TW202019872A - Preparation method for fused tricyclic [gamma]-amino acid derivative and intermediate thereof - Google Patents

Abstract

A preparation method for a fused tricyclic [gamma]-amino acid derivative and an intermediate thereof, and a method for preparing an intermediate of the fused tricyclic [gamma]-amino acid derivative. The fused tricyclic [gamma]-amino acid derivative has a structure as represented by formula (I). The preparation method uses readily available raw materials and comprises simple steps; the entire synthesis process uses crystallization purification, while silica gel column chromatography or other preparatory chromatography methods are not used, being suitable for large-scale industrial production.

Description

Preparation method and intermediate of condensed tricyclic γ-amino acid derivative

The present invention relates to the field of medicine. Specifically, the present invention relates to a method for preparing condensed tricyclic γ-amino acid derivatives and intermediates.

The voltage-gated calcium channel is composed of the α1 subunit and the accessory protein α2δ, β, and γ subunits. α2δ protein can regulate the density of calcium ion channels and the voltage-dependent dynamics of calcium ion channels (Felix et al (199 7) 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. Pharmacol. 62:485-496). It has been demonstrated that compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ can effectively treat pain, such as pregabalin and gabapentin. In mammals, the α2δ protein has four subtypes, and each subtype is encoded by a different gene. α2δ subtype 1 and subtype 2 showed high affinity with pregabalin, while α2δ subtype 3 and subtype 4 had no significant drug binding force.

However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy who improved the pain to a large extent is about 60% (Acta Neurol. Scand. 101:359-371, 2000). For pregabalin, although its tolerance is better than gabapentin , But its safety is lower, and it is possible to abuse or make patients dependent (Am J Health Syst Pharm. 2007;64(14):1475-1482).

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

An object of the present invention is to provide a method for preparing condensed tricyclic γ-amino acid derivatives.

Another object of the present invention is to provide intermediates for preparing fused tricyclic γ-amino acid derivatives.

To achieve the above objective, on the one hand, the present invention provides a method for preparing a compound represented by formula (I), wherein the method comprises preparing the compound of formula (III) as a raw material,

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from carboxy protecting group or C _1-6 alkyl;

R ^{11 is} selected from C _1-6 alkyl.

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

According to some specific embodiments of the invention, wherein R ^{2 is} selected from methyl, ethyl, propyl, n-butyl or tertiary butyl.

According to some specific embodiments of the invention, wherein R ^{2 is} selected from the third butyl group.

According to some specific embodiments of the invention, wherein R ^{11 is} selected from methyl, ethyl, propyl or butyl.

According to some specific embodiments of the invention, wherein R ^{11 is} selected from methyl.

It can be understood that the compound of formula (III) is reacted to prepare the compound of formula (I), which can be hydrolyzed to obtain a free base, and then acid A is added to remove the carboxyl protecting group and form a salt. It is also possible to remove the carboxyl protecting group first, and then hydrolyze to obtain the free base, and then form a salt with the acid A.

（I）

（II）The present invention provides a method for preparing a compound represented by formula (I), wherein the method includes preparing the compound of formula (II) as a raw material for reaction;

(I)

(II)

R ^{2 is} defined as above.

（I） A定義同前。Among them, the compound represented by formula (I) is as follows:

(I) A is defined as above.

（II），

（III）The invention provides a method for preparing a compound of formula (II), which is prepared by using a compound of formula (III) as a raw material

(II),

(III)

The definitions of R ¹ and R ² are the same as above.

According to some specific embodiments of the present invention, the method includes first preparing the compound of formula (II) from the compound of formula (III), and then preparing the compound of formula (I) from the compound of formula (II),

A, R ¹ and R ^{2 are} as defined above.

According to some specific embodiments of the present invention, wherein the method includes first preparing the compound of formula (II) from the compound of formula (III), and then reacting the compound of formula (II) in the presence of acid A to obtain the formula ( I) Compound.

The present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes reacting a compound of formula (II) as a raw material to prepare a compound represented by formula (I).

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group.

According to some specific embodiments of the invention, wherein R ^{2 is} selected from the third butyl group.

According to some specific embodiments of the present invention, the compound of formula (II) is reacted with acid A to prepare the compound of formula (I).

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

According to some specific embodiments of the present invention, the molar ratio of acid A to the 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 specific embodiments of the present invention, wherein the reaction of the compound of formula (II) and acid A can be performed from room temperature to reflux;

In some specific embodiments, the reaction temperature is 70-90°C;

In some specific embodiments, the reaction temperature is 80-85°C.

In some embodiments, the solvent of the compound of formula (II) and acid A is selected from any solvent that is compatible with the compound of formula (II), such as acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water , Toluene, dioxane and their combined solvents.

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) and acid A are reacted in a solvent that is compatible with the compound of formula (II) to obtain the compound of formula (I), the solvent is 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 1.1:1 to 5:1, at 70-90℃ More preferably, 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°C; still more preferably, the solvent is selected from acetonitrile and dichloromethane Or isopropyl acetate.

According to some specific embodiments of the present invention, wherein the method further includes the step of preparing the compound represented by formula (II) using the compound of formula (III) as a raw material,

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from carboxy protecting group or C _1-6 alkyl;

R ^{11 is} selected from C _1-6 alkyl.

According to some specific embodiments of the invention, wherein R ^{2 is} selected from the third butyl group.

According to some specific embodiments of the invention, wherein R ^{11 is} selected from methyl.

（IV）The present invention also provides a method for preparing a compound of formula (III), wherein the method includes the step of reacting with a compound of formula (IV) as a raw material to obtain a compound of formula (III),

(IV)

R ^{2 is} as defined above.

（III），Among them, the compound of formula (III) is as follows:

(III),

R ^{1 is} defined as above.

According to some specific embodiments of the present invention, a method for preparing the compound of formula (III), wherein the preparation of the compound (III) includes preparing the compound of formula (III) using the compound of formula (IV) and palmitic acid as raw materials.

（XI）The palmitic acid of the present invention is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diethyl-L-tartaric acid, L-aspartic acid or dextroquinic acid,

(XI)

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ; R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl.

。According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein:

.

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from carboxy protecting group or C _1-6 alkyl;

R ^{11 is} selected from C _1-6 alkyl.

According to some specific embodiments of the invention, wherein R ^{2 is} selected from the third butyl group.

According to some specific embodiments of the invention, wherein R ^{11 is} selected from methyl.

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

According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the molar ratio of the palmitic acid to the compound of formula (IV) is 0.5:1 to 1:1.

According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein palmitic acid and a compound of formula (IV) are reacted under room temperature to reflux conditions.

According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the palmitic acid is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diethyl acetyl -L-tartaric acid, L-aspartic acid or dextroquinic acid; further preferably, the molar ratio of the palmitic acid to the compound of formula (IV) is 0.5:1-1:1 at room temperature React under reflux conditions.

According to some specific embodiments of the present invention, wherein the method includes reacting the compound of formula (IV) as a raw material to obtain the compound of formula (III), and then recrystallizing (recrystallizing) the compound of formula (III).

（III）The invention also provides a method for refining the compound represented by formula (III). The compound of formula (III) is recrystallized in a recrystallization solvent:

(III)

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl.

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

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

According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the organic solvent is selected from a mixture of one or more of isopropyl alcohol, acetonitrile, or ethanol;

According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the organic solvent is isopropyl alcohol.

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

According to some specific 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):1.

According to some specific 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 10:1-30:1.

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

According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the preparation of the compound of formula (III) includes first preparing the compound of formula (III) from the compound of formula (IV) and palmitic acid, Then, the compound of formula (III) is recrystallized to obtain a purified compound.

（XI）According to some specific embodiments of the present invention, wherein the palmitic acid is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid or D-quinic acid,

(XI)

Wherein R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{11 is} selected from C _1-6 alkyl;

In some specific embodiments, R ^{11 is} selected from methyl, ethyl, propyl, or butyl;

In some specific embodiments, R ^{11 is} selected from methyl.

（XI）According to some specific embodiments of the invention, wherein the palmitic acid is selected from compounds of formula (XI),

(XI)

Wherein R ^{1 is} selected from H or -C(=O)R ¹¹ ;

R ^{11 is} selected from methyl.

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

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

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

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

According to some specific embodiments of the present invention, the compound of formula (XI) and the compound of formula (IV) are reacted at 80-90°C.

According to some specific embodiments of the present invention, wherein the method includes reacting the compound of formula (IV) as a raw material to obtain a crude compound of formula (III), and then using a recrystallization solvent, such as an organic solvent and/or water The crude product is recrystallized.

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

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

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

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

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

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

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

According to some specific embodiments of the present invention, wherein the recrystallization step includes dissolving the crude product of formula (III) in a recrystallization solvent, stirring the reaction for 0.5 to 1 hour, and then crystallizing.

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

It can be understood that the repetition is repeated on the basis of the first time. For example, if it is repeated once, it is recrystallized twice; if it is repeated twice, it is equivalent to recrystallized three times.

According to some specific embodiments of the present invention, wherein the method further comprises the step of preparing the compound of formula (IV) using the compound of formula (V) as a raw material,

R ^{2 is} as defined above.

According to some specific embodiments of the present invention, the preparation of the compound of formula (IV) includes: using the compound of formula (V) as a raw material in the presence of a catalyst and a reducing agent to prepare the compound of formula (IV) at 0-40°C.

In some embodiments, the catalyst/reducing agent where compound (V) undergoes a reduction reaction to form compound (IV) may be selected from Raney nickel/hydrazine hydrate, nickel chloride hexahydrate/sodium borohydride, iron powder/chlorination Ammonium, 10% palladium carbon/triethylsilicon, Raney nickel/hydrogen, 10% palladium 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 carbon/hydrogen.

In some embodiments, the reduction conditions are: 0-40°C, in alcohol solvent, nickel chloride hexahydrate as a catalyst, and sodium borohydride as a reducing agent; or, 0-40°C, in alcohol solvent, palladium Carbon acts as a catalyst and hydrogen acts as a reducing agent. In certain embodiments, the alcohol solvent is methanol or ethanol.

In certain embodiments, the temperature of the reduction reaction is 20°C to 30°C.

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

In some embodiments, the molar ratio of the compound of formula (V) to the reducing agent is 1:2~1:10, in some embodiments, the molar ratio is 1:2.5~1:5, in some implementations In the scheme, the molar ratio is 1:2.5, 1:3, 1:4, 1:5.

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

According to some specific embodiments of the present invention, wherein the method further includes the preparation of the compound of formula (V): including preparing the compound of formula (V) from the compound of formula (VI),

R ^{2 is} as defined above.

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

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

According to some specific embodiments of the present invention, wherein the base is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.

According to some specific embodiments of the present invention, the temperature of the addition reaction is from 60°C to reflux.

According to some specific embodiments of the present invention, the temperature of the addition reaction is 80°C to 100°C.

According to some specific embodiments of the present invention, the temperature of the addition reaction ranges from 85°C to 90°C.

According to some specific embodiments of the present invention, the temperature of the addition reaction ranges from 80°C to 85°C.

According to some specific embodiments of the present invention, in the presence of a base, compound (VI) and nitromethane undergo an addition reaction to form compound (V); alternatively, a solvent may be present, the solvent selected from dimethyl sulfoxide Or N,N-dimethylformamide.

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

In some embodiments, the molar ratio of the compound (V) reacted with 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 specific embodiments of the present invention, wherein the method further includes the preparation of the compound of formula (VI): including preparing the compound of formula (VI) from the compound of formula (VII),

.

According to some specific embodiments of the present invention, wherein the preparation of the compound of formula (VI) includes: in the presence of a base, the compound of formula (VII) is selected from the group consisting of dimethoxyphosphonoacetate third butyl acetate, diethoxyphosphorus A compound of formula (VI) can be produced by reacting any of the compounds of the third butyl acetyl acetate, the third butyl bromoacetate, the third butyl chloroacetate, or the third butyl acetyl acetate.

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

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

According to some specific embodiments of the present invention, the temperature at which the compound of formula (VII) reacts with the third butyl dimethoxyphosphonoacetate is 10°C to 40°C.

According to some specific embodiments of the present invention, the temperature at which the compound of formula (VII) reacts with the third butyl dimethoxyphosphonoacetate is 10°C to 30°C.

According to some specific embodiments of the present invention, the temperature at which the compound of formula (VII) reacts with the third butyl dimethoxyphosphonoacetate is 10°C to 15°C.

According to some specific embodiments of the present invention, the temperature at which the compound of formula (VII) reacts with the third butyl dimethoxyphosphonoacetate is 20°C to 40°C.

According to some specific embodiments of the present invention, the temperature at which the compound of formula (VII) reacts with the third butyl dimethoxyphosphonoacetate is 30°C to 40°C.

According to some specific embodiments of the present invention, wherein the third butyl dimethoxyphosphonoacetate can be replaced with third butyl diethoxyphosphonoacetate, third butyl bromoacetate, and third butyl chloroacetate Ethyl acetate or tertiary butyl acetate.

According to some specific embodiments of the present invention, wherein the molar ratio of compound (VII) to the third butyl dimethoxyphosphonoacetate is from 1:1 to 1:10.

According to some specific embodiments of the present invention, wherein the molar ratio of compound (VII) to the third butyl dimethoxyphosphonoacetate is 1:1.1~1:5.

According to some specific embodiments of the present invention, the molar ratio of compound (VII) to the third butyl dimethoxyphosphonoacetate is 1:1.1~1:2.

According to some specific embodiments of the present invention, wherein the molar ratio of compound (VII) to the third butyl dimethoxyphosphonoacetate is 1:1.1~1:1.5.

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

The present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes preparing a compound of formula (VII) using a compound of formula (VIII) as a raw material,

R ³ and R ⁴ are each independently selected from C _1-6 alkyl;

Optionally, R ³ and R ⁴ together with the carbon atom to which they are attached form a ring.

According to some specific embodiments of the present invention, wherein R ³ and R ⁴ are each independently selected from methyl, ethyl or isopropyl.

According to some specific embodiments of the invention, wherein R ³ and R ⁴ form a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom.

According to some specific embodiments of the invention, wherein R ³ and R ⁴ form a tetrahydropyrrole ring with the attached nitrogen atom.

According to some specific embodiments of the present invention, wherein the method includes preparing the compound of formula (VII) by reacting the compound of formula (VIII) with an acid anhydride in the presence of a pyridine base.

The acid anhydride of the present invention is selected from trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride.

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

According to some specific embodiments of the present invention, wherein the method includes preparing the compound of formula (VII) by reacting the compound of formula (VIII) with trifluoromethanesulfonic anhydride and a base of pyridine.

According to some specific embodiments of the present invention, after the reaction between the compound of formula (VIII) and the base of pyridine and trifluoromethanesulfonic anhydride is completed, a step of alkali treatment of the reaction solution with an alkali is further included.

According to some specific embodiments of the present invention, wherein, after the reaction between the compound of formula (VIII) and the base of pyridine and trifluoromethanesulfonic anhydride, the reaction solution is subjected to alkali treatment with an alkali to adjust the pH to alkaline; in some implementations In the scheme, the pH is adjusted to 10-11.

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; pH to basic may be selected from a pH of 8- 14, 8-11, 9-11 or 10-11.

According to some specific embodiments of the present invention, wherein, after the reaction between the compound of formula (VIII) and the base of pyridine and trifluoromethanesulfonic anhydride, the reaction solution is subjected to alkali treatment with a base, and then the reaction is continued until the intermediate reaction is completed, further including The step of acidifying the reaction liquid with acid.

The acidification treatment in the present invention refers to adjusting the pH of the reaction solution to be acidic with acid.

According to some specific embodiments of the present invention, the acidizing treatment refers to adjusting the reaction solution to be acidic with an inorganic acid.

According to some specific embodiments of the present invention, the acidification treatment refers to adjusting the pH of the reaction solution to 1-4.

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

According to some specific embodiments of the present invention, wherein, after the reaction between the compound of formula (VIII) and the base of pyridine and trifluoromethanesulfonic anhydride, the reaction solution is subjected to alkali treatment with a base, and then the reaction is continued until the intermediate reaction is completed, further including Acidify the reaction solution with acid and adjust the pH to 1-2;

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

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

In some embodiments, the method for preparing the compound represented by formula (VII) includes the following steps:

(1) The compound of formula (VIII) in acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and pyridine base (preferably 2,4,6-trimethylpyridine, 2,6-dimethyl Pyridine or pyridine) reaction;

(2) Adjust the pH of the reaction solution obtained in step (1) to alkali with alkali (preferably inorganic alkali, further preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate or cesium carbonate) Sex, preferably adjust the pH to 8-11;

(3) The mixture obtained in step (2) is acidified with an inorganic acid (preferably sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid) to obtain the compound of formula (VII).

According to some specific embodiments of the present invention, wherein the method for preparing the compound represented by formula (VII) includes the following steps:

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

(2) The inorganic base adjusts the pH of the reaction solution to alkaline, and is hydrolyzed to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and carbonic acid Sodium hydrogen, cesium fluoride or cesium carbonate;

(3) Under acidic conditions, acidify the reaction solution, adjust the pH to 1-4, and rearrange the compound of formula (VII-1) in the mixture obtained in step (2) to obtain the compound of formula (VII); Wherein, the acid is an inorganic acid, which is one or more kinds selected from sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.

In some embodiments, the method for preparing the compound represented by formula (VII) includes the following steps:

(1) Dichloromethane or 1,2-dichloroethane is used as a solvent. In the presence of a pyridine base and trifluoromethanesulfonic anhydride, an addition reaction of formula (VIII) occurs; where the pyridine base refers to a structure containing pyridine Base, such as 2,4,6-trimethylpyridine, 2,6-lutidine or pyridine;

(2) The inorganic base adjusts the pH of the reaction solution to alkaline, and is hydrolyzed to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and carbonic acid Sodium hydrogen, cesium fluoride or cesium carbonate; pH to basic can be selected from pH values of 8-14, 8-11, 9-11 or 10-11;

(3) Under acidic conditions, the rearrangement of the compound of formula (VII-1) in the mixture of formula (VII) and formula (VII-1) is converted into the compound of formula (VII), where the solvent of the reaction may be any acid stable The solvent, in certain embodiments, is selected from acetone or acetonitrile. The acidic conditions may be selected from pH values of 1-4, 1-3 or 1-2, and in certain embodiments from pH values of 1-2. The acidic conditions can be adjusted using common inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.

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

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

According to some specific embodiments of the present invention, the method for preparing the compound represented by formula (VIII) further includes reacting the compound of formula (IX) with a secondary amine NH(R ³ )(R ⁴ ) to prepare a compound of formula (VIII) step,

R ³ and R ^{4 are} as defined above.

According to some specific embodiments of the present invention, wherein the compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) are reacted in the presence of a condensing agent to prepare the compound of formula (VIII).

The definition of R ³ and R ^{4 of the} secondary amine is as described above in the present invention. In some specific embodiments, R ³ and R ⁴ form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.

According to some specific embodiments of the present invention, wherein the condensing agent is selected from oxalyl chloride, dichloromethane, 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 some embodiments, the molar ratio is 1:1 to 5, in certain embodiments, the molar ratio It is 1:1~2, in some embodiments, the molar ratio is 1:1.1.

In certain embodiments, the reaction temperature of the compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) to prepare the compound of formula (VIII) is room temperature, in certain embodiments, the reaction temperature is 20 ~30℃.

。According to some specific embodiments of the present invention, wherein the method further comprises the step of preparing the compound of formula (IX) from the compound of formula (X),

.

According to some specific embodiments of the present invention, the compound of formula (IX) is prepared from the compound of formula (X) and the isopropyl malonate ring.

According to some specific embodiments of the present invention, wherein, under the catalysis of triethylamine formate, the compound of formula (X) reacts with the malonic acid cyclic (iso)isopropyl ester to form the compound of formula (IX).

According to some specific embodiments of the present invention, wherein the method includes the reaction of a compound of formula (X) with a malonic acid cyclic (methylene) isopropyl ester catalyzed by triethylamine formate, and is reduced to decarboxylate to formula (IX) Compound.

According to some specific embodiments of the present invention, wherein the triethylamine formate can be prepared from formic acid and triethylamine.

According to some specific embodiments of the present invention, wherein the compound of formula (X) and the malonate cyclic (iso)isopropyl ester are reacted with anhydrous formic acid as the reaction medium.

In certain embodiments, the molar ratio of the compound of formula (X) to the malonate cyclic (iso)isopropyl ester is not greater than 1, in some embodiments, the molar ratio is 1:1 to 5, in a certain In some embodiments, the molar ratio is 1:1 to 2, in some embodiments, the molar ratio is 1:1.

According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (X) and the malonic acid cyclic (iso)isopropyl ester is 100-180°C. In some embodiments, the reaction temperature is 140-160°C. In some embodiments, the reaction temperature is 140-150°C.

According to some specific embodiments of the present invention, after the reaction of the compound of formula (X) and the malonic acid cyclic (iso)isopropyl ester, the reductive decarboxylation reaction is carried out under acidic conditions, where the acidic conditions are pH 1-5, 1-4 in certain embodiments, 1-3 in certain embodiments, 1-2 in certain embodiments. The acid conditions are provided by common inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.

The present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes the following steps:

(1) The compound of formula (X) reacts with malonic acid ring (iso)isopropyl ester to form the compound of formula (IX);

(2) The compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) to produce the compound of formula (VIII);

(3) The compound of formula (VIII) reacts to form the compound of formula (VII);

R ³ and R ⁴ are each independently selected from C _1-6 alkyl;

Optionally, R ³ and R ⁴ together with the carbon atom to which they are attached form a ring.

According to some specific embodiments of the invention, wherein R ³ and R ⁴ form a tetrahydropyrrole ring with the attached nitrogen atom.

According to some specific embodiments of the present invention, wherein the method includes the following steps:

(1) Under the catalysis of triethylamine formate, the compound of formula (X) reacts with the malonic acid ring (iso)isopropyl ester to produce the compound of formula (IX);

(2) The compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) to produce the compound of formula (VIII);

(3) Dichloromethane or 1,2-dichloroethane is used as a solvent. In the presence of a pyridine base, after formula (VIII) reacts with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to alkaline, and then The compound of formula (VII) is prepared under acidic conditions.

According to some specific embodiments of the present invention, wherein the method includes the following steps:

(1) Under the catalysis of triethylamine formate, the compound of formula (X) reacts with the malonic acid ring (iso)isopropyl ester, and is reduced and decarboxylated to produce the compound of formula (IX);

(2) The compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) undergo a condensation reaction to form the compound of formula (VIII);

(3) Dichloromethane or 1,2-dichloroethane is used as a solvent. In the presence of a pyridine base, after formula (VIII) reacts with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to alkaline, and then The compound of formula (VII) is prepared under acidic conditions.

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

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

The definition of R ³ and R ^{4 of the} secondary amine is as described above in the present invention.

In some specific embodiments, R ³ and R ⁴ form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.

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

(1) Under the catalysis of triethylamine formate, the compound of formula (X) reacts with the malonic acid cyclic (iso)isopropyl ester, and is reduced and decarboxylated to produce the compound of formula (IX);

(2) The compound of formula (IX) undergoes condensation reaction with tetrahydropyrrole to form the compound of formula (VIII);

(3), dichloromethane or 1,2-dichloroethane as a solvent, in the presence of 2,4,6-trimethylpyridine and trifluoromethanesulfonic anhydride, the addition reaction of formula (VIII) occurs, and then use inorganic The base adjusts the pH of the reaction solution to alkaline to undergo a hydrolysis reaction, and then undergo a rearrangement reaction under acidic conditions to obtain the compound of formula (VII).

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

(VII)

The method includes adding a compound of formula (VII) and sodium bisulfite at room temperature to form a salt, extracting impurities with an organic solvent, and then adding acid or alkali at room temperature to complete the reaction and after the post-treatment.

In some embodiments, the method includes adding a compound of formula (VII) to sodium bisulfite to form a salt, extracting impurities with an organic solvent, and then adding an acid or an alkali at room temperature to complete the post-treatment to obtain a high-purity formula (VII) Compound:

According to some specific embodiments of the present invention, the above-mentioned post-treatment includes one or more operations of extraction, filtration, concentration, drying, and the like.

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

According to some specific embodiments of the present invention, wherein the aforementioned acid is selected from inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.

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

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

According to some specific embodiments of the present invention, the addition salt of the compound of formula (VI) and sodium bisulfite is carried out at room temperature.

The present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:

(1) Compound (VII) undergoes Horner–Wadsworth–Emmons reaction or Wittig reaction to produce compound of formula (VI);

(2) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

(3) After the reduction reaction of the compound of formula (V), react with palmitic acid to obtain the compound of formula (III);

(4) The compound of formula (III) reacts to form the compound of formula (I).

According to some specific embodiments of the present invention, the compound of formula (III) is first reacted to obtain the compound of formula (II), and then the compound of formula (II) is reacted with acid A to form the compound of formula (I).

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

(XII);

R ^{1 is} selected from H, a hydroxy protecting group, or -C(=O)R ¹¹ .

The present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:

(1) Compound (VII) is prepared by using compound (VII) as raw material;

(2) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

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

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

;

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl.

According to some specific embodiments of the present invention, the method includes the following steps:

(1) Compound (VII) undergoes Horner–Wadsworth–Emmons reaction or Wittig reaction to produce compound of formula (VI);

(2) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

(3) After the reduction reaction of the compound of formula (V), react with palmitic acid to obtain the compound of formula (III);

(4) The compound of formula (III) reacts to form the compound of formula (I);

According to some specific embodiments of the present invention, the compound of formula (III) is first reacted to obtain the compound of formula (II), and then the compound of formula (II) is reacted with acid A to form the compound of formula (I).

According to some embodiments of the present invention, after the reduction reaction of the compound of formula (V), after hydrolysis, it is reacted with palmitic acid (preferably compound of formula (XI)) to obtain the compound of formula (XII), formula (XII) The compound is hydrolyzed and then reacted with acid A to form the compound of formula (I);

（XII）；According to some specific embodiments of the present invention, after the compound of formula (V) undergoes a reduction reaction, the compound of formula (XII) is first reacted, and then the compound of formula (XII) is reacted to form the compound of formula (I);

(XII);

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl.

According to some specific embodiments of the invention,

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl;

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

According to some specific embodiments of the present invention, wherein the method includes the following steps:

(1) In the presence of a base, compound (VII) and tert-butyl dimethoxyphosphonoacetate react at 10°C~40°C to form compound (VI);

(2) In the presence of alkali, compound (VI) and nitromethane react at 80°C~100°C to form compound (V);

(3) In methanol solvent, nickel chloride hexahydrate is used as a catalyst and sodium borohydride is used as a reducing agent. After reduction of compound (V), it reacts with palmitic acid at 0-40°C to obtain compound of formula (III) ;

(4) The compound of formula (III) is hydrolyzed to obtain the compound of formula (II);

(5) The compound of formula (II) reacts with A to obtain the compound of formula (I).

According to some specific embodiments of the present invention, wherein the method includes the following steps:

(1) In the presence of 10°C~40°C and a base, compound (VII) reacts with the third butyl dimethoxyphosphonoacetate to form compound (VI);

(2) At 80°C~100°C, compound (VI) reacts with nitromethane to form compound (V) in the presence of alkali;

(3) At 0-40°C, in a methanol solvent, nickel chloride hexahydrate is used as a catalyst, and sodium borohydride is used as a reducing agent. After reduction of compound (V), it reacts with palmitic acid to obtain compound of formula (III);

(4) The compound of formula (III) is hydrolyzed to obtain the compound of formula (II);

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

According to some specific embodiments of the present invention, wherein the base of step (1) is selected from potassium tributoxide or 1,8-diazabicycloundec-7-ene.

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

（XI）According to some specific embodiments of the present invention, wherein the palmitic acid of step (3) is selected from compounds of formula (XI);

(XI)

R ^{1 is} defined as above.

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

The present invention also provides a method for preparing a compound represented by formula (I), which includes the following steps:

(1) The compound of formula (X) reacts with malonic acid ring (iso)isopropyl ester to form the compound of formula (IX);

(2) The compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) to produce the compound of formula (VIII);

(3) The compound of formula (VIII) reacts to form the compound of formula (VII);

(4) Compound (VII) is prepared by using compound (VII) as raw material;

(5) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

(6) After the reduction reaction of the compound of formula (V), react with palmitic acid (preferably compound of formula (XI)) to obtain the compound of formula (III);

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

（V）

（XII）；Or after the reduction reaction of the compound of formula (V), after hydrolysis, it is reacted with palmitic acid (preferably compound of formula (XI)) to obtain the compound of formula (XII), the compound of formula (XII) is hydrolyzed and then reacted with acid A The reaction generates the compound of formula (I);

(V)

(XII);

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl;

R ³ and R ⁴ are each independently selected from C _1-6 alkyl;

Optionally, R ³ and R ⁴ together with the carbon atom to which they are attached form a ring (preferably R ³ and R ⁴ form a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom).

The present invention also provides a method for preparing a compound represented by formula (I), which includes the following steps:

(1) The compound of formula (X) reacts with malonic acid ring (iso)isopropyl ester to form the compound of formula (IX);

(2) The compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) undergo a condensation reaction to form the compound of formula (VIII);

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

(4) Compound (VII) undergoes Horner–Wadsworth–Emmons reaction or Wittig reaction to produce compound of formula (VI);

(5) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

(6) After the reduction reaction of the compound of formula (V), react with palmitic acid to obtain the compound of formula (III);

(7) The compound of formula (III) reacts to form the compound of formula (I).

According to some specific embodiments of the present invention, the compound of formula (III) is first reacted to obtain the compound of formula (II), and then the compound of formula (II) is reacted with acid A to form the compound of formula (I).

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

(XII);

A, R ¹ , R ² , R ³ , R ⁴ and other related definitions are the same as above.

The invention also provides a method for preparing the compound represented by formula (I), which includes the following steps:

(1) The compound of formula (X) reacts with malonic acid ring (iso)isopropyl ester to form the compound of formula (IX);

(2) The compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) undergo a condensation reaction to form the compound of formula (VIII);

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

(4) Compound (VII) undergoes Horner–Wadsworth–Emmons reaction or Wittig reaction to produce compound of formula (VI);

(5) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

(6) After the reduction reaction of the compound of formula (V), react with palmitic acid to obtain the compound of formula (III);

(7) The compound of formula (III) is hydrolyzed to obtain the compound of formula (II);

；(8) The compound of formula (II) reacts with acid A to form the compound of formula (I).

;

A, R ¹ , R ² , R ³ , R ⁴ and other related definitions are the same as above.

The invention also provides a method for preparing the compound represented by formula (I), which includes the following steps:

(1) The compound of formula (X) reacts with malonic acid ring (iso)isopropyl ester to form the compound of formula (IX);

(2) The compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) undergo a condensation reaction to form the compound of formula (VIII);

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

(4) Compound (VII) undergoes HWE reaction or Wittig reaction to form compound of formula (VI);

(5) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V);

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

(7) Compound 2B reacts with palmitic acid to obtain the compound of formula (XII);

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

（III）On the other hand, the present invention also provides compounds represented by formula (III),

(III)

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ; R ^{11 is} selected from C _1-6 alkyl;

R ^{2 is} selected from carboxy protecting agent or C _1-6 alkyl;

R ³ and R ⁴ are each independently selected from C _1-6 alkyl;

Optionally, R ³ and R ⁴ together with the carbon atom to which they are attached form a ring (preferably R ³ and R ⁴ form a pyridine ring or a tetrahydropyrrole ring with the attached nitrogen atom).

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

According to some specific embodiments of the invention, wherein R ^{11 is} selected from methyl, ethyl, propyl or tertiary butyl.

According to some specific embodiments of the invention, wherein R ^{2 is} selected from methyl, ethyl, propyl, or tertiary butyl.

(Ⅱ)The present invention also provides a compound represented by formula (II),

(Ⅱ)

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl group.

(Ⅲ)。The present invention also provides a method for preparing a compound represented by formula (II). The method includes using a compound of formula (IV) as a raw material, reacting with palmitic acid to prepare a compound of formula (III), and then hydrolyzing to obtain a compound of formula (II).

(Ⅲ).

（XI）。According to some specific embodiments of the present invention, wherein the palmitic acid is a compound represented by formula (XI),

(XI).

According to some specific embodiments of the invention, wherein the palmitic acid is L-mandelic acid.

The invention also provides the application of the compound represented by formula (XI) in the preparation of a reference compound of the compound of formula (II).

(VIII)The present invention also provides a compound represented by formula (VIII) and a preparation method thereof,

(VIII)

among them

R ³ and R ⁴ are each independently selected from C _1-6 alkyl or R ³ and R ⁴ form a ring;

The condition is that R ³ and R ^{4 are} not simultaneously methyl.

According to some specific embodiments of the invention, wherein R ³ and R ⁴ form a tetrahydropyrrole ring with the attached nitrogen atom.

、

、

、

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

,

,

,

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl.

(II)、

（III）

、

、

、

(VIII)、

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

(II),

(III)

,

,

,

(VIII),

,

R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ;

R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl;

R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl;

R ³ and R ⁴ are each independently selected from C _1-6 alkyl or R ³ and R ⁴ form a ring (preferably R ³ and R ⁴ form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached);

The condition is that R ³ and R ^{4 are} not simultaneously methyl.

（I）；The invention also provides a method for purifying the compound represented by formula (I), wherein the compound of formula (I) is heated to dissolve in an organic solvent (preferably N-methylpyrrolidone or dimethylsulfoxide), and acetic acid is added Isopropyl ester and/or water, stirred and crystallized, filtered, dried under reduced pressure, that is:

(I);

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

According to some specific embodiments of the present invention, wherein the crude compound of formula (I) is heated to 80±5°C in N-methylpyrrolidone, after the solid is completely dissolved, activated carbon is added to stir, filtered while hot, and the filtrate is added with isoacetic acid Propyl ester, stir and crystallize, filter, you get it.

According to some specific embodiments of the present invention, wherein the crude compound of formula (I) and dimethyl sulfoxide are heated to 50±5°C, and after the solid is completely dissolved, purified water is added and crystallized by stirring. Filter, you get it.

It can be understood that the preparation method involved in the present invention enumerates the reaction steps that the method goes through, and some are literally two or more reaction steps in the present invention, but in practice, they can be reacted at one time Completed in the operation (that is, after feeding, there is no need to discharge the intermediate product to continue the next reaction in the reaction solution, such as the so-called "one-pot boiling" method), which makes people mistakenly think that it is a one-step reaction, or literally in the present invention It is a one-step reaction, but it can be split into two or more reaction steps in practice, which makes people mistakenly believe that it is a multi-step reaction, which is within the protection scope of the present invention.

For example, in the embodiment of the present invention, the compound of formula (III) is used to prepare the compound of formula (II), and then the compound of formula (II) is used to prepare the compound of formula (I) in a one-step reaction operation, it should be understood that both reactions in this step It is described in the examples of the invention.

Similarly, in the embodiment of the present invention, the compound of formula (V) is used to prepare the compound of formula (IV), and then the compound of formula (IV) is used to prepare the compound of formula (III) in a one-step reaction operation. It is described in the embodiments of the present invention.

In the chemical structural formula of the present invention, (+/-) represents a mixture of enantiomers whose structure is completely opposite to that of the structure shown.

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

In summary, the present invention provides a method for preparing condensed tricyclic γ-amino acid derivatives and intermediates. The preparation method of the present invention has the following advantages:

The compound of formula (VII) of the present invention is very polar, easily soluble in most solvents, and has a low melting point, making it difficult to recrystallize and purify. And because it is solid at normal temperature, it is easy to sublimate and block the distillation device when heated, and it is not resistant to high temperature. Routine distillation or vacuum distillation cannot be purified. The purity of the crude product is only 50%, and after purification by the present invention, the purity can be above 98%.

The preparation method of the invention shortens the synthesis steps, simplifies the synthesis operation, and the raw materials are cheap and readily available, which greatly reduces the production of finished products; secondly, the entire synthesis process uses crystal purification, without using silica gel column chromatography or other preparation chromatography The method is suitable for large-scale industrial production.

The technical solutions of the present invention are described in detail below with reference to the drawings and embodiments, but the protection scope of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic instruments, and the solvent was 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).

For the measurement of MS, Agilent 6120B (ESI) and Agilent 6120B (APCI) were used.

For the HPLC measurement, an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification used for thin layer chromatography (TLC) is 0.15 mm~0.20 mm. The specification used for thin layer chromatography separation and purification products is 0.4 mm~0.5 mm.

Column chromatography generally uses Yantai Yellow Sea silicone 200~300 mesh silicone as the carrier.

The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from Titan Technology, Anage Chemicals, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology And other companies.

The ratio shown in the silica gel column chromatography of the present invention is the volume ratio. Example 1

2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-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)

Step 1: 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 kettle, and the pumping was completed. Cool down to 10°C. Add triethylamine (16.53 kg, 163.64mol) dropwise to the reaction solution, add it, and stir for 20 minutes. When the internal temperature is 10°C, dissolve the isopropyl malonate (7.86 kg, 54.55 mol) ) Add to the reaction kettle, and then add 3-cyclohexene-1-carbaldehyde (6.00 kg, 54.55 mol) to the reaction solution dropwise at an internal temperature of 40°C. After the addition is completed, the temperature will be raised to 140-150°C until no gas is generated. Then release. Adjust the pH of the reaction solution between 1-2 with 6 N hydrochloric acid (24.0 L). The aqueous phase was extracted with dichloromethane (12L × 2), the organic phases were combined, and washed with saturated brine (10L × 2). The organic phase was dried with anhydrous sodium sulfate (2.0 kg) for 1 hour, filtered, and the filtrate was concentrated and evaporated to dryness to give a yellow oil 1B (8.80 kg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.23 (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].

The second step: 3-(cyclohexyl-3-en-1-yl)-1-(pyrrolidin-1-yl)propyl-1-one (1C)

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

After dissolving 1B (11.20kg, 72.727mol) with dichloromethane (60.0L), pump it 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 solution. After the addition, the mixture was stirred at room temperature for 2.0 hours. Tetrahydropyrrole (5.689kg, 79.999mol) and triethylamine (8.814kg, 87.272mol) were added dropwise to the reactor. Control the internal temperature to be lower than 10°C, add it, and stir at room temperature overnight. The reaction liquid was cooled to 10°C. 3N hydrochloric acid (20.0 L) was added dropwise to adjust the pH of the reaction solution between 1-2. After standing, the liquid was separated, and the aqueous phase was extracted with dichloromethane (10.0 L×1). The organic phases were combined and washed successively with 5% sodium hydroxide solution (10.0 L×1) and saturated ammonium chloride solution (20.0 L×1). The organic phase was dried with anhydrous sodium sulfate (2.0 kg) for 30 minutes, filtered, and the filtrate was concentrated to obtain a brown liquid 1C (15.00 kg, yield 99.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.73 – 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].

Step 3: Tricyclo[4.2.1.0 ^3,8 ]nonan-2-one (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate) (1D)

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

After dissolving 1C (5.64 kg, 27.22 mol) with dichloromethane (40.0 L), draw into a 100L reactor. The temperature was lowered to -10°C, and 2,4,6-trimethylpyridine (4.94 kg, 40.83 mol) was added. A methylene chloride solution (16.0 L) of trifluoromethanesulfonic anhydride (11.50 kg, 40.83 mol) was added dropwise to the reaction solution, and the addition was completed. Heat to reflux for 12 hours. After the reaction was detected by the central control system, an aqueous solution (23.0 L) of sodium hydroxide (3.10 kg, 77.5 mol) was added dropwise to the reaction solution to adjust the pH of the reaction solution between 10-11. Continue to reflux for 5-6 hours. The liquid was left to stand for separation, the aqueous phase was extracted with dichloromethane (5.0 L × 1), and the organic phases were combined. The organic phase was drawn into the reactor and the temperature was lowered to 10°C. Add 2.0 N hydrochloric acid solution (20.0 L) dropwise to adjust the pH of the reaction solution between 1-2. After standing for liquid separation, the organic phase was washed with saturated brine (20 L×1) and concentrated. The residue was dissolved in acetone (20.0 L), pumped into a 100 L reactor and stirred, and concentrated sulfuric acid (4.0 L) and water were added dropwise. 20.0 L) of the prepared solution, and reflux for 2 hours after addition. The temperature was lowered to 15°C, saturated saline (20.0 L) was added to the reaction solution, and extracted with n-hexane (15.0 L×2). The organic phases were combined and washed with saturated brine (20.0 L×1). The organic phase was dried with anhydrous sodium sulfate overnight. After filtration, the filtrate was concentrated under reduced pressure to obtain crude yellow solid 1D (3.00kg, yield 81%) with a purity of 50%.

1D further purification steps:

Method 1: Dissolve anhydrous sodium bisulfite (5.735kg, 55.147mol) in 66L of purified water and add it to a 100L reactor, add 1D crude product (3.00kg, 22.059mol) of ethanol (3.0L) with stirring at room temperature The solution was stirred overnight at room temperature, extracted with ethyl acetate (20L×2), the aqueous phase was added to the reactor and stirred and cooled to 10°C, and sodium hydroxide (2.250kg, 56.250mol) was added dropwise (10L) solution, adjust the pH to 10-12, add and stir at room temperature for 2 hours, extract with n-hexane (20L×2), combine organic phases and wash with purified water (20L×1), organic phase with anhydrous sulfuric acid Sodium (2kg) was dried for 1 hour, filtered, and the filtrate was evaporated to dryness to obtain 1D . The colorless crystalline solid (2.7kg, yield 90%) had a purity of 98.3%.

Method 2: Dissolve sodium bisulfite (1529 g, 14.706 mol) in 22 L of water, add 1D crude product (1000 g, 7.353 mol) in absolute ethanol (1000 mL) dropwise with stirring, and stir at room temperature overnight (24 hours) ). The reaction solution was extracted with dichloromethane (5L×2) to remove impurities, and a sulfuric acid solution (prepared by 6.4L concentrated sulfuric acid and 6 kg of crushed ice) was added dropwise to the aqueous phase, and stirred at room temperature for 5 hours. The reaction solution was n-hexane ( Extract 3-4 times, 4L each time) extract, combine organic phases and wash with saturated aqueous sodium chloride solution (5L×2), dry the organic phase with 1kg of anhydrous sodium sulfate for 2 hours, filter, and evaporate the filtrate to give 1D , white solid ( 900g, yield: 90%), the measured purity was 98.1%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.39 (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].

The fourth step: tert-butyl 2-(tricyclo[4.2.1.0 ^3,8 ]nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S Body) (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 (6.20 L) were added to the 20 L reactor. The temperature was lowered to 5°C, and the third butyl dimethoxyphosphonoacetate (1480 g, 6.62 mol, 1.1 eq) was added dropwise to the reaction solution, the reaction temperature was controlled at 10°C-15°C, and stirring was continued for 1 hour. Then, a solution of 1D (820.0 g, 6.02 mol, 1.0 eq) in tetrahydrofuran (2.0 L) was added dropwise to the reaction solution, the addition was completed within 1 hour, and the temperature was naturally raised to room temperature for 2 hours after the addition was completed. Saturated ammonium chloride (2.0 L) solution and purified water (2.0 L) were sequentially added to the reaction kettle. After stirring for 20 minutes, the layers were left to stand, and the aqueous phase was extracted with methyl tert-butyl ether (1.5 L×2). The organic phases were combined, washed with saturated brine (2 L×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].

Step 5: Third 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) (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)

Into a 20L reactor, 1E (1.40 kg, 5.97 mol, 1.0 eq), nitromethane (1.82 kg, 29.85 mol, 5.0 eq) and dimethyl sulfoxide (9.8 L) were added in this order. Stir and add cesium carbonate (2.34 kg, 7.16 mol, 1.2 eq) to the reaction solution. After the addition is complete, heat to 80°C-85°C, continue to hold the reaction for 5 hours, then cool to room temperature, add purified water (20.0 L) to the reaction kettle, and extract the aqueous phase with methyl tert-butyl ether (8.0 L×3) . The organic phases were combined, washed with saturated brine (8.0 L×2), and dried over anhydrous sodium sulfate. Filtration and concentration gave a brown liquid 1F (1.62 kg, yield: 92%).

LCMS m/z = 318.1 [M+23].

Step 6: Third butyl 2-((1S, 2S, 3R, 6S, 8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonan-2-yl)ethane Acid ester (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 (7.3 L). With stirring, nickel chloride hexahydrate (118 g, 0.49 mol, 0.2 eq) was added to the reaction, the reaction solution was cooled to 5°C, and sodium borohydride (374 g, 9.88 mol, 4.0 eq) was added in portions to maintain the reaction The system temperature is 20℃-30℃, and the addition is completed in about 3 hours. After the completion of the reaction, the reaction was stirred for 2 hours. Ice water (16.4 L) was added to the reaction kettle, and the aqueous phase was filtered through celite. The filtrate was extracted with dichloromethane (3.0 L×2) and the combined organic phases were washed with saturated brine (4 L×1) and dried over anhydrous sodium sulfate. Filter, add (S)-(+)-O-acetyl-L-mandelic acid (384 g, 1.97 mol, 0.8 eq) to the filtrate, and stir for 20 minutes after the addition. After the organic phase was distilled and concentrated until no solvent was distilled off, the slurry was stirred and beaten with isopropyl alcohol (5.9 L) for 2 hours, and the temperature was lowered to 5°C and stirred for 1 hour. After filtration, the filter cake was washed with isopropanol (0.4 L×1) and dried to obtain a white solid product 1H crude product (422 g, yield: 34.96%). After derivation of the solid, the ee value was determined to be 48.35%.

The first crystallization: the crude product 1H (420.0 g, 0.92 mol), isopropanol (4.20 L) and water (0.21 L) were added to the reactor in turn. The temperature was programmed to 82°C to completely dissolve the solids and kept for 0.5 hours. The temperature was lowered to 20°C and crystallized for about 6 hours. When the internal temperature reached 20°C, it was filtered, and the filter cake was washed with isopropyl alcohol (0.40 L×1). Combine the solids, dry at 60-65°C for 4 hours, and dry to constant weight. The first crystallized product of 1H (260 g, yield: 62%) was obtained, and the ee value was determined to be 81.25% after taking the solid derivative.

Second crystallization: 1H first crystallization (177 g, 0.39 mol), isopropanol (2.53 L) and water (0.126 L) were added to the reactor in sequence. The temperature was programmed to 82°C to completely dissolve the solids and kept for 0.5 hours. The temperature was lowered to 20°C and crystallized for about 4.5 hours. When the internal temperature reaches 30°C, filter, and the filter cake is washed with isopropyl alcohol (0.10 L×1). Combine the solids, dry at 60-65°C for 4 hours, and dry to constant weight. A white solid 1H pure product (128 g, yield: 72%) was obtained, and the ee value was 99.73% after derivation of the solid.

LCMS m/z = 266.3 [M+1].

Step 7: 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonan-2-yl)acetic acid benzenesulfonic acid compound (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)

1H pure product (100.0 g, 0.218 mol) and purified water (0.8 L) were added to the reactor in turn, and the temperature was lowered to 0-10°C. When the internal temperature reached 0-10 ℃, add 1 mol / L NaOH (218 mL) aqueous solution dropwise to the reaction kettle to adjust the pH of the reaction solution to 9-10. After standing for a while, the aqueous phase was extracted with dichloromethane (0.30 L×2). The organic phases were combined and washed sequentially with 1 mol/L NaOH (0.10 L×1) solution and saturated brine (0.15 L×1). Activated carbon (5.0 g) was added to the organic phase for decolorization and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue in the concentration kettle was dissolved with acetonitrile (280 mL). Benzenesulfonic acid monohydrate (77.0 g, 0.437 mol) was prepared with purified water (280 mL) and added dropwise to the above acetonitrile solution. The temperature is programmed to 80-85°C, and the reaction is incubated for 4-6 hours. The reaction solution was cooled to 10-20°C and crystallized for about 4-6 hours. When the internal temperature reached 10-20°C, filter, and the filter cake was washed with water (30 mL×1) and acetonitrile (50 mL×1) in sequence. And dried to give compound 1 as a white solid (72 g, yield: 90%).

¹ H NMR (400 MHz, MeOD) δ 7.83 (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, 0.2 ml of water and 0.2 ml of dimethyl sulfoxide were added and the temperature was raised to 80 degrees Celsius to dissolve. After 5 minutes, the temperature was naturally lowered to room temperature to obtain rod-shaped crystals.

Hot stage polarized light microscope (PLM) and single crystal diffractometer (see Table 1), Table 1 detection methods

表3單晶掌性解析結果

The results are shown in Table 2, Table 3, Figure 1-3: Table 2 Single crystal structure data

Table 3 Single crystal palm analysis results

和

。實施例 2 In the same way as above, after the residue in the concentration kettle is dissolved with acetonitrile, p-toluenesulfonic acid or methanesulfonic acid is separately prepared as a solution and added dropwise to the acetonitrile solution. After the reaction is completed, after-treatment, the following products are obtained respectively :

with

. Example 2

Tertiary butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-2-yl)acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S , 3R, 6S, 8S racemate) (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 ]nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S Body) (1E)

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

At room temperature, 1,8-diazabicycloundec-7-ene (288 g, 1.90 mol) and tert-butyl dimethoxyphosphonoacetate (197 g, 0.88 mol) were reacted In the bottle, add and continue stirring for 20 minutes. 1D (100 g, 0.73 mol) was added to the reaction night, and the addition was completed. The temperature was raised to 40°C and reacted for 6 hours. A yellow liquid was obtained and the next reaction 1E (172 g) was directly carried out.

LCMS m/z = 257.1 [M+23].

The second step: 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) (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)

To the 2L reactor, add 1E reaction solution (172 g, 0.73 mol), nitromethane (224 g, 3.67 mol), 1,8-diazabicycloundec-7-ene (134 g, 0.88 mol) ) And dimethyl sulfoxide (500 mL). Heated to 80 ℃ -85 ℃, continue to hold the reaction for 5 hours. After cooling to room temperature, purified water (2.0 L) was added to the reaction kettle, and the aqueous phase was extracted with methyl tert-butyl ether (800 mL×3). The organic phases were combined, washed with saturated brine (800 mL×2), and dried over anhydrous sodium sulfate. Filtration and concentration gave a brown liquid 1F (193g, yield: 90%).

LCMS m/z = 318.1 [M+23]. Example 3

Tertiary butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-2-yl)acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S , 3R, 6S, 8S racemate) (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 ]nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S Body) (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 (9.06 g, 80.76 mmol) and tetrahydrofuran (150 mL) were added to the 1 L reactor. The temperature was lowered to 5°C, and the third butyl dimethoxyphosphonoacetate (18.11 g, 80.76 mmol, 1.1 eq) was added dropwise to the reaction solution. The reaction temperature was controlled at 10°C-15°C, and the addition was completed in about 20 minutes. The stirring was continued for 0.5 hours, and the temperature was controlled at 10°C-15°C. Then, a solution of 1D (10.0 g, 73.42 mmol, 1.0 eq) in tetrahydrofuran (50.0 mL) was added dropwise to the reaction solution. The dropwise addition was completed within 0.5 hours, and the temperature was naturally raised to room temperature for 2 hours after the addition was completed. Saturated ammonium chloride (100.0 mL) was sequentially added to the reaction kettle, and purified water (100.0 mL) was used to quench the reaction. After stirring for 20 minutes, the layers were left to stand, and the aqueous phase was extracted with methyl tert-butyl ether (50.0 mL×1). The organic phases were combined, washed with saturated brine (100.0 mL×1), and dried over anhydrous sodium sulfate. Filtration and concentration gave a yellow liquid 1E (17.5g).

LCMS m/z = 257.1 [M+23].

The second step: 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) (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)

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

LCMS m/z = 318.1 [M+23]. Example 4

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

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

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 (10.0 L) were added to the 50 L reactor. The temperature was lowered to 5°C, and the third butyl dimethoxyphosphonoacetate (2.50 kg, 11.0 mol, 1.1 eq) was added dropwise to the reaction solution. The reaction temperature was controlled at 10°C-15°C, and the addition was completed in about 40 minutes. The stirring was continued for 0.5 hours, and the temperature was controlled at 10°C-15°C. Then, a solution of 1D (1.36 kg, 10.0 mol, 1.0 eq) in tetrahydrofuran (3.60 L) was added dropwise to the reaction solution, and the addition was completed within 0.5 hour. After the addition, it was naturally raised to room temperature and reacted for 2 hours. After the raw material reaction was detected by the central control, the reaction kettle was successively added with 5% ammonium chloride solution (6.0 L) to quench the reaction. After stirring for 20 minutes, the layers were left to stand, and the aqueous phase was extracted with dichloromethane (5.0 L×1). The organic phases were combined, washed with 5% brine (5.0 L×1), and dried over anhydrous sodium sulfate. Filtration and concentration gave a yellow liquid 1E (2.40 kg).

LCMS m/z = 257.1 [M+23].

The second step: 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) (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)

Into a 50L reactor, 1E (2.34 kg, 10.0mol, 1.0 eq), nitromethane (1.53kg, 25.0mol, 2.5eq) and dimethyl sulfoxide (2.34L) were added in sequence. Turn on stirring and add potassium tertiary butoxide (15.8 g, 0.14 mol, 2.0 eq) to the reaction solution. After the addition is complete, heat to 85°C-90°C and continue to hold the reaction for 10 hours. Centrally controlled. When the raw material is less than 2%, cool to 25°C, add purified water (8.50L) to the reaction kettle, and extract the aqueous phase with dichloromethane (3.50L×3). The organic phases were combined and washed with 0.5 mol/L hydrochloric acid solution (2.0 L×1), 0.5 mol/L sodium hydroxide solution (2.0 L×1) and 5% sodium chloride solution (2.0 L×1) in sequence. Filtration, and the filtrate temperature is controlled under 35±5℃ and concentrated under reduced pressure until no large fraction flows out. Raise the temperature to 55±5℃ and continue to distill off the nitromethane under reduced pressure. Sampling is controlled to control the nitromethane content to be less than 5%. A brown liquid 1F (2.95 kg) was obtained.

LCMS m/z = 318.1 [M+23]. Example 5

Tertiary butyl 2-(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) ( 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 reaction flask were added 1F (90 g, 0.31 mol), methanol (900 mL), palladium-carbon 10% (9.0 g), hydrogen gas was exchanged three times, and the reaction was hydrogenated at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow liquid 2A (73.5 g, yield: 91%).

Ms m/z (ESI): 266.1(M+1). Example 6

Tertiary butyl 2-(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) ( 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)

Add 1F (70 g, 0.24 mol), ethanol (360 mL) and water (120 mL) to the reaction flask, add iron powder (67.2 g, 1.2 mol) and ammonium chloride (38.5 g, 0.72 mol), and then add The reaction was carried out at 90°C for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, purified water (450 mL) was added, and the aqueous phase was extracted with dichloromethane (150 mL×3). The organic phases were combined, washed with saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. Filtration and concentration gave yellow liquid 2A (55 g, yield: 88%).

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 ]nonan-2-yl)acetate (S )-2-acetoxy-2phenylacetic acid (1H) recrystallization

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

method one:

The crude product 1H (80.0 g, 0.17 mol), isopropanol (750 mL) and water (50 mL, v:v=15:1) were added to the reaction bottle in sequence. The temperature is raised to completely dissolve the solid, and the temperature is kept for 0.5 hours. The temperature was lowered to 20°C and crystallized, and the filter cake was washed with isopropanol (0.40 L×1) and dried at 60-65°C for 4 hours. The first recrystallized product of 1H (60 g, yield: 75%) was obtained, and the ee value was 97.22% after derivation of the solid.

Second recrystallization: 1H first recrystallized product (137 g, 0.30 mol), isopropanol (1284 mL) and water (85.6 mL, v:v=15:1) were added to the reactor in sequence. The temperature is raised to completely dissolve the solid, and the temperature is kept for 0.5 hours. The temperature was lowered to 20°C for crystallization, filtered, and the filter cake was washed with isopropanol (0.10 L×1) and dried at 60-65°C. The white solid 1H was recrystallized for the second time (112g, yield: 82%), and the ee value was 99.72% after derivation of the solid.

LCMS m/z = 266.3 [M+1].

Method Two:

Second recrystallization: 1H first recrystallized product (10.0g, 21.76 mmol, ee%=77%), isopropyl alcohol and water (290mL/10mL, v:v=29:1) were added to the reaction bottle in sequence . The temperature is raised to completely dissolve the solid, and the temperature is kept for 0.5 hours. The temperature was lowered to 30°C and crystallized, filtered, and the filter cake was washed with isopropyl alcohol (10.0 mL × 1). The solids were combined and dried at 60-65°C. The white solid 1H was recrystallized for the second time (6.1 g, yield: 61%), and the ee value was 97.3% after derivation of the solid.

LCMS m/z = 266.3 [M+1]. Example 8

2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-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)

Add 1H (10.0 g, 21.77 mol) and purified water (100.0 mL) to the reaction bottle in sequence. Cool down to 0-10°C. When the internal temperature reached 0-10 ℃, add 25% ammonia solution (4.0 mL) dropwise to the reaction solution to adjust the pH of the reaction solution to 9-10. After standing for a while, the aqueous phase was extracted with isopropyl acetate (50.0 mL×2). The organic phases were combined and washed with saturated brine (50.0 mL×1). Activated carbon (0.5 g) was added to the organic phase for decolorization and dried over anhydrous sodium sulfate. Filter, add benzenesulfonic acid monohydrate (8.06 g, 43.54 mmol) to the filtrate, and add. Heating up to 80-85°C. Incubate the reaction for 4-6 hours, the central control detects the raw material reaction is complete. The ice water was cooled to 20-25°C and crystallized for about 2 hours. When the internal temperature reached 20-25°C, it was filtered, and the filter cake was washed with isopropyl acetate (10 mL×1). After drying, Compound 1 was obtained as a white solid (7.8 g, yield: 97.6%). Example 9

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

Add 1H (4.59 g, 10.0 mmol) and purified water (40.0 mL) to the reaction bottle in sequence. Cool down to 0-10°C. When the internal temperature reached 0-10 ℃, 1.0mol/L sodium hydroxide solution (11.0 mL) was added dropwise to the reaction solution to adjust the pH of the reaction solution to 9-10. After standing for a while, the aqueous phase was extracted with dichloromethane (25.0 mL×2). The organic phases were combined and washed successively with 0.5 mol/L sodium hydroxide solution (20.0 mL×1) and saturated brine (25.0 mL×1). Activated carbon (0.5 g) was added to the organic phase for decolorization and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and acetonitrile (26.0 mL) and benzenesulfonic acid monohydrate (3.50 g, 20.0 mmol) were added. Heated to 80 ℃. Incubate the reaction for 4-6 hours, the central control detects the raw material reaction is complete. The ice water was cooled to 25°C and crystallized for about 2 hours. When the internal temperature reached 25°C, it was filtered, and the filter cake was washed with acetonitrile (3.0 mL×2). After drying, Compound 1 was obtained as a white solid (3.4 g, yield: 92.6%). Example 10

2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-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)

Add 1H (150 g, 0.33 mol) and purified water (1500 mL) to the reaction bottle in sequence. The temperature was lowered to 0-10°C, 1.0mol/L sodium hydroxide solution (360 mL) was added dropwise to the reaction solution, the pH of the reaction solution was adjusted to 9-10 and stirred for 1 hour. After standing for a while, the aqueous phase was extracted with dichloromethane (800 mL×2). The organic phases were combined and washed sequentially with 1.0 mol/L sodium hydroxide solution (300.0 mL×1) and 10% saline solution (300.0 mL×1). Activated carbon (5.0 g) was added to the organic phase and stirred to decolorize. Diatomaceous earth was filtered, and after the filtrate was concentrated, acetonitrile (328.0 mL) was added. Purified water (328.0 mL) and benzenesulfonic acid monohydrate (114 g, 0.66 mol) were added. Heated to 80 ℃. Incubate for 12 hours, and the raw material is less than 0.2% detected by the central control. The reaction is complete. The ice water was cooled to 10±5°C and stirred for about 6 hours to crystallize. When the internal temperature reached 10°C, it was filtered, and the filter cake was washed with acetonitrile and water (V:V=1:1, 150 mL×1), dichloromethane (150 mL×1), and drained. The solid was dried under reduced pressure to obtain compound 1 (104 g, yield: 86.9%) as a white solid.

Compound 1 can be further purified by the following method:

Method 1: Compound 1 (430.0g, 1.17mol) and N-methylpyrrolidone (2.15L) were added to a 5L reaction flask. After the addition, heat to 80±5℃ and keep for 0.5 hours. After the solid is completely dissolved, add activated carbon (10g) and continue stirring for 10 minutes. While hot filtering, the filter cake was washed with N-methylpyrrolidone (400 mL×1) and drained. Isopropyl acetate (7.5L) was added dropwise to the filtered solution. After the addition was completed, stirring and crystallization were continued for 2 hours. It was filtered, and the filter cake was washed with isopropyl acetate (500.0 mL), suction dried, and dried under reduced pressure for 8 hours to obtain Compound 1 (420.0 g, yield: 97.7%) as a white solid.

Method 2: Compound 1 (410g, 1.12mol) and dimethyl sulfoxide (1230 mL) were added to the 5L reaction flask. After the addition, heat to 50±5℃ and keep for 0.5 hours. After the solid was completely dissolved, add purified water (2460 mL) dropwise. After the addition, the water bath was cooled to 15°C and stirring was continued for 2 hours. After filtration, the filter cake was washed successively with purified water (400.0 mL×1), dichloromethane (400.0 mL×2), dried with suction, and dried under reduced pressure to obtain 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 ]nonyl-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 ]nonan-2-yl)acetic acid (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R , 6S, 8S racemate) (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, 2A (44.45 g, 0.17 mol) and dichloromethane (150.0 mL) were added in sequence. Stir and lower the temperature to 0°C-5°C, and add trifluoroacetic acid (60.0 mL) dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 0°C-10°C for 6 hours. TLC monitored the complete conversion of the raw materials, and the reaction solution was concentrated to remove the solvent. Dichloromethane (150.0 mL) was added to the residue, and the temperature was lowered to 0°C to 5°C. Adjust the pH to 7-8 with triethylamine (60.0 mL), precipitate a white solid and stir for 1 hour. It was filtered, the filter cake was washed with dichloromethane (50.0 mL), and the combined solids were dried to give a white solid 2B (22.0 g, yield: 68.4%).

LCMS m/z = 210.1 [M+1].

The second step: (S)-2-hydroxy-2-phenylacetic acid 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]non Alkyl-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)

To a 100 mL reaction flask, 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) were added in sequence. After the addition is completed, the temperature is raised to 82°C to completely dissolve the solid, and the temperature is naturally reduced to 20°C and crystallized for about 6 hours after holding for 0.5 hours. When the internal temperature reached 20°C, it was filtered, and the filter cake was washed with isopropanol (5.0 mL×2). The solid was dried for 1 hour to obtain a white solid (3.2 g, yield: 24.2%).

The first crystallization: white solid salt (3.2 g), isopropyl alcohol (32 mL) and water (5.2 mL) were added to a 100 mL reaction flask in sequence. After heating, the temperature is raised to 82°C to completely dissolve the solid. After holding for 0.5 hours, the temperature is reduced to 20°C for crystallization, about 6 hours. When the internal temperature reached 20°C, it was filtered, and the filter cake was washed with isopropanol (5.0 mL×2). The solids were combined and dried for 1 hour to obtain the first crystals (2.0 g, yield: 62.5%), and the ee value was 53% after derivation.

Second crystallization: The first crystallization (1.0 g), ethanol (16.0 mL) and water (1.3 mL) were added to the 100 mL reaction flask in sequence. Heat to 82°C to completely dissolve the solid. After holding for 0.5 hours, lower the temperature to 20°C for crystallization, about 4.5 hours. When the internal temperature reached 30°C, filter and filter cake was washed with ethanol (1.0 mL×2). The solids were combined, dried for 1 hour, and dried to constant weight to obtain compound 2 (0.63 g, yield 63%). After derivatization, the ee value was determined to be 72%.

Compound 2 was prepared in a similar manner to Example 1 to obtain Compound 1. Example 12

3-(cyclohexyl-3-en-1-yl)-1-(pyrrolidin-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, 26.68 mol, 1 eq) was dissolved in dichloromethane (20.0 L) and added to a 50 L reaction kettle, and the addition was completed. The temperature was lowered to 20°C, and triethylamine (4.04 Kg, 40.03 mol, 1.5 eq) was added. Then add 1-hydroxybenzotriazole (4.32 kg, 32.02 mol, 1.2 eq), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (6.11 kg, 32.02 mol, 1.2eq), and stirred for 30 minutes. When the temperature was lowered to 0°C, tetrahydropyrrole (2.46 kg, 34.69 mol, 1.3 eq) was added dropwise. After the addition, the mixture was stirred at room temperature overnight. The reaction solution was washed with purified water (15.0 L×2) and 2.0 mol/L hydrochloric acid (15.0 L×3). The organic phase was dried with anhydrous sodium sulfate (2.0 kg), filtered, and the filtrate was concentrated and evaporated to dryness to give a brown oil 1C (6.60 kg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.73 – 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]. Example 13

(R)-2-hydroxy-2-phenylacetic acid 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8 ]nonyl-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)

After dissolving 2A (1.0 g, 3.77 mmol) with acetonitrile (25.0 mL). D-mandelic acid (286.0 mg, 1.89 mmol, 0.5 eq) dissolved in acetonitrile (5 mL) was added dropwise to the reaction, and the mixture was stirred at room temperature for 4 hours. After filtration, the filter cake was washed with acetonitrile (2.0 mL×1) and dried to obtain a crude white solid compound 3 (0.48g, yield: 37%). After taking the solid derivative, the ee value was determined to be 41.9%.

Recrystallization: The crude compound 3 (0.48 g, 1.15 mmol) and acetonitrile (15.0 mL) were added to the reaction flask. After the addition, the mixture was stirred at room temperature for 3 hours. After filtration, the filter cake was washed with acetonitrile (2.0 mL×1) and dried to obtain compound 3 (0.22g, yield: 45%) as a white solid. The ee value of the sample derivation was 73.00%.

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

FIG. 2 is a single-molecular ball-and-rod model of compound 1.

Figure 3 is the absolute configuration of compound 1.

Claims (23)

A method for preparing a compound represented by formula (I), wherein the method comprises preparing the compound of formula (III) as a raw material,

(I)

(III) A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid; R ^{1 is} selected from H, hydroxyl protecting group or -C(=O)R ¹¹ ; R ^{2 is} selected from carboxy protecting group or C _1-6 Alkyl; preferably R ^{2 is} selected from the third butyl; R ^{11 is} selected from C _1-6 alkyl; preferably R ^{11 is} selected from methyl. A method for preparing a compound represented by formula (I), wherein the method comprises preparing the compound of formula (II) as a raw material;

(I),

(II) The definition of A and R ² is the same as the first item in the scope of patent application. A method for preparing a compound of formula (II) is obtained by using a compound of formula (III) as a raw material

(II),

(III) The definitions of R ¹ and R ² are the same as the first item in the scope of patent application. The preparation method according to item 1, 2 or 3 of the patent application scope, wherein the method comprises first preparing the compound of formula (II) using the compound of formula (III) as a raw material, and then preparing the compound of formula (II) as a raw material The compound of formula (I) is obtained. The preparation method according to item 2 or 4 of the patent application scope, wherein The compound of formula (II) and acid A are reacted in a solvent compatible with the compound of formula (II) to obtain the compound of formula (I), the solvent is 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 1.1:1 to 5:1, reacted at 70-90°C; Preferably, 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°C; even more preferably, the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate. A method for preparing a compound of formula (III), wherein the method includes the step of reacting with a compound of formula (IV) as a raw material to obtain a compound of formula (III),

(III),

(IV) The definitions of R ¹ and R ² are the same as the first item in the scope of patent application. The preparation method according to item 6 of the patent application scope, wherein the preparation of the compound (III) includes the preparation of the compound of formula (III) from the compound of formula (IV) and palmitic acid; preferably, the palmitic acid It is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diethyl-L-tartaric acid, L-aspartic acid or dextroquinic acid; further preferably, The molar ratio of palmitic acid to the compound of formula (IV) is 0.5:1 to 1:1, and the reaction is carried out under room temperature to reflux conditions;

(XI) The definition of R ¹ is the same as the first item in the scope of patent application. A method for refining the compound of formula (III) is to recrystallize the compound of formula (III) in a recrystallization solvent;

(III) R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ; R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl group; R ^{11 is} selected from C _1-6 alkyl groups; preferably R ^{11 is} selected from methyl groups; preferably, the mass volume ratio of the compound of formula (III) and the recrystallization solvent is 1:10-1:30; further preferred , The recrystallization is repeated 1-2 times; wherein the recrystallization solvent is an organic solvent and/or water; preferably, the organic solvent is selected from a mixture of one or more of isopropanol, acetonitrile or ethanol; Preferably, the organic solvent is isopropyl alcohol; preferably, the recrystallization solvent is isopropyl alcohol and water; further preferably, the volume ratio of isopropyl alcohol to water is 10:1-30:1. The preparation method according to any one of items 6 to 7 of the patent application scope, wherein the method further comprises the step of preparing the compound of formula (IV) from the compound of formula (V) as a raw material; preferably in a catalyst/reducing agent In the presence of, the compound of formula (IV) is prepared at 0-40°C; further preferably, the catalyst/reducing agent is selected from Raney nickel/hydrazine hydrate, nickel chloride hexahydrate/sodium borohydride, iron powder/ Ammonium chloride, 10% palladium carbon/triethylsilicon, Raney nickel/hydrogen, 10% palladium carbon/hydrogen or zinc powder/acetic acid; even more preferably, the catalyst/reducing agent is selected from nickel chloride Hydrate/sodium borohydride or 10% palladium carbon/hydrogen,

(V) The definition of R ² is the same as the first item in the scope of patent application. The preparation method according to item 9 of the patent application scope, wherein the method further comprises the preparation of the compound of formula (V): including the preparation of the compound of formula (V) using the compound of formula (VI) as a raw material, preferably in the base (more The preferred base is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene), and the compound (VI) reacts with nitromethane (the preferred reaction temperature is 60 °C ~ reflux, more preferably 80 °C ~ 100 °C) to generate compound (V); alternatively, there may be a solvent, the solvent is selected from dimethyl sulfoxide, N, N-dimethyl methyl Acetamide, N-methylpyrrolidone or tetrahydrofuran, preferably dimethylsulfoxide or N,N-dimethylformamide,

(VI) The definition of R ² is the same as the first item in the scope of patent application. The preparation method according to item 10 of the patent application scope, wherein the method further includes the preparation of the compound of formula (VI): including the preparation of the compound of formula (VI) using the compound of formula (VII) as a raw material, preferably in the base (more The preferred base is selected from potassium tert-butoxide, 1,8-diazabicycloundec-7-ene, lithium diisopropylamide, potassium carbonate or lithium hydride), the compound of formula (VII) and Selected from the group consisting of tert-butyl dimethoxyphosphonoacetate, tert-butyl diethoxyphosphonoacetate, tert-butyl bromoacetate, tert-butyl chloroacetate or tert-butyl acetoacetate Any compound reacts to form the compound of formula (VI): (the preferred reaction temperature is 10°C~40°C, more preferably 20°C~40°C),

(VII). A method for preparing a compound represented by formula (VII), wherein the method includes preparing a compound of formula (VII) using a compound of formula (VIII) as a raw material,

(VIII),

(VII), R ³ and R ⁴ are each independently selected from C _1-6 alkyl groups; alternatively, R ³ and R ⁴ and the carbon atom to which they are connected together form a ring (preferably R ³ and R ⁴ are The connected nitrogen atom forms a pyridine ring or a tetrahydropyrrole ring). The preparation method according to item 12 of the patent application scope, wherein the method includes the following steps: (1) The compound of formula (VIII) in acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and pyridine base (preferably 2,4,6-trimethylpyridine, 2,6-dimethylpyridine Or pyridine) reaction; (2) Adjust the pH of the reaction solution obtained in step (1) to alkaline with alkali (preferably inorganic alkali, further preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate or cesium carbonate), It is better to adjust the pH to 8-11; (3) The mixture obtained in step (2) is acidified with an inorganic acid (preferably sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid) to obtain the compound of formula (VII). The preparation method according to item 12 or 13 of the patent application scope, wherein the method further comprises reacting the compound of formula (IX) with a secondary amine NH(R ³ )(R ⁴ ) to prepare the compound of formula (VIII) Steps; the compound of the preferred formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) are in the condensing agent (preferably the condensing agent is selected from oxalyl chloride, dichlorosulfite, 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N,N'-carbonyldiimidazole) to prepare the compound of formula (VIII),

(IX). The preparation method according to item 14 of the patent application scope, wherein the method further comprises the compound of formula (X) as a raw material (preferably the compound of formula (X) and a malonic acid cyclic (methylene) isopropyl ester as raw materials ) The step of preparing the compound of formula (IX) (preferably, under the catalysis of triethylamine formate, the compound of formula (X) reacts with the malonic acid cyclic (iso)isopropyl ester to produce the compound of formula (IX))

(X). A method for preparing a compound represented by formula (VII), wherein the method includes the following steps:

(1) The compound of formula (X) reacts with malonic acid cyclic (iso)isopropyl ester to form the compound of formula (IX); (2) The compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) Compound of formula (VIII); (3) Compound of formula (VIII) is reacted to form compound of formula (VII); R ³ and R ⁴ are each independently selected from C _1-6 alkyl groups; optionally, R ³ and R ⁴ It forms a ring with the carbon atom to which it is attached (preferably R ³ and R ⁴ form a tetrahydropyrrole ring with the nitrogen atom to which it is attached). The method according to item 16 of the patent application scope, wherein the method comprises the following steps: (1) under the catalysis of triethylamine formate, a compound of formula (X) reacts with a malonic acid ring (iso)isopropyl ester , To generate the compound of formula (IX); (2) the compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) to generate the compound of formula (VIII); (3) dichloromethane or 1,2-dichloro Ethane is used as a solvent, in the presence of a pyridine base, after the formula (VIII) is reacted with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to basic, and then the compound of formula (VII) is prepared under acidic conditions. A method for purifying the compound represented by formula (VII):

(VII) The method includes adding a compound of formula (VII) to sodium bisulfite at room temperature to form a salt, using an organic solvent (preferably the organic solvent is selected from ethyl acetate, dichloromethane or methyl tertiary butyl Base ether) to extract impurities, and then add acid (preferably hydrochloric acid or sulfuric acid) or alkali (preferably sodium hydroxide) at room temperature to complete the reaction after the reaction. A method for preparing a compound represented by formula (I), wherein the method includes the following steps: (1) a compound of formula (VI) is prepared by using compound (VII) as a raw material; (2) a compound of formula (VI) and Nitromethane reacts to form the compound of formula (V); (3) The compound of formula (V) undergoes reduction reaction to obtain (IV), and then reacts with palmitic acid (preferably compound of formula (XI)) to obtain compound of formula (III) (4) The compound of formula (III) is reacted to obtain the compound of formula (II), and then reacted with acid A to obtain the compound of formula (I);

Preferably, the compound of formula (III) is first reacted to obtain the compound of formula (II), and then the compound of formula (II) is reacted with acid A to form the compound of formula (I); or the compound of formula (V) undergoes a reduction reaction, after hydrolysis , And then react with palmitic acid (preferably compound of formula (XI)) to obtain compound of formula (XII), the compound of formula (XII) is hydrolyzed and then reacted with acid A to form compound of formula (I);

(XII); The definition of A, R ¹ and R ² is the same as the first item in the scope of patent application. The preparation method according to item 19 of the patent application scope, wherein the method includes the following steps: (1) Base (preferably, the base is selected from potassium tributoxide or 1,8-diazabicycloundec-7-ene), compound (VII) and dimethoxyphosphonoacetyl Third butyl acetate reacts at 10°C~40°C to form compound (VI); (2) In the presence of a base (preferably the base is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene), compound (VI) and nitromethane are 80°C~100°C react to form compound (V); (3) In methanol solvent, nickel chloride hexahydrate is used as a catalyst, sodium borohydride is used as a reducing agent, and compound (V) undergoes a reduction reaction with palmitic acid (preferably the palmitic acid is selected from formula (XI) Compounds, further preferably (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid) are reacted at 0-40°C to obtain the compound of formula (III); (4) The compound of formula (III) is hydrolyzed to obtain the compound of formula (II); (5) The compound of formula (II) reacts with A to obtain the compound of formula (I). A method for preparing a compound represented by formula (I), wherein the method includes the following steps: (1) a compound of formula (X) reacts with a malonic acid ring (iso)isopropyl ester to produce a compound of formula (IX); ( 2) The compound of formula (IX) reacts with the secondary amine NH(R ³ )(R ⁴ ) to form the compound of formula (VIII); (3) The compound of formula (VIII) reacts to form the compound of formula (VII); (4) Compound (VII) is used as a raw material to prepare the compound of formula (VI); (5) The compound of formula (VI) reacts with nitromethane to form the compound of formula (V); (6) After the compound of formula (V) undergoes a reduction reaction, Acidic compounds (preferably compounds of formula (XI)) are reacted to obtain compounds of formula (III); (7) Compounds of formula (III) are reacted to obtain compounds of formula (II), which are then reacted with acid A to form compounds of formula (I);

Or after the reduction reaction of the compound of formula (V), after hydrolysis, it is reacted with palmitic acid (preferably compound of formula (XI)) to obtain the compound of formula (XII). Generating compounds of formula (I);

(V)

(XII); The definitions of A, R ¹ and R ² are the same as the first item in the scope of patent application; The definitions of R ³ and R ⁴ are the same as the 12th item in the patent application. A compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable salts thereof,

(II),

(III),

,

,

,

(VIII),

, R ^{1 is} selected from H, a hydroxy protecting group or -C(=O)R ¹¹ ; R ^{2 is} selected from a carboxy protecting group or a C _1-6 alkyl group; preferably R ^{2 is} selected from a third butyl group; R ^{11 is} selected From C _1-6 alkyl; preferably R ^{11 is} selected from methyl; R ³ and R ⁴ are each independently selected from C _1-6 alkyl or R ³ and R ⁴ form a ring (preferably R ³ and R ⁴ It forms a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which it is attached; provided that R ³ and R ^{4 are} not methyl groups at the same time. A method for purifying a compound represented by formula (I), wherein the compound of formula (I) is heated to dissolve in an organic solvent (preferably N-methylpyrrolidone or dimethylsulfoxide), isopropyl acetate and/ Or water, stir and crystallize, filter, dry under reduced pressure, you get:

(I); A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.

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