resulting epoxide was dissolved in 10 ml of CHC13 and cooled to -60 ° c. Freshly distilled TMSC1 (0.25 ml, 1.95 mmol) was added to _60χ: solution The mixture was stirred for 1 hour. TMSC1 (0.5 ml, 3.9 mol) was added, and stirring was continued for 2 hours between -60 ° C and -40 ° C. The solution was warmed to room temperature, and TMSC1 (0.25 ml, 1.95 mmol) Ear) was added again. After stirring at room temperature for 30 minutes, the solution was concentrated, purified by preparative HPLC, and the resulting gas alcohol was separated. This purification obtained 0.1 g (22%) of the desired gas alcohol: [to] 20D + 47.9. (C 〇 · 75 CHC13); ln NMR (300 MHz, CDC13) ^ 7.5-7.2 (m? 6 H) 5 7.13. 7.10 (dd, 1 H, J = 8.4, 1.9 Hz), 6.91-6.88 ( d, 1 H, J = 8.5 Hz) 6.87-6.75 (m, 1 H), 5.85-5.8 (d, 1 H, J = 14.9 Hz), 5.75-5.6 (m, 1 H), 5.22-5.1 (m , 3 H), 5.0-4.9 (m, 2 H), 4.8-4.72 (m, 1 H), 4.7i_ 4.68 (d, 1 H, J = 9.6 Hz) 4.07-4.03 (d, 1 H, J = 9.5 Hz), 3.9 (s 3 H), 3.45-3.38 (dd, 1 H, J = 13.4, 8.5 Hz), 3.31-3.26 (d, 1 h J = 6.4 Hz), 3.25_3.0 (m, 4 H), 2.8-2.65 (bd, 1 H), 2.6-2.35 (m, 2 H), 1.9_1.7 (m, 3 H), 1.47 (s , 10 H), 1.27 (s, 3 H), 1.25 (s, 6 h), 1.22 (s, 3 H), 1.09-1.07 (d, 3 H, J = 7.0 Hz), 0.98-0.96 (m, 6 H); 13C NMR (75 MHz, CDC13) β 177.5, 170.5, 165.2, 153.9, -148-This paper size applies to China National Standard (CNS) A4 (21〇X 297 mm) (Please read the back Please fill in this page for the matters needing attention.) Order 533206 Μ B7 V. Description of the invention (146) 142.5, 137.0, 130.8, 129.8, 128.2, 124.5, 122.4, 112.2 79.1, ψ 76.1, 73.9, 71.1, 65.6, 61.7, 56.1, 54.5 , 48.2, 46.4, 43.7, 42.7, 39.6, 38.4, 36.3, 35.2, 28.3, 24.8, 23.0, 22.9, 22.8, 22.7, 21.5, 8.6; IR (CHC13) 3426, 2967, 2934, 2873, 2841 , 1715, 1684, 1605, 1504, 1485, 1474, 1442, 1368, 1305, 1258, 1151 cm1; FAB HRMS [M-BOC + H] (C42H58Cl2N3O10) calculation: 834.3499, actual measurement: 834.3487. Example 4 9 A 4 M solution of hydrogenated gas in 1,4-dioxolane (0.11 ml, 0.43 mmol) was added to a solution of gas alcohol (0.08 g, 0.086 mmol) in 0.35 ml of CH2C12. The resulting mixture is stirred at room temperature for 3 hours, concentrated in the air, printed in the air; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) and leave it for 3 days to move Remove the residue of 4-dioxolane to obtain the desired hydrochloride (as shown above). Quantitative yield: ["] 2.0 + 28.0. (C 0.5, CH3OH); 4 NMR (300 MHz , CD3OH) d 8.52-8.49 (d, 1 H, J = 7.5 Hz), 7.84-7.81 (d, 2 H, J = 9.6 Hz), 7.49-7.39 (q, 4 H, J = 8.3 Hz), 7.32 -7.31 (d, 1 H, J = 1.9 Hz), 7.22-7.19 (dd, 1 H, J = 8.4, 2.1 Hz), 7.02-7.0 (d, 1 H, J = 8.4 Hz), 6.8-6.7 ( m, 1 H), 6.0-5.9 (dd, 1 H, J = 15.4, 1.0 Hz), 5.22 (s, 2 H), 5.2-5.0 (m, 2 H), 4.85_4.81 (d, 1 H , J = 9.6 Hz), 4.6-4.5 (m, 1 H), 4.06-4.03 (dd, 1 H, J = 9.6, 1.5 Hz), 3.9 (s, 3 H), 3.54-3.46 (dd, 1 H , J = 13.5, 9.7 Hz), 3.25- ____ -149- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2ΐϋ7 public attack) &quot; ~ — 533206 A7 B7 V. Description of the invention (147) 3.11 (m, 2 H), 3.11 (s, 2 H), 2.8-2.7 (m, 2 H), 2.6-2.3 (m, 2 H), ψ 1.9-1.5 (m, 3 H), 1.3 (s, 7 H), 1.25 (s, 3 H), 1.2 (s, 3 H), 1.06 and 1.03 (d, 3 H, J = 6.9 Hz), 1.02-1.01 (d, 3 H, J = 3.2 Hz), 1.0-0.99 (d, 3 H, J = 3.4 Hz); 13C NMR (63 MHz, CD3OH) Xi 178.9, 176.5, 173.8 , 171.8, 168.3, 155.3, 144.2, 141.6, 137 · 4, 132.3, 131.5, 129.8, 129.4, 129.3, 125.2, 123.3, 113.5, 77.2, 74 · 7, 72 · 6, 67 · 8, 63.5, 57.6 , 56.7, 47.7, 47.6, 44.1, 42.3, 41.1, 40.4, 37.9, 36.5, 26.2, 23.7, 23.4, 22.2, 9 · 0; IR (CHC13) 3421, 2964, 2935, 2873, 2841 , 1717, 1676, 1528, 1504, 1477, 1464, 1405, 1282, 1259, 1185, 1152, 1067 cm1; FAB HRMS [M-C1] (CuHmCUNsOk)) is calculated as 834.3499, and measured as 834.3504. Example 5 0 (Please read the precautions on the back before filling this page)

The acetophenone (shown above) (0.67 g) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is made of aldehyde 18 (1.0 g, 1.73 mol) and gasified 3-methylbenzyltriphenyl rust (0.886 (G, 2.2 mmol), prepared according to the above-mentioned procedure of styrene 20, yield 58%: [meter] 20d + 33.1. (C ι · 〇, Ch3〇h); Tun NMR (300 MHz, CDC13) d 7.24-7.0 (m, 7H), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.82-6.7 (m, 1 H), 6.39-6.34 (d, 1 H, J = 15.8 Hz), 6.03-5.95 (dd, 1 H, J = 15.8, 8.7 Hz), 5.78-5.73 (d, 1 H, J = 15.2 Hz) , 5.67-5.64 (d, 1 H, J = 7.8 Hz), 5.1-5.0 (m, 1 H), 4.87-4.83 (dd, 1 H, J = 10.2, 3.5 Hz), 4.8- 4.7 (m, 1 H), 3.9 (s, 3 H), 3.45- -150- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 533206 A7 __ —______ B7 V. Description of the invention (148 ) 3.38 (dd, 1 H, J = 13.4, 8.6 Ηζ), 3 · 2 · 3 · 0 (η, 3 H), 2.6-2.3 (m, 3 ψ H), 2.32 (s, 3 H), 1 75-1 · 25 (π, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), 1.13-l.ll (d, 3 H, J = 6.8 Hz), 0.75-0.72 ( t, 6 H, J = 5.7 Hz); 13C NMR (63 MHz, CDC13) d 177.9, 170.5, 170.3, 165.1, 154.0, 142.1, 138.0 136.6, 135.6, 131.8, 130.8, 129.9, 129.6, 128.4, 128.22, 128.17 , 126.7, 124.5, 123.3, 122.5, 112.3, 71.4, 56.1, 54.3, 46.4, 42.7, 42.2, 39.4, 36.5, 35.3, 24.5, 22.8, 22.6, 22.56, 21.2, 21.1, 17.2; IR (CHC13) 3424, 3021, 3017, 2965, 1747, 1711, 1680, 1652, 1528, 1503, 1485, 1259, 1151, 1067 cm-1 〇 Example 5 1 (Please read the precautions on the back first (Fill in this page again)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

3-chloroperoxybenzoic acid (0.19 g, 1.1 mmol) was added to styrene (as shown above) (0.667 g, 1.0 mmol) in 5.0 ml of ch2C12. The resulting solution was stirred overnight and concentrated in the air to obtain Lu and epoxide, ratio 8: i, which is beneficial to yS. Two epoxides were separated by reverse-phase HPLC (70:30) CH3CN: H20 to obtain 0.20 g of the main epoxide as a white solid: 4 NMR (300 MHz, CDC13) d 7.3_7.0 (m, 7 H ), 6.9-6.87 (d, 1 H, J = 8.4 Hz), 6.87-6.75 (m, 1H), 5.79-5.74 (d, 1H, J = 14.8Hz), 5.54 · 5.51 (d, 1 H, J = 7.8 Hz), 5.28-5.22 (m, 1 H), 4.89-4.85 (dd, 1 H, J = 10.4, 3.5 Hz), 4.82-4.75 (m, 1 H), 3.9 (s, 3 H), 3.69-3.68 (d, 1 H, J = 1.6 Hz), 3.51-3.44 (dd, 1 H, J = 13.4, 8.6 Hz), 3.2-3.1 (m, 2 -151-This paper size applies to Chinese national standards ( CNS) A4 specification (210X 297 public attack) 533206 A7 B7 V. Description of the invention (149) H), 2.98-2.95 (dd, 1 H, J = 7.6, 1.6 Hz), 2.65-2.32 (m, 3 H), ψ 2.32 (s, 3 H), 1.85-1.6 (m, 3 H), 1.4-1.25 (s, 3 H), 1.27 (s, 3 H), 1.21 (s, 3 H), 1.21-1.18 (d , 3 H, J = 7.5 Hz), 0.90-0.86 (t, 6 H, J = 6.13 Hz "Example 5 2

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) in the solution of A epoxy (as shown above) (0.1 g, 0.147 mmol) in 5.0 ml of CHC13 in Add chlorotrimethylsilicon (0.093 ml, 0.74 mmol) at -60 ° C. The solution was stirred at -60 ° C for 30 minutes and at room temperature for 1.5 hours, then concentrated under vacuum. The resulting residue contained a 50:50 mixture of cis and trans chlorohydrin and was purified by reverse phase HPLC to obtain 0.028 g (27%) of the desired trans isomer: 4 NMR (300 MHz, CDC13) d 7.28- 7.2〇, 5 H), 7.13-7.1 (dd, 1 H, J = 8.3, 1.9 Hz), 6.91-6.88 (d, 1 H, J = 8.5 Hz), 6.88-6.78 (m, 1 H), 5.86 -5.81 (d, 1 H, J = 15.0 Hz), 5.73-5.71 (d, 1H, J = 7.8Hz), 5.24-5.17 (t, 1H, J = 9.4Hz), 5.0-4.96 (dd, 1 H , J = 9.6, 2.9 Hz), 4.81-4.74 (m, 1 H), 4.67-4.64 (d, 1H, J = 9.7 Hz), 4.06-4.03 (dd, 1H, J = 9.6, 1.1 Hz), 3.92 (s, 3 H), 3.47-3.39 (dd, 1 H, J = 13.2, 8.3 Hz), 3.42-3.0 (m, 3 H), 2 · 8 · 2 · 4 (m, 2 H), 2.4 ( s, 3 H), 1.9_1.4 (m, 4 H), L28 (s, 3 H), 1.22 (s, 3 H), 1.09-1.07 (d, 3 H, J = 7.0 Hz), 0.98- 0.96 (d, 6 H, J = 6.4 Hz). Example 5 3 -152- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7 V. Description of Invention (150)

Styrene (shown above) (0.095 g) is based on aldehyde 18 (0 g, 0345 mmol and gasified 3,4-monomethylbenzyldiphenyl scale (0.26 g, 0.62 mmol) ) Prepared according to the above procedure of styrene 20, yield 63/0: [called '+27 8. 豕 0.576, CHCls); NMR (300 MHz, CDC13) ^ 7.22-7 18 (d 1 H, J = 1.6 Hz), 7.12_7.02 (m, 5 H), 6.87-6.81 (d, 1 H, J = 8 3 Hz) 6.80-6.71 (m, 1 H), 6.40-6.30 (d, 1 H, J = 15.8 Hz), 6.00-5 88 (dd 1 H, J = 15.8, 8.8 Hz), 5.80-5.70 (d, 1 H, J = 15.1 Hz), 5.55-5 45

(d, 1 H, J = 7.7 Hz), 5.10-4.97 (m, 1 H), 4.90-4.80 (dd, 1 HJ = 9.4, 2.8 Hz), 4.80-4.70 (m, 1 H), 3.88 (s , 3 H), 3.50-3.35 (dd, 1 H, J = 13.3, 4.8 Hz), 3.20-3.00 (m, 3 H), 2.60-2.48 (m, 2 H), 2.45-2.30 (m, 1 H ), 2.23 (s, 3 H), 2.24 (s, 3 H), 1.80-1.55 (m, 2 H), 1.40-1.30 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.14.1.10 (d, 3 H, J = 6.8 Hz), 0.80-0.73 (m, 6 H); 13C NMR (63 MHz, CDC13) d 177.9, 170.5, 170.3, 165.1, 154.0, 142.2 , 136.5, 135.9, 134.3, 131.6, 130.8, 129.7, 125.5, 128.8, 128.1, 127.2, 124.4, 123.6, 122.4, 112.2, 71 · 4, 56 · 0, 54.2, 46.4, 42.6, 42.1, 39.4 , 36 · 4, 35.2, 24.5, 22.7, 22.6, 22.5, 21.1, 19.6, 19.3, 17.2; IR (CHC13) 3424, 2965, 2935, 1746, 1711, 1681, 1652, 1527, 1503, 1485 , 1259, 1187, 1164, 1151, 1067, 970, 727 cm1; min -153- _ This paper size applies to China National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling this page } -Order · 533206 Employees' Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Α7 Β7 five system, description of the invention (151) Analysis (C38H49C1N207) C, H, N. R Example 54

This β-epoxide (0.06 g) was prepared from styrene (as shown above) (0.3 g, 0.44 mol) using 3-chloroperoxybenzoic acid (0.081 g, 0.47 mmol) according to the above procedure. Yield 20%: [a] 2 () D + 20.0. (C 1.43, CHC13); 4 NMR (300 MHz, CDCl3) d 7.26-6.96 (m, 6H), 6.98 (s, 1H), 6.84 · 6.82 (d, 1 H, J = 8.5 Hz), 6.79-6.65 (m, 1 H), 5.73-5.69 (d, 1 H, J = 11.9 Hz), 5.68-5.67 (d, 1 J = 4.6 Hz), 5.29-5.15 (m, 1 H), 4.83-4.76 (dd , 1 H, J = 9.7, 2.8 Hz), 4.75-4.58 (m, 1 H), 3.86 (s, 3 H), 3.61-3.60 (d, 1 H, J = 1.6 Hz), 3.46-3.38 (dd , 1 H, J = 13.4, • t 8 · 8 Hz), 3.14-2.97 (m, 3 H), 2.92-2.89 (dd, 1 H, J = 7.7, 1.6 Hz), 2.59-2.35 (m , 2 H), 2.25 (s, 6 H), 1.78-1.58 (m, 3 H), 1.28-1.09 (m, 1 H), 1.21 (s, 3 H), 1.15 (s, 3 H), 1.15 -1.12 (d, 3 H, J = 7.8 Hz), 0.85-0.77 (m, 6 H); 13C NMR (63 MHz, CDC13) d 177.8, 170.4, 170.3, 164.9, 154.0, 141.7, 137.0, 136 · 9 , 134.0, 130,8, 129.9 129.5, 128.1, 126.7, 124.6, 123.2, 122.4, 122.3, 75.9, 71.Q4, 62.8, 59.1, 56.1, 54.3, 46.4, 42.7, 40.7, 39.2, 36.8, 35.2, 24.4, 22.8, 22.6, 21.0, 19.7, 19.4, 13.6; IR (KBr) 3419, 2962, 1752, 1721, 1681, 1654, 1534, 1504, 1473, 1442, 1302, 1282, -154- Paper size applies to China Standard (CNS) Α4 specifications (210Χ29? Mm) (Please read the back of the precautions to fill out this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 ______________ B7 V. Description of Invention (152) 1259, 1192, 1126, 1066 cm · 1; Analysis (C38H49C1N2〇8) c, H, N. £ H5 5 ci

To a solution of styrene (shown above) (0.492 g, 0.72 mol) in 24 ml of CH2Cl2 was added 3 · peroxybenzoic acid (0137 g, 〇79 亳 mol) at 0 ° C and Toluene (1.2 ml), stirring was continued at 0 ° C for 30 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 hours. After diluting with 10 ml of ch2C12, the solution was washed with 10% Na2S05 (1 x 10 ml), h20 (1 x 10 ml), 100 / i NaHC03 (10 ml), and dried over Na2S04. Concentrate to obtain a mixture of crude b / a epoxides in a ratio of 2: 1. The crude epoxide (0.445 g, 0.638 mmol) was dissolved in 10 mL of anhydrous CHC13, cooled to -60 ° C, and treated with trimethylsilyl gas (0.2 mL, ι · 5 mmol). Stirring was continued for 90 minutes, and the solution was concentrated in the air. The crude chlorohydrin was purified by reverse-phase HPLC (CH3CN / H2O) to obtain the product (as shown above) (0.115 g) in a 21% yield as a white solid: [to] 20D 45 9. (C 〇59, CHCU); 4 NMR (300 MHz, CDC13) d 7β26 · 7 · 01 (η, 5 H), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.80-6.71 (m, 1 H), 5.71-5.66 (d, 1 H, J = 15.1 Hz), 5.50-5.47 (d, 1 H, J = 7.6 Hz), 5.13-5.08 (t, 1 H, J = 8.8 Hz), 4.89 -4.84 (m, 2 H), 4.81-4.71 (m, 1 H), 4.09-4.06 (d, 1 H, J = 9.4 Hz), 3.87 (s, 3 H), 3.44-3.37 (dd, 1 H , J = 13.4, 8 · 4 Hz), 3.16 __ -155- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; 一 '&quot; (Please read the precautions on the back before filling (This page)

533206 A7 B7 V. Description of the invention (153) 3.06 (m, 3 H), 2.60-2.54 (m, 2 H), 2.26 (s, 6 Η), 2.26-2 · 14 (ιη, 1 ψ Η) , 1.89-1.81 (m, 1 Η), 1.70-1.62 (m, 2 Η), 1.58-1.46 (η, 2 Η), 1.23 (s, 3 Η), 1.17 (s, 3 Η) , 0.97-0.95 (d, 3 Η, J = 6.6 Ηζ), 0.93-0.90 (m, 6 H); 13C NMR (63 ΜΗζ, CDC13) d 177.7, 170.5, 170.1, 165.2, 153.9, 142.3, 137.7 , 137.3, 135.1, 130 · 7, 130.2, 129.8, 128 · 5, 128.1, 124.6, 124.4, 122.3, 112.2, 75.9, 74.2, 71.2, 68.8, 56.0, 54.4, 46.4, 42.7, 39.6, 38.4, 36 · 2, 35 · 2, 24.8, 22.9, 22.7, 21.7, 19.8, 19.5, 8.6; IR (KBr) 3421, 2960, 1756, 1721, 1675, 1504, 1258, 1195, 1151, 1126, 1066 cm- 1; Analysis (C38H50Cl2N208) C, H, N. Example 5 6 (Please read the precautions on the back and fill in this page)

, 1T styrene (as shown above) (0.21 g) is based on aldehyde 18 (0.5 g, 0.87 mmol) and 4 · methoxybenzyl triphenyl chloride (0.47 g, 1.12 mmol) ) Prepared according to the above procedure of styrene 20, yield 36%: [called '+31 6. (C L〇3, CHCls);! H NMR (300 MHz? CDC13) ^ 7.26_7.23 (d, 3 H, J = 8.4 Hz), 7.20-7.19 (d, 1 H, J = 1.8 Hz), 7.07-7.03 (dd, 1 H, J = 8.4, 1.9 Hz), 6.84-6.81 (d, 3 H, J = 8.5 Hz), 6.80-6.7 (m, 1 H), 6.36-6.31 (d, 1 H , J = 15.8 Hz), 5.89-5.81 (dd, 1 H, J = 15.8, 8.8 Hz), 5.78_5.73 (d, 1 H, J = 13.7 Hz), 5.68-5.66 (d, 1 H, J = 7.9 Hz), 5.05-4.99 (ddd, 1 H, J = 10.6, 6.6 1.6 Hz), 4.87-4.82 (dd, -156-) This paper size applies the Chinese National Standard (CNS) A4 specification (21 Ox 297 mm ) 1. Printed by the Central Standards Bureau of the Ministry of Economic Affairs ^^ Printed by the Industrial and Consumer Cooperatives, printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (154) 1H, J = 9.7, 3.1 Hz), 4.78-4.7 (m , 1 H), 3.86 (s, 3 H), 3.79 (s, 3 r H), 3.45-3.37 (dd, 1H, J = 13.4, 8.6 Hz), 3.15_3.0 (m, 3H), 2.6- 2.25 (m, 3 H), 1.7-1.3 (m, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), 1.12-ll (d, 3H, J = 6.8Hz), 0.76- 0.75 (d, 3H, J = 2.9Hz), 0.74-〇.73 (d, 3 H, J = 2.8 Hz); 13C NMR (63 MHz, CDC13) β 177.8, 170.5, 170.4, 165.1, 159.1, 153.9 , 142.1, 135.8, 131.0, 130.8, 129.7, 129.5, 128.2, 127.9, 127.2, 124.5, 122.4, 113.9, 112.3 77 · 1, 71.4, 56.0, 55.2, 54.4, 46.4, 42. 7, 42.1, 39.4, 36 · 4 35.3, 24.5, 22.8, 22.6, 21.2, 17.3; IR (CHC13) 3422, 3003, 2964, 2936, 2873, 2840, 1746, 1712, 1681, 1651, 1607, 1527, 1512, 1504, 1485, 1465 , 1301, 1251 cm1; analysis (C37H47C1N208) C, H, N. Example 5 7

To styrene (shown above) (0.3 g, 0.44 mol) was added 19 ml of acetone, 9 ml of gadolinium 20, 9 ml of CH2C12, and solid NaHC03 (1.2 g, 14.5 mmol), and the mixture was cooled. To 0 ° C. A solution of 0xone (1.08 g, 1.8 mmol) in 9 ml of Ηβ was prepared (2 ml) and added to the cold styrene mixture. Vigorously at 0 C: After mixing for 30 minutes, 2 ml of oxon solution was added, and after 30 minutes, 2 ml of oxon was added again, for a total of 6 ml of oxon solution. The progress of the reaction was checked by reverse-phase HPLC and found to be complete after stirring for 2.5 hours. Allow to stand at 0 ° C. The reaction mixture is quenched with saturated NaHC03 aqueous solution (50ml), 50 亳 L of CH2C12 -157- This paper is in accordance with Chinese National Standard (CNS) A4 specification (210x297 meal) (Please read the back first (Notes for filling in this page)

533206 A7 B7 5. Description of the invention (155) Added. The layers were separated, and the organic layer was washed with 10% Na2SO4 aqueous solution (50 ml), then saturated NaHC03 aqueous solution (50 ml), then washed with brine, finally dried over Na2S04, filtered, and concentrated in the air. The mixture of b and a epoxide was separated by reverse-phase HPLC (45: 5 5) CH3CN: H20 to obtain 0.12 g of b epoxide as a white solid, yield 39%: [from] 20D + 25.8. (C 0.66, CHC13); NMR (300 MHz, CDC13) ^ 7.26_7.15 (m, 4 H), 7.05-7.03 (d, 1 H, J = 8.6 Hz), 6.9-6.87 (d, 2 H, J = 8.6 Hz), 6.85-6.82 (d, 1 H, J = 8.5 Hz), 6.82-6.7 (m, 1 H), 5.74-5.69 (d, 1 H, J = 15.1 Hz), 5.54-5.52 ( d, 1 H, J = 7.8 Hz), 5.22-5.16 (m, 1 H), 4.84-4.7 (m, 2 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.63 (s , 1 H), 3.46-3.38 (dd, 1 H, J = 13.5, 8.8 Hz), 3.2-3.0 (m, 3 H), 2 · 91-2 · 89 (d, 1H, J = 7.4 Hz), 2.6-2.38 (m, 2H), 1.8-1.6 (m, 3H), /1.4- I. 23 (m, 1 H), 1.22 (s, 3 H), 1.15 (s, 3 H), 1.15-1.12 (d, 3 H, J = 8.9 Hz), 0.84-0.80 (t, 6 H, J = 6.0 Hz); 13C NMR (63 MHz, CDC13) ^ 177.7, 170.5, 170.4, 165.1, 159.8, 153.9, 141.6, i Printed by 136.8, 130.7, 129.7, 128.6, 128.1, 126.9, 124.6, 122.3, 114.1, 112.2, 75.9, 71.0, 62.8, 58.9, 56.0, 55.2, 54.6, 46.3, 42.7, 40.6 , 39.2, 36.8, 35.2, 24.4, 22.8, 22.7, 22.6, 21.1, 13.5; IR (CHC13) 3423, 3009, 2964, 2936, 2874, 2840, 1751, 1713, 1 681, 1653, 1614, 1517, 1504, 1486, 1464, 1442, 1303, 1281, 1257, 1183, 1173, 1152 cm1; Analysis (C37H47C1N208) C, H, N. Example 5 8

TBDMS

(Read the precautions on the back before reading this page, and then fill in this page) ° γ〇〇ΗΝγγγα Producer 〇 ^ A〇Me -158 This paper size is applicable to China National Standard (CNS) A4 (21〇 × 297mm) 533206 A7 B7 V. Description of the invention (156) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs-Industrial and Consumer Cooperatives (please read the precautions on the back before filling this page) Styrene (as shown above) (0.649 g) Bayeraldehyde 18 (0.911 g, 1.57 Mmol) and 4- (third butyldimethylsilyloxy) benzyltriphenylphosphonium chloride (L7 g, 3.27 mmol) were prepared according to the procedure of styrene 20 above, yield 53%: [^] 20d + 3〇.83〇 (c 0.52, CHC13); ^ NMR (300 MHz, CDC13) 7.25 (s, 1H), 7.26-7.20 (d, 2H, J = 8.5Hz), 7.12 -7.06 (dd, 1H, J = 8.3, 1.6 Hz), 6.92-6.86 (d, 1H, J = 8.5 Hz), 6.84-6.78 (d, 2H, J = 8.5 Hz), 6.44-6.33 (d, 1H , J = 15.9 Hz), 5.95-5.85 (dd, 1H, J = 15.8, 8.8 Hz), 5.85-5.77 (d, 1H, J = 15.5 Hz), 5.68-5.55 (bd, 1H, J = 7.9 Hz), 5.15-5.00 (m, 1H), 4.95-4.80 (dd, 1H, J = 10.0, 3.0 Hz), 4.85-4.75 (m, 1H), 3.91 (s, 3H), 3.53-3.43 (dd 1H, J = 13.4, 8.6Hz), 3.23-3.08 (m, 3H), 2.65-2.50 (m, 2H), 2.50-2.35 (m, 3H), 1.75-1.60 (m, 2H), 1.45-1.36 ( m, 1H), 1.27 (s, 3H), 1.20 (s, 3H), 1.16-1.13 (d, 3H, J = 6.8Hz), 1.01 (s, 9H), 0.85-0.74 (m, 6H), 0.22 (s, 6H); 13C NMR (63 MHz, CDC13) β 177.8, 170.5, 170.4, 165.1, 155.2, 153.9, 142.1, 131.1, 130.8, 130.1, 129.7, 128.2, 128.1, 127.1, 124.5, 122.4, 120.2 112.2, 71.4, 56.0, 54.4, 46.4, 42.7, 42.2, 39.4, 36.5, 35.3, 25.6, 24.5, 22.8, 22.7, 21.2, 18.1, 17.3, -4.5; IR (CHC13) 3422, 3030, 3008, 2961, 2932 , 2899, 2860, 1745, 1712, 1681, 1604, 1527, 1509, 1485, 1442, 1370, 1339, 1303, 1258, 1169, 1151, 1067, 1007, 970, 912, 841, 822, 792 cm1; Analysis (C42H59ClN208Si) C, H, N. Example 5 9

-159- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (157) Silyl protected phenol (0.084 g) , 0.107 mmol) was added to a solution of -70 ° C in 4 ml of anhydrous THF. A 1.0 M solution of THF (0.11 ml, 0.11 mmol) of tetrabutylammonium fluoride (TBAF) was added. The light yellow solution was stirred at _70 ° C for 30 minutes, then quenched with 2 ml of saturated NH4C1, and extracted with CH2C12 (3 X 25 ml). The combined organic extracts were dried over MgS04, filtered, and concentrated in the air. The crude product was purified by radial PLC (silica gel, 50-100% EtOAc / hexane) to obtain the desired alcohol (0.067 g), yield 93%, white solid: [from] 2Od + 30.83 0 (c 0.52, CHC13) ; 4 NMR (300 MHz, CDC13) d 7.40-7.32 (m, 1H), 7.28_7.20 (m, 3H), 7.13, 7.05 (dd, 1H, J = 8.3, 1.6 Hz), 6.95-6.75 (m , 5H), 6.57 (s, 1H), 6.42-6.33 (d, 1H, J = 15.9 Hz), 5.93-5.83 (dd5 1H, J = 15.8, 8.8 Hz), 5.83-5.78 (d, 1H, J = 15.5 Hz), 5.75-5.73 (bd, lH, J = 7.9Hz), 5.15-5.00 (m, lH), 4.93 · 4.55 (dd, 1H, J = 10.0, 3.0 Hz), 4.85-4.75 (m , 1H), 3.90 (s, 3 H), 3.54-3.40 (dd, 1H, J = 13.4, 8.6Hz), 3.25-3.02 (m, 3H), 2.65-2.35 (m, 3H), 1.80_1.60 (m, 2H), 1.45-1.36 (m, 1H), 1.27 (s, 3H), 1.20 (s, 3 H), 1.17-1.12 (d, 3H, J = 6.8 Hz), 0.86-0.74 (d, 6H, J = 5.0 Hz); 13C NMR (63 MHz, CDC13) d 177.9, 170.7, 170.6, 156.0, 154.0, 142.6, 137.1, 131.3, 130.8, 129.5, 128.9, 128.1, 127.4, 124.3, 122.5, 115.6, 112.3 , 77.2, 71.5, 56.1, 54.5, 46.5, 42.7, 42.1, 39.4, 36.5, 35.3, 24 · 6, 22 · 8, 22.7, 21.2, 17.3; IR (CHC 13) 3597, 3421, 3319, 2964, 2935, 2874, 2841, 1746, 1711, 1680, 1652, 1610, 1513, 1504, 1485, 1464, 1259, 1170, 1152, 1067 cm · 1; Analysis (C36H46C1N208) C , Η, N. Example 6 0 ___ _ -160-_ This paper size is applicable to Chinese National Standard (CNS) A4 (2! Ϋ 297 mm) (Please read the precautions on the back before filling this page), 1T · Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 533206 A7 — — _____B7 V. Description of Invention (158)

Fragment C, a solution of acid (0.040 g, 0.184 mmol) and carbonyldiimidazole (CDI) (0.040 g, 0.25¾ mole) in 2 ml of toluene heated at 45 t under nitrogen for 45 hours minute. After the addition of an alcohol (as above) (0.10 g, 0.15 mmol) to 1 ml of methyl form, the reaction mixture was heated at 45 C for 4 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), 0 N N jjdG X 10 liters), water (1 X 10 mL), saturated NaHC03 (1 x 10 mL), and brine (1 X 10 mL). wash. The organic layer was dried over MgS04, filtered, and concentrated in the air to obtain a crude ester as a yellow foam. Purified by radial PLC (silica gel, 50% EtOAc / hexane) to obtain pure ester (0.097 g), yield 75%, as a yellow solid: [from] 20d + 17.2 (c 0.58, CHC13); 4 NMR ( 300 MHz, CDC13) ^ 7.40-7.34 (d, 2 H, J = 8.5 Hz), 7.29-7.22 (m? 3 H)? 7.13-7.00 (m, 3 H), 6.92-6.86 (d, 1 H, J = 8.8 Hz), 6.86-6.76 (m, 1 H), 6.50-6.38 (d, 1 H, J = 15.9 Hz), 6.10-5.97 (dd, 1 H, J = 15.8, 8 · 8 Hz), 5.85-5.75 (d, 1 H, J = 15.1 Hz), 5.55-5.45 (d, 1 H, J = 7.9 Hz), 5.15-5. 06, 1 H), 5.06-4.96 (m, 1 H) , 4.95-4.85 (m, 1 H), 4.83-4.72 (dd, 1 H, J = 10.0, 3.0 Hz), 3.92 (s, 3 H), 3.53-3.35 (m, 3 H), 3.22- 3.06 (m, 3 H), 2.65-2.50 (m, 2 H), 2.48 · 2 · 35 (ιη, 1 H), 1.80-1.65 (m, 2 H), 1.49 (s, 9 H), 1.40 (s, 6 H), 1.27 (s, 3 H), 1.21 (s, 3 H), 1.20-1.15 (d, 3 H, J = 6.9 Hz), 0.86-0.77 (d, 6 H, J = 6.3 Hz); 13C NMR (63 MHz, CDC13) β 177.8, 170.5, 170.4, _____ -161 This paper size applies to China National Standard (CNS) A4 specification (2IOX297 mm) (Please read the precautions on the back before filling in this page)

533206 A7 ____B7 V. Description of the invention (159) 165.1, 156.0, 153.9 150.0, 142.0, 134.5, 130.8, 130.6, 130.4, 129.6, r 128.2, 126.9, 124.6, 122.4, 121.5, 112.2, 79.2, 71.3, 56.0, 54.4, 48.2, 46.4, 44.0, 42.7, 42.1, 39.5, 36.5, 35.2, 28.3, 24.9, 24.5, 22.9, 22.8 22 · 7, 21.3, 17.2; IR (CHC13) 3425, 2970, 2934, 2874 , 1746, 1711, 1684, 1604, 1505, 1442, 1394, 1368, 1305, 1258, 1166, 1123, 1067, 1015, 971 cm · 1; Analysis (C41H55ClN3〇9) C, H, N 〇 Example 6 1 ( (Please read the notes on the back before filling out this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Add 12 ml of acetone 'to 6 ml of H20, 6 ml of CH2C12, and solid NaHCO3 (0.84 g, 10 mmol) and the mixture was cooled to 0 ° C. A solution of 0xone (078 g, 1.27 mmol) in 6 * liters Ηζ0 (2 ml) was added to the cold styrene mixture. Vigorously at 0 C; after 30 minutes of mixing, the 2 'liter of oxon solution was added, and after 30 minutes, 2 ml was added again, for a total of 6 liters of oxon solution. The reaction progressed by reverse phase HPLC and found to be complete after 2.5 hours of incubation. At 0x; standing, the reaction mixture was quenched with saturated aqueous NaHCCb solution (50 mL), and 50 mL of CH2C12 was added. The layers were separated and the organic layer was washed with 10% aqueous Na2SO3 solution (50 ml), then with saturated aqueous NkHCO3 solution (50 ml), then washed with brine, dried over NadO4, filtered, and concentrated in the air to obtain 0.272 g. Crude epoxy with yellow foam. __ _ -162- This paper size applies to the Chinese National Standard (CNS) A4 specification (2 × 0297 mm) 533206 The Central Standards Bureau of the Ministry of Economic Affairs (printed by the Industrial and Consumer Cooperatives A7 B7 V. Description of the invention (160) in epoxy The solution in 4 ml of CHsCl2 is intrinsically 60 ×: trimethylsilyl chloride (0.2 ml, 1.54 mol) is added. After 3 hours at 6 ° C, 5 ml of 0.1 N HC1 was added to hydrolyze any trimethylsilyl ether, and the mixture was warmed to room temperature. Each layer was separated from the organic layer and dried with MgS04, passed through an oven, Concentrated in the air. The crude chlorohydrin was purified twice with radial PLC (silica gel, 50_60_70_100% EtOAc / hexane), and finally reverse-phase HPLC (CH3CN / H20) to obtain the product (as above) (0.090 g, 31%) , As a white solid: [to] 2〇d + 42 7. (c 3 〇, CHC13);! H NMR (300 MHz? CDC13); 7.48-7.44 (d? 1 H, J = 8.4 Hz), 7.31-7.26 (m, 4 H), 7.16-7 "0 (m, 3 H), 6.92-6e89 (d, 1H, J = 8.4 Hz), 6.87 · 6 · 81〇, 1 H), 5.84-5.79 ( d, 1 H, J = 15.1 Hz), 5.58-5.55 (d, 1 H, J = 7.8 Hz), 5.24-5.19 (t, 1 H, J = 8.9 Hz), 5.05-4.95 (m, 2 H) , 4.79-4.75 (m, 1H), 4.72-4.69 (d, 1 H, J = 9.5 Hz), 4.04-4.01 (dd, 1H, J = 1.3, 9.3Hz), 3.93 (s, 3H), 3.47- 3.40 (m, 3 H), 3.25-3.06 (m, 3 H), 2.75-2.70 (d, 1 H, J = 13.9 Hz), 2.55-2.41 (m, 2 H), 1.90-1 · 71 (η, 2 H), 1.63 (s, 1 H), 1.48 (s, 9 H), 1.39 (s, 6 H), 1.28 (s, 3 H), 1.22 (s, 3 H), 1.09-1.06 (d , 3 H, J = 6.9 Hz), 1.0-0.96 (m, 6 H); 13C NMR (63 MHz, CDC13) d 177.6, 170.4, 170.2, 165.2, 153.9, 142.3, 136.1, 130.8, 129.7 , 129.1, 128.2, 124.5, 122.4, 121.9, 112.2, 76.1, 74.0, 71.1, 61.5, 56.5, 54.4, 46.4, 44.1, 42.7, 39.6, 38.4, 36.3, 35.2, 28.3, 24.8, 22.9, 22.8, 22.7 , 21.5, 8.6; IR (CHC13) 3417, 2974, 2934, 1755, 1720, 1677, 1505, 1473, 1368, 1320, 1258, 1205, 1167, 1153, 1123, 1066 cm1; FAB HRMS [M-BOC] ( C41H56C12N301 ()). The calculated value is 値 820.3343, and the measured value is 0.3820.3354. -163- This paper size applies to China National Standard (CNS) A4 (2 丨 0X 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 ------- B7 V. Description of the invention (161) Example 6 2 ψ

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The amine protected by BOC (as above) (〇〇〇〇, 0,067mmol) on CH2C12 (0 · 25 Ml) was added to a 4 M HC1 solution (0.1 ml, 0.4 mmol) in ι, 4-dioxolane. After stirring at room temperature for 2 hours, the solvent was removed under a vacuum and the resulting residue was maintained under high vacuum for 2 days. The product was obtained as a white solid (0.062 g) with a yield of 95%: [called 20D + 27.68. (C2.5, CHC13); hNMR (300 MHz, CDC13) d 7.79-7.76 (d, 1 H, J = 7.9 Ηζ), 7.48-7 · 38 (m, 2 H), 7.27.7.26 (d , 1 H, J = 1.2 Hz), 7.17-7.08 (m, 3 H), 6.98-6.95 (d, 1 H, J = 8.5 Hz), 6.71-6.60 (m, 1 H), 5.95-5.90 (d , 1 H, J = 15.2 Hz), 5.14-5.01 (m, 2 H), 4.50-4.46 (dd, 1 H, J = 3.0, 11.0 Hz), 3.99-3.96 (d, 1 H, J = 9.1 Hz), 3.82 (s, 3 H), 3.49-3.42 (m, 1 H), 3.19 (s, 2 H), 3.2-3.06 (m, 2 H), 2.77_2.68 (m, 2 H) , 2.49-2.46 (t, 1 H, J = 6.8 Hz), 2.44-2.31 (q, 1 H, J = 11.4 Hz), 1.85-1.65 (m, 2 H), 1.60_1.50 (m, 1 H ), 1.46 (s, 6 H), 1.20 (s, 3 H), 1.16 (s, 3 H), 1.08-0.94 (m, 9 H); 13C NMR (63 MHz, CDC13) β 178.9, 175.6, 173.8 , 171.9, 155.3, 151.8, 144.2, 139.5, 132.2, 131.5, 130.7, 129.4, 125.2, 123.3, 122.6, 113 · 5, 77 · 2, 74 · 8 72.6, 63.2, 57.6, 56.7, 50.1, 48.3, 48.0, 47.4, 44.1, 42.7, 41.1, 40.4, 37.8, 36 · 5, 28.8, 26.2, 23 · 6, 23 · 4, 22.2, 9.0; IR (KBr) 3418, 2961, 2934, 1751, 1724, 1671, 1608, 1505, 1474, 1464, -164- this paper Applicable to China National Standard (CNS) A4 specifications (210X297 ^ 5 ^ 533206 Printed by A7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. V. Description of the invention (162) 1442, 1303, 1282, 1259, 12 ^ 3, 1169, 1152, 1126, 1065, 1018; FAB HRMS [M-C1] (C4iH56Cl2N301 ()). Calculated 値 82〇.3343, measured 値 820.3354. Example 6 3

A 1.0 M drop of tetrabutyl fluoride (TBAF) (4.0 ml, 4.1 mmol) in THF was added dropwise to the protected alcohol 20 (3.1 g, 3.69 mmol) in 120 ml of THF. -78 ° C solution. The solution was stirred at -78 ° C for 10 minutes, removed from the dry ice bath, and warmed to room temperature. After 30 minutes at room temperature, the reaction was quenched with water (80 ml) and acetic acid (100 ml). The layers were separated and the aqueous layer was extracted with Cjj2ci2 (3 X 50 liters). The combined organic layers were dried over anhydrous Na2S04, filtered, and washed in water; Chen shrink 'to obtain free alcohol. Purified by column chromatography (silica gel, 50-70-100% EtOAc / hexane) to obtain 2 51 g (99/0) of pure alcohol 29 as a white solid:

[a] d + 30.0 (c 1.0? CHC13); lR NMR (300 MHz, CDC13) S 7.31 (s, 4 H), 7.26-7.21 (m, 1 H), 7.2-7.19 (d, 1 H, J = 1.8 Hz), 7.07, 7.03 (dd, 1 H, J = 8.4, 1.7 Hz), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.82-6.7 (m, 1 H), 6.43-6.37 (d, 1 H, J = 15.9 Hz), 6.05-5.97 (dd, 1 H, J = 15.9, 8.7 Hz), 5.77-5.72 (d, 1 H, J = 15.0 Hz), 5.58-5.55 (d, lH, J = 7.9Hz), 5.08-5.02 (dd, lH, J = 9.4, 6.3Hz), 4.87-4.8.3 (dd, 1 H, J = l0.2, 3.1 Hz), 4.8-4.67 ( m, 1 H), 4.67 (s, 2 H), 3.87 (s 3 H), 3.44-3.37 (dd, 1 H, J = 13.5, 8.5 Hz), 3.2.3 · 0 (ιη, _____ -165- (cns) (210x297 ^ * 7 (Read the precautions on the back before filling this page) Order! · 533206 A7 _ B7 V. Description of the invention (163) 3H), 2 · 6-2 · 3 (ιη, 3 H ), 1.8-1.6 (m, 3 H), 1.4-1.25 (m, 1 H), ψ 1.22 (s, 3H), 1.15 (s, 3H), 1.14-1.12 (d, 3H, J = 6.8Hz) , 0.76-〇.73 (t, 6 Η, J = 5.5 Hz); 13C NMR (63 MHz, CDC13) δ 177.7, 170.7, 170.5, 165.4, 153.8, 142.0, 140.5, 135.9, 131.3, 130.7, 130.0, 129.9 , 128.1, 127.1, 126.1, 124.5, 122.2, 112.2, 77 0, 71.3, 64.6, 56.0, 54.6, 46.4, 42.7, 42.1, 39.4, 36.4, 35.2, 24.5, 22.8, 22.6, 21.2, 17.2; IR (CHC13) 3423, 3011, 2965, 2935, 2874, 2841, 1747, 1712, 1681, 1652, 1528, 1503, 1485 1442, 1371 1303, 1259, 1151 cm1; analysis (C37H47C1N208) C, H, N. (Example 6 4 C Please read the notes on the back and fill in this page)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Triphenylphosphine (0.065 g, 0.25 mmol) was added to a solution of alcohol 29 (0.13 g, 0.19 mmol) in 2.0 ml of THF, and phthalimidine (0.037 g, 0.25 mmol) and finally diethyl azodicarboxylate (DEAD) (0.04 ml, 0.25 mmol). The resulting yellow solution was stirred at room temperature for 2 hours and quenched with H2O (10 ml) and CH2C12 (10 ml). The aqueous layer was extracted with CH2C12 (2 × 10 ml), and the combined organic layers were dried over MgS04, filtered, and concentrated in the air. The resulting residue was purified by radial PLC (silica gel, 50-60-70% EtOAc / hexane) to obtain phthalimidine 30 (0.14 g) as a white solid, yield 90%: [from] 2GD + 19.2 ° (c 1.0, CHC13); 4 NMR (300 MHz, CDC13) d 7 · 9-7 · 8 (ιη, 2 H), 7.72-7.69 (m, 2 H), 7.39-7 · 36 (d, 2 H, J = 8.0 Hz), 7.28-7.26 (d, -166 · This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) & 533206 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs t A7 B7 V. Description of the invention (164) 2 H, J = 5.3 Ηζ), 7.25 · 7 · 2〇, 1 H), 7.19-7.18 (d, 1 H, J = 1.9 Hz), ψ 7.06- 7.03 (dd, 1 H, J = 8.5, 1.9 Hz), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.81-6.7 (m, 1 H), 6.39-6.33 (d, 1 H, J = 15.9 Hz), 6.01-5.93 (dd, 1 H, J = 15.8, 8.8 Hz), 5.75-5.7 (d, 1 H, J = 15.4 Hz), 5.47-5.44 (d, 1 H, J = 7.9 Hz ), 5.05-5.0 (dd, 1 H, J = 9.4, 6.3 Hz), 4.8 (s, 2 H), 4.83-4.7 (m, 2 H), 3.87 (s, 3 H), 3.4_3.36 ( dd, 1 H, J = 13.4, 8.6 Hz), 3.18-3.02 (m, 3 H), 2.6-2.25 (m, 3 H), 1.65-1.5 (m, 2 H), 1.35 · 1 · 22 (γπ, 1 H), 1.21 (s, 3 H), 1.14 (s, 3 H), 1.12-1.09 (d 3 H, J = 6.8 Hz), 0.71-0.69 (d, 3 H, J = 6.4 Hz), 0.65-0.63 (d , 3 H, J = 6.4 Hz); l3C NMR (63 MHz, CDC13) d 177.8, 170.5, 170.4, 167.8, 165.2, 153.9, 142.0, 136.3, 135.6, 133.9, 131.9, 131.1, 130.7, 130.6 , 129.8, 128.9, 128.6, 128.5, 128.1, 126.3, 124.6, 123.2, 122.3, 112.2, 76.9, 71.3, 56.0, 54.5, 46.4, 42.6, 42.1, 41.2, 39.4, 36.4, 35.2, 24.4, 22.8, 22.6, 22.5, 21.1, 17.2, IR (CHC13) 3421, 2967, 2935, 2873, 2840, 1747, 1716, 1682, • i 1527, 1503, 1485, 1433, 1395, 1259, 1151. Example 6 5

To 8 ml of EtOH was added n-butylamine (0.04 ml, 0.369 mmol) to phthalimide 30 (0.1 g, 0.123 mole). The solution was at 75. 〇Heating for 2 days, concentrating in the air, using radial PLC (silicone, 10-25 // MeOH / CH2Cl2) pure ____167-This paper size is applicable to China National Standard (CNS) A4 specifications ((Please read the back (Please fill in this note before buying)

533206 A7 __ B7 V. Description of the invention (165) The free amine 31 (0.048 g) was obtained with a yield of 57%. ψ Example 6 6

To N · (third butoxycarbonyl) carnitine (0.07 g, 037 mmol) in 15 ml of DMF was added 1-hydroxybenzotriazole hydrate (HOBT) (〇〇5 G, 037 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (0.071 g, 0.37 mmol). After stirring at room temperature for 45 minutes, amine 31 (0.17 g &apos; 0.25¾ mole) was added dropwise to the solution in 2.5 ml of DMF via a double pointed needle. The resulting mixture was stirred; stirred for 3 hours, quenched with h20 (10 ml) and extracted with CHWhp x 10 ml). The combined organic extracts were dried over MgS04, dried, filtered, and concentrated in the air. The resulting crude product was purified with radial PLc (silica gel, 70-80-100% EtOAc / hexane) to obtain the desired sulfamine 32 (0.15 g), yield 71%, as a white solid: [" 〇d + 22 4. (ci 〇, CHC13); lR NMR (300 MHz, CDC13) ά 7.27-7. L (m? 6 H)? (Please read the notes on the back before filling this page

, 1T Printed by the Consumer Cooperatives of the Central Standard Bureau of the Ministry of Economic Affairs 7.04-7.0 (dd, 1 H, J = 8.5, 1.9 Hz), 6.82-6.79 (d, 1 H, J = 8 „5 Hz), 6.79-6.65 ( m, 1 H), 6.38-6.32 (d, 1 H, J = 15.9 Hz), 6.3-6.2 (bs, 1 H), 6.01-5.92 (dd, 1 H, J = 15.9, 8.7 Hz), 5.75- 5.70 (d, 1 H, J = 15.0 Hz), 5.65-5.6 (m, 1 H) 5.0-4.99 (dd, 1 H, J = 9.3, 6.1 Hz), 4.84-4.79 (dd, 1H, J = 9.6 , 3.6Hz), 4.74-4.67 (m, 1H), 4.42-4.4 (d, 2 H, J = 5.7 Hz), 3.87 (s, 2 H), 3.84 (s, 3 H), 3.42-3.34 (dd , 1 H, J = 13.5, 8.6 Hz), 3.15-3.0 (m, 3 H), 2.9 (s, 3 H), 2.6- -168- This paper size applies to China National Standard (CNS) A4 specifications ( 210X29T mm) 533206 A7 _________B7 V. Description of the invention (166) 2.25 (m, 3 H), 1.8_1.5 (m, 2 H), 1.4 (s, 9 Η), 1.39 · 1 · 25 (ηι , 1 H), ψ 1.19 (s, 3 Η), 1.12 (s, 3 Η), 11-1.08 (d, 3 Η, J = 6.8 Ηζ), 0.73-0.72 (d, 3 Η) , J = 4.4 Ηζ), 0.71-0.69 (d, 3 Η, J = 4.3 Hz); 13C NMR (63 MHz, CDC13) d 177.7, 170.5, 170.4, 169.2, 165.2, 153.9, 141.9, 137.3, 136.0 , 131.1, 130.7, 130.3, 129 .8, 128.6, 128.1, 127.7, 126.3, 124.6, 122.3, 112.2, 80.6, 76.9, 71.3, 56.0, 54.5, 53.1, 46.4, 42.8, 42.7, 42.0, 39.4, 36.4, 35.8, 35.2, 28.2, 24.5, 22.8 , 22.6, 21.2, 17.1; IR (CHC13) 3427, 2967, 2935, 2874, 2841, 1747, 1680, 1526, 1504, 1484, 1464, 1442, 1393, 1369, 1302, 1281, 1259, 1151, 1067 (Please read the notes on the back before filling this page)

Example 6 7

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs • t-Amine 32 (0.34 g, 0.398 mmol) was epoxidized in 1.2 ml of CHWh using inCPBA (0.072 g, 0.42 mmol) in accordance with the above procedure to obtain b &amp; a Epoxide, ratio 2: 1. The resulting crude mixture of epoxides (0.3 g, 0.345 mmol) was dissolved in CHC13, cooled to -60 ° C ° and TMSC1 (0.22 ml, 1.73 mmol) was added, and the solution was at -50 ° Stir for 2 hours between C and -20 ° C. D] ^ (: 1 (0.44 ml, 0.173 mol)) was added again, and the solution was heated to room temperature. The solution was concentrated in the air, and the resulting product was subjected to column chromatography (70-80% EtOAc / hexane) twice. And radial PLC (silicone, 2_50 / 〇Me〇H / CH2Cl2) secondary purification, to obtain the reaction gas alcohol 34 (0.1 g), yield 48%, a white solid: -169- This paper size applies to Chinese national standards (CNS) A4 specifications (210X 297 mm) 533206 A7 B7 V. Description of the invention (167) [Called 20d + 46.9〇 (c 0.85, CHC13); 4 NMR (300 MHz, CDC13) dr Staff of Central Bureau of Standards, Ministry of Economic Affairs Cooperative printed 7.36-7.34 (d, 2 H, J = 7.9 Hz), 7.29-7.26 (d, 2 H, J = 8.3 Hz), 7.21 (s, 2 H), 7.08-7.05 (d, 1 H, J = 8.3 Hz), 6.86-6.83 (d, 1 H, J = 8.5 Hz), 6.8-6.7 (m, 1 H), 6.5-6.2 (bs, 1 H), 5.79-5.74 (d, 1 H, J = 15, 2 Hz), 5.64-5.62 (d, 1H, J = 7.7 Hz), 5.18-5.12 (t, 1 H, J = 9.1 Hz), 4.94-4.9 (dd, 1 H, J = 9.9, 3.5 Hz), 4.8-4.67 (m, 1 H), 4.66-4.63 (d, 1 H, J = 9.6 Hz), 4.47-4.45 (d, 2 H, J = 5.3 Hz), 4.02-3.98 (d, lH, J = 9.5Hz), 3.89 (s, 2H), 3.88 (s, 3H), 3.41 -3.34 (dd, 1 H, J = 13.6, 8.5 Hz), 3.2-3.0 (m, 3 H), 2.94 (s, 3 H), 2.69-2.68 (bdd, 1H, J = 14.3, 2.1Hz ), 2.51-2.3 (m, 2H), 1.8-1.6 (m, 3H), 1.42 (s, 10H), 1.22 (s, 3H), 1.17 (s, 3H), 1.03-1.01 (d, 3 H, J = 6.9 Hz), 0.94-0.9 (t, 6 H, J = 5.5 Hz); 13C NMR (63 MHz, CDC13) 177.6, 170.4, 170.2, 165.2, 153.9, 142.4, 139.1, 130.8, 129.7, 128.3, 128.2 , 127.9, 124.4, 122.4, 112.2, 80.7, 76.1, 73.9, 71.2, 61.8, 56.1, 54.4, 53.1 46.4, 42.7, 39.6, 38.4, 36.3, 35.9, 35.2, 28.2, 24.8, 23.0, 22.9, 22.7, 21.5, 8.5; IR (KBr) 3419, 3317, 2964, 2932, 1755, 1670, 1538, 1504, 1473, 1392, 1368, 1301, 1258, 1151, 1066; FAB HRMS [M + H] (CcHaChN ^ On). The calculated value is 905.3870, and the measured value is 905.3876. Example 6 8

(Please read the notes on the back before filling in this page) ΪΪ HNv ^ YYc, -170 · This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 533206 A7 ____ B7 V. Description of the invention (168) BOC-protected amine 34 (0.045 g, '05 μmol) hydrochloride 35 (〇41 g) was prepared according to the above procedure using 4 M HC1 in 1,4-dioxolane, quantitative yield. : 4 NMR (300 MHz, MeOH) d 8.47-8.45 (d, 1 H, J = 7.7 Hz), 7.79-7.76 (d, 1 H, J = 8.9 Hz), 7.39-7.36 (d, 2 H, J = 8.1 Hz), 7,3-7.27 (d, 3H, J = 9.0Hz), 7.17-7, 14 (d, 1H, J = 8.5Hz), 6.98-6.95 (d, 1 H, J = 8.5 Hz ), 6.75-6.6 (m, 1 H), 5.94-5.89 (d, 1 H, J = 15.1Hz), 5.2-5.0 (m, 2H), 4.78-4.75 (d, 1H, J = 9.4Hz), 4.5-4.42 (m, 1 H), 4.41 (s, 2 H), 4.01-3.98 (d, 1 H, J = 9.5 Hz), 3.82 (s, 3 H), 3.8 (s, 2 H), 3 5-3 · 4 (ιη, 1 H), 3 „19-3, 13 (dd, 1 H, J = 14.4, 3.4 Hz), 3.11-3.06 (dd, 1 H, J = 13.2, 1.9 Hz) , 2.8-2.6 (m, 2 H), 2.7 (s, 3 H), 2.5-2.2 (m, 2 H), 1.85-1.45 (m, 3 H), 1.3-1.2 (m, 1 H), 1.2 (s, 3 H), 1.15 (s, 3 H) 1.0-〇.94 (q, 9 H, J = 11.3, 6.0 Hz); 13C NMR (63 MHz, CDC13) Θ 178.9, 173.7, 171.9, 168.3, 166.3, 155.4 144.2, 140.5, 139.7, 132.2, 131.5, 129.7 , 129.4, 128.8, 125.2, 123.3, 113.5, 77.2, 74.5, 72.6, 63.7, 57.6, # 56.6, 50.7, 47.4, 44.1, 43.9, 41.1, 40.4, 37.8, 36.5, 33.7, 26.2, employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives (Please read the notes on the back before filling out this page) 23.6, 23.4, 22.1, 9.0; IR (KBr) 3410, 3058, 2961, 2933, 1752, 1721, 1675, 1539, 1504, 1463, 1440 , 1282, 1259, 1196, 1154, 1127, 1066 Examples 6 9

-171-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (169) Sodium hydride (60% suspension) ( 0.041 g, 1.0 mmol) and 4-methoxycarbonylbenzyltriphenylphosphonium bromide (0.5 g, 1.0 mmol) in 10 ml of THF was heated at 65 ° C for 1 hour , Cool back to room temperature. The orange mixture was added dropwise to aldehyde 18 (0.46 g, 0.79 mmol) in 1 mL (10 mL) at -78. (:. The resulting solution was warmed to room temperature, allowed to fall for 2 hours, and quenched with saturated NH4C1 (30 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were treated with It was washed with brine (30 ml), dried over MgS04, filtered, and concentrated in the air. Crude styrene was purified by column chromatography (silica gel, 50-65% EtOAc / hexane) to obtain transparent styrene (0.129 g). Rate 23%: [^] 20d + 29.7 ° (c 1.15, CHC13); 1U NMR (300 MHz, CDC13) d 8_03_8.0 (d, 2 H, J = 8.2 Hz), 7.44-7.41 (d, 2 H , J = 8.3 Hz), 7.3-7.25 (m? 1 H), 7.24-7.23 (d, 1 H, J = 1.6 Hz), 7.11-7.08 (dd, 1 H, J = 8.3, 1.9 Hz), 6.89 -6.86 (d, 1 H, J = 8.5 Hz), 6.86-6.8 (m, 1 H), 6.52-6.46 (d, 1 H, J = 15.9 Hz), 6.23-6.15 (dd, 1 H, J = 15.8, 8.8 Hz), 5.83-5.8 (d, 1 H, J = 15.3 Hz), 5.64-5.61 (d, 1H, J = 7.9Hz), 5.14-5.09 (dd, 1H, J = 9.4, 6.5Hz) , 4.91-4.87 (dd, 1 H, J = 10.2, 3.6 Hz), 4.85-4.75 (m, 1 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.5-3.4 (dd, 1 H, J = 13.5, 8.7 Hz), 3.2-3.1 (m, 3 H), 2.9-2.3 (m, 3 H), 1.8-1.6 (m, 3 H), 1.4-1.3 (m, 1 H), 1.26 (s, 3 H), 1.2 (s, 3 H), 1.2-1.18 (d, 3 H, J = 6.9 Hz), 0.8- 0.78 (d, 3 H, J = 5.6 Hz), 0.78-0.76 (d, 3 H, J = 6.0 Hz); 13C NMR (63 MHz, CDC13) ^ 177.8, 170.4, 166.7, 165.1, 153.9, 141.8, 141.1 133.1, 130.8, 129.9, 129.7 ,, 128.9, 128.2, 125.9, 124.6, 122.4, 112.2, 76.8, 71.3, 56.0, 54.4, 52.0, 46.4, 42.7, 42.2, 39.5, -172- This paper is applicable to the standard Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) (Please read the notes on the back before filling out this page). 533206 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (170) 36.5, 35.2, 24.5, 22.8, 22.6, 21.2, 17.1; IR (CHC13) 3424, 2964, 2936, 2874, 2841, 1748, 1716 ,, 1681, 1608, 1528, 1503, 1485, 1437, 1283, 1259 cm · 1; Analysis (C38h47C1N2O9) c, H, n. Example 70

To phenylethylamidine (as above) (0.42 g, 0.59 mmol) was added 30 ml of acetone, 15 ml of rubidium 20, 15 ml of CH2C12, and solid NaHC03 (1.7 g, 20.2 mmol), and the mixture was cooled to 0 ° C. A solution of 0xone (1.4 g, 2.3 mmol) in 12 ml of H20 was prepared and (2 ml) was added to the cold styrene mixture. After vigorously stirring at 0 ° C for 30 minutes, 2 ml of a oxone solution was added, and the solution was warmed to room temperature. Add 2 ml of Oxone solution every 2 hours until 12 ml are consumed. The reaction mixture was stirred for a total of 5 hours, quenched with saturated NaHC03 aqueous solution (50 ml) and 50 ml of CH2C12, the layers were separated, and the organic layer was 10% Na2SO3 aqueous solution (50 ml), then saturated Na2HC03 aqueous solution (50 ml), and then washed with brine , Finally dried over Na2S04, filtered, and concentrated in the air. The crude mixture was purified by reverse-phase HPLC (45:55) CH3CN ·· H20 to obtain 0.14 g (33% yield) of the b and a epoxides and 0.14 g of the bicyclized mixture. A mixture of b / a epoxide (0.14 g, 0.19 mmol) was dissolved in 3.0 ml of CHC13 and cooled to -60 ° C. Chlorotrimethylsilane (0.1 ml, 0.777 mol) was added to the -60 ° C solution, and the mixture was stirred for 1.5 hours. TMSC1 (0.1 milli -173- (Please read the notes on the back first to fill in this animal.

1T ^ Paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm 1 to 533206 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ________ B7 V. Description of the invention (171) liters, 0.77 ® Moore) added , Dissolve, and warm to room temperature. After stirring at room temperature for hours, the solution was concentrated and purified by radial PLC (1-2% MeOH / CH2Cl2) to obtain 0.044 g (30% yield) of the desired chlorohydrin (as described above) as a white solid: [ a] 20d + 5〇.〇 (c 0.75? CHC13); 1U NMR (300 MHz? CDC13) ^ 8.1-8.08 (d, 2H, J = 8.1Hz), 7.54-7.51 (d, 2H, J = 8.2Hz ), 7.3 · 7.25 (m, 1 H), 7.25 (s, 1 H), 7.13-7.09 (dd, 1H, J = 8.5, 1.5 Hz), 6.91-6.88 (d, 1 H, J = 8.3 Hz) , 6.87-6.78 (m, 1 H), 5.86_5.8 (d, 1 H, J = 15.5 Hz), 5.7-5.6 (m, 1 H), 5.24-5.18 (t, 1 H, J = 9.2 Hz ), 4.99-4.95 (dd, 1H, J = 1.0, 3.6 Hz), 4.8_4.7 (m, 1H), 4.76-4.73 (d, 1 H, J = 9.5 Hz), 4.09-4.06 ( d, 1 H, J = 9.6 Hz), 3.97 (s, 3 H), 3.93 (s, 3 H), 3.45-3.38 (dd, 1 H, J = 13.6, 8.6 Hz), 3.25-3.0 (m, 3 H), 2.75-2.62 (m, 1 H), 2.6-2.4 (m, 2 H), 1.9-1.6 (m, 3 H), 1.5-1.4 (m, 1 H), 1.27 (s, 3 H ), 1.22 (s, 3 H), ll-1.07 (d, 3 H, J = 6.95 Hz), 0.98-0.95 (t, 6 H, J = 5.3 Hz); 13C NMR (63 MHz, CDC13) δ 177.5 , 170.6, 170.3, 166.3, 165.4, 153.9, 143.8, 142.2, 138.7, 130.7, 130.4, 1 29.9, 128.1, 128.08, 124.6, 122.3 112.2, 76.1, 73.8, 71.1, 61.4, 56.0, 54.6, 52.2, 46.4, 42.7, 39.6, 38.4, 36.3, 35.1, 24.8, 23.0, 22.9, 22.7, 21.5, 8.7; IR (CHC13) 3425, 2962, 2935, 2873, 2842, 1750, 1720, 1680, 1528, 1504, 1484, 1438, 1284, 1259, 1194, 1152, 1114, 1067 cm · 1; Analysis (C38H48Cl2N2O10) C, H, N. Example 7 1

This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

1T 533206 A7 ______B7 V. Description of the invention (172) To a solution of alcohol 23 (0.32 g, 0.46 mmol) in 8.5 l of CH2Cl2 was added solid NaHC〇3 (0.19 g, 2.29 mmol). ), Triphenylphosphine (0.88 g '0.69 mmol) and finally N-gassuccinimide (0.092 g, 069 mmol). The mixture was allowed to fall at 0 ° C for 20 minutes, and was quenched with a saturated aqueous solution of NaHC03 (20 ml). The layers were separated and the aqueous layer was extracted with CH2C12 (3 X 10 mL). The combined organic layers were washed with brine ', dried over Na2S04, filtered, and concentrated in the air. The crude yellow solid was purified by radial PLC (silica gel, 20-50% EtOAc / hexane) to obtain 0.26 g of benzyl chloride 36 in 79% yield as a white solid: [from] 20D + 25.6. (C 0.9, CHC13); 4 NMR (300 MHz, CDC13) d 7.4-7.38 (d, 2H, J = 7.9Hz), 7.26-7.23 (d, 3H, J = 8.3Hz), 7.19-7.18 (d, 1 H, J = 1.9 Hz), 7.06-7.03 (dd, 1 H, J = 8.3, 1.9 Hz), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.8-6.7 (m, 1 H) , 5.74-5.69 (d, 1 H, J = 15.4 Hz), 5.49-5.47 (d, 1 H, J = 7.8 Hz), 5.22-5.17 (m, 1 H), printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) 4.85- 4.8 (dd, 1 H, J = 9.7, 3.0 Hz), 4.78-4.7 (m, 1 H), 4.6 (s, 2 H), 3.9 (s, 3 H), 3.69-3.68 (d, 1 H, J = 1.3 Hz), 3.45-3.38 (dd, 1 H, J = 13.4, 8.6 Hz), 3.2-3.0 (m, 3 H), 2.92 -2.89 (dd, 1 H, J = 7.6, 1.6 Hz), 2.6-2.4 (m, 2 H), 1.8-1.6 (m, 3 H), 1.4-1.3 (m, 1 H), 1.22 ( s, 3H), 1.16 (s, 3H), 1.16-1.13 (d, 3H, J = 8.6Hz), 0.86-0.82 (t, 6 H, J = 6.8 Hz); 13C NMR (63 MHz, CDC13) d 177.8, 175.1, 170.3, 164.9 154.0, 141.6, 137.7, 137.1, 130.8, 129.5, 128.9, 128 · 1, 125.9, 124.6, 122.4, 112.3, 77,2, 75.8, 71.1 63.1, 58.5, 56.1, 54.4, 46.4, 45.7, 42.7, 4 0.5, 39.3, 36.8, 35.2, 24.5, 22.8, 22.6, 21.2, 13.5; IR (CHC13) 3416, 3284, 2961, 2933, 2873, 2839, 1752, 1721, 1680, 1658, 1536, 1504, 1473, 1442, -175- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 __B7 V. Description of the Invention (173) 1321, 1302, 1281, 1259, 1192, 1150, 1126, 1066 cnf1; Analysis (C37H46C12N208) C, H, N. Example 72

Diethylamine (0.09 ml, 0.84 mmol) was added with benzyl gas 36 (2003 g, 0.042 mmol) in 0.3 ml of THF. The mixture was stirred at room temperature overnight and quenched with saturated aqueous NaHC03 (5 ml). The aqueous layer was extracted with ch2C12 (3 X 5 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. The crude yellow solid was purified by radial PLC (silica gel, 50-70-80% EtOAc / hexane) to obtain 0.026 g of amine 37 with a yield of 82% as a white solid: [instrument] 20d + 25.9. (C 0.9, CHC13); NMR (300 MHz, CDC13) β 7.35-7.32 (d, 2 H, J = 7.9 Hz), 7.25-7.12 (m, 4 Η), 7.60-7 · 02 (dd , LH, J = 8_4, 1.6Hz), 6.84-6.82 (d, lH, J = 8.5Hz), 6.82-6.7 (m, 1 H), 5.74-5.69 (d, 1 H, J = 15.2 Hz), 5.57-5.55 (d, 1 H, J = 7.8 Hz), 5.22-5.17 (m, 1 H), 4.85-4.7 (m, 2 H), 3.86 (s, 3 H), 3.66 (s, 1 H) , 3.57 (s, 2 H), 3.46-3.38 (dd, 1 H, J = 13, 4, 8, 7 Hz), 3.2-3.0 (m, 3 H), 2.93-2.91 (d, 1 H, J = 7.4 Hz), 2.6-2.4 (m, 6 H), 1.8_1.6 (m, 3 H), 1.4-1.3 (m, 1 H), 1.22 (s, 3 H), 1.15 (s, 3 H ), 1.15_1.12 (d, 3 H, J = 9.2 Hz), 1.07_1.03 (t, 6 H, J = 7.1 Hz), 0.86_0.82 (t, 6 H, J = 6.3 Hz); 13C NMR (63 MHz, CDC13) ^ 177.9, 170.4, 170.3, 164.9, 154.0, 141.7, 140.1, 135.2, 130.8, _ -176- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Read the precautions on the back before you fill out this page). __ 533206 A7 B7 V. Description of the Invention (174) 129.6, 129.1, 128.1, 125.4 ,, 124.6, 122.4, 112.3, 77.2, 75.8, 71.1, 62 · 9, 58.9, 57.1, 56.0 , 54.4 46.6, 46.4, 42 · 7, 40 · 6, 39.3, 36.8, 35.2, 24.5, 22.8, 22 · 6, 21.2, 13.5, 11.5; IR (CHC13) 3424, 2969, 2936, 2874, 1752, 1711, 1682, 1605, 1527, 1503, 1485, 1303, 1259, 1190, 1151, 1067 cm1; Analysis (C4iH56C1N3〇8) c, Η, N 0 Example 7 3

To epoxide 37 (0.05 g, 0.066 mmol) in 0.8 ml (^ 110: 13 of -66 C solution was added dropwise a solution of HC1 in 1,4-dioxolane 4 M ( (04 ml, 0.166 mmol). The mixture was stirred at -66 ° C for 10 minutes, at which time the dry ice bath was removed, and the solution was slowly warmed to room temperature. The solvent was removed in the air, and the resulting salt was under high air. It was left for 3 days to remove the residue of dioxan, and 0.054 g of the desired chlorohydrin 3 8 was obtained. Quantitative yield ... [α] 2〇d + 29 3. i 〇 Staff Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs Printed (Please read the notes on the back before filling in this page)

MeOH); NMR (300 MHz, MeOD) Θ 8.5-8.47 (d, 1 HJ = 75 Hz), 7.79-7.76 (d, 1 H, J = 8.8 Hz), 7.53 (s, 4 H), 7.26 -7e25 (d, 1 H, J-1.6 Hz), 7.17-7.14 (dd, 1 H, J = 8.6, 1.6 Hz), 6.97-6 94 (d 1 H, J = 8.4 Hz), 6.75-6.6 ( m, 1 H), 5.96-5.90 (d, 1 H, J = 15 3 Hz), 5.2-5.0 (m, 2 H), 4.85-4.82 (d, 1 H, J = 8.9 Hz), 4.5 -4 · 4 (ιη, 1 H &gt;, 4.33 (s, 2 H), 4.02-3.98 (d, 1 H, J = 9.3 Hz), 3.8 (s, 3 H): 3.49-3.42 (dd, 1 H , J = 13.3, 9.9 Hz), 3.2-3.0 (m, 6 H), 2.8-2.6 (m, -177-This paper size applies to China National Standard (CNS) A4 specifications (210, 乂 297 mm) 533206 A7 B7 V. Description of the invention (175) 2H), 2.5-5-2 (ιη, 2 H), 1.8-1.5 (m, 3 H), 1.34_1.3 (m, 7 H), 1.2 (s, ψ 3 H), 1.15 (S, 3 h), 1.01-0.99 (d, 3 H, J = 7.2 Hz), 0.98-0.94 (t, 6 J = 5.4 Hz); 13C NMR (63 MHz, CDC13) Θ 178.9, 173.8, 171.8, 168.3, 155.4, 144.1, 143.4, 132.3, 132.2, 131.5, 131.1, 130.4, 129.4, 125.2, 123, 3, 113.5, 77.2, 74.8, 72.6, 63.2, 57.6, 56.7, 56.66, 48.0, 47.5, 44 ″, 41.1, 40.4, 37.8, 36.5 26.2, 23.6, 23.4, 22.2, 9.07, 9.0; IR (KBr) 3414, 2960, 2934, 1751, 1721, 1671, 1521, 1504, 1463, 1443, 1259, 1197, 1155, 1127, 1065 cm · 1 〇 Examples 7 4

(Please read the precautions on the back before filling this page) Epoxide (as above) (0.147 g) is based on benzyl gas 36 (0.15 g, 0.21 mil) and N- (No. Tributoxycarbonyl) hexamethylpyridine (0.1 gram, 1.05 mmol) was prepared with a yield of 81%: [none] 20D + 25.4. (C 〇 · 65 CHC13); NMR (300 MHz, CDC13) ά 7.37-7.23 (m, 5 H), printed from 7.11-7.08 (d, lH, J = 8.6Hz) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 6.9-6.87 (d, lH, J = 8.5Hz), 6.86-6.72 (m, 1 H), 5.78-5.73 (d, 1 H, J = 15.2 Hz), 5.53-5.5 (d, 1 H, J = 7.7 Hz), 5.28-5.23 (m, 1 H), 4.88-4.70 (m, 2 H), 3.9 (s, 3 H), 3.7 (s, 2 H), 3.54 (s, 2 H), 3.5- 3.4 (m, 5 H), 3.2 · 3β05 (ιη, 3 H), 3.0r2.95 (d, 1 H, J-7.4 Hz), 2.65-2.4 (m, 6 H), 1.85- 1.6 (m, 3 H), 1.5 (s, 9 H), 1.45-1.4 (m, 1 H), 1.27 (s, 3 H), 1.2 (s, 3 H), 1.2 · -178 Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 _______B7 V. Description of the invention (176)

1.18 (d, 3 H, J = 8.3 Hz), 0.91-0.87 (t, 6 H, J = 6.1 Hz); 13C NMR r (63 MHz, CDC13) d 177.9, 170.3, 170.26, 164.9, 154.7, 154.0, 141.7, 138.4, 135.6, 130.8, 129.5, 129.3, 128.1, 125.5, 124.6, 122.4, 112.3, 79.5, 77 · 2, 75 · 8, 71 · 1, 62.9, 62 · 6, 58.8, 56 · 1, 54.4, 52.8, 46.3, 42.7, 40.6, 39.3, 36.7, 35.2, 28.3, 24.5, 22.8 22.6, 21.2, 13.4; IR (CHC13) 3425, 3008, 2965, 2937, 2874, 2817, 1752, 1709 , 1683, 1527, 1484, 1463, 1459, 1427, 1367, 1259, 1167, 1150 cm1; FAB HRMS [M-BOC] (C46H64ClN4O10) calculation: 867.4311, measured: 867.4300. Example 7 5

Trimethylsilyl chloride (016 ml, 1.2 mmol) was added dropwise to a solution of epoxide (as above) (0.135 g, 0.156 mmol) in 3 ml of CHC13 at -66 ° C. The mixture was stirred at -66 ° C for 2 hours, and TMSC1 (0.16 ml, 1.2 mmol) was added. After 1 hour at -66 ° C, the ice bath was removed and the solution was slowly warmed to room temperature. The solvent was removed in the air, and the resulting solid was purified by radial PLC (silicone '2-5% MeOH / CH2Cl2) to obtain 0.13 g of gas alcohol (as described above) with a yield of 92%. [A] 2OD + 50.0. (Ch〇, ChC13); 4 NMR (300 MHz, CDC13) d 7.34 (s, 4 H), 7.21-7.2 (d, 2 H, J = 1.4 Hz), 7.08-7.05 (dd, 1 H, J = 8.6, 1.6 Hz), 6.86-6.83 (d, 1 H, J = 8.4 Hz), 6.82_ 6.7 (m, 1 H), 5.8-5.75 (d, 1 H, J = 15.1 Hz), 5.65- 5.62 (d, 1) _____ -179_ This paper size applies the Chinese National Standard (CNS) A4 specification 71 ° &gt; &lt; 297 mm) '~ 一 ~ (Please read the precautions on the back before filling this page)

、 1T 533206 Μ V. Description of the invention (177) J = 7.8 Ηζ), 5. 2-5 · 1 (η, 1 H), 5.0-4.7 (m, 2 H), 4.66-4.63 (d 1 Η, ψ J = 9.7Hz), 4.02-4.0 (d, 1H, J = 9.6Hz), 3.88 (s, 3H), 3e49-3.48 (d, 2 Η, J = 4.2 Ηζ), 3.45-3.3 (m, 5 Η ), 3.2-3.0 (m, 3 Η), 2.7-2.3 (m, 7 Η), 1.8-1.6 (m, 3 Η), 1.45 (s, 10 Η), 1.23 (s, 3 Η), 1.17 ( s, 3 Η), 1.04 · 1.02 ((1, 3 Η, J = 6.9 Ηζ), 0.93-0.91 (d, 6 Η, J = 6.3 Hz); 13C NMR (63 ΜΗζ, CDC13) β 177.5, 170.5, 170.2, 165.2, 154.6, 153.9, 142.3, 139, 1, 137. 3, 130, 8, 129. 8, 129.5, 128.1, 127.9, 124.5, 122.3, 112.2, 79.5, 76 · 0, 73 · 9, 71 · 1, 62 · 4, 61.9, 56.1, 54.5, 52.8, 46.4, 42.7, 39.6, 38 · 4 36 · 4, 35.2, 28.3, 24.7, 23.0, 22.9, 22.7, 21.5, 8.6; IR (CHC13 ) 3424, 3007, 2966, 2936, 2872, 2820, 1751, 1712, 1682, 1528, 1504, 1483, 1426, 1367, 1259, 1168, 1150, 1127, 1067, 1006 cm1; Analysis (C46H64Cl2N4O10) C, H, Nv Example 76 (Please read the notes on the back before filling this page)

The Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of India printed the dihydrochloride (0.116 g) of hexahydropyridine (0.122 g, 0.13 mmol) protected by BOC according to the above procedure using 4 μ HC1 in dioxolane ( (0.32 ml, 1.3 mmol), quantitative yield: 4; 200 + 26 3. (C 〇7, Me〇H); lR NMR (300 MHz, MeOD) δ 8.47-8.45 (d? 1 H, J = 7.5 Hz), 7.78-7.75 (d, 1 H, J = 9.2 Hz), 7.6 -7.52 (q, 4 H, J = 16.9, 7.9 Hz), 7.27_7.26 (d, 1 H, J = 1.15 Hz), 7.18-7.14 (dd, 1 H, J = 8.6, 1.8 _____ -180-This paper size is applicable to China National Standard (CNS) A4 specification (210X297). &Quot; 533206 A7 ____ B7_ V. Description of the invention (178)

Hz), 6.98-6.95 (d, 1 H, J = 8.4 Hz), 6.75-6.6 (m, 1 H), 5.95-5. 9 ψ (d, 1 H, J = 15.4 Hz), 5, 2-5.0 (m, 2 H), 4.85-4.82 (d, 1 H, J = 9.9 Hz), 4.5-4.4 (m, 1 H), 4.4 (s, 2 H), 4.0-3.98 (d, 1 H, J = 9.3 Hz), 3.8 (s, 3 H), 3.6-3.4 (m, 9 H), 3.32-3.29 (d, 1 H, J = 11.3 Hz), 3.19-3.13 (dd, 1 H, J = 14.8, 3.5 Hz), 3.1-3.06 (d, 1 H, J = 13.7 Ηζ), 2 · 8-2 · 6 (ηι, 2Η), 2.5 · 2.3 · 3 (ηι, 2Η), 1 · 85 · 1.5 (η, 3ι), 1β3-1.2 (m, 1 H), 1.2 (s, 3 H), 1.15 (s, 3 H), le02-0.95 (q, 9 H, J = 13.4 , 6.3 Hz); 13C NMR (63 MHz, CDC13) d 178.8, 173.7, 171.9, 168.3, 155.4, 144.2, 143.7, 132.8, 132.2, 131.5, 130.4, 129.9, 129.4, 125.2, 123.3, 113.5, 77.2, 74.8, 72.6, 63.1, 61.2, 57.6, 56.7, 49.2, 47.5, 44.1, 42.1, 41.1, 40.3, 37.8, 36.5, 26.3, 23.7, 23.4, 22.2, 9.0; IR (KBr) 3415, 2960, 2933, 2455, 1749, 1721, 1671, 1504, 1475, 1442, 1304, 1258, 1197, 1152, 1126, 1065, 1012 cm1; FAB HRMS [M-HC12] (C41H57C12N408) calculation: 803.3553, measured: 803,3563. · (Example 77

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Epoxide (as above) (0.15 g) is made from benzyl gas 36 (0.16 g, 0.22 mmol) according to the above procedure Mol) and tertiary butyl-fluorene (2-aminoethyl) carbamate (0.35 g, 2.22 mmol), yield 78%: [from] '+ 22 3. (C 1.0, CHC13); 4 NMR (300 MHz, CDC13) d 7.41-7.38 (d, 2 H, _ -181- This paper size applies the Chinese National Standard (CNS) A4 specification (210x ^ 97mm f)) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 533206 A7 B7 V. Description of the invention (179) J = 7.8 Hz), 7.31 (s, 1 H), 7.26-7.24 (d, 3 H, J = 8.0 Ηζ), 7 »11 · Ψ 7.08 (dd, 1 H, J = 8.4, 1.7 Hz), 6.88_6.86 (d, 1 H, J = 8.4 Hz), 6.86_6.72 (m, 1 H), 5.88-5.8 (bs, 1 H), 5.78-5.73 (d, 1 H, J = 15.2 Hz), 5.28-5.22 (m, 1H), 5.2-5.08 (bs, 1 H), 4.95-4.7 (m, 2 H), 3.91 ( s, 3 H), 3.87 (s, 2 H), 3.7 (s, 1 H), 3.45-3.38 (dd, 1 H, J = 13.4, 8.4 Hz), 3.35-3.0 (m, 5 H) , 2.96-2.93 (dd, 1 H, J = 7.5, 1.2 Hz), 2.89-2.78 (m, 2 H), 2.65-2.4 (m, 2 H), 1.85-1.65 (m, 3 H), 1.49 ( s, 9 H), 1.48-1.3 (m, 1 H), 1.27 (s, 3 H), 1.2 (s, 3 H), 1.19-1.17 (d, 3 H, 7.1 Hz), 0.91-0.87 (t , 6 H, J = 6.8 Hz; 13C NMR (63 MHz, CDC13) d 177.7, 170.4, 165.0, 156.0, 153.9, 141.5, 139.9, 135.6, 130.7, 129.7, 128.5, 128.1, 125.6, 124.7, 122.3, 112.2, 7 7.2, 75.7, 71.0, 63.0, 58.8, 56.0, 54.5, 52.9, 48.5, 46.3, 42.7, 40.5, 39.3, 36.8, 35.2, 28.3, 24.5, 22.83, 22.8, 22.6, 21.2, 13.5; IR (CHC13) 3425, 3009, 2967, 2936, 2874, 2841, 1751, 1709, 1685, 1504, 1368, 1280, 1259, 1165, .1 1153, 1067 cm analysis (C44H61C1N401 ()) C, H, N. Example 7 8

To a solution of epoxide (as above) (0.065 g, 0.076 mmol) in 0.9 ml of CH2C12 at -78 ° C was added dropwise 4 M HC1 in 1,4-dioxolane (0.90 ml, 〇 · 38 millimoles). The solution was stirred at -78 ° C for 30 minutes, and then slowly -182- This paper size applies the Chinese National Standard (CNS) Regulation 8 ^ 210X297 mm (please read the precautions on the back before filling this page)

1T 533206 A7 B7 V. Description of the invention (180) Slowly warm to room temperature. It was stirred at room temperature for 2 hours, and concentrated in the air to obtain chloro ψ alcohol (as described above) (0.063 g). Quantitative yield: [from] 2OD + 16 6. (C! 〇, MeOH); NMR (300 MHz, CDC13) ^ 8.54-8.52 (d, 1 H, J = 7.7 Hz), 7.84-7.81 (dd, 1 H, J = 8.8, 1.7 Hz), 7.63- 7.53 (q, 4 H, J = 20.0, 8.2 Hz), 7.31-7.3 (d, 1 H, J = 2.0 Hz), 7.22-7.18 (dd, 1 H, J = 8.4, 2.0 Hz), 7.02 -6.99 (d, 1 H, J = 8.5 Hz), 6.8-6.7 (m, 1 H), 6.0-5.92 (d, 1 H, J = 15.0 Hz), 5.2-5.0 (m, 2 H), 4.9 -4.8 (m, 1 H), 4.6-4.4 (m, 1 H), 4.3 (s, 2 H), 4.07-4.03 (dd, 1 H, J = 9.5, 1.4 Hz), 3.86 (s, 3 H ), 3.6-3.1 (m, 7 H) 2.82-2.7 (m, 2 H), 2 · 6-2 · 3 (π, 2 H), 1.9-1.6 (m, 3 H), 1.25 (s, 3 H), 1.2 (s, 3 H), 1,05-0.99 (m, 9 H); 13C NMR (63 MHz, CDC13) β 178.8, 173.8, 171.9, 168.3, 155.3, 144.2, 143.1, 132.2, 131.5, 131.4, 130.3, 129.4, 125.2, 123.2, 113.5, 77.2, 74.7, 72.6, 63.2, 57.6, 56.7, 52.4, 47.5, 45.5, 44.1, 41.1, 40.3, 37.8, 36.9, 36.5, 26.3, 23.7, 23.5, 22.2, 9 · 0; IR (KBr) 3412, 2961, 2933, 1749, 1721, 1663, 1504, 1462, 1442, 1259, 1199, 1152, 1126, 1065 cm1; FAB HRMS [M -HC12] (C39H55C12N408) calculation 値777.3397, real Zhi 777.3407. Example 7 9

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Styrene (as above) (1.2 g) The mixture of E: Z isomers is made from aldehyde 18 (1.0 g, 1.73 millimolar) and 4- (ethyl-2-tert-butyldimethylsilyloxy) bromide -183- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 533206 Μ B7 V. Description of the invention (181) Benzyltriphenyl scale (1.23 g, 2.08 mmol) was prepared according to the above procedure of styrene 20 with a yield of 86%. A mixture of isomers was dissolved in toluene (50 ml), and ι, ι · -azobis (cyclohexanenitrile) (VAZO) (0.040 g, 0.16 mmol) and thiophenol (61 ml, (0.59 mmol) in the presence of 3 hours. After concentration, the residue was purified by radial PLC (20-75% EtOAc / hexane) to obtain the E isomer (0.813 g, 68%) as a white foam: [a] 20d + 35.6. (C 0.56, MeOH); 4 NMR (300 MHz, CDC13) β 7.26-7.12 (m, 6 H), 7.07-7.04 (d, 1 H, J = 8.5 Hz), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.83-6 „70 (m, 1 H), 6.40_6.35 (d, 1 H, J = 15.8 Hz), 6.0-5.92 (dd, 1 H, J = 15.4, 8.7 Hz) , 5.77-5.72 (d, 1 H, J = 15.2 Hz), 5.46-5.43 (d, 1 H, J = 7.7 Hz), 5.07-5.02 (m, 1 H), 4.86-4.83 (m, 1 H) , 4.82-4.74 (m, 1H), 3.88 (s, 3 H), 3.78_3.74 (t, 2 H, J = 7.1 Hz), 3.44-3.37 (dd, 1 H, J = 12.5, 8.6 Hz) , 3.15-3.08 (m? 3 H)? 2.81-2.77 (t? 2 H, J = 7J Hz), 2.57 · 2 · 52 (η, 2 H), 2.43-2.35 (m, 1 H), 1.74-1.56 (m, 2 H), I. 38-1.23 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.13_l.ll (d, 3 H, J = 6.8 Hz), 0.88 (s, 9 H), 0.84-0.72 (m, 6 H) 0.0 (s, 6 H); l3C NMR (75 MHz, CDC13) ^ 177.9, 170.5, 170.3, 165.1, 154.0, Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page) 142.2, 138.6, 134.6, 131.5, 130.9, 129.6, 129.4, 128.2, 126.0, 125.3, 124.5, 122.5, 112.3, 92.9 , 77.0, 71.4, 64.4, 56.1, 54.3, 46.5, 42.7, 4 2.2, 39.4, 36.5, 35.3, 25.9, 24.5, 22.8, 22.7, 22.6, 21.2, 17.2, -5.44; IR (CHC13) 3423, 2959, 2931, 2858, 1747, 1712, 1681, 1605, 1527, 1503 , 1485, 1442, 1370, 1339, 1303, 1281, 1258, 1194, 1151, 1095, 1067, 1025, 1007, 838 cm · 1; min -184- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 -------------------------------- 丨 丨 _ B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs System five, description of the invention (182) analysis (C44H63ClN208Si) C, H, N. Example 8 0

Ratio / i (0.06 I liter '0.76 mol), then Dess_Martin reagent (0.161 g, 0.379¾ mol) was added to styrene (as above) free alcohol (ο "" g, 0.189¾ mol ) In 4.5 millimoles. The mixture was stirred for 30 minutes at room temperature, and stirred for 20 minutes at room temperature, then filtered through EtoAc, and then concentrated in the air. The crude product was radial pCL (silica gel, EtOAc / CH). ^ Cl2) was quickly purified to obtain the desired aldehyde (008 g), yield 59%, as a white solid: 4 NMR (300 MHz, CDC13) J 9.77 1 HJ = 2.0 Hz), 7.3-7.2 (m, 6 H), 7.06-7.02 (dd, 1 H, J = 8.3, 2.0 Hz) 6.85_6.82 (d, 1 H, J = 8.4 Hz), 6.81-6.7 (m, 1H), 5.74_5.68 (d , 1 H, J = 15.3 Hz), 5.51-5.48 (d, 1 H, J = 7.8 Hz), 5.22-5.17 (m,! H) 4.85-4.81 (dd, 1 H, J = 10.3, 3.6 Hz) , 4.77-4.71 (m, 1 H), 3 87 (s 3 H), 3.2-3.71 (d, 2 H, J = 2.0 Hz), 3.69-3.68 (d, 1 H, J = 1.5 Hz) 3.45- 3.38 (dd, lH, J = 13.5, 8.7Hz), 3.17_3.0 (m, 3H), 2.92-2.89 (dd, 1 H, J = 7.6, 1.8 Hz) 2.6-2.4 (m 2 H), 1.8 -l.6 (m, 3 H) 1.4_1.3 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.16-l.13 ( d, 3 H, J = 8.3 Hz), 0.86-0.82 (t, 6 H, J = 6.3 Hz). Example 8 1 (Read the precautions on the back before filling this page)

、 1T ___-185- This paper size applies to Chinese National Standard (CNS) A4 (21 OX297 mm) 533206 kl Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (183)

Tetrahydrofuran (3.2 liters) and hydrazone: 20 (3.2 ml) were added to the aldehyde (as described above) (0.8 g, 0.112 mmol), and the mixture was cooled to zero. (3. 2-methyl-2-butanidine (32 liters) 'then NaCl〇2 (〇.〇81 g' 0.896 亳 mol) and NaH2P〇4.H2〇 (0.139 g '1 · 0 millimoles) were successively added. The mixture was heated to room temperature and stirred vigorously for 5 hours. The solution was diluted with 10 ml of CH ^ Cb and the layers were separated. The aqueous layer was extracted with CH: 2C12 (3 x 10 ml), and the combined organic extracts were Na2S04 was dried, filtered, and concentrated in the air. The crude product was purified twice with radial PLC (silica gel, S-lO-iS% MeOH / CH2Cl2) to obtain 0.03 g of carboxylic acid (as described above) with a yield of 37%. , As a white solid: [Meter] 20D + 24.5. (C 0.33, MeOH); 4 NMR (300 MHz, CD3OD) (ί 7.75-7.71 (dd, 1H, J = 10.3, 1.9 Hz), 7.31-7.2 (m , 5H), 7.16-7.13 (dd, 1H, J = 8.4, 1.9 Hz) 6.97-6.95 (d, 1 H, J = 8.4 Hz), 6.8-6.60, 1 H), 5.87-5.81 (d, 1 H, J = 15.3 Hz), 5.19-5.14 (dd, 1H, J = 11.0, 5.0 Hz), 4.9-4.8 (m, 2 H), 4.48-4.43 (dd, 1H, J = 11.5, 3.5 Hz), 3.8 (s, 3 H), 3.77 (s, 1 H), 3.53 (s, 2 H), 3.5-3.4 (m, 1 H), 3.17-3.11 (dd, 1 H, J = 14.3, 3.5 Hz), 3.05-3.0 (d, 1 H, J = 13.6 Hz), 2. 95-2.92 (dd, 1 H, J = 7.7, 1.7 Hz), 2.8-2.6 (m, 2 H), 2.5-2.3 (m, 1 Η), 1.8 · 1.6 · (3η) , 1.4-1.2 (m, 1 H), 1.17 (s, 3 H), 1.13 (s, 3 H), 1.13-ll (d, 3 H, J = 9 "2 Hz), 0.83-0.81 (d, 6 H, J = 6.3 Hz); 13C NMR (126 MHz, CDC13) ά 178.8, 173.7, 172. 0, 168 · 2, 155.4, 143.4, 138.1, -186- This paper size applies to Chinese national standards (CNS ) Α4 size (210 × 297 mm) (Read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 533206 A7 B7 V. Description of the invention (184) 136.8, 132.2, 131.2, 130.8, 129.3, 126.8, 125.4, 123.3, 113.5, ψ 77.7, 72.4, 64.4, 60.0, 57.5 , 56.6, 47.4, 44.1, 41.7, 40.7, 38.6, 36.5, 25.9, 23.4, 23.3, 21 · 65 14.0; IR (KBr) 3417, 2961, 2934, 2874, 1750, 1721, 1674, 1561, 1504, 1464, 1441, 1300, 1259, 1194, 1151, 1066 cm · 1; FAB HRMS [M + H] (C38H48ClN2O10) calculation: 727.2997, actual measurement: 727.33005. Example 8 2

In a mixture of [(2-methyl_4_oxazolyl) methyl] triphenylscale (0.496 g, 1.2 mmol) in 10 ml of THF at a temperature of 78 ° (: 1.6 M solution of butyllithium (0.8 ml, 1.2 mmol). The mixture was slowly warmed to room temperature and stirred for 45 minutes. In aldehyde 18 (0.5 g, 0.865 mmol) in 15 ml of THF at- 78 ° C was added dropwise into the light-colored solution through a double-pointed needle. The resulting mixture was dropped at -781 for 2 hours and stirred at room temperature for 1.5 hours. Saturated NH4C1 (30 ml) and ethyl acetate (30 ml) were added The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 X 20 ml). The combined organic layers were washed with water (2 X 20 ml) and brine, dried over MgS04, filtered, and concentrated in the air. The yellow residue formed Purified by column chromatography (silica gel, 50-70-80% EtOAc / hexane) to obtain 0.4 g of the desired styrene and triphenylphosphine oxide. Triphenylphosphine oxide was used as reverse phase HELC using CH3CN: H2O ( 50: 50) Easy removal to obtain 〇2g (34%) pure azole (as above), as a white solid: [仪] 20d + 16.7. (C 1.0, CHC13); -187- this paper Of the applicable Chinese National Standard (CNS) Α4 size (210X297 mm) (Please read the Notes on the back page and then fill in}

1T 533206 A7 B7 V. Description of the invention (185) 4 NMR (300 MHz, CDC13) d 7.3-7.2 (m, 1 H), 7.18-7.17 (d, 1 r H, J = 1.7 Hz), 7.06_7. 03 (dd, 1 H, J = 8.5, 1.8 Hz), 6.83 (s, 1H), 6.83-6.8 (d, 1 H, J = 9.0 Hz), 6 „8-6.67 (m, 1 H), 6.37 -6.35 (m, 2 H), 5.85-5.82 (d, 1 H, J = 7.9 Hz), 5.76-5.71 (d, 1 H, J = 15.1 Hz), 5.05-5.0 (dd, 1 H, J = 9.0, 6,0 Hz), 4.86-4.82 (dd, 1 H, J = 10.2 3.6 Hz), 4.77-4.68 (m, 1 H), 3.85 (s, 3 H), 3.44-3.37 (dd, 1 H , J = 13.4, 8.6 Hz), 3.2-3.0 (s, 3 H), 2.68 (s, 3 H), 2.6-2.3 (m, 3 H), L8-1.6 (m, 2 H), 143 · 1 · 3 (η, 1 H), L2 (s, 3 H), 1.14 (s, 3 H), 1.12-ll (d, 3H, J = 6.9Hz), 0.79-0.78 (d, 3H, J = 3.1Hz), 0.77-〇.76 (d, 3 H, J = 3.1 Hz); 13C NMR (63 MHz, CDC13) d 177.8, 170.5, 166.0, 165.2, 153.9, 153.0, 142.1, 136.7, 132.7, 130.8 , 129.8, 128.1, 124.6, 124.4, 122 · 3, 114.1, 112.2, 76.9, 71. 4, 56.0, 54.4, 46 · 4, 42.7, 41.9, 39 · 3, 36 · 5, 35.3, 24.5, 22 · 8 , 22.7, 22.6, 21.2, 19.2, 17.1; IR (CHC13) 3423, 3027, 3008, 2965, 2935, 2 874, 1747, 1712, 1681, 1652, 1604, 1528, 1504, 1485, 1259, 1181, 1152, 1067 cm1; Analysis (C34H44C1N307S) C, H, N. Example 8 3

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Add 15 ml of acetone and 6 ml of H20 to styrene (as above) (0.25 g, 0.37 mmol) , 6 ml of CH2C12, and solid NaHCO3 (1.0 g, 119 mmol), and the mixture was cooled to 0 ° C. Preparation 〇xone (.92 g, 1.5 mmol-188-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 533206 A7 B7 V. Description of invention (186) Employees' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed (read the precautions on the back before filling this page) ear) solution in 8 ml HsO, (2 ml) added to the cold phenylethyl hydrazone mixture. After 30 minutes of vigorous teaching at 0 C, the 2 'oxon solution was added. After 30 minutes, 2 ml was added again, for a total of 6 ml of oxontle solution. The progress of the reaction was checked by reverse phase HPLC and found to be complete after stirring for 2.0 hours. After standing at 0 ° C, the reaction mixture was quenched with a saturated aqueous solution of NaHC03 (40 ml) and 40 ml of CH2C12. The layers were separated, and the organic layer was washed with 10% aqueous Na2S03 solution (40 mL), then with saturated aqueous NaHC03 solution (40 ml), then washed with brine, dried over Na2S04, filtered, and concentrated in the air. A mixture of b and a epoxide (54:46) was separated by reverse-phase HPLC (50:50) (CH3CN: H20) to obtain 0.09 g of b epoxide (as described above) as a white solid with a yield of 35%: [^] 2〇d + 26.0 ° (c 1.0, CHC13); lVL NMR (300 MHz, CDC13) ^ 7.19-7.18 (d, 2 H, J = 1.8 Hz), 7.1 (s, 1 H), 7.06- 7.03 (dd, 1 H, J = 8.5, 1.9 Hz), 6.85-6.82 (d, 1 H, J = 8.4 Hz), 6.82-6.7 (m, 1 H) 5.76-5.71 (d, 1 H, J = 15.2 Hz), 5.49-5.47 (d, 1 H, J = 7.8 Hz), 5.23-5.18 (m, 1 H), 4.88-4.84 (dd, 1 H, J = 10.3, 3.6 Hz), 4.8-4.7 ( m, 1 H), 3.88 (s, 3 H), 3.79 (d, 1 H, J = 0.93 Hz), 3.45-3.38 (dd, 1 H, J = 13.4, 8_6 Hz), 3.35_3.32 (d , 1 H, J = 7.2 Hz), 3.2-3.0 (m, 3 H), 2.7 (s, 3 H), 2.6-2.4 (m, 2 H), 1.8-1.6 (m, 3 H), 1.4- 1.3 (m, 1 H), 1.23 (s, 3 H), 1.16 (s, 3 H), 1.14-1.12 (d, 3 H, J = 6.8 Hz), 0.89-0.87 (d, 3 H, J = 6.5 Hz), 0.86-0.84 (d, 3 H, J = 6.4 Hz); 13C NMR (63 MHz, CDC13) β 177.9, 170.33, 170.3, 166.9, 165.0, 154.0, 151.9, 141.8, 130.8, 129.5, 128.2, 124.5, 122. 4, 116.4, 112.3, 75.8, 71.1, 61.3, 56.1 , 55.2, 54.3, 46.4, 42.7, 40.3, 39 · 3, 36.6, 35.2, 24.5, 22.85, 22.8, 22.6, 21.2, 19.1, 13. · 3; IR (CHC13) -189- This paper standard applies to Chinese national standards ( CNS) A4 specification (210X 297 mm) 533206 A7 B7 V. Description of the invention (187) 3425, 3007, 2964, 2936, 2874, 2841, 1751, 1711, 1682, 1604, ψ 1528, 1503, 1485, 1464, 1303 , 1259, 1185, 1152, 1067 cm · 1; Analysis (C34H44C1N308S) C, H, N. Example 84

Phenyl # (as above) (0.5 g) is based on acid 18 (1.3 g, 2.2 mmol) and 2-fluorobenzyl triphenyl scale bromide (1.7 g, 3.8 mmol) based on the above phenethyl印 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (read the precautions on the back before filling out this page) 20 procedures, yield 33%: | &>; 20D + 17.0. (C ΐ · ΐ6, CHC13); 4 NMR (300 MHz, CDC13) d 7.40-7.34 (m, 1 H), 7.23.6.96 (m, 6 H), 6.83-6.80 (d, 1H, J = 8.4Hz ), 6.78-6.70 (m, lH), 6.57-6.52 (d, 1 H, J = 16.0 Hz), 6.10-6.02 (dd, 1 H, J = 8.8, 16.0 Hz), 5.76-5.71 (d, 1 H, J = 15.3 Hz), 5.50-5.47 (d, 1 H, J = 7.8 Hz), 5.05-4.95 (m, lli), 4.85-4.80 (dd, 1H, J = 9.6, 3.1HZ), 4.75 · 4.69 (m, 1 H), 3.85 (s, 3 H), 3.42-3.34 (dd, 1 H, J = 13.5, 8.7 Hz), 3.13-3.05 (m, 3 H), 2.56-2.51 (m, 2 H), 2.37-2.33 (m, 1 H), 1.68_1.58 (m, 2 H), 1.34_1.23 (m, 1 H), 1.20 (s, 3 H), 1.13 (s, 3 H) , 1.13-l.ll (d, 3 H, J = 7.3 Hz), 0.79-0.70 (m, 6 H); 13C NMR (63 MHz, CDCl3) d 177 · 9, 170.5, 170.4, 165.1, 154.0, 142.0 , 137.4, 133.0, 132.9, 130.8, 129.6, 128.8, 128.2, 127.0, 126.9, 124.6, 124.1, 115.9, 115.5, 112.3, 76.9, 71.4, 56.1, 54.4, 46.4, 42.7, 42,6, 39.4, 36.5, 35.3 , 24.5, 22.8, 22.7, 22.6, 21.1, 17.2; ___- 190-_ This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 Μ B7 V. Description of the invention (188) IR (CHC13) 3423, 2965, 2935, 2874, 1747, 1711, 1681, 1605, 1527, 1503, 1487, 1457, 1441, 1370, 1340, 1321, 1280, 1259, 1151, 1093, 1067, 1009, 970 cm1; Analysis (C36H44C1FN207) C, Η, N. Example 8 5

To a solution of styrene (as above) (0.26 g, 0.387 mmol) in 1.3 ml of CH2C12 was added 3-chloroperoxybenzoic acid (0.07 g, 0.41 mmol) at 0Ό and Toluene (0.65 ml) was stirred at 0 ° C for 30 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 hours. After concentration, the residue was purified with reverse phase hpLC (CH3CN / H2O) to obtain b-epoxide (as described above) as a white foam (0.058 g, 24%, corrected for the recovered acetophenone): [ "] 200 + 18 98. (c Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) 1.41, CHC13); Go NMR (300 MHz, CDC13) d 7.30- 7.00 (m, 6 H), 6.86-6.83 (d, lH, J = 8.5Hz), 6.80-6.75 (m, lH), 5.76 · 5.11 (d, lH, J = 15.1Hz), 5.47-5.45 (d , LH, J = 7.8HZ), 5.23 · 5 · 20 (η, 1 H), 4.86-4.82 (dd, 1 H, J = 10.3, 3.5 Hz), 4.78-4.70 (m, 1 H), 4.01 ( S? 1H)? 3.88 (s? 3 H), 3.45-3.38 (dd, 1 H? J = 13.4? 8.6

Hz), 3.12-3.08 (m, 3H), 2.91-2.88 (d, 1H, J = 7.8Hz), 2.59-2.53 (m, 2 H), 1.80-1.71 (m, 3 H), 1.46-1.25 ( m, 1 H), 1.23 (s 3 H) "1.16 (s, 3 H), 1.16-1.14 (d, 3 H, J = 7.2 Hz), 0.87-0.83 (m, 6 H); 13C NMR (63 MHz, CDC13) d 178.1, 170.5, 170.3, 165 · 〇-191-rs J 千 I 一 \ * '

4 A

0 y ZX 533206 A7 B7 V. Description of the invention (189) 142.0, 131.0, 129.7, 129.6, 128.3, 126.1, 126.08, 124.65, ψ 124.5, 122.6, 115.5, 115.2, 112.4, 76.0, 71.2, 62.6, 56.2, 54.4, 53.5, 46.5, 42.8, 40.6, 39.4, 36.9, 35.3, 24.7, 22.9, 22.8, 21.3, 13.8; IR (CHC13) 3417, 2962, 2948, 1754, 1721, 1681, 1653, 1534, 1504, 1473, 1459, 1441, 1303, 1282, 1258, 1191, 1148, 1127, 1066 cm · 1; Calculation of FAB HRMS [M + H] (C36H45C1FN208) 値 687.2848, measured 値 687.2857. Example 8 6

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (谙 Please read the notes on the back before filling this page) The E / Z mixture of styrene (as above) (0.85 g) is made of aldehyde 18 (2.0 g, 3.45 mmol ) And 3-fluorobenzyltriphenylphosphonium bromide (1.92 g, 4.25 mmol) were prepared according to the above procedure of styrene 20 with a yield of 37%. A mixture of isomers was dissolved in benzene (25 ml), and i, r-azobis (cyclohexanenitrile) (VAZO) (0.04 g, 0.16 mol) and thiophenol (0.06 ml, 58 millimoles) in the presence of 20 hours. After concentration, the 'residue was purified with radial plc (20-100% EtOAC / hexane) to obtain the e isomer (〇 ¢ 52 g, 77%) as a white foam: | &gt;] 2V30. 55. (C 0.98, CHC13); N1V1R (300 MHz, CDC13) 7.30-7.01 (m, 8 Η), 6.95 · 6 · 88〇, 1 H), 6.86_6.83 (d, 1 H, J = 8.5 Hz), 6.81-6.72 (m, 1 H), 6.40-6.35 (d, 1 H, J = 15.9 Hz), 6.07-5.99 (dd, 1 H, J = 8.8, 15.9 Hz), 5.78- 5.73 (d, 1 H, J = 15.1 Hz), 5.50-5.47 (d, 1 H, J = 7.9 Hz), 5.08-5.02 (dd, 1 H, -192-

This paper size is applicable to the national standard (CNS) A4 size of the towel (210xT ^ tT printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (19) J = 9.7, 6.7 Hz), 4.87-4.82 dd, 1 H, J = 9.7, 3.0 Hz), 4.78-4.71 (m, ψ lH), 3.88 (s, 3H), 3.45-3.37 (dd, lH, J = 13.5, 8.6Hz), 3.15 · 3.08 ( m, 3H), 2.59-2.52 (m, 2H), 2.43-2.34 (m, 1H), 1.72 · 1.63 (m, 2 H), 1.36-1.26 (m, 1 H), 1.22 (s, 3 H) , 1.16 (s, 3 H), 1.15_1.12 (d, 3 H, J = 6, 9 Hz), 0 · 80 · 0 · 73 (ηι9 6 H); 13C NMR (63 MHz, CDC13) δ 177.8 , 170.5, 170.4, 165.1, 165.0, 153.9, 141.9, 137.3, 131.7, 130.8, 130.6, 130.0, 129.6, 128.1, 124 · 6, 122 · 4, 114.4, 114.1, 112.6, 112.2, 76 · 8, 71.3, 56.0 , 54.4, 46.4, 42.7, 42.1, 39.5, 36.5, 35.2, 24.5, 22.8, 22.64, 22.6, 21.2, 17.2; IR (CHC13) 3423, 3008, 2965, 2936, 2874, 1747, 1712, 1680 , 1652, 1585, 1528 1503, 1486, 1464, 1442, 1320, 1303, 1259, 1193, 1147, 1127, 1067, 973 cm · 1; Analysis (C36H44C1FN207) C, H, N 〇 Example 8 7

To a solution of the above styrene (0.622 g, 0.927 mmol) in 3.0 ml of CH2Cl2 was added 3-gas peroxybenzoic acid (0.770 g, 0 985 mmol) and toluene ( 1.5 ml), continue stirring at 0 ° C for 30 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 22 hours. After concentration, the residue was purified with reversed phase 11]? 1 ^ (CH: 3CN / H2〇) to obtain b-epoxide (as described above) with a yellow foam.

(0.067 g, 11%): U] 2〇d + 26.3 ° (c 1.54, CHC13); 4 NMR -193- This paper uses Chinese National Standard (CNS) A4 specification (210X297 mm) ~ ------ -(Please read the notes on the back before filling this page)

533206 A7 B7 V. Description of the invention (191) (300 MHz, CDCls) ^ 7.37-6.92 (m, 7 H), 6.86-6.83 (d, 1 H, r J = 8.4 Hz), 6.82-6.73 (m, 1 H), 5.75-5.70 (d, 1 H, J = 15.5 Hz), 5.48-5.45 (d, 1 H, J = 7.8 Hz), 5.22-5.17 (m, 1 H), 4.85-4.81 (dd, 1 H? J = 3.1? 9.8 Hz) 9 4.76-4〇70 (m, 1 H) 9 3.88 (s, 3 H) 5 3.68-3.67 (d, 1 H, J = 0.89 Hz), 3.46-3.38 (dd , 1 H, J = 8.6, 13.5 Hz), 3.13-3.07 (m, 3 H), 2.90-2.87 (dd, 1 H, J = 1.5, 7.4 Hz), 2.60-2.37 (m, 2 H), 1.82 -1.64 (m, 3 H), 1.36-1.25 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.15-1.12 (d, 3 H, J = 6.9 Hz), 0,88-0.83 (m, 6 H); 13C NMR (63 MHz, CDC13) β 177 · 9, 170.4, 165.0, 154.0, 141.6, 139.5, 130.8, 130.4, 130.2, 129.6, 128.2, 124.7, 122.4 , 121.3, 115.6, 115.3, 112.3, 112.2, 75.8, 71.1, 63.2, 58.2, 56 · 1, 54.5, 46.4, 42.8, 40.4, 39 · 4, 36.8, 35.3, 24 · 5, 22 · 85, 22 82, 22.7, 21.2, 13.4; IR (KBr) 3416, 3034, 2963, 2934, 2874, 1751, 1721, 1680, 1658, 1539, 1504, 1473, 1442, 1304, 1280, 1258, 1192, 1144, 1066 cnT1; points (C36H44C1FN208) C, Η, Ν. Example 8 8 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) E / Z mixture of acetophenone (as above) (1.24 g) is made from aldehyde 18 (1.5 g 2.6 mmol) and 4-fluorobenzyl triphenyl scale (1.4 g, 3.1 mmol) were prepared according to the procedure of styrene 20 above, yield 71. / ❶. The mixture of isomers is dissolved in benzene (40 ml), and u, · Azobis (cyclohexanenitrile) (vaZO) (0.050 ______ ^ 194- This paper size applies to China @ 家 标 '(CNS) M specifications (2) 〇 &gt; &lt; 297 public attack) '— 533206 A7 _________B7 V. Description of the invention (192) (Please read the notes on the back before filling out this page) Gram' 0.20¾ Mol) and thiophenol (〇〇 (76 ml, 0,74 mmol) was heated to reflux for 24 hours. After concentration, the residue was purified by radial pLC (20-100% EtOAC / hexane) to obtain the E isomer (106 g) as a white foam, which was detected by NMR and contained triphenylphosphine oxide Welding. 015 g of sample was purified by reverse-phase HPLC (60 · 40) CH3CN: H20 to obtain 〇092 g of pure solid: [a] 20d + 27.49 ° (c 1.05? CHC13);! H NMR (300 MHz, CDC13) d 7.31_6.96 (m, 7 H), 6.85-6.83 (d, 1 H, J = 8.5 Hz), 6.81-6.74 (m, 1 H), 6.39-6.34 (d, 1 H, J = 15,8 Hz), 5.96-5.88 (dd, 1 H, J = 8.8, 15〇8 Hz)? 5.77-5.72 (d? 1 H, J = 15.2 Hz), 5.49-5.47 (d? 1 H, J = 7.7 Hz ), 5.07-5.02 (m, 1 H), 4.86-4.83 (dd, 1 H, J = 9.2, 2.5 Hz), 4.82-4.73, 1 H), 3.87 (s, 3 H ), 3.45-3.38 (dd, 1 H, J = 13.4, 8.5 Hz), 3, 14-3.08 (m, 3H), 2.57-2.52 (m, 2H), 2.43-2.34 (m, 1 H), 1.71 -1.58 (m, 2 H), 1.36-1.29 (m, 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.14_l.ll (d, 3 H, J = 6.9 Hz) , 0.78-0.73 (m, 6 H); 13C NMR (63 MHz, CDC13) d 177.8, 170.5, 170.3, 165.1, 160.2, 154.0, 142.0, 137.6, 132.9, 132.8, 130.8, 130.4, 130.0, 129.6, 128.2, 127.6, 127.5, 124.6, 122.4, 115.6, 115.2, 112.2, 71.3, 56.0, 54.4, 46.4, 42.7, 42.1, 39.5, 36.4, 35.2, 24.5, 22.8, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 22.6, 21.2, 17.2; IR (KBr) 3421, 3289, 2862, 2933, 1751, 1722, 1678, 1604, 1534, 1509, 1259, 1228, 1149, 1066, 1024, 1011, 971, 815 cnT1; Analysis (C30H44C1FN207) C, H , N. Example 8 9

-195- This paper size applies Chinese National Standard (CNS) A4 (210 '乂 297 mm) 533206 A7 B7 V. Description of Invention (193) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Please fill in this page again.) To a solution of styrene (as above) (0.906 g, 1.35 mmol) in 4.5 ml of CH2C1: 2, add 3-chloroperoxybenzoic acid (0.25 g, 1.45 Millimoles) and toluene (2.2 ml). Stirring was continued for 30 minutes at 0 ° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 3 hours. After diluting with 20 ml of CH2C12, the reaction mixture was washed with 10% Na2S205 (1 x 10 ml), water (1 x 10 ml), saturated NaHC03 (1 x 10 ml), and brine (1 x 10 ml), and finally dried over Na2SO4. Filtration and concentration gave 0.814 g of product as a b / a epoxide mixture. 0.23 g portions were purified by reverse-phase HPLC (CH3CN / H20) 9 to obtain 0.073 g of b-epoxide (as above), a white foam: [from] 2GD + 25.6 ° (c 0.626, CHCls); XH NMR (300 MHz , CDC13) δ 7.26-7.03 (m, 7 H), 6.85-6.83 (d, 1 H, J = 8.4 Hz) 6.82-6.72 (m, 1 H), 5.74-5.69 (d, 1 H, J = 15.2 Hz), 5.44-5.42 (d, 1 H, J = 7.9 Hz)? 5.23-5.18 (m? 1 H), 4.85-4.81 (dd, 1 H, J = 9.7, 2 · 9 Hz), 4.77-4.73 (m, 1 H), 3.88 (s, 3 H), 3.66 (s, 1 H), 3.46-3.39 (dd, 1H, J = 13.5, 8.8 Hz), 3.12-3.07 (m, 3H), 2.89- 2.87 (dd, 1 H, J = 1.5, 7.7 Hz), 2.60-2.54 (m, 1 H), 2.49-2.41 (m, 1 H), 1.81-1.65 (m, 3 H), 1.34-1.25 (m , 1 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.15-1.13 (d, 3 H, J = 7.0 Hz), 0.87_0.82 (m, 6 H); 13C NMR ( 63 MHz, CDC13) d 177.8, 170.3, 164.9, 164.7, 154.0, 141.6, 137.8, 132.4, 130.7, 129.6, 128.1, 127.3, 127.2, 124.6, 122.4, 115.8, 115.5, 112.2, 75.8, 71.0, 63.0, 58.2, 56.0, 54.4, 46.3, 42.7, 40.4, 39.3, 36.7, 35.2, 23.5, 22.8, 22.76, 22.6, 21.1 13.3; IR (CHC13) 3426, 3030, 3006, 2964, 2936, 1752, 17 11, 1683, 1608, 1514, 1485, 1442, 1303, 1281, 1259, 1188, 1155, 1067, 838 cm · 1; Analysis (C36H44C1FN208) C, H, N. -196- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (194) Example 9 0

HC1 in a 4 M solution of dioxolane (0.4 liters, L6 mmol) was added dropwise b-epoxide (as above) (0.44 g, 0.64 mmol) at 30 minutes over 30 minutes. -70 ° C solution in ml of CHKl2. At _70. (: After being stirred for 2 hours, the solution was concentrated in the air. The crude product was subjected to radial PLC (silica gel, 30-5 (mol%)

EtOAc / CH2Cl2) and then purified by reverse-phase HPLC (50:50) CH3CN: H20 to obtain 0,152 g (33%) of the desired chlorohydrin (as described above) as a white foam: [a] 20d + 60.0 ° (c 2.62 , CHC13); lH NMR (300 MHz, CDC13) ά 7,41-7.05 (m, 7H), 6.87-6.84 (d, 1H, J = 8.4 Hz), 6.83-6.77 (m, 1H), 5.80-5.75 (d, 1H, J = 15.4Hz), 5.52-5.49 (d, 1H, J = 7.8 Hz), 5.13-5.21 (m, 1H), 4.94-4.90 (dd, 1H, J = 9.7, 3.2 Hz), '4.75-4.72 (m, 1H), 4.67-4.63 (d, 1H, J = 9.5 Hz), 4.00-3.95 (m, 1H), 3.89 (s, 3H), 3.42-3.35 (dd, 1H, J = 8.3, 13.5 Hz), 3.20-3.02 (m, 3H), 2.71-2.65 (m, m), 2,49-2.37 (m, 2H), 1.82-1.63 (m, 2H), le51-1.38 (m, 2H), 1.23 (s, 3H), 1.17 (s, 3H), 1.04-1.02 (d, 3H, J = 7.0 Hz), 0.97-0.85 (m, 6H); 13C NMR (63 MHz, CDC13) Θ 177.6 , 170.5, 170.3, 165.3, 160.7, 153.9, 142.2, 137.5, 134.5, 130.8, 129 · 8, 129 · 7, 128 · 2, 124.6, 122.2, 76.1, 74.0, 71.1, 61.4, 56.1, 54.5., 46.4, 42.7, 39.6, 38.4, 36.3, 35.1, 24.8, 23.0, 22.9, 22.7, 21.5, 8.6; IR (CHC13) 3423, 2965, 293 5, 2873, 1751, 1715, -197- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page), 1T Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative 533206 A7 B7 V. Description of the invention (195) 1679, 1607, 1528, 1504, 1485, 1464, 1442, 1302, 1281, 1193, r 1159, 1152, 1127, 1067 cm · 1; Analysis (C36H45C12N208) C , H, N. Example 9 1 Cryptocin-151, -152, -153, -154, -155, -156, -159, 160, _161, 466, -167, -172, -181, -188, 234, 236, 238 , 247, 251 and 255 ° Table 1

Cryptocin # aryl or alkyl yield (E + Z)%% trans isomer (approximately) 151 72 90 152 80. 70 155 60 &lt; 10 156 51 70 160 61 67 172 ocrh 78 90 255 〇τδγ 85 60 -198- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Read the precautions on the back before filling in this page)

533206 Α7 Β7 V. Description of the invention (196)

Cl Ar-, (1.5 equivalents)

THF / -78 &gt; C νδ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs # Ar Yield UM)% E% Isomers (approximately) 153 80 90 154 Η, οο OCH, 63 90 159 75 90 161 61 80 166 cr1 38 90 167 * CH, 48 90 181 Ί3 75 188 Λρτ * 1 ψ 85 80 234 TeOMSOHjC ^^ 81 85 236 if1 ^ ΒοοΗΝΗ, Ο ^^ 59 90 247 ^ BoeMN ^ v ^ S XX 51 &gt; 90 251 XT1 HOOCH 43 &gt; 90 199 This paper size is applicable to Chinese National Standard (CNS) A4 size (210 × 297 mm) 533206 A7 B7 V. Description of the invention (197) Suitable for Hermitin-108 and a variety of triphenylphosphoranes A typical procedure for (phosphorane) coupling is described below, using the preparation of Cryptocin-152 as an example. Cryptocin-152: Cinnamonyl triphenyl orthophosphine is composed of cinnamyl triphenylphosphonium chloride scale (0.311 g '0.750 mmol) in THF (5.7 ml) with butyl bell ( 300 μl, 2.5 M solution in hexane, 0.075 mmol) was generated at -78 ° C and then slowly heated to room temperature. In this reaction mixture, cinnamyltriphenylorthophosphine (1.46 ml, 0.182 mmol) was slowly added to the aldehyde (68.6 mg, 0.122 mmol) in THF (3 ml) at 78 ° F, and stirring was continued for 2 hours. The reaction mixture was brought to ambient temperature, treated with saturated NH4C1 (5 ml), then treated with water (15 ml), and extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over MgS04, and evaporated. The residue was added to a small ODDS column and dissolved with 1: 1 H20 / CH3CN and 1: 3 H20 / CH3CN. The eluate was evaporated to obtain a mixture of cryptocin-152 and its Z isomer (E / Z 7 ·· 3, 64.3 mg, 80%). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page). Using the same experimental procedure, aldehyde (cryptocin-108) and 1-fluorenylmethyltriphenylphosphorane 3-methoxybenzyltriphenylphosphorane, 3,5 · dimethoxybenzyltriphenylphosphorane, methoxymethyltriphenylphosphorane, 2,4-dimethylbenzene Methyltriphenylphosphorane, 3-furanmethyltriphenylphosphorane, p-trifluoromethylbenzyltriphenylphosphorane, 2-methylbenzyltriphenylphosphorane, 3,5 · Dimethylbenzyltriphenylphosphorane, 2-fluorenylmethyltriphenylphosphorane, 2-fluorobenzyltriphenylphosphorane, 3,5-difluorobenzyltriphenylphosphorane Phosphine, 4-hydroxymethylbenzyltriphenylphosphorane, 4-〇Boc-aminomethyl) benzyltriphenylphosphorane, 3- (Nt-Boc-amino) benzyltriphenyl The reaction of orthophosphine and phenylthiomethyltriphenyl rust, respectively, obtained cryptocryptin-151, -153, -154, -156, -159, -160, -161, -200- This paper size applies to Chinese national standards (CNS) A4 size (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (198) 466, -167, -172, -181, -188, · 234, -236, -247, and 255. Butyl lithium was used as a base in the production of cryptofucin from the corresponding chlorinated or brominated triphenyl rust salts, but in the preparation of methoxymethyltriphenylphosphorane, 3-furanmethyltriphenylphosphorane, As the 4-hydroxymethylbenzyltriphenylphosphorane, phenyl J 罜 was used. A similar reaction involving brominated hydroxymethyl triphenyl rust, n-butyl noodles, and Cryptocin-1 10 yields an unexpected analogue Cryptocin d 55. A slightly modified procedure was used to prepare the carboxymethyl analog Cryptocin-251. A solution of 4- (carboxymethyl) benzyltriphenylrust (0.289 g, 0.59 ml) in THF (5 ml) bromide with lithium phenyl (1.8 M, 653 μl; 1.18 mmol) After processing at -78 ° C for 5 minutes, the flask was transferred to an ice-water bath. After 30 minutes, 0.9 ml of the reaction mixture was slowly added to a flask containing -cryptocin-108 (35 mg) in 3 ml of THF at -78 ° C and stirred for 2 hours. The reaction mixture was acidified with IN HC1 (1 ml), water (30 ml) was added, and extracted with ethyl acetate (30 ml x 2). The organic layer was dried over MgS04 and evaporated. The residue was subjected to flash chromatography on ODS silica, and was dissolved with 1: 1 H20 / CH3CN and 35: 65 H20 / CH3CN. The post-evaporation fraction was purified on a reverse-phase HPLC column (Econosil C18, 10 &quot;, 250X22 mm '6 ml / min, 35: 65 H20 / CH3CN) to obtain an impure sample of Cryptocin-251. Purification by reverse phase chromatography (Econosil C18, 10 //, 250 X 10 mm, 3 ml / min, acetic acid in a 0.5% solution in 2: 3 H20 / CH3CN), to obtain Cryptocin-251 (10 mg) . The main experimental data and cytotoxicity data for producing styrene analogs are shown in Tables 1 and 2. Triphenylphosphonium salt: cinnamyl triphenylphosphonium chloride, 1 · methylmethyl chloride-201-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read first Note on the back page, please fill in this page), -port 533206 A7 --- B7 V. Description of invention (199) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the note on the back page before filling out this page) Benzyl chloride's methoxymethyl triphenyl rust and 2-methylbenzyl triphenyl rust are commercially available, while 3-methoxybenzyl triphenyl chloride is commercially available. '3,5-Dimethoxybenzyltriphenyl rust, 2,4-Dimethylbenzyl diphenyl chloride scales are composed of triphenylphosphine and a slight excess of the corresponding vapor in toluene. Prepared under reflux for 4 hours. 4_trifluoromethylbenzyltriphenylphosphonium bromide, 3-furanmethyltriphenylbromide bromide, 2-fluorenylmethyltriphenyl bromide bromide, 3,5_ monofluorobenzyl bromide Triphenylphosphonium, 4- (third-butyldimethylsilyloxymethyl) benzyl triphenyl scale, 4- (N_t_B〇c_aminomethyl) benzyl triphenyl bromide The basic scale 'and 3- (Nt-Boc_amino) benzyltriphenyl scale are prepared from the corresponding brookate by treating triphenylphosphine in toluene at room temperature for 12 hours. 4- (carboxymethyl) benzylated triphenyl scales are prepared from bromide treated with triphenylphosphine in a $: 1 toluene / THF solution at room temperature for 48 hours. 3-furan methyl bromide, 2-fluorenyl bromide, and 3- (N + Boc_amino) benzyl bromide are composed of 3 · furan methanol, 2-benzyl alcohol, and 3- (N-t_Boo Amino) benzyl alcohol was produced by treating PBr # THF at -78.0. 3-furan methanol and 2-fluorene methanol are commercially available. 3_ (N-t_Booamino) benzyl alcohol is prepared from commercially available samples of 3-aminobenzyl alcohol. 4- (Third-butyldimethylsilyloxymethyl) benzyl bromide and 4- (Nt-Bocaminomethyl) benzyl bromide Commercially available samples of 4-aminomethylbenzoic acid were prepared using the following experimental procedures. 4- (Third-butyldimethylsilyloxymethyl) benzyl bromide: "Methyl methylbenzoate (2 g) and triethylamine (3.36 ml) The mixture in ml) was treated with tert-butyldimethylsilyl trifluoromethyl ester (4.47 g) at -78C. After 30 minutes, the mixture was added to room temperature, -202- This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (200) Continue to stir for 30 minutes. Water (30 ml) and ethyl acetate (60 Ml) was added to the reaction mixture, and the organic layer was washed with 0.3 M KHS04, water, and brine, dried over MgS04, and filtered. The solvent was evaporated and the residue was subjected to flash chromatography on a silica column and dissolved in 10% EtOAc / hexane. To obtain methyl 4 · (third butyldimethylsilyloxymethyl) benzoate (3.3 g, yield 95%). Lithium aluminum hydride (0.21 g) was dispersed in diethyl ether (20 ml). Cool to -78 ° C under argon with methyl 4- (third butyldimethylsilyloxymethyl) benzoate (2.0 5 g) were treated dropwise in 10 ml of acetic acid. After 30 minutes, ethyl acetate (2 ml) was added to quench the excess hydride and then saturated ammonium chloride (1.5 ml) was added. The precipitate was separated by filtration, Wash with ether. Evaporate the solvent to obtain 4- (third butyldimethylsilyloxymethyl) benzyl alcohol (1.71 g, yield 93%). 〇4- (third butyldimethylsilyloxy) Methylmethyl) benzyl alcohol (1.7 g) was dissolved in THF (15 ml) and treated with phosphorus tribromide (0.609 g) at -78 ° C. After 30 minutes, the reaction mixture was diluted with ether (80 ml), Wash with saturated sodium bicarbonate (30 mL), water and brine, and dry over MgS04. The ether layer was evaporated, and the residue (2.0 g) was subjected to flash chromatography on silica using 5% EtOAc / hexane as the eluent to obtain 4 -(Third butyldimethylsilyloxymethyl) benzyl bromide (1.05 g, yield 49%). 4- (NtBoc-aminofluorenyl) benzyl bromide: in dicarbonic acid 4- (Aminomethyl) was added to a solution of di-t-butyl ester (2.18 g, 10 mmol) in triethylamine · dimethylformamide (9: 7.5 ml) at room temperature. ) Benzoic acid (0.75 g, 5 mmol), the reaction mixture was heated at 40-50 ° C. for 10 minutes. After the amino acid was dissolved, continued to incubate at room temperature for 1 hour. The solvent was removed in the air, and the residue was Rare ____-203-This paper size is applicable to Chinese National Standard (CNS) M specification (21 × 297 mm) (Please read the precautions on the back before filling this page), 1T Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 _______ ^ 5. Description of the invention (201) HCl (pH &gt; 2) was acidified, immediately extracted with EtOAc, and the organic layer was dried over MgS04. After the solvent was removed, the obtained residue was treated with excess diazomethane (produced by diazald) in ether for 30 minutes, and the excess diazomethane was decomposed with acetic acid. After the solvent was removed, the obtained residue was chromatographed on a silica column (20 g) using hexane / Et0Ac (9: j) to obtain 4_ (N-t_Boc · aminomethyl) benzoic acid Ester (07 g, yield 81/0). In a cold suspension of LiAlH4 (60 ^: g, 1.5 mmol) in ether (5 ml) · 78 ×: Dropwise addition of methyl 4- (Nt-Boc-aminomethyl) benzoate (〇8 G '3 mmol) in ether (5 ml) and the mixture was heated to ambient temperature. After 3 hours, LiAlHWi (100 mg) was added again, and the reaction mixture was continued at room temperature for 10 minutes. The excess LiAIH4 was destroyed with EtOAc and then with saturated ammonium vaporization (1.0 mL). The precipitated solid was filtered and washed with ether. The filtrate was evaporated to obtain 4- (N_t-Boc_aminomethyl) benzyl alcohol (250 mg, 35%).

A solution of 4_ (N_t-Boc • aminomethyl) benzyl alcohol (250 mg, 1.1 mmol) in THF (5 ml) with phosphorus tribromide (30 μl, 032 mmol) at -78 . (: Treatment for 2 hours. After this period, the reaction was quenched with solid NaHCO3 (50 mg) and filtered to remove the solids, and the filtrate was evaporated to obtain 4-() ^ +; 6〇 (:-aminomethyl) benzyl Bromide (300 mg, 95%). The desired E isomer is crystallized from an ethyl acetate / ether solution and the corresponding E / Z mixture is separated. In the cinnamyl group with few e / Z selectivity and a few In the case of other analogues, the crude mixture is isomerized using the following procedure of the cinnamyl analogue Cryptocin-152. Isomerization: Cryptocin-152 and its cis isomer mixture (E / Z 7: 3, 62 mg, 0.10 millimolar) dissolved in benzene (3 ml), and thiophenol (10 microliters, _ -204-) This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) (Please read the notes on the back before filling in this page), \-口

If printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 Μ B7 ____ V. Description of the invention (202) 0.10 moles and M'-azobis (cyclohexanenitrile) (12 mg, 0.05 mg ) Backflow. After 16 hours, the mixture was brought to ambient temperature and added to a small silica column. The column was washed with dichloromethane and the compound was eluted with 1: 1 ethyl acetate / dichloromethane. The solvent was evaporated to obtain cryptocryptin-151 (53 mg, 85%), which contained about 5% cis-isomer. Cryptocin-151: EIMS m / z (relative intensity) 688/690 (3.3 / 1.5), 412/414 (18/6), 277 (100), 233 (18), 195/197 (16/6) , 193 (29), 141 (38); high-resolution EIMS m / z 688.2900 (calculation of C38H45C1N207 値 △ 1.5 mnrn). 4 NMR data, see Table 3; 13C NMR data, see Table 4 0 Cryptocin-152: EIMS m / z (relative intensity) 664/666 (24/7), 412/414 (21/7), 253 ( 100), 91 (85); high-resolution EIMS m / z 664.2939 (calculation of 37Λ-2.3 mmu for C37H45C1N207). 4 NMR data, see Table 3; 13CNMR data, see Table 4. Cryptocin-153: EIMS m / z (relative intensity) 668/670 (3.7 / 1.4), 412/414 (32/12), 257 (62), 198 (100), 195/197 (36/11) ; High-resolution EIMS m / z 668.2817 (calculation of C36H45C1N208 値 △ 4.7 mmu) 〇4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-154: EIMS m / z (relative intensity) 698/700 (2.5 / 0. 8), 412/414 (18/5), 287 (28), 28 (35), 195/197 ( 18/6), 139 (100); high-resolution EIMS m / z 698.2946 (calculation of C37H47C1N209 値 △ 2.5 mmii). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptophyllin-155: EIMS m / z (relative intensity) 604/606 (20/6), 412/414 (24/8), 280/282 (24/8), 195/197 (100/33); High resolution EIMS m / z -____- 205 -__ This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

1T 533206 A7 B7 V. Description of the invention (203) 604.2894 (calculation of C32H45C1N207 値 △ 2.1 mmu). 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) A 5.76 (2, d; 15.5), 6.66 (3, ddd; 15.5, 9.5 and 5.9), 2.32-2 · 44 (4-Η2, m), 4.92 (5, m), 2.66-2.76 (6, m), 0.98 (6-Me, d; 6.8), 5.21 (7, t; 10.9), 5.46 ( 8, dt; 10.9 and 7.4), 2.00 (9-Η2, m), 1.38 (10-H2, m), 0.91 (10-Me, t; 7.5); B 4.81 (2, m) , 5.70 (2-NH, d; 8.5), 3.04 (3, dd; · 14 · 5 and 7.2), 3.14 (3, dd; -14 · 5 and 5.6) 7.22 (5, d; 2.2), 3.87 (7-OMe, s) 6.84 (8, d; 8.5), 7.08 (9, dd; 8.5 and 2.2); € 2.66 2.76 (2, m), 1.22 (2-Me, d; 7.4) , 3.27 (3, dt; 13.5 and 6.8), 3.52 (3, m), 6.93 (3-NH, brt; 6.4); D4.86 (2, dd; 9.8 &amp; 3.5), 1.49 (3, m), 1.71-1.80 (3/4, m), 0.90 (4-Me, d; 6.0), 0.94 (5, d; 6.5); 13C NMR (CDC13) unit d (carbon position) A 165.5 ( 1), 125,0 (2), 141.6 (3), 36 · 5 (4), 77 · 9 (5), 36.2 (6), 17.7 (6-Me), 130.0 (7), 131.6 ( 8), 29.6 (9 · Η2), 22.8 (10-Η2), 13.8 (11-H3); Β 171.0a (1), 53.5 (2), 35.1 (3), 129.9 (4 ), 131.0 (5), 122.4 (6), 153.9 (7), 56.1 (7-OCH3)? 112. 2 (8), 128.4 (9); C 175.6 (1)? 38.3 (2), 14.0 (2-Me), 41.2 (4); D 170.9a (1), 71.6 (2), 39 · 5 (3), 24.7 (4), 21.4 (4-Me), 23.1 (5). a The signals are interchangeable. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) , 280/282 (22/6), 195/197 (100/33); high-resolution EIMS m / z 592.2568 (calculation of 3Λ-1.6 mmu for C30H41C1N208). 4 NMR data, see Table 3; 13C NMR data, see Table 4.

Cryptocin 159: EIMS m / z (relative intensity) 666 (3), 412.41 (16/4), 396 (52), 255 (100), 195/197 (30/8), 91 (54 ); High-resolution EIMS-206- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 Α7 B7 V. Description of the invention (204) m / z 666.3060 (Calculation of C37H47C1N207 値 △ 1.1 mmu) . 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-160: EIMS m / z (relative intensity) 628/630 (9/4), 412/414 (63/23), 280 (25), 217 (89), 195/197 (89/30) ; High resolution EIMS m / z 628.2532 (calculation of C33H41C1N208 値 △ 2.0 mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-161 ·· EIMS m / z (relative intensity) 706/708 (6/2), 412/414 (49/18), 295 (15), 280/282 (25/7), 195/197 (100/34); high-resolution EIMS m / z 706.2623 (calculation of C36H42C1F3N207 値 △ 1.0mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-166: EIMS m / z (relative intensity) 652/654 (1.1 / 0.4), 412/414 (18/5), 241 (37), 195/197 (64/20) high resolution EIMS m / z 652.2918 (calculation of C38H45C1N207 値 △ -0.2 mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin_167: EIMS m / z (relative intensity) 666/668 (3.4 / 1.1), 412/414 (26/9), 280 (11) 255 (67), 195/197 (46/15); High resolution EIMS m / z 666.3058 (calculation of C37H47C1N207 値 △ 1.4 mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Cryptophyllin-172: EIMS m / z (relative strength) 688/690 (3/2), 412/414 ( 12/4), 277 (67), 218 (100), 195/197 (29/10), 141 (63); high-resolution EIMS m / z 688.2916 (calculation of C39H45C1N207 値 ^ -0.1 mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-181: EIMS m / z (relative intensity) 656/658 (9.0 / 3.3), 412/414 (84/34), 245 (71), 195/197 (47/7); high-resolution EIMS m / z _____- 207- _ This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the consumer cooperation of the Central Bureau of Standards of the Ministry of Economy 533206 kl B7 V. Description of Invention (205) 656.2674 (C35H42C1FN207 The calculation (値 △ ·· 9 mmu). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-188: EIMS m / z (relative intensity) 674/676 (20/4), 412/414 (57/20), 280/282 (20/7), 263 (13), 195/197 ( 89/27); high-resolution EIMS m / z 674.2551 (calculation of C35H41ClF2N2 0 値 Δ 1 · 9 nrnm). 4 NMR data, see Table 3; 13C NMR data, see Table 4. Cryptocin-234: A mixture containing Cryptocin-234 and 15% of its Z isomer (58.3 mg) was repeatedly crystallized in an EtOAc / ether solution to obtain Cryptocin-234 (47 mg) and its Z isomer (11 mg). NMR (CDC13) amino or hydroxy acid unit 0 '(carbon position, multiplicity; J Hz) A 5.77 (2, d; 15.2), 6.68 (3, ddd; 15.2, 9, 7 and 5 4), 2.37 (4, dt; 14.2 and 10.5), 2.52 (4, m), 4.99 (5, m), 2.55 (6, m), 1.13 (6-Me, d; 6.8), 5.99 (7, dd; 15.8 and 8.8), 6.40 (8, d; 15.8), 7.25a (276f, d; 8.2), 7.29a (375 *, d; 8.2), 4.71 (4, CE2OTBDMS, brs) , 0 · 08 (6Η) and 0.93 (9Η) (4, -CH2OTB, DMS); B 4.81 (2, m), 5.77 (2-NH, masked by other signals), 3.03 (3, dd;- 14.4 and 7.3), 3.14 (3, dd; -14.4 and 5.4), 7.22 (5, d; 2.0), 3.86 (7-〇Me, s), 6.83 (8, d; 8.4), 7.07 (9 , dd; 8 · 4 and 2.0); C 2.71 (2, m), 1.22 (2-Me, d; 7.2), 3.29 (3, m), 3.49 (3, m), 6.98 (3 · NH, br t; 5.6); D 4.84 (2, m), 1.36 (3, m), 1.59-1.71 (3/4, m), 0.73 (4-Me, d, 6.4), 0.77 (5, d, 6.2). 3 interchangeable; 13C NMR (CDC13) unit β (carbon position) a 165.5 (1), 125.2 (2), 141.4 (3), 36.4 (4), 77.4 (5), 42.2 (6), 17 · 3 ( 6-Me), 129.6 (7), 131.6 (8), 136.4 (l1), 126.0a (276 ·), 126.3a (375 丨), 140.9 (4 丨), 64 · 7 (4, QH20 ·), 25 9 and -5.3 (4 ^ CH2OT ^ DMS); B 171.0b ⑴, 53.6 (2), ___-208-This paper size applies to China National Standard (CNS) A4 (21 OX 297 mm) (Please read first (Notes on the back then fill out this page)

1T if- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 Α7 Β7 V. Description of the invention (206) 35.1 (3), 129.9 (4), 131.0 (5), 122.4 (6), 153.9 ( 7), 56 · 1 (7-OCH3), 11 · 2 (8), 128.4 (9); C 175 · 6 (1), 38.3 (2), 14.0 (2-Me), 41.1 (3) D 170.9b (1), 71.5 (2), 39.5 (3)? 24,5 (4)? 22.7 (4-Me), 21.2 (5). a &amp; b signals are interchangeable. Cryptonin-236 ·· H NMR (CDCI3) amine or acyl unit d (carbon position, multiplicity; J Hz) A 5.76 (2, d; 15 · 2), 6.68 (3, ddd; 15.2, 9.6 &amp; 5.6), 2,37 (4, ιη), 2.51 (4, η), 5.0 (5, π), 2.54 (6, η), 1.13 (6- Me, d; 6,9), 6 ^ 0 (7, dd; 15.9 &amp; 8.6), 6.39 (8, d; 15.9), 7.20-7.30 (2737576 \ br m), 4.28 (4, -CH2NH- t-Boc5 d; 4.9), 4.80 (4f-CH2NH-t-Boc, d; 4.9)? 1.46 (4, -CH9NH-t-Boc: s); B 4.80 (2, m), 5.65 (2 · NΗ, d; 8.5), 3.04 (3, dd; -14.4 and 6.9), 3.13 (3, dd; -14 · 4 and 55 ·), 7.22 (5, d; 2.2 ·), 3.87 (7- OMe, s), 6.83 (8, d; 8.4), 7.08 (9, dd; 8.4 and 2.2); C 2.71 (2, m) 1.22 (2-Me, d; 7.3), 3.27 (3 , m), 3.51 (3, m), 6.93 (3-NH, br t; 5.6); D 4.84 (2, dd; 9.9 and 3.5), 1.36 (3, m), 1.58-1.70 (3 / 4, m), 0.74 (4-Me, d, 6.4), 0.78 (5, d, 6.4); 13C NMR (CDC13) unit d (carbon position) A 165.4 (1), 125.2 (2), 141.4 (3 ), 36.5 (4), * (5), 42.2 (6), 17.3 (6-Me), 130.1 (7), 131.4 (8), 135.9 (Γ), 126.4 (276 丨), 127.8 (375 丨), 138.4 (4 *), 44.4 (4, -CH2NH -t-Boc), 28.4 (4, -CH.NH-t-Boc &gt;): B 170.9 (1), 53.5 (2), 35.1 (3), 129.9 (4), 131.1 (5), (6) , 154.0 (7), 56.2 (7-OCH3), 112.3 (8), 128.4 (9); C 175.6 (1), 38.3 (2)? 14.0 (2-Me), 41.2 (3); D 170 · 9 (1), 71.6 (2), 39.6 (3), 24.5 (4), 22.7 (4-Me), 21.3 (5). * Hidden under the solvent signal. Cryptophyllin-238: Cryptophyllin-234 (14 mg) in THF (1.5 ml) with fluorine _ -209- _, this paper size applies Chinese National Standard (CNS) A4 specification (210 × 29 * 7 mm) ( Read the precautions on the back before you fill out this page) — • | click | | -port 533206 A7 B7 V. Description of the invention (207) Tetrabutylammonium solution (25 μl, 1) ^ in Ding 1117 ) At 0. € Handling. After 1 hour, saturated NH4C1 (5 ml) was added to the reaction mixture, then water (15 ml) was added 'and extracted with EtOAc (50 ml). The EtOAc layer was dried over MgS04 and evaporated. The residue was purified on a small silica column using cH2Cl2 &amp; EtAc, as the eluent. After the eluate was evaporated, cryptocryptin 238 (118 mg) was obtained. EIMS m / z (relative strength) 668/670 (3 / 0.5), 412/414 (38/14), 257 (29), 195/197 (25/10); high-resolution EIMS m / z 668.2898 (C36H45ClN208i calculation値 a _3 4 mmu). 4 NMR (CDC13) Amine-based printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)

Or hydroxy acid unit β (carbon position, multiplicity; j Hz) A 5.76 (2, d; 15.6), 6.68 (3, ddd; 15.6, 9.8 and 5.5), 2.36 (4, dt; 14.4 and 10.4) , 2.51 (4, br dd; 14.4 and 5.1); 5.00 (5, m), 2.55 (6, m), 1.13 (6-Me, d; 6.8), 6.01 (7, dd; 15.9 and 8.8), 6.40 (8, d; 15.9), 7.31 (27375, / 6, br s), 4.47 (4, -CII2OH, brs); B 4.80 (2, m), 5.78 (2-NH, d; 8.4), 3.01 (3, dd; -14 · 4 and 7.4), 3.13 (3, dd; -14.4 and 5.5), 7.21 (5, d; 2.0), 3,86 (7-OMe, s), 6.83 (8, d 8.5), 7.07 (9, dd; 8.5 and 2.0); C 2.71 (2, m), 1.21 (2-Me, d; 7.1), 3.28 (3, m), 3,49 (3, m), 6.98 (3 · NH, br t; 6.0); D 4.84 (2, dd; 9.9 and 3.2), 1.35 (3,11〇, 1.58 · 1.71 (3/4, m), 0.74 (4_Me, d; 6 · 4), 0.77 (5, d; 6,3); 13C NMR (CDC13) unit β (carbon position) A 165.5 (1), 125.2 (2), 141.4 (3), 36.4 (4), 77.4 (5), 42.2 (6), 17.3 (6-Me), 130 · 1 (7), 131.4 (8), 136.1 (Γ), 126.3a (276 ^), 127.2a (375 ^), 140.4 ( 4f)? 64.9 (4 ^ £ H2OH); B 171.0b (1), 53.7 (2), 35.0 (3), 129.9 (4), 131.0 (5), 122.3 (6), 153.9 (7), 56.1 (7-OCH3), 112.2 (8), 128.4 (9); C 175.6 (1), 38.2 (2), 14.0 (2-Me), 41.1 (3); D 170,8b (1), 71.5 (2), 39.5 -210- This paper size applies to Chinese National Standard (CNS) A4 (2 OX 297 mm l Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (208) (3), 24.5 (4), 22.7 (4-Me), 21.3 (5). The signals are interchangeable. Cryptophyllin-246: Cryptocin-236 (9 mg, 0.002 mmol) in CH2C12 (50 μl) with 4N HC1 in dioxolane (20 μl, 0.08 mmol) Ear) at room temperature. After 1 hour, the solvent was evaporated, and the residue was flash-chromatographed on a small C18 stone-cutting column (Alltech, 500 mg) using methanol / water (j: j) to dissolve it. The first eluate (3 ml), after evaporation of the solvent, Cryptocin-246 (7 mg, 85%) was obtained. NMR (CD3OD) amine or hydroxy acid units (carbon position, multiplicity J Hz) A 5.92 (2, dd; 15.2 and 1.7), 6.69 (3, ddd; 15.2, 11.1 and 3.8), 2.35 ( 4, m), 2.68 (4, m), 5.06 (5, m), 2.63 (6, m), 1.15 (6-Me, d; 7.4), 6.18 (7, dd; 15.9 and 8.9), 6.50 ( 8, d; 15.9), 7.40 (276, br d; 8.2), 7.46 (375 *, br d; 8.2), 4.08 (4 * · CH2NH2HC1, s); B 4.51 (2, dd; 11.1 and 3.4), 2.75 (3, m), 3.17 (3, dd; -14.5 and 3.9), 7.27 (5, d; 2.0), 3.83 (7-OMe, s), 6.97 (8, d; 8.5), 7.16 (9, dd; 8.5 and 2.0); C 2.73 (2, m), 1.17 (2-Me, d; 8.0), 3.26 (3, m), 3.56 (3, m); D 4.92 (2, dd; 9.8 and 3 · 9), 1.35 (3, m), 1.54 · 1 · 65 (3/4, m), 0.71 (4_Me, d; 6.4), 0.75 (5, d; 6.4); 13C NMR ( CD3OD) unit d (carbon position) A 168.4 (1), 125.7 (2) 143.5 (3), 37.7 (4), 78.6 (5), 43.5 (6), 17.5 (6_Me), 133.6 (7), 131.9 ( 8), 139.5a (l '), 128.0 (2, / 6,), 130.3 (375'), 133.3a (4,), 44.0 (4'-C_H2NH2HC1); B 174.1 (1), 57.4 (2) , 36.3 (3), 132.2 (4), 131.5 (5), 123.3 (6), 155.4 (7), 56.6 (7-OCH3), 1 13.5 (8), 129.3 (9); C 177.5 (1), 39.0 (2), 15.1 (2-Me), 41.2 (3); D 172.3 (1), 72.8 (2), 41.0 (3), 25.7 (4), 21.7 (4-Me), 23.2 (5). a signal can be mutually. Cryptophyllin-250: Cryptophyllin-247 (5.1 mg) in digas methane (80 microliters). The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back first) (Fill in this page again) Dingquan 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. The solution of the invention description (209) is treated with hydrochloride (40 microliters, 4 N in dioxolane). After 2 hours the reaction mixture was concentrated and diluted with water and passed through a short ODs column. The column was washed with water (5 ml) 'and then with CH3CN (3 ml). The eluate was evaporated to obtain Cryptocin-250 (5 mg). Purification on reverse-phase HPLC (EConosii C18, 25 cm x 10 mm, 10 β, 35% H20 / CH3CN, 4 l / min), a pure sample was obtained (4 mg, tR for 18 minutes). EIMS m / z (relative strength) 653/655 (15/10), 533 (33), 242 (48), 195/197 (36/13); high resolution EIMS m / z 653.2865 (calculation of C35H44C1N307) △△ 〇 .3 mmu). 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) Α 5.78 (2, d; 15.1), 6.68 (3, ddd; 15.1,9.6 and 5.4), 2.35 (4 , dt; 14.4 and 10.7), 2.48 (4, br dd; 14.4 and 5.1), 5.01 (5, m), 2.53 (6, m), 1.12 (6-Me, d; 6.8), 6.01 (7, dd; 15.9 inverse 8.7), 6.33 (8, d; 15.9), 6.81m, 6.89 d, 6.94 s and 6.99 m (273, -NH3 / 476,), 7.15 (5 ', t 7.8); B 4 · 79 (2, m), 5.95 (2-NΗ), 3.02 (3, dd; -14 · 4 and 7.3), 3 · 15 (3, dd; · 14 · 4 and 5. 5), 7.22 (5, d; 2.0), 3.86 (7-OMe, s), 6.84 (8, d; 8.4), 7.08 (9, dd; 8.4 and 2.0); C 2.70 ( 2, m), 1.23 (2-Me, d; 7.1), 3.27 (3, m), 3.51 (3, m), 6.99 (3-NH, m); D 4.87 (2, dd; 9.8 and 3.2) , 1.39 (3, m), 1.59-1.73 (3/4, m), 0.76 (4-Me, d, 5.4), 0.80 (5, d, 5.6); A 165.8 (1), 125.2 (2 ), 141.5 (3), 36.4 (4), 77.3 (5), 42.0 (6), 17.1 (6-Me), 131.0 mm, 131.3 (8), 138.3 (Γ), 116.0 (2 丨), 121 · 1 (4,), 130.0 (5 丨), 118.0 (6 '); B 171.2 (1), 54.0 (2), 35.0 (3), 129.8 (4), 131.0 (5), 122.4 ( 6), 153.9 (7), 56.1 (7-O CH3), 112.3 (8), 128 · 4 (9); C 175 · 6 (1), 38.2 (2), 14 · 2 (2_Me), 41.0 (3); D 170.9 (1), 71.5 ( 2), 39.6 (3), 24 · 6 (4), -212- This paper size applies to China National Standard (CNS) A4 specifications (21〇 ×; 297 mm) (Please read the precautions on the back before filling in this page)

533206 A7 B7 V. Description of the invention (210) 22.8 (4-Me), 21.4 (5) 〇 Cryptocin-251: EIMS m / z (relative strength) 696 (0.7, 652 (M +-C02; 0.7), 412 / 414 (4/2), 285 (6), 241 (5), 195/197 (11/3); high-resolution EIMS m / z (calculation of C37H45ClN2 09 値 β △ mmu). 4 NMR data, see Table 3;] 3C NMR data, see Table 4. Cryptocin-255: 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity J Hz) A 5.78 (2, d; 15.1), 6.67 (3, ddd; 15.1, 9.5 and 5.9), 2.37 (4, dt; 14.9 and 10.3), 2.45 (4, m), 4.96 (5, m), 2.52 (6, m), 1.09 (6-Me, d; 6.8), 5.74 (7, dd; 15.1 and 8.9), 6.24 (8, d; 15.1), 7.20-7 · 33 (2, / 3, / 4 '/ 576' M); B 4.83 (2, m), 5.64 (2-NH, d; 8.8), 3.05 (3, dd; -14.6 and 7.1), 3.14 (3, dd; -14.6 and 5.4), 7.22 (5 , d; 2.0), 3.88 (7-OMe, s), 6.85 (8, d; 8.5), 7.08 (9, dd; 8.5 and 2.0); C 2.72 (2, m), 1.23 (2-Me , D; 7.3), 3.29 (3, m), 3.50 (3, m), 6,95 (3-NH, m); D 4.86 (2, dd; 10.0 and 3.4), 1.49 (3,111 ), 1.63 · 1.85 (3/4, m), 0.89 (4-Me, d, 6.4), 0.94 (5, d, 6.4) Table 3. Cryptocin-3, -151, -152, -153, -154, -156, -159, -160, -161, -166, _167, · 172, _181, _188 and 251 at 500 MHz Cryptomycin for NMR data (Please read the notes on the back before filling this page)

， 1T Printed by the Employees 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-213- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 533206 A7 B7 V. Description of invention (211) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Printed P = position P 3 151 152 153 154 156 159 160 161 166 167 172 181 188 251 A 5.77 5.78 5.77 5.77 5.77 5.76 5.76 5.77 5.78 5.77 5.77 5.78 5.78 5.78 5.78 2 d 3 6.68 6.71 6.67 6.68 6.66 6.66 6.68 6.68 6.68 6.68 6.68 6.68 6.68 6.68 6.68 6.68 6.70 6.68 6.68 6.68 ddd AR 2.37 2.45 2.37 2.37 2.37 2.34 2.38 2.35 2.36 2.39 2.37 2.41 2.36 2.35 2.35 dt 4S 2.54 brdd 2.58 2.47 2.52 2.52 2.41 2.51 2.49 2.53 2.52 2.51 2.55 2.54 2.52 2.51 5 5.01 5.10 4.97 5.00 5.00 4.88 5.02 5.03 4.99 5.04 5.00 5.01 5.00 ddd 6 2.S6 xa 2.71 2.47 2.54 2.54 2.27 2.56 2.49 2.59 2.59 2.54 2.61 2.57 2.58 2.55 6_ Me 1.14 d 1.22 1.09 1.13 1.13 1.04 1.13 1.10 1.15 1.15 1.12 1.17 1.15 1.14 1.13 7 6.01 6.09 5.63 6.00 5.99 4.53 5.87 5.70 6.13 5.92 5.97 6.14 6.09 6.05 6.00 dd dd dd 8 6.41 7.19 6.23 6.38 6.34 6.31 6.59 6.26 6.45 6.63 6.34 6.57 6.58 6.34 6.39 d dd d 9 6.71 dd 10 6.49 dd 8/10. 7.67 br s Ar 1 '1' * 2 * 7.28 7 41 M 7.36 6.85 6.68 2.31 7 · 37 7.42 2.33 6.94 6.83 7.30 to br dtds br sds br smd 31 7.34 7.58 7.30 3.80 3.79 6.95 7.55 7.11 2.29 7.54 7.09 7.23 mm br tss brs d to smmd 4 '7.23 7.77 7.22 6.78 6.36 2.31 6.47 7.39 6.87 7.78 7.40 6.68 3.63 mdm br dds br s irv br smmms 5 '7.28 7.94 7.30 7.21 3.79 6.95 7.35 7.55 &quot; 2.29 7.78 7.02 7.23 to d br ttsd br sdsmmd 6 · 7.34 7 丄 41 7.36 6.92 6.68 7.28 7.42 If 7.44 7.19 6.83 7.30 xn to br ddddd br smmmd 7 '7.58 7.44 dm 8' 8.07 7.78 dm D 4.84 4.85 4.87 4.84 4.84 4.87 4.84 4.83 4.84 4.85 4. 85 4.86 4.85 4.84 4.84 2 dd 3 1.62 m 1.64 1.72 1.65 1.66 1.75 1.68 1.67 1.65 1.69 1.66 1.67 1.66 1.67 1.36 3 '1.36 1.35 1.47 1.37 1.38 1.48 1.38 1.36 1.31 1.38 1.38 1.38 1.36 1.32 1.58 m to 4 1.62 1.64 1.72 1.65 1.66 1.75 1.75 1.68 1.67 1.65 1.69 1.66 1.64 1.66 1.67 1.70 mm 4_ Me 0.77 d 7.00 0.87 0.77 0.79 0.94 0.79 0.B0 0.76 0.79 0.78 0.74 0.78 0.79 0.77 5 0.73d 0.64 0.86 0.74 0.77 0.91 0.77 0.79 0.72 0.76 0.75 0.65 0.74 0.77 0.73 -214- This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) ··! »丨

1T € 533206 A7 ___ V. Description of the invention (212) ^ ~-~~ The light is recorded in CDC! 3; chemical shifts are functional for protons or methyl or methoxy or hydroxymethyl groups on the carbon shown in the table base. The chemical shift of the proton in the unit B &amp; c is in the soil 値 · 2 corresponding to Cryptocin-3, and the coupling constant is in the soil.

Within Hz. 151 J (H, H) Hz: 3 ', 4' = 8.3; 5, 6, = 8.0; 7, 8, = 8 · 1; 152 J (H? H) Hz · 6, 7 = 8.7; 7,8 = 15.3; 8,9 = 10.5; 9,10 = 15.7; 2f, 3f = 3 ', 4' = 4 ', 5f = 5', 6 '= 7.4; J (H, H of 153 ) Hz ·· 2 ^ 4, = 2 ^ 6, = 2.0: 4f, 5 * = 5 », 6, == 7 · 9; 154 of J (H, H) Hz: 2, 4, 4, 4f, 6f = 2.2; d of 9-OCH3 of unit A in 156 is 3.51: J (H, H) HZ of 156: 6,7 = 9n3; 7,8 = 12 · 6; J (H, H) Hz of 159 Hz · · 5, 6, = 8 · 3; J (H, H) Hz of 161: 2, 3, = 4, 5, 5, = 8 · 1; J (H, H) Hz of 251: 2'3 5Hz 内。 · = 5 ', 6, = 8 · 2; The measurable coupling constants of the remaining protons in the table are in the soil corresponding to 3, 0.5 Hz. Table 4. Cryptocin-3, -151, -152, -153, _154, -156, -159, -160, -161, -166, -167, -172, -181, -188 and 251 125 MHz 13C NMR data. (Please read the notes on the back before filling this page} -Order

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ____- 215- This paper size applies to the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 533206 A7 _____B7 V. Description of the invention (213) P = Location of the Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau P 3 151 152 153 154 156 159 160 161 166 167 172 181 188 25 1 A 165 165 165 165 165 165 165 165 165 165 165. 165 165 165 165 165.4 165 16 1.4.5.4 .4 .4 .5 .5 .6 4 • 4, 5 .4 • 3 5. 5 12 2 125 125 125 125 125 125 125 125 125 125. 125 125 125 125 125 • 2 .3 .1 .2 .2. 0 .3 .0 3 .2 .1 .1 .3 .3 5 · 2 14 3 141 141 141 141 141 141 141 141 141 141. 141 141 141 141 141 .4 .4 .4 .4 .7 .5 .7 2 .5 .5 .4 .3 .1 1. 4 35 4 36. 36. 36. 36. 36. 36. 36. 36. 36.5 36. 36. 36. 36. 36. 5 6 4 4 5 3 5 4 5 5 5 5 .0 5 77. ΊΊ · ΊΊ · 77. 77. 77. ΊΊ · ★ 77.1 77. 77. 77.. * 77. 77 1 5 3 4 3 9 5 4 5 4 1. 2 6 42. 38. 41. 42. 42. 37. 42. 42. 42.3 42. 42. 42. 42. 7 42. 42 3 3 9 2 2 Ί 3 2 3 3 3 1 .2 6- Me 17. 17. 17. 17. 17. 18. 17. 17. 1 7.2 17. 17. 17. 17. 17. 17 3 4 2 3 3 5 4 3 4 4 4 3 2 .3 7 130 133 134 130 130 103 129 129 130. 130 129 130 127 .1 133 13 .0 .3 .4 .4 .6 .0 .4 .8 5 .4 .3 .5 .1 0. 2 13 8 130 128 132 131 132 148 130 121 133. 131 132 131 132 130 .α .9 .3 • 7. 0 .6 .3 .5 0 .3 • 0 .8 .8 .0 1. 3 9 128 • 4 10 132 .0 8/136 134 137 138 138 55. 134 140. 135 136 126 ★ ie 13 10 • 7 .4 .1 .2 .7 9 卞 • 8 2 .8 .6 .0 5. Surface 9 Ar * 1 '2, 126 123 126 111 104 132 143 125. 135 124 134 ** 108 12 .1 .6. 2 • 7 .4 .9 .6 6 .0 .0 .1 .8 6. d 4 3 * 128 125 128 159 161 131 123 126. 127 138 128 115 12 • 6 .5 .6 .9 .0 .1 .8 3 .5 .1 .2 .8 9. 6 13 4 '128 128 127 118 99. 137 107 141. 126 129 126 128 102 .4 .0 .5 .8 7 .2 • 3 2 .1 • 6 .3 .8 .8 2. t 8 5 · 128 123 128 129 161 126 140 126. 129 138 127 124 * ★ 12 • 6 .5 .6 • 6 .0 .8 .1 3 .5 .1 .8. 2 9, 6 12 6 '126 125 126 11 3 104 125 125. 125 124 123 124 108 .1 • 8a .2 • 1. .4 • 2 6 .4 .0 .3 .2 .8 6. 4 7 »126 125 * .la • 8 8» 128 127. 6 .6 9 * 131 133 .0 .5 ft — (Please read the precautions on the back before filling in this page) _-216 · This paper size is applicable to China National Standard (CNS) A4 (2l0X 29: 7) (Centimeter) 533,206 μ B7, invention description (214)

10 t D 4- He 5 170 71 · 6 39 · 5 24. 521. 2 22. 6 133 .7 171.0 71. 5 39. 5 24. 521. 122. 170.8 71. 5 39 · 6 24. 621. 422 9 170 .9 71. 5 39. 5 24. 521. 2 22. 170 .9 71. 6 39. 5 24. 521. 222. 170 .9 71 · 6 39. 6 24. 721. 4 23. 0 170 .9 71. 5 39. 6 24. 521. 322. 170 .9 71 · 6 39. 5 24. 521. 322. 8 170. 8 71.5 39.6 24.5 21.2 22.7 170 .9 71. 5 39. 6 24. 5 21. 222. 8 171.0 71. 6 39 · 5 24. 521. 222. 132 .9 170 .9 71. 5 39. 5 24. 521. 2 22. 6 170 -8 71. 5 39. 5 24. 521. 222. 170 .9 71. 5 39. 6 24. 5 21. 322. 8 170. 9 71 .5 39.6 24 .5 21.2 22 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and recorded in CDCI3; The chemical shift of carbon in the unit B &amp; c is within ± 0.5 ppm of cryptocin_3 値. * Signal potential for CDCl3. Under signal; ** signal can not be found. + The signal of unit Ai8_OCH3; the signals in 3 blocks are interchangeable. The 3, _OCH3 carbon of unit A in Cryptocin-153 resonates at d 55.1, the 154 O of 3, and 5, _ OCH3 carbon at (J 55.3 resonance, 159 2 'and κΗ3 carbon signals are measured at J 19.7 and 20.9 166 2'-CH3 carbon signal was measured at J 19.8. 167 3, and 5, 〇: 113 carbon signal was measured at (^ 21.2. 4,-(: 1120: 0011 methylene and carboxyl carbon) Resonates at 640, 4 and 174.5 respectively. Example 9 2 Epoxide analog Cryptocin-157, 158, 164, 165, 168, 169, 170, 171, 173, 174, 177, 178, 179, 180, 182 183, 200, 242 and 269 0 Table 5 -217- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

,-mouth

533206 kl B7 V. Description of the invention (215) ° ^ J ^ XXX phenylethyl hydrazone 1 01 MCPBA, 3 when it

Sr RR Epoxide ^ ss Epoxide · 80-85% Combined Yield Cryptophyllin printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs # Ar epoxide # 立 《ίChemy RR / SS Ratio 151 157 158 RR SS 2.4: 1 153 168 169 RR SS 2.4: 1 159 η, ο- ^ χη, 170 RR 2.8: 1 166 〇C 177 178 RR SS 2,0: 1 167 CH 179 180 RR SS 2.7.: 1 172 ccr '173 174 RR SS 1.5: 1 181 〇C 182 183 RR SS 2.0: 1 188 F 200 RR SS 1.4: 1 236 jct1 242 RR 55 2: 1 238 XX1 269 RR SS 2: 1 ** * 188 requires 6 equivalent MCPBA And 36 hours, 70% was converted to epoxide. ** Inseparable mixture. -218- This paper size applies to China National Standards (CNS) Α4 size (210X 297mm) Please read the notes and fill in this page 533206 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description ( 216) General procedure for epoxidation of styrene analogs: a solution of styrene analog (0.1 mmol) and m-chloroperoxybenzoic acid (0.3 mmol) in 3 ml of dichloromethane, stirred at room temperature . After 16 hours, the reaction mixture was diluted with dichloromethane (3 ml) and washed with phosphate buffer (0.1 M, pH 8, 5 ml) to remove 3-chlorobenzoic acid produced during the reaction. The organic layer was separated, treated with dimethylsulfide (20 μl) to quench excess peracid, and washed a second time with buffer. The dichloromethane layer was separated, dried over MgS04, evaporated, and kept under air for 24 hours. The residue was subjected to HPLC on a reverse-phase column (Econosil C18, 10 //, 250 mm x 22 mm, 35% H20 / CH3CN, 6 ml / min) to obtain RR and SS-epoxide. Experimental details and cytotoxicity data are shown in Table 3. Cryptocin-157 and -158: Cryptocin-151 was treated with m-CPBA, and the product was separated using reverse-phase HPLC to obtain Cryptocin-157 and 158. Cryptocin-157: EIMS m / z (relative intensity) 704/706 (1 / 0,3), 195/197 (14/4), 141 (100), 115 (27); high resolution EIMS m / z 704.2865 (calculated for C39H45ClN2 0, -0.1 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin-158: EIMS m / z (relative intensity) 704/706 (2.2 / 1.9), 195/197 (25/9), 141 (100); high resolution EIMS m / z 704.2862 (calculation of C39H45C1N208), 0.3 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin 164 and -165: Crytocin-152 (53 mg, 0.08 mmol) and m-chloroperoxybenzoic acid (15 mg, 0.087 mmol) in 3 ml of dichloromethane Stir at room temperature for 16 hours. The reaction mixture is treated the same and is pure.

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-219- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) 533206 A7 _ V. Description of the invention (217) The procedures for obtaining compounds W4 / 165A and 164 / 165B (5 mg each) , Starting materials (10 mg), and other isolated products. The analysis of the crude structure was cryptocryptin 164 and -165, but the stereochemistry of the epoxy group in the compound could not be determined. Cryptocin-164 / 165A: 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) A 5.77 (2, d; 15.1), 6.67 (3, ddd; 15.1, 9.7 and 5.4), 2.37 (4, m), 2.44 (4, m), 4.98 (5, m), 2.48 (6, m), 1.06 (6-Me, d; 6.7), 5.83 (7, dd 15.6 and 8.5), 5.40 (8, dd; 15.6 and 7.8), 3.32 (9, dd; 7,9 and 2.0), 3.75 (10, d; 2.0), 7.26 (276 ', m) , 7.31-7.37 (374, / 5 ,, m); B 4.82 (2, m), 5.75 (2-NΗ9 d; 9.2), 3.04 (3, dd; -14.5 and 7.3 ), 3.14 (3, dd; -14,5 and 5.5), 7.23 (5, d; 2.2), 3.87 (7-OMs, s), 6.84 (8, d; 8.2), 7.09 (9 , dd; 8 · 2 and 2.2); C 2 · 73 (2, m), 1.23 (2-Me, d; 7.2), 3.29 (3, m), 3.51 (3, m), 6.97 (3-ΝΗ, br t; 6.3); D 4.88 (2, dd; 10.0 and 3, 7), 1.52 (3, m), 1.79 (3/4, m), 0.92 (4-Me, d 6 · 5), 0.95 (5, d; 6.5). 13C NMR (CDC13) unit d (carbon position) A 165.4 (1), 125.3 (2), 141.2 (3), 36.5 (4), 77.0 (5), 41.3 (6), 17.0 (6-Me), 136.2 (7), 129.4 (8), 62.5 (9), 60 · 1 (10), 136.9 (Γ), 125.4 (276 ·), 128.7 (375 ·), 128.4 (4 '); B 171.0 (1), Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 53.6 (2), 35.0 (3), 129.9 (4), 131.0 (5), 122.4 (6), 154.0 (7), 56.1 (7-OMe) , 112 · 3 (8), 128.3 (9); C 175,6 (1), 38.3 (2), 14.1 (2-Me), 41.2 (3); D 170.8 ⑴, 71.5 (2) , 39.6 (3), 24.7 (4), 21] (4-Me), 22.9 (5). Cryptocin-164 / 165B · 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) A 5.76 (2, d; 15.3), 6.66 (3, ddd; 15.3, 9.6 And 5.7), 2.36 (4, m), 2.40 (4, m), 5.00 (5, m), 2.47 (6, m), _-220-_ This paper size applies to China National Standard (CNS) A4 specifications ( 210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of Invention (218) 1.08 (6-Me, d; 6.8), 5.85 (7, dd; 15.5 and 8.5), 5.43 (8 , ddd; 15.5, 7.6 and 0.6), 3.35 (9, dd; 7.6 and 1.9), 3.75 (10, d; 1.9), 7.27-7.37 (273747 576 ,, m); B 4.82 (2, m), 5 65 (2-ΝΗ, d; 8.5), 3.04 (3, dd; -14.4 and 7.2), 3.14 (3, dd; -14.4 and 5.5), 7.22 (5, d; 2.1), 3.87 (7-OMe , S), 6.84 (8, d; 8.5), 7.08 (9, dd; 8.5 and 2.1); C 2.72 (2, m), 1.22 (2-Me, d; 7 · 2), 3.27 (3, m), 3.52 (3, m), 6.90 (3_ΝΗ, br t; 6.3), D 4.87 (2, dd; 9.8 and 3.8), 1.48 (3, m), 1.77 ( 3, m), 1.73 (4, m), 0.89 (4-Me, d; 6.4), 0.90 (5, d; 6.6). 13C NMR (CDC13) unit β (carbon position) A 165.4 (1), 125.2 (2), 141.2 (3), 36.4 (4), 41.3 (6), 16.9 (6-Me), 135.9 (7), 129.1 (8), 62.3 (9), 60.4 (10), 136.8 (Γ), 125.5 (2761), 128.6 (375 '), 128.4 (4 丨); B 170.9 (1), 53.6 (2), 35.1 (3 ), 129.8 (4), 131.0 (5),

122.4 (6), 154.0 (7), 56.1 (7-OMe), 112.2 (8), 128.4 (9); C 175.5 (1), 38.3 (2), 14.0 (2-Me), 41.2 (3 ); D 170.8 (1), 71.4 (2), 39.7 (3), 24.7 (4), 21.5 (4-Me), 22.9 (5). Cryptocin-168 and -169: Cryptonin-153 was treated with m-CPBA, and the product was separated using reverse-phase HPLC to obtain Cryptocin-168 and -169. Cryptophytin_168: EIMS m / z (relative intensity) 684/686 (7/2), 412/414 (17/6), 280/282 (12/6), 257 (20), 212/214 ( 14/4), 195/197 (69/24), 121 (100); high-resolution EIMS m / z 684.2789 (calculated 値 for C36H45C1N209, 2.6 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin-169: 4 NMR data, see Table 6; 13C NMR data, see Table 7. __- 221-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1T 533206 A7 B7___ V. Description of the invention (219) Cryptocin-170 and -171: Cryptocin-159 was treated with m-CPBA, and the product was separated using reverse-phase HPLC to obtain Cryptocin-170 and -m. Cryptocin-170: EIMS m / z (relative intensity) 682/684 (4/3), 412.41 (11/4), 280/282 (15/4), 255 (25), 195/197 ( 52/17); high-resolution EIMS m / z 682.3043 (calculated 値 for C37H47ClN208, -2.2 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin-171: EIMS m / z (relative intensity) 682/684 (2.0 · 0.7), 412.41 (7/4), 280/282 (14/4), 255 (19), 195 / 197 (50/17); high-resolution EIMS m / z 682.3006 (calculated for C37H47C1N208, 1.5 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin_173 and 174: Cryptocin-171 was treated with m_CPBA, and the product was separated using reverse phase HPLC to obtain Cryptocin-173 and -174. Cryptocin-173: EIMS m / z (relative intensity) 704/706 (1.3 / 0.4), 412/414 (5.1 / 1.9), 277 (6.3), 141 (100); high-resolution EIMS m / z 704.2838 ( Calculation of C39H45C1N208208, 2.7 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin-174: 4 NMR data, see Table 6; 13C NMR data, refer to Table 7 〇 Cryptocin-I77 and 178 printed by Cryptophyllin-166 and m-CPBA After processing, the product was separated using reverse-phase HPLC to obtain cryptocryptin-177 and -178. Cryptocin-177: EIMS m / z (relative intensity) 688 (2.7), 41/414 (9/3), 280/282 (11/4), 241 (16), 195/197 (45/17) , 105 (100); high-resolution EIMS m / z 668.2835 (calculated for C36H45C1N208, 2.9 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. ____ -222- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 533206 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (220) Cryptophyllin-178 ·· EIMS m / z (relative intensity) 668/670 (4 / 1.4), 412/414 (17/6), 280/282 (12/4), 241 (24), 195/197 (59/18), 105 (100 ); High-resolution EIMS m / z 668.2836 (calculated for C36H45C1N208, 2.9 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin_179 and 180: Cryptocin_167 was treated with m-CPBA, and the product was separated using the same procedure described above for the epoxidation of Cryptocin-151 to obtain Cryptocin-179 and -180. Cryptocin-179: EIMS m / z (relative intensity) 682/683 (25/13), 412/414 (100/43), 280/282 (100/50), 255 (100), 211 ( 100), 195/197 (100/100), 121 (100); high-resolution EIMS m / z 682.2992 (calculated for C37H47C1N208, 2.9 mmu error); 4 NMR data 'see Table 6; 13C NMR data, see Table 7 . Cryptocin-180 ·· EIMS m / z (relative intensity) 682/684 (4/3), 412/414 (14/7), 280/282 (16/11), 255 (10), 195/197 (58/21), 119 (100); high-resolution EIMS m / z 682.3021 (calculated 値 for C37H47C1N208, 0 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin_182 and -183: Cryptocin-181 was treated with m-CPBA, and the product was separated using reverse-phase HPLC to obtain Cryptocin-182 and -183. Cryptocyanin-182 ·· EIMS m / z (relative intensity) 672 (1), 412/414 (11/4), 280/282 (10/4), 245 (12) 195/197 (40/12) 109 (77); high-resolution EIMS m / z 672.2590 (calculated for C35H42ClFN208, 2.3 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin_183: EIMS m / z (relative intensity) 672/674 (5/2), 412/414 (32/12), 280/282 (13/4), 245 (29), 195/197 ( 92/30), 109 -223- • ring (read the precautions on the back before filling this page)

L,-The size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (221) (100); and analysis of the calculation of EIMS m / z 672.2620 (C35H42C1FN208) 値, -0.7 mmu error); NMR data, see Table 6; NMR ^ data, see Table 7. Cryptocin_200: Cryptocin-188 was treated with m-CPBA, and the product was separated using the same procedure, but after 12 hours, peracid (3 equivalents) was added, and it continued to stir for 36 hours to obtain Cryptocin-200 And SS-epoxide. Cryptophyllin-200: EIMS m / z (relative intensity) 690/692 (42/16), 412/414 (7/1), 263 (19), 195/197 (27); high resolution EIMS m / z 690.2494 (calculated for C35H4iC1F2N208, 2.6 mmu error); 4 NMR data, see Table 6; 13C NMR data, see Table 7. Cryptocin-242: Cryptocin-236 was treated with m-CPBA, and the product was separated using the same procedure to obtain Cryptocin-242 and its SS · epoxide. Cryptocin-242 was purified by normal-phase HPLC (Econosil Si, 250 X 10 mm, 10 #, EtOAc: hexane, 1: 1, 3 ml / min, tR: 81 minutes). Cryptocin 242: 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, printed multiplicity by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; J Hz) A 5.73 (2, d; 15.4), 6.64 (3 , ddd; 15.4, 10.2 and 5.0), 2.42 (4, m), 2.57 (4, m), 5.14 (5, m) 1.79 (6, m), 1.12 (6-Me, d; 6.7), 2.93 ( 7, dd; 8.4 and 1.6), 3.69 (8, d; 1.6), 7.26a (276 ,, d; 8.2), 7.22a (375 ,, d; 8.2), 4.28 (4, -Cii2NH_t-Boc, d 5 · 9), 4.96 (4, -CH2NH_t-Boc, brs), 1.44 (4, -CH2NH-t-Boc, s); B 4.66 (2, m), 5.66 (2-NH, d; 7.8) , 2.92 (3, dd; -14.5 and 7.2), 3.14 (3, dd; -14.5 and 5.0), 7.21 (5, d; 2.0) 3.85 (7-OMe, s), 6.88 (8, d; 8 · 5), 7.09 (9, dd; 8.5 and 2.0); C 2.68 (2, m), 1.17 (2-Me, d; 7.4), 3.33 (3, m), 3.39 (3, m), 6 · 95 (3-NΗ, br t; 6.1); D 4.85 (2, dd; 10.0 and 3.3), -224- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 533206 ΚΊ B7 V. Description of the invention (222) 1.37 (3, m), 1.67-1.73 (3/4, m), 0.84 (4_Me, d; 6.7), 0.86 (5, d; ό · 7); 13C NMR (CDC13) unit j (carbon position) A 165 · 7 u ), 125 4 (2), 141.7 (3), 37.2 (4), 76.6 (5), 40 · 9 (6), 13.7 (6-Me), 63.4 (7), 59.0 ( 8), 136.4 (Γ), 126.2b (2 '/ 6,), 127.9b (375,), 140 · 2 (4,), 44.5 (4, -CH2NH-t-Boc), 28.5 (4 , -CH2NH-t-Boc); Β 171.2 (1), 54.6 (2), 35.5 (3), 130.5 (4), 131.2 (5), 122.5 (6), 154.4 ( 7), 56.5 (7-OCH3), 112 · 7 (8), 128.8 (9); C * (1), 38.6 (2), 1 (4 (2-Me), 41.1 (3); D 171.2 (1), 71.6 (2), 39.9 (3), 24.9 (4), 23_1 (4-Me), 21.4 (5). The signals with the same upper corners and ^^ are interchangeable. Cryptocin-269: Cryptocin-243 (6 mg) was treated with solid KWO3 in acetone (1 · 2 ml) in a reactor under vigorous drying at room temperature. After 2 hours, the reaction mixture was filtered 'and the solvent was evaporated. The residue was purified on a short crushed stone column using a mixture of CHW12 and EtOAc to obtain Cryptocin · 269 (5 "mg). lH NMR (CDCI3) Carbon position of amine or carboxylic acid unit, multiplicity; j Hz) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

A 5.70 (2, d; 15.4), 6.67 (3, m), 2.42 (4, dt; 14.4 and 10.4), 2.53 (4, m), 5.11-5.19 (5, m), 1.63-1.83 (6, m), 1.14 (6-Me d; 6.8), 2.92 (7, d; 7.6), 3.69 (8, br s), 7.37a (276,, d; 7.9), 7.24a (375f, d; 7, 9), 4.71 (4'-CH2OH, s); B 4.74-4.85 (2, m), 5.76 (2-ΝΗ, d; 8.3), 2.98 (3, dd; -14 · 5 and 7.7 ), 3.13 (3, dd; -14.5 and 5.3), 7.20 (5, br s), 3.86 (7 cans OMe, s), 6.82 (8, d; 8.3), 7.05 (9, br d; 8.3); C 2.68 (2, m), 1.14 (2-Me, d; 7.3), 3.32 (3, m), 3.45 (3, m), 6.98 (3-NH, br m); D 4.74-4.85 (2, m), 1.35 (3, m), 1.63-1.83 (3/4, m), 0.85 (4-Me, d; 6 1), 0.87 (5, d; 6.1). 3 The signals with the same upper corner are interchangeable. -225- This paper size applies Chinese National Standard (CNS) A4 specification (210X29? Mm) 533206 --- Μ B7 V. Description of the invention (223) 1H NMR data of 168, -169, -170, -173, -174, -177, ψ-178, -179, -180, -182, -183 and 200. Ρ = printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs P 1 157 158 168 169 170 173 174 177 178 179 180 182 183 200 A 2 5.74 5.7 5.82 5.73 5.82 5.75 5.73 5.83 5.76 5.82 5.74 5.82 5.76 5.81 5.7 d 2, 5 3 6.68 6.7 6.72 6.67 6.70 6.68 6.68 6.72 6.69 6.70 6.66 6.71 6.69 6.70 6.6 ddd 0 7 4R 2.45 2.5 2.72 2.45 2.67 2.49 2.46 2.70 2.51 2.58 2.45 2.57 2.55 2.57 2.4 dt 6 mmmmm 2 AS 2.55 2.6 2.62 2.54 2.56 2.54 2.59 2.60 2.54 2.69 2.54 2.69 2.56 2.68 2.5 brdd 3 mmmmm 3 5 5.16 5 · 2 5.21 5.15 5.14 5.17 5.18 5.17 5.18 5.15 5.14 5.13 5.17 5.15 5.1 ddd 4 mm XQ 4 6 1.80 2.0 1.93 1.78 1.78 1.86 1.85 1.83 2.87 1,77 1.76 1.75 1.82 1.79 1.8 m 4 m 1 6- Me 1.14 d 1,2 0 1.20 1.14 1.05 1.14 1.18 1.08 1.14 1.10 1.14 1.14 1.14 1.08 1.1 1 7 2.92 2.9 2.92 2.90 2.87 2.86 3.03 3.01 2.87 2.80 2.92 2.89 2.90 2.87 2.8 dd 9 5 8 3.69 4.4 4.26 3.66 3.58 3.85 3.85 3.77 3.88 3.74 3.61 3.53 4.01 3.88 3.6 9 d 1 6 10 8/1 7.77 7.75 0- br s br s Ar- 1 '2' 7.25 7.4 7.42 6.77 6.76 2.38 2.42 2.40 6.85 6.86 6.7 m Id br d br s br sssss br s br s 7 m 3 '7.34 to 7.4 7.47 3.81 3.81 6.99 7.29 7.30 7.11 7.15 2.31 2.31 7.05 7.03 6 t dd 3 s brs dd d to 3 to 4 '7.39 7.8 7.82 6.87 6.85 2.30 7.82 7.83 7.24 7.22 6.96 6.95 7.33 7.31 6.7 m 2d br d br ddsd to mm br s br smm 7 m 5 * 9f 7.9 7.91 7.27 7.26 7.00 7.84 7.83 Vf fl 2.31 2.31 ”ft Id dtt 3 d zn ss 6 '7.25 7.5 7.53 € .85 6.85 7.00 7.50 7.46 &quot; vv 6.85 6.86 If 9f 6.7 7 mm 3 td ddd dd 3 m. to br s br s 7 · 7.5 7.57 7 · 50 7.52 7 ddd mm td 81 8.0 8.07 7.84 7.83 8 dddm D 2 4.83 dd 4.8 1 4.91 4.82 4.91 4.83 4.81 4.92 4.84 4.90 4.82 4.92 4.84 4.91 4.8 ( Please read the notes on the back before filling in this page) 丨, 11 -226- This paper size applies to Chinese national standards ( CNS) A4 specification (210 × 297 mm) 533206 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (224) 3 1.36 m 1-3 4 1.48 1.36 1.50 1.36 1.31 1.49 1,39 1.50 1.33 1.51 1.39 1.56 1.3 a 3 * 1.70 zn 1.6 8 1.71 1.70 1.74 1.70 1. ^ 6 1.72 1.73 1.68 1.71 1.75 1.72 1.76 0 1.6 7 4 1.70 χα 1.6 3 1.71 1.70 1-74 1.70 1.64 1.72 1.73 1.68 1.71 1.75 1.72 1.76 to 1.8 0 m 0.8 9 0.8 7 4- Me 0.86 d '0.7 8 0.87 0.87 0.91 0.85 0.79 〇87 0.86 0.91 0.85 0.92 0 · 87 0.92 5 0.85 d 0.7 4 0.85 0.85 0.89 0.84 0.75 0.87 0.85 0.89 0.84 0.89 0.85 0.90 The spectrum is recorded in CDCI3 ; Chemical shifts are for protons or methyl or methoxy functional groups on the carbons shown in the table. The chemical shift of the protons in the unit is within Cryptocin_1 値 ± 0.2 ppm, and the coupling constant is within Shiyan HZ: ,, 3. = 3., 4 .--, 7; 5., 6,6 , 7,7,8, = 7.9; 5 ,， = 1V; 6 \ 8 ^ 1.1; 168 ^ J (H? H) Hz: 4 ^ 95 ^ 5 *? 6-8.0; 173 ^ 1 (Η, Η)

Hz: 3 ', 4' = 8.5;; T, 3 '= 1 · 4; 5', 6 '= 7 ,, 8' = 8.3; 158, 169, and 174 aryl groups can be measured for coupling Within the soil of 157, 168, and 173 〇 〇5 Ηζ. The coupling constants for the remaining protons in the table can be measured within 0.5 Hz of Cryptophytin_ i. 13C NMR data of 177, · 178, -179, -180, -182, -183 and 200. P = Position (Please read the notes on the back before filling this page) ΦΙ 攀 —

1T P 157 158 168 169 170 173 174 177 178 A 165. 165 165 165 165 165 165 165 165 165 1 3 • 5 .3 .5 .3 .3 .4 .5 2 125. 125 125 125 125 125 125 125 125 3 .2 .3 • 2 3 141. 141 141 141 141 141 141 141 141 141 0 .4 .0 .4 .0 .4 .1 .4 4 36.6 36. 36. 36. 36. 36. 36 36. 36. 8 7 7 6 8 Θ 5 8 5 76.1 ★ 76. * 76. 76. Yu 76. ★ 1 0 2 0 6 ′ 40.1 41. 40. 41. 40. 40. 41. 40. 41. 0 6 0 3 7 0 2 0 ΠΒ 165.3 3 125. 2 141.2 2 36.8 76.2 40.8 180 165 .5 125.2 141 .5 36. 41.0 0 182 165 .3 125.2 141.2 36. 7 76. 2 40. 5 18 5 4 5 3 1 3 · 6 4 2 3 4 3 6 1113 76.8 40.9 200 165 .3 125 .4 140 .8 36. 7 75. 9 40. 2 -227- This paper size applies Chinese National Standard (CNS) A4 Specifications (21〇 &gt; &lt; 297 mm) 533206 A7 __B7 V. Description of invention (225) Member of the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperation, Printing 6 * Me 13.1 13. 8 13. 6 13. 5 13. 3 13 . 6 13. 5 13. 1 13. 8 13.7 13. 6 13. 7 13.3 13. 3 7 62.6 62. 63. 63. 62. 63. 64. 62. 62. 62.9 63. 62. 62.6 63. 7 0 1 4 Z 3 4 7 1 5 3 8 56.3 54. 58 56. 56. 59. 56. 56. 54. 59.2 56. 53. 51.1 57. 7 9 3 3 3 5 2 5 4 4 6 8 / 132. 133 138 138 137 125 124 134 135 136. 137 124 ** 141 10 6 .0 • 4 .8 .8 .3 .9 .9 • 3 6 .0 .3 .1 Arm m 1 * 2 * 122. 122 110 110 135 133 133 135 135 123. 123 161 108 4 • 4卞 .9 .5 .8 .5 .3 • 9 .6 4 • 1.2 .4 3 »d 125. 125 160 160 131 122 122 130 129 138. 138 115 115. 163 .4 5 .5 .0. 0 • 0 .6 .7 .2 .9 4 .3 .3 2 dd 4 '128. 128 114 111 131 128 128 128 128 130. 128 129 129. 103 5 .3 .0 4.0 .8 .7 .5. 0 .8 3 .4 .7 5 .9 5 «129. 128 129 129 124 127 127 124 124 138. 138 124 129. U 163.. 4 0 .9 • 8 .7 .3 .8 .7a, 2. 0 4 .3 .5 5 6 · dd 126. 126 118 117 127 126 126 126 126 123 · 123 126 124. 108 0 .0 .0 .9 .0 .3a • 2b .4 .3 4 .1 .1 4 .4 7 '126. 126 126 126 6 .5 .6a • 5b 8' 122. 122 127 127 3 .3+ .8 .8a 9 * 131. 131 133 133 4 .2 .2 .2 10 133. 133 134 134 4 .3 .2 .5 D 170. 170 170 170 170 170 170 170 170 170 170. 171 170 170. 170 .7 1 7 .8 .7 .9 • 1 .8 .9 .1 .9 8 -9 • 7 8 2 71.4 71. 71. 71. 71. 71. 71. 71. 71. 71. 71.3 71. 71.5 71. 5 i 5 3 3 5 4 5 5 3 3 39.4 39. 39. 39. 39. 39. 39. 39 39. 39.4 39. 39. 39.3 39. 3 4 3 4 4 3 5 3 3 4 5 4 24.5 24. 24. 24. 24. 24. 24. 24. 24. 24.5 24. 24. 24.7 24. 6 5 7 5 5 7 6 7 7 6 6 4- Me 22.8 23. 21. 21. 21. 21. 21. 21. 21.2 21. 21. 21.4 21. 0 3 4 3 2 4 4 4 3 3 5 21.3 21. 22. 23. 22. 22. 23. 22. 23. 22.9 23. 22. 23.1 22. 3 9 1 Θ 8 0 9 1 1 9 9 The spectrum is recorded in CDC13. The chemical shifts of carbon in units B and C Within 0.5 ppm of Crytodin-1. * Signal is under CDC13 signal. ** Signal cannot be found. +, The signals with the same upper corner in a &amp; b block are interchangeable. The OCH3 signal of 3 in 168 and 169 was measured at d 55 · 3. 170 2 'and f-CH3 carbon signals are at _____-228-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this 100

, 1T

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 533206 M 5. Invention Description (226) d 18.9 and 21.0 Measured. The 2′-CH3 carbons of 177 and 178 resonate at d 19.0 and 18.9 ψ, respectively. The 3 'of 179 and the signal were measured at d21.3, and 180 were measured at d21.2. Example 9 3 Chlorohydrin analog Cryptocin-163, 184, 185, 186, 187, 191, 192, 193, 194, 195, 212, 216, 217, 222, 223, 224, 243, 252, 253, 263 , 264, 265, 272, and 273 〇 Table 8 · Gum 'cis-isoepoxide' cryptocryptin # Ar * j 醇 '# ί 体 化学 y trans / cis β ratio 157 191 192 trans 1.1: 1 168 195 trans-cis1: &lt; 0.1 170 h, c ^ Ch, 216 217 trans-cis1: 2.6, 179 CH, 222 trans-cis &lt; 0.1: 1 -229- This paper size applies to China Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

533206 A7 ______ ^ V. Description of the invention (227) 172 CCrs 193, 194 trans-cis 1: 2 181 〇ί 223 trans-cis 1: &lt; 〇. 1 200 F 212 trans-cis · 1: &lt; 0.1 ★ * Go &amp; 184 trans: χΤΊ 224 186 trans-cis 1: 2 + ★ * 243 trans-cis 1: &lt; 0.1 * Cryptocin-200 under these conditions only performs 30% conversion. ** Mixture of rr epoxides of 3,4- and 2,3-dimethylphenyl analogs. *** Mixture of RR and SS epoxide. (Please read the notes on the back before filling this page)

1, 1T printed Cryptocin _163 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: Add m-CPBA (0) in a solution of Cryptocyanin-81 (12 mg, 0.018 mmol) in CH2Cl2 (1.5 liters) 5 μg, 0.029¾ mole), then add HC1 in acetic acid solution (25 μl), the temperature was raised to room temperature, and stirring was continued for 6 hours. The solvent was evaporated, and the residue was subjected to flash chromatography on a C18 second stone column (12 cm x 1 cm) using a mixture of η20 and CH3CN to obtain a mixture of chlorohydrins (2 mg, 93%). Purification by reverse phase HPLC resulted in hydrolysis of the fraction to a diol. However, purifying with normal phase hplc (Econosil silica, 250 mm X 100 mm, j:! EtoAc / hexane), Cryptothelin-163 (tR 37.2 minutes, 3.0 mg) was obtained. Proton and carbon NMR data are shown in Tables 9 and 10, respectively. -230- This paper size is applicable to Chinese National Standard (CNS) A4 specification (21G &gt; ^^ y A7 ', — βί 5. Description of the invention (228) — Crypto depth -184, -185, -186, 187, 224: A mixture of 3,4-dimethylbenzyl chloride-benzyl chloride and 2,3-dimethylbenzyltriphenyl chloride (7: 3) is converted into 3,4- and 2,3 -Dimethyl benzyl triphenyl orthophosphine, and then treated with Cryptocin 108 using the same procedure as described above for the preparation of Cryptocin-152. An inseparable mixture of phenylethyl and Greek isomers was obtained with a combined yield of 68% The mixture (45 mM) in CHAlW ml) was treated with m-CPBA (25 mg) at room temperature and held for 15 hours. The solvent was removed, and the residue was subjected to HpLC (Ecnosil O-H, 8 '25x22 mm, 7: 3 H2O / CH3cN, 6 ml / min), and the di / valley fraction I was collected (tR 54 · 0 minutes, 20 mg) and II (tR 61.5 minutes, 12 mg). The 'fraction K9 mg' was treated with TMSC1 (40 microliters) in CH2C12 (2.0 ml) at 78C. The temperature was gradually raised to room temperature. After 3 hours, the solvent was evaporated and then chromatographed on reverse-phase HPLC (Econosil C_18, 10 meters, 250 X 22 mm, 35.65 H20 / CH3CN, 6 ml / min) to obtain Cryptocin-186 ( tR 57 · 8 minutes, 4.7 mg), Cryptocin-224 (tR 74.5 minutes, 2.3 mg) 'and Phytoxin-184 (tR 78.2 minutes, 2.6 mg). The same procedure was used for the dissociation fraction II and TMSC1, and the compounds were separated to obtain Cryptocin 85 (tR 65.0 minutes, 0.7 mg), and Cryptocin 187 (tR 69 2 minutes, 800 mg). Cryptocin-184: EIMS m / z (relative intensity) 682/684 (1.1 / 0.4), 236 (10), 195 (9), 135 (100), 119 (83); high resolution EIMS m / z 682.2999 (M + -Ηα, calculated for C37H47C1N208, 2.2 mmii error); proton and carbon data are shown in Tables 9 and 10, respectively. Cryptocin_185: EIMS m / z (relative intensity) 682/684 (6/2), 412/414 (14/5), 280/282 (14/5), 255 (10), 195/197 ( 50/16), 119 ____- 231-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) -5 _ 鬌 Staff of the Central Bureau of Standards Printed by the Consumer Cooperative 533206 kl B7_____ V. Description of the invention (229) (100); High-resolution EIMS m / z 682.3015 (calculation of M + -HC and C37H47C1N208 値, 0.6 mmu error); proton and carbon data are shown in the table respectively 9 and 10. Cryptocin-186: EIMS m / z (relative intensity) 682/684 (1.3 / 0.6), 412/414 (2.5 / 0.8), 254 (7), 195 (11), 119 (100); high-resolution EIMS m / z 682.3015 (M + -Ha, calculated for C37H47ClN2 0, 0.6 mmij error); proton and carbon data are shown in Tables 9 and 10, respectively. Cryptocin-187 ·· EIMS m / z (relative intensity) 682/684 (0.9 / 0.2), 412/414 (3/1), 255 (3), 254 (7), 195 (11), 135 ( 100), 119 (94); high-resolution EIMS m / z 682.3044 (M + -HC1, C37H47ClN208i calculation 値, -2.3 mmu error); proton and breaking data are shown in Tables 9 and 10, respectively. Cryptocin-224: EIMS m / z (relative intensity) 682/684 (3/1), 412/414 (3/1), 225 (4), 254 (9), 195/197 (28/6) , 119 (100); high-resolution EIMS m / z 682.3064 (calculated for M + -HC1, C37H47C1N208, -4.3 mmu error); proton and carbon data are shown in Table 9 and 10, respectively. Cryptocin -191, 192, _193, -194, -195, -212, -216, -217, -222 and -223: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before (Fill in this page) General Procedures for the Preparation of Gas Alcohols ... The solution of RR-epoxide in aerosol is cooled to -60X: and treated with excess trimethylsilyl chloride (10 equivalents). After 2 hours, the solvent was evaporated and the residue was purified by reverse-phase HPLC (Econosil C18, 10 #, 3 5% H20 / CH3CN, 3 ml / min) to obtain trans and cis-chlorohydrin. The experimental details and cytotoxicity for the preparation of cryptocryptin-191, -192, -193, -194, -195, -212, -216, -217, 222, -223 and -224 are shown in Table 8. Cryptophyllin-195: EIMS m / z (relative strength) 684/686 (3/2), 412/414 ____ -232- —___ This paper size applies to China National Standard (CNS) A4 (210 X 2SH mm) ) 533206 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (23〇) (12/4), 257 (11), 195/197 (46/15); High Resolution EIMS m / z 684.2784 ( Calculation of M + -HC1, C36H45C1N209 (値 3.0 mmu error); NMR data, see Table 9; 13CNMR data, see Table 10. Cryptophyllin-212 ·· EIMS m / z (relative intensity); high-resolution EIMS m / z (calculation of M + -HC1, C35H41C1F2N208 値, △ mmu error); 4 NMR data, see Table 9; 13C NMR data, see Table 1 0. Cryptocin-216 ·· EIMS m / z (relative intensity) 682/684 (6/3), 412/414 (6/2), 255 (4), 195/197 (21/7); high resolution EIMS m / z 682.2990 (calculation of M + -HC1, C37H47C1N208, 33.1 mmu error); 4 NMR (CDC13) amino or hydroxy acid unit (carbon position, multiplicity; J Hz) A 5.79 (2, d; 15.4 ), 6.70 (3, ddd; 15.4, 9.5 and 5.4), 2.36 (4, m), 2.67 (4, br, dd; 14.9 and 4.9), 5.01 (5, m), 2.52 (6, m), 1.07 (6-Me, d; 7.1), 4.07 (7, br d; 9.8), 5.01 (8, d; 9.8), 2.36 (2 丨 _CH3, s), 7.01 (2 ,, br s), 2.31 ( 4f-CH3, s), 7.06 (5 ,, brd; 8.1), 7.32 (6 ', d, 8.1); B4.81 (2, m), 5.71 (2-NH, d; 8.5), 3.02 (3 , Dd; -14.4 &amp; 7.4), 3.16 (3, dd; -14 · 4 and 5.6), 7.23 (5, d; 2.0), 3.88 (7-OMe, s) 5 6.85 (8, d; 8.3) , 7.09 (9, dd; 8.3 and 2.0); C 2.74 (2, m), 1.23 (2-Me, d; 7.1), 3.25 (3, m), 3.53 (3, m), 6.93 (3 -NΗ, br m); D 4.93 (2, dd; 10.2 and 3.2), 1.49 (3, m), 1.68-1.85 (3/4, m), 0.95 (4-Me, d; 6.4), 0.96 ( 5, d; 6.4). Cryptocin-217 ·· EIMS m / z (relative intensity) 682/684 (3/1), 412/414 (6/1), 255 (5), 195/197 (23/7); high resolution EIMS m / z 682.2920 (calculation of M + -HC1, C37H47ClN2 0, Δ10.1 mmu error); 4 NMR (CDC13) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) -233- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

， '' 口 · Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 Α7 Β7 V. Description of the Invention (231) A 5.72 (2, d; 15.4), 6.66 (3, ddd; 15.4,9.7 and 5.4), 2.17 (4, dt; 13.9 and 10.9), 2.53 (4, br dd; 13.9 and 5.0), 5.08 (5, m), 1.61 (6, m) 5 0.88 (6-Me, d; 6.8 ), 4.28 (7, br d; 9.6), 5.13 (8, d; 9.6), 2.38 (2 丨 _ CH3, s), 7.03 (2 丨, br s), 2.32 (4 丨 -CH3, s), 7.03 (5 丨, brd; 8.5), 7 · 17 (6 ', d; 8.5); B 4.80 (2, m), 5.66 (2-NH, d; 8.1) 3.03 (3, dd; -14.4 and 7.2 ), 3.14 (3, 4 (1; -14.4 and 5.6), 7.21 (5, (1; 1.6) 3.87 (7-OMe, s), 6.83 (8, d; 8.3), 7.08 (9, dd 8.3 and 1.7); C 2.74 (2, m), 1.24 (2-Me, d; 7.1), 3.29 (3, m), 3.50 (3, m), 6.96 (3-NH, bi * m); D 4.89 (2, dd; 9.8 and 3.4), 1.52 (3, m), 1.87 (3, m), 1.72 (4, m), 0.94 (4-Me, d; 6.3), 0.97 (5, d; 6 · 8). Cryptocin-222: EIMS m / z (relative intensity) 718/720 (0.4 / 0.2), 682/684 (13/7), 412/414 (15/5), 280/282 ( 16/5), 255 (12), 195/197 (59/19), 119 (100); high-resolution EIMS m / z 718.2767 (calculation of C37H48C12N208), △ 2 1 mmu error); 4 NMR data, see Table 9; 13C NMR data, see Table 10 Cryptocin_223: EIMS m / z (relative intensity) 672/674 (1 / 0.8), 412/414 (3 / 1), 195/197 (15/3), 149 (100), 109 (35); high resolution EIMS m / z 708.2373 (calculated 値 for C37H43FC12N208, △ 0.7 mmu error); 4 NMR data, see Table 9; 13C NMR data, see Table 10 0 Cryptocin-243: Epoxidation of Cryptocin 238: Cryptocin-238 (1 1.8 mg) was dissolved in dichloromethane (1.5 ml), and MCPBA (9.6 mg) deal with. After 15 hours, the reaction mixture was diluted with dichloromethane (3 ml), and 0.1 · M phosphate buffer solution-234- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read first Note on the back, please fill out this page again), -tx 533206 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (232) Wash at pH 8 (3 ml). The organic layer was treated with dimethylsulfide (200 µl), and the buffer was washed repeatedly. The organic layer was evaporated and the residue (12 mg) was not successfully purified on the reverse phase (Ecnosll C18, 25 cm x 22 mm, 10 &quot;, 35% H20 / CH3CN, 6 ml / min), and RR and Mixture of SS epoxides (6.2 mg). 0 TMSC1 treatment: The mixture was dissolved in chloroform (1 ml) and treated with TMSC1 (15 μl) at -60 ° C. After 2 hours, the solvent was evaporated, and the residue (7 mg) was subjected to normal phase HPCL (Econo silSi '25 cm χΐ〇φ 米, 10 &quot;, 85% EtO Ac / hexane' 4 l / min). The fractions collected at 30 minutes were purified by reverse-phase HPLC (Econosil C18, 25 cm x 10 mm, 10 &quot;, 45% H2O / CH3CN, 3 ml / min) to obtain Cryptocin-243 (2.4 Mg). Cryptocin-243: 4 NMR (CDC3) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) A 5.76 (2, d; 15.0), 6.67 (3, ddd; 15.0, 9.6 and 5.4) , 2.35 (4, dt; 14.4 and 10.4), 2.64 (4, br dd; 14.4 and 5.1), 5.07 (5, m), 2.50 (6, m), 1.04 (6-Me, d; 6.8) , 4.02 (7, br d; 9.8), 4.68 (8, d; 9.8), 7.39 (2737576 ', br s)? 4.70 (4, -CH2OH? Brs); B 4.74 (2, m), 5.72 (2 -NH, d; 7.8), 2.99 (3, dd; 14.4 and 7.3), 3.14 (3, dd; -14.4 and 5.6), 7.22 (5, d; 2.0), 3.88 (7-OMe, s ), 6.84 (8, d; 8.4), 7.08 (9, dd; 8.4K2.0); C2.73 (2, m), 1.21 (2-Me, d; 7.1), 3.23 (3, to; 13.7 And 7.1), 3.50 (3, to; 13.7 and 4.5), 6.93 (3- &gt; 111, 1 ^ dd; 7.1 and 4.5); D 4.91 (2, dd; 10.0 &amp; 3.4), 1.47 (3, m ), 1.64-1.84 (3/4, m), 0.94 (4-Me, d; 6.4), 0.95 (5, d; 6.3); 13C NMR (CDC13) unit d (carbon position) A 165.6 (1 ), 125.0 (2), 141.9 (3), 36.3 (4), 76.4 (5), 38.3 (6), 8.7 (6-Me), 74.0 (7), 62.0 (8), -235- ·· (Please read the notes on the back before filling this page)

L 、-口 丁 § This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 V. Invention Description (233) 137.7 (Γ), 127.4a (276f)? 128.2a (375f)? 142.2 (4f)? 64.6 (4?-£ _H2〇H); B 171.1b (1), 53 6 (2), 35.1 (3), 129.9 (4) , 131.0 (5),

122.4 (6), 154.0 (7) 56.2 (7-OCH3), 112.3 (8), 128.4 (9); C 175.4 (1), 38.5 (2), 14.1 (2-Me), 41.2 (3); D 170.5b (1), 71.4 (2), 39.7 (3), 24.8 (4), 23.2 (4-Me), 21.6 (5). The signals of a &amp; b having the same upper corner are interchangeable. Cryptophyllin-252 and 253: Ink_drug ring-247's ring_1 ^: Cryptocin-247 (12 mg) was dissolved in dichloromethane (1 ml) and treated with MCPB A (9.8 mg). After 15 hours, the reaction mixture was diluted with dichloromethane (3 ml) and washed with 0.1 μ phosphate buffer at pH 8 (3 ml). The organic layer was separated, and after adding dimethylsulfide (5 ml), the buffer washing was repeated. The organic layer was evaporated and the residue (11.5 mg) was purified by reverse-phase HPLC (Econosil C18, 25 cm x 10 mm, 10 &quot;, 35% H20 / CH3CN, 3 ml / min) to obtain the main RR-epoxy Compounds (5 mg) and minor SS-epoxides (3 mg). RR-epoxide · 4 NMR (CDCI3) amine or hydroxy acid unit d (carbon position, multiplicity; J Hz) A 5.74 (2, d; 15.6), 6.67 (3, ddd; 15.6, 9.5 and 5.6 ), 2.44 (4, dt; 14.7 and 10.5), 2.50-2.58 (4, m), 5.15 (5, m), 1.62-1.81 (6, m), 1.12 (6-Me, d; 6.8), 2.91 (7, dd; 7.3 and 1.5), 3.66 (8, d; 1.5), 7.38 (2 丨, br s), 6.54 (3 丨 right, 8), 1.51 (3- 丨

Boc), 7.21-7.30 (475f? M)? 6.91 (6 ^ br d; 6.8); B 4.79 (2, m), 5.69 (2-NH, d; 8.5), 3.00 (3, dd; 14.5 and 7.3 ), 3.13 (3, dd; 14.5 and 5.5), 7.20 (5, d; 2.0), 3.86 (7-OMe, s), 6.83 (8, d; 8.3), 7.06 (9, dd; 8.3 and 2.0) C 2.70 (2, m), 1.22 (2-Me, d; 7.1), 3.30 (3, m), -236- This paper size is applicable to Zhongguanjia Standard (CNS) A4 specification (210X 297 public celebration) ~ (Read the precautions on the back before filling this page)

1T 533206 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy ΑΊ B7 V. Description of the invention (234) 3.46 (3, m), 6.97 (3-NH, m), D 4.83 (2, dd; 10.0 and 3.4 ), 1.36 (3, m), 1.62-1.81 (3/4, m), 0.85 (4-Me, d; 5.9), 0.87 (5, d; 5.6).

A solution of Mercury deprotected and chlorohydrin H: RR-epoxide (8.0 mg) in dichloromethane (100 µl) was treated with hydrochloric acid (50 µl, 4N in dioxolane). After 30 minutes, the solvent was evaporated and the residue was purified on reverse phase hplC (Econosil C18, 25 cm X 10 mm, 10 &quot;, 40% H20 / CH3CN, 3.5 ml / min) to obtain Cryptophyta _252 (5 mg, tR minutes) and Hidden bath 253 (2¾g 'tR minutes). Crytocin-252 cytotoxicity data: cell lines (# times more effective than cryptocin) KB (1 · 20) and LoVo (1.25) Crytocin-252: EIMS m / z (relative intensity) 670/672 (7.2 / 2/2), 669/671 (19.2 / 7.8), 280/282 (6.8 / 2.4), 242 (4.7), 195/197 (43/12); High-resolution EIMS m / z 669.285 6 (M + -2 HC1_H) Calculation of C35H44C1N308 値, -3.9 mmu error); 4 NMR (MeOH) amine or hydroxy acid unit (carbon position, multiplicity; J Hz) A 5.93 (2, d; 15.1), 6.61-6.78 (3, m), 2.33 (4, dt; 14.7 and 9.8), 2.69-2.80 (4, m), 5.11 (5, m), 2.46 (6, m), 0.95-1.04 (6-Me, m), 3.99 (7, brd; 9.4), 4.62 (8, d; 9.4), 7.28 (2 ', br s), 7.17 (4 ,, brd; 8.1), 7.07 (5 ,, t; 8.1), 6.98 (6 ,, d; 8.1); B 4.50 (2, dd; 10.5 and 3.2), 2.69-2.80 (3, m), 3.18 (bi * d; 13.7), 6.61-6.78 (5, 8 &amp; 9, m), 3.86 (7-OMe, s); C 2.69-2.80 (2, m), 1.19 (2-Me, d; 7.3), 3.28 (3, brd; 13.4), 3.58 (3, br d; 13.4); D 5.01 (2, dd; 9.8 and 2.7), 1.53 (3, m) 1.70-1.84 (3/4, m), 0.95-1.04 (4 / 5-Me, m). Cryptocin-253: 4 NMR (MeOH) amino or hydroxy acid unit j (carbon position, multiplicity; J Hz) A 5.84 (2, dd; 15.3 and 1.6), 6.60-6.74 (3, m),- 237- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) '-------- # 摹 | (Please read the precautions on the back before filling this page), !!.鸾 · 533206

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (235) 2.10 (4, dt; 14.9 and 11.2), 2.64 (4, m), 5.05 (5, m), 1. 5〇 (6 0.90 (6-Me, d; 6.8), 4.01 (7, dd; 9.5 and 1.2), 4.75 (8, d; 9.5) 6 6〇 '6.74 (2' / 4 '/ 67, m) , 7.09 (5 ', t; 7.8); B 4.48 (2, dd; 11.4 and 3 9) 2.71 (3, dd; 14.4 and 11.4), 3.16 (3, dd; 14.4 and 3.7), 7.26 (5 2.2 ), 3.86 (7-OMe, s), 6.96 (8, d; 8.4), 7.15 (9, dd; 8.4 and 2 2) c 2.76 (2, m), 1.18 (2-Me, d; 7.3) , 3.26 (3, m), 3.58 (3, dd; 13 5 and 3.1); D 4.94 (2, dd; 9.4 and 3.8), 1.58 (3, m), 1.80 (3, m), i 7 〇 (4 m), 0.97 (4_Me, d; 6.1), 0.98 (5, d; 6.3) 〇 'Cryptocin-263, 264 and 265: Cryptophytin-242 and its SS-epoxide mixture ( 26 mg) in cold, CH2C12 (5 ml), treated with TMSC1 (1.0M solution in CH2C12, 120 microliters) at -78 C. After 3 hours, the solvent evaporated and the residue (27 mg) was fed into " Reverse-phase HPLC (Econosil C18, 250 mm X 22 mm, 10 &quot;, 65 35 CH3CN / H20, 6 ml / min) to obtain Cryptocin-264 (6 0 亳G, t 43 minutes), and a mixture of Cryptocin-263 and 205 (15.8 mg, tR 59 ^ min). Cryptocin-263 and 265 were tested by normal phase HPLC (Econosil silica, 250 mm x 10 mm, 10 A, 55: 45 EtOAc / hexane, 3 ml / min), Cryptocin-265 (7.1 mg, 51 minutes) and Cryptocin-203 (7.8 mg, 7 9.0 minutes) were obtained.素 # Cytotoxicity, which is relatively low for lethal prime 1 &quot; 1 piece -¾— | KB LoVo 263 1.67 0 ^ 56 264 0.044 0.023 265 0.0033 0.021 —1 -238- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm)

f Please read the notes on the back before filling in this hundred C

-Order 533206 A7 B7 V. Description of the invention (236) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Cryptocin-263: 4 NMR (CDC13) Amine or hydroxyl Acid unit d (carbon position, multiplicity; J Hz) A 5.79 (2, d; 15.6), 6.68 (3, m), 2.37 (4, m), 2.66 (4, br dd; 14.2 and 4.2), 5.10 (5, m), 2.49 (6, m), 1.03 (6-Me, d; 6.8), 4.00 (7, br d; 9.4), 4.64 (8, d; 9.4), 7.35 (276 丨, br d 7.9), 7.29 (375 ,, brd; 7.9), 4.31 (4'-CIi2NH, t-BOC, d; 4.8), 4.92 (4f-CH2NH-t-BOC? Brs), 1.45 (4,- CH2NH-t-BOC.? S); B 4.79 (2, 111), 5.76 (2-1 ^ 11, (1; 8.6), 3.01 (3, (1 (1; -14.4 and 7.3) 53.15 (3, (11 -14.4 &amp; 4.9), 7.23 (5, d; 1.3), 3.87 (7-OMe, s), 6.84 (8, d; 8.4), 7.09 (9, br d; 8.4); C 2.73 (2 , m), 1.22 (2-Me, d; 7.2), 3.24 (3, m), 3.53 (3, m), 6.93 (3-NH, brt; 5.5); D4.92 (2, dd; 9.7 &amp; 3.1), 1.48 (3, m), 1.78 (3, m), 1.73 (4, m), 0.93 (4-Me, d; 6.4), 0.94 (5, d; 6.4); 13C NMR (CDC13) Unit d (carbon position) A 165.6 (1), 125.3 (2), 141.6 (3), 36.4 (4), 7 6 · 5 (5), 38.3 (6), 8.7 (6-Me), 74.1 (7), 61.8 (8), 137.5a (1 '), 128.3 (276 丨), 128.0 (3 丨 / 5 丨) 140.3a (4f)? 44.2 (4r-CH2NH-t-BOC)? 28.4 &amp; 155.9 (4, -CH2NH-t-BjOC); B 171.lb (1), 53.7 (2), 35.1 (3) , 130.0 (4), 131.1 (5), 122.4 (6), 154.0 (7), 56.2 (7-〇CH3), 112.3 (8), 128.5 (9); C 175.4 (1), 38.4 (2), 14.1 (2-Me), 41.3 (3); D 170.6b (1), 71.4 (2), 39.8 (3), 24.8 (4), 23.2 (4-Me), 21.6 (5). The signals of a &amp; b having the same upper corner are interchangeable. Cryptocin-264: 4 NMR (CDC13) amine or hydroxy acid unit π (carbon position, multiplicity; J Ήζ) A 5.71 (2, d; 15.4), 6.63 (3, ddd; 15.4, 9.9 and 5.5) , 2.12 (4, m), 2.51 (4, br dd; 14.2 and 5.0), 5.05 (5, m), 1.47 (6, m), 0.92 (6-Me, d; 6.8), 4.06 (7, dd 9.6 and 1.5), 4.87 (8, d; ___-239 _ This paper size is applicable to the national standard of the country (CNS) A4 (21 OX297 mm)-533206 A7 B7 V. Description of the invention (237) 9.6), 7.29 (276, br d; 8.4), 7.27 (375 ,, brd; 8.4), 4.33 (4,-CH2NH-t-BOC? Brs), 1.47 (4, -CH2NH-t-BOC? S); B 4.80 (2, m) 5.69 (2-NH, brS), 3.01 (3, dd; -14.5 &amp; 7.2), 3.13 (3, dd; _l4.5 &amp; 5.4), 7.21 (5, d; 2.0), 3.86 (7-OMe, s), 6.83 (8, d; 8.4), 7.07 (9 dd; 8.4 and 2.0); C 2.73 (2, m), 1.23 (2-Me, d; 7 · 3), 3.28 (3, m) 3.52 (3, m), 6.93 (3-NH, br t; 5.7); D 4.86 (2, m), ι · 50 (3, m)

1.86 (3, m), 1.73 (4, m), 0.95 (4-Me, d; 6.6), 0.98 (5, d; 6.8); 13C NMR (CDC13) unit β (carbon position) A 165.4 (1) , 125.1 (2), 141 4 (3), 36.2 (4), 76.0 (5), 38.3 (6), 8.8 (6-Me), 74.3 (7), 68.4 (8) 136.6a (Γ), 128.0 (276 丨), 127.7 (375 丨), 140.3a (4 丨), 44 2 ⑷ CH2NH-t-BOC)? 28.4 (4-CH2NH-t-BOC); B 171.0b ⑴, 53 6 ⑺ 35.0 (3 ), 129.9 (4), 131.0 (5), 122.4 (6), 153.9 mm, 56.1 (7_ OCH3), 112.2 (8), 128.4 (9); C 175.4 (1), 38.5 (2), 14j

Me), 41.2 (3); D 170.4b (1), 71.4 (2), 39.8 (3), 24.8 (4), 23.2 (4-Me), 21.7 (5). The signals of a &amp; b having the same upper corner are interchangeable. Cryptocin-265: 4 NMR (CDC13) amine or hydroxy acid unit d (printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Carbon Economy (please read the precautions on the back before filling this page), multiplicity; J Hz) A 5.74 (2, d; 15.5), 6.68 (3, ddd; 15.5, 9.9 and 5.3), 2.36 (4, m), 2.54 (4, br dd; 14.2 and 4.9), 5.40 (5, m) , 1.87 (6, m), 1.05 (6-Me, d; 7.0), 3.71 (7, br t; 5.8), 5.07 (8, d; 5.3), 7.36 (276 ', br d; 8.2), 7.28 (375 丨, brd; 8.2), 4.30 (4, _ CH2NH-t-BOC, brs), 4.91 (4'-CH2NH-t-BOC, brs), 1.46 (4'-CH, NH- t-BOC. s); B 4.78 (2, m), 5.70 (2-ΝΗ, brs), 3.03 (3, dd; _14.5 17.1), 3.12 (3, dd; -14.5 &amp; 5.5) , 7.21 (5, d; 1.8), 3.87 (7-OMe, s), 6.84 (8, d; 8.4), 7.70 (9, dd; 8.4 and 1.8); C 2.72 (2, m), -240- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 kl B7 V. Description of the invention (238) 1.23 (2-Me9 d; 7.1), 3.33 (3, m)? 3.48 (3, m ), 6.97 (3-NH? Br t; 5.7); D 4.83 (2, dd, 9.7 and 4.3), 1 43 (3, m), i 70 (3, m), i 63 (4, m), 0.93 (4-Me, d; 6.4), 0.88 ( 5, d; 6.4); 13C NMR (CDC13) unit β (carbon position) A 165.5 (1), 125.0 (2), 142.0 (3), 34.6 (4), 74.4 (5), 39.8 (6) , 12.9 (6-Me), 77.5 (7), 66.7 (8), 137.3a (1 丨), 127.9 (2 '/ 6'), 127.8 (3 '/ 5'), 139.9a (4 '), 44.2 (4_XH2NH_t_B〇c), 28 4 (4-CH2NH-t-stupid); B 171.0b ⑴, 53 6 (2), 351 (3), 129 9 ⑷, 131.0 (5), 122.4 (6), 154.0 (7), 56 i (7-〇CH3), 112 3 (8), 128.4 (9); C 175.6 (1), 38.4 (2), 14.1 (2-Me), 41.3 (3); D 170.3b (1), 71.5 (2), 39.4 (3) 24.7 (4), 22.8 (4-Me), 21.6 (5). Signals with 3 and b having the same upper corner are interchangeable. Cryptocin-272: Cryptocin-263 (4.9 mg, 0.006 mmol) in ch2C12 (30 μl) with 4N HC1 in dioxolane (30 μl, 0.0%) 12 mmol) at room temperature. After 3 hours' the solvent was removed and the residue was kept under sacrifice for 2 days to remove the last trace of dioxan, and Cryptocin-272 (4.4 mg, 98%) was obtained. NMR (CDgOD) amino or hydroxy acid unit j (carbon position, multiplicity; J Hz) A 5.94 (2, dd; 15.0, 1.8), 6.69 (3, ddd; 15.0, 11.1 and 4.9), 2.36 (4, m)? 2.72 (4, m)? 5.13 (5, m), 2.48 (6, m), 1.01 (6- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before Fill out this page}

Me, d; 7.1), 4.02 (7, dd; 9.4 and 2.0), 4.84 (8, d; 9.4), 7.45 (276, d; 8.4), 7.51 (375 ', d; 8.4), 4.ll (4, Cil2NH2HCl, s); B 4.51 (2, dd; 11.2 and 3.9), 2.74 (3, m), 3.18 (3, dd; -14.5 and 3.9), 7.28 (5, d; 2.2), 3.84 ( 7-OMe, s), 6.98 (8, d; 8.4), 7.17 (9, dd; 8.4 &amp;2.3); C 2.77 (2, m), 1.19 (2-Me, d; 7.5), 3.29 (3 , m), 3.58 (3, dd; 13.7 and 3.3); D 5.02 (2, dd; 9.5 and 3.8), 1.56 (3, m), 1.78 (3, m), 1.78 (4 -241-present The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 533206 A7 Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and Consumer Cooperatives. V. Invention Description (239) m), 0.97 (4-Me, d; 6.6), 0.99 (, 5, d; 6.6); 13C NMR (CD3OD) unit β (carbon position) A 168.4 (1), 125.4 (2), 144.0 ⑺, 317 (4), 77.3 (5), 40.4 ( 6), 8.1 (6-Me), 74.8 (7), 63.3 (8), 142.5a (Γ), 130.0

(276 ^), 130.3 ^ (375 ^ 134.6 ^ (4-)? 44.0 (4.CH2NH2HC1); B 174.1 ⑴, 57.4 (2), 36.3 (3), 132.2 (4), 131.5 (5), 123.3 ( 6), 155.4 (7), 56.6 (7-OCH3)? 113.5 (8), 129.3 (9); C 177.5 (1), 39.1 (2), 15.1 (2-Me), 41.2 (3); D 172.1 (1)? 72.8 (2), 41.2 (3) 26.0 (4), 22.1 (4-Me), 23.6 (5). 3 signals are interchangeable. Cryptocin-273: 3-chloroperbenzoic acid (128 mg ) Add Crypterosin-234 (146 pens) in a solution of CH2C12 (8 liters) at 0 ° C. The solution was slowly warmed to room temperature and continued to stir for 12 hours. The reaction mixture was diluted with CH2cl2 (7 ml). , Washed with phosphate buffer solution (2 × 10 ml, ο ″ μ, pH 8). The organic layer was separated and treated with dimethyl sulfur (50 ml) to quench the excess peracid and washed with buffer solution. The organic layer was evaporated. The residue was subjected to reverse-phase HpLC (25 mm x 22 mm, 10 ', 15% H20 / CH3CN, 6 ml / min) to obtain RR-epoxide (74 mg, 50%).

A solution of epoxide (74 mg) in THF (3 ml) was treated with a 1 M solution (115 µl) of tetrabutylammonium fluoride in CH2C12. After L5 hours, a saturated NHW1 solution was added to the reaction mixture and extracted with EtoAc (2 × 30 ml). The organic extract was dried over MgS04 and evaporated. The residue is made on a small silica pipe column -242- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) i! (Please read the precautions on the back before filling this page) -δ .¾. 533206 A7 B7 V. Description of the invention (240) Purified with 50-100% EtOAc / CH2Cl2 to obtain cryptocin-269 (62 mg r 98%).

DCC (160 μl, 1M solution) was added to a solution of cryptocryptin-269 (62 mg), N- (t-BOC) glycine (30 mg) and DMAP (8 mg) in CH2C12 (3 ml). CH2Cl2f) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes and at room temperature for 2 hours. At the end of this period, the mixture was filtered and concentrated in the air. The residue was subjected to flash chromatography on ODS silica using 75-30% H20 / CH3CN to obtain N-t-BOC-glycine (64.4 mg, 85%) of Cryptocin-269. (Read the precautions on the back before filling this page)

1T

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

To a solution of glycine (64.4 mg) in chloroform (3 ml) at -60 ° C was added 200 microliters of a 1M solution of TMSC1 in CH2C12. After 1 hour, the solvent was evaporated and the residue was purified on a small silica column using 40-90% EtOAc / hexanes to give the glycine trans-chlorohydrin (60 mg, 89%). TY This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 192, 194, 195 A7 B7 printed by Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (241) The solution in dichloromethane (0.25 ml) was treated with a 4M solution (oj ml) of hydrogen chloride in M-dioxozone. The resulting mixture was stirred at a high temperature for 2 hours, concentrated in a high temperature, and dried in a freeze dryer for 1 hour. Cryptocin-273 was obtained as a white solid.

Cryptocin-273 Table 9. 1H NMR data of Cryptocin-8, 163, 184 185, 186, 187, 191 212, 222, 223 and 224 P = position P 8 163 184 185 186 187 191 192 193 194 195 212 222 223 224 A 2 5.79 d 5.80 5.79 5.74 5.71 5.75 5.80 5.68 5.80 5.67 5.79 5.80 5,71 5.80 5.79 3 6.69 ddd 6.70 6.70 6.68 6.64 6.69 6.70 6.63 6.70 6.62 6.69 6.68 .6.6 5 6.69 6.69 AR 2.37 2.35 2, 38 2.36 2.15 2.37 2.40 2.10 2.40 2.09 2.37 2.40 2.17 2.39 2.37 mmmmmm 4S 2.67 2.75 2.70 2.55 2.53 2.59 2.70 2.47 2.69 2.51 2.68 2.64 2.54 2.60 2.68 m zn mm zn m 5 5.10 5.00 5.12 5.32 5.06 5.40 5.14 5.07 5.13 5.07 5.XI 5.10 5.XI 5.10 5.07 5.11 5.11 ddd mm xn brt 6 2.50 2.85 2.54 1.91 1.50 1.83 2.65 1.64 2.55 1.57 2.49 2,47 1.51 2.48 2.50 mmm 6- Me 1.05 d 1.13 1.09 1.09 0.93 1.06 1.18 0.95 1.09 0.90 1.04 1.03 0.93 1.04 1.04 7 4.00 brdt 4.41 4.09 3.84 4.07 3.74 4.35 4.48 4.12 4.20 3.99 3.95 4.07 4.16 3.98 8 9 4.65 d 4.80 5.12 5.46 4.83 5.02 5.66 5.72 4.84 5.06 4.61 4.59 4.81 5.03 4. 60 -244- This paper size applies to Chinese National Standard (CNS) Α4 size (210 × 297 mm) (Please read the precautions on the back before filling this page)

533206 A7 B7 V. Description of the invention (242 ί 8/1 0- Ar- 1 '2' 3 4 * 5 '6' 8 'D 2 3 3' 4- He KB4 m 7.76 brs U6 to 7.40 m 4.92 dd 1.45 m 1.78 m 1.76 zn 0.94 d 0.93 d 7.25 d 6.88 d 3.81 9 6.88 d 7.25 d 4.93 1.41 1.78 1.78 0.95 0.92 2.30 s 2.31 a 7.13 to 7.17 4.93 1.50 1.79 1.79 0.95 0.95 2.28 2-30 7.13 to 7.16 m 1.43 m 1.43 1.68 1.63 0.91 7.06 d 2.27 d 2.27 d 7.13 d 7.03 dd 4.86 1.53 1.85 1.85 0.97 0.94 7.15 br s 2.24 s 2.26 3 7.11 br s 4.81 1.42 1.69 1.59 0.91 0.86 7.72 brs 7.50 brm 7.88 d 7.90 d 7.54 t 7.59 t 8.13 s , 93 1.47 1.74 1.74 0.93 brs 7.56 7.49 7.88 7.92 7.52 to 7.63 m 8.13 brs 4.86 1.51 1.86 1.64 0.93 7.52 m 7.89 d 7.84 m 7.52 m 7.52 m 7.84 m 4.93 dd 1.46 1.70 to 1.81 m 0.95 7.42 dd 7.88 d 7.85 m 7.51 to 7.56 m 7.85 m 4.84 dd 1.46 1.84 1.58 0.97 6.97 brd 7.30 t 6.88 dd 3.81 s 6.93 t 4.92 1.45 1.7 to 1.82 m 0.93 6.94 m 6.80 tt 6.94 m 4.91 1.43 1.66 K 1-82 m 0.94 6.90 br s 2.32 6.99 br 3 2.32 6.90 bs 4.87 dd 1.54 1.85 1.70 0.97 6 6 .0 to .4m 7 7 4.92 dd 1.50 1.74- to 1.84 χα 0.95 7.15 br s 2.26 2.26 7.12 to 7.15 m 4.93 m 1.46 m 1.72 to 1.82 m 0.98 0.87 0.90 0.96 0.94

(Read the precautions on the back before you fill in this page.) The spectra printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs are recorded in CDCh; The chemical shift of the protons in the unit is within ± 0.2 ppm of cryptocin_8 値, and the coupling constant is in the soil 〇 5 Hz. 163 (H, H) Hz: 2 ', 3' = 5 ', 6' = 8.7; 186 of J (h, H) Hz: 2, 6, 6, = 2.0; 5, 6, 6 = 7 · 7; m and 194 J (H, H) Hz: 3, 4, 4, = 8.5; 195 J (H, H) Hz: 2 ', 3' = 3 ', 4' = 7 · 9; 2 ' , 6 '= 4'6' = 2.4; the remaining protons in the table can be measured

The coupling constant is within ± 0.5 Hz of the oxaxin-8. J (HH) and J (H, F) Hz of 212: 3'-F, 4-H> 4-H, 5-F = 8.7; 2 ', 4, = 4f, 6, = 2.3. Table IQ. Cryptocin-8, 163, -184, -185, -186, 187, 191, 192, 194, 195, 222, 223, and 224 at 125 MHz 13C NMR data. -245 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 533206

A V. Description of the invention (243) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs p == Reset P 8 163 184 185 186 187 191+ 192+ 194 195 212 222 223 224 A 165 165 165 165 165 165 165.5 165.4 165 . 165.5 165.5 165.4 165.5 165.5 1 .5 .4 .5 .4 .5 4 2 125 125 125 124 125 125 125.1 125.4 125. 125.1 125.4 125.1 125.3 125.2 .1 .3 .2 .9 .0 .0 1 3 141 141 141 142 141 142 141.7 141.6 141. 141.7 141.3 141.6 141.4 141.6 .6 .1 .7 .0 .6 .1 5 4 36. 36. 36. 36. 34. 36. 34. 36.5 36.2 36.1 36.4 36.3 36.1 36.4 36.4 3 9 5 9 2 6 5 76. 75. 76. 74. 76. 74. 76.4 76.3 76.1 76.3 76.3 76.2 76.4 ★ * 3 8 4 7 2 3 6 38. 39. 38. 39. 38. 39. 38.3 38.3 38.3 38.3 38.5 38.4 38.5 38.4 2 5 3 9 3 6 Μ; 8.7 9.6 8.7 13. 3 8.7 12. 9 8.8 9.2 8.7 8.7 8.7 8.7 8.6 8.7 7 74. 65. 74. 76. 74. 77. 74.0 73.9 74.3 74.0 74.0 74.3 73.1 74.0 0 1 1 4 3 7 8 61. 62. 57. 63. 69. 67. 57.2 62.8 67.1 61.9 60.7 69.1 55.3 62.0 9 10 9 3 5 6 0 3 8/138 131 135 133 135 135 ★ ★ 126. 139.7 142.7 137.4 130.7 135.5 10 .3 .2 .9 .6 .0 .5 9 Ar 1, 2 '128 128 137 137 128 128 * ★ ★ 114.1 111.2 125.1 160.6 129.1 .0 .8 .7 .7. 5 .6 .7 ad 3 '129 114 137 136 137 137 125.2 125.0 124. 160.0 163.0 138.7 116.1 137.5 .1 .1 .7 .1 .4 .3 0 dd 4' 129 160 130 130 137 137 129.2 127.1 129. 114.2 104.5 130.9 129.3 138.0 .2 .1 .5 .4 .9 .5 3 at 5 '129 114 126 126 130 130 129.2 129.4 127. 130.2 163.0 138.7 124.8 130.3 • 1.. 4 .1 ί 3 .1 8 6' 128 128 124 125 124 124 127.0 126.3 127. 120.0 111.2 125.1 130.7 125.3 • 0 .8 .5 .7 .7 .9 0 d 7 '126.2 126.3 127.1 1 81 ★ ★ 128. 〇9' * 130.5 * 10 1 134.5 ★ 134.7 7 D 170 170 170 170 170 170 170 170.6 170.4 170. 170.6 170.7 170.4 170.7 170.6 1 .6 .2 .6 .2 .4 .3 9 2 71. 71. 71. 71. 71. 71, 71.3 71.4 71.4 71.3 71.3 71.4 71.4 71.4 3 3 3 5 4 5 3 39. 39. 39. 39. 39. 39. 39.6 39.7 39.7 39.7 39.9 39. 7 39.6 39.7 7 6 7 3 7 4 4 24. 24. 24. 24. 24. 24. 24.0 24.8 24.8 24.7 24.7 24.8 '24.7 24.7 7. 8 7 6 8 7 4- 23. 23. 23. 22. 23. 22. 23.1 23.1 23.1 23.0 23.0 23.1 23.1 23.1 Me 1 3 2 8 1 7 — 5 21. | 21. 21. 21. 21. 21. 21.5 21.7 21.7 21.4 21.5 21.8 21.4 21.5 5 1 5 5 6 7 6 (Please first Read the notes on the reverse side and fill out this page)-? 口 -246- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 Α7 Β7 V. Description of the invention (244) The spectrum is recorded in CDC13. The chemical shifts of carbon in units B and C are within 0.5 Ppm of Cryptocin-8. * Signal cannot be found because the sample is small. + Arrangement is experimental. ** Combined solvent signals. The 4-OMe carbons of 163 and 195 resonate at β 55.3. 2 '-] ^ 6 and 3'-^^ carbons of 185 appeared at (^ 15.0 and 20.9. 3 of 186,-] \ / ^ and 4,-] ^^ carbons measured at (^ 19.6 and 19.9, respectively) The same carbon of 187 was measured at β 19.5 and 19.8, and the same carbon of 224 was measured at d 19.5 and 19.8. The 3 '-] ^^ and 5'-1 ^ 6 carbons of 223 were measured at 6 21.3. Example The general group R in 9 4 2 '(below) includes an ether substituent and several fluorenyl substituents, as shown in Table 1 (below). The novel cryptocryptin analogs are prepared by esterification technology in medium to high yields. See 'Mulzer, J., Trost BM Fleming, I., Ed. Comprehensive Organic Synthesis; 6: 323-380, (Pergamon press: Oxford, 1991); Benz, G. Trost, BM, Fleming, I. Ed., Comprehensive Organic Synthesis, 6: 381-417, (Pergamon press: Oxford, 1991). Amine hydrochloride is prepared in high yield by treating the corresponding third butyl carbamate with hydrochloric acid. The disodium salt 7 'system Derived from the 6 ′ cleavage of the third butyl ester induced by hydrochloric acid and sodium hydroxide treatment to obtain a 0 ρ ratio mirror; the salt 9 ′ is derived from 1 * by Nicolaou. Nicolauo, et. Al. Angew · Chem. Int. Ed. Engl ., 33: 1583+ (1994) Preparation.

(355702) 1, 2r. (Used in the description of the following synthetic method) Table 1-General structure 2, R group (above). -247- This paper size is applicable to Chinese National Standard (CNS) M specifications (210 × 297 mm) (Please read the precautions on the back before filling this page)

533206 A7B7 V. Description of the invention (245 | Compounds

R compound 2 € 28 · 29 6 ′

30. 31 32 33 Λ ΛΛ

R NHC02t-Bu, NH2 ¥ HCI NHC〇2t-Bu NH, ¥ HCI 11, κχχ ° 34. 36 · 12 · 13, OMe NH ^ HCl

Sr,, NH ¥ HCI 36 37 · 38 39 '40 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 15.16 · 17. 18' 19. 20 '21. 22' 25. ^ Vj ^ CX) 2t-Bu O 2 ^ γΝΗ ¥ ΗΟ ^ X ^ NHC〇2t-Bu

7 ^^ NHC〇2t-Bu -248- 42 4Λ 44 · jlA ^ NHCO ^ -Bu V ^ s ^ NHC〇2t-Bu χΛγΝΗ2 ¥ Ηα k ^ &gt; v ^ NH2 ¥ HCI rAs ^ NHCOjt-Bu S ^ v ^ NHC〇2t-Bu 2 ^ A ^ NH2 ¥ Ha v ^ s ^ NH2 ¥ HCI ^ Xs ^ NHC〇2t-Bu k ^ C〇2t * Bu τΑγ, ΝΗ2 ¥ Ηα V ^ COjH O 2 &gt; Jtvr.NHC02t- Bu 〇C〇2t-Bu 2> Xs ^ NH2VHCI ^ A ^ NHCOjt-Bu 〇, C〇2t-Bu, C〇2H C02t-Bu 〇NHC02t-Bu 7 (K ^^ C〇2H NH ^ HCI 〇k ^ NHC02t.Bu ^ NHCXD2t-Bu ϊ— (Please read the precautions on the back before filling out this page, 1Τ 45_ 46 47 '48 ·

NH2 ¥ HCI NH2VHCI NHC02t-Bu OH

This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 533206 A7 B7 V. Description of the invention (246) The production system of the conjugates described in Table 1 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Several methods are available, typically involving an activated ester method, followed by chromatography and, if necessary, deprotection by acid initiation. Therefore, 1, acetic anhydride was treated in the presence of triethylamine and 4-dimethylaminopyridine, and after flash chromatography, 3, was obtained with a yield of 89%. Similarly, 5, can be prepared by treating with succinic anhydride and then purifying by reverse phase HPLC. Alternatively, 5, is prepared from mono-tert-butyl ester 4 in high yield by acid treatment. The pyridine solution was exposed to the commercially available nicotinylfluorenyl chloride hydrochloride in the presence of triethylamine and n-dimethylaminopyridine, and then subjected to chromatography and hydrogen chloride treatment to obtain 8, high yields. Pyridinium salt 9 was prepared in 47% yield in accordance with the method of "Qi (the above)", of which 1, was treated with commercially available p-toluenesulfonic acid fluorine "· methylpyridine, and then reversed Phase HPLC purification combined anion exchange (acetate vs. p-toluenesulfonate) and lyophilization. The rest of the esters are available in medium to high yields, and are commercially available (except in the case of 4, 6, 6, 10, 43, 43, and 45). The iN_t_boc protected amino acid is 1,3-di Cyclohexylcarbodiimide is prepared by activation in the presence of melamine pyridine. The hydrochloride is prepared in high yield from the treatment of tritium 4.0 in hydrogen chloride in dioxolane and the removal of the solvent in the air. Disodium salt 7 is derived from the 6 ′ cleavage of the third butyl ester induced by hydrochloric acid and sodium hydroxide treatment. The 24 'required for the preparation of 5' was synthesized by adding a phosphoric acid functional group in a 5-step sequence of the Johns method at a yield of 63%. Perich, jW; Johns RB et al, except "Ex. 1988: 142." 〇P (〇) (OBu) 2 24-(379402) Several novel conjugates have been evaluated for in vitro cytotoxicity in the Gc3 tumor cell model -249- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -------- ·! # — 1 (Please read the precautions on the back before filling this page) I-I i 1 I-. 533206 kl B7 V. Description of the invention (247 properties, as described above. These results are shown in the following Table 2: I 2. Crypto-algalin-derived in vitro cytotoxicity compounds 7, 9 丨IV 13, 15, 17, 19, 21, 25, 0.065 83 31 3.7 116 2.2 6.8 7.0 60 3.6 0.10 21 230 28, 30 32 34 36 38 40 42 44 46 47 48 -g £ jjC50 (nM) 2.6 30 7.2 6.5 2.8 1.6 2.0 15 28 50 2.5 10 The machine was used to print the stability research conducted by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Ion Economy in an aqueous solution in the pH range of 4-8, and the percentage of the product was measured. The third butyl carbamate was converted into the corresponding Salts can be made with strong acids, namely helmet acids, including hydrogen halides, stones! Hydrogen acid, phosphoric acid, ammonia nitrate, perchloric acid or strong organic acids such as trifluoroacetate Acids, p-toluenesulfonic acid, and methanesulfonic acid. ^ Uses the same acid to produce a salt of 8, from a corresponding free base. A variety of counterions (positives) can form 7 'salts, including alkali metals and alkaline earth metals. A variety of balances The ion (anion) can form a 9 'salt, that is, any conjugate base of an acid (organic or inorganic). Preparation of Cryptocin 5 5 Acetate (3,) (LSN 382376). At 11 (93 g, 0.13 Penmole) To a solution of 659 microliters of dichloromethane was added diethylamine (55 microliters, 0.4 mmol), 4-dimethylaminopyridine (1.6 mg, 0.008 mg). 13 millimoles), and acetic anhydride (19 microliters, 0.20 millimoles). After stirring off for 0.0 hours, the reaction mixture was quenched with 19 microliters of methanol and concentrated to 0.5 volumes,

I £ L -250- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 533206 A7 B7 V. Description of the invention (248) Connected to the flash chromatography column (19g flash silica gel). Dissolve in ethyl acetate-hexane (3: 1) to obtain 88 mg (89%) of the title compound as a white foam: 500 MHz NMR (CDC13) β 7,38-7,31 (m, 5H), 7.24 ( d, 1H, J 2.1 Hz), 7.22-7.18 (m, 1H), 7.10 (dd, 1H, J = 8.5, 2.1 Hz), 6.88 (d, 1H, J = 8.5 Hz), 6.75 (ddd , 1H, J = 15, 13, 4.6 Hz), 5.78 (dd, 1H, J = 15, 1.0 Hz), 5.55 (d, 1H, J = 7.9 Hz), 5.46 (dd 1H, J = 9.8, 1.2 Hz ), 4.95 (dd, 1H, J = ll, 2.9 Hz), 4.89 (ddd, 1H, J = 9.9, 9.9, 1.7 Hz), 4.81 (d, 1H, J = 9.8 Hz), 4.79_4.74 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8.1 Hz), 3.22 (dd, 1H, J = 13, 4.1 Hz), 3.16 (dd, 1H, J = 14 , 5.1 Hz), 3.07 (dd, 1H, J = 14, 7.6 Hz), 2.65-2.55 (m, 2H), 2.47-2.39 (m, 1H), 1.95 (ddd, 1H, J = 14, 13 , 4.6 H), 1.86-1.77 (m, 1H), 1.73-1.66 (m, 1H), 1.68 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H), 1.09 (d, 3H, J = 7.1 Hz), 1.03 (d, 3H, J = 6.7 Hz), 0.97 (d, 3H, J = 6.6 Hz). Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Preparation of Cryptophyll 55 tert-butyl succinate (4f) (LSN 384665). At Γ (133 mg, 0.1S8 mmol), succinic monobutyl ester (66 mg, 0.377 mmol) and 4-dimethylaminopyridine (2.3 mg, 0.019 mmol) at 850 μm A solution of 1,3-dicyclohexylcarbodiimide (78 mg, 0.377 mmol) in 92 microliters of dichloromethane was added to one liter of the solution in anhydrous dichloromethane at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was treated with 150 mg of celite, diluted with 1 ml of ethyl acetate-hexane (3: 1), filtered through a ceiite plug, and washed with ethyl acetate-hexane (3: 1). . The filtrate and washings were concentrated in the air to a off-white oil. Chromatography (25 g of rapid silica gel) with ethyl acetate-hexane (2: dissociation to obtain 157 mg (97%) of the title compound as a white foam: 500-251 _ This paper size applies to Chinese national standards (CNS ) A4 specification (210X297 mm) '&quot; 533206 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Β7 _V. Description of the invention (249) MHz lU NMR (CDCI3) δ 7.38-7.30 (m, 5H)? 7.24 ( d, 1H, J-2.0 Hz), 7.22-7.18 (m, 1H), 7.09 (dd, 1H, J = 8.5, 2.0Hz), 6.88 (d, 1H, J = 8.5 Hz), 6.74 (ddd, 1H , J = 15, 10, 4.6 Hz), 5.76 (d, 1H, J = 15 Hz), 5.51 (d, 1H, J = 8.0 Hz), 5.47 (d, 1H, J = 9.6 Hz), 4.97 (dd , 1H, J = 11, 3.1 Hz), 4.90 (t, 1H, J = 9.3 Hz), 4.83 (d, 1H, J = 9.6 Hz), 4.79_4.73, 1H), 3.91 (s , 3H), 3.39 (dd, 1H, J = 13, 8.0 Hz), 3.22 (dd, 1H, J = 13, 4.0 Hz), 3.16 (dd, 1H, J = 14, 5.1 Hz), 3.08 (dd, 1H, J = 14, 7.6 Hz), 2.63-2.55 (m, 2H), 2.44-2.37 m, 1H), 2.32-2.21 (m, 2H), 2.19-2.06 (m, 2H), 1.99-1.92 (m , 1H), 1.85-1.68 (m, 2H), 1.42 (s, 9H), 1.27 (s, 3H), 1.19 (s, 3H), 1. 08 (d, 3H, J = 7.0 Hz), 1.03 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H, J = 6.5 Hz). Cryptocin 55 succinate (5,) (LSN 377〇92) was prepared from Cryptocin 55 third butyl succinate. To a solution of 4 '(127 mg, 0.147 millimoles) in 491 microliters of dichloromethane was added a 40μ solution of hydrogen chloride in 14-dioxolane (184 microliters, 0.737 millimoles) at room temperature. . The solution was stirred at room temperature for 5 hours. Concentrated in the air, 119 mg (100%) of the title compound was obtained as a white foam. Cryptocin 5 5 succinate (5,) (LSN 377092) is prepared from succinic anhydride. Triethylamine (6 microliters) was added to a solution of ^ (microgram, 0.038 millimoles) and succinic anhydride (5.7 mg, 0.057 millimoles) in 3 83 microliters of dichloromethane at room temperature. , 0.115 mol) and 4-dimethylaminopyridine (4.7 mg, 0 038 mmol). After stirring for 19 hours, 5.7 mg (0.057 mmol) of succinic anhydride and 47 mg (0.038 mole) of 4-dimethylaminop ratio were added, followed by stirring for another 9 hours. 7 Paper Standards Shicai Guanjia County (CNS) Α4 Specification ⑺Gx297 Public Attack y------- (Please read the precautions on the back before filling this page)

Order V. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 A7 B7 V. Description of the invention (25) The reaction mixture was treated with 0.5 ml of 1% aqueous hydrochloric acid solution and washed with dichloromethane (3 X 0.5 ml). The combined organic extracts were dried (Na2S04), filtered, and concentrated in the air to a white foam. Purification by reverse phase HPLC gave 10 mg (32%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) β 7.36-7.31 (m, 6Η), 7.22 (br s, 1Η), 7.08 (d, 1Η) , J = 8.4 Ηζ), 7.02 (brs, lH), 6.87 (d, lH, J = 8.4Hz), 6.61 (m, lH), 5.94-5.87 (m, 2H), 5.51 (d, 1H, J = 9.8 Hz), 4.95 (dd, 1H, J = 10, 2.8 Hz), 4.87-4.76 (m, 3H), 3.90 (s, 3H), 3.39 (dd, 1H, J = 16, 5.6 Hz), 3.28 ( dd, 1H, J = 16, 8.2 Hz), 3.17 (dd, 1H, J = 16, 5.6 Hz), 3,05 (dd, 1H, J = 16, 8.2 Hz), 2.68-2.62 (m, 1H) , 2.60-2.46 (m, 2H), 2.45-2.28 (m, 3H), 2.01-1.93 (m, 2H), 1.88-1.70 (m, 2H), 1.26 (s, 3H), 1.18 (s, 3H) , 1.12 (d, 3H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.6 Hz), L00 (d, 3H, J = 6.5 Hz). Preparation of Cryptocin 55 (2f-di-tert-butyl phosphate) phenyl acetate (6 ') (LSN 379407). Inside a solution of Γ (0.102 mmol), 24f (46 mg, 0.134 mmol) and 4-dimethylaminopyridine (12 mg, 0.102 mmol) in 250 µl of anhydrous dichloromethane A solution of 1,3-dicyclohexylcarbodiimide (27 mg, 0.134 mmol) in 50 microliters of dichloromethane was warmly added. After stirring at room temperature for 6 hours, the reaction mixture was diluted with 1 ml of ethyl acetate-hexane (3: 1), filtered through a celite plug, and washed with ethyl acetate · hexane (3: 1). The filtrate and washings were concentrated into a purple foam in the air. Chromatography (15 g of flash silica) and dissolution with ethyl acetate-hexane (4: 1) gave 86 mg (82%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) 7.35 (d, 1H , J = 8.3

Hz), 7.30-7.19 (m, 8H), 7.11 (dd, 1H, J = 8.4, 2.0 Hz), 7.02 (t, -253-) This paper size applies to the Chinese National Standard (CNS) A4 specification (2l0X 297 Mm) (Please read the notes on the back before filling out this page}

533206 A7 B7 V. Description of the invention (251) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) 1H, J = 7.5 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.84 (d, 1H, J = 7.5 Hz), 6.73 ddd, 1H, J = 15, 13, 4.7 Hz), 5.92 (d, 1H, J = 7.9 Hz), 5.79 (dd, 1H, J = 15, 1.0 Hz), 5.43 (dd, 1H, J = 9.4, 1.8 Hz), 4.98 (dd, 1H, J = 12, 3.1 Hz), 4.81 (ddd, 1H, J = 9.9, 9.9, 1.8 Hz ), 4.75 (d, 1H, J = 9.4 Hz), 4.73-4.67 (m, 1H), 3.90 (s, 3H), 3.49 (d, 1H, J = 16 Hz), 3.44-3.38 (m, 1H), 3.38 (d, 1H, J = 16Ηζ), 3.27-3.17 (m, 2H), 3.10 (dd, 1H, J = 14, 8 · 2 Hz), 2.55-2.46 (m, 2H), 2.37-2.27 m, lH), 1.95 (ddd, lH, J = 14, 12, 4.5 Hz), 1.83-1.70 (m, 2H), 1.49 (s, 18H), 1.27 (s, 3H), 1.20 (s , 3H), 1.03 (d, 3H, J = 6.5 Hz), 0.97 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 7.0 Hz). Preparation of 2,-(di-tert-butyl phosphate) phenylacetic acid (24f) (LSN 379402). To a solution of 21-hydroxyphenethyl alcohol (1.05 g, 7.60 mmol) in 15.2 ml of N, N-dimethylformamide was added imidazole (621 mg, 9.11 mmol) and the Tributyldimethylsilyl chloride (1.26 g, 8.34 mmol). After stirring at 0 ° C for 40 minutes and at room temperature for 4 5 minutes, 155 mg (2.28 mmol) of imidazole and 229 mg (1.52 mmol) and tertiary butyl dimethyl sulfonium chloride Join. The reaction mixture was stirred for 15 minutes' at which time 150 ml of third butyl methyl ether was added. The mixture was washed with cold 1 hydrochloric acid aqueous solution (1 x 15 ml) and then with water (1 x 15 ml). The organic layer was dried (Na2S04), filtered, and concentrated in the air to a yellow oil. Chromatography (70 g of rapid silica gel) was dissolved with ethyl hexanoate (5: 1) to obtain 1.81 g (94%) of a grade silyl ether as an off-white oil. In a solution of shiyanakamic acid (506 mg '2.00¾ mole) and diethyl butyl phosphite (600 µl, 93%, 2.00 mmol) in 2 ml of tetrahydrofuran at room temperature Added 1H-Sijun (421 mg, 6.01 mmol-254-) This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 533206 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (252) ears). After stirring for 45 minutes, the reaction mixture was cooled to d and quickly treated with a solution of m-chloroperbenzoic acid (99%, 450 mg, 2.61 mmol) in 3.6 ml of dichloromethane. The white reaction mixture was turbid to room temperature, and the mixture was stirred for 5 minutes. The reaction was quenched with 4 ml of a 10% aqueous solution of hydrogen sulfite steel, violently dropped for 10 minutes, diluted with 15 liters of third butyl methyl ether, and then with an aqueous solution of sodium hydrogen sulfite (2 x 10 liters). 0.5 HA aqueous sodium oxide solution (2 X 10 ml) was washed. The organic layer was dried (NajCU), filtered, and concentrated in the air to a colorless oil (941 mg), which was used directly in the next step. The crude acid salt was dissolved in 10 liters of tetrazine, and the cold section to 0 C was treated with ratified tetra-n-butyl tetrahydrofuran in a 1M solution (2.4 ml, 2.4 mmol). After stirring at 0 ° C for 20 minutes and at room temperature for 1.5 hours, the reaction mixture was diluted with 60 ml of tert-butyl methyl ether, washed with water (1 x 10 ml), and then brine (10 ml). The organic layer was dried (NasSCU), filtered, and concentrated in the air to a yellow oil. Chromatography (50 g of flash silica) and dissolution with ethyl acetate-hexane: u gave 525 mg (79%) of 1 ° alcohol as an off-white oil. In a solution of alcohol (123 mg, 0.372 mmol) in acetonitrile · carbon tetrachloride (1: 1, 1.49 ml), water (1.1 ml) was added at room temperature, and then sodium peroxoate (239 mg) was added. , 1.12 mmoles) and ruthenium (III) chloride hydrate (1.8 mg, 0.0082 mmoles). The brown mixture was stirred rapidly at room temperature for 5 5 minutes. Concentrated in the air and chromatographed (8 g of flash silica gel, dissolved with 10% methanol-ethyl acetate) to obtain 109 mg (85%) of the title compound as a purple oil: 500 MHz 4 NMR (CDC13) d 7.49 ( d, 1H, J = 7.53 Hz), 7.30-7.15 (m, 3H), 3.77 (s, 2H), 1.51 (s, 18H). Preparation of Cryptocin 5 5 (2'-phosphate) phenyl acetate disodium salt (7,) (LSN 3 74122). ________- 255- __ in 6 '(84 g, 0.081 millimoles) in 4,000 µl of methylene chloride This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) {Please first Read the notes on the back and fill in this page)-Order 533206 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (253) Add hydrogen chloride to the solution at room temperature, 4.0 in 1,4-dioxolane M solution (81 μl, 0.33 mmol). The light yellow solution was stirred at room temperature for 2 hours. After concentrating into an off-white foam in the air, the crude dihydrogen phosphate was dissolved in 614 µl of tetrahydrofuran and treated with a 5.00 N aqueous solution of sodium hydroxide (33 µl, 0.163 mmol). After stirring for 10 minutes, the mixture was concentrated in the air to a yellow-brown foam. The crude salt was absorbed into 1 ml of hot acetonitrile and 0.1 ml of hot water. The insoluble matter was filtered off, and the filtrate was concentrated in the air to obtain 69 mg (87%) of the title compound as a white solid: 500 MHz NMR (MeOH-d4) d 7.58 (d, 1%, J = 8.2 Hz), 7.38-7.32 (m, 2H), 7.32-7.28 (m, 3H), 7.28 (d, 1H, J = 2.1 Hz), 7.17 (dd, 1H, J = 8.5, 2.1 Hz), 7.09 (ddd, 1H, J = 7.8 , 7.8, 1.7 Hz), 6.98 (d, 1H, J = 8.5 Hz), 6.79-6.70 (m, 2H), 6.67 (d, 1H, J = 7.4 Hz), 5.91 (dd, 1H, J = 15, 1.7 Hz), 5.45 (dd, 1H, J = 9.4, 1.6 Hz), 5.06 (dd, 1H, J = 10, 2.7Hz), 5.01 (d, lH, J = 9.4Hz), 4.89-4.80 (m, 1H), 4.47 (dd, 1H, J = ll, 3.8 Hz), 3.84 (s, 3H), 3.67 (d, 1H, J = 16 Hz), 3.45 (d, 1H, J = 14 Hz), 3.42 ( d, 1H, J = 16 Hz), 3.18 (dd, 1H, J = 14, 3.8 Hz), 3.12 (d, 1H, J = 14 Hz), 2.77 (dd, lH, J = 14, llHz), 2.67-2.60 (m, lH), 2.56-2.48 (m, lH), 2.31-2.22 (m, 1H), 1.96 · 1.88, 1H), 1.85-1.77 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 1.03 (d, 3H, J = 6.2 Hz), 0.98 (d, 3H, J = 6.1 Hz), 0.93 (d, 3H, J = 7.1 Hz). Preparation of cryptocin 55 nicotinate hydrochloride (8 ') (LSN 368265). To a solution of i, (50 mg, 0.071 mmol) in 354 μl of pipidolide was added nicotinyl chloro chloride hydrochloride (15 mg, 0.085 mmol) at room temperature, followed by triethylamine. (23 μl, 0.1 70 mmol). After stirring for 1.5 hours, 4-dimethylamino group -256- This paper size applies Chinese National Standard (CNS) A4 specification (2〗 〇29 × 7mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T. 533206 A7 ____ B7 5. Description of the invention (254) Pyridine (8.6 mg, 0.071 mmol) was added. After 5 hours of stirring, triethylamine (23 μl, 0.170 mmol), dimethylaminopyridine (86 mg, 0.071 mmol), and nicotinyl chloro chloride hydrochloride (15 mg, 0.085 millimolar) was added and rinsed with 50 μl of pyridine. After stirring for 18 hours, the reaction mixture was treated with 0.5 ml of a saturated aqueous solution of sodium hydrogen peroxide and washed with dichloromethane (* X 1 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to a light brown oil. Chromatography (14 g of flash silica gel) was dissolved with ethyl acetate-hexane (io: 1) to obtain 49 g (85%) of the free test, showing a white foam. Dissolved in 1¾ liters of dichloromethane, and treated with a 1.0 M solution of hydrogen chloride in acetic acid (90 µl '0.090 φmol). The clear, colorless solution was left at room temperature for 5 minutes. The solvent was removed in the air, and 51 mg of the title compound was produced as a white foam: 500 MHz 4 NMR (CDC13) d 8.94 (s, 1Η), 8.78 (br s, 1H), 8.29 (d 1H, J = 7.0 Hz ), 7.57 (br s, 1H), 7.38 (d, 2H, J = 7.1 Hz), 7.30-7.16 (m, 5H), 7,10 (dd, 1H, J = 8.4, 1.7 Hz), 6.88 (d , 1H, J = 8.4 Hz), 6.71 (m, 1H), 5.80 (d, 1H, J = 15 Hz), 5.74 (d, 1H, J = 9.6 Hz), 5.56 (br s, 1H), 5.00 ( d, 1H, J = 9.6 Hz), 4.95 (t, 1H, J = 8.9 Hz), 4.84 (d, 1H, J = 9.8 Hz), 4.77-4.72 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8.2 Hz), 3.23-3.14 (m, 2H) 3.06 (dd, 1H, J = 14, 7.6 Hz), 2.81-2.74 (m, 1H), 2.62-2.45 (m , 2H), 1.93 (ddd, 1H, J = 14, 12, 4.8 Hz), 1.78-1.70 (m, 1H), 1.66-1 · 59〇, 1H), 1.25 (s, 3H), 1.20 (d, 3H, J = 7.0 Hz), 1.19 (s, 3H), 0.98 (d, 3H, J = 6.7 Hz), 0.84 (d, 3H, J = 6.5 Hz). Preparation of Cryptocin 55 N-methylpyridine acetate (9 ') (LSN 366550). In the solution of 1 '(53 mg, 0.075 mmol) in 751 microliters of dichloromethane-257- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back first (Please fill in this page again)

533206 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (triethylamine 03 μl added to 255 〇Λ, 0.0 millimolar), and then 2-xiang-1-methyl egot P-Toluenesulfonate (mg, 0.083 mmol). The heterogeneous reaction mixture was warmed to room temperature and stirred for 35 hours, at which time ηmg (〇39mmol) of 2-fluoro-1-methylpyridine p-toluenesulfonate was added. After stirring for ⑷ hours, 11 gram (0.039¾ mole) of 2-fluoro-1-methylpyridine p-toluate was added, and then after 2.5 hours, U mg (0.039 millimoles ... ^ Methylpyridine p-toluenesulfonate and 13 microliters (0,090 mol) of triethylamine were added. After «mixing 1 small 0 # ', the reaction mixture was concentrated in the air to a light-colored foam. Reverse phase HPLC and accompanying anion exchange (acetate vs. p-toluenesulfonate) purification followed by lyophilization gave 30 mg (47%) of the title compound as a white solid: 500 MHz NMR (DMSO-d6) J 8.65-8.58 (m, 2H), 8.36 (t, 1H, J = 7.8 Hz), 7.68 (d, 1H, &gt; 8.9 Hz), 7.60 (d, 1H, J-6.6 Hz), 7.48 (t , 1H, J = 6.6 Hz), 7.35-7.21 (m, 6H), 7.19 (dd, 1H, J = 8.5, 1.9 Hz), 7.05 (d, 1H, J = 8.5 Hz), 6.49 (ddd, 1H, J = 16, 13, 4.0 Hz), 5.91 (d, 1H, J = 16 Hz), 5.72 (d, 1H, J = 8.0 Hz), 5.66 (dd, 1H, J = 8.0, 1.9 Hz), 5.32-5.27 (m, 1H), 4.73 (dd, 1H, J = 9.7, 4.3 Hz), 4.24 (ddd, 1H, J = ll, 9.8, 3.7 Hz), 3.93 (s, 3H), 3.81 (s, 3H), 3.32 (dd, 1H, J = 13, 9.3 Hz), 3.05-2.97 (m, 2H), 2.77, 2.57 (m, 3H), 2.54-2.47 (m, 1H), 1.76 (s, 3H), 1.68-1.62 (m, 1H), 1.55-1.46 (m, 1H) ), 1.37-1.30 (m, 1H), 1.15 (d, 3H, J = 7.0 Hz), 1.13 (s, 3H), 1.00 (s, 3H), 0.88 (d, 3H, &gt; 6.7 Hz) , 0.73 (d, 3H, J = 6.5 Hz). Cryptocin 55 Nt-Boc-3- (3-chloro-4-methoxyphenyl)-(D) -alanine (10,) (LSN 382049). At 1, (23 mg, 0.033 millimolar), this paper applies Chinese National Standard (CNS) A4 (210X297 mm) (please read the precautions on the back before filling this page), 11. 533206 A7 ___ ^ ____ B7____ V. Description of the invention (256)

Boc-3- (3-chloro-4-methoxyphenyl)-(d) -alanine (16 mg, 0.049 mmol) and a few crystals of 4-dimethylaminopyridine) at 143 μl anhydrous To the solution in dichloromethane was added a solution of 1,3-dicyclohexylcarbodiimide (10 mg, 0.049 mmol) in 20 µl of dichloromethane at room temperature. After stirring for 2 hours, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (2: 1.1 ml), stirred for 10 minutes, filtered through a celite plug, and washed with ethyl acetate-hexane (2: 1). . The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (4 g of flash silica, 2: 1 ethyl acetate hexane) gave 29 mg (88%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) Θ 7.42-7.27 (5H), 7.24 (d, 1H, J = 2.0 Hz), 7.25-7.18 (m, 1H), 7.09 (dd, 1H, J = 8.4, 1.9 Hz), 6.91-6.86 (m, 2H), 6.84-6.70 (m, 3H ), 5.75 (d, 1H, J = 15 Hz), 5.53 (d, 1H, J = 9.6 Hz), 5.47 (d, 1H, J = 7.6 Hz), 5.00 (dd, 1H, J = 10, 2.9 Hz), 4.90-4.80 (m, 2H), 4.78-4.71 (m, 1H), 4.63 (d, 1H, J = 8.3 Hz), 4.19-4.12 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.40 (dd, 1H, J = 13, 8.1 Hz), 3.25-3.12 (m, 2H), 3.07 (dd, 1H, J = 14, 7.6 Hz), 2.67-2.57 (m, 2H ), 2.39-2.27 (m, 2H), 2.15 (dd, 1H, J = 14, 0.8 Hz), 2.01 (ddd, 1H, J = 14, 12, 4.2 Hz), 1.87-1.76 (m, 2H ), 1.39 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1. 〇9_1 .04 (m, 6H), 1.01 (d, 3H, J = 6.3 Hz) 〇1¾ Algin 55-(3-Ga-4-methoxyphenyl)-(D) -Alanine @ Purpose Hydrochloride( 11 ') (LSN 382048). To a solution of 10 ′ (27 mg, 0.027 mmol) in 265 μl of dichloromethane was added hydrogen chloride at room temperature! A 4.0 M solution in 4_dioxolane (33 microliters' 〇. 133 millimoles). After stirring for 3 hours, the transparent and colorless reaction mixture was concentrated in the air to 26 ml (96〇 / 〇, for 5% by weight _ -259- This paper size applies Chinese National Standard (CNS) M specifications (210 &gt; &lt; 297 (Mm) 533206 A7 B7 V. Description of the invention (257) Dioxolane correction) The title compound was a white foam: 500 MHz iH NMR (MeOH_d4) d7.79 (d, 1H, J = 7.3Hz), 7.49_7. 45 (m, 2H), 7.43-7.48 (m, 3H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.13 (d, 1H, J = 2.2 Hz), 7.07-6.95, 3H), 6.71 (ddd, 1H, 15, 13, 3.8 Hz), 5.98 (dd, 1H, J = 15, 1.8 Hz), 5.69 (d, 1H, J = 10 Hz), 5.22 (d, lH, J = 10Hz), 5.18 (dd, lH, J = 10, 2.5Hz), 4.89 · 4.80 (m, 1H), 4.53 (dd, 1H, J = ll, 3.7 Hz), 4.16 (dd, 1H, J = 10, 4.4 Hz), 3.88 (s 3H), 3.87 (s, 3H), 3.51 (dd, 1H, J = 13, 9.9 Hz), 3.20 (dd , LH, J = 14, 3.7Hz), 3.14 (dd, lH, J = 13, 2.3Hz), 2.82-2.75 (m, 3H), 2.45 (dd, 1H, J = 15, 4.5 Hz), 2.42- 2.34 (m, 1H), 2.08-2.00 (m, 1H), 1.97-1.86 (m, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.16 (d, 3 H, J = 7.1 Hz), 1.10 (d, 3H, J = 6.1 Hz), 1.06 (d, 3H, J = 6.0 Hz). Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (Read the precautions on the back before filling this page) Preparation of Cryptophyll 55 Nt-Boc- (L) -phenylalanine (12,) (LSN 382235) . At Γ (29 mg, 0.041 mmol), Nt-Boc- (L) -phenylalanine (16 mg, 0.062 mmol), and 4-dimethylaminopyridine (0.5 mg, 0.0041 mmol) in a solution of 165 microliters of anhydrous dichloromethane at room temperature was added with 1,3-dicyclohexanecarbodiimide (13 mg, 0.062 millimoles) in 42 microliters of dichloromethane. Solution. After being stirred for 40 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (2: 1, 0.5 ml), stirred for 10 minutes, filtered through a celite plug, and ethyl acetate-hexane (2: 1) Wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (12 g of flash silica, 2: 1 ethyl acetate-hexane) gave 20 mg (50%) of the title compound as a white foam: 500 MHz Mi NMR (MeOH-d4) d 7.40-7.47 (m , 2H), 7.26-7.37 -260- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 533206 Μ 5. Description of the invention (258) (m, 6Η), 7.12-7.22 (m, 4Η) ), 7.00 (d, 1Η, J = 8.4 H), 6.78_6.71 (m, 1H), 5.94 (d, 1H, J = 15 Hz), 5.48 (d, 1H, J = 9.5 Hz), 5.15- 5.10 (m, 1H), 5.06 (d, 1H, J = 9.5 Hz), 4.68 (t, 1H, J = 9.7 Hz), 4.52 (dd, 1H, J = ll, 3.7 Hz), 4.14-4.10 (m , 1H), 3.87 (s, 3H), 3.49 (d, 1H, J = 13 Hz), 3.20 (dd, 1H, J = 14, 3.7 Hz), 3.14 (d, 1H, J = 13 Hz), 2.77 (dd, lH, J = 14, llHz), 2.67 (dd, lH, J = 14, 6.2Hz), 2.62-2.57 (m, 2H), 2.51 (dd, 1H, J = 14, 9.1 Hz), 2.31 -2.23 (m, 1H), 2.00-1.92 (m, 1H), 1.91-1.82 (m, 2H), 1.38 (s, 9H), 1.26 (s, 3H), 1.24 (s, 3H), 1.08 (d , 3H, J = 5.9 Hz), 1.03 (d, 3H, J = 5.8 Hz), 0.87 (d, 3H, J = 7.0 Hz). Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Preparation of Cryptophytin 55 (L) -phenylalanine hydrochloride (13,) (LSN 382236). To a solution of 12 '(18 mg, 0.019 mmol) in 189 microliters of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (24 microliters, 0.094 milliliters) at room temperature. Moore). After stirring for 4 hours, the transparent, colorless reaction mixture was concentrated in the air to obtain 15 mg (88%, corrected for 2% by weight of dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH_d4) d 7.79 ( d, 1H, J = 7.6 Hz), 7.48-7.23 (m, 11H), 7.20 (dd, 1H, J = 8.6, 1.6 Hz), 6.75-6.68 (m, 1H), 5.97 (d, 1H, J = 16 Hz), 5.55 (d, 1H, J = 9.2 Hz), 5.15-5.11 (m, 2H), 4.71 (t, 1H, J = 10 Hz), 4.55-4.51 (m, 1H), 3.87 (s, 3H), 3.21 (dd, 1H, J = 14, 3.8 Hz), 3.17-3.10 (m, 2H), 2.94 (dd, 1H, J = 15, 8.1 Hz), 2.78 (dd, 1H, J = 14, 12 Hz), 2.69-2.63 (m, 2H), 2.34-2.27 (m, 1H), 1.98-1.92 (m, 1H), 1.89_ 1.82 (m, 2H), 1.25 (s, 3H), 1.22 (s , 3H), 1.06 (d, 3H, J = 6.2 Hz), 1.03 (d, 3H, J = 6.1 Hz), 0.89 (d, 3H, J = 7.0 Hz). -261-^ The paper size applies the Chinese National Standard (CNS) specifications (210X 297 mm) '533206 A7 ____ B7 V. Description of the invention (259) Cryptocin 55 (L) -histamine dihydrochloride (15 Preparation of Li (LSN 3 84046). At 1 (19 mg, 0.027 mmol), n, N, -di_t_Boc_ (L) · histidine benzene complex (18 mg, 0.040 mmol) Ear), and 4-dimethylaminopyridine (0.3 mg '0.0027 mmol) in a solution of 100 microliters of anhydrous dichloromethane at room temperature was added with 1,3-dicyclohexylcarbodiimide A solution of amine (8.3 mg, 0.040 mmol) in 35 microliters of dioxane. After stirring for 60 minutes, 18 mg (0.040 mmol) of N, N'-di-t -Boc- (L) -histidine benzene complex and 8.3 mg (0.040 mmol) of 1,3-dicyclohexylcarbodiimide were added. The cloudy white reaction mixture was stirred for 4 hours with ethyl acetate-hexane (3: 1, 0.5 ml), diluted for 10 minutes, filtered through a celite plug, and washed with ethyl acetate-Jiyuan (3: 1). The filtrate and washing solution were concentrated in the air to a colorless oil. Layer (I 3 grams of flash silicone, 3: 1 acetic acid Ester-hexane) to obtain 17 mg (61%) of the n, N, -di · tBoc-compound (14,) as a white foam. At 14, (17 mg, 0.016 mmol) at 160 μm To a solution in liters of dichloromethane was added a 4.0 M solution of hydrogen chloride in J, 'dioxolane (24 μl, 0.098 mmol) at room temperature. After stirring for 5 hours, the cloudy white reaction mixture was concentrated in the air To obtain 5.7 mg (100%, corrected for 4% by weight of dioxolane) of the title compound, which was printed in white foam by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Mo: 500 MHz NMR (MeOH_d4) d 8.91 (s, 1H), 7.77 (d, 1H, J = 9.5 Hz), 7.51-7.37 (m, 6H), 7.31 (d, 1H, J = 2.1 Hz), 7.20 ( dd, 1H, J = 8.4, 2.1 Hz), 6.66-6 · 58〇, 1H), 5.99 (d, 1H, J = 15 Hz), 5.57 (d, 1H, J = 9.6 Hz), 5.20 (d, 1H, J = 9.6 Hz), 5.15 (dd, 1H, J = 10, 3.0 Hz), 4.58 (t, 1H, J = ll Hz), 4.53 (dd, 1H, 11, 3.8 Hz), 4.14 (t, m, J = 6.4Hz), 3.87 (s, 3H), 3.55-3.47 (m, lH), 3.27-3.12 (m, 3H), 2.81-2.68 (m, 3H), 2.40 ^ 2.31 ( m, 1 H), 1.98-1.81 (m -262- ^ Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) &quot;-533206 Α7 Β7 V. Description of the invention (260) 3H), 1.25 (s, 3H) , 1.21 (s, 3H), 1.10-1.04 (m, 6H), 1.04 (d, 3H, J = 6.1 Hz). Preparation of cryptocryptin 55 N-t-Boc- (L) .proline (16 ') (LSN 382926). At 1 · (19 mg, 0.027 mmol), N-t_Boc- (L) -proline (8.7 mg, 0.040 mmol), and 4-dimethylaminopyridine (0.3 mg, 0.0027 mmol) ) A solution of 1,3-dicyclohexylcarbodiimide (8.3 mg, 0.040 mmol) in 35 µl of dichloromethane was added to 100 µl of the solution in anhydrous dichloromethane at room temperature. After stirring for 4 to 5 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3, 1, 0.5 ml), stirred for 10 minutes, filtered through a ceute plug, and ethyl acetate-hexane (3: 1) Wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (15 g of flash silica gel, 3: 1 ethyl acetate-hexane) yielded 11 mg (46%) of the title compound as a white foam · 500 MHz 4 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs ( Please read the notes on the back before filling in this page) NMR (CDC13) β 7.39-7.30 (m, 5H), 7.24 (d, 1H, J = 2.0 Hz), 7 · 21-7 · 18 (ιη, 1H) , 7.09 (dd, 1H, J = 8.4, 2.0 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.80-6.68 (m, 1H), 5.77 (d, 1H, J = 15 Hz), 5.61 ( br s, 1H), 5.56 (t, 1H, J = 9.5 Hz), 5.04-4.68 (m, 4H), 4.19-4.15 (m, lH), 3.90 (s, 3H), 3.41-3.34 (m, 2H ), 3.27-3.02 (m, 4H), 2.64_ 2.50 (m, 2H), 2.35_2.25 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.72 (m, 3H), 1.70- 1.50 (m, 3H), 1.44 (s, 9H), 1.28 (s, 3H), 1.20 (s, 3H), 1.08-0.90 (m, 9H). Preparation of Cryptocin 55 (10-Proline Hydrochloride (17,) (1 ^ 1 ^ 3 82927). At 16 · (11 mg, 0.012 mmol) at 122 µl of dichloride A 4.0 M solution of hydrogen chloride in 1,4-dioxolane (15 μl, 0.061 mmol) was added to the solution in methane at room temperature. After stirring for 5 hours, the transparent and colorless mixture was in the air. Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (261) Concentrated to obtain 10 mg (100%) of the title compound as a white solid: 500 MHz lU NMR (MeOH- d4) δΊ.ΊΊ (άά, 1H, J = 9.4? 2.3 Hz)? 7.48-7.42 (m, 2H), 7.39 · 7 · 35〇, 3H), 7.31 (d, 1H, J = 2.2 Hz) , 7.20 (dd, 1H, J = 8.4, 2.2 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.68 (ddd, 1H, J = 15, 13, 3.8 Hz), 5.98 (dd, 1H , J = 15, 1.4 Hz), 5.52 (d, 1H, J = 9.8 Hz), 5.18 (d, 1H, J = 9.8 Hz), 5.18-5.14 (m, 1H), 4.78 (t, 1H, J = 10 Hz), 4.52 (dd, 1H, J = ll, 3.9 Hz), 3.99 (t, 1H, J = 7.3 Hz), 3.87 (s, 3H), 3.48 (dd, 1H, J = 14, 9.7 Hz) , 3.28-3.12 (m, 4H), 2.82-2.73 (m, 3H), 2.42_ 2.34 (m, 2H), 2.09-1.79 (m, 6H), 1.24 (s, 3H), 1.88 (s, 3H), 1.16 (d, 3H, J = 7.0 Hz), 1.07 (d, 3H, J = 6 „3 Hz), 1.04 (d, 3H, J = 6.2 Hz). Preparation of Cryptoxin 55 N_t-Boc-Glycine (18,) (LSN 379403). At 1 · (118 mg, 0.167 mmol) Moore), Nt-Boc-Glycine (44 mg, 0.251 printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) millimolar), and 4-dimethylamine Dipyridylcarbodiimide (52 mg, 0.251 mmol) was added to a solution of 490 μl of anhydrous dichloromethane in 490 μl of anhydrous dichloromethane at room temperature (67 mg). The solution in dichloromethane. After stirring: stirring for 50 minutes, the turbid white reaction mixture was diluted with ethyl acetate-hexane: fe (3: 1 '1 ml) and stirred for 10 minutes, stoppered by ceiife, Wash with vinegar and ethyl vinegar-Ji Hang (3: 1). Liquid soap and lotion are concentrated in the air to a colorless oil. Chromatography (19 g of flash silica, 3: 1 ethyl acetate-hexane) gave 138 mg (96%) of the title compound as a white foam: 5000 ΜΗζ ιΗ NMR (CDCl3) d 7.34 (s, 5H) , 7.24 (d, 1H, &gt; 2.0 Hz), 7.23-7.19 (m, 1H), 7.10 (dd, 1H, J = 8.4, 2.0 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.79- 6.70 (m, 1H), 5.77 (d, 1H, J = 13 Hz), 5.50 (d, 1H, J = 8.0 -264- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 533206 A7 B7 V. Invention Description (262)

Hz), 5.47 (d, 1H, J = 9.8 Hz), 4.97 (dd, 1H, J = ll, 2.7 Hz), 4.89 (t, 1H, J = 10 Hz), 4.83 (d, 1H, J = 9.8 Hz) 4.79-4.72 (m, 1H), 4,68 (brs, lH), 3.91 (s, 3H), 3.66 (dd, lH, J = 18, 5.3Hz), 3.42-3.35 (m, 2H ), 3.21 (dd, 1H, J = 13, 4.0 Hz), 3.17 (dd, 1H, J = 15, 5.1Hz), 3.08 (dd, 1H, J = 15, 7.6Hz), 2.66-2.57 (m, 2H), 2.47-2.38 (m, 1H), 1.95 (ddd, 1H, J = 14, 12, 4.7 Hz) 1.85-1.77 (m, 1H), 1.75-1.67 (m, 1H), 1.43 (s, 9H ), 1.27 (s 3H), 1.20 (s, 3H), 1.08 (d, 3H, J = 7.0 Hz), 1.03 (d 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.5 Hz). Preparation of cryptocryptin 55 glycine hydrochloride (19 (LSN 368422). In a solution of 18f (122 mg, 0.141 mmol) in 471 μl of dichloromethane was added hydrogen chloride at room temperature at 1, A 4.0 M solution in 4-dioxolane (178 μl, 0.707 mmol). After stirring for 1 hour and 20 minutes, the transparent and colorless reaction mixture was concentrated in the air to obtain 120 mg (99%, 7%). (Weight% dioxolane correction) the title compound as a white foam: 500 MHz 1HNMR (MeOH-d4) ^ 7.81 (dd, 1H, J = 8.5, 2.2 Hz), 7.46-7.41 (m, 2H), 7.40-7.36 ( m, 3H), 7.31 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.70 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.97 (dd, 1H, J = 15, 1.7 Hz), 5.55 (d, 1H, J = 9.9 Hz), 5.18 (d, 1H, J = 9.9 Hz), 5.14 (dd , 1H, J = 10, 2.8 Hz), 4.84 (t, 1H, J = 10 Hz), 4.52 (dd, 1H, J = ll, 3.7 Hz), 3.87 (s, 3H), 3.78 (d, 1H, J = 18 Hz), 3.50 (dd, 1H, J = 13, 9.8 Hz), 3.23 (d, 1H, J = 18 Hz), 3.20 (dd, lH, J = 14, 3.6Hz), 3.13 (dd, lH, J = 13, 2.4Hz), 2.80-2.69 (m, 3H), 2.41-2.32 (m, 1H), 1.99- 1.92 (m, 1H), 1.91-1.81 (m, __-265 _ This paper size applies to China National Standard (CNS) A4 specification (21 OX 297 mm) (Please read the precautions on the back before filling this page)

1T 533206 M ____ Zhu 7 V. Description of the invention (263) 2H), 1.25 (s, 3H), 1.20 (s, 3H), 1.12 (d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.04 (d, 3H, 6.2 Hz). (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Preparation of Cryptophyll 55N-t-Boc-/?-Alanine (20,) (LSN 3 79404). At l '(102 mg, 0.145 mmol), Nt-Boc_-alanine (41 mg, 0.217 mmol), and 4-dimethylamino p-pyridine (18 mg, 0.145 mmol) ) A solution of 13-dicyclohexylcarbodiimide (45 mg, 0.217 mmol) in 82 µl of dichloromethane was added to 400 µl of the solution in anhydrous dichloromethane gauge at room temperature. After stirring for 3.5 hours, the turbid white reaction mixture was diluted with ethyl acetate-hexane (3: 1.1 ml), stirred for 10 minutes, filtered through a ceHte plug, and ethyl acetate-hexane ( 3 ·· 1) Wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (21 grams of flash silica, 2 ·· 1, then 4: 1 ethyl acetate-hexane) gave 121 mg (95%) of the title compound as a white foam. 500 MHz 4 NMR (CDC13) β 7.44 -7.39 (m, 2H), 7.37-7.31 (m, 3H), 7.32 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.72 (ddd, lH, J = 15, 13, 3.7 Hz), 5.96 (dd, 1H, J = 15, 1.6 Hz), 5.51 (d, 1H, J = 9.8 Hz), 5.11-5.06 (m, 1H), 5.08 (d, 1H, J = 9.8 Hz), 4.90-4 · 83〇, 1H), 4.50 (dd, 1H, J = ll, 3.6 Hz), 3.86 (s, 3H), 3.52-3.46 (m, 1H), 3.20 (dd, 1H, J = 14, 3.6 Hz), 3.13 (br d, 1H, J = 14 Hz), 3.05-2.92 (m, 2H), 2.79- 2.63 (m, 3H), 2.45-2.37 (m, 1H), 2.24 (dt, 1H, J: 16, 7.0Hz), 2.08-1.99 (m, 1H), 1.96-1.79 (m, 3H), 1.43 ( s, 9H), 1.25 (s, 3H), 1.21 (s, 3H), 1,12 (d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.02 (d, 3H , J = 6.1 Hz). Preparation of Cryptocin 55々-alanine hydrochloride (2Γ) (LSN 377718). In _-266- This paper size applies the Chinese national standard (CNS> A4 specification (21 OX 297 mm) 533206 kl ____B7 V. Description of the invention (264) 20 '(119 mg, 0.136 mmol) at 452 microliters To the solution in dichloromethane was added a solution of hydrogen chloride in 1,4 · dioxolane 4.0 (170 µl, 0 · 679 mmol) at room temperature. After being stirred for 2 hours and 15 minutes, it became cloudy and white. The reaction mixture was concentrated in the air to obtain 110 mg (96%, corrected for 4% by weight of dioxolane) of the title compound as a white foam. 500 MHz 1HNMR (MeOH-d4) ci7.80 (dd, m, J = 9.7 , 2.3Hz), 7.45-7.40 (m, 2H), 7.39-7.32 (m, 3H), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 ((1, 1H, J = 8.4 Hz), 6.68 (ddd, 1H, J = 15, 13, 3.8 Hz), 5.98 (dd, 1H, J = 15, 1.7

Hz), 5.48 (dd, 1H, J = 9.4, 1.0 Hz), 5.15-5.11 (m, 1H)? 5.13 (d, 1H, J = 9.4 Hz), 4.82 (t, 1H, J = 10 Hz), 4.51 (dd, 1H, J = ll, 3.7 Hz), 3.90 (s, 3H), 3.50 (dd, 1H, J = 14, 9.8 Hz), 3.20 (dd, 1H, J = 14, 3.7 Hz), 3.14 (dd, 1H, J = 14, 2.4 Hz), 2.85 (t, 2H, J = 7.0 Hz), 2.80-2.65 (m, 5H), 2.54 (dt, 1H, J = 17, 7.4 Hz), 2.42- 2.33 (m, 1H), 2.22 (dt, 1H, J = 17., 6.7 Hz), 1.90-1.81 (m, 3H), 1.25 (s, 3H), 1.20 (s, 3H) 1.13 (d, 3H, J = 7.1 Hz), 1.08 (d, 3H, J = 6.3 Hz), 1.04 (d, 3H, J = 6.2 Hz). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) Preparation of Cryptophytin 55 N-t-Boc- r Amino Butyrate (22,) (LSN 379401). At Γ (48 mg, 0.068 mmol), Nt-Boc-4-aminobutyric acid (18 mg, 0.088 mmol), and 4-dimethylaminopyridine (8 mg, 0.068 mmol) To a solution of 150 microliters of anhydrous dichloromethane was added a solution of 13-dicyclohexylcarbodiimide (18 mg, 0.088 mmol) in 50 microliters of dichloromethane at room temperature. After stirring for 45 minutes, the turbid white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 0.5 ml), stirred for 5 minutes, filtered through a celite plug, and 'ethyl acetate-hexane (3: 1) wash. The filtrate and washing liquid are concentrated in the air. -267- The paper size is in accordance with the Chinese National Standard (CNS) A4 (210 X 297 mm) 533206 A7 B7. 5. Description of the invention (265) becomes a colorless oil. Chromatography (15 g of flash silica gel, 3: 1 ethyl acetate-hexane) gave 55 mg (90%) of the title compound as a white foam. 500 MHz NMR (CDC13) 7.38-7.32 (m, 5H) , 7.24 (d, 1H, J = 1.9 Hz), 7.22-7.19 (m, 1H), 7.10 (dd, 1H, J = 8.4, 1.9 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.75 (ddd, m, J = 15,13,3.9Hz), 5.78 (d, m, J = 15Hz), 5.60 · 5.55 (m, 1H), 5.49 (dd, 1H, J = 9.8,1.4 Hz), 4.96 (dd, 1H, J = ll, 3.0 Hz), 4.89 (t, 1H, J = 9.2 Hz), 4.81 (d, 1H, J = 9.8 Hz), 4.78 · 4.70 (m, 1H) 4.44 (br s , 1H), 3.91 (s, 3H), 3.40 (dd, 1H, J = 14, 8.1 Hz), 3.22 (dd, 1H, J = 14, 4.1 Hz), 3.2 · 2-3 · 15〇, 1H) , 3.08 (dd, 1H, J = 14, 7.8 Hz), 2.89-2.82〇, 2H), 2.67_2.56 (m, 2H), 2.47-2.38 (m, 1H), 2.11-2.04 ( m, 2H), 2.00-1.77 (m, 3H), 1.75_ 1.67 (m, 1H), 1.45 (s, 9H), 1.50-1.40 (m, 2H), 1.27 (s, 3H), 1.20 (s, 3H), 1.09 (d, 3H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H, J = 6.6 Hz). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Preparation of Cryptophyll 55 r-aminobutyrate hydrochloride (25 ′) (LSN 368513). To a solution of 22 '(53 mg, 0.059 mmol) in 297 µl of dichloromethane was added a 1.0 M solution of hydrogen chloride in ether (297 µl, 0.297 mmol) at room temperature. The starting material precipitated as a white paste, which was redissolved by adding 150 microliters of dichloromethane. After stirring for 4 hours, 59 microliters (0.059 mmol) of hydrogen chloride solution was added. Continue to stir for 14 hours. The reaction mixture was concentrated in the air to obtain 49 mg (100 00 / 〇) of the title compound as a white foam: 500 MHz 4 NMR (DMSO-d6) d8.49 (d, 1H, J = 8.0 Hz), 7.72 (br s, 3H), 7.44-7.33 (m, 5H), 7.32 (d, 1H, J = 1.9 Hz), 7.29 (dd, 1H, J = 9.4, 2.6 Hz), 7.20 (dd, 1H, J = 8.5, 1.9 Hz), 7.06 (d, 1H, J = 8.5 Hz), 6.48 (ddd, -268 · This paper size applies to Chinese National Standard (CNS) A4 specification (210 X297 mm) 533206 Β7 V. Description of the invention (266) 1H, J = 15, 13, 3.9 Hz), 5.87 (d, 1H, J = 15 Hz), 5.37 (d, 1H, J = 9.7 Hz), 5.33 (d, 1H, J = 9.7 Hz), 5.04-5.01 (m, 1H), 4.73 (t, 1H, J = ll Hz), 4.25 (ddd, 1H, J = 12, 9.8, 3.5 Hz), 3.82 (s, 3H), 3.40 -3.30 (m, 1H), 3.07-3.01 (m, 2H), 2.72 (dd, 1H, J = 14, 12 Hz), 2.65-2.47 (m, 4H), 2.38-2.28 (m, 1H), 2.21 (dt, 1H, J = 17, 7.5HZ), 1.97 (dt, 1H, J = 17, 7.5Hz), 1.80-1.70 (m, 3H), 1.54-1.46 (m, 2H), 1.17 (s, 3H ), 1.03 (s, 3H), 1.01 (d, 3H, J = 7.0 Hz), 0.99 (d, 3H, J = 5.8 Hz), 0.95 (d, 3H, J = 5.8 Hz). Preparation of cryptocryptin 55 N_t-Boc- (L) _alanine (26 ') (LSN 379405). At Γ (103 mg, 0.146 mmol), N_t-Boo (L) -alanine (41 mg, 0.219 mmol), and 4-dimethylaminopyridine (18 mg, 0.146 mmol) Add 400 μl of dicyclohexylcarbodiimide (45 mg, 0.129 mmol) in 87 μl of dichloromethane to a solution in 400 μl of anhydrous dichloromethane; After stirring for 5 hours and 50 minutes, the cloudy white reaction mixture was treated with 5.5 mg (0.029 mmol) of N_t-Boc- (L) · alanine, 6.0 mg (0.029 mmol) of 1,3-dicyclohexyl Carbodiimide and some 4-dimethylaminopyridine crystallized. After stirring for 1 hour, the reaction mixture was printed with ethyl acetate-hexane: printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1 '1 ml) diluted' stirred for 10 minutes After plugging the furnace through celite and washing with acetic acid ethyl acetate: (3 · 1). The filter, liquid and washing liquid are concentrated in the air to a colorless oil. Chromatography (22 g of flash silica, 1.5: 1, then 2: 1, then 4: 1 ethyl acetate-hexane) to obtain 96 g (75%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13 ) d 7.35-7.30 (m, 5H), 7.26-7.21 (m, 2H), 7.10 (dd, 1H, J = 8.4, 1.9 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.76 ( ddd, 1H, J = 15, 13, 4.2 Hz), 5.77 (d, 1H, J = 15 Hz), 5.52 (d, 1H, 7.6 Hz), ___-269-This paper size applies to Chinese National Standard (CNS) A4 specifications (210x297 mm) &quot; &quot; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 B7 V. Description of the invention (267) 5.44 (d, 1H, J = 9.7 Hz), 4.98 (dd, 1H, J = ll, 2.5 Ηζ), 4.85 · 4 · 81 (m, 2H), 4.75 (q, m, J = 6.8Hz), 4.56 (d, lH, J = 7.8Hz), 4.01-3.96 (m, 1H ), 3.91 (s, 3H), 3.41 (dd, 1H, J = 13, 8.3 Hz), 3.20 (dd, 1H, J = 13, 4.0 Hz), 3.16 (dd, 1H, J = 15, 5.9 Hz), 3.08 (dd, 1H, J = 15, 7.6 Hz), 2.65-2.57 (m, 2H), 2.40-2.31 (m, 1H), 2.02-1.96 (m, 1H), 1.87-1.73 (m, 2H), 1.43 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.1-1.02 (m, 9H), 0.99 (d, 3H, J = 6.3 Hz). Preparation of Cryptocin 55 (L) -alanine hydrochloride (28) (LSN 377719). Add to a solution of 26 '(95 mg, 0.108 mmol) in 361 microliters of dichloromethane at room temperature. A 4.0 M solution of hydrogen chloride in 1,4-dioxolane (135 µl, 0.542 mmol). After stirring for 2.5 hours, the cloudy white reaction mixture was concentrated in the air to obtain 90 mg (96%, 6% by weight dioxolane correction) The title compound as a white foam. 500 MHz 4 NMR (MeOH-d4) d 8.54 (d, 1H, 7.6 Hz), 7.81 (br d, 1H, J = 9.7 Hz ), 7.46-7.44 (m, 2H), 7.39-7.37 (m, 3H), 7.32 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.0 Hz), 7.01 (d, 1H, J = 2.0 Hz), 6.69 (ddd, 1H, J = 15, 11, 3.7 Hz), 5.99 (d, 1H, 15 Hz), 5.55 (d, 1H, J = 9.8 Hz), 5.20 (d, 1H, J = 9.8 Hz), 5.15 (dd, 1H, J = ll, 2.7 Hz), 4.78 (t, 1H, J = ll Hz), 4.553-4 · 50〇, 1H), 3.87 (s, 3H), 3.65 (q, 1H, J = 7.3 Hz), 3.50 (dd, 1H, J = 13, 9.8 Hz), 3.20 (dd, 1H, J = 14, 3.5 Hz), 3.14 (br d, 1H, J = 13 Hz), 2.81-2.71 (m, 3H), 2.41-2 · 34〇, 1H), 1.98_1.93 (m, 1H ), 1.88-1.82 (m, 2H), 1.41 (d, 3H, J = 7.3 Hz), 1.25 (s, 3H), 1.20 (s, 3H), 1.13 (d, 3H, J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.04 (d, 3H, 6.0 Hz). -270- This paper size applies to China National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

533206 Α7 Β7 V. Description of the invention (268) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Cryptophyll 55 Nt-Boc- (D) -Alanine (29 ') (LSN 382426). At 1 · (25 mg, 0.035 mmol), NtBOC- (D) -alanine (10 mg, 0.053 mmol), and 4-dimethylaminopyridine (0.4 mg, 0.0035 mmol) To a solution of 130 microliters of anhydrous dichloromethane was added a solution of 1,3-dicyclohexylcarbodiimide (11 mg, 0.053 mmol) in 47 microliters of dichloromethane at room temperature. After stirring for 5.5 hours, the turbid white reaction mixture was diluted with ethyl acetate-hexane (3.1 ml, 0.5 ml), which was removed for 10 minutes, filtered through a celite plug, and ethyl acetate · hexane (3: 1) Wash. The filtrate and washings were concentrated in the air to a colorless oil. Chromatography (15 g of flash silica gel, 2: 1 ethyl acetate-hexane) gave 26 mg (83%) of the title compound as a white foam. 500 MHz 4 NMR (CDC13) β 7.49-7.29 (m, 5H), 7.24 (d, 1H, J = 2.0 Hz), 7.22-7.18 (m, 1H), 7.09 (dd, 1H, 8.4, 2.0 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.76 (ddd, 1H, J = 15, 13, 4.4 Hz), 5.77 (d, 1H, 15 Hz), 5.56 (d, 1H, J = 9.9 Hz), 5.48 (d, 1H, J = 7.7 Hz), 5.01 (dd, 1H, J = 10, 2.6 Hz), 4.91 (t, 1H, J = 9.4 Hz), 4.84 (d, 1H, J = 9.9 Hz), 4.81-4.73 (m, 2H), 3.99-3.93 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8 · 0 Hz), 3.22 (dd, 1H, J = 13 , 3.6 Hz), 3.17 (dd, 1H, J = 14, 5.0Hz), 3.08 (dd, 1H, J = 14Hz), 2.68-2.58 (m, 2H), 2.42-2.35 (m, 1H), 2.04- 1.94 (m, 1H), 1.87-1.50 (m, 2H), 1.42 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.09 (d, 3H, J = 7.1 Hz), 1.04 (d, 3H, J = 6.4 Hz), 0.99 (d, 3H, J = 6.3 Hz), 0.65 (d, 3H, J = 6.8 Hz) 0 Cryptocin 55 (D) -alanine hydrochloride ( 30 ·) (LSN 3 82425). To a solution of 29 '(24 mg, 0.027 mmol) in 274 µl of dichloromethane at room temperature was added a 4.0 M solution of hydrogenated gas in 1,4-dioxolane (34 µl, -271-The size of this paper applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 A7 B7 V. Description of the invention (269) 0.13 7 millimoles). After stirring for 3.5 hours, the transparent colorless reaction mixture was concentrated in the air to obtain 24 mg (100%, corrected for 8% by weight of dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) d 7.79 (d, 1H, J = 9.5 Hz), 7.47-7.40 (m, 2H), 7.40, 7.36 (m, 3H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.5, 2.0 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.71 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.98 (dd 1H, J = 15, 1.6 Hz), 5.65 ( d, 1H, J = 10 Hz), 5.20 (d, 1H, J = 10 Hz), 5.17 (dd, 1H, J = ll, 2.5 Hz), 4.88-4.78 (m, 1H), 4.53 (dd, 1H , J = ll, 3.7 Hz), 3.95 (q, 1H, J = 7.2 Hz), 3.87 (s, 3H), 3.51 (dd, 1H, J-2 13, 9 · 8 Hz), 3.20 (dd, 1H, J = 14, 3.6 Hz), 3.14 (dd, 1H, J = 13, 2.3 Hz), 2.81-2.74 (m, 3H), 2.41-2.34 (m, 1H), 2.07-1.99 (m, 1H) , 1.96-1.84 (m, 2H), 1.26 (s, 3H), 1.21 (s, 3H), 1.15 (d, 3H, J = 7.1 Hz), 1.09 (d, 3H, J = 6.0 Hz), 1.05 ( d, 3H, J = 6.0 Hz), 0.80 (d, 3H, J = 7.4 Hz). Cryptocin 55Nα-Nε-di-Boc (L) -lysinate (3Γ) (LSN 3 79406) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page ) Preparation. At Γ (105 mg, 0.149 mmol), Nd-dilysine (67 mg, 0.193 mmol), and 4-dimethylaminopyridine (18 mg, 0.149 mmol) ) In 400 microliters of anhydrous dichloromethane, add 1,3-monocyclohexylcarbodiimide (40 mg, 0.193 mmol) to 96 microliters of monochloromethane at room temperature. Burning solution. After stirring for 4 hours, the turbid white reaction mixture was charged with 10 g (0.030 mmol) of Nd-di-t-Boc- (L) -lysine and 6.1 mg (0.03 mmol). Mol) A solution of 1,3-dicyclohexylcarbodiimide in 1 μl of dichloromethane. After stirring for 丨 hours, the turbid white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 1 ml), stirred for 10 minutes, and ------ a ___- Specifications (21〇 &lt; 297) 533206 A7 B7 5. Description of the invention (270) Celite plug filtration, washing with ethyl acetate-hexane (3: 1). The filtrate and washings were concentrated into a white foam in the air, and the above conditions were followed, using 34 mg (0.097 mmol), Nπ · Νε-bis_t_Boc_ (L) _ lysine, 20 mg (0.097 mmol) Ear) 1,3-dicyclohexylcarbodiimide, and 9.1 mg (0.075 mmol) 4-dimethylaminopyridine. After stirring for 1.5 hours, the reaction mixture was treated as described above to obtain a crude white foam. Chromatography (21 g of flash silica, 1: 1, then 4: 1 ethyl acetate · hexane) gave 112 mg (73%) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) d 7 · 42-7 · 37〇, 2H), 7.36- 7.29 (m, 3Η), 7.27 (br s, 1Η), 7.16 (br d, 1Η, J = 8.5 Ηζ), 6.97 (d, 1H, J = 8.5 Hz), 6.72 (ddd, 1H, J = 15, 13, 3.5 Hz), 5.92 (d, 1H, J = 15 Hz), 5.50 (d, 1H, J = ll Hz), 5.11-5.04 (m, 2H ), 4.84 (t, 1H, J = 10 Hz), 4.48 (dd, 1H, J = ll, 3.6 Hz), 3.84 (s, 3H), 3.75 (br s, 1H), 3.50-3.43 (m , 1H), 3.17 (dd, 1H, J = 14, 3.6 Hz), 3.11 (d, 1H, J = 14 Hz), 2.97-2.91 (m, 2H), 2.76-2.58 (m, 3H), 2.36- 2.27 (m, 1H), 1.98-1 · 80 (M, 3H), 1.48-1.38 (m, 2H), 1.43 (s, 9H), 1.40 (s, 9H), 1.35_1.25 (m, 2H), 1.23 (s, 3H), 1.20 (s, 3H), 1.15-1.09 (m, 2H), 1.07 (d, 3H, J = 6.8 Hz), 1.06 (d, 3H, J = 6.0 Hz), 1.01 (d, 3H, J = 6.1 Hz). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Preparation of Cryptophytin 55 (L) -ionine dihydrochloride (32,) (LSN 377562). To a solution of 3Γ (107 mg, 0.103 millimoles) in 345 microliters of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (155 microliters' 0.621 millimoles) at room temperature. . After stirring for 4 hours, the cloudy white reaction mixture was filtered. The collected white solid was washed with dichloromethane (2 × 1 ml), and dried in the air at room temperature to obtain 87 mg (93%) of the title compound: 500 MHz 4 ________ -273- This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 533206 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs kl B7 V. Description of the invention (271) NMR (MeOH-d4) d 8.61 (d, 1H, J = 7.7 Hz), 7.81 (d, 1H, J = 7.7 Hz), 7.47-7.44 (m, 2H), 7.40-7.38 (m, 3H), 7.31 (d, 1H, J = 2.2 Hz), 7.20 (dd, 1H, J = 8.4, 2.2 Hz ), 7.00 (d, 1H, J = 8.4 Hz), 6.63 (ddd, 1H, J = 15, 13, 4.0 Hz), 6.00 (dd, 1H, J = 15, 1.6 Hz), 5.55 (d, 1H, J = 9.8 Hz), 5.20 (d, 1H, J = 9.8 Hz), 5.15 (dd, 1H, J = 10, 2.9 Hz), 4.68 (t, 1H, J = 11 Hz), 4.55-4.49 (m , 1H), 3.87 (s, 3H), 3.79 (t, 1H, J = 5.6 Hz), 3.52 (dd, 1H, J = 14, 9.9 Hz), 3.20 (dd, 1H, J = 14, 3.6 Hz) , 3.13 (dd, 1H, J = 13, 2.4 Hz), 3.06-2.98〇, 1H), 2.94-2.87 (m, 1H), 2.85-2 · 74〇, 3H), 2.45- 2.38 (m, 1H), 1.98-1.76 (m, 5H), 1.71-1.64 (m, 2H), 1.39-1.30 (m, 2H), 1.25 ( s, 3H), 1.18 (d, 3H, J = 8.2 Hz), 1.17 (s, 3H), 1.08 (d, 3H, J = 6.2 Hz), 1.05 (d, 3H, J = 6.1 Hz) . Preparation of Cryptocin 55 N ^ Nε-bis-t-Boc- (D) 1 ^ amino acid ester (33,) (LSN 382504). At Γ (24 mg, 0.0035 mmol), Nd_di_BOC- (D) -lysine (247 mg, 0.069 mmol), and 4-dimethylaminopyridine ( 4 g, 0.0035 mmol) in a solution of 140 µl of anhydrous dichloromethane at room temperature was added 1,3-dicyclohexylcarbodiimide (14 mg, 0.069 mmol) to 30 µl Solution in methyl chloride. After stirring for 70 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3 :; 0.5 ml), stirred for 10 minutes, filtered through a celite plug, and filtered with ethyl acetate-hexane (3 : "Washing. The filtrate and washings were concentrated in it to an off-white oil. Chromatography (15 g of rapid stone gum, 2: 1 ethyl acetate · hexane) gave 30 mg (87%) of the title compound, White foam: 500 MHZ1HNMR (MeOH-d4) (7.46-7 · 40 (m, 2H), 7.39-7.31 (m, 3H), 7.31 (d, 1H, J = 1.8 Hz), 7.20 ( dd, 1H, J = 8.4, 1.8 · (Please read the precautions on the back before filling this page)

、 1T -274- Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 533206 kl ___B7 V. Description of Invention (272)

Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.75 (ddd, 1H, J = 16, 11, 3 · 7 Hz), 5.93 (d, 1H, J = 16 Hz), 5.59 (d, 1H , J = 10 Hz), 5.13-5.09 (m, 2H), 4.92 (t, 1H, J = 9.8 Hz), 4.52 (dd, 1H, J = ll, 3.6 Hz) 3.87 (s, 3H), 3.79- 3.75 (m, 1H), 3.48 (d, 1H, J = 13 Hz), 3.21 (dd, 1H, J = 14, 3.7 Hz), 3.12 (d, 1H, J = 13 Hz), 2.97-2.91 (m , 2H), 2.80-2.62 (m, 3H), 2.41-2.32 (m, 1H) 1.98-1.82 (m, 3H), 1.48-1.38 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H), 1.35-1.20 (m, 2H), 1.25 (s, 3H), 1.21 (s, 3H), 1.15-0 · 09〇, 2H), 1.14 (d, 3H, J = 7.0 Hz), 1.07 (d, 3H, J = 6.0 Hz), 1.03 (d, 3H, J = 6.0 Hz). Preparation of cryptocryptin 55 (D) -lysine dihydrochloride (34 ') (LSN 377503). To a solution of 33 '(28 mg, 0.027 millimoles) in 181 microliters of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (41 microliters, 0.162 millimoles) at room temperature. ). After stirring for 5.5 hours, the cloudy white reaction mixture was concentrated in S 'to obtain 25 mg (96%, corrected for 4.5% by weight of dioxolane) of the title compound as a white solid: 500 MHz NMR (MeOH-d4) d 8.47 (d, 1H, J = 7.6 Hz), 7.76 (dd, 1H, J = 9.6, 2.1 Hz), 7.47-7.36 (m, 5H), 7.28 (d, 1H, J = 2.1 Hz), 7.17 (dd , 1H, J = 8.4, 2.1 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.68 (ddd, 1H, J = 15, 11, 3.7 Hz), 5.95 (dd, 1H, J = 15, 1.1 Hz), 5.67 (d, 1H, J = 10 Hz), 5.21 (d, 1H, J = 10Hz), 5.14 (dd, 1H, J = 10, 2.5Hz), 4.83-4.77 (m, lH), 4.52 -4.49 (m, 1H &gt;, 3.92 (t, 1H, J = 6.1 Hz), 3.84 (s, 3H), 3.47 (dd, 1H, J = 14, 9.8 Hz), 3.18 (dd, 1H, J = 14 , 3.6 Hz), 3.12 (dd, 1H, J = 14, 2.2 Hz), 2.83 (t, 2H, J = 7.6 Hz), 2.78-2.70 (m, 3H), 2.38-2.30 (m, 1H), 2.02 -1.82 (m, 3H), 1.52-1.43 (m, 2H), 1.23 (s, 3H), 1.22- _ -275 -__ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 533206 V. Description of the invention (273) 1.00 (m, 4H), 1.18 (s, 3H), 1.13 (d, 3H, J = 8.2 Hz) 1.06 (d, 3H, J = 6.2 Hz), 1.02 (d, 3H, J = 6.1 Hz). Preparation of cryptocryptin 55 (L) -glutamic acid N-t-Boc-r-third butyl ester (35,) (LSN 3 823 66). At 1, (27 mg, 038 mol), ^ 30 (&gt; (B) · glutamic acid r-third butyl ester (17 mg, 0.057 mol), and 4-di To a solution of methylamine (0.5 mg, 0.0038 mmol) in 150 µl of anhydrous dichloromethane was added 1,3-dicyclohexylcarbodiimide (12 mg, 0.057 mmol) at room temperature. ) In 41 microliters of diclofenac. After stirring for 60 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (2: 1, 2 ml) for 10 minutes. Filtered with a celite plug and washed with ethyl acetate-hexane (2: 1). The filtrate and washings were concentrated in the air to an off-white oil. Chromatography (5 g of flash silica gel, 1: 1 ethyl acetate-hexane), 28 mg (74%) of the title compound was obtained as a white foam: 500 MHz 4 NMR (CDC13) d 7.39-7.29〇, 5H), 7.24 (d, 1H, J = 1.9 Hz), 7.22-7.18 (m, 1H ), 7.10 (dd, 1H, J = 8.5, 1.9 Hz), 6.87 (d, 1H, J = 8.5 Hz), 6.76 (ddd, 1H, J = 15, 13, 4.5 Hz), 5.78 (d, 1H, J = 15 Hz), 5.65 (d, 1H, J = 7.6 Hz), 5.43 (d, 1H, J = 9.7 Hz), 4.99 (dd, 1H, J = 10, 2.7 Hz), 4.90-4. 80 (m, 1H), 4.83 (d, 1H, J = 9.7 Hz), 4.69-4.61 (m, 1H), 4.55 (d, 1H, J = 8.4 Hz), 4.01-3.96 (m, 1H), 3.90 (s, 3H), 3.40 (dd, 1H, J = 13, 8.0 Hz), 3.24 (dd, 1H, J = 13, 4.1 Hz), 3.18 (dd, 1H, J = 15, 5.0 Hz), 3.1 l (dd, 1H, J = 15, 7.9 Hz), 2.65-2.57 (m, 2H), 2.39, 2.30 (m, 1H), 2.14-2.09 (m, 2H), 2.00-1.92 (m, 1H), 1.87 -1.73 (m, 3H), 1.60-1.50 (m, 1H), 1.44 (s, 18H), 1.27 (s, 3H), 1.21 (s, 3H), 1. 〇8 (d, 3H: J = 7.0 Hz), 1.05 (d, 3H, J = 6.4 Hz), 1.00 (d, 3H, ___- 276- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Read the precautions on the back before reading) Fill out this page again), 11 zero. 533206 A7 B7 V. Description of the invention (274) J = 6.3 Hz). Preparation of Cryptocin 55 (L) -α-facial amine hydrochloride (36,) (LSN 382367). To a solution of 35 '(23 mg, 0.023 millimoles) in 232 microliters of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (29 microliters, 0.116 millimoles) at room temperature. ). After stirring for 8 · 5 hours, the transparent colorless reaction mixture was concentrated in the air to obtain 20 mg (97%, corrected for 3% by weight of dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Chi · d7.79 (d, 1H, J = 7.6 Ηζ), 7.50-7 · 36〇5H), 7.31 ( d, 1H, J = 2.0 Hz), 7.20 (dd, lH, J = 8.6, 2.0Hz), 7.01 (d, lH, J = 8.6Hz), 6.75 · 65 (m, 1H), 5.98 (d, 1H , 15 Hz), 5.57 (d, 1H, J = 9.7 Hz), 5.20 (d, 1H, J = 9.7 Hz), 5.15 (dd, 1H, J = ll, 3.0 Hz), 4.90 · 4 80, 1H), 4.52 (dd, 1H, J = ll, 3.7 Hz), 3.87 (s, 3H), 3.80-3.66 (m, 1H), 3.49 (dd, 1H, J = 13, 10 Hz) , 3.21 (dd, 1H, J = 14, 3.6 Hz), 3.15 (dd, 1H, J = 14, 2.3 Hz), 2.82-2.72 (m, 3H), 2.41-2.30 (m, 3H), 2.05_1. 81 (m, 5H), 1.25 (s, 3H), 1.20 (s, 3H), 1.15 (d, 3H, J = 7.1 Hz), 1.07 (d, 3H, J = 6.2 Hz), 1.05 (d, 3H , J = 6.1 Hz). Cryptocin 55 (L) -aspartic acid Nt-Boc_々-tert-butyl ester (37,) (LSN 3 82501) and Cryptocin 55 (D) -aspartic acid N_t-Boc_ Preparation of third butyl ester (39 ') (LSN 387040). At 1 '(176 mg, 0.249 mmol), Nt-Boc- (L) -aspartic acid /?-Tert-butyl ester (144 mg, 0.499 mmol), and 4-dimethylamino A solution of pyridine (2.0 mg, 0.066 mmol) in 1.0 ml of dry dichloromethane was added at room temperature to 1,3-dicyclohexylcarbodiimide (103 mg, 0.499 mmol) in 200 µl. Solution in dichloromethane. After stirring for 45 minutes, the turbid white reaction mixture was treated with 88 mg of celite and ethyl acetate-____- 277- _ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 533206 Central Bureau of Standards, Ministry of Economic Affairs Kl B7 printed by the employee consumer cooperative V. Description of the invention (275) Diluted with hexane (3, 1.2 ml), stirred for 10 minutes, filtered through a celite plug, and washed with ethyl acetate-hexane (3: 1) . The filtrate and washings were concentrated in the air to a gray-white oil. Chromatography (30 g of rapid stone gelatin, 2: 1 ethyl acetate @ purpose-hexamidine), to obtain pure 37 · (lower Rf) and mixed dissolved fractions. Mixed fraction chromatography (25 g of rapid stone gelatin, 1: 1, then 2 ·· 1, and then 3 ·· 1 ethyl acetate g-Tiger) to obtain more pure 37 'and pure 39, (higher Rf). All dissolved fractions containing about 37 'were combined to obtain 149 mg (61%) of white foam, while all dissolved fractions containing pure 39, were combined to serve 56 mg (23%) of white foam beads · 500 MHz of 37' 4 NMR (CD C1 data: i7.39-7.30 (m, 5H), 7.24 (d, 1H, J = 2.0 Hz), 7.24-7.18 (m, 1H), 7.09 (dd, 1H, J = 8.4, 2.0 Hz ), 6.88 (d, 1H, J = 8.4 Hz), 6.76 (ddd, 1H, J = 15, 13, 4.3 Hz), 5.75 (d, 1H, J = 15 Hz), 5.50 (d, 1H, J = 7.9 Hz) 5.46 (d, 1H, J = 9.2 Hz), 5.01-4.98 (m, 2H), 4.93 (t, 1H, J = 9.9 Hz), 4.85 (d, 1H, J = 9.2 Hz), 4.78- 4.71 (m, 1H), 4.17-4.10 (m, 1H), 3.91 (s, 3H), 3.41 (dd, 1H, J = 13, 8.2 Hz) 3.22 (dd, 1H, J = 13, 3.9 Hz ), 3.17 (dd, 1H, J = 14, 5.1 Hz), 3.09 (dd, 1H, J = 14, 7.7 Hz), 2.61-2.50 (m, 4H), 2.36-2.28 (m, 1H), 2.02- 1.97 (m, 1H), 1.83-1.76 (m, 2H) 1.45 (s, 9H), 1.41 (s, 9H), 1.28 (s, 3H), 1.20 (s, 3H), 1.06-1.01 (m, 6H ), 0.99 (d, 3H, J = 6.2 Hz). 39, 500 MHz 4 NMR (CDC13) data: ci 7.39-7.30 (m, 5H), 7.24 (d, 1H, J = 2.0 Hz), 7.24- 7.18 (m, 1H), 7.09 (dd, 1H J = 8.4, 2.0 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.73 (ddd, 1H, J = 15, 13, 4.3 Hz), 5.74 (d, 1H, 15 Hz), 547 (d, 1H, J = 7.9 Hz), 5.42 (d, 1H, J = 9.1 Hz), 5.29 (d, 1H, J = 9.0 Hz), 4.98 (dd 1H, J = 10, 3.0 Hz), 4.92 (t, 1H , J = 9.6 Hz), 4.85 (d, 1H, J = 9.1 Hz), 4.77-4.71 (m, _ __278 -__ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm 1 (please first Read the notes on the back and fill in this page) Order 533206 A7 B7 V. Description of the invention (276) 1H), 4.18-4.12 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 8.1 Hz), 3.21 (dd, 1H, J = 13, 4.0 Hz), 3.16 (dd, 1H, J = 14, 5.2 Hz), 3.07 (dd, 1H, J = 14, 7.6 Hz), 2.63-2.52 ( m, 2H), 2.45 (dd, 1H, J = 1, 7 5.8 Hz), 2.36-2.26 (m, 1H), 2.22 (dd, 1H, J = 17, 4.5 Hz), 1.99-1.90 (m, 1H ), 1.86_1.69 (m, 2H), 147 (s, 9H), 1.43 (s, 9H), 1.25 (s, 3H), 1.19 (s, 3H), l.ll (d, 3H, J = 7.0 Hz), 1.03 (d, 3H, J = 6.5 Hz), 0.99 (d, 3H, J = 6.4 Hz) o Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back first) Complete this page) cryptophycin 55 (L) - aspartic ester amine hydrochloride ((LSN 3 82503) of Preparation 38 '). To a solution of 37 · (146 mg, 0.149 mmol) in 498 µl of diclofenac was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (374 µl, 1.49 mmol) at room temperature. ear). After stirring for 19 hours, the transparent colorless reaction mixture was concentrated in the air to obtain 131 mg (100%, corrected for 2% by weight of dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) J7 „79 (d, 1H, J = 7.6 Ηζ), 7.45 · 7.36〇, 5H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.6, 2.0 Hz), 7.01 (d , 1H, J = 8.6 Hz), 6.75 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.96 (dd, 1H, 15, 1.8 Hz), 5.54 (d, 1H, J = 10 Hz), 5.17 (d, 1H, J = 10 Hz), 5.14 (dd, 1H, J = li, 2.1 Hz), 4.89 (t, 1H, J = ll Hz), 4.52 (dd, 1H, J = ll, 3.7 Hz) , 3.87 (s, 3H), 3.55 (t, 1H, J = 4.4 Hz), 3.52-3.47 (m, 1H), 3.21 (dd, 1H, J = 14, 3.6 Hz), 3.13 (d, 1H, J = 14 Hz), 2.99 (dd, 1H, J = 18, 5.0 Hz), 2.83 (dd, 1H, J = 18, 3.9 Hz), 2.81-2.68 (m, 3H), 2.35-2.28 (m5 1H), 2.02-1.84 (m, 3H), 1.26 (s, 3H), 1.21 (s, 3H), 1.08] 02 (m, 9H) 〇 Cryptocin 55 (D) -aspartate hydrochloride (40 () (LSN 3 87039). -279- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ~ ^ Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperative 533206 A7 B7 V. Description of the Invention (277) In a solution of 39 · (53 mg, 0.054 mmol) in 271 µl of dichloromethane, hydrogen chloride was added at room temperature to 1,4-dioxygen. 4.0 μL solution in Lupin (136 μl, 0.542 mmol). After stirring for 14 hours, the transparent, colorless reaction mixture was concentrated in the air to obtain 47 mg (94%, 6% by weight of dioxin).圜 correction) The title compound appears as a white foam. 500 MHz iH NMr (Me〇H_d4) j 7.79 (d, 1H, J = 7.6 Hz), 7.45-7.36 (m, 5H), 7.31 (d, 1H, J = 2.0 Hz), 7.20 (dd, 1H, J = 8.6, 2.0 Hz), 7.01 (d, 1H, J = 8.6 Hz), 6.71 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.96 (dd, 1H, 15, 1.8 Hz), 5.63 (d, 1H, J = 10 HZ), 5.19 (d, 1H, J = 10 Hz), 5.15 (dd, 1H, J = ll, 2.1 Hz), 4.86-4.80 ( m, 1H), 4.55-4.50 (m, 1H), 4.24 (dd, 1H, J = 8.4, 4.0 Hz), 3.87 (s, 3H), 3.50 (dd, 1H, J = 13, 9.7 Hz), 3.21 (dd, 1H, J = 14, 3.6 Hz), 3.14 (dd, 1H, J = 13, 2.5 Hz), 2.80-2.70 (m, 3H), 2.40-2.32 (m, 1H), 2.21 (dd, 1H , J = 18, 4.0 Hz), 2.09-1.97 (m, 2H) 1.92-1.84 (m, 2H), 1.26 (s, 3H), 1.21 (s, 3H), 1.15 (d, 3H, J = 7.1 Hz), 1.08 (d, 3H, J = 6.1 Hz), 1.04 (d, 3H, J = 6.0 Hz). Preparation of Cryptocin 55 (L) -N-t-Boc-Thirteen-Butyl Ester (41 丨) (LSN 382572). At Γ (23 mg, 0.033 mmol), Nt-Boc- (L) -hexamine α-tert-butyl @ imine (15 mg, 0.049 mmol), and 4-dimethylaminoacetic acid (0.4 mg, 0.0033 mmol) in a solution of 120 µl of anhydrous dichloromethane at room temperature was added with 1,3-dicyclohexylcarbodiimide (0.00 mg, 0.049 mmol) to 40 µl of dichloride Solution in methane. After stirring for 45 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 0.5 ml), stirred for 10 minutes, filtered through a celite plug, and ethyl acetate · hexane (3: 1) wash. The filtrate and washings were concentrated in the air to a gray-white oil. Chromatography (丨 5 grams of rapid silicone, -280-This paper size is applicable to China National Standard (CNS) A4 size (210X297 mm) (read the precautions on the back before filling out this page),-mouth. Help · Economy Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Education 533206 M. 5. Description of the invention (278) 2: 1 ethyl acetate-hexane), to obtain 24 mg (75%) of the title compound as a white foam: 500 MHz 4 NMR (CDC13) $ 7 39-7.3〇 (m, 5H), 7.24 (d, 1H, J = 2.1 Hz), 7.20-7.16 (m, 1H), 7.09 (dd, 1H, J = 8.4, 2.1 Hz) 6.87 ( d, 1H, J = 8.4 Hz), 6.74 (ddd, 1H, J = 15, 13, 4.6 Hz) 5.78 (d, 1H, J = 15 Hz), 5.55 (br d, 1H, J = 6.4 Hz), 5.46 (dd, 1H, J = 9.6, 1.0 Hz), 4.96 (dd, 1H, J = ll, 3.0 Hz), 4.91-4.80 (m, 2H), 4.83 (d, 1H, J = 9.6 Hz), 4.72 (br s, 1H), 3.99 (br s, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J = 13, 7.9 Hz), 3.24 (dd, 1H, J = 13, 3.9 Hz), 3.18 (dd, lH, J = 14, 4.5Hz), 3.09 (dd, lH, J = 14, 7.8Hz), 2.63 · 2.55 (m, 2H), 2.44-2.37 (m, 1H), 2.10- (1.992, 3H), 1.85-1.78 (m, 1H), 1.76-1.61 (m, 3H), 1.46 (s, 9H) 1.45 (s, 9H), 1.27 (s, 3H), 1.20 (s, 3H), 1.08 (d, 3H, J = 7.0 Hz), 1.04 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H , J = 6.4 Hz). Preparation of cryptocryptin 55 (L) -r-glutamate hydrochloride (42,) (LSN 382514). To a solution of 41 '(21 mg, 0.021 millimoles) in 212 microliters of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (53 microliters' 0.212 moles) at room temperature. ). After 2-3 hours, the reaction mixture was diluted with methanol and passed through a small plug of celite. Concentrated in tritium air to obtain 20 mg (100%, corrected for 6% by weight dioxolane) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) d 7.79 (d, 1H, J = 7.6 Hz) , 7.50-7.29 (m, 6H), 7.20 (dd, 1H, J = 8.4, 2.0 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.66 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.97 (dd, 1H, 15, 1.5 Hz), 5.52 (dd, 1H, J = 10, 0.8 Hz), 5.14 (dd, 1H, J = ll, 3.0 Hz), 5.10 (d, 1H, J = 10 Hz), 4.90-4.80 (m, 1H), 4.51 (dd, 1H, 281-This paper size applies to China National Standard (CNS) A4 size (210X 297 mm) (Please read the note on the back first) (Please fill in this page again)

7./V 533206 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (279) J = ll, 3.7 Hz), 3.90-3.80 (m, 1H), 3.87 (s, 3H), 3.50 ( dd, 1H, J = 13, 10 Hz), 3.19 (dd, 1H, J = 14, 3.7 Hz), 3.13 (dd, 1H, J = 14, 2.3 Hz), 2.81-2.67 (m, 3H), 2 41-2 · 32 (η, 2H), 2.15-2.06 (m, 1H), 197- 1.79 (m, 5H), 1.25 (s, 3H), 1.19 (s, 3H), 1.13 (d, 3H, J = 7.1 Hz), 1.08 (d, 3H, J = 5.9 Hz), 1.04 (d, 3H, J = 5.8 Hz). Preparation of Cryptocin 55 N, N, -di-t_Boc- (S) -2,3-diaminopropionic acid (43,) (LSN 382765). At i, (21 mg, 0.030 mmol), N, N, -di-t · Boc_ (S) -2,3-diaminopropionic acid (18 mg, 0.060 mmol), and 4 -A solution of dimethylaminopyridine (0.3 mg, 0.0030 mmol) in 110 µl of anhydrous digas methane was added at room temperature to 1,3-dicyclohexylcarbodiimide (12 mg, 0.060 mmol) Solution in 39 µl of dichloromethane. After stirring for 70 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3: 1, 0.5 ml), stirred for 10 minutes, filtered through a celite plug, and washed with ethyl acetate-hexane (3: 1). . The filtrate and washings were concentrated to a pale white oil in the air. Chromatography (15 g of flash silica, 2: 1 ethyl acetate-hexane) gave 24 mg (80%) of the title compound as a white foam: 500 MHz 1HNMR (MeOH-d4) cy7.49-7.40 (m, 2H ), 7.38-7.30 (m, 4H), 7.19 (dd, 1H, J = 8.5, 1.9 Hz), 7.00 (d, 1H, J = 8.5 Hz), 6.74 (ddd, 1H, J = 16, 11, 3 5 Hz), 5.95 (d, 1H, J = 16 Hz), 5.49 (d, 1H, J = 10 Hz), 5.16-5.08 (m, 2H), 4.90-4.80 (m, 1H), 4.51 (dd , 1H, J = 11, 3.7 Hz), 4.06-4 · 10 (ιη, 1H), 3.87 (s, 3H), 3.48 (d, 1H, J = 13 Hz), 3.19 (dd, 1H, J = 14, 3.7 Hz), 3.14 (d, 1H, J = 13 Hz), 3.03 (dd, 1H, J = 14, 4.2 Hz), 2.94-2.87 (m, m), 2.80-2.59 (m, 3H) , 2.39-2.30 (m, lH), 1.98-1.81 (m, 3H), 1.43 (s, 18H), 1.25 (s, 3H), 1.21 (s, 3H), 1.10 (d, ____- 282 -__ present Paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

1T 533206 A7 B7 V. Description of the invention (280) 3H, J = 7.0 Hz), 1.07 (d, 3H, J = 6.0 Hz), 1.03 (d, 3H, J = 5.8 Hz). Preparation of Cryptocin 55 (S) -2,3-diaminopropionate dihydrochloride (44,) (LSN 382764). In a solution of 43 乂 21 mg, 0.021 mmol) in 211 µl of dichloromethane, a 4.0 volume solution of hydrogen chloride in 1,4-dioxolane (42 µl, 0.169 mmol) was added at room temperature. . After stirring for 5 hours, the reaction mixture was concentrated in the air to obtain 18.5 mg (100%, corrected for 3% by weight of dioxolane) of the title compound as a white solid: 500 MHz 4 NMR (MeOH-d4) β 7.50- 7.39 (m, 5Η), 7.31 (d, 1Η, J = 2.0 Hz), 7.20 (dd, 1Η, J = 8.4, 2.0 Hz), 7.01 (d, 1H, J = 8.4 Hz), 6.68 (ddd, 1H, J = 15, 11, 3.8 Hz), 5.99 (dd, 1H, 15, 1.7 Hz), 5.56 (d, 1H, J = 9.6 Hz), 5.24 (d, 1H, J = 9.6 Hz) 5.16 (dd, 1H , J = 10, 3.1 Hz), 4.90-4.80 (m, 1H), 4.51 (dd, 1H, J = ll, 3.8 Hz), 4.04 · 4 · 00 (ιη, 1H), 3.87 (s, 3H ), 3.50- 3.45 (m, 1H), 3.26 (dd, 1H, J = 14, 4.0 Hz), 3.22-3.12 (m, 3H), 2.81-2.75 (m, 3H), 2.42-2.32 (m, 1H ), 1.98-1.78 (m, 3H), 1.25 (s, 3H), 1.19 (s 3H), 1.22-1.16 (m, 3H), 1.07 (d, 3H, J = 6.4

Hz), 1.04 (d, 3H, J = 6.3 Hz). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Preparation of Cryptophyll 55 N_t-Boc- (L) _serine (45,) (LSN 384340). At 1 '(38 mg, 0.053 mmol), N_t_Boc-0-Third-Butyldimethylxanthyl- (L) -serine (51 mg, 0.160 mmol), and 4 · Dimethylaminopyridine (0.6 mg, 0.0053 mmol) was added to a solution in 200 µl of anhydrous dichloromethane at room temperature. 1,3-Dicyclohexylcarbodiimide (33 mg, 0.160 mol) ) In 6.9 microliters of dichloromethane. After stirring for 4 hours, the turbid white reaction mixture was diluted with ethyl acetate-hexane (2: 1, 1 ml) and stirred; dropped for 10 minutes, Filtered with celite plug, washed with ethyl acetate and sautéed (2: 1). Liquid soap __- 283 -___ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1 ~ '-533206 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards, Ministry of Standards and Laboratories A7 B7 5. The invention description (281) and the lotion are concentrated in the air to a colorless oil, which is used directly in the next step. Ether (54 mg, 0.054 mmol) in a solution of 268 microliters of tetrahydrofuran was added at room temperature to 268 microliters of a hydrogen fluoride pyridine stock solution (from 0.5 g of HF · p Aldrich, 4 ml of tetrahydrofuran) And 1 ml of pibidium). After stirring for 4 hours, 67 microliters of HF-pyridine stock solution was added again. After stirring for 30 minutes, the reaction mixture was treated with 0.6 ml of a saturated aqueous sodium hydrogen carbonate solution to Wash with ethyl acetate (〖mL x 3). The combined organic phases are dried (Na2S04), filtered, and concentrated in the air to a light yellow foam. Chromatography (16 g of SiO2, 3: 1, then 6: 1) Ethyl acetate hexane was dissolved) to obtain 26 mg (44%) of the title compound as a white foam: 500 MHz 4 NMR (MeOH-d4) d 7.79 (dd, 1H, J = 9.5, 2.4 Hz), 7.45-7.38 (m, 2H), 7.37-7.29 (m, 3H), 7.29 (d, 1H, J = 2.0 Hz), 7.18 (dd, 1H, J = 8.4, 2.0 Hz), 6.99 (d, 1H, J = 8.4 Hz), 6.72 (ddd, 1H, J = 15, 13, 3 · 7 Hz), 5.95 (dd, 1H, J = 15, 1.6 Hz), 5.53 (d, 1H, J = 9.5 Hz), 5.12-5.08 (m, 2H), 4.94 (t, 1H, J = 10 Hz), 4.52 (dd, 1H, J = 12, 3.6 Hz), 3.92 (t, 1H , J = 4.6 Hz), 3.85 (s, 3H), 3.52-3.46 (m, 3H), 3.20 (dd, 1H, J = 14, 3.5 Hz), 3.14 (dd, 1H, J = 13, 3.0 Hz) , 2.75 (dd, 1H, J = 14, 11 Hz), 2.73-2.66 (m, 1H), 2.65-2.59 (m, 1H), 2.38-2.29 (m, 1H), 2.00-1.82 (m, 3H) , 1.43 (S, 9H), 1.25 (S, 3H), 1.22 (S, 3H), 1.10-1.06 (m, 6H), 1.03 (d, 3H, 6.0 Hz). Preparation of Cryptocin 55 (L) -serine hydrochloride (46f) (LSN 384339). To a solution of 45 '(26 mg, 0.029 mmol) in 291 µl of dichloromethane was added a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (36 µl, 0.146 mmol) at room temperature. Moore). After 2.5 hours of dressing, the transparent and colorless reaction mixture is in _____- 284 -____ This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) (Please read the precautions on the back before filling this page}髻 · 533206 A7 B7 V. Description of the invention (282) 眞 Concentrated in the air to obtain 23 mg (94%, corrected for 2% by weight of dioxolane) The title compound was a white foam: 500 MHz 4 NMR (MeOH-d4 ) d 7.48-7.40 (m, 2H), 7.39-7.31 (m, 3H), 7.31 (d, 1H, J = 2.2 Hz), 7.20 (dd, 1H, J = 8.5, 2.0 Hz), 7.01 (d, 1H, J = 8.5 Hz), 6.70 (ddd, 1H, J = 15, 13, 3.7 Hz), 5.95 (dd, 1H, 15, 1.8 Hz), 5.59 (d, 1H, J = 10 Hz), 5.20 ( d, 1H, J = 10 Hz), 5.14 (dd, 1H, J = ll, 2.1 Hz), 4.94 (t, 1H, J = 10 Hz), 4.52 (dd, 1H, J = 3.5 Hz), 3.96 ( dd, 1H, J = ll, 3.9 Hz) 3.83 (dd, 1H, J = ll, 2.8 Hz), 3.66 (t, 1H, J = 3.2 Hz), 3.50 (d, 1H, J = 14 Hz), 3.20 (dd, 1H, J = 14, 3.5 Hz) 3.13 (d, 1H5 J = 14 Hz), 2.80-2.71 (m? 3H), 2.38-2.28 (m, 1H), 2.01-1.82 (m, 3H), 1.26 (s, 3H), 1.21 (s, 3H), 1.13 (d, 3H, J = 7.0 Hz), 1.07 (d , 3H, J = 6.1 Hz), 1.05 (d, 3H, J = 6.1 Hz). Preparation of Cryptocin 55 Glycidyl Glycine Hydrochloride (47,) (LSN 387750). At Γ (18 (Mg, 0.026 mmol), Nt-Boc · glycidyl glycanol ^: ^ (12¾g '0.051¾mol) and 4-dimethylamino p ratio (0.3¾g, 0.0026 mmol) 128 microliters of anhydrous dichloromethane and 28 microliters of N, N-dimethyl printed by the Consumer Cooperative of the Central Standards Bureau (please read the precautions on the back before filling this page) The solution in formamidine is at room temperature Add 1,3_dicyclohexylcarbodiimide (II 耄 g '0.051 耄 Mole) in 28 microliters of dichloromethane. After stirring for 3 hours,' 24¾ g (0.102 ¾ Wuer)] Si-t-Boc-glycidyl glycine and 22 mg (0. 02 mmol) of 1,3-dicyclohexylcarbodiimide in 30 μl of N, N-dimethylformamide Join. After stirring for 15 hours, the turbid white reaction mixture was diluted with ethyl acetate-hexane (3: 1,05 ml), stirred for 0 minutes, filtered through a celite plug, and washed with ethyl acetate-hexane (3: " .The filtrate and washing solution are concentrated in 呉 2 to a colorless oil. Chromatography (丨 2 grams of rapid silica gel, 1% methanol ____- 28fS-This paper size applies to Chinese National Standard (CNS) A4 specification (210x197 mm)-533206 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (283) in ethyl acetate) to obtain 12 mg of white foam, which was used in the next experiment. In the above N-Boc-glycidol A solution of glycyl glycinate (12 mg, 0.003 mmol) in 130 µl of dichloromethane was added at room temperature to a 4.0 M solution of hydrogen chloride in 1,4-dioxolane (16 µl, 0.065 mmol). After stirring for 3.5 hours, the reaction mixture was concentrated in the air to obtain 11 mg (100%) of the title compound as a white foam: 500 MHz 4 NMR (MeOH_d4) d 7.45-7.29 (m, 5H), 7.31 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 8.4, 2.1 Hz), 7.01 (d, 1H, J = 8. 4 Hz), 6.72 (ddd, 1H, J = 15, 11, 3.8 Hz), 5.96 (dd, 1H, 15, 1.4 Hz), 5.49 (dd, 1H, J = 10, 0.8 Hz) , 5.14-5.09 (m, 2H), 4.90-4.80 (m, 1H), 4.51 (dd, 1H, J = ll, 3.9 Hz), 3.91-3.84 (m, 1H), 3.87 (s, 3H), 3.70 -3.65 (m, 2H), 3.50 (d, 1H, J = 14Hz), 3.38 (d, 1H, J = 18 Hz), 3.19 (dd, 1H, J = 14, 3.6 Hz), 3.12 (d, 1H , J = 14 Hz), 2.82-2.63 (m, 3H), 2.40-2.30 (m, 1H), 1.97-1.80 (m, 3H), 1.25 (s, 3H), 1.20 (s, 3H), 1.12 ( d, 3H, J = 7.0 H z), 1.06 (d, 3H, J = 6.0 Hz), 1.03 (d, 3H, J = 5.9 Hz). Cryptocin 55 3,6,9-trioxin (oxa) Preparation of Decanoate (48 ') (LSN 387414). At 1' (18 mg, 0.026 mmol), 3,6,9-Misaki Decanoic Acid (7.8 µl, 0.051 * mol), And 4-dimethylaminopyridine (0.3 mg, 0.0026 millimoles) in a solution of 100 microliters of anhydrous dichloromethane at room temperature, and 3-dicyclohexylcarbodiimide ( 11 mg, 0.051 mmol) in 28 µl of dichloromethane. After stirring for 30 minutes, the cloudy white reaction mixture was diluted with ethyl acetate-hexane (3: 1,5 ml), stirred for 10 minutes, filtered through a celite plug, and filtered with ethyl acetate-hexane (3: 1) Wash. The filtrate and washings were concentrated in the air to a off-white oil. Chromatography (12 grams of Rapid Rock Gel, 2% methanol in ethyl acetate (please read the precautions on the back before filling this page)

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___ -286-

Industry 3206 Printed A7 B7 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. In the description of the invention (284)), 19 mg (86%) of the title compound was obtained as a white foam: 500 MHz 4 NMR (CDC13) d 7.49-7.29 ( m, 5H), 7.24 (d, 1H, J = 1.8 Hz), 7.22-7.19 (m, 1H), 7.10 (dd, 1H, J = 8.4, 1.8 Hz), 6.87 (d, 1H, J = 8.4 Hz ), 6.74 (ddd, 1H, J = 15, 10, 4.5 Hz), 5.32-5.28 (m, 2H), 5.56 (d, 1H, J = 9.7 Hz), 4.98-4.90 (m, 2H), 4.83 ( d, 1H, J = 9.7 Hz), 4.77-4.71 (m, 1H), 3.90 (s, 3H), 3.83 (d, 1H, J = 17 Hz), 3.65-3.55 (m, 7H), 3.42-3.33 (m, 6H), 3.24 · 3.18 (ιη, 2H), 3.03 (dd, 1H, J = 15, 8.1 Hz), 2.69-2.61 (m, 1H), 2.61-2.56 (m, 1H), 2.54-2.46 (m, 1H), 2.00_1.93 (m, 1H), 1.85_1.77 (m, 1H), 1.72_ 1.66 (m, 1H), 1.26 (s, 3H), 1.19 (s, 3H), 1.09 (d, 3H, J = 7.0 Hz), 1.02 (d, 3H, J = 6.6 Hz), 0.97 (d, 3H, J = 6.5 Hz). ____ _-287- Paper size applies to Chinese National Standard (CNS) M size (210x297 mm) (Please read the precautions on the back before filling this page)

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1 6.V application date \ .......—........... * .........—............ ........... 86. 12. 17. Case No. ------ 86119087 Class 1 Hi__ '

L A4 C4 Invention Patent Chinese Specification Correction Page (90 years! Month) Specification 533206 Invention Name Chinese Novel Cryptophyllin Compound and Its Pharmaceutical Composition Human

English I Name Country I. Li Ma Sha Lin Ya-Watt ΓΓΤ --- ~~~ 3 Trends J. Tamo P Tumkara Ilf 1 # &gt; ιίί 9: ll ¢ 11 | S II. John Aiden; which 10.Shi Chuan 1. Λ Country Indiana State Ocarina Soil Claw Worker, Scholar ~, Up, · Outfit, Residence, Residence $ # 国 夏 4 表 椟 畚 ί 晶 S Jin Road 4524_i_ 书号 定12. State of Indiana, Wu State $ Name (Name) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative, and printed the applicant's nationality residence, residence (office) Representative name 1. Eli Lilly and Co. of the United States 2. University of Hawaii, USA 3. Wayne State University, U., 3 in the United States; · ί = 2 ί = 丨 Lilly Company Center, Indianapolis, United States ^^ 2 Wulan Road, Shanshan City Investigator • Wu Guozhi, Shigen Prefecture, Lilu City Administration Management Building Room 0412 1. Elicia A. Deguzos 2. Gram K. Nakamora 3. George E. Danbach Line

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Claims (1)

533206 8 8 8 8 A B c D No. 086119087 Patent Application Chinese Patent Application Replacement (February 1992) 々, Patent Application-Scope I wherein Ar is winteryl, each radical, sulfanyl, 2-methylp-syr-4-yl, styryl, phenyl substituted with one or two substituents selected from the group consisting of : Fluoro'methyl, and methoxy, phenyl substituted with a substituent selected from the group consisting of: nitro, via, methoxycarbonyl, trifluoromethyl, (third-butoxycarbonyl- ) Amine, ((N- [third-butoxycarbonyl]) amino acid) amine, (amino acid) amine, N- [fluorenylmethoxymethoxycarbonyl] glycamine, (amine (Methyl), (hydroxy) methyl, (chloro) methyl, (methylamino) methyl '(carbonyl) methyl, (phthaloamino) methyl, (triisopropylsiloxy) Methyl '(tertiary-butanedimethylsiloxy) methyl, ((N- [tertiary-butoxycarbonyl])-amino acid) oxy) methyl, ((amino acid) oxy) methyl , ((Third-butoxycarbonyl) amine) methyl '((((N- [third-butoxycarbonyl]) _ amino acid) amine) methyl, ((amino acid) amine) methyl , (2- (tertiary-butoxycarbonyl) aminoethyl) aminomethyl, ((2 aminoethyl-1-yl) amine) methyl, (4- (Third-butoxycarbonyl) _ This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 533206 Hexahydro-1: Mizuki-1 -yl) methyl, (Hydroxy-1.yl-1) yl, (2- (Third-butyldimethylsilyl) eth-1-yl) Amine, and (diethylamine) methyl, phenolthio, methoxy, or propyl; R1 is oxygen and R2 is bromine; or R1 is hydroxyl and R2 is chlorine or bromine; or r1 is chlorine or bromine and R2 Is hydroxyl or OR31; or R8 is hydrogen or methyl; R is ethyl's white alcohol group, in the test group, (2'-di-tertiary-butylphosphonic acid group) phenethyl, N- [Third-butoxycarbonyl] 3- (3-chloro-4-fluorenyloxyphenyl) propylaminofluorenyl, 3- (3-chloro-4-fluorenyloxyphenyl) propylaminofluorenyl, N • methylpyridine. , (N- [third-butoxycarbonyl]) amino acid, or amino acid; or a pharmaceutically acceptable salt or solvate thereof, except when Ar is phenyl, fluorophenyl 'or chlorobenzene And R8 are hydrogen, and R2 must be OR3 1. 2 · According to the scope of patent application! A compound of the formula wherein Ar is phenyl, r1 is chlorine, R2 is OR31, and is methyl. 3. The compound according to item 2 of the patent application, wherein r31 is an amine ester. (= According to the patent claim No. 3 compound, wherein the compound is cryptodine 55 amino acetate hydrogen chloride It is selected from the group consisting of compounds according to item 1 of the scope of patent application -2- 533206 8 8 8 8 A B c D Scope of patent application Crowd: Cryptocin 1 2 9 C1 OCH3 Crytodin 1 3 8 OH C 丄 OCH, 0 CI OCH3 • 3- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 533206 8 8 8 8 ABCD Cl OCH3 Cryptocin 1 4 Ο Cl OCHi and cryptocin 1 4 1 ; Or its pharmaceutically acceptable salt 4- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 533206 A8 B8 C8 D8 533206 Patent Application Cryptocin 1 5 4 Cryptocin 1 6 1 Cryptocyanin 2 3 4 Cryptocyanin 2 3 6 8 8 8 8 A BCD -6- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 533206 8 8 8 8 A BCD Application scope of patent Cryptocin 247 t-B〇cNH Crytodin 2 5 1 Crytodin 2 3 8 And Crytodin 3 0 9 Or this paper size applies the Chinese National Standard (CNS) A4 specification (210x 297 mm) 533206 8 8 8 8 A B c D 々, patent application scope Pharmaceutically acceptable salt. 7. The compound according to item 1 of the scope of patent application, which is Cryptocin 3 0 9 Hydrochloride 3 09-HC1 C! CH3 8. A pharmaceutical composition for treating mammalian neoplasms, which comprises an effective amount of a compound as claimed in any one of claims 1 to 7 and one or more pharmaceutically acceptable diluents or carriers. -8- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)