CN111194304B - Preparation method of bridged ring compound - Google Patents

Preparation method of bridged ring compound Download PDF

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CN111194304B
CN111194304B CN201980004915.0A CN201980004915A CN111194304B CN 111194304 B CN111194304 B CN 111194304B CN 201980004915 A CN201980004915 A CN 201980004915A CN 111194304 B CN111194304 B CN 111194304B
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enantiomer
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CN111194304A (en
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赖金强
丰亚辉
王仲清
孙国栋
徐文倡
罗忠华
黄芳芳
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Yichang Hec Changjiang Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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Abstract

The invention relates to a preparation method of a bridged ring compound, belonging to the technical field of chemical industry. The method of the invention comprises the following steps: the diester compound reacts under the action of enzyme to obtain the monoester compound. The obtained monoester compound is subjected to sulfonation reaction and then is subjected to reaction with compounds such as boroxine, and the like, so that various medicines or medicine intermediates with single configuration can be prepared. The method of the invention can obtain the monoester compound with ee value more than 40%, which is beneficial to the preparation of the compound with high optical purity and the cost control.

Description

Preparation method of bridged ring compound
Technical Field
The invention relates to a preparation method of a bridged ring compound, belonging to the technical field of chemical industry.
Background
Bridged ring structure represented by the formula (wherein the dotted line represents a possible site for attachment of other groups/fragments)
Figure GPA0000287164670000021
And isomers thereof
Figure GPA0000287164670000022
Is an important structure in a plurality of drug structures, and the compound containing the structure in a single configuration is more related to the difficulty degree of the preparation of the final drug molecule. For example, it is desirable to prepare a drug (AB-1) or a drug (AB-2) represented by the following formula, wherein RA and RB refer to the same or different molecular structural fragments, respectively,
Figure GPA0000287164670000023
in the prior art, the preparation method is generally adopted as follows: the starting material containing the bridge ring segment is bi-sulfonated, a series of steps are carried out to obtain each racemic intermediate, a racemic compound (AB-i) is prepared, and then the (AB-i) is resolved to obtain a compound (AB-1) or (AB-2) with a target configuration, wherein Tf refers to trifluoromethanesulfonyl:
Figure GPA0000287164670000024
in this case, the presence of bis-sulfonate disubstituted product is unavoidable during the ligation of RA fragments, and in the resolution process, the resolution yields are only 50% at the maximum, which leads to loss of multiple steps prior to the final product, leading to increase and complication in cost and the like. Therefore, if a single configuration of the bridged ring structure compound can be obtained in the previous step of the preparation of the final product, it is advantageous in terms of the control of the aspects of the preparation of the final product such as cost, operation, and the like.
Disclosure of Invention
The present invention aims to provide a process for producing a bridged ring compound, which can easily obtain a monohydroxy compound having a high optical purity and an enantiomeric excess (ee value) of more than 40%, and further can easily obtain a monosulfonated intermediate, and is useful for producing a single-configuration final product.
A process for preparing a compound of formula (03) or an enantiomer thereof, comprising: reacting the compound shown in the formula (02) under the action of enzyme to obtain the compound shown in the formula (03) or an enantiomer thereof,
Figure GPA0000287164670000031
wherein the content of the first and second substances,
the dotted line represents a bond or is absent;
r is hydrogen; or R is C1-C20 linear or branched chain alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, C1-C6 alkoxy, aryloxy, heteroaryloxy, alkoxycarbonyl, amino, and hydrogen in the R group is optionally substituted by halogen;
the enzyme is lipase, esterase, protease, or a mixture thereof.
The inventors have found, through studies, that in the above-mentioned method for producing a compound represented by the formula (03) or an enantiomer thereof, the optical purity of the compound (03) or an enantiomer thereof may exceed 70% or 90%, and the ee value may exceed 40%. In some embodiments, in the above method for preparing a compound represented by formula (03) or an enantiomer thereof, the ee value of compound (03) or an enantiomer thereof is more than 60%. In some embodiments, in the above method for preparing a compound represented by formula (03) or an enantiomer thereof, the ee value of compound (03) or an enantiomer thereof is more than 70%. In some embodiments, in a method of preparing a compound represented by formula (03) or an enantiomer thereof, the ee of compound (03) or an enantiomer thereof is greater than 80%.
In the above reaction for producing the compound (03) or an enantiomer thereof from the compound (02), the mass ratio of the enzyme to the compound (02) is 0:1 to 10.0: 1. The mass ratio of the enzyme to the compound (02) is preferably 0.0001: 1-5.0: 1, more preferably 0.001: 1-2.0: 1, which is beneficial to reaction, control and treatment.
In the above reaction for producing compound (03) or an enantiomer thereof from compound (02), a buffer may not be added, or a buffer may be added. When the buffer solution is added, the pH value of the buffer solution can be controlled to be 3.0-12.0, preferably 4.0-11.0, and more preferably 5.0-11.0. The concentration of the buffer solution can be controlled to be 0 to 1.0mol/L, preferably 0.02 to 0.5mol/L, and more preferably 0.03 to 0.3 mol/L. The mass ratio of the total mass of the buffer solution to the compound (02) may be 0:1 to 50.0:1, preferably 1.0: 1 to 40.0: 1, and more preferably 2.0: 1 to 30.0: 1.
The buffer may be water or a solution with water. The buffer solution can also be at least one selected from sodium dihydrogen phosphate-citric acid buffer solution, citric acid-sodium citrate buffer solution, triethanolamine-hydrochloric acid buffer solution, sodium dihydrogen phosphate-sodium hydroxide buffer solution, sodium dihydrogen phosphate-potassium dihydrogen phosphate buffer solution, potassium dihydrogen phosphate-sodium hydroxide buffer solution, boric acid-borax buffer solution, glycine-sodium hydroxide buffer solution, sodium carbonate-sodium bicarbonate buffer solution and sodium bicarbonate-sodium hydroxide buffer solution.
In the above reaction for preparing the compound (03) or the enantiomer thereof from the compound (02), a cosolvent may be added, and the mass ratio of the cosolvent to the compound (02) may be 0:1 to 50.0:1, preferably 1.0: 1 to 40.0: 1, and more preferably 2.0: 1 to 30.0: 1. The cosolvent can be at least one of dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, methyl cyclopentyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, acetone, butanone, methyl isobutyl ketone, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, N-pentane, N-hexane, N-heptane, N-octane, heptane, cyclohexane, alcohols such as methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-butanol and the like. In some embodiments, the co-solvent is at least one of ethanol, isopropanol, ethyl acetate, cyclohexane, toluene, dichloromethane, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, N-Dimethylformamide (DMF).
In the above reaction for preparing the compound (03) or an enantiomer thereof from the compound (02), the reaction temperature may be from-10 ℃ to 80 ℃. In some embodiments, in the above reaction for preparing compound (03) or an enantiomer thereof from compound (02), the reaction temperature is 0 ℃ to 70 ℃. In some embodiments, in the above reaction for preparing compound (03) or an enantiomer thereof from compound (02), the reaction temperature is 0 ℃ to 50 ℃ for ease of handling and control.
In some embodiments, the above reaction to prepare compound (03) or an enantiomer thereof from compound (02), when the dotted line is a bond, is represented by the formula:
Figure GPA0000287164670000041
in some embodiments, the above reaction to prepare compound (03) or an enantiomer thereof from compound (02), when the dashed line indicates absence, is represented by the formula:
Figure GPA0000287164670000042
in the compound (03) or the enantiomer thereof, when the dotted line is a bond, the compound (03) or the enantiomer thereof may be directly subjected to the next reaction, or the double bond may be reduced under the conditions of hydrogen and palladium carbon, and then the next reaction may be carried out under the action of an enzyme.
For compound (03) or an enantiomer thereof, wherein the dotted line is a bond, the double bond of compound (03) or the enantiomer thereof, where the dotted line is located, can be reduced to provide a compound in which the dotted line is absent, as shown in the following formula:
Figure GPA0000287164670000043
the inventor finds that the enzyme class has a large influence on the configuration of the product, and the configuration of the product obtained by using different enzymes is different. In some embodiments, in the aforementioned methods, the enzyme is a recombinant escherichia coli esterase, candida rugosa lipase, pseudomonas fluorescens lipase, aspergillus niger lipase, burkholderia lipase, pseudomonas cepacia lipase, myceliophthora thermophila lipase, or a combination thereof, to yield the compound of formula (03); the enzyme is lipase Novixin 435, aspergillus fungal protease, bacillus protease or a combination thereof, and an enantiomer of the compound shown in the formula (03) is obtained.
A process for producing a compound represented by the above formula (02) comprises: the compound shown in the formula (01) and a compound containing or capable of providing an R group such as carboxylic acid, acyl chloride or acid anhydride are subjected to esterification reaction to obtain a compound shown in the formula (02), wherein a dotted line represents a bond or is absent, R is defined as the above,
Figure GPA0000287164670000051
in the esterification reaction, the molar ratio of the compound containing or capable of providing an R group, such as carboxylic acid, acyl chloride or anhydride, to the compound (01) is 1.2: 1-10.0: 1, preferably 1.6: 1-5.0: 1, and more preferably 2.0: 1-4.0: 1, which is beneficial to obtaining a target product.
The carboxylic acid, acid chloride or acid anhydride or the like containing or capable of providing an R group may be acetyl chloride, propionyl chloride, butyryl chloride, dodecanoyl chloride, methoxyacetyl chloride, 5-chlorovaleroyl chloride, benzoyl chloride, cyclopropylformyl chloride, acetic anhydride, propionic anhydride, formic acid, acetic acid or the like.
In the esterification reaction, the reaction solvent may be at least one selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, methylcyclopentyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, N-pentane, N-hexane, N-heptane, N-octane, heptane, and cyclohexane. In some embodiments, the esterification reaction is carried out in the presence of at least one solvent selected from ethyl acetate, isopropyl acetate, cyclohexane, toluene, methylene chloride, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, and N, N-Dimethylformamide (DMF). In the esterification reaction, the mass ratio of the reaction solvent to the compound (01) may be 0.5: 1 to 50.0:1, preferably 1.0: 1 to 40.0: 1, and more preferably 2.0: 1 to 30.0: 1.
In the esterification reaction, an acid-binding agent can be added, and the molar ratio of the acid-binding agent to the compound (01) can be 1.2: 1-10: 1, preferably 1.6: 1-5.0: 1, and more preferably 2.0: 1-4.0: 1. The acid-binding agent can be at least one of pyridine, trimethylamine, triethylamine, N-diisopropylethylamine, N-methylmorpholine and N, N-dimethylamino pyridine.
In the esterification reaction, a catalyst may or may not be added, for example, N-Dimethylaminopyridine (DMAP) may be added as a catalyst, and the molar ratio of N, N-dimethylaminopyridine to the compound (01) may be 0:1 to 10:1, preferably 0.001: 1 to 5.0: 1, and more preferably 0.01: 1 to 2.0: 1.
In the esterification reaction, the reaction temperature can be 0-80 ℃, preferably 0-60 ℃, and more preferably 10-40 ℃, which is beneficial to reaction control and generation and obtaining of products.
In some embodiments, when the dotted line represents a bond in the esterification reaction described above, the reaction is represented by the following formula:
Figure GPA0000287164670000052
in some embodiments, in the above esterification reaction, when the dotted line is absent, the reaction is represented by the following formula:
Figure GPA0000287164670000061
in some embodiments, for compound (02) where the dotted line is a bond, the double bond of compound (02) where the dotted line is located can be reduced to provide a compound where the dotted line is absent, as shown in the following formula:
Figure GPA0000287164670000062
in some embodiments, when the dotted line is a bond, compound (02) may be directly subjected to the next reaction, or the double bond may be reduced using conditions such as hydrogen and palladium on carbon, and then subjected to the next reaction using conditions such as under the action of the enzyme.
In some embodiments, the compound represented by formula (01) is subjected to an esterification reaction with a compound containing or capable of providing an R group, such as a carboxylic acid, an acid chloride, or an acid anhydride, to obtain the compound represented by formula (02); reacting the compound shown in the formula (02) under the action of enzyme to obtain the compound shown in the formula (03) or an enantiomer thereof; the compound represented by the formula (02) may be isolated or may not be isolated.
The compound shown in the formula (03) or the enantiomer thereof and a sulfonation reagent body are subjected to sulfonation reaction to prepare a compound shown in the formula (04) or an enantiomer thereof:
Figure GPA0000287164670000063
wherein the dotted line represents a bond or is absent, R 2 Is trifluoromethyl, methyl, phenyl, p-methylphenyl, N, N-dimethylamino or optionally substituted phenyl.
In some embodiments, R 2 Is trifluoromethyl, methyl, phenyl, p-methylphenyl or N, N-dimethylamino. In some embodiments, R 2 Is trifluoromethyl, methyl, phenyl or p-methylphenyl.
The sulfonation reagent may be at least one of methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, dimethylaminosulfonyl chloride, trifluoromethanesulfonic anhydride, 4-toluenesulphonic anhydride, and methanesulfonic anhydride.
The sulfonation reaction, as described above, and in some embodiments when the dashed line represents a bond, is represented by the following formula:
Figure GPA0000287164670000071
the sulfonation reaction described above, in some embodiments, when the dashed line is absent, is represented by the following formula:
Figure GPA0000287164670000072
in some embodiments, for compound (04) or an enantiomer thereof where the dashed line is a bond, the double bond of compound (04) or an enantiomer thereof where the dashed line is located may be reduced to provide a compound where the dashed line is absent, as shown in the following formula:
Figure GPA0000287164670000073
in the above sulfonation reaction, the reaction solvent may be the same as or different from that in the above esterification reaction.
In some embodiments, the compound represented by formula (01) is subjected to an esterification reaction with a compound containing or capable of providing an R group, such as a carboxylic acid, an acid chloride, or an acid anhydride, to obtain a compound represented by formula (02); reacting the compound shown in the formula (02) under the action of enzyme to obtain the compound shown in the formula (03) or an enantiomer thereof; performing sulfonation reaction on the compound shown in the formula (03) or an enantiomer thereof to prepare the compound shown in the formula (04) or an enantiomer thereof; the compound represented by the formula (02) may be isolated or may not be isolated.
In another aspect, the present invention provides a compound having a structure represented by the following formula (03), or an enantiomer of a compound represented by formula (03):
Figure GPA0000287164670000074
wherein, the dotted line represents a bond or is absent, R is a linear or branched alkyl group of C1-C20, a cycloalkyl group of C3-C10, an aryl group, a heteroaryl group, an alkoxy group of C1-C6, an aryloxy group, a heteroaryloxy group, an alkoxycarbonyl group, an amino group, and hydrogen in the R group is optionally substituted by halogen; or R is hydrogen.
In some embodiments, in each of the compounds represented by the above formulae (02), (03) and (04) or an enantiomer thereof, R represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pivaloyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, dimethylamino, dimethylaminomethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 5-chloropentyl, methoxycarbonyl, ethoxycarbonyl, phenyl, benzyl, phenethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In some embodiments, in each of the compounds represented by the above formula (02), formula (03), formula (04), or an enantiomer thereof, r is hydrogen, ethyl, n-propyl, isopropyl, n-butyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, n-octadecyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, dimethylamino, dimethylaminomethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 5-chloropentyl, methoxycarbonyl, ethoxycarbonyl, phenyl, benzyl, phenethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In some embodiments, when the dashed line is absent, R is not methyl, t-butyl, or n-heptadecyl. In some embodiments, when the dashed line is a bond, R is not ethyl.
In some embodiments, the structure of compound (03) is selected from one of the following formulae:
Figure GPA0000287164670000081
Figure GPA0000287164670000091
in some embodiments, the structure of compound (03) is selected from one of the following formulae:
Figure GPA0000287164670000092
Figure GPA0000287164670000101
in some embodiments, compound represented by formula (03) or an enantiomer thereof may be prepared by sulfonation with a reagent such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, or N, N-dimethylaminosulfonyl chloride in an aprotic solvent such as ethers such as tetrahydrofuran, esters such as ethyl acetate, alkanes such as cyclohexane, or DMF. In some embodiments, compound (04) or an enantiomer thereof is prepared by sulfonating a compound of formula (03) or an enantiomer thereof with a reagent such as methanesulfonyl chloride in an ether solvent such as tetrahydrofuran. In some embodiments, compound (04) or an enantiomer thereof may be prepared by sulfonating a compound represented by formula (03) or an enantiomer thereof with a reagent such as p-toluenesulfonyl chloride in a solvent such as an ester of ethyl acetate.
In some embodiments, an acid-binding agent may be added during the sulfonation reaction, and the molar ratio of the acid-binding agent to the compound (03) may be 1.2:1 to 10:1, preferably 1.2:1 to 5.0: 1, and more preferably 1.2:1 to 3.0: 1. The acid-binding agent can be at least one of pyridine, trimethylamine, triethylamine, N-diisopropylethylamine and N-methylmorpholine.
In some embodiments, the reaction temperature in the sulfonation reaction may be 0 ℃ to 80 ℃, preferably 0 ℃ to 60 ℃, and more preferably 0 ℃ to 30 ℃, which is beneficial for reaction control and product formation and availability.
In the present invention, the reaction involving reduction of the double bond may be carried out by using palladium on carbon and hydrogen, or by using another suitable reducing agent.
The compound (04) or an enantiomer thereof obtained by the above method can be further subjected to coupling reaction with a boronic acid compound, a boroxine compound or a derivative thereof, and the like to obtain a compound with a single configuration.
The method provided by the invention can obtain the target compound with higher optical purity, and is beneficial to the acquisition and cost control of single-configuration drugs or drug intermediates.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the invention, g: g; mL or mL: ml; mmol: millimole; DEG C: c, centigrade degree; h: h; MS (ESI, pos. ion) m/z: mass spectrometry (electrospray ionization, positive ion) mass to charge ratio; CDCl 3 : deuterated chloroform; DMSO (dimethylsulfoxide): dimethyl sulfoxide; DMF: n, N-dimethylformamide; DMAP: 4-dimethylaminopyridine; NaCl: sodium chloride; MHz: megahertz.
In the chemical structure, Ph represents a phenyl group.
In the present invention, the reaction is considered complete when the remaining amount of the reaction raw material is not more than 5% of the charged amount or the theoretical yield, or not more than 2% of the charged amount or the theoretical yield, or not more than 0.5% of the charged amount or the theoretical yield in the reaction.
In the present invention, the expression "a compound represented by the formula (1)" or the like, and the expression "a compound (1)" or the like, do not substantially differ, and refer to the same compound,
in the present invention, room temperature means a temperature of 15 ℃ to 30 ℃.
ee (enantiomeric excess) value calculation method: ee ═ SR]-[RS])/([SR]+[RS]) ＊ 100% or ee ═ ([ RS [)]-[SR])/([SR]+[RS]) ＊ 100%, in the invention, the main product is SR configuration product or its enantiomer RS configuration product, therefore only the ee value of the main product is calculated; wherein [ SR]Represents the SR configuration product content, [ RS ]]Represents the content of RS configuration.
Figure GPA0000287164670000121
Dissolving a compound (01) (25.0g, 141.9mmol, 1.0eq.) in 428g of tetrahydrofuran, adding DMAP (3.42g, 28.0mmol, 0.20eq.) and triethylamine (45.2g, 446.7mmol, 3.0eq.), cooling the reaction system to 0 ℃, dropwise adding acetyl chloride (28.46g, 364.9mmol, 2.6eq.) into the system, stirring at room temperature after dropwise adding, stopping the reaction, adding 200ml of water into the system, separating, extracting the water phase with 70ml of ethyl acetate, organically laminating and distilling under reduced pressure to obtain a crude product, and recrystallizing the crude product with 175g of cyclohexane to obtain the compound (02-1): 34.5g of an off-white solid with a yield of 93.5%; 1 H NMR(400MHz，CDCl 3 )δ6.79(s，2H)，3.37(s，2H)，2.33(s，6H)，1.88(d，J＝7.2Hz，2H)，1.80(d，J＝8.9Hz，1H)，1.53(d，J＝8.9Hz，1H)，1.34(dd，J＝7.3，2.1Hz，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝261.1，[M+NH 4 ] + ＝278.1。
example 2
Figure GPA0000287164670000122
Dissolving a compound (01) (25.0g, 141.9mmol, 1.0eq.) in 428g of tetrahydrofuran, adding DMAP (3.42g, 28.0mmol, 0.20eq.) and triethylamine (45.2g, 446.7mmol, 3.0eq.), cooling the reaction system to 0 ℃, dropwise adding propionyl chloride (33.67g, 364.9mmol, 2.6eq.) into the system, stirring the reaction mixture at room temperature after the dropwise adding is finished, stopping the reaction, adding 200ml of water into the system, separating the liquid phase, extracting the water phase with 70ml of ethyl acetate, organically laminating and distilling under reduced pressure to obtain a crude product, dissolving the crude product with 30g of ethanol, dropwise adding 120g of water to precipitate a solid, filtering and drying to obtain a compound (02-2): 38.1g, off-white solid, yield 95.1%; 1 H NMR(400MHz，CDCl 3 )δ6.77(s，2H)，3.33(s，2H)，2.60(q，J＝7.6Hz，4H)，1.85(d，J＝7.1Hz，2H)，1.78(d，J＝8.9Hz，1H)，1.50(d，J＝8.9Hz，1H)，1.36-1.31(m，2H)，1.28(t，J＝7.6Hz，6H)；MS(ESI，pos.ion)m/z：[M+H] + ＝289.1，[M+NH 4 ] + ＝306.1。
example 3
Figure GPA0000287164670000123
Compound (01) (25.0g, 141.9mmol, 1.0eq.) was dissolved in 428g of ethyl acetate, DMAP (3.42g, 28.0mmol, 0.20eq.) and triethylamine (45.2g, 446.7mmol, 3.0eq.) were then added, the reaction system was cooled to 0 ℃, butyryl chloride (38.67g, 364.9mmol, 2.6eq.) was added dropwise thereto, the reaction mixture was stirred at room temperature after completion of the dropwise addition, the reaction mixture was stirred at room temperature for 4 hours, the reaction was stopped, 200ml of water was added to the system, liquid separation was carried out, the aqueous phase was extracted with 70ml of ethyl acetate, the organic layer was distilled to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane: 5: 1, volume ratio) to obtain compound (02-4): 41.5g of colorless liquid, and the yield is 92.4%; 1 H NMR(400MHz，CDCl 3 )δ6.76(s，2H)，3.33(s，2H)，2.55(t，J＝7.4Hz，4H)，1.93-1.72(m，7H)，1.50(d，J＝8.9Hz，1H)，1.32(dd，J＝7.2，2.0Hz，2H)，1.06(t，J＝7.4Hz，6H)；MS(ESI，pos.ion)m/z：[M+H] + ＝317.2，[M+NH 4 ] + ＝334.2。
example 5
Figure GPA0000287164670000131
Dissolving a compound (01) (5.0g, 28.4mmol, 1.0eq.) in 20g of cyclohexane, adding DMAP (0.34g, 2.84mmol, 0.10eq.) and triethylamine (8.04g, 79.5mmol, 2.8eq.), cooling the reaction system to 0 ℃, dropwise adding dodecanoyl chloride (16.14g, 73.8mmol, 2.6eq.), stirring at room temperature after dropwise adding, stopping reaction, adding 25ml of water into the system, separating, extracting an aqueous phase with 70ml of cyclohexane, distilling an organic layer under reduced pressure until the organic layer is dried to obtain a crude product, pulping the crude product with 65g of DMSO, and purifying to obtain a compound (02-14): 14.0g, off-white solid, yield 91.2%; 1 H NMR(400MHz，CDCl 3 )δ6.75(s，2H)，3.33(s，2H)，2.56(t，J＝7.5Hz，4H)，1.85(d，J＝7.4Hz，2H)，1.81-1.71(m，4H)，1.68-1.55(m，1H)，1.49(d，J＝8.9Hz，1H)，1.46-1.22(m，34H)，0.88(t，J＝6.7Hz，6H)；MS(ESI，pos.ion)m/z：[M+H] + ＝541.4，[M+NH 4 ] + ＝558.4。
example 6
Figure GPA0000287164670000132
Dissolving a compound (01) (5.0g, 28.4mmol, 1.0eq.) in 20g of acetonitrile, adding 4-dimethylaminopyridine (DMAP, 0.34g, 2.84mmol, 0.10eq.) and triethylamine (8.04g, 79.5mmol, 2.8eq.), cooling the reaction system to 0 ℃, dropwise adding methoxyacetyl chloride (8.00g, 73.8mmol, 2.6eq.), stirring at room temperature after dropwise adding, stopping the reaction, adding 50ml of water into the system, separating, extracting the aqueous phase twice with 70ml of ethyl acetate, distilling the organic layer under reduced pressure to dryness,the residue was recrystallized from 50g of a solvent of n-hexane/ethyl acetate 5: 1 by volume to give compound (02-17): 8.3g, off-white solid, yield 91.3%; 1 H NMR(400MHz，CDCl 3 )δ6.83(s，2H)，4.33(s，4H)，3.56(s，6H)，3.36(s，2H)，1.88(d，J＝7.3Hz，2H)，1.80(d，J＝8.9Hz，1H)，1.53(d，J＝9.0Hz，1H)，1.36(dd，J＝7.3，2.0Hz，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝321.1，[M+Na] + ＝343.1。
example 7
Figure GPA0000287164670000141
Compound (01) (5.0g, 28.4mmol, 1.0eq.) was dissolved in 20g cyclohexane, DMAP (0.34g, 2.84mmol, 0.10eq.) and triethylamine (8.04g, 79.5mmol, 2.8eq.) were then added, the reaction system was cooled to 0 ℃, 5-chloropentanoyl chloride (11.44g, 73.8mmol, 2.6eq.) was added dropwise thereto, the reaction was stirred at room temperature after completion of the dropwise addition, stirring was carried out for 2h to stop the reaction, 25ml water was added to the system, liquid separation was carried out, the aqueous phase was extracted with 70ml ethyl acetate, the organic layer was distilled under reduced pressure to dryness, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane: 5: 1, volume ratio) to obtain compound (02-21): 11.0g of colorless liquid, yield 93.6%; 1H NMR (400MHz, CDCl) 3 )δ6.78(s，2H)，3.62(t，J＝6.1Hz，4H)，3.34(s，2H)，2.64(t，J＝6.9Hz，4H)，2.01-1.75(m，11H)，1.53(d，J＝8.9Hz，1H)，1.37-1.29(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝413.1，[M+NH 4 ] + ＝430.1。
Example 8
Figure GPA0000287164670000142
Compound (01) (5.0g, 28.4mmol, 1.0eq.) was dissolved in 20g DMF, DMAP (0.34g, 2.84mmol, 0.10eq.) and triethylamine (8.04g, 79.5mmol, 2.8eq.) were then added, the reaction system was cooled to 0 ℃ and benzoyl chloride (10.37g, 73.8mmol, 2.6eq.) was added dropwise to the system,after the completion of the dropwise addition, the reaction was stirred at room temperature for 4 hours to stop the reaction, 50ml of water was added to the system, the reaction solution was separated, the aqueous phase was extracted twice with 70ml of ethyl acetate, the organic layer was washed with 45ml of a saturated sodium chloride solution and then distilled to dryness under reduced pressure, and the residue was recrystallized with 30g of toluene to obtain a compound (02-24): 9.9g, off-white solid, yield 90.8%; 1 H NMR(400MHz，CDCl 3 )δ8.30-8.20(m，4H)，7.66(dd，J＝8.9，6.0Hz，2H)，7.54(t，J＝7.7Hz，4H)，6.97(s，2H)，3.44(s，2H)，1.87(dd，J＝8.8，3.8Hz，3H)，1.52(d，J＝8.9Hz，1H)，1.46-1.41(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝385.1，[M+NH 4 ] + ＝402.1。
example 9
Figure GPA0000287164670000151
Compound (01) (5.0g, 28.4mmol, 1.0eq.) was dissolved in 30g dichloromethane, DMAP (0.34g, 2.84mmol, 0.10eq.) and triethylamine (8.04g, 79.5mmol, 2.8eq.) were then added, the reaction system was cooled to 0 ℃, cyclopropylcarbonyl chloride (7.71g, 73.8mmol, 2.6eq.) was added dropwise to the system, the reaction was stirred at room temperature after completion of the dropwise addition, stirring was carried out for 4h to stop the reaction, 30ml water was added to the system, the liquid phase was separated, the aqueous phase was extracted with 70ml ethyl acetate, the organic layer was distilled to dryness under reduced pressure, and the residue was subjected to silica gel (n-hexane: ethyl acetate: 5: 1, volume ratio) to give compound (02-27): 7.9g of oil, 89.3% yield; 1H NMR (400MHz, CDCl) 3 )δ6.65(s，2H)，3.30(s，2H)，2.06-1.91(m，2H)，1.88(d，J＝7.2Hz，2H)，1.80(d，J＝8.9Hz，1H)，1.53(d，J＝8.9Hz，1H)，1.34(dd，J＝7.3，2.1Hz，2H)，1.15-1.03(m，4H)，0.99-0.89(m，4H)；MS(ESI，pos.ion)m/z：[M+H] + ＝313.1，[M+NH 4 ] + ＝330.1。
Example 10
Figure GPA0000287164670000152
Formic acid (65.3g, 1419mmol, 10.0eq) was added to acetic anhydride (115.9g, 1135mmol, 8.0eq) at room temperature, mixed well and heated to 60 ℃ and stirred at 60 ℃ for 1 hour and cooled to room temperature. The above liquid was added dropwise to a mixture of compound (01) (25.0g, 141.9mmol, 1.0eq.) and sodium acetate (11.6g, 141.9mmol, 1.0eq.) with stirring, and the reaction was stirred at room temperature for 4 hours. Toluene (500ml) was added to the reaction mixture, and the system was washed with water (200 ml) ＊ 3 times), drying the organic layer with sodium sulfate, and then distilling under reduced pressure to dryness to obtain a crude product, and performing silica gel column chromatography on the crude product (n-hexane: ethyl acetate: 6: 1, volume ratio) to obtain a compound (02-31): 24.7g, colorless oil, yield 75.0%; 1 H NMR(400MHz，CDCl 3 )δ8.30(s，2H)，6.85(s，2H)，3.43(s，2H)，1.90(d，J＝7.4Hz，2H)，1.79(d，J＝9.0Hz，1H)，1.54(d，J＝9.0Hz，1H)，1.34-1.27(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝233.2，[M+NH 4 ] + ＝250.2。
example 11
Figure GPA0000287164670000161
40.0g of buffer (0.1mol/L NaH) was added to the reaction flask 2 PO 4 pH 8.0), 5.0g tetrahydrofuran, 5.0g compound (02-1) and 0.5g recombinant Escherichia coli esterase, stirring at 25 ℃, adjusting pH 8.0 with saturated sodium bicarbonate solution during the reaction, stirring for 4h, sampling and detecting, and stopping the reaction when the content of the compound (02-1) is less than 5%. The reaction system was extracted twice with 70ml ethyl acetate, the organic layer was washed with saturated sodium chloride and the organic layer was evaporated to dryness to give crude compound (03-1). The crude compound (03-1) was recrystallized from 20g of toluene to obtain compound (03-1): off-white solid, 3.4g, 80.9% yield, 81% ee; 1 H NMR(400MHz，CDCl 3 )δ6.64(d，J＝8.6Hz，1H)，6.54(d，J＝8.6Hz，1H)，4.69(s，1H)，3.52(d，J＝1.1Hz，1H)，3.32(d，J＝1.4Hz，1H)，2.29(s，3H)，1.88(ddd，J＝10.7，6.3，3.2Hz，2H)，1.75(d，J＝8.8Hz，1H)，1.51(d，J＝8.8Hz，1H)，1.45-1.41(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝219.1，[M+NH 4 ] + ＝236.1。
preparation of Compound (03-1) with different enzymes:
40.0g of buffer (0.1mol/L NaH) was added to the reaction flask 2 PO 4 pH 9.0), 20.0g ethanol, 5.0g compound (02-1) and 1.0g Pseudomonas cepacia lipase, stirring at 25 ℃, adjusting pH 9.0 with saturated sodium carbonate solution during the reaction, stirring for 4h, sampling and detecting, and stopping the reaction when the content of the compound (02-1) is less than 5%. The reaction system was extracted twice with 70ml ethyl acetate, the organic layer was washed with saturated sodium chloride and the organic layer was evaporated to dryness to give crude compound (03-1). The crude compound (03-1) was recrystallized from 20g of toluene to obtain compound (03-1): off-white solid, 3.3g, 78.8% yield, 65% ee; 1 H NMR(400MHz，CDCl 3 )δ6.64(d，J＝8.6Hz，1H)，6.54(d，J＝8.6Hz，1H)，4.69(s，1H)，3.52(d，J＝1.1Hz，1H)，3.32(d，J＝1.4Hz，1H)，2.29(s，3H)，1.88(ddd，J＝10.7，6.3，3.2Hz，2H)，1.75(d，J＝8.8Hz，1H)，1.51(d，J＝8.8Hz，1H)，1.45-1.41(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝219.1，[M+NH 4 ] + ＝236.1。
preparation of the enantiomer of compound (03-1) with different enzymes:
Figure GPA0000287164670000162
40.0g of buffer (0.1mol/L NaH) was added to the reaction flask 2 PO 4 Stirring at 25 ℃, adjusting the pH to 9.0 by using a saturated sodium carbonate solution during the reaction, stirring for 4h, sampling and detecting, and stopping the reaction when the content of the compound (02-1) is less than 5%. The reaction system was extracted twice with 70ml ethyl acetate, the organic layer was washed with saturated sodium chloride and the organic layer was evaporated to dryness to give crude compound (03-1). The crude compound (03-1) was recrystallized from 20g of toluene to obtain the enantiomer of the compound (03-1): off-white solid, 3.4g, yield 80.9%, ee value 70%; 1 H NMR(400MHz，CDCl 3 )δ6.64(d，J＝8.6Hz，1H)，6.54(d，J＝8.6Hz，1H)，4.69(s，1H)，3.52(d，J＝1.1Hz，1H)，3.32(d，J＝1.4Hz，1H)，2.29(s，3H)，1.88(ddd，J＝10.7，6.3，3.2Hz，2H)，1.75(d，J＝8.8Hz，1H)，1.51(d，J＝8.8Hz，1H)，1.45-1.41(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝219.1，[M+NH 4 ] + ＝236.1。
when the same conditions and procedures were used except that an Aspergillus fungal protease or Bacillus protease was used instead of the enzyme in example 11, respectively, the product was obtained as the major (03-1) enantiomer with ee values of 60% and 88%, respectively.
Example 12
Figure GPA0000287164670000171
40.0g of a buffer (0.2mol/L triethanolamine-HCl buffer salt, pH 6.0), 20.0g of methyl tert-butyl ether, 5.0g of compound (02-2) and 0.5g of Pseudomonas Fluorescens Lipase (PFL) were added to a reaction flask, and the reaction was stopped at 25 ℃ by stirring, adjusting the pH to 6.0 with a saturated sodium bicarbonate solution during the reaction, and sampling for 4 hours to detect that the content of compound (02-2) was less than 5%. The reaction system was extracted twice with 70ml ethyl acetate, the organic layer was washed with saturated sodium chloride, and the organic layer was evaporated to dryness under reduced pressure to give crude compound (03-2). The crude compound (03-2) was recrystallized from 10g of a solvent of n-hexane/ethyl acetate (6: 1) to give a compound (03-2): off-white solid, 3.4g, 84.6% yield, 95% ee; 1 H NMR(400MHz，CDCl 3 )δ6.61(d，J＝8.6Hz，1H)，6.47(d，J＝8.6Hz，1H)，3.52(d，J＝1.4Hz，1H)，3.29(d，J＝1.4Hz，1H)，2.59(q，J＝7.6Hz，2H)，1.94-1.76(m，2H)，1.73(d，J＝8.9Hz，1H)，1.48(d，J＝8.8Hz，1H)，1.33-1.20(m，5H)；MS(ESI，pos.ion)m/z：[M+H] + ＝233.1，[M+NH 4 ] + ＝250.1。
Figure GPA0000287164670000172
40.0g of buffer (0.1mol/L NaH) was added to the reaction flask 2 PO 4 pH 8.0), 20.0g isopropyl acetate, 5.0g compound (02-2) and 0.5g bacillus protease, stirring at 25 deg.C, adjusting pH 8.0 with saturated sodium bicarbonate solution during reaction, stirring for 4h, sampling and detecting, and stopping reaction when the content of compound (02-2) is less than 5%. The reaction system is extracted twice by 70ml isopropyl acetate, the organic layer is washed by saturated sodium chloride, and the organic layer is decompressed and evaporated to dryness to obtain a crude product of the enantiomer of the compound (03-2). The crude enantiomer of compound (03-2) was recrystallized from 10g by volume of cyclohexane to give the enantiomer of compound (03-2): off-white solid, 3.1g, 77.0% yield, 65% ee; 1 H NMR(400MHz，CDCl 3 )δ6.61(d，J＝8.6Hz，1H)，6.47(d，J＝8.6Hz，1H)，3.52(d，J＝1.4Hz，1H)，3.29(d，J＝1.4Hz，1H)，2.59(q，J＝7.6Hz，2H)，1.94-1.76(m，2H)，1.73(d，J＝8.9Hz，1H)，1.48(d，J＝8.8Hz，1H)，1.33-1.20(m，5H)；MS(ESI，pos.ion)m/z：[M+H] + ＝233.1，[M+NH 4 ] + ＝250.1。
when the lipase Novovirin 435 or the Aspergillus fungal protease, respectively, were used instead of the Pseudomonas Fluorescens Lipase (PFL) in example 12, otherwise the same conditions and procedures were used, a product was obtained that was predominantly the (03-2) enantiomer, with ee values of 40%, 47%, respectively.
Example 13
Figure GPA0000287164670000181
40.0g of buffer (0.1mol/L KH) was added to the reaction flask 2 PO 4 pH 7.0), 20.0g of ethyl acetate, 5.0g of the compound (02-4) and 0.3g of Thermomyces Lanuginosus Lipase (TLL) were stirred at 15 ℃, the pH was adjusted to 7.0 by a saturated sodium carbonate solution during the reaction, and sampling was carried out for 6 hours to detect that the content of the compound (02-4) was less than 5%, thereby stopping the reaction. The reaction system is extracted twice by 70ml ethyl acetate, the organic layer is washed by saturated sodium chloride and evaporated to dryness to obtain the compound (03-4) And (5) crude product. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate 4: 1, volume ratio) to give compound (03-4): colorless oil, 3.7g, 95.1% yield, 97% ee; 1 H NMR(400MHz，CDCl 3 )δ6.61(d，J＝8.6Hz，1H)，6.49(d，J＝8.6Hz，1H)，5.10(s，1H)，3.52(d，J＝1.2Hz，1H)，3.30(s，1H)，2.54(t，J＝7.4Hz，2H)，1.89-1.72(m，5H)，1.49(d，J＝8.8Hz，1H)，1.29-1.21(m，2H)，1.05(t，J＝7.4Hz，3H)；MS(ESI，pos.ion)m/z：[M+H] + ＝247.1，[M+NH 4 ] + ＝264.1。
when the lipase Novoxin 435, the Aspergillus fungal protease or the Bacillus protease, respectively, was used instead of Thermomyces Lanuginosus Lipase (TLL) of example 13, otherwise the same conditions and procedures were used, the products were obtained as predominantly the (03-4) enantiomer with ee values of 32%, 20%, 50%, respectively.
Example 14
Figure GPA0000287164670000182
40.0g of buffer (0.1M NaH) was added to the reaction flask 2 PO 4 Stirring at 35 ℃ with 20.0g of tetrahydrofuran, 5.0g of compound (02-5) and 0.8g of Pseudomonas Fluorescens Lipase (PFL), adjusting the pH to 9.0 with a sodium carbonate solution during the reaction, stirring for 8h, sampling and detecting, and stopping the reaction when the content of the compound (02-5) is less than 5%. The reaction system was extracted twice with 70ml of ethyl acetate, the organic layer was washed with saturated sodium chloride, and the organic layer was distilled under reduced pressure to give a crude compound (03-5). The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate 4: 1, volume ratio) to give compound (03-5): viscous liquid, 2.9g, 77.6% yield, 87% ee; 1 H NMR(400MHz，CDCl 3 )δ6.71(d，J＝8.6Hz，1H)，6.64(d，J＝8.6Hz，1H)，4.96(s，1H)，3.52(d，J＝1.1Hz，1H)，3.32(d，J＝1.4Hz，1H)，1.89-1.73(m，2H)，1.74(d，J＝8.8Hz，1H)，1.50(d，J＝8.8Hz，1H)，1.45-1.41(m，11H)；MS(ESI，pos.ion)m/z：[M+H] + ＝261.1，[M+NH 4 ] + ＝278.1。
when the lipase Novovirin 435, the Aspergillus fungal protease or the Bacillus protease, respectively, were used instead of the Pseudomonas Fluorescens Lipase (PFL) in example 14, otherwise the same conditions and procedures were used, a product was obtained which was predominantly the (03-5) enantiomer.
Example 15
Figure GPA0000287164670000191
40.0g of buffer (0.1mol/L glycine-sodium hydroxide buffer salt, pH 9.5), 20.0g of cyclohexane, 5.0g of compound (02-17) and 0.3g of Candida Rugosa Lipase (CRL) were added to a reaction flask, and the reaction was stopped at 10 ℃ by stirring, adjusting the pH to 9.5 with a sodium carbonate solution during the reaction, and sampling for 4 hours to detect that the content of compound (02-17) was less than 5%. The reaction system is extracted twice by 70ml ethyl acetate, the organic layer is washed by saturated sodium chloride, and the organic layer is decompressed and evaporated to dryness to obtain a crude product of the compound (03-17). The crude product was recrystallized from 20g of ethyl acetate/n-hexane (vol/vol) 1:10 to give compound (03-17): off-white solid, 3.2g, 83.2% yield, 90% ee; 1 H NMR(400MHz，CDCl 3 )δ6.65(d，J＝8.6Hz，1H)，6.49(d，J＝8.6Hz，1H)，5.35(s，1H)，4.32(s，2H)，3.55(s，3H)，3.52(d，J＝1.4Hz，1H)，3.30(d，J＝1.4Hz，1H)，1.95-1.78(m，2H)，1.74(d，J＝8.9Hz，1H)，1.49(d，J＝8.8Hz，1H)，1.30-1.21(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝249.3，[M+NH 4 ] + ＝266.3。
example 16
Figure GPA0000287164670000192
40.0g of buffer ((0.1mol/L NaH) was added to the reaction flask 2 PO 4 pH 9.5)), 40.0g isopropyl acetate, 5.0g compound (02-24) and 1.0g Candida Rugosa Lipase (CRL), stirring at 40 ℃, adjusting pH 9.5 with sodium carbonate aqueous solution during the reaction, stirring for 6h, and samplingAnd detecting that the content of the compound (02-24) is less than 5 percent to stop the reaction. Extracting the reaction system twice by using 70ml isopropyl acetate, washing an organic layer by using saturated sodium chloride, and evaporating the organic layer under reduced pressure to obtain a crude compound (03-24); the crude product was recrystallized from 20g of toluene to give compound (03-24): off-white solid, 2.7g, 74.8% yield, 40% ee; 1 H NMR(400MHz，CDCl 3 )δ8.32-8.23(m，2H)，7.62-7.59(m，1H)，7.55-7.50(m，2H)，6.87(d，J＝8.6Hz，1H)，6.65(d，J＝8.6Hz，1H)，6.05(s，1H)，3.54(d，J＝1.4Hz，1H)，3.33(d，J＝1.4Hz，1H)，2.03-1.80(m，3H)，1.78(d，J＝8.9Hz，1H)，1.32-1.23(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝281.1，[M+NH 4 ] + ＝298.1。
example 17
Figure GPA0000287164670000201
2.18g of the compound (03-1) and 30g of tetrahydrofuran were charged into a reaction flask, the temperature was lowered to 0 ℃ under nitrogen protection, 1.52g of triethylamine (1.5eq) was added, 2.10g of p-toluenesulfonyl chloride (1.1eq) was slowly added, stirring was carried out at 0 ℃ for 0.5h, and then reaction was carried out at room temperature for 1.5 h. 100ml of ice water was added to the reaction system, the tetrahydrofuran layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml) ＊ 2 times), the organic layers were combined and washed with saturated NaCl solution (20 ml) ＊ 2 times), reduced pressure evaporation to dryness to obtain a crude compound, and silica gel column chromatography (n-hexane: ethyl acetate: 8: 1, volume ratio) is performed on the crude compound to obtain a compound (04-1): 3.50g of a colorless oil, yield 94.1%. Detection of the resulting Compound (04-1): 1 H NMR(400MHz，CDCl 3 )δ7.73(d，J＝8.2Hz，2H)，7.31(d，J＝8.1Hz，2H)，6.75-6.64(m，2H)，3.29(d，J＝5.7Hz，2H)，2.44(s，3H)，2.29(s，3H)，1.85-1.67(m，2H)，1.51(d，J＝9.0Hz，1H)，1.39(d，J＝9.0Hz，1H)，1.29-1.14(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝373.0，[M+NH 4 ] + ＝390.1，[M+Na] + ＝395.1。
example 18
Figure GPA0000287164670000202
2.32g of the compound (03-2) and 30g of tetrahydrofuran were added to a reaction flask, the temperature was lowered to-10 ℃ under nitrogen protection, 2.69g of pyridine (3.4eq) was added, 4.23g of trifluoromethanesulfonic anhydride (1.5eq) was added dropwise in portions, stirred at-10 ℃ for 1 hour, and then reacted at room temperature for 1.5 hours. 100ml of ice water was added to the reaction system, the pH of the aqueous phase was adjusted to 3 with 4N hydrochloric acid, the tetrahydrofuran layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml) ＊ 2 times), the organic layers were combined and washed with saturated NaCl solution (20 ml) ＊ 2 times), and evaporated to dryness under reduced pressure to give an oil, which was subjected to silica gel column chromatography (n-hexane: ethyl acetate 50: 1, volume ratio) to give compound (04-2): 3.40g of a colorless oil, yield 93.3%. Detection of the resulting Compound (04-2): 1 H NMR(400MHz，CDCl 3 )δ6.96(d，J＝8.9Hz，1H)，6.84(d，J＝8.9Hz，1H)，3.65(d，J＝2.0Hz，1H)，3.38(d，J＝2.0Hz，1H)，2.62(q，J＝7.6Hz，2H)，1.95-1.80(m，3H)，1.58(d，J＝9.2Hz，1H)，1.31(dt，J＝15.1，7.5Hz，5H)；MS(ESI，pos.ion)m/z：[M+H] + ＝365.0，[M+Na] + ＝386.9。
example 19
Figure GPA0000287164670000211
2.32g of the compound (03-2) and 30g of tetrahydrofuran were charged into a reaction flask, and cooled to 0 ℃ under nitrogen, 1.52g of triethylamine (1.5eq) was added thereto, 1.37g of methanesulfonyl chloride (1.2eq) was slowly added thereto, stirred at 0 ℃ for 0.5h, and then reacted at room temperature for 1.5 hours. 100ml of ice water was added to the reaction system, the tetrahydrofuran layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml) ＊ 2 times), the organic layers were combined and washed with saturated NaCl solution (20 ml) ＊ 2 times), reduced pressure evaporation to dryness to obtain a crude product of the compound (04-3), and silica gel column chromatography is carried out on the crude product (n-hexane: ethyl acetate: 7: 1, volume ratio) to obtain the compound (04-3): 2.95g of a colorless oil, yield 95.2%. Formation ofDetection of Compound (04-3): 1 H NMR(400MHz，CDCl 3 )δ6.98(d，J＝8.8Hz，1H)，6.81(d，J＝8.8Hz，1H)，3.67(s，1H)，3.36(d，J＝1.7Hz，1H)，3.17(s，3H)，2.61(q，J＝7.6Hz，2H)，2.01-1.83(m，2H)，1.79(d，J＝9.0Hz，1H)，1.55(d，J＝9.0Hz，1H)，1.32(m，5H)；MS(ESI，pos.ion)m/z：[M+H] + ＝311.1，[M+NH 4 ] + ＝328.1，[M+Na] + ＝333.1。
example 20
Figure GPA0000287164670000212
Dissolving a compound (00) (5.0g, 28.7mmol, 1.0eq.) in 50g of ethyl acetate, adding DMAP (0.35g, 2.9mmol, 0.10eq.) and triethylamine (7.3g, 71.8mmol, 2.5eq.), cooling the reaction system to 0 ℃, dropwise adding acetic anhydride (6.4g, 63.1mmol, 2.2eq.), stirring at room temperature after dropwise adding, stirring the reaction mixture at room temperature for 4h, stopping the reaction, adding 50ml of water into the system, separating, extracting the water phase with 25ml of ethyl acetate, organically laminating, distilling under reduced pressure to obtain a crude product, and recrystallizing the crude product with 20g of cyclohexane to obtain a compound (02-32): 7.0g, off-white solid, yield 94.5%; 1H NMR (600MHz, CDCl) 3 )δ6.81(s，2H)，6.65(s，2H)，3.89(s，2H)，2.32(s，6H)，2.23(dd，J＝17.2，7.1Hz，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝259.1，[M+NH 4 ] + ＝276.1。
Example 21
Figure GPA0000287164670000221
Dissolving a compound (00) (5.0g, 28.7mmol, 1.0eq.) in 50g of ethyl acetate, adding DMAP (0.35g, 2.9mmol, 0.10eq.) and triethylamine (7.3g, 71.8mmol, 2.5eq.), cooling the reaction system to 0 ℃, dropwise adding propionic anhydride (9.3g, 63.1mmol, 2.2eq.) into the reaction system, stirring at room temperature after dropwise adding, stirring the reaction mixture at room temperature for 4h to stop the reaction, and stirring the reaction mixture at room temperature to obtain the final productTo the system, 50ml of water was added, liquid separation was performed, the aqueous phase was extracted with 25ml of ethyl acetate, organic layers were combined and distilled under reduced pressure to dryness to obtain a crude product, which was recrystallized from 22g of cyclohexane to obtain a compound (02-32): 7.9g, off-white solid, yield 96.1%; 1H NMR (400MHz, CDCl3) δ 6.80(s, 2H), 6.64(s, 2H), 3.87(s, 2H), 2.61(q, J ═ 7.6Hz, 4H), 2.22(dd, J ═ 16.2, 7.3Hz, 2H), 1.29(t, J ═ 7.6Hz, 6H); MS (ESI, pos. ion) m/z: [ M + H ]] + ＝287.1，[M+NH 4 ] + ＝304.1。
Example 22
Figure GPA0000287164670000222
40.0g of a buffer (0.1mol/L sodium dihydrogenphosphate-sodium hydroxide buffer salt, pH 7.5), 30.0g of ethyl acetate, 5.0g of the compound (02-31) and 0.5g of Pseudomonas Fluorescens Lipase (PFL) were added to a reaction flask, and the reaction was stopped by stirring at 20 ℃ while adjusting the pH to 7.5 with a saturated sodium bicarbonate solution, and sampling was carried out to detect that the content of the compound (02-31) was less than 5%. The reaction system is extracted twice by 30ml ethyl acetate, the organic layer is washed by saturated sodium chloride, and the organic layer is decompressed and evaporated to dryness to obtain a crude product of the compound (03-31). Subjecting the crude compound (03-31) to silica gel column chromatography (n-hexane: ethyl acetate 4: 1, volume ratio) to obtain compound (03-31): viscous liquid, 4.0g, yield 91.0%, ee value 50%; 1H NMR (400MHz, CDCl) 3 )δ8.30(s，1H)，6.69(d，J＝8.7Hz，1H)，6.56(d，J＝8.7Hz，1H)，4.92(s，1H)，3.55(d，J＝1.1Hz，1H)，3.39(d，J＝1.2Hz，1H)，1.97-1.81(m，2H)，1.75(d，J＝8.9Hz，1H)，1.52(d，J＝8.9Hz，1H)，1.26-1.22(m，2H)；MS(ESI，pos.ion)m/z：[M+H] + ＝205.2，[M+NH 4 ] + ＝222.2，[M+Na] + ＝227.2。
Example 23
Figure GPA0000287164670000231
40.0g of buffer was added to the reaction flask(0.1mol/L sodium dihydrogen phosphate-sodium hydroxide buffer salt, pH 7.5), 30.0g isopropyl acetate, 5.0g compound (02-32) and 0.5g Pseudomonas Fluorescens Lipase (PFL), stirring at 20 ℃, adjusting pH 7.5 with saturated sodium bicarbonate solution during the reaction, sampling and detecting, and stopping the reaction, wherein the content of the compound (02-32) is less than 5%. The reaction system is extracted twice by 30ml isopropyl acetate, the organic layer is washed by saturated sodium chloride, and the organic layer is decompressed and evaporated to dryness to obtain a crude product of the compound (03-32). Performing silica gel column chromatography (n-hexane: ethyl acetate: 4: 1, volume ratio) on the crude compound (03-32) to obtain a compound (03-32): viscous liquid, 3.9g, yield 93.2%, ee value 65%; 1H NMR (600MHz, CDCl3) δ 6.79(dt, J ═ 8.1, 5.1Hz, 2H), 6.50(d, J ═ 8.6Hz, 1H), 6.39(d, J ═ 8.6Hz, 1H), 5.12(d, J ═ 6.1Hz, 1H), 4.10(s, 1H), 3.86(s, 1H), 2.31(s, 3H), 2.25-2.17(m, 2H); MS (ESI, pos. ion) m/z: [ M + H ]] + ＝217.1，[M+NH 4 ] + ＝234.1。
Example 24
Figure GPA0000287164670000232
40.0g of a buffer (0.1mol/L sodium dihydrogenphosphate-sodium hydroxide buffer salt, pH 7.5), 30.0g of methyl t-butyl ether, 5.0g of the compound (02-33) and 0.5g of Pseudomonas Fluorescens Lipase (PFL) were added to a reaction flask, and the reaction was stopped at 20 ℃ by adjusting the pH to 7.5 with a saturated sodium bicarbonate solution during the reaction, and sampling was carried out to detect that the content of the compound (02-33) was less than 5%. The reaction system is extracted twice by 30ml methyl tert-ether, the organic layer is washed by saturated sodium chloride, and the organic layer is decompressed and evaporated to dryness to obtain a crude product of the compound (03-33). Subjecting the crude compound (03-33) to silica gel column chromatography (n-hexane: ethyl acetate 4: 1, volume ratio) to obtain a compound (03-33): white solid, 3.8g, 92.1% yield, 88% ee; 1H NMR (600MHz, CDCl) 3 )δ6.79(ddd，J＝8.0，5.1，3.3Hz，2H)，6.50(d，J＝8.6Hz，1H)，6.39(d，J＝8.6Hz，1H)，4.94(s，1H)，4.09(s，1H)，3.84(s，1H)，2.60(q，J＝7.6Hz，2H)，2.21(s，2H)，1.29(t，J＝7.6Hz，3H)；MS(ESI，pos.ion)m/z：[M+H] + ＝231.2，[M+NH 4 ] + ＝248.2。
Example 25
Figure GPA0000287164670000241
2.30g of the compound (03-33) and 30g of ethyl acetate were added to a reaction flask, the temperature was reduced to 0 ℃ under nitrogen protection, 1.52g of triethylamine (1.5eq) was added, 1.37g of methanesulfonyl chloride (1.2eq) was slowly added, the mixture was stirred at 0 ℃ for 0.5h, and then the reaction was carried out at room temperature for 3 hours. 100ml of ice water was added to the reaction system, an ethyl acetate layer was separated, and a water layer was extracted with ethyl acetate (20 ml) ＊ 2 times), the organic layers were combined and washed with saturated NaCl solution (20 ml) ＊ 2 times), reduced pressure evaporation to dryness to obtain a crude product of the compound (04-4), and silica gel column chromatography is carried out on the crude product (n-hexane: ethyl acetate: 5: 1, volume ratio) to obtain the compound (04-4): 2.9g of a colorless oil, yield 94.0%. Detection of the resulting Compound (04-4): 1H NMR (400MHz, CDCl) 3 )δ6.88-6.76(m，3H)，6.69(d，J＝8.8Hz，1H)，4.24(s，1H)，3.90(s，1H)，3.12(s，3H)，2.62(q，J＝7.6Hz，2H)，2.26(s，2H)，1.30(t，J＝7.6Hz，3H)；MS(ESI，pos.ion)m/z：[M+H] + ＝309.1，[M+NH 4 ] + ＝326.1，[M+Na] + ＝331.1。
Example 26
Figure GPA0000287164670000242
2.86g of the compound (02-33) and 30g of ethyl acetate were charged into a reaction flask, 500mg of 10% palladium on carbon was added under nitrogen protection, hydrogen was substituted three times, and then the reaction system was stirred under a hydrogen balloon atmosphere at room temperature and reacted at room temperature for 5 hours. Filtering the reaction solution, rinsing with 15g of ethyl acetate, combining the filtrates, and evaporating to dryness under reduced pressure to obtain a compound (02-2): 2.86g of a white solid, yield 99.3%. Detection of the resulting Compound (04-3): 1 H NMR(400MHz，CDCl 3 )δ6.77(s，2H)，3.33(s，2H)，2.60(q，J＝7.6Hz，4H)，1.85(d，J＝7.1Hz，2H)，1.78(d，J＝8.9Hz，1H)，1.50(d，J＝8.9Hz，1H)，1.36-1.31(m，2H)，1.28(t，J＝7.6Hz，6H)；MS(ESI，pos.ion)m/z：[M+H] + ＝289.1，[M+NH 4 ] + ＝306.1。
example 27
Figure GPA0000287164670000243
2.30g of the compound (03-33) and 30g of ethyl acetate were charged into a reaction flask, 450mg of 10% palladium on carbon was added under nitrogen protection, hydrogen was substituted three times, and then the reaction system was stirred under a hydrogen balloon atmosphere at room temperature and reacted at room temperature for 5 hours. Filtering the reaction liquid, leaching 15g of ethyl acetate, combining the filtrates, and evaporating to dryness under reduced pressure to obtain a compound (03-2): 2.30g of a white solid, yield 99.1%. Detection of the resulting Compound (03-2): 1H NMR (600MHz, CDCl3) δ 6.79(ddd, J ═ 8.0, 5.1, 3.3Hz, 2H), 6.50(d, J ═ 8.6Hz, 1H), 6.39(d, J ═ 8.6Hz, 1H), 4.94(s, 1H), 4.09(s, 1H), 3.84(s, 1H), 2.60(q, J ═ 7.6Hz, 2H), 2.21(s, 2H), 1.29(t, J ═ 7.6Hz, 3H); MS (ESI, pos. ion) m/z: [ M + H ]] + ＝231.2，[M+NH 4 ] + ＝248.2。
Example 28
Figure GPA0000287164670000251
2.0g of the compound (04-4) and 30g of ethyl acetate were added to a reaction flask, 400mg of 10% palladium on carbon was added under nitrogen protection, hydrogen was substituted three times, and then the reaction system was stirred under a hydrogen balloon atmosphere at room temperature and reacted at room temperature for 5 hours. Filtering the reaction solution, rinsing with 15g of ethyl acetate, combining the filtrates, and evaporating to dryness under reduced pressure to obtain a compound (04-3): 2.0g of a colorless liquid, yield 99.5%. Detection of the resulting Compound (04-3): 1 H NMR(400MHz，CDCl 3 )δ6.98(d，J＝8.8Hz，1H)，6.81(d，J＝8.8Hz，1H)，3.67(s，1H)，3.36(d，J＝1.7Hz，1H)，3.17(s，3H)，2.61(q，J＝7.6Hz，2H)，2.01-1.83(m，2H)，1.79(d，J＝9.0Hz，1H)，1.55(d，J＝9.0Hz，1H)，1.32(m，5H)；MS(ESI，pos.ion)m/z：[M+H] + ＝311.1，[M+NH 4 ] + ＝328.1，[M+Na] + ＝333.1。
while the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (16)

1. A process for preparing a compound of formula (03), or an enantiomer thereof, comprising: reacting the compound shown in the formula (02) under the action of enzyme to obtain the compound shown in the formula (03) or an enantiomer thereof,
Figure FDA0003696896880000011
wherein, the first and the second end of the pipe are connected with each other,
the dotted line represents a bond or is absent;
r is hydrogen, or R is C1-C20 linear or branched alkyl, methoxymethyl, methoxyethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, C3-C10 cycloalkyl, phenyl, benzyl, phenethyl, phenylpropyl or C1-C6 alkoxy, and hydrogen in the R group is optionally substituted by halogen;
the enzyme is recombinant escherichia coli esterase, candida rugosa lipase, pseudomonas fluorescens lipase, pseudomonas cepacia lipase or thermomyces lanuginosus lipase to obtain a compound shown in a formula (03); the enzyme is lipase Novixin 435, Aspergillus fungal protease, or Bacillus protease, and the enantiomer of formula (03) is obtained.
2. A method of preparing a compound of formula (04) or an enantiomer thereof, comprising: preparing a compound represented by formula (03) or an enantiomer thereof according to the method of claim 1, sulfonating the compound represented by formula (03) or the enantiomer thereof prepared according to the method of claim 1 with a sulfonating agent to obtain a compound represented by formula (04) or an enantiomer thereof,
Figure FDA0003696896880000012
wherein the dotted line represents a bond or is absent; r is hydrogen, or R is C1-C20 linear or branched alkyl, methoxymethyl, methoxyethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 5-chloropentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, C3-C10 cycloalkyl, phenyl, benzyl, phenethyl, phenylpropyl or C1-C6 alkoxy, the hydrogen in the R group being optionally substituted by halogen; r 2 Is methyl, trifluoromethyl, phenyl or p-methylphenyl.
3. The method of claim 1, further comprising: carrying out esterification reaction on the compound shown in the formula (01) and carboxylic acid, acyl chloride or acid anhydride to obtain a compound shown in the formula (02),
Figure FDA0003696896880000021
4. the method according to claim 1, wherein the mass ratio of the enzyme to the compound (02) is 0:1 to 10.0: 1.
5. The method according to claim 1, wherein a buffer is added, the mass ratio of the buffer to the compound (02) is 0:1 to 50.0:1, and the buffer concentration is 0 to 1.0 mol/L.
6. The method of claim 1, wherein a buffer is added, the buffer being selected from at least one of a sodium dihydrogen phosphate-citric acid buffer, a citric acid-sodium citrate buffer, a triethanolamine-hydrochloric acid buffer, a sodium dihydrogen phosphate-sodium hydroxide buffer, a sodium dihydrogen phosphate-potassium dihydrogen phosphate buffer, a potassium dihydrogen phosphate-sodium hydroxide buffer, a boric acid-borax buffer, a glycine-sodium hydroxide buffer, a sodium carbonate-sodium bicarbonate buffer, and a sodium bicarbonate-sodium hydroxide buffer.
7. The method according to claim 1, wherein a buffer is added, and the pH of the buffer is 3.0 to 12.0.
8. The method according to claim 1, wherein a cosolvent is added, and the mass ratio of the cosolvent to the compound (02) is 0: 1-50.0: 1.
9. The method of claim 1, wherein a co-solvent is added, the co-solvent being selected from at least one of dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, methyl cyclopentyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, acetone, butanone, methyl isobutyl ketone, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, N-pentane, N-hexane, N-heptane, N-octane, heptane, cyclohexane, methanol, ethanol, N-propanol, isopropanol, N-butanol, and t-butanol.
10. The process of claim 1, wherein the reaction is carried out at-10 ℃ to 80 ℃.
11. The process according to claim 3, wherein the molar ratio of the compound represented by the formula (01) to the carboxylic acid, acid chloride or acid anhydride is from 1:1.2 to 1: 10.
12. The process according to claim 3, wherein the reaction solvent in the esterification reaction is at least one selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, isopropyl ether, methylcyclopentyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, N-pentane, N-hexane, N-heptane, N-octane, heptane and cyclohexane.
13. The method of claim 3, wherein an acid-binding agent is added in the esterification reaction, the molar ratio of the acid-binding agent to the compound represented by the formula (01) is 1.2: 1-10: 1, and the acid-binding agent is selected from at least one of pyridine, trimethylamine, triethylamine, N-diisopropylethylamine, N-methylmorpholine and N, N-dimethylaminopyridine.
14. The process of claim 3, wherein the esterification reaction is carried out at a temperature of from 0 ℃ to 80 ℃.
15. The process of any of claims 1-14, wherein the dotted line is absent and R is hydrogen, ethyl, n-propyl, isopropyl, n-butyl, pivaloyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, n-octadecyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 5-chloropentyl, phenyl, benzyl, phenethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
16. The process of any one of claims 1 to 14, wherein the dotted line is a bond and R is hydrogen, methyl, n-propyl, isopropyl, n-butyl, tert-butyl, pivaloyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 5-chloropentyl, phenyl, benzyl, phenethyl, phenylpropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
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