CN107540564B

CN107540564B - Preparation method of Vorapaxar intermediate

Info

Publication number: CN107540564B
Application number: CN201610480060.7A
Authority: CN
Inventors: 刘飞; 刘彦龙; 丰巍伟; 王小宁; 胡中元
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2016-06-27
Filing date: 2016-06-27
Publication date: 2020-05-22
Anticipated expiration: 2036-06-27
Also published as: CN107540564A

Abstract

The invention belongs to the field of organic synthesis and drug synthesis, and relates to a preparation method of an intermediate of Vorapaxar. The preparation method comprises the steps of reacting racemic (E) -3- (5-aminocyclohex-1-en-1-yl) acrylic acid or ester compounds thereof with D-malic acid, splitting to obtain optically pure (R, E) -3- (5-aminocyclohex-1-en-1-yl) acrylic acid or ester D-malate, converting the compound into (R, E) -3- (5- ((ethoxycarbonyl) amino) cyclohex-1-en-1-yl) acrylic acid, and converting the intermediate into a subsequent intermediate of the Volapapsa. Compared with the method in the prior art, the preparation method provided by the invention has the advantages that the yield is obviously improved, the raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, the reaction reagent is environment-friendly, is obviously superior to the prior art, and is particularly suitable for industrial production.

Description

Preparation method of Vorapaxar intermediate

Technical Field

The invention belongs to the field of organic synthesis and drug synthesis, and relates to a preparation method of an intermediate of Vorapaxar (Vorapaxar).

Background

Vorapaxate (Vorapaxar) is a protease activated receptor-1 (PAR-1) antagonist developed by mershato, marketed in the united states under the trade name zontivty, in oral tablets containing 2.5mg of vorapax sulfate per tablet, for the reduction of thrombotic cardiovascular events in patients with either Myocardial Infarction (MI) or Peripheral Arterial Disease (PAD).

The chemical name of the valapasha sulfate is as follows: n- [ (1R,3aR,4aR,6R,8aR,9S,9aS) -9- [ (1E) -2- [5- (3-fluorobenzene) -2-pyridyl ] vinyl ] dodecahydro-1-methyl-3-oxonaphthalen [2,3-c ] furan-6-yl ] -carbamic acid ethyl ester sulfate, the chemical structural formula of which is shown in the specification

The Vorapaxar contains a plurality of chiral centers, so that in the synthesis process, a certain racemic intermediate obtained by reaction needs to be separated to obtain an optically pure intermediate compound for further subsequent reaction.

CN101137636A discloses the following method:

in the method, the intermediate 1 is prepared into the intermediate 2, and the following reaction process steps are carried out: 1) reacting the intermediate 1 with p-toluenesulfonic acid for 20 hours; 2) with NaCNBH₃Reacting for 2 days; 3) reacting with ethyl chloroformate to obtain racemic intermediate 2, resolving racemic intermediate 2 by preparative chiral HPLC to obtain intermediate 2, and performing subsequent reaction on intermediate 2 to obtain intermediate 8. The method is complex to operate and long in reaction time, the yield of the obtained racemic intermediate 2 is only 26%, and the racemic product needs to be further resolved by preparative chiral HPLC, so that the method is difficult to adapt to industrial production.

Aiming at the existing process defects, a process technology which is simple in process, green and environment-friendly, high in yield and purity and suitable for industrial production is developed, and the method has important practical significance for the synthesis of the Vorapa sand and the improvement of economic and social benefits.

Disclosure of Invention

In one aspect, the present invention provides a process for the preparation of a compound of formula ii, comprising: reacting the compound shown in the formula I with D-malic acid in the presence of a solvent to obtain a compound shown in the formula II,

wherein R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more of the following substituents: halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio and aryl or heteroaryl optionally substituted by one or more of halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio;

preferably, R is selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio and aryl or heteroaryl optionally substituted by one or more of halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio;

more preferably, R is selected from C₁-C₆Alkyl, allyl or benzyl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halogen substituted C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy and halogen substituted C₁-C₆An alkoxy group;

most preferably, R is selected from C₁-C₄Alkyl, allyl or benzyl, wherein the above radicals are optionalSubstituted with one or more of the following substituents: halogen, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and C₁-C₄An alkoxy group.

In some embodiments of the invention, R is selected from ethyl; when R is selected from ethyl, the compound of the formula I is a compound of a formula Ia, and the compound of the formula II is a compound of a formula IIa

Wherein the solvent is selected from one or more of alcohol and ketone, preferably alcohol or mixed solvent of alcohol and ketone, more preferably mixed solvent of one alcohol and one ketone; when the solvent is selected from a mixed solvent of an alcohol and a ketone, the volume ratio may be not less than 1, or may be less than 1, and for example, may be 0.1 to 10: 1, preferably 0.5 to 5: 1, more preferably 0.5 to 1.5: 1; in some embodiments of the invention, the volume ratio is 1.5: 1. 1:1 or 0.67: 1.

wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol, preferably methanol or ethanol; wherein the ketone is selected from acetone, butanone, pentanone, cyclopentanone, hexanone or cyclohexanone, preferably acetone.

In some embodiments of the present invention, the solvent is selected from one or more of methanol, ethanol and acetone, preferably methanol, ethanol, a mixed solvent of methanol and acetone or a mixed solvent of ethanol and acetone.

In some embodiments of the present invention, the solvent is a mixed solvent of methanol and acetone, wherein the volume ratio of methanol to acetone may be not less than 1, or less than 1, for example, the volume ratio may be 0.1 to 10: 1, preferably 0.5 to 5: 1, more preferably 0.5 to 1.5: 1; in some embodiments of the invention, the volume ratio of methanol to acetone is 1.5: 1. 1:1 or 0.67: 1.

in other embodiments of the present invention, the solvent is a mixed solvent of ethanol and acetone, wherein the ethanol and acetone may be selected according to the requirement in a suitable volume ratio, and the volume ratio may be not less than 1, or less than 1, for example, the volume ratio may be 0.1 to 10: 1, preferably 0.5 to 5: 1, more preferably 0.5 to 1: 1; in some embodiments of the invention, the volume ratio of ethanol to acetone is 1:1 or 0.67: 1.

wherein the molar ratio of the D-malic acid to the compound of formula I can be selected as required, for example, the molar ratio of the D-malic acid to the compound of formula I is not less than 1; in some embodiments of the invention, the molar ratio of D-malic acid to the compound of formula i is 1: 1.

Wherein the compound of formula II is prepared by selecting a suitable reaction temperature as desired, in some embodiments of the present invention, the reaction temperature is from 0 ℃ to the boiling point of the reaction system, preferably from 25 ℃ to the boiling point of the reaction system; in some embodiments of the invention, the reaction temperature is first raised to no greater than the boiling point of the reaction system and then lowered to 25 ℃; in some embodiments of the invention, the reaction temperature is raised to 60 ℃ and then lowered to 25 ℃

The reaction time of the compound of formula ii may be selected as desired, and may be, for example, within 48 hours, within 24 hours, or not less than 1 hour, and in some embodiments of the present invention, the reaction time is 2 to 5 hours.

Wherein the preparation of the compound of formula ii may further comprise the step of separating the compound of formula ii obtained from the reaction and treating with a second solvent selected from alcohols, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol, preferably methanol; wherein the treatment with the second solvent comprises separating the compound of formula II obtained by the reaction, mixing with the second solvent, and then separating the compound of formula II. The separation may be, for example, filtration.

Wherein the preparation of the compound of formula ii may further comprise a step of crystallizing the compound of formula ii as required, for example, in some embodiments of the present invention, the compound of formula ii is crystallized in a mixed solvent of an alcohol and water, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol, preferably ethanol. The volume ratio of the alcohol to the water can be selected according to the requirement, and the volume ratio can be not less than 1, and can also be less than 1, for example, the volume ratio can be 0.1-10: in some embodiments of the invention, the alcohol and water volume ratio is 9: 1.

wherein the optical purity of the compound of formula II is not less than 70%, preferably not less than 80%, more preferably not less than 90%, and most preferably not less than 95%, and in some embodiments of the invention, the optical purity of the compound of formula II is not less than 98%.

Preferably, the preparation of the compound of formula ii comprises the steps of:

(1) mixing the compound of formula I with a solvent;

(2) mixing the D-malic acid with a solvent;

(3) reacting the mixture of the step (1) and the mixture of the step (2).

Wherein the solvent in the step (1) is selected from one or more of alcohol and ketone, preferably alcohol or a mixed solvent of alcohol and ketone, and more preferably a mixed solvent of alcohol and ketone; wherein the alcohols and ketones are as previously defined;

wherein the solvent of step (2) is selected from alcohols; wherein the alcohol is as defined above;

wherein step (1) is carried out under heating conditions, in some embodiments of the invention, to no greater than the boiling point of the system; in some embodiments of the invention, heating is to 60 ℃;

wherein step (3) is carried out under heating conditions, in some embodiments of the invention, to no greater than the boiling point of the system; the heating condition may be selected as appropriate, and for example, the reaction time may be within 24 hours, or not less than 1 hour, for example, in some embodiments of the present invention, the reaction time is 2 hours.

Wherein step (3) continues the reaction by decreasing the temperature after heating, and in some embodiments of the invention continues the reaction after decreasing the temperature to room temperature; after the temperature is reduced, a suitable time for continuing the reaction can be selected according to needs, for example, within 24 hours, or not less than 1 hour; in some embodiments of the invention, the time for continuing the reaction is 3 hours.

In another aspect, the present invention provides a process for the preparation of a compound of formula I, comprising: reacting the compound of formula I-1 to obtain the compound of formula I,

wherein R is as previously defined, and in some embodiments of the invention R is selected from ethyl; when R is selected from ethyl, the compound of the formula I is a compound of a formula I-1a, and the compound of the formula II is a compound of a formula Ia

The compound of formula I can be prepared by selecting a suitable reducing agent according to the need, such as metal (e.g. zinc, iron, etc.), hydrogen, stannous chloride, lithium aluminum hydride, sodium borohydride, diborane or aluminum isopropoxide, etc., preferably stannous chloride.

Wherein, the molar ratio of the reducing agent to the compound of formula I can be selected as required, and can be not less than 1, and can also be less than 1, preferably, the molar ratio of the reducing agent to the compound of formula I is not less than 1; in some embodiments of the invention, the molar ratio of reducing agent to compound of formula i is 4: 1.

wherein the compound of formula I can be prepared by selecting a suitable solvent according to the need, wherein the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, and preferably ethyl acetate.

Wherein the compound of formula I is prepared by selecting a suitable reaction temperature as desired, in some embodiments of the invention, the reaction temperature is from 0 ℃ to the boiling point of the reaction system; in some embodiments of the invention, the reaction temperature is 75 ℃.

The reaction time of the compound of formula i may be selected as desired, and may be, for example, within 48 hours, within 24 hours, or not less than 1 hour, and in some embodiments of the present invention, the reaction time is 3 to 5 hours.

Wherein the preparation of the compound of formula I further comprises the steps of:

(1) after the reaction is finished, adding water and an organic solvent which is not miscible with water;

(2) adding a base to bring the pH of the aqueous layer to greater than 7;

(3) the organic layer was separated and concentrated to dryness.

Wherein the organic solvent immiscible with water in the step (1) comprises but is not limited to one or more mixed solvents of ethyl ether, isopropyl ether, dichloromethane, ethyl acetate or butyl acetate, and preferably ethyl acetate;

wherein the base of step (2) is selected from inorganic bases, examples of which include sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate or potassium bicarbonate; in some embodiments of the invention, the base is selected from potassium carbonate.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula I-1, comprising: reacting the compound of formula I-0 with ROH to obtain a compound of formula I-1,

wherein R is as defined above and R is not hydrogen; in some embodiments of the invention, R is selected from ethyl, ROH is selected from ethanol; when R is selected from ethyl, the compound of formula I-1 is a compound of formula I-1a

Wherein the preparation of the compound of formula I-1 is carried out in the presence of an acid, which may be various organic and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid or citric acid, etc., as long as the above reaction can be carried out; in some embodiments of the invention, the acid is sulfuric acid.

Wherein the compound of formula I-1 is prepared by selecting an appropriate reaction temperature as desired, in some embodiments of the present invention, the reaction temperature is from 0 ℃ to the boiling point of the reaction system; in some embodiments of the invention, the reaction temperature is 75 ℃.

Wherein the compound of formula I-1 can be prepared by selecting a suitable reaction time according to the need, for example, within 48 hours, within 24 hours, or not less than 1 hour, and in some embodiments of the present invention, the reaction time is 6 to 10 hours.

Wherein the compound of formula I-0 is commercially available, or can be prepared by methods known in the art, for example by the method of example 1 in CN 101193880A.

In another aspect, the present invention provides a process for the preparation of a compound of formula iii, comprising: converting the compound of formula II and ethyl chloroformate into a compound of formula III;

wherein R is as previously defined, and in some embodiments of the invention R is selected from ethyl; when R is selected from ethyl, the compound of the formula II is a compound of a formula IIa, and the compound of the formula III is a compound of a formula IIIa

Wherein the conversion is carried out by reacting the compound of formula II with a base and then with ethyl chloroformate.

The alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium N-propoxide, sodium isopropoxide, sodium N-butoxide, sodium t-butoxide, N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, N-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate or potassium bicarbonate, and preferably potassium carbonate.

Wherein, the mole ratio of the ethyl chloroformate to the compound of formula II can be selected as required, and can be not less than 1, and also can be less than 1, preferably, the mole ratio of the ethyl chloroformate to the compound of formula II is not less than 1; in some embodiments of the invention, the molar ratio of ethyl chloroformate to compound of formula II is 1.05: 1.

wherein the conversion or reaction may be selected as desired at a suitable temperature, in some embodiments of the invention, from 0 ℃ to the boiling point of the reaction system; in some embodiments of the invention, the temperature is 25 ℃.

The compound of formula iii can be prepared by selecting a suitable solvent as required, wherein the solvent is one or more selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, and DMSO, and preferably ethanol.

In yet another aspect, the present invention provides a process for preparing a compound of formula iv, comprising: reacting the compound shown in the formula III to obtain a compound shown in the formula IV,

wherein R is as defined above and R is not hydrogen; in some embodiments of the invention, R is selected from ethyl; when R is selected from ethyl, the compound of formula III is a compound of formula IIIa

Wherein the preparation of the compound of formula IV is carried out in the presence of a base selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium N-propoxide, sodium isopropoxide, sodium N-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, N-butyllithium, lithium tert-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate or potassium bicarbonate, preferably sodium hydroxide.

Wherein the compound of formula IV can be prepared by selecting a suitable solvent according to requirements, wherein the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, and preferably ethanol.

Wherein the compound of formula IV can be prepared by selecting a suitable reaction temperature as required, in some embodiments of the present invention, the reaction temperature is from 0 ℃ to the boiling point of the reaction system, preferably from 25 ℃ to 75 ℃; in some embodiments of the invention, the reaction temperature is 45 ℃.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula VI comprising: converting the compound of formula IV and the compound of formula V into the compound of formula VI,

wherein the molar ratio of the compound of formula V to the compound of formula IV can be selected as required, and can be not less than 1, and also can be less than 1, preferably, the molar ratio of the compound of formula V to the compound of formula IV is not less than 1; in some embodiments of the invention, the molar ratio of the compound of formula v to the compound of formula iv is 1.1: 1.

wherein the transformation comprises the steps of:

(1) converting the compound of formula iv to an anhydride;

(2) and (2) reacting the anhydride obtained in the step (1) with a compound shown in the formula V to obtain a compound shown in the formula VI.

Wherein the conversion of step (1) is carried out by reacting a compound of formula IV with pivaloyl chloride.

Wherein the mole ratio of pivaloyl chloride to the compound of formula iv can be selected as appropriate, and can be not less than 1, and can also be less than 1, preferably, the mole ratio of pivaloyl chloride to the compound of formula iv is not less than 1, for example, in some embodiments of the invention, the mole ratio of pivaloyl chloride to the compound of formula iv is 1.05: 1.

it will be appreciated that step (1) may be optionally converted to the appropriate acid anhydride as required, provided that the anhydride is capable of reacting with the compound of formula V to give the compound of formula VI.

Wherein, the transformation in step (1) can select a suitable base according to requirements, and the base is selected from one or more of N-methylmorpholine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium N-propoxide, sodium isopropoxide, sodium N-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, N-butyllithium, lithium tert-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate or potassium bicarbonate, and is preferably N-methylmorpholine.

Wherein, in step (1), a suitable solvent can be selected according to requirements, and the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, and is preferably tetrahydrofuran.

Wherein the conversion in step (1) may be carried out at a temperature selected from-20 to 20 ℃, preferably-10 to 10 ℃, most preferably-5 to 0 ℃ as desired.

Wherein, in step (2), a suitable solvent can be selected according to requirements, and the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, and is preferably tetrahydrofuran.

Wherein the step (2) can select a proper reaction temperature according to the requirement, and the temperature is selected from-20-20 ℃, preferably-10-10 ℃, and most preferably 0-5 ℃.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula vii, comprising: the compound of the formula VI is subjected to reduction reaction to obtain a compound of a formula VII,

wherein the reaction is carried out in the presence of palladium, a catalytic inhibitor and a hydrogen source; wherein the palladium is Pd/CaCO₃Or Pd/BaSO₄In the form of palladium, the palladium content is generally from 5% to 10% (parts by weight); wherein the hydrogen source can be hydrogen; wherein the catalytic inhibitor is selected from lead acetate, lead oxide or quinoline.

In some embodiments of the invention, the reaction is at 5% Pd/CaCO₃Quinoline and hydrogen.

Wherein the compound of formula VII can be prepared by selecting a suitable solvent as required, wherein the solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1, 4-dioxane, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably ethyl acetate.

Wherein the reaction may be carried out at a temperature selected from the range of 0 to 30 deg.C, preferably 5 to 20 deg.C, and in some embodiments of the invention, the reaction temperature is 15 deg.C.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula viii, comprising: reacting the compound shown in the formula VII to obtain a compound shown in the formula VIII,

wherein the solvent is selected from N-methyl pyrrolidone.

Wherein the reaction comprises the steps of heating the compound shown in the formula VII for reaction, and then reducing the temperature to continue the reaction in the presence of alkali.

Wherein the heating reaction can select proper heating temperature according to the requirement, and the heating temperature is not more than the boiling point of the reaction system; in some embodiments of the invention, the heating temperature is 140 ℃; after heating for a period of time, the reaction temperature may be reduced to a suitable temperature, as desired, in some embodiments of the invention, to 40 ℃.

Wherein the reaction may be carried out with the selection of a suitable base as desired, in some embodiments of the invention the base is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

The heating reaction may be carried out for a suitable time, for example, within 48 hours, within 24 hours, or not less than 1 hour, and in some embodiments of the present invention, the reaction time is 6 hours.

The reaction time can be within 48 hours, 24 hours or not less than 1 hour, and in some embodiments of the invention, the reaction time is 10 hours.

In a further aspect, the present invention provides a process for the preparation of a compound of formula VIII comprising the steps of:

(1) reacting the compound shown in the formula I with D-malic acid in the presence of a solvent to obtain a compound shown in the formula II,

(2) converting the compound of the formula II and ethyl chloroformate into a compound of a formula III,

(3) reacting the compound shown in the formula III to obtain a compound shown in the formula IV,

(4) converting the compound of formula IV and the compound of formula V into the compound of formula VI,

(5) the compound of the formula VI is subjected to reduction reaction to obtain a compound of a formula VII,

(6) reacting the compound shown in the formula VII to obtain a compound shown in the formula VIII,

wherein R is as defined above, and when R is hydrogen, the compound of formula III is the same compound as the compound of formula IV, and step (3) is absent.

In a further aspect, the present invention provides a compound of formula I or a salt or solvate thereof, a compound of formula II or a solvate thereof,

most preferably, R is selected from C₁-C₄Alkyl, allyl or benzyl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and C₁-C₄An alkoxy group.

In some embodiments of the invention, R is selected from ethyl.

In a further aspect, the present invention provides a compound of formula III or a solvate thereof,

wherein R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more of the following substituents: halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio and aryl or heteroaryl optionally substituted by one or more of halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio;

preferably, R is selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, lower alkyl, halogen-substituted lower alkylAlkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen-substituted lower alkylthio and aryl or heteroaryl optionally substituted with one or more of halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio;

In some embodiments of the invention, R is selected from ethyl.

In a further aspect, the present invention provides the use of a compound of formula I or a salt or solvate thereof, a compound of formula II or a solvate thereof, a compound of formula III or a solvate thereof, in the preparation of (R, E) -3- (5- ((ethoxycarbonyl) amino) cyclohex-1-en-1-yl) acrylic acid (a compound of formula IV).

Related definition

Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls. If a URL or other such identifier or address is referenced, it will be appreciated that such identifier may change, freeing up specific information on the Internet, but finding the corresponding information may be done by searching the Internet or other suitable reference resource. The citation herein indicates the availability and public dissemination of such information.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.

Unless otherwise indicated, the use of general chemical terms such as, but not limited to, "alkyl" and "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" as defined below refers to "alkyl" or "substituted alkyl". Furthermore, the optionally substituted group may be unsubstituted (e.g. CH)₂CH₃) Completely substituted (e.g. CF)₂CF₃) Monosubstituted (e.g. CH)₂CH₂F) Or a degree of substitution between fully and mono-substituted (e.g. CH)₂CHF₂、CF₂CH₃、CFHCHF₂Etc.).

As used herein C₁-C_nComprising C₁-C₂、C₁-C₃、……C₁-C_n. For example, the "C" is₁-C₄By "group" is meant a moiety having 1 to 4 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms, C₁-C₂And C₁-C₃As well as the same. Thus, for example, "C₁-C₄Alkyl "means having 1-4 carbonsAn atomic alkyl group, i.e. the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Herein, a numerical range, such as "1 to 10" refers to each integer in the given range, such as "1 to 10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The term "hetero", as used herein, alone or in combination, refers to an atom other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent saturated hydrocarbon. The "alkyl" groups herein may have from 1 to about 18 carbon atoms, or from 1 to about 10 carbon atoms, preferably from 1 to 6 carbon atoms. "lower alkyl" as used herein, alone or in combination, refers to a lower carbon number alkyl group, e.g., having from 1 to about 8 carbon atoms, preferably from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-methyl-l-pentyl, 2-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-methyl-l-pentyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl and octyl, and the like. When numerical ranges appear herein, e.g. "C₁-C₆Alkyl "or" C_1-6Alkyl "refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkyl groups herein also includeThe case of designating numerical ranges.

"alkyl" as used in combination herein includes, but is not limited to, "alkyl" as contained in "alkoxy", "alkylthio", "mono-alkylamino" and "di-alkylamino" and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent hydrocarbon having one or more carbon-carbon double bonds. The alkenyl group, for example, has from 2 to about 18 carbon atoms, or from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans configuration and should be understood to encompass both isomers. "lower alkenyl" as used herein, alone or in combination, refers to alkenyl groups having a relatively small number of carbon atoms, e.g., from 2 to about 8 carbon atoms, preferably from 2 to about 6 carbon atoms, or from 2 to about 4 carbon atoms. Examples include, but are not limited to, ethenyl (-CH ═ CH)₂) 1-propenyl (-CH)₂CH＝CH₂) Isopropenyl (-C (CH)₃)＝CH₂) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C₂-C₆Alkenyl "or" C_2-6The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.

The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent hydrocarbon having one or more carbon-carbon triple bonds. For example, the alkynyl group has 2 to about 18 carbon atoms or 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. "lower alkynyl" as used herein, alone or in combination, refers to alkynyl groups of relatively small carbon number, e.g., having from 2 to about 8 carbon atoms, preferably from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C₂-C₆Alkynyl "or" C₂-₆Alkynyl means a group that can be substituted with 2,3, 4, 5, or 6 carbon atomsAlkynyl groups, where alkynyl is not a member of the group, also encompass embodiments where no numerical range is specified.

The term "member" refers to the number of backbone atoms that make up the ring. Thus, for example, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.

The term "cycloalkyl", as used herein, alone or in combination, refers to an optionally substituted monovalent saturated hydrocarbon ring containing from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms, and may also include as substituents other non-ring-forming carbon atoms (e.g., methylcyclopropyl). The cycloalkyl group may have 3 to about 10 or 3 to about 8 or 3 to about 6 or 3 to 5 ring-forming atoms, and examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

The term "lower cycloalkyl" as used herein, alone or in combination, refers to a cycloalkyl group having a relatively small number of ring-forming atoms, e.g., containing from 5 to about 10 or from 5 to about 6 or from 5 to 6 ring-forming atoms or from 3 to 6 ring-forming atoms, e.g., having 3, 4, 5 or 6 ring-forming atoms.

Non-limiting examples of "heterocycloalkyl" include azinyl (azinyl), azetidinyl (azidinyl), oxetanyl (oxolanyl), thietanyl, homopiperidinyl (homopiperidinyl), oxepanyl (oxepanyl), thiepinyl (oxazepinyl), diazepinyl (diazepinyl), azepinyl (thiazepinyl), 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl (dioxanyl), 1,3-dioxolanyl (1, 3-dioxanyl), pyrazolinyl, dithiocyclohexyl (dithianyl), dithiocyclopentyl (dithiolanyl), dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolidinyl (pyrazolidinyl), imidazolidinylidinyl (pyrazolidinyl), pyrazolidinyl (oxolanyl), thiodinyl (oxadinyl), oxazepinyl (oxadinyl), thiodinyl (oxadinyl), 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, quinolizinyl, and the like. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides.

The term "aryl" as used herein, alone or in combination, refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, most preferably having 6 carbon atoms. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" as used herein, alone or in combination, refers to a monocyclic or fused ring of 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1,2,3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkoxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group, an O-alkyl group, which includes O-aliphatic groups and O-carbocyclic groups, wherein the alkyl, aliphatic and carbocyclic groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclic groups are as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term "alkylthio", as used herein, alone or in combination, refers to "-S-alkyl" including-S-aliphatic and-S-carbocyclic groups. Wherein the alkyl, aliphatic and carbocyclic groups are as defined above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, and the like.

The terms "lower alkyl", "lower alkoxy", "lower alkylthio", as used herein alone or in combination, refer to alkyl, alkoxy and alkylthio groups having from 1 to about 8, or from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3, or from 1 to 2 carbon atoms as recited.

Examples of the term "salt" as used herein include salts prepared by reacting a compound described herein with a mineral or an organic acid or an inorganic base. These salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate (hexyne-1,6-dioate), hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-isethionate, 2-hydroxymethanesulfonate, bisulfite, dihydrogenate, dihydrogensulfate, dihydrogenate, camphorsulfonate, caprylate, chloride, citrate, cyclopentanepronate, caprate, gluconate, dihydrogenate, dinitrobenzoate, dihydrogensulfate, glycolate, hydrobromide, lev, Iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, jellrate (pectate), persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolic acid (propiolate), phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate (undeconate), and xylenesulfonate.

The term "solvate" as used herein refers to a combination of a compound of the invention formed by solvation with a solvent molecule. In some instances, a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the present invention and water forms a hydrate.

In the present application, the reaction is optionally carried out in a solvent, all solvents used in the present application are commercially available and can be used without further purification, and the reaction is generally carried out under inert nitrogen in an anhydrous solvent.

The compound is made by hand or

The software names, and the commercial compounds are under the supplier catalog name.

In the present application, proton NMR data are recorded on a BRUKER AV-300(300MHz) spectrometer with chemical shifts expressed in terms of (ppm) at tetramethylsilane low field; mass spectra were determined on an AB SCIEX Triple TOF 4600. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode. The HPLC column adopts a chromatographic column: dasailu AD-H (250X 4.6mm, 5 um); mobile phase: n-hexane-isopropanol-diethylamine (95: 5: 0.1); detection wavelength: 254 nm.

According to the preparation method, a racemic compound shown as the formula I reacts with D-malic acid, the compound is split to obtain an optically pure compound shown as the formula II, the optically pure compound is converted into a compound shown as the formula III and a compound shown as the formula IV, and the intermediate is further converted into a subsequent intermediate of the Volappa sand.

Detailed Description

The following examples further illustrate the technical solution of the present invention in non-limiting detail. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. The solvents, reagents, raw materials and the like used in the present invention are all commercially available chemically pure or analytically pure products.

Example 1: (E) preparation of ethyl (E) -3- (5-nitrocyclohex-1-en-1-yl) acrylate (Compound of formula I-1 a)

Adding the compound (285g) of the formula I-0 and absolute ethyl alcohol (1.8L) into a reaction bottle while stirring at room temperature, stirring uniformly, slowly adding 98% concentrated sulfuric acid (50g), heating to 75 ℃ for reacting for 6-10 hours, cooling to room temperature after the reaction is finished, and concentrating under reduced pressureMost of the ethanol was distilled off, 1.5L of ethyl acetate and 1.5L of water were added to the residue, the ethyl acetate layer was separated, the aqueous layer was back-extracted with 500ml of ethyl acetate, the ethyl acetate layers were combined, the organic layer was washed twice with 3L of saturated saline water, the organic layer was dried over anhydrous sodium sulfate for 5 hours, filtered, and the filtrate was concentrated under reduced pressure at 35 ℃ to give 322g of the compound of formula I-1a in 98.9% yield. ESI-MS M/z [ M + H ]]⁺:226.24。

¹H-NMR(CDCl₃):7.40-7.25(1H,d),6.20-6.15(1H,s),5.90-5.70(1H,d,),4.80-4.60 (1H,m),4.40-4.25(2H,m),2.85-2.70(2H,m),2.50-2.40(2H,s),2.40-2.10(2H,m),1.40-1.20(3H,m)。

Example 2: (E) preparation of ethyl (E) -3- (5-aminocyclohex-1-en-1-yl) acrylate, a compound of formula Ia

Adding a compound (315g) of a formula I-1a and ethyl acetate (2L) into a reactor, stirring for dissolving, adding stannous chloride dihydrate (1.2kg) under stirring, heating to 75 ℃ for reacting for 3-5 hours, cooling the reaction liquid to room temperature, adding 4L of ethyl acetate and 3L of water, stirring, adjusting the pH of a water layer to 10 by using a potassium carbonate saturated solution, filtering and separating an organic layer, washing the water layer by using 2L of ethyl acetate, combining the organic layers, washing the organic layer twice, drying the organic layer by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 35 ℃ to obtain 199g of a racemic compound (I a) of the formula I, wherein the yield is 73%. ESI-MS M/z [ M + H ]]⁺:196.13。

¹H-NMR(CDCl₃):7.40-7.25(1H,d),6.20-6.15(1H,s),5.90-5.70(1H,d,),4.40-4.25(2H,m), 3.50-3.30(1H,m),2.85-2.70(2H,m),2.50-2.40(2H,s),2.40-2.10(2H,m),1.40-1.20(3H,m)。

Example 3: preparation of ethyl (R, E) -3- (5-aminocyclohex-1-en-1-yl) acrylate D-malate (compound of formula IIa)

Method 1

Adding methanol (1L), acetone (1L) and racemic compound (173g) of formula Ia into a reaction bottle under the stirring condition, heating to 60 ℃, adding D-malic acid (118g) into 500ml of methanol, stirring to dissolve clearly to obtain a D-malic acid methanol solution, adding the D-malic acid methanol solution into the reaction bottle, continuing to heat and stir for reaction for 2 hours, cooling to room temperature, stirring for 3 hours, filtering to obtain a pale yellow solid, refluxing and pulping with 500ml of methanol for 1 hour, filtering, recrystallizing with ethanol and water (volume ratio of 9: 1) to obtain compound of formula IIa, drying under reduced pressure to obtain 94.7g, yield of 32%, and detecting the content of S-configuration isomer of the compound of formula Ia by HPLC (high performance liquid chromatography) to obtain 1%.

Method 2

Dissolving 0.5g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.172g of D-malic acid, stirring for 1 hour at the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.26g of solid, and detecting the content ratio of the R configurational isomer (target configuration) to the S configurational isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 82.93: 17.07.

Method 3

Dissolving 1g of racemic compound Ia in 15ml of acetone and 15ml of methanol, heating to the boiling point of the system, adding 0.343g of D-malic acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.64g of solid, and detecting the content ratio of the R-configuration isomer to the S-configuration isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 90.04: 9.96.

Method 4

Dissolving 1g of racemic compound Ia in 18ml of acetone and 12ml of methanol, heating to the boiling point of the system, adding 0.343g of D-malic acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.65g of solid, and detecting the content ratio of the R-configuration isomer to the S-configuration isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 88.64: 11.36.

Method 5

Dissolving 1g of racemic compound Ia in 15ml of acetone and 15ml of ethanol, heating to the boiling point of the system, adding 0.343g of D-malic acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.50g of solid, and detecting the content ratio of the R-configuration isomer to the S-configuration isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 82.22: 17.51.

Method 6

Dissolving 1g of racemic compound Ia in 18ml of acetone and 12ml of ethanol, heating to the boiling point of the system, adding 0.343g of D-malic acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.45g of solid, and detecting the content ratio of the R-configuration isomer to the S-configuration isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 80.31: 19.25.

Method 7

Dissolving 0.5g of racemic compound Ia in 15ml of methanol, heating to the boiling point of the system, adding 0.172g of D-malic acid, stirring for 1 hour at the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.2g of solid, and detecting the content ratio of the R-configurational isomer to the S-configurational isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 71.74: 28.26.

Example 4: preparation of ethyl (R, E) -3- (5- ((ethoxycarbonyl) amino) cyclohex-1-en-1-yl) acrylate (compound of formula IIIa)

Adding the compound (40g) of the formula IIa prepared in the method 1 of the embodiment 3 and ethanol (300ml) into a reaction bottle under the stirring condition, stirring and dissolving the mixture at 25 ℃, adding a potassium carbonate solution (33g of potassium carbonate is dissolved in 300ml of water), stirring the mixture for about 15min, controlling the temperature to be less than 20 ℃, dropwise adding ethyl chloroformate (17.1g), reacting the mixture at 25 ℃ for 1 hour, adding 400ml of ethyl acetate, extracting and separating liquid, and back-extracting a water layer by using 200ml of ethyl acetate; the ethyl acetate layers were combined, washed with 1.5L of aqueous sodium chloride solution for 3 times, concentrated under reduced pressure to give a off-white solid, and directly subjected to the next reaction.

Example 5: preparation of (R, E) -3- (5- ((ethoxycarbonyl) amino) cyclohex-1-en-1-yl) acrylic acid (compound of formula IV)

The compound of formula IIIa prepared in example 4 and 300ml of absolute ethanol are added and stirredAfter stirring, an aqueous sodium hydroxide solution (15g of sodium hydroxide in 200ml of water) was added, the mixture was heated to 45 ℃ to react for 1 hour, 2L of ethyl acetate was added to conduct extraction, 2L of purified water was washed, and the organic layer was concentrated under reduced pressure to obtain 27g of an off-white solid (yield in two steps, examples 4 and 5, 93%). ESI-MS M/z [ M + H ]]⁺: 240.27。

¹H-NMR(CDCl₃):7.40-7.30(1H,d,J＝15.75),6.20(1H,s),5.80-5.70(1H,d,J＝15.72), 4.80-4.60(1H,brs),4.20-4.10(2H,m),4.00-3.80(1H,s),2.70-2.50(1H,m),2.40-2.30(2H,s),2.10-1.90(2H ,m),1.70-1.50(1H,m),1.45-1.20(3H,m)。

Example 6: preparation of Compounds of formula VI

Adding a compound (23.9g) of the formula IV, tetrahydrofuran (200ml) and N-methylmorpholine (30ml) into a reaction bottle, stirring to dissolve, cooling, dropwise adding pivaloyl chloride (12.7g) at the temperature of below 0 ℃, reacting for 3-5 hours at the temperature of-5-0 ℃, dropwise adding a tetrahydrofuran solution (26.5g of a compound (V) of the formula V into 150ml of tetrahydrofuran) into the reaction system, reacting for 3 hours at the temperature of 5 ℃, adding water into the reaction solution, stirring for 0.5 hour, adding 400ml of ethyl acetate, stirring and separating, extracting the water phase with 200ml of ethyl acetate, combining organic phases, washing with saturated potassium carbonate (500ml), washing twice with saturated saline solution, adding anhydrous sodium sulfate, stirring for 3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain 49.1g of yellow oily matter. ESI-MS M/z [ M + H ]]⁺:487.2242。

Example 7: preparation of the Compound of formula VII

A reaction flask was charged with compound of formula VI (47.4g) and ethyl acetate (350ml) and stirred to dissolve it, quinoline and Lindla catalyst (5% Pd/CaCO)₃7g), controlling the temperature to be 15 ℃, introducing hydrogen, stirring and reacting for 6-10 hours, filtering, and concentrating the filtrate under reduced pressure to obtain yellow oily matter42g。ESI-MS m/z[M+H]⁺:489.2388。

Example 8: preparation of compounds of formula VIII

Adding a compound (40g) of formula VII and N-methylpyrrolidone (50ml) into a reaction bottle, heating, stirring and dissolving, heating to 140 ℃, reacting for 6 hours, cooling the reaction liquid to 40 ℃, adding DBU, reacting for 10 hours, adding 200ml of ethyl acetate, dissolving, washing twice with water, and concentrating the organic layer under reduced pressure to obtain 33g of off-white solid. ESI-MS M/z [ M + H ]]⁺:489.2384。

¹H-NMR(CDCl₃):7.50-7.18(10H,m),5.28(1H,s),4.69(1H,m),4.58(1H,brs),4.09(2H,q,J＝7.02), 3.42(1H,brs),2.94(1H,m),2.61(3H,m),2.46(1H,m),2.10(2H,m),1.88(1H,m),1.67(1H,s),1.52(3H,d,J＝ 5.94),1.22(3H,t,J＝5.94),0.98(1H,m)。

Example 9: preparation of a Compound of formula IX

Dissolving a compound of a formula VIII (12.5g) in methanol (250ml), adding 10% palladium carbon (3g), transferring to a hydrogenation kettle, reacting for 10 hours at 25 ℃ under the pressure of 2MPa, filtering, concentrating under reduced pressure to dryness, heating the residue to 50 ℃ by using acetone (100ml), pulping, filtering, and drying to obtain 9.7g of an off-white solid. ESI-MS M/z [ M + H ]]⁺:491.2543。

¹H-NMR(CDCl₃):7.60-7.45(2H,t),7.45-7.40(1H,t),7.36-7.32(2H,m),7.32-7.28(2H,d), 7.28-7.25(2H,m),7.23-7.18(1H,m),4.94-4.85(1H,m),4.70-4.50(1H,s),4.20-4.00(2H,m), 3.60-3.40(1H,s)2.45-2.35(2H,m),2.30-2.20(1H,m),2.10-2.00(2H,m),2.00-1.90(1H,d), 1.85-1.75(1H,m),1.65-1.55(1H,m),1.55-1.45(3H,m),1.28-1.15(3H,m),1.10-0.95(3H,m), 0.95-0.85(1H,m)。

Comparative example 1 resolution of racemic Compound of formula Ia by Camphorsulfonic acid

Method 1

Dissolving 1g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.595g of D-camphorsulfonic acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, filtering to obtain 0.6g of solid, and detecting the content ratio of the R configurational isomer to the S configurational isomer of the compound Ia by HPLC (high performance liquid chromatography) to be 44.78: 55.22.

Method 2

Dissolving 1g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.595g of L-camphorsulfonic acid, stirring for 1 hour while maintaining the temperature, stopping heating, and naturally cooling overnight. Filtration gave 0.65g of solid, and HPLC determined the content ratio of R-isomer to S-isomer of the compound of formula Ia was 54.14: 45.86.

Method 3

Dissolving 1g of racemic compound Ia in 30ml of methanol, heating to the boiling point of the system, adding 0.595g of D-camphorsulfonic acid, stirring for 1 hour while maintaining the temperature, stopping heating, naturally cooling overnight, and no solid is separated out.

Method 4

Dissolving 1g of racemic compound Ia in 30ml of methanol, heating to the boiling point of the system, adding 0.595g of L-camphorsulfonic acid, stirring for 1 hour while maintaining the temperature, stopping heating, naturally cooling overnight, and no solid is separated out.

Method 5

Dissolving 1g of racemic compound Ia in 30ml of dichloromethane, heating to the boiling point of the system, adding 0.595g of D-camphorsulfonic acid, stirring for 1 hour while maintaining the temperature, stopping heating, naturally cooling overnight, and no solid is precipitated.

Method 6

Dissolving 1g of racemic compound Ia in 30ml of dichloromethane, heating to the boiling point of the system, adding 0.595g of L-camphorsulfonic acid, stirring for 1 hour while maintaining the temperature, stopping heating, naturally cooling overnight, and no solid is precipitated.

Comparative example 2 resolution of racemic Compound of formula Ia by tartaric acid

Method 1

Dissolving 0.5g of racemic compound Ia in 15ml of methanol, heating to the boiling point of the system, adding 0.192g of D-tartaric acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, and no solid is separated out.

Method 2

Dissolving 0.5g of racemic compound Ia in 15ml of methanol, heating to the boiling point of the system, adding 0.192g of L-tartaric acid, stirring for 1 hour under the temperature, stopping heating, naturally cooling overnight, and no solid is separated out.

Method 3

Dissolving 0.5g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.192g of D-tartaric acid, stirring for 1 hour at the temperature, stopping heating, naturally cooling overnight, and filtering to obtain a very small amount of solid.

Method 4

Dissolving 0.5g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.192g of L-tartaric acid, stirring for 1 hour at the temperature, stopping heating, naturally cooling overnight, and filtering to obtain a very small amount of solid.

Comparative example 3 resolution of racemic Compound of formula Ia by mandelic acid

Method 1

Dissolving 0.5g of racemic compound Ia in 15ml of methanol, heating to the boiling point of the system, adding 0.19g of D-mandelic acid, stirring for 1 hour at the temperature, naturally cooling overnight, and filtering to obtain almost no solid.

Method 2

Dissolving 0.5g of racemic compound Ia in 15ml of methanol, heating to the boiling point of the system, adding 0.19g of L-mandelic acid, stirring at the temperature for 1 hour, stopping heating, naturally cooling overnight, and filtering to obtain almost no solid.

Method 3

Dissolving 0.5g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.19g of D-mandelic acid, stirring at the temperature for 1 hour, stopping heating, naturally cooling overnight, and filtering to obtain almost no solid.

Method 4

Dissolving 0.5g of racemic compound Ia in 15ml of acetone, heating to the boiling point of the system, adding 0.19g of L-mandelic acid, stirring at the temperature for 1 hour, stopping heating, naturally cooling overnight, and filtering to obtain almost no solid.

Comparative example 4 resolution of racemic Compound of formula Ia in dichloromethane by D-malic acid

Dissolving 0.5g of racemic compound Ia in 30ml of dichloromethane, heating to the boiling point of the system, adding 0.172g of D-malic acid, stirring for 1 hour under the temperature, stopping heating, and naturally cooling overnight. Filtration gave 0.1g of solid, and HPLC determined the content ratio of R-isomer to S-isomer of the compound of formula Ia was 51: 49.

Claims

1. A process for preparing a compound of formula ii, comprising: reacting the compound shown in the formula I with D-malic acid in the presence of a solvent to obtain a compound shown in the formula II,

wherein R is selected from hydrogen and C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, wherein C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl are optionally substituted with one or more of the following substituents: halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halogen substituted C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, halogen substituted C₁-C₆Alkylthio and optionally substituted by one or more halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio-substituted 6-12 membered aryl or 5-12 membered heteroaryl.

2. The process of claim 1 wherein R is selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halogen substituted C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, halogen substituted C₁-C₆Alkylthio and optionally substituted by one or more halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio-substituted 6-12 membered aryl or 5-12 membered heteroaryl.

3. The process of claim 2 wherein R is selected from C₁-C₆Alkyl, allyl, propargyl or benzyl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halogen substituted C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy and halogen substituted C₁-C₆An alkoxy group.

4. The process according to claim 3, wherein R is selected from C₁-C₄Alkyl, allyl, propargyl or benzyl, wherein the above groups are optionally substituted with one or more of the following substituents: halogen, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and C₁-C₄An alkoxy group.

5. The process according to claim 4, wherein R is selected from ethyl.

6. The production process according to claim 1, wherein the solvent is one or more selected from the group consisting of alcohols and ketones.

7. The production process according to claim 6, wherein the solvent is selected from alcohols or a mixed solvent of an alcohol and a ketone.

8. The process according to claim 6, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and tert-butanol.

9. The process according to claim 8, wherein the alcohol is selected from methanol and ethanol.

10. The process of claim 6, wherein the ketone is selected from the group consisting of acetone, butanone, pentanone, cyclopentanone, hexanone, and cyclohexanone.

11. The process of claim 10 wherein the ketone is acetone.

12. The preparation process according to claim 6, wherein the solvent is one or more selected from the group consisting of methanol, ethanol and acetone.

13. The preparation method according to claim 12, wherein the solvent is selected from methanol, ethanol, a mixed solvent of methanol and acetone, or a mixed solvent of ethanol and acetone.

14. A process as claimed in claim 1, wherein the molar ratio of D-malic acid to compound of formula i is 1: 1.

15. the production process according to claim 1, wherein the reaction temperature of the reaction is first raised to not more than the boiling point of the reaction system and then lowered to 25 ℃.

16. The process according to claim 1, wherein the reaction temperature of the reaction is increased by 60 ℃ and then decreased to 25 ℃.

17. The process of claim 1 wherein the preparation of the compound of formula ii further comprises the step of isolating the compound of formula ii obtained from the reaction and treating with a second solvent selected from the group consisting of alcohols.

18. The preparation method of claim 17, wherein the second solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, or t-butanol.

19. The preparation process according to claim 17, wherein the second solvent is methanol.

20. The process of claim 17 wherein said treating with a second solvent comprises separating the compound of formula ii obtained by the reaction, mixing with the second solvent, and then separating the compound of formula ii.

21. The process of claim 1 wherein the preparation of the compound of formula ii further comprises the step of crystallizing the compound of formula ii.

22. The process according to claim 21, wherein the compound of formula ii is crystallized in a mixed solvent of an alcohol and water, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol.

23. The process according to claim 21, wherein the compound of formula ii is crystallized from a mixed solvent of an alcohol and water, wherein the alcohol is selected from ethanol.

24. A process according to claim 1, wherein the preparation of the compound of formula ii comprises the steps of:

(1) mixing the compound of formula I with a solvent;

(2) mixing the D-malic acid with a solvent;

(3) reacting the mixture of the step (1) and the mixture of the step (2).

25. The preparation method according to any one of claims 1 to 24, further comprising: reacting the compound of formula I-1 to obtain the compound of formula I,

26. the process of claim 25, wherein the compound of formula i is prepared using a reducing agent.

27. The method of claim 26, wherein the reducing agent is stannous chloride.

28. The process of claim 27, wherein the molar ratio of reducing agent to compound of formula i is 4: 1.

29. the process of claim 25 wherein the solvent used in the preparation of the compound of formula i is ethyl acetate.

30. The process of claim 25, wherein the reaction temperature for the preparation of the compound of formula i is 75 ℃.

31. The process of claim 25, wherein the preparation of the compound of formula i further comprises the steps of:

(2) adding a base to bring the pH of the aqueous layer to greater than 7;

(3) the organic layer was separated and concentrated to dryness.

32. The preparation process as claimed in claim 31, wherein the water-immiscible organic solvent in the step (1) is ethyl acetate.

33. The method of claim 31, wherein the base of step (2) is potassium carbonate.

34. The method of claim 25, further comprising: reacting the compound of formula I-0 with ROH to obtain a compound of formula I-1,

wherein R is not hydrogen.

35. The process as claimed in claim 34, wherein the preparation of the compound of the formula i-1 is carried out in the presence of an acid.

36. The method of claim 34, wherein the acid is sulfuric acid.

37. The process of claim 34, wherein the compound of formula i-1 is prepared at a reaction temperature of 75 ℃.

38. A process for the preparation of a compound of formula iii comprising the steps of:

(a) a compound of formula II prepared by the process of any one of claims 1 to 24,

(b) converting the compound of the formula II and ethyl chloroformate into a compound of a formula III,

39. the process of claim 38 wherein said conversion is by reaction of the compound of formula ii with a base followed by reaction with ethyl chloroformate.

40. The process of claim 39 wherein the base is potassium carbonate.

41. The method of claim 38 wherein the molar ratio of ethyl chloroformate to compound of formula ii is 1.05: 1.

42. the process of claim 38, wherein the temperature of the conversion is 25 ℃.

43. The process of claim 38, wherein the solvent used for the preparation of the compound of formula iii is ethanol.

44. A process for the preparation of a compound of formula iv comprising the steps of:

(a) a compound of formula III prepared by the process of claim 38, wherein R is other than hydrogen,

(b) reacting the compound shown in the formula III to obtain a compound shown in the formula IV,

45. the process of claim 44, wherein the preparation of the compound of formula IV is carried out in the presence of a base.

46. The method of claim 45, wherein the base is sodium hydroxide.

47. The process according to claim 44, wherein the solvent used for the preparation of the compound of formula III is ethanol.

48. The process of claim 44, wherein the compound of formula IV is prepared at a reaction temperature of 45 ℃.

49. A process for the preparation of a compound of formula vi comprising the steps of:

(a) a compound of formula III prepared by the process of claim 38,

(b) converting the compound of formula IV and the compound of formula V into the compound of formula VI,

wherein the content of the first and second substances,

the compound of formula III and the compound of formula IV are the same compound.

50. A process for the preparation of a compound of formula vi comprising the steps of:

(a) a compound of formula IV prepared by the process of claim 44,

51. the process according to claim 49 or 50, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1.1: 1.

52. the production method according to claim 49 or 50, wherein the transformation comprises the steps of:

(1) converting the compound of formula iv to an anhydride;

53. The process according to claim 52, wherein the conversion in step (1) is carried out by reacting the compound of formula IV with pivaloyl chloride.

54. The process of claim 53 wherein the molar ratio of pivaloyl chloride to compound of formula IV is 1.05: 1.

55. the process of claim 52, wherein the conversion in step (1) is carried out using a base.

56. The process of claim 55 wherein the base used in the step (1) is N-methylmorpholine.

57. The process according to claim 52, wherein the solvent used in step (1) is tetrahydrofuran.

58. The process according to claim 52, wherein the temperature of the conversion in step (1) is from-5 to 0 ℃.

59. The process according to claim 52, wherein the solvent used in the step (2) is tetrahydrofuran.

60. The process according to claim 52, wherein the reaction temperature in the step (2) is 0 to 5 ℃.

61. A process for the preparation of a compound of formula vii, comprising the steps of:

(a) a compound of formula VI prepared by the process of claim 49 or 50,

(b) the compound of the formula VI is subjected to reduction reaction to obtain a compound of a formula VII,

62. the method of claim 61, wherein the reaction is carried out in the presence of palladium, a catalytic inhibitor, and a hydrogen source.

63. The process of claim 62 wherein the palladium is Pd/CaCO₃Or Pd/BaSO₄Wherein the hydrogen source is hydrogen and wherein the catalytic inhibitor is selected from lead acetate, lead oxide or quinoline.

64. The method of claim 61, wherein the reaction is carried out at 5% Pd/CaCO₃Quinoline and hydrogen.

65. The process as claimed in claim 61, wherein the solvent used in the reaction is ethyl acetate.

66. The method of claim 61, wherein the reaction temperature is 15 ℃.

67. A process for the preparation of a compound of formula viii comprising the steps of:

(a) a compound of formula VII prepared by the preparation process of claim 61,

(b) reacting the compound shown in the formula VII to obtain a compound shown in the formula VIII,

68. the process of claim 67 wherein the solvent of the reaction is selected from the group consisting of N-methylpyrrolidone.

69. A process as in claim 67 wherein said reacting comprises heating the compound of formula VII and then reducing the temperature to continue the reaction in the presence of a base.

70. The process of claim 69 wherein the heating temperature for the heating reaction is 140 ℃ and the temperature is reduced to 40 ℃.

71. The method of claim 67, wherein the reaction uses a base that is 1, 8-diazabicyclo [5.4.0] undec-7-ene.