CN112384493B

CN112384493B - Process for preparing fused tricyclic gamma-amino acid derivatives and intermediates

Info

Publication number: CN112384493B
Application number: CN201980045725.3A
Authority: CN
Inventors: 范江; 陈清平; 汪成涛; 冯建川
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2018-08-09
Filing date: 2019-07-18
Publication date: 2023-06-06
Anticipated expiration: 2039-07-18
Also published as: CN112384493A; TWI777079B; WO2020029762A1; TW202019872A

Abstract

A method and an intermediate for preparing a fused tricyclic gamma-amino acid derivative, and a method for preparing an intermediate for the fused tricyclic gamma-amino acid derivative. The fused tricyclic gamma-amino acid derivative has a structure shown in formula (I). The preparation method has the advantages of easily available raw materials, simple steps, crystallization and purification in the whole synthesis process, no silica gel column chromatography or other preparation chromatographic methods, and suitability for large-scale industrial production.

Description

Process for preparing fused tricyclic gamma-amino acid derivatives and intermediates

Technical Field

The invention relates to the field of medicines, in particular to a preparation method and an intermediate of a fused tricyclic gamma-amino acid derivative.

Background

The voltage-gated calcium channel is composed of an α1 subunit and helper proteins α2δ, β, γ subunits together. The α2δ protein can modulate the density of calcium channels and the kinetics of calcium channel voltage dependence (Felix et al (1997) J. Neuroscience 17:6884-6891;Klugbauer et al (1999) J. Neuroscience 19:684-691; hobom et al (2000) Eur. J. Neuroscience 12:1217-1226;and Qin et al (2002) mol. Phacol 62:485-496). Compounds exhibiting high affinity binding to voltage-dependent calcium channel subunit α2δ have been demonstrated to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, the α2δ protein has 4 subtypes, each of which is encoded by a different gene. α2δ subtype 1 and subtype 2 show high affinity for pregabalin, while α2δ subtype 3 and subtype 4 have no significant drug binding force.

However, for gabapentin, the rate of pain improvement in patients with diabetic peripheral neuropathy is about 60% to a large extent (Acta neurol. Scand.101:359-371, 2000), for pregabalin, although it is better tolerated than gabapentin, it is less safe and there is a potential for abuse or patient dependency (Am J Health System pharm.2007;64 (14): 1475-1482).

There remains a great need to develop new compounds that exhibit high affinity binding for the voltage-dependent calcium channel subunit α2δ.

Disclosure of Invention

It is an object of the present invention to provide a process for the preparation of a fused tricyclic gamma-amino acid derivative.

It is another object of the present invention to provide intermediates for preparing fused tricyclic gamma-amino acid derivatives.

In order to achieve the above object, in one aspect, the present invention provides a method for preparing a compound represented by formula (I), wherein the method comprises the steps of preparing the compound represented by formula (III) by reacting the compound represented by formula (III),

a is selected from benzene sulfonic acid, p-toluene sulfonic acid or methane sulfonic acid;

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ² Selected from carboxyl protecting groups or C _1-6 Alkyl of (a);

R ¹¹ selected from C _1-6 Is a hydrocarbon group.

According to some embodiments of the invention, wherein a is selected from benzenesulfonic acid.

According to some embodiments of the invention, itWherein R is ² Selected from methyl, ethyl, propyl, n-butyl or tert-butyl.

According to some embodiments of the invention, wherein R ² Selected from the group consisting of t-butyl.

According to some embodiments of the invention, wherein R ¹¹ Selected from methyl, ethyl, propyl or butyl.

According to some embodiments of the invention, wherein R ¹¹ Selected from methyl groups.

It is understood that the compound of formula (III) is used as raw material to react to prepare the compound of formula (I), which can be hydrolyzed to obtain free base, and then acid A is added to remove carboxyl protecting group and salify. Or removing the carboxyl protecting group, hydrolyzing to obtain free base, and salifying with acid A.

The invention provides a preparation method of a compound shown in a formula (I), wherein the method comprises the steps of taking a compound shown in a formula (II) as a raw material for reaction to prepare the compound;

R ² the definition is the same as before.

Wherein the compound of formula (I) is as follows:

a is as defined above.

The invention provides a preparation method of a compound of a formula (II), which takes a compound of a formula (III) as a raw material to prepare

R ¹ 、R ² Is as defined above.

According to some embodiments of the invention, the method comprises preparing a compound of formula (II) from a compound of formula (III) as a starting material, preparing a compound of formula (I) from a compound of formula (II) as a starting material,

A、R ¹ 、R ² The definition is the same as above.

According to some embodiments of the invention, the method comprises preparing a compound of formula (II) from a compound of formula (III), and reacting the compound of formula (II) in the presence of an acid a.

The invention also provides a preparation method of the compound shown in the formula (I), wherein the method comprises the step of preparing the compound shown in the formula (I) by taking the compound shown in the formula (II) as a raw material for reaction.

R ² selected from carboxyl protecting groups or C _1-6 Is a hydrocarbon group.

According to some embodiments of the invention, the compound of formula (I) is prepared by reacting a compound of formula (II) with an acid A.

According to some embodiments of the invention, the molar ratio of acid A to the compound of formula (II) is from 1.1:1 to 5:1.

According to some embodiments of the invention, the molar ratio of acid A to compound of formula (II) is 1.1:1, 1.2:1, 1.3:1, 1.5:1, 2:1, 3:1, 4:1 or 5:1.

According to some embodiments of the invention, wherein the reaction of the compound of formula (II) and the acid a may be carried out at room temperature to reflux;

In some embodiments, the reaction temperature is 70 to 90 ℃;

in some embodiments, the reaction temperature is 80 to 85 ℃.

In some embodiments, the solvent in which the compound of formula (II) is reacted with acid a is selected from any solvent that is compatible with the compound of formula (II), such as acetonitrile, methylene chloride, ethanol, methanol, isopropyl acetate, water, toluene, dioxane, and combinations thereof.

In some embodiments, the solvent is selected from water, acetonitrile, isopropyl acetate, acetonitrile/water.

In some embodiments, the solvent is selected from acetonitrile/water (v/v=1:1).

In some embodiments, the compound of formula (II) is reacted with an acid a in a solvent that is compatible with the compound of formula (II) to provide the compound of formula (I), the solvent being selected from acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water, toluene, dioxane, or a combination thereof; further preferably, the molar ratio of acid A to the compound of formula (II) is from 1.1:1 to 5:1, at 70-90 ℃; still more preferably, the molar ratio of acid A to the compound of formula (II) is 1.1:1, and is reacted at 80-85 ℃; still more preferably, the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate.

According to some embodiments of the invention, wherein the method further comprises the step of preparing the compound of formula (II) starting from the compound of formula (III),

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ² Selected from carboxyl protecting groups or C _1-6 Alkyl of (a);

R ¹¹ selected from C _1-6 Is a hydrocarbon group.

The invention also provides a preparation method of the compound shown in the formula (III), wherein the method comprises the step of obtaining the compound shown in the formula (III) by taking the compound shown in the formula (IV) as a raw material and reacting,

R ² the definition is the same as above.

Wherein the compound of formula (III) is as follows:

R ¹ the definition is the same as above.

According to some embodiments of the invention, a process for the preparation of a compound of formula (III), wherein the preparation of the compound of formula (III) comprises preparing the compound of formula (III) starting from the compound of formula (IV) and a chiral acid.

The chiral acid is selected from the group consisting of a compound of formula (XI), R-alpha-methylphenylacetic acid, (-) -diacetyl-L-tartaric acid, L-aspartic acid or dextro-quinic acid,

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；R ¹¹ Selected from C _1-6 Alkyl of (a); preferably R ¹¹ Selected from methyl groups.

According to some embodiments of the invention, a process for the preparation of a compound of formula (III), wherein:

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ² Selected from carboxyl protecting groups or C _1-6 Alkyl of (a);

R ¹¹ selected from C _1-6 Is a hydrocarbon group.

According to some embodiments of the inventionScheme, wherein R ¹¹ Selected from methyl groups.

According to some embodiments of the invention, the chiral acid is (S) - (+) -O-acetyl-L-mandelic acid or L-mandelic acid.

According to some embodiments of the invention, a process for the preparation of a compound of formula (III), wherein the molar ratio of chiral acid to compound of formula (IV) is from 0.5:1 to 1:1.

According to some embodiments of the invention, a process for the preparation of a compound of formula (III) wherein a chiral acid and a compound of formula (IV) are reacted under conditions from room temperature to reflux.

According to some embodiments of the invention, a process for the preparation of a compound of formula (III), wherein the chiral acid is selected from the group consisting of a compound of formula (XI), R- α -methylphenylacetic acid, (-) -diacetyl-L-tartaric acid, L-aspartic acid or dextro-quinic acid; it is further preferred that the molar ratio of chiral acid to compound of formula (IV) is from 0.5:1 to 1:1, and that the reaction is carried out at room temperature to reflux.

According to some embodiments of the invention, the method comprises reacting a compound of formula (IV) to obtain a compound of formula (III), and then recrystallizing the compound of formula (III).

The invention also provides a refining method of the compound shown in the formula (III), which comprises the steps of recrystallizing the compound shown in the formula (III) in a recrystallization solvent:

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ² Selected from carboxyl protecting groups or C _1-6 Alkyl of (a); preferably R ² Selected from t-butyl;

R ¹¹ selected from C _1-6 Alkyl of (a); preferably R ¹¹ Selected from methyl groups.

According to some embodiments of the present invention, a method for purifying a compound of formula (III), wherein the compound of formula (III) is recrystallized in a recrystallization solvent, which is an organic solvent and/or water, preferably 1-2 times.

According to some embodiments of the present invention, a method for purifying a compound of formula (III) wherein the mass to volume ratio of the compound of formula (III) to the recrystallization solvent is 1:10 to 1:30.

According to some embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the organic solvent is selected from the group consisting of isopropanol, acetonitrile and ethanol;

According to some embodiments of the invention, a method for purifying a compound of formula (III), wherein the organic solvent is isopropanol.

According to some embodiments of the present invention, a method for purifying a compound of formula (III), wherein the recrystallization solvent is isopropanol and water.

According to some embodiments of the present invention, a method for purifying a compound represented by formula (III) wherein the volume ratio of isopropyl alcohol to water is (10-20) to 1.

According to some embodiments of the present invention, a method for purifying a compound of formula (III) wherein the volume ratio of isopropanol to water is from 10:1 to 30:1.

According to some embodiments of the invention, a method for refining a compound of formula (III), wherein the recrystallization is repeated 1-2 times.

According to some embodiments of the present invention, a method for purifying a compound of formula (III), wherein the preparation of the compound of formula (III) comprises first preparing the compound of formula (III) from the compound of formula (IV) and a chiral acid, and then recrystallizing the compound of formula (III) to obtain the purified compound.

According to some embodiments of the invention, wherein the chiral acid is selected from the group consisting of a compound of formula (XI), R-alpha-methylphenylacetic acid, (-) -diacetyl-L-tartaric acid, L-aspartic acid or dextroquinic acid,

Wherein R is ¹ Selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ¹¹ Selected from C _1-6 Alkyl of (a);

in some embodiments, R ¹¹ Selected from methyl, ethyl, propyl or butyl;

in some embodiments, R ¹¹ Selected from methyl groups.

According to some embodiments of the invention, wherein the chiral acid is selected from the group consisting of compounds of formula (XI),

wherein R is ¹ Selected from H or-C (=O) R ¹¹ ；

R ¹¹ Selected from methyl groups.

According to some embodiments of the invention, the molar ratio of the compound of formula (XI) to the compound of formula (IV) is between 0.5:1 and 1:1.

In some embodiments, the molar ratio of the compound of formula (XI) to the compound of formula (IV) is in the range of 0.5:1 to 0.8:1.

According to some embodiments of the invention, wherein the compound of formula (IV) and the compound of formula (XI) are reacted under conditions of room temperature to reflux;

according to some embodiments of the invention, the compound of formula (XI) and the compound of formula (IV) are reacted at 80-90 ℃.

According to some embodiments of the invention, the process comprises reacting a compound of formula (IV) to obtain a crude compound of formula (III), and then recrystallizing the crude compound using a recrystallization solvent, such as an organic solvent and/or water.

According to some embodiments of the invention, wherein the organic solvent is selected from the group consisting of isopropanol, acetonitrile, ethanol, and water; preferably a mixture of isopropanol and water, or a mixture of ethanol and water.

According to some embodiments of the invention, the volume ratio of isopropyl alcohol to water is (10-30) to 1.

According to some embodiments of the invention, the volume ratio of isopropyl alcohol to water is (10-20) to 1.

According to some embodiments of the invention, the volume ratio of ethanol to water is (10-30) to 1.

In some embodiments, the volume ratio of ethanol to water is (10-20) to 1.

According to some embodiments of the invention, wherein the mass to volume ratio of the compound of formula (III) to the recrystallization solvent is from 1:10 to 1:30; in some embodiments, the mass to volume ratio is from 1:10 to 1:20.

According to some embodiments of the invention, the recrystallization solvent is isopropanol and water, and the volume ratio of isopropanol to water is 10:1-30:1.

According to some embodiments of the invention, the step of recrystallizing comprises dissolving the crude product of formula (III) in a recrystallization solvent, stirring and reacting for 0.5-1 hour, and crystallizing.

According to some embodiments of the invention, wherein the recrystallization is repeated 1-2 times.

It will be appreciated that the repetition is performed on a first basis, for example, 1 repetition and 2 repetitions; repeating the process 2 times corresponds to 3 times of recrystallization.

According to some embodiments of the invention, wherein the process further comprises the step of preparing the compound of formula (IV) starting from the compound of formula (V),

R ² the definition is the same as above.

According to some embodiments of the invention, wherein the preparation of the compound of formula (IV) comprises: the compound of formula (IV) is prepared by using the compound of formula (V) as raw material under the existence of catalyst and reducing agent at 0-40 ℃.

In certain embodiments, the catalyst/reducing agent at which the reduction of compound (V) occurs to form compound (IV) may be selected from raney nickel/hydrazine hydrate, nickel chloride hexahydrate/sodium borohydride, iron powder/ammonium chloride, 10% palladium on carbon/triethylsilicon, raney nickel/hydrogen, 10% palladium on carbon/hydrogen, or zinc powder/acetic acid.

In certain embodiments, the catalyst/reducing agent is selected from nickel chloride hexahydrate/sodium borohydride or 10% palladium on carbon/hydrogen.

In certain embodiments, the reducing conditions are: in an alcohol solvent at 0-40 ℃, nickel chloride hexahydrate is used as a catalyst, and sodium borohydride is used as a reducing agent; or, in alcohol solvent at 0-40 deg.c, pd-C as catalyst and hydrogen as reductant. In certain embodiments, the alcoholic solvent is methanol or ethanol.

In certain embodiments, the temperature of the reduction reaction is from 20 ℃ to 30 ℃.

In certain embodiments, the molar ratio of the compound of formula (V) to the catalyst is from 1:1 to 10:1, in certain embodiments from 2:1 to 5:1, and in certain embodiments, from 2:1, 3:1, 4:1, 5:1.

In certain embodiments, the molar ratio of the compound of formula (V) to the reducing agent is from 1:2 to 1:10, in certain embodiments from 1:2.5 to 1:5, and in certain embodiments, from 1:2.5, 1:3, 1:4, 1:5.

In certain embodiments, the molar ratio of the compound of formula (V) to catalyst to reducing agent is from 1:0.2:2.5 to 1:0.5:5. In certain embodiments, the molar ratio is 1:0.2:2.5, 1:0.2:5, 1:0.2:4, 1:0.5:5, and in certain embodiments, the molar ratio is 1:0.2:4.

According to some embodiments of the invention, wherein the method further comprises the preparation of a compound of formula (V): comprising preparing a compound of formula (V) from a compound of formula (VI),

R ² the definition is the same as above.

According to some embodiments of the invention, wherein the compound (VI) undergoes an addition reaction with nitromethane in the presence of a base to form compound (V); alternatively, a solvent may be present, selected from dimethylsulfoxide, N-dimethylformamide, N-methylpyrrolidone or tetrahydrofuran.

According to some embodiments of the invention, wherein the preparation of the compound of formula (V) comprises: the compound of formula (VI) and nitromethane are reacted in the presence of a base in the absence of other solvents to produce the compound of formula (V).

According to some embodiments of the invention, wherein the base is selected from cesium carbonate, potassium t-butoxide or 1, 8-diazabicyclo undec-7-ene.

According to some embodiments of the invention, the temperature of the addition reaction is 60 ℃ to reflux.

According to some embodiments of the invention, the temperature of the addition reaction is 80 ℃ to 100 ℃.

According to some embodiments of the invention, the temperature of the addition reaction is between 85 ℃ and 90 ℃.

According to some embodiments of the invention, the temperature of the addition reaction is 80 ℃ to 85 ℃.

According to some embodiments of the invention, wherein the compound (VI) undergoes an addition reaction with nitromethane in the presence of a base to form compound (V); alternatively, a solvent selected from dimethylsulfoxide or N, N-dimethylformamide may be present.

According to some embodiments of the invention, wherein the molar ratio of compound (V) to nitromethane is 1:2.5 to 1:10, 1:3 to 1:9, 1:3 to 1:8, 1:3 to 1:7, 1:3 to 1:6, 1:3 to 1:5 or 1:3 to 1:4.

In certain embodiments, the molar ratio of compound (V) to nitromethane is 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

According to some embodiments of the invention, wherein the method further comprises the preparation of a compound of formula (VI): comprising preparing a compound of formula (VI) from a compound of formula (VII),

according to some embodiments of the invention, wherein the preparation of the compound of formula (VI) comprises: in the presence of a base, the compound of the formula (VII) reacts with any one compound selected from dimethoxy phosphono acetic acid tert-butyl ester, diethoxy phosphono acetic acid tert-butyl ester, bromoacetic acid tert-butyl ester, chloroacetic acid tert-butyl ester or acetoacetic acid tert-butyl ester to generate the compound of the formula (VI).

According to some embodiments of the invention, wherein the base used for preparing the compound (VI) is selected from potassium tert-butoxide, 1, 8-diazabicyclo undec-7-ene, lithium diisopropylamide, potassium carbonate or lithium hydride.

According to some embodiments of the invention, wherein the base used for the preparation of compound (VI) is selected from potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene.

According to some embodiments of the invention, wherein the temperature at which the compound of formula (VII) is reacted with t-butyl dimethoxyphosphonoacetate is in the range of 10 ℃ to 40 ℃.

According to some embodiments of the invention, wherein the temperature at which the compound of formula (VII) is reacted with t-butyl dimethoxyphosphonoacetate is in the range of 10 ℃ to 30 ℃.

According to some embodiments of the invention, wherein the temperature at which the compound of formula (VII) is reacted with t-butyl dimethoxyphosphonoacetate is from 10 ℃ to 15 ℃.

According to some embodiments of the invention, wherein the temperature at which the compound of formula (VII) is reacted with t-butyl dimethoxyphosphonoacetate is from 20 ℃ to 40 ℃.

According to some embodiments of the invention, wherein the temperature at which the compound of formula (VII) is reacted with t-butyl dimethoxyphosphonoacetate is from 30 ℃ to 40 ℃.

According to some embodiments of the invention, wherein the t-butyl dimethoxyphosphonoacetate may be replaced with t-butyl diethoxyphosphorylacetate, t-butyl bromoacetate, t-butyl chloroacetate or t-butyl acetoacetate.

According to some embodiments of the invention, the molar ratio of compound (VII) to t-butyl dimethoxyphosphonoacetate is from 1:1 to 1:10.

According to some embodiments of the invention, the molar ratio of compound (VII) to t-butyl dimethoxyphosphonoacetate is from 1:1.1 to 1:5.

According to some embodiments of the invention, the molar ratio of compound (VII) to t-butyl dimethoxyphosphonoacetate is from 1:1.1 to 1:2.

According to some embodiments of the invention, the molar ratio of compound (VII) to t-butyl dimethoxyphosphonoacetate is from 1:1.1 to 1:1.5.

According to some embodiments of the invention, wherein compound (VII) is reacted with t-butyl dimethoxyphosphonoacetate in a solvent. In certain embodiments, the solvent is selected from tetrahydrofuran.

The invention also provides a preparation method of the compound shown in the formula (VII), wherein the method comprises the steps of preparing the compound shown in the formula (VII) by taking the compound shown in the formula (VIII) as a raw material,

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

alternatively, R ³ And R is ⁴ And the carbon atoms to which they are attached together form a ring.

According to some embodiments of the invention, wherein R ³ And R is ⁴ Each independently selected from methyl, ethyl or isopropyl.

According to the inventionParticular embodiments are disclosed wherein R ³ And R is ⁴ Forming a piperidine ring or a tetrahydropyrrole ring with the attached nitrogen atom.

According to some embodiments of the invention, wherein R ³ And R is ⁴ And forms a tetrahydropyrrole ring with the attached nitrogen atom.

According to some embodiments of the invention, wherein the method comprises reacting a compound of formula (VIII) with an anhydride in the presence of a pyridine base to produce the compound of formula (VII).

The anhydride is selected from trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride.

The pyridine base of the present invention refers to a base containing a pyridine structure, such as 2,4, 6-trimethylpyridine, 2, 6-dimethylpyridine or pyridine.

According to some embodiments of the invention, wherein the process comprises reacting a compound of formula (VIII) with a base of the class of trifluoromethanesulfonic anhydride and pyridine to prepare the compound of formula (VII).

According to some embodiments of the invention, after the reaction of the compound of formula (VIII) with pyridine base and trifluoromethanesulfonic anhydride is completed, the method further comprises a step of treating the reaction solution with a base.

According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base, and the pH value is adjusted to be alkaline; in certain embodiments, the pH is adjusted to a value of 10 to 11.

In certain embodiments, the base may be selected from inorganic bases.

In certain embodiments, the inorganic base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride, or cesium carbonate; the pH to alkaline may be selected from pH 8-14, 8-11, 9-11 or 10-11.

According to some embodiments of the invention, after the reaction of the compound of formula (VIII) with pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is treated with base, and then the reaction is continued until the intermediate reaction is completed, and the step of acidifying the reaction solution with acid is further included.

The acidification treatment refers to the adjustment of the pH value of the reaction solution to be acidic by acid.

According to some embodiments of the invention, the acidification treatment refers to the adjustment of the reaction solution to acidity with mineral acid.

According to some embodiments of the invention, the acidification treatment is to adjust the pH of the reaction solution to I-4.

According to some embodiments of the invention, the mineral acid is sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid.

According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is treated with base, and then the reaction is continued until the intermediate reaction is completed, and the reaction solution is acidified with acid, and the pH is adjusted to 1-2;

According to some embodiments of the invention, wherein the acid is an inorganic acid; in certain embodiments, a mixture of one or more of sulfuric acid, hydrochloric acid, phosphoric acid, and nitric acid.

According to some embodiments of the invention, wherein the compound of formula (VIII) and the pyridine base, trifluoromethanesulfonic anhydride are reacted at room temperature to reflux. In certain embodiments, the reaction is carried out under reflux.

In certain embodiments, the method of preparing a compound of formula (VII) comprises the steps of:

(1) The compound of formula (VIII) is reacted in the presence of an anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and a pyridine base (preferably 2,4, 6-trimethylpyridine, 2, 6-lutidine or pyridine);

(2) Adjusting the pH of the reaction solution obtained in the step (1) to be alkaline with a base (preferably an inorganic base, more preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate or cesium carbonate), preferably adjusting the pH to 8 to 11;

(3) Acidifying the mixture obtained in step (2) with a mineral acid, preferably sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid, to obtain the compound of formula (VII).

According to some embodiments of the invention, the method for preparing the compound of formula (VII) comprises the steps of:

(1) The compound of formula (VIII) undergoes an addition reaction in the presence of trifluoromethanesulfonic anhydride and a pyridine base;

(2) Regulating the pH of the reaction solution to be alkaline by inorganic alkali, and hydrolyzing to obtain a mixture of the formula (VII) and the formula (VII-1); wherein the inorganic base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride or cesium carbonate;

(3) Acidifying the reaction solution under an acidic condition, adjusting the pH to 1-4, and carrying out rearrangement reaction on the compound of the formula (VII-1) in the mixture obtained in the step (2) to obtain the compound of the formula (VII); wherein the acid is inorganic acid and is selected from one or more of sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.

(1) In the presence of pyridine base and trifluoromethanesulfonic anhydride, the addition reaction of the formula (VIII) takes place by using methylene dichloride or 1, 2-dichloroethane as a solvent; wherein the pyridine base refers to a base containing a pyridine structure such as 2,4, 6-trimethylpyridine, 2, 6-lutidine or pyridine;

(2) Regulating the pH of the reaction solution to be alkaline by inorganic alkali, and hydrolyzing to obtain a mixture of the formula (VII) and the formula (VII-1); wherein the inorganic base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride or cesium carbonate; the pH to alkaline may be selected from pH 8-14, 8-11, 9-11 or 10-11;

(3) The rearrangement of the compound of formula (VII-1) to the compound of formula (VII) under acidic conditions in a mixture of formula (VII) and formula (VII-1) is carried out in which the solvent for the reaction may be any solvent which is acid stable, in certain embodiments selected from acetone or acetonitrile. Wherein the acidic condition may be selected from a pH of 1-4, 1-3, or 1-2, and in certain embodiments from a pH of 1-2. The acidic conditions may be adjusted using common mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid.

In certain embodiments, the molar ratio of the compound of formula (VIII) to pyridine base to trifluoromethanesulfonic anhydride is 1:1: (1.1-2.0) to (1.1-2.0), 1: (1.1-1.5) to (1.1-1.5) or 1:1.5:1.5.

In certain embodiments, wherein the compound of formula (VIII) and the pyridine base, trifluoromethanesulfonic anhydride are reacted at room temperature to reflux. In certain embodiments, the reaction is carried out under reflux.

According to some embodiments of the invention, the process for preparing the compound of formula (VIII) further comprises starting from the compound of formula (IX) with a secondary amine NH (R) ³ )(R ⁴ ) A step of preparing a compound of formula (VIII) by reaction,

R ³ 、R ⁴ the definition is the same as above.

According to some embodiments of the invention, wherein the compound of formula (IX) is reacted with a secondary amine NH (R ³ )(R ⁴ ) The compound of formula (VIII) is prepared by reaction in the presence of a condensing agent.

Wherein R of secondary amine ³ And R is ⁴ The definition is as described in the foregoing. In some embodiments, R ³ And R is ⁴ And forms a tetrahydropyrrole ring with the attached nitrogen atom.

According to some embodiments of the invention, wherein the condensing agent is selected from oxalyl chloride, thionyl chloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N, N' -carbonyldiimidazole.

In certain embodiments, the molar ratio of the compound of formula (IX) to the secondary amine is not greater than 1, in certain embodiments from 1:1 to 5, in certain embodiments from 1:1 to 2, and in certain embodiments from 1:1.1.

In certain embodiments, the compound of formula (IX) is reacted with a secondary amine NH (R ³ )(R ⁴ ) The reaction temperature at which the compounds of formula (VIII) are prepared is room temperature, and in certain embodiments, 20 to 30 ℃.

According to some embodiments of the invention, wherein the process further comprises the step of preparing the compound of formula (IX) starting from the compound of formula (X),

according to some embodiments of the invention, the compound of formula (IX) is prepared starting from the compound of formula (X) and isopropyl malonate.

According to some embodiments of the invention, the compound of formula (X) is reacted with isopropyl malonate under the catalysis of triethylamine formate to form the compound of formula (IX).

According to some embodiments of the invention, wherein the process comprises reacting a compound of formula (X) with isopropyl malonate under the catalysis of triethylamine formate and subjecting the resulting compound to reductive decarboxylation to produce a compound of formula (IX).

According to some embodiments of the invention, wherein the triethylamine formate is prepared from formic acid and triethylamine.

According to some embodiments of the invention, wherein the compound of formula (X) and the isopropyl malonate are reacted using anhydrous formic acid as reaction medium.

In certain embodiments, the molar ratio of the compound of formula (X) to isopropyl malonate is no greater than 1, in certain embodiments from 1:1 to 5, in certain embodiments from 1:1 to 2, and in certain embodiments from 1:1.

According to some embodiments of the present invention, the reaction temperature of the compound of formula (X) and the isopropyl malonate is 100 to 180deg.C, in certain embodiments 140 to 160deg.C, and in certain embodiments 140 to 150deg.C.

According to some embodiments of the present invention, the reductive decarboxylation reaction is carried out under acidic conditions after the reaction of the compound of formula (X) and the isopropyl malonate, wherein the acidic conditions are at a pH of from 1 to 5, in certain embodiments from 1 to 4, in certain embodiments from 1 to 3, and in certain embodiments from 1 to 2. Wherein the acid conditions are provided by commonly used mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.

The invention also provides a preparation method of the compound shown in the formula (VII), wherein the method comprises the following steps:

(1) Reacting a compound of formula (X) with isopropyl malonate to produce a compound of formula (IX);

(2) Compounds of formula (IX) and secondary amines NH (R) ³ )(R ⁴ ) Reacting to form a compound of formula (VIII);

(3) Reacting the compound of formula (VIII) to form a compound of formula (VII);

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

According to some embodiments of the invention, the method comprises the steps of:

(1) Reacting a compound of formula (X) with isopropyl malonate under the catalysis of triethylamine formate to generate a compound of formula (IX);

(3) In the presence of pyridine base, dichloromethane or 1, 2-dichloroethane is used as solvent, after the reaction of formula (VIII) and trifluoromethanesulfonic anhydride, inorganic base regulates the pH of the reaction solution to be alkaline, and then the compound of formula (VII) is prepared under acidic condition.

(1) The compound of formula (X) is reacted with isopropyl malonate under the catalysis of triethylamine formate, and is subjected to reductive decarboxylation to produce the compound of formula (IX);

(2) Compounds of formula (IX) and secondary amines NH (R) ³ )(R ⁴ ) Generating a compound of a formula (VIII) through condensation reaction;

According to some embodiments of the invention, step (2) is a condensation reaction in the presence of a condensing agent.

According to some embodiments of the invention, wherein the condensing agent of step (2) is selected from oxalyl chloride, thionyl chloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N, N' -carbonyldiimidazole.

Wherein R of secondary amine ³ And R is ⁴ The definition is as described in the foregoing.

In some embodiments, R ³ And R is ⁴ And forms a tetrahydropyrrole ring with the attached nitrogen atom.

In some embodiments, the method of preparing a compound of formula (VII) comprises the steps of:

(1) Reacting the compound of formula (X) with isopropyl malonate under the catalysis of triethylamine formate, and performing reductive decarboxylation to generate a compound of formula (IX);

(2) The compound of formula (IX) and the pyrrolidine undergo condensation reaction to generate a compound of formula (VIII);

(3) In the presence of 2,4, 6-trimethyl pyridine and trifluoromethanesulfonic anhydride, the addition reaction of formula (VIII) takes place, then inorganic base is used for regulating the pH value of the reaction solution to be alkaline to carry out hydrolysis reaction, and then rearrangement reaction takes place under acidic condition to obtain the compound of formula (VII).

The invention also provides a method for purifying a compound represented by formula (VII):

the method comprises the steps of adding a compound of a formula (VII) and sodium bisulphite into salt at normal temperature, extracting impurities by using an organic solvent, and then adding acid or alkali at normal temperature to react and performing post-treatment.

In some embodiments, the method comprises adding a compound of formula (VII) to sodium bisulfite to form a salt, extracting impurities with an organic solvent, and then post-treating after the reaction of adding an acid or a base at room temperature is completed to obtain a compound of formula (VII) with high purity:

According to some embodiments of the invention, the post-treatment comprises one or more of extraction, filtration, concentration, drying, and the like.

According to some embodiments of the invention, wherein the organic solvent may be selected from ethyl acetate, methylene chloride or methyl tert-butyl ether.

According to some embodiments of the invention, the acid is selected from mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid.

According to some embodiments of the invention, the acid is selected from hydrochloric acid or sulfuric acid.

According to some embodiments of the invention, wherein the base is selected from inorganic bases such as sodium hydroxide.

According to some embodiments of the invention, wherein the addition of the compound of formula (VI) with sodium bisulphite to form a salt is performed at room temperature.

The invention also provides a preparation method of the compound shown in the formula (I), wherein the method comprises the following steps:

(1) The compound (VII) generates a Horner-Wadsworth-Emmons reaction or a Wittig reaction to generate a compound of formula (VI);

(2) Reacting the compound of formula (VI) with nitromethane to produce a compound of formula (V);

(3) After the compound of the formula (V) undergoes a reduction reaction, the compound of the formula (V) reacts with chiral acid to obtain a compound of the formula (III);

(4) The compound of formula (III) is reacted to produce the compound of formula (I).

According to some embodiments of the invention, the compound of formula (III) is reacted to give the compound of formula (II) and then the compound of formula (I) is reacted with acid A.

According to some embodiments of the present invention, the compound of formula (IV) is reacted to give the compound of formula (XII) and then reacted from the compound of formula (XII) to give the compound of formula (I),

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ 。

(1) Preparing a compound of formula (VI) by taking the compound (VII) as a raw material;

(3) The compound of formula (V) undergoes a reduction reaction to obtain (IV), and then reacts with chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);

(4) The compound of the formula (III) is reacted to obtain a compound of the formula (II), and then the compound of the formula (II) is reacted with acid A to obtain a compound of the formula (I);

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

(4) Reacting a compound of formula (III) to produce a compound of formula (I);

According to some embodiments of the present invention, the compound of formula (V) is reduced, hydrolyzed, and then reacted with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII), and the compound of formula (XII) is hydrolyzed and then reacted with an acid a to obtain a compound of formula (I);

according to some embodiments of the present invention, after the reduction reaction of the compound of formula (V), the compound of formula (XII) is obtained by first reacting the compound of formula (XII) to form the compound of formula (I);

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

According to some embodiments of the present invention,

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ¹¹ selected from C _1-6 Alkyl of (a); preferably R ¹¹ Selected from methyl;

a is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.

(1) In the presence of alkali, the compound (VII) reacts with dimethoxy phosphonoacetic acid tert-butyl ester at the temperature of 10-40 ℃ to generate a compound (VI);

(2) Reacting the compound (VI) with nitromethane at 80-100 ℃ in the presence of alkali to generate a compound (V);

(3) In methanol solvent, nickel chloride hexahydrate is used as a catalyst, sodium borohydride is used as a reducing agent, and after the reduction reaction of the compound (V), the compound (V) reacts with chiral acid at 0-40 ℃ to obtain a compound of formula (III);

(4) Hydrolyzing the compound of formula (III) to obtain a compound of formula (II);

(5) The compound of formula (II) is reacted with A to give the compound of formula (I).

(1) Reacting the compound (VII) with dimethoxy phosphono acetic acid tert-butyl ester at the temperature of 10-40 ℃ and in the presence of alkali to generate a compound (VI);

(3) In a methanol solvent at 0-40 ℃, nickel chloride hexahydrate is used as a catalyst, sodium borohydride is used as a reducing agent, and after the reduction reaction of the compound (V), the compound (V) reacts with chiral acid to obtain a compound shown in a formula (III);

(5) The compound of formula (II) is reacted with benzenesulfonic acid to obtain the compound of formula (I).

According to some embodiments of the invention, wherein the base of step (1) is selected from potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene.

According to some embodiments of the invention, wherein the base of step (2) is selected from cesium carbonate, potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene.

According to some embodiments of the invention, wherein the chiral acid of step (3) is selected from the group consisting of compounds of formula (XI);

R ¹ the definition is the same as above.

According to some embodiments of the invention, wherein the chiral acid of step (3) is selected from (S) - (+) -O-acetyl-L-mandelic acid or L-mandelic acid.

The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:

(4) Preparing a compound of formula (VI) by taking the compound (VII) as a raw material;

(5) Reacting the compound of formula (VI) with nitromethane to produce a compound of formula (V);

(6) After the compound of formula (V) undergoes a reduction reaction, the compound of formula (V) reacts with chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);

(7) The compound of the formula (III) is reacted to obtain a compound of the formula (II), and then the compound of the formula (II) is reacted with acid A to generate a compound of the formula (I);

or the compound of the formula (V) undergoes a reduction reaction, is hydrolyzed and then reacts with chiral acid (preferably the compound of the formula (XI)) to obtain the compound of the formula (XII), and the compound of the formula (XII) undergoes hydrolysis and then reacts with acid A to generate the compound of the formula (I);

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

alternatively, R ³ And R is ⁴ Together with the carbon atom to which it is attached form a ring (preferably R ³ And R is ⁴ Forming a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom).

(2) Compounds of formula (IX) and secondary amines NH (R) ³ )(R ⁴ ) Takes place in condensation reactionA compound of formula (VIII);

(3) The compound of the formula (VIII) undergoes a ring closure reaction to produce a compound of the formula (VII);

(4) The compound (VII) generates a Horner-Wadsworth-Emmons reaction or a Wittig reaction to generate a compound of formula (VI);

(6) After the compound of the formula (V) undergoes a reduction reaction, the compound of the formula (V) reacts with chiral acid to obtain a compound of the formula (III);

(7) The compound of formula (III) is reacted to produce the compound of formula (I).

According to some embodiments of the present invention, the compound of formula (IV) is reacted first to give the compound of formula (XII), and then the compound of formula (XII) is reacted to give the compound of formula (I);

A、R ¹ 、R ² 、R ³ 、R ⁴ and the like are as defined above.

(7) Hydrolyzing the compound of formula (III) to obtain a compound of formula (II);

(8) The compound of formula (II) is reacted with an acid A to produce the compound of formula (I).

A、R ¹ 、R ² 、R ³ 、R ⁴ And the like are as defined above.

(4) The compound (VII) is subjected to HWE reaction or Wittig reaction to generate a compound of formula (VI);

(6) After the compound of the formula (V) undergoes a reduction reaction, hydrolyzing to obtain a compound 2B;

(7) Reacting the compound 2B with a chiral acid to obtain a compound of formula (XII);

(8) The compound of formula (XII) is reacted to form the compound of formula (I).

In another aspect, the present invention also provides a compound of formula (III),

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；R ¹¹ Selected from C _1-6 Alkyl of (a);

R ² selected from carboxyl protecting agents or C _1-6 Alkyl of (a);

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

The compound represented by the formula (III) can be used as an intermediate for producing the compound represented by the formula (I).

According to some embodiments of the invention, wherein R ¹¹ Selected from methyl, ethyl, propyl or tert-butyl.

According to some embodiments of the invention, wherein R ² Selected from methyl, ethyl, propyl, or tert-butyl.

The invention also provides a compound shown in a formula (II),

R ² selected from carboxyl protecting groups or C _1-6 Alkyl of (a); preferably R ² Selected from the group consisting of t-butyl.

The invention also provides a preparation method of the compound shown in the formula (II), which comprises the steps of taking the compound shown in the formula (IV) as a raw material, preparing the compound shown in the formula (III) by reacting with chiral acid, hydrolyzing to obtain the compound shown in the formula (II),

According to some embodiments of the invention, wherein the chiral acid is a compound of formula (XI),

according to some embodiments of the invention, the chiral acid is L-mandelic acid.

The invention also provides application of the compound shown in the formula (XI) in preparing a reference substance of the compound shown in the formula (II).

The invention also provides a compound shown in the formula (VIII) and a preparation method thereof,

wherein the method comprises the steps of

R ³ And R is ⁴ Each independently selected from C _1-6 Alkyl or R ³ And R is ⁴ Forming a ring;

provided that R ³ And R is ⁴ And are not methyl at the same time.

The invention also provides the following compounds and preparation methods thereof:

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

The invention also provides compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable salts thereof,

R ¹ selected from H, hydroxy protecting groups or-C (=O) R ¹¹ ；

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl or R ³ And R is ⁴ Looping (preferably R) ³ And R is ⁴ Forming a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom);

provided that R ³ And R is ⁴ And are not methyl at the same time.

The invention also provides a refining method of the compound shown in the formula (I), wherein the compound shown in the formula (I) is heated in an organic solvent (preferably N-methylpyrrolidone or dimethyl sulfoxide) until the compound is dissolved, isopropyl acetate and/or water are added, stirred for crystallization, filtered and dried under reduced pressure, and the compound is obtained:

According to some specific embodiments of the invention, the crude product of the compound of formula (I) is heated to 80+/-5 ℃ in N-methyl pyrrolidone, active carbon is added for stirring after the solid is completely dissolved, the mixture is filtered while the mixture is hot, isopropyl acetate is added into the filtrate, and the mixture is stirred for crystallization and filtered to obtain the compound.

According to some embodiments of the invention, wherein the crude compound of formula (I) and dimethyl sulfoxide are heated to 50±5 ℃, and after complete dissolution of the solid, purified water is added and stirred for crystallization. Filtering to obtain the final product.

It is understood that the preparation method according to the present invention includes two or more reaction steps in the word of the present invention, but may be actually performed in one reaction operation (i.e., the intermediate product is obtained without discharging after feeding, and the next reaction is performed in the reaction solution, for example, in a so-called "one-pot" manner), so that the preparation method may be mistakenly performed as one step, or the preparation method may be literally performed as one step, but may be actually split into two or more reaction steps, so that the preparation method may be mistakenly performed as multiple steps, which is within the scope of the present invention.

For example, in the examples of the present invention, the preparation of the compound of formula (II) from the compound of formula (III) and the preparation of the compound of formula (I) from the compound of formula (II) are combined in a single reaction operation, and it is understood that both reactions are described in the examples of the present invention.

Also, in the examples of the present invention, the preparation of the compound of formula (IV) from the compound of formula (V) and the preparation of the compound of formula (III) from the compound of formula (IV) are combined in a single reaction operation, and it should be understood that both reactions are described in the examples of the present invention.

In the chemical formulas of the present invention (+/-) represents a mixture of enantiomers of the indicated structure with exactly opposite chirality to the indicated structure.

The reaction process of the invention is generally monitored by TLC, MS, LCMS or/and nuclear magnetic resonance.

In summary, the invention provides a preparation method and an intermediate of a fused tricyclic gamma-amino acid derivative. The preparation method of the invention has the following advantages:

the compound of formula (VII) of the present invention has very low polarity, is very soluble in most solvents, has a low melting point, and is difficult to recrystallize and purify. And because it is solid at normal temperature, it is easy to sublimate and block the distillation apparatus by heating, and it is not tolerant to high temperature, and conventional distillation or reduced pressure distillation cannot purify. The purity of the crude product is only 50%, and the purity can be more than 98% after the refining of the invention.

The preparation method shortens the synthesis steps, simplifies the synthesis operation, has cheap and easily obtained raw materials, and greatly reduces the production of finished products; and secondly, the whole synthesis process adopts crystallization and purification, and silica gel column chromatography or other preparation chromatographic methods are not used, so that the method is suitable for large-scale industrial production.

Drawings

FIG. 1 is an X-ray single crystal diffraction pattern of Compound 1.

FIG. 2 is a molecular club model in single crystal of Compound 1.

Fig. 3 is an absolute configuration of compound 1.

Detailed Description

The following describes the technical scheme of the present invention in detail with reference to the drawings and the embodiments, but the protection scope of the present invention includes but is not limited to the same.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 300) with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), deuterated acetonitrile (CD ₃ CN), internal standard is Tetramethylsilane (TMS).

Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS measurement.

HPLC was determined using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X10.6mm).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies of tetan technology, an Naiji chemistry, shanghai de mer, chengdu Kelong chemical, shaoshan chemical technology, carbofuran technology, etc.

The proportion shown by the silica gel column chromatography is the volume ratio.

Example 1

2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid benzenesulfonate (1:1) (Compound 1)

2-((1S，2S，3R，6S，8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3，8 ]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1∶1)

The first step: 3- (cyclohexyl-3-en-1-yl) propionic acid (1B)

3-(cyclohex-3-en-1-yl)propanoic acid

Anhydrous formic acid (18.82 kg,409.09 mol) was pumped into a 100 liter reaction vessel, and the pumping was completed. Cooling to 10 ℃. Triethylamine (16.53 kg,163.64 mol) was added dropwise to the reaction mixture, stirred for 20 minutes, and when the internal temperature was 10 ℃, isopropyl malonate (7.86 kg,54.55 mol) was added to the reaction vessel, and 3-cyclohexene-1-carbaldehyde (6.00 kg,54.55 mol) was added dropwise to the reaction mixture at an internal temperature of 40℃until the addition was completed, and the temperature was programmed to 140-150℃until no gas was evolved. The pH of the reaction mixture was adjusted to 1-2 with 6N hydrochloric acid (24.0L). The aqueous phase was extracted with dichloromethane (12 L×2), the organic phases were combined and washed with saturated brine (10 L×2). The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 1 hour, filtered, and the filtrate was concentrated to dryness to give yellow oil 1B (8.80 kg).

¹ H NMR(400MHz，CDCl ₃ )δ10.23(s，1H)，5.73-5.55(m，2H)，2.46-2.30(m，2H)，2.09-1.96(m，2H)，1.81-1.53(m，6H)，1.35-1.17(m，1H)。

LCMS m/z＝153.1[M-1]。

And a second step of: 3- (cyclohexyl-3-en-1-yl) -1- (pyrrolidinyl-1-yl) propyl-1-one (1C)

3-(cyclohex-3-en-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

1B (11.20 kg,72.727 mol) was dissolved in methylene chloride (60.0L) and then pumped into a 100L reactor. DMF (3.0 mL) was added and oxalyl chloride (9.046 kg,71.272 mol) was added dropwise to the reaction. After the addition, the mixture was stirred at room temperature for 2.0 hours. Tetrahydropyrrole (5.689 kg,79.999 mol) followed by triethylamine (8.814 kg,87.272 mol) were added dropwise to the reaction vessel. The internal temperature is controlled to be lower than 10 ℃, and the mixture is stirred at room temperature overnight after the addition. The reaction solution was cooled to 10 ℃. 3N hydrochloric acid (20.0L) is added dropwise to adjust the pH of the reaction solution to be between 1 and 2. Standing, separating, and extracting the aqueous phase with dichloromethane (10.0 L×1). The organic phases were combined and washed successively with 5% sodium hydroxide solution (10.0 L.times.1) and saturated ammonium chloride solution (20.0 L.times.1). The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 30 minutes, filtered, and the filtrate was concentrated to give brown liquid 1C (15.00 kg, yield 99.6%).

¹ H NMR(400MHz，CDCl ₃ )δ5.73-5.56(m，2H)，3.43(dd，4H)，2.37-2.22(m，2H)，2.16-2.01(m，4H)，1.90(dt，4H)，1.81-1.51(m，6H)，1.30-1.15(m，2H)。

LCMS m/z＝208.1[M+1]。

And a third step of: tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-ones (1R, 3S,6R,8R and 1S,3R,6S,8S racemates) (1D)

tricyclo[4.2.1.0 ^3，8 ]nonan-2-one(1R，3S，6R，8R and 1S，3R，6S，8S racemate)

1C (5.64 kg,27.22 mol) was dissolved in methylene chloride (40.0L) and then pumped into a 100L reaction vessel. Cooled to-10℃and 2,4, 6-trimethylpyridine (4.94 kg,40.83 mol) was added. A methylene chloride solution (16.0L) of trifluoromethanesulfonic anhydride (11.50 kg,40.83 mol) was added dropwise to the reaction solution. Reflux was performed for 12 hours. After the completion of the reaction for the center control detection, an aqueous solution (23.0L) of sodium hydroxide (3.10 kg,77.5 mol) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted to 10-11. Reflux was continued for 5-6 hours. The mixture was allowed to stand to separate, the aqueous phase was extracted with methylene chloride (5.0L. Times.1), and the organic phases were combined. The organic phase is pumped into a reaction kettle and cooled to 10 ℃. 2.0N hydrochloric acid solution (20.0L) is added dropwise to adjust the pH of the reaction solution to 1-2. The mixture was allowed to stand and separated, the organic phase was washed with saturated brine (20 L.times.1), concentrated, and the residue was dissolved in acetone (20.0L), and then, the mixture was pumped into a 100L reactor, stirred, and a solution of concentrated sulfuric acid (4.0L) and water (20.0L) was added dropwise, followed by refluxing for 2 hours. The temperature was lowered to 15℃and saturated brine (20.0L) was added to the reaction mixture, followed by extraction with n-hexane (15.0L. Times.2). The organic phases were combined, washed with saturated brine (20.0L. Times.1), and dried over anhydrous sodium sulfate overnight. After filtration and concentration of the filtrate under reduced pressure, crude 1D (3.00 kg, yield 81%) as a yellow solid was obtained with a purity of 50%.

1D further purification step:

method 1: anhydrous sodium bisulphite (5.730 kg,55.147 mol) was dissolved in 66L of purified water and added to a 100L reaction vessel, a solution of crude 1D (3.00 kg,22.059 mol) in ethanol (3.0L) was added with stirring at room temperature, stirred overnight at room temperature, extracted with ethyl acetate (20 l×2), the aqueous phase was added to the reaction vessel with stirring and cooling to 10 ℃, a solution of sodium hydroxide (2.250 kg,56.250 mol) in water (10L) was added dropwise, pH was adjusted to 10-12, after addition, stirred at room temperature for 2 hours, extracted with n-hexane (20 l×2), the organic phase was combined and washed with purified water (20 l×1), dried for 1 hour with anhydrous sodium sulfate (2 kg), filtered, the filtrate was evaporated to dryness to give 1D as a colorless crystalline solid (2.7 kg, yield 90%) with purity of 98.3%.

Method 2: sodium bisulphite (1529 g,14.706 mol) was dissolved in 22L of water, and a solution of the crude 1D (1000 g,7.353 mol) in absolute ethanol (1000 mL) was added dropwise with stirring, and stirred overnight (24 hours) at room temperature after the addition. The reaction solution was extracted with methylene chloride (5 L.times.2) to remove impurities, a sulfuric acid solution (prepared by adding 6.4L of concentrated sulfuric acid and 6 kg of crushed ice) was added dropwise to the aqueous phase, stirred at room temperature for 5 hours, the reaction solution was extracted with n-hexane (3-4 times each time by 4L) and the organic phases were combined and washed with a saturated aqueous sodium chloride solution (5 L.times.2), the organic phases were dried over 1kg of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was evaporated to dryness to give 1D as a white solid (900 g, yield: 90%) with a purity of 98.1% determined.

¹ H NMR(400MHz，CDCl ₃ )δ3.39(m，1H)，3.19(m，1H)，2.77(m，1H)，2.38(m，1H)，2.05(m，1H)，1.93(d，1H)，1.77(m，1H)，1.45(m，4H)，1.20(m，1H)。

LCMS m/z＝137.1[M+1]。

Fourth step: tert-butyl 2- (tricyclo [ 4.2.1.0) ^3，8 ]Nonylalkyl-2-ylidene) acetate (1R, 3S,6R,8R and 1S,3R,6S,8S racemates) (1E)

tert-butyl 2-tricyclo[4.2.1.0 ^3，8 ]nonan-2-ylidene)acetate(1R，3S，6R，8Rand 1S，3R，6S，8S racemate)

Potassium tert-butoxide (742.0 g,6.62 mol) and tetrahydrofuran (6.20L) were charged into a 20L reaction vessel. Reducing the temperature to 5 ℃, dropwise adding dimethoxy phosphonoacetic acid tert-butyl ester (1480 g,6.62mol,1.1 eq) into the reaction liquid, controlling the reaction temperature to 10-15 ℃ and continuously stirring for 1 hour. Then, a solution of 1D (820.0 g,6.02mol,1.0 eq) in tetrahydrofuran (2.0L) was added dropwise to the reaction mixture over 1 hour, and the mixture was allowed to naturally warm to room temperature after the addition for 2 hours. Saturated ammonium chloride (2.0L) solution and purified water (2.0L) were sequentially added to the reaction vessel. After stirring for 20 minutes, the mixture was allowed to stand for separation, and the aqueous phase was extracted with methyl tert-butyl ether (1.5L. Times.2). The organic phases were combined, washed with saturated brine (2L. Times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1E as a yellow liquid (1.50 kg).

LCMS m/z＝235.3[M+1]。

Fifth step: tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetates (1R, 2R,3S,6R,8R and 1S,2S,3R,6S,8S racemates) (1F)

tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.03，8]nonan-2-yl)acetate(1R，2R，3S，6R，8R and 1S，2S，3R，6S，8S racemate)

To a 20L reactor was added 1E (1.40 kg,5.97mol,1.0 eq), nitromethane (1.82 kg,29.85mol,5.0 eq) and dimethyl sulfoxide (9.8L) in that order. Cesium carbonate (2.34 kg,7.16mol,1.2 eq) was added to the reaction solution with stirring. After the addition, the mixture is heated to 80-85 ℃, the reaction is continued for 5 hours at a temperature, then the mixture is cooled to room temperature, purified water (20.0L) is added into a reaction kettle, and the aqueous phase is extracted by methyl tertiary butyl ether (8.0L multiplied by 3). The organic phases were combined, washed with saturated brine (8.0L. Times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave brown liquid 1F (1.62 kg, yield: 92%).

LCMS m/z＝318.1[M+23]。

Sixth step: tert-butyl 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetate (S) -2-acetoxy-2-phenylacetic acid (1H)

tert-butyl2-((1S，2S，3R，6S，8S)-2-(aminomethyl)tricyclo[4.2.1.03，8]nonan-2-yl)acetate(S)-2-acetoxy-2-phenylacetate

To a 50L reactor was added 1F (730.0 g,2.47 mol) and methanol (7.3L). Nickel chloride hexahydrate (118 g,0.49mol,0.2 eq) was added to the reaction under stirring, the reaction mixture was cooled to 5℃and sodium borohydride (264 g,9.88mol,4.0 eq) was added in portions, and the reaction system was maintained at a temperature of 20℃to 30℃for about 3 hours. The reaction was continued with stirring for 2 hours after the addition. Ice water (16.4L) was added to the reaction vessel and the aqueous phase was filtered through celite. The filtrate was extracted with dichloromethane (3.0 L.times.2) and the organic phases were combined, washed with saturated brine (4 L.times.1), and dried over anhydrous sodium sulfate. The mixture was filtered, and (S) - (+) -O-acetyl-L-mandelic acid (384 g,1.97mol,0.8 eq) was added to the filtrate, followed by stirring for 20 minutes. The organic phase was concentrated by distillation until no solvent was distilled off, and then, stirred and slurried with isopropyl alcohol (5.9L) for 2 hours, cooled to 5℃and stirred for 1 hour. Filtration, washing of the filter cake with isopropanol (0.4 L.times.1) and drying gave crude product 1H as a white solid (422 g, yield: 34.96%). The ee value of the solid obtained after derivatization was determined to be 48.35%.

First crystallization: crude product 1H (420.0 g,0.92 mol), isopropanol (4.20L) and water (0.21L) were added sequentially to the reaction vessel. The temperature was programmed to 82℃to dissolve the solid completely and the temperature was maintained for 0.5 hours. Cooling to 20 ℃ for crystallization for about 6 hours. At an internal temperature of 20 ℃, filtration and washing of the filter cake with isopropanol (0.40 l×1). The solids were combined and air dried at 60-65 ℃ for 4 hours to constant weight. A first crystal of 1H (260 g, yield: 62%) was obtained, and the ee value was determined to be 81.25% after derivatization of the solid.

And (3) secondary crystallization: 1H first crystals (177 g,0.39 mol), isopropyl alcohol (2.53L) and water (0.126L) were sequentially added to the reaction vessel. The temperature was programmed to 82℃to dissolve the solid completely and the temperature was maintained for 0.5 hours. Cooling to 20 ℃ for crystallization for about 4.5 hours. At an internal temperature of 30 ℃, filtration and washing of the filter cake with isopropanol (0.10 l×1). The solids were combined and air dried at 60-65 ℃ for 4 hours to constant weight. A pure 1H product (128 g, yield: 72%) was obtained as a white solid, the ee value was 99.73% after derivatization of the solid.

LCMS m/z＝266.3[M+1]。

Seventh step: 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid benzenesulfonic acid compound (1:1) (Compound 1)

1H pure (100.0 g,0.218 mol) and purified water (0.8L) were added sequentially to the reaction vessel, and the temperature was lowered to 0-10 ℃. The internal temperature is 0-10 ℃, 1mol/L NaOH (218 mL) aqueous solution is added into the reaction kettle in a dropwise manner, and the pH of the reaction liquid is adjusted to 9-10. The mixture was allowed to stand and separated, and the aqueous phase was extracted with methylene chloride (0.30L. Times.2). The organic phases were combined and washed successively with 1mol/L NaOH (0.10LX1) solution and saturated brine (0.15LX1). Activated carbon (5.0 g) was added to the organic phase to decolorize and dry over anhydrous sodium sulfate. The filtrate was filtered and concentrated, and the residue in the concentrating tank was dissolved with acetonitrile (280 mL). Benzenesulfonic acid monohydrate (77.0 g,0.437 mol) was prepared as a solution in purified water (280 mL) and added dropwise to the acetonitrile solution. The temperature is programmed to 80-85 ℃, and the reaction is kept for 4-6 hours. Cooling the reaction liquid to 10-20 ℃ for crystallization for about 4-6 hours. At an internal temperature of 10-20deg.C, the mixture was filtered, and the filter cake was washed with water (30 mL. Times.1) and acetonitrile (50 mL. Times.1) in this order. Compound 1 is obtained after drying as a white solid (72 g, yield: 90%).

¹ H NMR(400MHz，MeOD)δ7.83(m，2H)，7.42(m，3H)，3.31(dt，4H)，2.86(m，1H)，2.55(d，2H)，2.48(ddd，1H)，2.32(dd，1H)，2.15(m，1H)，2.04(m，1H)，1.77(m，1H)，1.62(m，4H)，1.45(m，1H)，1.28(dt，1H)。

LCMS m/z＝210.1[M+1]。

Compound 1 (100 mg) was placed in a glass vial, 0.2ml of water and 0.2ml of dimethyl sulfoxide were added, the temperature was raised to 80 degrees celsius for clearing, and after holding for 5 minutes, the temperature was naturally lowered to room temperature, to obtain a rod-like crystal.

Hot stage Polarized Light Microscopy (PLM) and single crystal diffractometer detection (see table 1),

table 1 detection method

The results are shown in Table 2, table 3, FIGS. 1-3;

TABLE 2 Single crystal structure data

TABLE 3 Single Crystal chiral resolution results

After the residues in the concentrating kettle are dissolved by acetonitrile by the same method, p-toluenesulfonic acid or methanesulfonic acid is respectively prepared into solutions, the solutions are dripped into the acetonitrile solutions, and after the reaction is finished, the following products are respectively obtained through post-treatment:

example 2

Tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetates (1R, 2R,3S,6R,8R and 1S,2S,3R,6S,8S racemates) (1F)

tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 ^3，8 ]nonan-2-yl)acetate(1R，2R，3S，6R，8R and 1S，2S，3R，6S，8S racemate)

The first step: tert-butyl 2- (tricyclo [ 4.2.1.0) ^3，8 ]Nonylalkyl-2-ylidene) acetate (1R, 3S,6R,8R and 1S,3R,6S,8S racemates) (1E)

tert-butyl 2-(tricyclo[4.2.1.0 ^3，8 ]nonan-2-ylidene)acetate(1R，3S，6R，8Rand 1S，3R，6S，8S racemate)

1, 8-diazabicyclo undec-7-ene (288 g,1.90 mol) and tert-butyl dimethoxyphosphonoacetate (197g, 0.88 mol) were placed in a reaction flask at room temperature and stirring was continued for 20 minutes after addition. 1D (100 g,0.73 mol) was then added to the reaction overnight. The temperature was raised to 40℃and the reaction was carried out for 6 hours. A yellow liquid was obtained and was directly subjected to the next reaction 1E (172 g).

LCMS m/z＝257.1[M+23]。

And a second step of: tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetates (1R, 2R,3S,6R,8R and 1S,2S,3R,6S,8S racemates) (1F)

To a 2L reactor was added, in order, 1E reaction solution (172 g,0.73 mol), nitromethane (224 g,3.67 mol), 1, 8-diazabicyclo undec-7-ene (134 g,0.88 mol) and dimethyl sulfoxide (500 mL). Heating to 80-85 deg.c, and maintaining the temperature for 5 hr. Cooled to room temperature, purified water (2.0L) was added to the reaction vessel, and the aqueous phase was extracted with methyl tert-butyl ether (800 mL. Times.3). The organic phases were combined, washed with saturated brine (800 mL. Times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave brown liquid 1F (193 g, yield: 90%).

LCMS m/z＝318.1[M+23]。

Example 3

Potassium tert-butoxide (9.06 g,80.76 mmol) and tetrahydrofuran (150 mL) were charged to a 1L reactor. The temperature is reduced to 5 ℃, and dimethoxy phosphonoacetic acid tert-butyl ester (18.11 g,80.76mmol,1.1 eq) is added dropwise into the reaction solution, the reaction temperature is controlled between 10 ℃ and 15 ℃, and the dropwise addition is completed about 20 minutes. Stirring is continued for 0.5 hour, and the temperature is controlled to be 10-15 ℃. A solution of 1D (10.0 g,73.42mmol,1.0 eq) in tetrahydrofuran (50.0 mL) was then added dropwise to the reaction solution over 0.5 hour, and the mixture was allowed to naturally warm to room temperature for 2 hours. Saturated ammonium chloride (100.0 mL) was added to the reaction vessel in sequence, and the reaction was quenched with purified water (100.0 mL). After stirring for 20 minutes, the mixture was allowed to stand for separation, and the aqueous phase was extracted with methyl tert-butyl ether (50.0 mL. Times.1). The organic phases were combined, washed with saturated brine (100.0 mL. Times.1), and dried over anhydrous sodium sulfate. Filtration and concentration gave yellow liquid 1E (17.5 g).

LCMS m/z＝257.1[M+23]。

To a 250mL reaction flask was added 1E (16.5 g,70.41mmol,1.0 eq), nitromethane (24.49 g,0.35mol,5.0 eq) and dimethyl sulfoxide (116 mL) in sequence. Potassium tert-butoxide (15.8 g,0.14mol,2.0 eq) was then added to the reaction solution. After the addition, heating to 80-85 ℃, and continuing to perform heat preservation reaction for 8 hours. Cooled to room temperature, purified water (450 mL) was added to the reaction vessel and the aqueous phase was extracted with methyl tert-butyl ether (150 mL. Times.3). The organic phases were combined, washed with saturated brine (150 mL. Times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave brown liquid 1F (20.8 g).

LCMS m/z＝318.1[M+23]。

Example 4

tert-butyl 2-(tricyclo[4.2.1.0 ^3，8 ]nonan-2-ylidene)acetate(1R，3S，6R，8R and 1S，3R，6S，8S racemate)

Potassium tert-butoxide (1.23 kg,11.0 mol) and tetrahydrofuran (10.0L) were charged into a 50L reaction vessel. Reducing the temperature to 5 ℃, dropwise adding dimethoxy phosphonoacetic acid tert-butyl ester (2.50 kg,11.0mol,1.1 eq) into the reaction liquid, controlling the reaction temperature to 10-15 ℃ and finishing the dropwise adding about 40 minutes. Stirring is continued for 0.5 hour, and the temperature is controlled to be 10-15 ℃. A solution of 1D (1.36 kg,10.0mol,1.0 eq) in tetrahydrofuran (3.60L) was then added dropwise to the reaction solution over 0.5 hour. Naturally heating to room temperature after the addition is finished, and reacting for 2 hours. After the reaction of the central control detection raw materials is completed, 5% ammonium chloride solution (6.0L) is sequentially added into the reaction kettle to quench the reaction. After stirring for 20 minutes, the mixture was allowed to stand for separation, and the aqueous phase was extracted with methylene chloride (5.0 L.times.1). The organic phases were combined, washed with 5% brine (5.0L. Times.1), and dried over anhydrous sodium sulfate. Filtration and concentration gave yellow liquid 1E (2.40 kg).

LCMS m/z＝257.1[M+23]。

To a 50L reactor was added 1E (2.34 kg,10.0mol,1.0 eq), nitromethane (1.53 kg,25.0mol,2.5 eq) and dimethyl sulfoxide (2.34L) in that order. Stirring was started and potassium tert-butoxide (15.8 g,0.14mol,2.0 eq) was added to the reaction solution. After the addition, heating to 85-90 ℃, and continuing to perform heat preservation reaction for 10 hours. When the concentration of the raw materials is less than 2%, the raw materials are cooled to 25 ℃, purified water (8.50L) is added into a reaction kettle, and the aqueous phase is extracted with dichloromethane (3.50L multiplied by 3). The organic phases were combined and washed successively with 0.5mol/L hydrochloric acid solution (2.0LX1), 0.5mol/L sodium hydroxide solution (2.0LX1) and 5% sodium chloride solution (2.0LX1). Filtering, concentrating the filtrate under reduced pressure at 35+ -5deg.C until no large amount of distillate flows out. Heating to 55+ -5deg.C, continuously evaporating under reduced pressure to remove nitromethane, sampling, and controlling nitromethane content to be less than 5%. Brown liquid 1F (2.95 kg) was obtained.

LCMS m/z＝318.1[M+23]。

Example 5

Tert-butyl 2- (2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetate (racemate of 1R,2R,3S,6R,8R and 1S,2S,3R,6S, 8S) (2A)

tert-butyl2-((1R，2R，3S，6R，8R)-2-(aminomethyl)tricyclo[4.2.1.0 ^3，8 ]nonan-2-yl)acetate(1R，2R，3S，6R，8R and 1S，2S，3R，6S，8S racemate)

To the flask was added 1F (90 g,0.31 mol), methanol (900 mL), palladium on carbon 10% (9.0 g), and hydrogen gas was purged three times to hydrogenate at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give yellow liquid 2A (73.5 g, yield: 91%).

Ms m/z(ESI)：266.1(M+1)。

Example 6

To the flask were added 1F (70 g,0.24 mol), ethanol (360 mL) and water (120 mL), and iron powder (67.2 g,1.2 mol) and ammonium chloride (38.5 g,0.72 mol) were added in this order, followed by a reaction at Bi Yu 90 ℃for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, purified water (450 mL) was added thereto, and the aqueous phase was extracted with methylene chloride (150 mL. Times.3). The organic phases were combined, washed with saturated brine (150 mL. Times.2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 2A (55 g, yield: 88%) as a yellow liquid.

Ms m/z(ESI)：266.1(M+1)。

Example 7

Tert-butyl 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Recrystallization of nonylalkyl-2-yl acetate (S) -2-acetoxy-2-phenylacetic acid (1H)

The method comprises the following steps:

crude 1H (80.0 g,0.17 mol), isopropanol (750 mL) and water (50 mL, v: v=15:1) were added sequentially to the reaction flask. The temperature was raised to dissolve the solid completely and the temperature was maintained for 0.5 hours. Cooling to 20deg.C, crystallizing, filtering, washing the filter cake with isopropanol (0.40LX1), and drying at 60-65deg.C for 4 hr. 60g of 1H first recrystallized product is obtained, yield: 75%) of a solid was obtained and the ee value was 97.22%.

And (3) secondary recrystallization: 1H the first recrystallized product (137 g,0.30 mol), isopropanol (1284 mL) and water (85.6 mL, v: v=15:1) were added sequentially to the reaction vessel. The temperature was raised to dissolve the solid completely and the temperature was maintained for 0.5 hours. Cooling to 20deg.C, crystallizing, filtering, washing the filter cake with isopropanol (0.10Lx1), and drying at 60-65deg.C. A second recrystallisation of 1H as a white solid (112 g, yield: 82%) was obtained, the ee value being 99.72% after derivatization of the solid.

LCMS m/z＝266.3[M+1]。

The second method is as follows:

and (3) secondary recrystallization: 1H the first recrystallized product (10.0 g,21.76mmol, ee% = 77%) was added sequentially to the reaction flask, isopropanol and water (290 mL/10mL, v: v = 29:1). The temperature was raised to dissolve the solid completely and the temperature was maintained for 0.5 hours. Cooling to 30deg.C, crystallizing, filtering, washing filter cake with isopropanol (10.0 m L ×1). The solids were combined and dried at 60-65 ℃. A second recrystallisation of 1H as a white solid (6.1 g, yield: 61%) was obtained, the ee value being determined to be 97.3% after derivatization of the solid.

LCMS m/z＝266.3[M+1]。

Example 8

1H (10.0 g,21.77 mol) and purified water (100.0 mL) were added sequentially to the reaction flask. Cooling to 0-10deg.C. When the internal temperature reaches 0-10 ℃, 25% ammonia water solution (4.0 mL) is added dropwise into the reaction solution, and the pH value of the reaction solution is regulated to 9-10. The mixture was allowed to stand and separated, and the aqueous phase was extracted with isopropyl acetate (50.0 mL. Times.2). The organic phases were combined and washed with saturated brine (50.0 mL. Times.1). Activated carbon (0.5 g) was added to the organic phase to decolorize and dry over anhydrous sodium sulfate. Filtration, and benzenesulfonic acid monohydrate (8.06 g,43.54 mmol) was added to the filtrate. Heating to 80-85 deg.C. And (3) preserving heat for reaction for 4-6 hours, and completely reacting the central control detection raw materials. Cooling to 20-25 deg.c with ice water for crystallization for about 2 hr. At an internal temperature of 20-25℃the filter cake was filtered and washed with isopropyl acetate (10 mL. Times.1). After drying, compound 1 (7.8 g, yield: 97.6%) was obtained as a white solid.

Example 9

2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid benzenesulfonic acid compound (1:1) (Compound 1)

1H (4.59 g,10.0 mmol) and purified water (40.0 mL) were added sequentially to the reaction flask. Cooling to 0-10deg.C. When the internal temperature reaches 0-10 ℃, 1.0mol/L sodium hydroxide solution (11.0 mL) is added dropwise into the reaction solution, and the pH value of the reaction solution is regulated to 9-10. The mixture was allowed to stand and separated, and the aqueous phase was extracted with methylene chloride (25.0 mL. Times.2). The organic phases were combined and washed successively with 0.5mol/L sodium hydroxide solution (20.0 mL. Times.1) and saturated brine (25.0 mL. Times.1). Activated carbon (0.5 g) was added to the organic phase to decolorize and dry over anhydrous sodium sulfate. After filtration, acetonitrile (26.0 mL) and benzenesulfonic acid monohydrate (3.50 g,20.0 mmol) were added after the filtrate was concentrated. Heating to 80 ℃. And (3) preserving heat for reaction for 4-6 hours, and completely reacting the central control detection raw materials. Cooling the ice water to 25 ℃ for crystallization for about 2 hours. At internal temperature to 25 ℃, filter cake was washed with acetonitrile (3.0 ml×2). After drying, compound 1 (3.4 g, yield: 92.6%) was obtained as a white solid.

Example 10

1H (150 g,0.33 mol) and purified water (1500 mL) were added sequentially to the reaction flask. Cooling to 0-10 ℃, dropwise adding 1.0mol/L sodium hydroxide solution (360 mL) into the reaction solution, adjusting the pH of the reaction solution to 9-10, and stirring for 1 hour. The mixture was allowed to stand and separated, and the aqueous phase was extracted with methylene chloride (800 mL. Times.2). The organic phases were combined and washed successively with 1.0mol/L sodium hydroxide solution (300.0 mL. Times.1) and 10% brine (300.0 mL. Times.1). Activated carbon (5.0 g) was added to the organic phase and decolorized with stirring. Diatomite was filtered, and acetonitrile (328.0 mL), purified water (328.0 mL) and benzenesulfonic acid monohydrate (114 g,0.66 mol) were added after the filtrate was concentrated. Heating to 80 ℃. The reaction is kept for 12 hours, and the reaction of the central control detection raw material is less than 0.2 percent and is complete. Cooling the ice water to 10+/-5 ℃, and stirring for about 6 hours for crystallization. At an internal temperature of 10 ℃, filtration, washing the filter cake with acetonitrile and water (V: v=1:1, 150ml×1), dichloromethane (150 ml×1) in this order, and draining. The solid was dried under reduced pressure to give compound 1 (104 g, yield: 86.9%) as a white solid.

Compound 1 may be further purified by the following method:

method 1: compound 1 (430.0 g,1.17 mol) and N-methylpyrrolidone (2.15L) were added to a 5L reaction flask. After the addition, the mixture was heated to 80.+ -. 5 ℃ and kept for 0.5 hours. After the solid was completely dissolved, activated carbon (10 g) was added and stirring was continued for 10 minutes. The mixture was filtered while it was still hot, and the filter cake was washed with N-methylpyrrolidone (400 mL. Times.1) and dried by suction. Isopropyl acetate (7.5L) was added dropwise to the filtrate, and the mixture was stirred and crystallized for 2 hours. The mixture was filtered, and the cake was washed with isopropyl acetate (500.0 mL), dried under reduced pressure for 8 hours to give compound 1 (420.0 g, yield: 97.7%) as a white solid.

Method 2: compound 1 (410 g,1.12 mol) and dimethyl sulfoxide (1230 mL) were added to a 5L reaction flask. After the addition, the mixture was heated to 50.+ -. 5 ℃ and kept for 0.5 hours. After the solid is completely dissolved, adding purified water (2460 mL) dropwise, cooling to 15 ℃ in a water bath after adding, and continuously stirring and crystallizing for 2 hours. The mixture was filtered, and the cake was washed successively with purified water (400.0 mL. Times.1), methylene chloride (400.0 mL. Times.2), and dried under reduced pressure to give compound 1 (352 g, yield: 85.8%) as a white solid.

Example 11

(S) -2-hydroxy-2-phenylacetic acid 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid (1:1) (Compound 2)

(S)-2-hydroxy-2-phenylacetic acid compound with 2-((1S，2S，3R，6S，8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3，8 ]nonan-2-yl)acetic acid(1∶1)

The first step: 2- (2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ](racemate of 1R,2R,3S,6R,8R and 1S,2S,3R,6S, 8S) nonylacetic acid (2B)

2-(2-(aminomethyl)tricyclo[4.2.1.03，8]nonan-2-yl)acetic acid(1R，2R，3S，6R，8Rand 1S，2S，3R，6S，8S racemate)

To the reaction flask was added 2A (44.45 g,0.17 mol) followed by methylene chloride (150.0 mL). Stirring and cooling to 0-5 ℃, and dripping trifluoroacetic acid (60.0 mL) into the reaction liquid. After the addition, the reaction was carried out at 0℃to 10℃for 6 hours, and TLC was used to monitor complete conversion of the starting material, and the reaction solution was concentrated to remove the solvent. Dichloromethane (150.0 mL) was added to the residue and the temperature was reduced to 0-5 ℃. The pH was adjusted to 7-8 with triethylamine (60.0 mL) and a white solid precipitated and stirred for 1 hour. Filtration and washing of the filter cake with dichloromethane (50.0 mL) combined solids dried gave 2B as a white solid (22.0 g, yield: 68.4%).

LCMS m/z＝210.1[M+1]。

And a second step of: (S) -2-hydroxy-2-phenylacetic acid 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid (1:1) (Compound 2)

To a 100mL reaction flask was added 2B (6.32 g,30.0 mmol), L-mandelic acid (8.86 g,45.0 mmol), isopropanol (62.0 mL) and water (12.4 mL) in this order. After the addition, heating to 82 ℃ to dissolve the solid completely, preserving the heat for 0.5 hour, naturally cooling to 20 ℃ and crystallizing for about 6 hours. At an internal temperature of 20 ℃, filtration and washing of the filter cake with isopropanol (5.0 ml×2). The solid was dried for 1 hour to give a white solid (3.2 g, yield: 24.2%).

First crystallization: a100 mL reaction flask was charged with the white solid salt (3.2 g), isopropanol (32 mL) and water (5.2 mL) in this order. Heating to 82 deg.c to dissolve the solid completely, maintaining for 0.5 hr, cooling to 20 deg.c and crystallizing for about 6 hr. At an internal temperature of 20 ℃, filtration and washing of the filter cake with isopropanol (5.0 ml×2). The solids were combined and dried for 1 hour to give a first crystals (2.0 g, yield: 62.5%) which were found to have an ee value of 53% after derivatization.

And (3) secondary crystallization: the first crystals (1.0 g), ethanol (16.0 mL) and water (1.3 mL) were added sequentially to a 100mL reaction flask. Heating to 82 deg.c to dissolve the solid completely, maintaining for 0.5 hr, cooling to 20 deg.c and crystallizing for about 4.5 hr. At an internal temperature of 30 ℃, filtration and washing of the filter cake with ethanol (1.0 ml×2) were carried out. The solids were combined, dried for 1 hour and dried to constant weight to give compound 2 (0.63 g, yield 63%) and the ee value was determined to be 72% after derivatization.

Compound 2 was prepared in a similar manner to example 1 to give compound 1.

Example 12

3- (cyclohexyl-3-en-1-yl) -1- (pyrrolidinyl-1-yl) propyl-1-one (1C)

3-(cyclohex-3-en-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

3-cyclohexene-1-propionic acid (4.11 kg,26.68mol, leq) was dissolved in methylene chloride (20.0L) and charged into a 50L reaction vessel. Cooled to 20℃and triethylamine (4.04 Kg,40.03mol,1.5 eq) was added. 1-hydroxybenzotriazole (4.32 kg,32.02mol,1.2 eq) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.11 kg,32.02mol,1.2 eq) were then added in sequence and stirred for 30 minutes after the addition. Tetrahydropyrrole (2.46 kg,34.69mol,1.3 eq) was added dropwise when the temperature was lowered to 0 ℃, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with purified water (15.0LX2), 2.0mol/L hydrochloric acid (15.0LX3). The organic phase was dried over anhydrous sodium sulfate (2.0 kg), filtered, and the filtrate was concentrated to dryness to give 1C (6.60 kg) as a brown oil.

LCMS m/z＝208.1[M+1]。

Example 13

(R) -2-hydroxy-2-phenylacetic acid 2- ((1S, 2S,3R,6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 ^3，8 ]Nonylalkyl-2-yl) acetic acid (1:1) (Compound 2)

2A (1.0 g,3.77 mmol) was dissolved in acetonitrile (25.0 mL). D-mandelic acid (286.0 mg,1.89mmol,0.5 eq) was dissolved in acetonitrile (5 mL) and was added dropwise to the reaction, followed by stirring at room temperature for 4 hours. Filtration, washing of the filter cake with acetonitrile (2.0 mL. Times.1) and drying gave a crude product of compound 3 as a white solid (0.48 g, yield: 37%). The ee value was determined to be 41.9% after derivatization of the solid.

And (5) recrystallizing: the crude compound 3 (0.48 g,1.15 mmol) and acetonitrile (15.0 mL) were added to the reaction flask. Stirring for 3 hours at room temperature after the addition. Filtration, washing of the filter cake with acetonitrile (2.0 mL. Times.1) and drying gave compound 3 (0.22 g, yield: 45%) as a white solid. The ee value of the sample derived assay was 73.00%.

Claims

1. A process for the preparation of a compound of formula (I), wherein the process comprises: preparing a compound of formula (VII) from a compound of formula (VIII) and an anhydride in the presence of a pyridine base; then in the presence of a base selected from potassium tert-butoxide, 1, 8-diazabicyclo undec-7-ene, lithium diisopropylamide, potassium carbonate or lithium hydride, reacting the compound of formula (VII) with any one compound selected from dimethoxy phosphonoacetic acid tert-butyl ester, diethoxy phosphonoacetic acid tert-butyl ester, bromoacetic acid tert-butyl ester, chloroacetic acid tert-butyl ester or acetoacetic acid tert-butyl ester to generate a compound of formula (VI); then reacting the compound (VI) with nitromethane at a temperature of 60-reflux in the presence of a base selected from cesium carbonate, potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene to generate a compound (V); then taking the compound of the formula (V) as a raw material, and preparing the compound of the formula (IV) at 0-40 ℃ in the presence of a catalyst/reducing agent; then the compound of the formula (IV) is taken as a raw material to obtain the compound of the formula (III) through reaction, then the compound of the formula (III) is taken as a raw material to prepare the compound of the formula (I),

R ¹ selected from H, or-C (=O) R ¹¹ ；

R ² Selected from C _1-6 Alkyl of (a);

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

alternatively, R ³ And R is ⁴ And the carbon atoms to which they are attached together form a ring;

R ¹¹ selected from C _1-6 Is a hydrocarbon group.

2. The preparation method according to claim 1, wherein R ² Selected from t-butyl; r is R ¹¹ Selected from methyl groups.

3. The production process according to claim 1, wherein the production of the compound (III) comprises producing the compound of formula (III) starting from the compound of formula (IV) and a chiral acid;

the chiral acid is selected from the group consisting of compounds of formula (XI);

R ¹ the definition is the same as claim 1.

4. The process according to claim 3, wherein the chiral acid and the compound of formula (IV) are reacted at a molar ratio of 0.5:1 to 1:1 under room temperature to reflux conditions.

5. A process for the preparation of a compound of formula (I), wherein the process comprises: preparing a compound of formula (VII) from a compound of formula (VIII) and an anhydride in the presence of a pyridine base; then in the presence of a base selected from potassium tert-butoxide, 1, 8-diazabicyclo undec-7-ene, lithium diisopropylamide, potassium carbonate or lithium hydride, reacting the compound of formula (VII) with any one compound selected from dimethoxy phosphonoacetic acid tert-butyl ester, diethoxy phosphonoacetic acid tert-butyl ester, bromoacetic acid tert-butyl ester, chloroacetic acid tert-butyl ester or acetoacetic acid tert-butyl ester to generate a compound of formula (VI); then reacting the compound (VI) with nitromethane at a temperature of 60-reflux in the presence of a base selected from cesium carbonate, potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene to generate a compound (V); then taking the compound of the formula (V) as a raw material, and preparing the compound of the formula (IV) at 0-40 ℃ in the presence of a catalyst/reducing agent; then, the compound of the formula (IV) is taken as a raw material to obtain a compound of the formula (III), then the compound of the formula (III) is taken as a raw material to obtain a compound of the formula (II), and the compound of the formula (II) is taken as a raw material to prepare the compound of the formula (I);

A、R ¹ 、R ² 、R ³ 、R ⁴ The definition is the same as claim 1.

6. The method of claim 5, wherein

Reacting a compound of formula (II) with an acid a in a solvent compatible with the compound of formula (II) to obtain a compound of formula (I), the solvent being selected from acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water, toluene, dioxane, or a combination thereof; the molar ratio of the acid A to the compound of formula (II) is 1.1:1-5:1, and the reaction is carried out at 70-90 ℃.

7. The process according to claim 6, wherein the molar ratio of acid A to the compound of formula (II) is 1.1:1, and the reaction is carried out at 80-85 ℃.

8. The process according to claim 6, wherein the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate.

9. The production process according to claim 1 or 5, wherein the process further comprises a refining process of the compound of formula (III), comprising recrystallizing the compound of formula (III) in a recrystallization solvent;

R ¹ selected from H or-C (=O) R ¹¹ ；

R ² Selected from C _1-6 Alkyl of (a);

R ¹¹ selected from C _1-6 Alkyl of (a);

the mass-volume ratio of the compound of the formula (III) to the recrystallization solvent is 1:10-1:30; repeating the recrystallization for 1-2 times; wherein the method comprises the steps of

The recrystallization solvent is isopropanol and water.

10. The preparation method according to claim 9, wherein R ² Selected from t-butyl; r is R ¹¹ Selected from methyl groups.

11. The preparation method according to claim 9, wherein the volume ratio of isopropanol to water is 10:1-30:1.

12. The production process according to any one of claims 1 to 5, wherein the catalyst/reducing agent is selected from raney nickel/hydrazine hydrate, nickel chloride hexahydrate/sodium borohydride, iron powder/ammonium chloride, 10% palladium on carbon/triethylsilicon, raney nickel/hydrogen, 10% palladium on carbon/hydrogen or zinc powder/acetic acid.

13. The process according to any one of claims 1 to 5, wherein the compound (VI) is reacted with nitromethane at a temperature of 80 ℃ to 100 ℃.

14. The process according to any one of claims 1 to 5, wherein the compound (VI) is reacted with nitromethane at a temperature of 60℃to reflux in the presence of a solvent selected from the group consisting of dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone and tetrahydrofuran to give the compound (V).

15. The process according to any one of claims 1 to 5, wherein the compound (VI) is reacted with nitromethane at a temperature of 60 ℃ to reflux in the presence of a solvent selected from dimethyl sulfoxide and N, N-dimethylformamide to produce the compound (V).

16. The process according to any one of claims 1 to 5, wherein the reaction temperature at which the compound of formula (VII) is reacted with any one compound selected from the group consisting of t-butyl dimethoxyphosphonoacetate, t-butyl diethoxyphosphorylacetate, t-butyl bromoacetate, t-butyl chloroacetate and t-butyl acetoacetate to give the compound of formula (VI) is 10℃to 40 ℃.

17. A process for producing a compound of formula (VII), wherein the process comprises producing a compound of formula (VII) starting from a compound of formula (VIII),

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

the method comprises the following steps:

(1) Reacting a compound of formula (VIII) in the presence of an anhydride and a pyridine base; the pyridine base is 2,4, 6-trimethyl pyridine, 2, 6-dimethyl pyridine or pyridine;

(2) Adjusting the pH value of the reaction solution obtained in the step (1) to 8-11 by using inorganic alkali;

(3) Acidifying the mixture obtained in the step (2) with inorganic acid to obtain the compound of the formula (VII).

18. The method of claim 17, wherein R ³ And R is ⁴ And forms a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom.

19. The production method according to claim 17, wherein the acid anhydride is trifluoromethanesulfonic acid anhydride or p-toluenesulfonic acid anhydride; the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate or cesium carbonate; the inorganic acid is sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid.

20. The process according to any one of claims 17 to 19, wherein the process further comprises reacting the compound of formula (IX) with a secondary amine NH (R ³ )(R ⁴ ) The method comprises the steps of (1) reacting in the presence of a condensing agent to prepare a compound shown in a formula (VIII), wherein the condensing agent is selected from oxalyl chloride, thionyl chloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N, N' -carbonyldiimidazole;

21. the process according to claim 20, wherein the process further comprises the step of reacting the compound of formula (X) with isopropyl malonate as starting material under the catalysis of triethylamine formate to form the compound of formula (IX),

22. a process for the preparation of a compound of formula (VII), wherein said process comprises the steps of:

(2) Compounds of formula (IX) and secondary amines NH (R) ³ )(R ⁴ ) Reacting in the presence of a condensing agent selected from oxalyl chloride, thionyl chloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N, N' -carbonyldiimidazole to form a compound of formula (VIII);

(3) In the presence of pyridine base, the compound of formula (VIII) reacts with trifluoromethanesulfonic anhydride, inorganic base adjusts the pH of the reaction solution to be alkaline, and then the compound of formula (VII) is prepared under acidic condition;

R ³ and R is ⁴ Each independently selected from C _1-6 Alkyl of (a);

23. The method of claim 22, wherein R ³ And R is ⁴ And forms a tetrahydropyrrole ring with the attached nitrogen atom.

24. The production method according to claim 17 or 22, wherein the method further comprises a method for purifying a compound represented by the formula (VII):

adding a compound of formula (VII) and sodium bisulphite into salt at normal temperature, extracting impurities by using an organic solvent, and then adding acid or alkali at normal temperature to react and performing post-treatment to obtain the sodium bisulphite; the organic solvent is selected from ethyl acetate, dichloromethane or methyl tertiary butyl ether; the acid is hydrochloric acid or sulfuric acid; the alkali is sodium hydroxide.

25. A process for the preparation of a compound of formula (I), wherein said process comprises the steps of:

(1) In the presence of pyridine base, after the compound of formula (VIII) reacts with trifluoromethanesulfonic anhydride, inorganic base adjusts the pH of the reaction solution to be alkaline, the reaction is continued until the intermediate reaction is completed, and acid is used for acidizing the reaction solution to obtain the compound of formula (VII);

(2) In the presence of alkali, the compound (VII) reacts with dimethoxy phosphonoacetic acid tert-butyl ester at the temperature of 10-40 ℃ to generate a compound (VI); the base is selected from potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene;

(3) Reacting the compound (VI) with nitromethane at 80-100 ℃ in the presence of alkali to generate a compound (V); the base is selected from cesium carbonate, potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene;

(4) In methanol solvent, nickel chloride hexahydrate is used as a catalyst, sodium borohydride is used as a reducing agent, the compound (V) is subjected to reduction reaction to obtain a compound (IV), and then the compound (IV) reacts with chiral acid at 0-40 ℃ to obtain a compound of formula (III); the chiral acid is selected from the group consisting of compounds of formula (XI);

(5) The compound of the formula (III) is reacted to obtain a compound of the formula (II), and then the compound of the formula (II) is reacted with acid A to obtain a compound of the formula (I);

or the compound of the formula (V) undergoes a reduction reaction, is hydrolyzed and then reacts with chiral acid to obtain the compound of the formula (XII), and the compound of the formula (XII) undergoes hydrolysis and then reacts with acid A to generate the compound of the formula (I); the chiral acid is a compound of formula (XI);

/>

A、R ¹ 、R ² The definition is the same as claim 1.

26. The method according to claim 25, wherein the chiral acid is selected from (S) - (+) -O-acetyl-L-mandelic acid or L-mandelic acid.

27. A process for the preparation of a compound of formula (I), wherein the process comprises the steps of:

(2) In the presence of a condensing agent, a compound of formula (IX) is reacted with a secondary amine NH (R ³ )(R ⁴ ) Generating a compound of a formula (VIII) through condensation reaction;

(4) In the presence of alkali, the compound (VII) reacts with dimethoxy phosphonoacetic acid tert-butyl ester at the temperature of 10-40 ℃ to generate a compound (VI);

(5) Reacting the compound (VI) with nitromethane at 80-100 ℃ in the presence of alkali to generate a compound (V);

(6) In methanol solvent, nickel chloride hexahydrate is used as a catalyst, sodium borohydride is used as a reducing agent, and after the reduction reaction of the compound (V), the compound (V) reacts with chiral acid at 0-40 ℃ to obtain a compound of formula (III); the chiral acid is a compound of formula (XI)

A、R ¹ 、R ² 、R ³ 、R ⁴ the definition is the same as claim 1.

28. A compound of formula (VIII) and isomers or pharmaceutically acceptable salts thereof,

R ³ and R is ⁴ Each independently selected from C _1-6 An alkyl group; or R is ³ And R is ⁴ Forming a ring;

provided that R ³ And R is ⁴ And are not methyl at the same time.

29. The compound of claim 28, wherein R ³ And R is ⁴ And forms a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom.

30. The process for producing according to claim 1, 5, 25 or 27, wherein the process further comprises a process for purifying a compound represented by the formula (I), wherein the compound of the formula (I) is heated in N-methylpyrrolidone or dimethylsulfoxide until it is dissolved, isopropyl acetate and/or water are added, stirred for crystallization, filtered, and dried under reduced pressure to obtain: