TWI777079B - Preparation method of condensed tricyclic γ-amino acid derivatives and intermediates thereof - Google Patents

Abstract

The invention provides a preparation method and an intermediate of a fused tricyclic γ-amino acid derivative, such as an intermediate for preparing the fused tricyclic γ-amino acid derivative. The fused tricyclic γ-amino acid derivative has the structure represented by formula (I). The preparation method has easy-to-obtain raw materials and simple steps, and the entire synthesis technology is purified by crystallization without using silica gel column chromatography or other preparation chromatography methods, and is suitable for large-scale industrial production.

Description

Preparation method of condensed tricyclic γ-amino acid derivatives and intermediates thereof

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

Voltage-gated calcium channels are composed of α1 subunit and accessory protein α2δ, β, γ subunits. α2δ protein can modulate calcium channel density and calcium channel voltage-dependent kinetics (Felix et al (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al (1999) J. Neuroscience 19:684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are four isoforms of α2δ proteins, each encoded by a different gene. α2δ isoforms 1 and 2 showed high affinity for pregabalin, while α2δ isoforms 3 and 4 showed no significant drug binding.

However, for gabapentin, it improved the proportion of patients with diabetic peripheral neuropathy to a greater extent in about 60% (Acta Neurol. Scand. 101:359-371, 2000), for pregabalin, although it was better tolerated than gabapentin , but its safety is lower, and there is the possibility of abuse or dependence of patients (Am J Health Syst Pharm. 2007;64(14):1475-1482).

There remains 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 preparation method of a fused tricyclic γ-amino acid derivative.

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

In order to achieve the above purpose, on the one hand, the present invention provides a method for preparing a compound represented by formula (I), wherein the method comprises using the compound of formula (III) as a raw material to prepare by reacting,

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

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from a carboxyl protecting group or a C _1-6 alkyl group;

R ¹¹ is selected from C _1-6 alkyl groups.

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

According to some specific embodiments of the present invention, wherein, R ² is selected from methyl, ethyl, propyl, n-butyl or tert-butyl.

According to some specific embodiments of the present invention, wherein, R ² is selected from tert-butyl.

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

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

It can be understood that to prepare the compound of formula (I) by reacting the compound of formula (III) as a raw material, the free base can be obtained by hydrolysis first, and then acid A is added to remove the carboxyl protecting group and form a salt. Alternatively, the carboxyl protecting group can be removed first, and then hydrolyzed to obtain the free base, which is then formed into a salt with acid A.

（I）

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

(I)

(II)

R ² is defined as before.

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

(I) A is as defined above.

（II），

（III）The present invention provides a method for preparing a compound of formula (II), which is prepared by using the 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 comprises first preparing the compound of formula (II) by using the compound of formula (III) as a raw material, and then preparing the compound of formula (I) by using the compound of formula (II) as a raw material,

A, R ¹ and R ² are as defined above.

According to some specific embodiments of the present invention, wherein, the method comprises first preparing the compound of formula (II) by using the compound of formula (III) as a raw material, and then reacting the compound of formula (II) as a raw material in the presence of acid A to obtain the compound of formula ( I) Compounds.

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

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

R ² is selected from a carboxyl protecting group or a C _1-6 alkyl group.

According to some specific embodiments of the present invention, wherein, R ² is selected from tert-butyl.

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

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

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

According to some specific embodiments of the present invention, wherein, the reaction of the compound of formula (II) and acid A can be reacted at 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 in which the compound of formula (II) is reacted with acid A is selected from any solvent that is compatible with the compound of formula (II), such as acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water , toluene, dioxane and their combined solvents.

In some embodiments, the solvent is selected from the group consisting of 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) reacts with acid A 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 1.1:1~5:1, at 70-90°C more preferably, the molar ratio of acid A and 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.

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

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from a carboxyl protecting group or a C _1-6 alkyl group;

R ¹¹ is selected from C _1-6 alkyl groups.

According to some specific embodiments of the present invention, wherein, R ² is selected from tert-butyl.

According to some specific embodiments of the present 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 obtaining a compound of formula (III) by reacting the compound of formula (IV) as a raw material,

(IV)

R ² is as defined above.

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

(III),

R ¹ is as defined above.

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

（XI）The chiral acid of the present invention is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid or d-quinic acid,

(XI)

R ¹ is selected from H, hydroxyl 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 preparation method of a compound of formula (III), wherein:

.

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from a carboxyl protecting group or a C _1-6 alkyl group;

R ¹¹ is selected from C _1-6 alkyl groups.

According to some specific embodiments of the present invention, wherein, R ² is selected from tert-butyl.

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

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

According to some specific embodiments of the present invention, a preparation method of the compound of formula (III), wherein the molar ratio of the chiral acid and the compound of formula (IV) is 0.5:1-1:1.

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

According to some specific embodiments of the present invention, a preparation method of the compound of formula (III), wherein the chiral acid is selected from the compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl group -L-tartaric acid, L-aspartic acid or d-quinic acid; further preferably, the molar ratio of the chiral acid and 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 comprises using the compound of formula (IV) as a raw material to obtain the compound of formula (III) through reaction, and then recrystallization (recrystallization) of the compound of formula (III).

（III）The present invention also provides a method for purifying the compound represented by formula (III), wherein the compound of formula (III) is recrystallized in a recrystallization solvent:

(III)

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-butyl group;

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 the compound represented by the formula (III), wherein the compound of the formula (III) is recrystallized in a recrystallization solvent, and the recrystallization solvent is an organic solvent and/or water, It is preferable to recrystallize 1-2 times.

According to some specific embodiments of the present invention, a method for purifying the compound represented by the formula (III), wherein the mass-volume ratio of the compound of the 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 isopropanol, acetonitrile or ethanol;

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

According to some specific embodiments of the present invention, a method for purifying the compound represented by formula (III), wherein the recrystallization solvents are isopropanol and water.

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

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

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

According to some specific embodiments of the present invention, a method for purifying the compound represented by the formula (III), wherein the preparation of the compound of the formula (III) comprises first preparing the compound of the formula (III) by using the compound of the formula (IV) and a chiral acid as raw materials, Then the compound of formula (III) is recrystallized to obtain a refined compound.

（XI）According to some specific embodiments of the present invention, wherein, the chiral 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, hydroxyl 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 present invention, wherein the chiral 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 embodiments of the invention, the chiral acid is (S)-(+)-O-acetyl-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) to the compound of formula (IV) is 0.5:1 to 1:1.

In some specific embodiments, the molar ratio of the compound of formula (XI) to the compound of formula (IV) is from 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 conditions;

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 comprises using the compound of formula (IV) as a raw material to obtain a crude product of the compound of formula (III) through a reaction, and then using a recrystallization solvent, such as an organic solvent and/or water for the described The crude product was 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, the volume ratio of isopropanol and water is (10-30):1.

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

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

According to some specific embodiments of the present invention, wherein, the step of recrystallization comprises dissolving the crude product of formula (III) in a recrystallization solvent, and crystallization after stirring and reacting for 0.5 to 1 hour.

According to some specific embodiments of the present 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 the repetition is repeated once, it is recrystallized twice; if the repetition is repeated twice, it is equivalent to the recrystallization 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) by 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, wherein, the preparation of the compound of formula (IV) comprises: preparing the compound of formula (IV) at 0-40° C. using the compound of formula (V) as a raw material in the presence of a catalyst and a reducing agent.

In certain embodiments, the catalyst/reducing agent for the reduction reaction of compound (V) to form compound (IV) can be selected from Raney nickel/hydrazine hydrate, nickel chloride hexahydrate/sodium borohydride, iron powder/chloride Ammonium, 10% palladium carbon/triethyl silicon, Raney nickel/hydrogen, 10% palladium carbon/hydrogen, or zinc dust/acetic acid.

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

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

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

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

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

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

According to some specific embodiments of the present invention, wherein, the method further comprises the preparation of the compound of formula (V): comprising preparing the compound of formula (V) by using the compound of formula (VI) as a raw material,

R ² is as defined above.

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

According to some specific embodiments of the present invention, wherein, the preparation of the compound of formula (V) comprises: the compound of formula (VI) and nitromethane are reacted in the presence of a base without other solvent environment 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, wherein, the temperature of addition reaction is 60 ℃～reflux.

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

According to some specific embodiments of the present invention, wherein, the temperature of addition reaction is 85 ℃～90 ℃.

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

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

According to some specific embodiments of the present invention, wherein, the molar ratio of compound (V) reacting 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 certain embodiments, the molar ratio of compound (V) reacting 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 comprises the preparation of the compound of formula (VI): comprising preparing the compound of formula (VI) by using the compound of formula (VII) as a raw material,

.

According to some specific embodiments of the present invention, wherein, the preparation of the compound of formula (VI) comprises: in the presence of a base, the compound of formula (VII) is combined with tertiary butyl dimethoxyphosphonoacetate, diethoxyphosphorus A compound of formula (VI) is formed by reacting any one of the compounds among tertiary butyl acyl acetate, 3 butyl bromoacetate, 3 butyl chloroacetate or 3 butyl acetoacetate.

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

According to some specific embodiments of the present invention, wherein, the temperature of the reaction of the compound of formula (VII) with tert-butyl dimethoxyphosphonoacetate is 10°C to 40°C.

According to some specific embodiments of the present invention, wherein, the temperature of the reaction of the compound of formula (VII) with tert-butyl dimethoxyphosphonoacetate is 10°C to 30°C.

According to some specific embodiments of the present invention, wherein, the temperature of the reaction of the compound of formula (VII) with tert-butyl dimethoxyphosphonoacetate is 10°C to 15°C.

According to some specific embodiments of the present invention, wherein, the temperature of the reaction of the compound of formula (VII) with tert-butyl dimethoxyphosphonoacetate is 20°C to 40°C.

According to some specific embodiments of the present invention, wherein, the temperature of the reaction of the compound of formula (VII) with tert-butyl dimethoxyphosphonoacetate is 30°C to 40°C.

According to some specific embodiments of the present invention, wherein, tertiary butyl dimethoxyphosphoronyl acetate can be replaced with tertiary butyl diethoxy phosphoronyl acetate, tertiary butyl bromoacetate, tertiary butyl chloroacetate ester or 3-butyl acetoacetate.

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

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

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

According to some specific embodiments of the present invention, wherein, 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 comprises using the compound of formula (VIII) as a raw material to prepare the compound of formula (VII),

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

Optionally, ^R3 and ^R4 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 present invention, wherein, R ³ and R ⁴ and the attached nitrogen atom form a pyridine ring or a tetrahydropyrrole ring.

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

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

The pyridine bases in the present invention refer to bases containing a pyridine structure, such as 2,4,6-collidine, 2,6-lutidine or pyridine.

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

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

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

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

In certain embodiments, the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride, or cesium carbonate; pH to basic can be selected from pH 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 pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the reaction of the intermediate is completed. The step of acidifying the reaction solution with an acid.

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

According to some specific embodiments of the present invention, the acidification treatment refers to adjusting the reaction liquid 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 pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the reaction of the intermediate is completed. The reaction solution is acidified with acid, and the pH is adjusted 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, wherein, 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 certain embodiments, the preparation method of the compound represented by formula (VII) comprises the following steps:

(1) Compound of formula (VIII) in acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and pyridine base (preferably 2,4,6-collidine, 2,6-dimethylpyridine) react in the presence of pyridine or pyridine);

(2) Adjust the pH of the reaction solution obtained in step (1) to an alkali with an alkali (preferably an inorganic alkali, more 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 mineral 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 preparation method of the compound represented by formula (VII) comprises the following steps:

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

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

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

In certain embodiments, the preparation method of the compound represented by formula (VII) comprises the following steps:

(1) In the presence of dichloromethane or 1,2-dichloroethane as a solvent, in the presence of a pyridine base and trifluoromethanesulfonic anhydride, the addition reaction of formula (VIII) occurs; wherein the pyridine base refers to a base containing a pyridine structure bases such as 2,4,6-collidine, 2,6-lutidine or pyridine;

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

(3) Under acidic conditions, the compound of formula (VII-1) in the mixture of formula (VII) and formula (VII-1) undergoes a rearrangement reaction and is converted into the compound of formula (VII), wherein the solvent of the reaction can 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 by common inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.

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

According to some specific embodiments of the present invention, the preparation method of the compound represented by the formula (VIII) further includes the preparation of the compound of the formula (VIII) by reacting the compound of the formula (IX) with a secondary amine NH(R ³ )(R ⁴ ) as a raw material 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) is reacted with a secondary amine NH(R ³ )(R ⁴ ) in the presence of a condensing agent to prepare the compound of formula (VIII).

wherein R ³ and R ⁴ of the secondary amine are as defined previously 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 the group consisting of oxalic chloride, dichlorosulfite, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-Hydroxybenzotriazole or N,N'-carbonyldiimidazole.

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

In certain embodiments, the reaction temperature of the compound of formula (IX) with the secondary amine NH( ^R3 )(R4) to prepare the compound of ^formula (VIII) is room temperature, in certain embodiments, the reaction temperature is 20 ~30°C.

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

.

According to some specific embodiments of the present invention, wherein, the compound of formula (IX) is prepared from the compound of formula (X) and cyclo()isopropyl malonate as raw materials.

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

According to some specific embodiments of the present invention, wherein, the method comprises the reaction of the compound of formula (X) with cyclo()isopropyl malonate under the catalysis of triethylamine formate, and reductive decarboxylation to generate 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 cyclo()isopropyl malonate are reacted with anhydrous formic acid as the reaction medium.

In certain embodiments, the molar ratio of the compound of formula (X) to cyclo()isopropyl malonate is not greater than 1, in certain embodiments, the molar ratio is 1:1 to 5, and in certain In some embodiments, the molar ratio is from 1:1 to 2, and in certain 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 cyclo()isopropyl malonate is 100-180°C, in some embodiments, the reaction temperature is 140-160°C, and in a certain 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 cyclo()isopropyl malonate, the reductive decarboxylation reaction is carried out under acidic conditions, wherein the acidic conditions are pH 1-5, In certain embodiments 1-4, in certain embodiments 1-3, in certain embodiments 1-2. Where acid conditions are provided by common mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid.

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

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

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

(3) The compound of formula (VIII) is reacted to generate the compound of formula (VII);

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

Optionally, ^R3 and ^R4 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 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.

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

(1) Under the catalysis of triethylamine formate, the compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

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

(3) Dichloromethane or 1,2-dichloroethane is used as a solvent, in the presence of a pyridine base, after the formula (VIII) is reacted with trifluoromethanesulfonic anhydride, the pH of the reaction solution is adjusted to alkaline with an inorganic base, and then Compounds of formula (VII) are prepared under acidic conditions.

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

(1) Under the catalysis of triethylamine formate, the compound of formula (X) reacts with cyclo()isopropyl malonate, and is reduced and decarboxylated to generate the compound of formula (IX);

(2) The compound of formula (IX) is subjected to condensation reaction with secondary amine NH(R ³ )(R ⁴ ) to generate the compound of formula (VIII);

(3) Dichloromethane or 1,2-dichloroethane is used as a solvent, in the presence of a pyridine base, after the formula (VIII) is reacted with trifluoromethanesulfonic anhydride, the pH of the reaction solution is adjusted to alkaline with an inorganic base, and then Compounds of formula (VII) are 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 condensing agent.

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

wherein R ³ and R ⁴ of the secondary amine are as defined previously 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, methods of preparing compounds of formula (VII) comprise the steps of:

(1), under the catalysis of triethylamine formate, the compound of formula (X) reacts with cyclo(idene) isopropyl malonate, and is reduced and decarboxylated to generate compound of formula (IX);

(2), the compound of formula (IX) reacts with tetrahydropyrrole to generate the compound of formula (VIII);

(3), dichloromethane or 1,2-dichloroethane as solvent, in the presence of 2,4,6-trimethylpyridine and trifluoromethanesulfonic anhydride, formula (VIII) undergoes an addition reaction, and then uses inorganic The pH of the reaction solution is adjusted by alkali to be basic, and hydrolysis reaction is carried out, and then rearrangement reaction is carried out under acidic conditions to obtain the compound of formula (VII).

(VII)The present invention also provides a method for purifying the compound shown in formula (VII):

(VII)

The method comprises the steps of adding the compound of formula (VII) and sodium hydrogen sulfite to a salt at room temperature, extracting impurities with an organic solvent, adding acid or base at room temperature and finishing the reaction after post-treatment.

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

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

According to some specific embodiments of the present invention, the above-mentioned 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 above 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 above acid is selected from hydrochloric acid or sulfuric acid.

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

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

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

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

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

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

(4) The compound of formula (III) is reacted 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 obtain 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 generate the compound of formula (I),

(XII);

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ .

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

(1) The compound of formula (VI) is prepared by using compound (VII) as a raw material;

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

(3) The compound of formula (V) undergoes reduction reaction to obtain (IV), and then reacts with chiral acid (preferably the compound of formula (XI)) to obtain the 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 hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-butyl group;

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 comprises the following steps:

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

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

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

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

According to some specific embodiments of the present invention, after the compound of formula (V) undergoes a reduction reaction, after hydrolysis, it is then reacted with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII), formula (XII) The compound is hydrolyzed, and then reacts with acid A to generate 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 to obtain the compound of formula (XII), and then the compound of formula (XII) is reacted to generate 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 hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-butyl group;

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,

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-butyl group;

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 comprises the following steps:

(1) In the presence of a base, compound (VII) is reacted with tert-butyl dimethoxyphosphonoacetate at 10°C to 40°C to generate compound (VI);

(2) In the presence of alkali, compound (VI) reacts with nitromethane at 80°C to 100°C to generate compound (V);

(3) In methanol solvent, nickel chloride hexahydrate is used as catalyst, sodium borohydride is used as reducing agent, after compound (V) undergoes reduction reaction, react with chiral 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) is reacted with A to obtain the compound of formula (I).

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

(1) Compound (VII) is reacted with tert-butyl dimethoxyphosphonoacetate at 10°C to 40°C and in the presence of a base to form compound (VI);

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

(3) 0-40 ℃, in methanol solvent, nickel chloride hexahydrate is used as catalyzer, sodium borohydride is used as reducing agent, after compound (V) takes place reduction reaction, react with chiral acid to obtain formula (III) compound;

(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 tertiary butoxide or 1,8-diazabicycloundec-7-ene.

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

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

(XI)

R ¹ is as defined above.

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

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

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

(2) Compound of formula (IX) reacts with secondary amine NH(R ³ )(R ⁴ ) to generate compound of formula (VIII);

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

(4) The compound of formula (VI) is prepared by using compound (VII) as a raw material;

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

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

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

（V）

（XII）；Or after the compound of formula (V) undergoes a reduction reaction, after hydrolysis, it reacts with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII), and the compound of formula (XII) is hydrolyzed and then reacted with 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 hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-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 groups;

Optionally, ^R3 and ^R4 together with the carbon atom to which they are attached form a ring (preferably ^R3 and ^R4 and the nitrogen atom to which they are attached form a pyridine ring or a tetrahydropyrrole ring).

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

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

(2) The compound of formula (IX) is subjected to condensation reaction with secondary amine NH(R ³ )(R ⁴ ) to generate the compound of formula (VIII);

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

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

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

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

(7) The compound of formula (III) is reacted 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 obtain 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);

The relevant definitions of A, R ¹ , R ² , R ³ and R ⁴ are the same as above.

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

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

(2) The compound of formula (IX) is subjected to condensation reaction with secondary amine NH(R ³ )(R ⁴ ) to generate the compound of formula (VIII);

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

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

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

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

;

The relevant definitions of A, R ¹ , R ² , R ³ and R ⁴ are the same as above.

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

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX);

(2) The compound of formula (IX) is subjected to condensation reaction with secondary amine NH(R ³ )(R ⁴ ) to generate the compound of formula (VIII);

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

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

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

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

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

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

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

(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 ¹¹ is selected from C _1-6 alkyl;

R ² is selected from carboxyl protecting agent or C _1-6 alkyl;

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

Optionally, ^R3 and ^R4 together with the carbon atom to which they are attached form a ring (preferably ^R3 and ^R4 and the nitrogen atom to which they are attached form a pyridine ring or a tetrahydropyrrole ring).

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

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

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

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

(II)

R ² is selected from carboxyl protecting groups or C _1-6 alkyl groups; preferably R ² is selected from tertiary butyl groups.

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

(III).

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

(XI).

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

The present invention also provides the application of the compound represented by the formula (XI) in preparing the reference substance of the compound of the formula (II).

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

(VIII)

in

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

^Provided that ^R3 and R4 are not both methyl.

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

、

、

、

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

,

,

,

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-butyl group;

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 isomers or pharmaceutically acceptable compounds thereof of salt,

(II),

(III)

,

,

,

(VIII),

,

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ;

R ² is selected from carboxyl protecting group or C _1-6 alkyl group; preferably R ² is selected from tert-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 and the attached nitrogen atom form a pyridine ring or a tetrahydropyrrole ring);

^Provided that ^R3 and R4 are not both methyl.

（I）；The present 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, stir and crystallize, filter, and dry under reduced pressure to obtain:

(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 isoacetic acid is added to the filtrate. Propyl ester, stirred for crystallization, filtered, and obtained.

According to some specific embodiments of the present invention, wherein the crude compound of formula (I) and dimethyl sulfite are heated to 50±5° C., after the solid is completely dissolved, purified water is added and stirred for crystallization. Filter and 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, one reaction can be performed in one reaction. It is completed in the operation (that is, after feeding, there is no need to discharge to obtain intermediate products, and continue to carry out the next step reaction in the reaction solution, such as the so-called "one-pot cooking" method) and people mistakenly think that it is a one-step reaction, or it is literally in the present invention. It is a one-step reaction, but it can be split into two or more reaction steps in practice to make people mistakenly think that it is a multi-step reaction, which is all 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 is described in the invention examples.

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

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

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

To sum up, the present invention provides a preparation method and an intermediate of a fused tricyclic γ-amino acid derivative. The preparation method of the present invention has the following advantages:

The compound of formula (VII) of the present invention has a very small polarity, is easily dissolved in most solvents, and has a low melting point, so it is difficult to recrystallize and purify. And because it is solid at room temperature, it is easy to sublime and block the distillation device when heated, and it cannot withstand high temperature, so it cannot be purified by routine distillation or vacuum distillation. The purity of the crude product is only 50%, and after being purified 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 easy to obtain, which greatly reduces the production of finished products; secondly, the entire synthesis process is purified by crystallization, 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 will be described in detail below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention includes but is not limited thereto.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic instruments, and the solvents were deuterated dimethylsulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), Deuterated acetonitrile (CD ₃ CN), the internal standard is tetramethylsilane (TMS).

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

The HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).

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

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, 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)

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

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

Anhydrous formic acid (18.82 kg, 409.09 mol) was pumped into a 100-liter reaction kettle, and the pumping was completed. Cool down to 10°C. Triethylamine (16.53 kg, 163.64 mol) was added dropwise to the reaction solution, the addition was completed, and the mixture was stirred for 20 minutes. When the internal temperature was 10 °C, cyclo(idene)isopropyl malonate (7.86 kg, 54.55 mol) was added. ) was added to the reaction kettle, and then 3-cyclohexene-1-carbaldehyde (6.00 kg, 54.55 mol) was added dropwise to the reaction solution at an internal temperature of 40 °C. release again. 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), and 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 obtain 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].

Step 2: 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) in dichloromethane (60.0L), it was pumped into a 100L reaction kettle. DMF (3.0 mL) was added and oxalic chloride (9.046 kg, 71.272 mol) was added dropwise to the reaction. After the addition was completed, 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 reaction kettle successively. The inner temperature was controlled to be lower than 10°C, the addition was completed, and the mixture was stirred 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 solution 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].

The third step: tricyclo[ ^4.2.1.03,8 ]nonyl-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), it was pumped into a 100 L reaction kettle. The temperature was lowered to -10°C, and 2,4,6-collidine (4.94 kg, 40.83 mol) was added. A dichloromethane 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 central control detection reaction was completed, an aqueous solution (23.0 L) of sodium hydroxide (3.10 kg, 77.5 mol) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted between 10-11. Continue to reflux for 5-6 hours. After standing for separation, the aqueous phase was extracted with dichloromethane (5.0L × 1), and the organic phases were combined. The organic phase was pumped into the reactor and cooled to 10°C. 2.0 N hydrochloric acid solution (20.0 L) was added dropwise to adjust the pH of the reaction solution between 1-2. Let stand for separation, the organic phase was washed with saturated brine (20L×1), concentrated, the residue was dissolved in acetone (20.0L), pumped into a 100L reaction kettle and stirred, and concentrated sulfuric acid (4.0L) and water ( 20.0 L) of the prepared solution, and refluxed for 2 hours after the addition. The temperature was lowered to 15°C, and saturated brine (20.0 L) was added to the reaction solution, followed by extraction with n-hexane (15.0 L×2). The organic phases were combined, washed with saturated brine (20.0 L×1), and the organic phases were dried over anhydrous sodium sulfate overnight. After filtering, the filtrate was concentrated under reduced pressure to obtain a yellow solid crude product 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 ethanol (3.0L) of 1D crude product (3.00kg, 22.059mol) under stirring at room temperature The solution was added and stirred overnight at room temperature, extracted with ethyl acetate (20L×2), the aqueous phase was added to the reaction kettle and stirred and cooled to 10°C, and water of sodium hydroxide (2.250kg, 56.250mol) was added dropwise. (10L) solution, adjust the pH to 10-12, stir at room temperature for 2 hours, extract with n-hexane (20L×2), combine the organic phases and wash with purified water (20L×1), the organic phase is washed with anhydrous sulfuric acid Sodium (2 kg) was dried for 1 hour, filtered, and the filtrate was evaporated to dryness to obtain 1D . The measured purity of the colorless crystalline solid (2.7 kg, yield 90%) was 98.3%.

Method 2: Dissolve sodium bisulfite (1529 g, 14.706 mol) in 22 L of water, add dropwise a solution of 1D crude product (1000 g, 7.353 mol) in absolute ethanol (1000 mL) under 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 with 6.4L concentrated sulfuric acid and 6 kg of crushed ice) was added dropwise to the aqueous phase, stirred at room temperature for 5 hours, and the reaction solution was washed with n-hexane ( Extract 3-4 times, 4L each time), combine the organic phases and wash with saturated aqueous sodium chloride solution (5L×2), dry the organic phase with 1kg anhydrous sodium sulfate for 2 hours, filter, and evaporate the filtrate to dryness to obtain 1D , a white solid ( 900 g, 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: tertiary butyl 2-(tricyclo[4.2.1.0 ^3,8 ]nonyl-2-ylidene) acetate (1R,3S,6R,8R and 1S,3R,6S,8S elimination Rotary 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 tertiary butoxide (742.0 g, 6.62 mol) and tetrahydrofuran (6.20 L) were added to a 20 L reaction kettle. The temperature was lowered to 5°C, tert-butyl dimethoxyphosphonoacetate (1480 g, 6.62 mol, 1.1 eq) was added dropwise to the reaction solution, the reaction temperature was controlled to 10°C-15°C, and stirring was continued for 1 hour. Then 1D (820.0 g, 6.02 mol, 1.0 eq) solution in tetrahydrofuran (2.0 L) was added dropwise to the reaction solution, the addition was completed within 1 hour, and the reaction was naturally raised to room temperature for 2 hours. Saturated ammonium chloride (2.0 L) solution and purified water (2.0 L) were successively added to the reaction kettle. After stirring for 20 minutes, the mixture was left to stand for layers, 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 IE as a yellow liquid (1.50 kg).

LCMS m/z = 235.3 [M+1].

The fifth step: 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)

1E (1.40 kg, 5.97 mol, 1.0 eq), nitromethane (1.82 kg, 29.85 mol, 5.0 eq) and dimethylsulfite (9.8 L) were sequentially added to the 20L reactor. With stirring, cesium carbonate (2.34 kg, 7.16 mol, 1.2 eq) was added to the reaction. After adding, heat to 80°C-85°C, continue the reaction for 5 hours and then cool to room temperature, add purified water (20.0 L) to the reactor, and extract the aqueous phase with methyl tertiary 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 brown liquid 1F (1.62 kg, yield: 92%).

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

The sixth step: tertiary butyl 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[ ^4.2.1.03,8 ]nonyl-2-yl)ethyl Acetate (S)-2-acetoxy-2-phenylacetic acid (1H)

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

To a 50L autoclave 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 batches to maintain the reaction The temperature of the system is 20°C-30°C, and the addition is completed in about 3 hours. After the addition was completed, stirring was continued for 2 hours. Ice water (16.4 L) was added to the autoclave, and the aqueous phase was filtered through celite. The filtrate was extracted with dichloromethane (3.0 L×2), and the organic phases were combined, 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. The organic phase was concentrated by distillation until no solvent was evaporated, and then stirred and slurried with isopropanol (5.9 L) for 2 hours, and then cooled to 5° C. and stirred for 1 hour. 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%). The ee value was determined to be 48.35% after the solid was derivatized.

The first crystallization: The crude product 1H (420.0 g, 0.92 mol), isopropanol (4.20 L) and water (0.21 L) were successively added to the reaction kettle. The temperature was programmed to 82°C to completely dissolve the solids and held for 0.5 hours. Cool to 20°C for crystallization for about 6 hours. When the internal temperature reaches 20 °C, filter, and wash the filter cake with isopropanol (0.40 L×1). The solids were combined and dried by blasting at 60-65°C for 4 hours to constant weight. The first 1H crystallized product (260 g, yield: 62%) was obtained, and the ee value was determined to be 81.25% after derivatization of the solid.

The second crystallization: The first 1H crystallized product (177 g, 0.39 mol), isopropanol (2.53 L) and water (0.126 L) were added to the reaction kettle in turn. The temperature was programmed to 82°C to completely dissolve the solids and held for 0.5 hours. Cool to 20°C for crystallization for about 4.5 hours. When the internal temperature reaches 30°C, filter, and wash the filter cake with isopropanol (0.10 L×1). The solids were combined and dried by blasting at 60-65°C for 4 hours to constant weight. A white solid 1H pure product (128 g, yield: 72%) was obtained, and the ee value was determined to be 99.73% after derivatization of the solid.

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

The seventh step: 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[ ^4.2.1.03,8 ]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)

1H pure product (100.0 g, 0.218 mol) and purified water (0.8 L) were added to the reaction kettle in turn, and the temperature was lowered to 0-10 °C. The internal temperature was raised to 0-10 °C, and 1 mol/L NaOH (218 mL) aqueous solution was added dropwise to the reaction kettle to adjust the pH of the reaction solution to 9-10. The layers were left to stand, and the aqueous phase was extracted with dichloromethane (0.30 L×2). The organic phases were combined and washed successively 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 to decolorize and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue in the concentrated kettle was dissolved in acetonitrile (280 mL). Benzenesulfonic acid monohydrate (77.0 g, 0.437 mol) was prepared as a solution with purified water (280 mL) and added dropwise to the above acetonitrile solution, and the addition was completed. Program the temperature to 80-85°C, and keep the temperature for 4-6 hours. The reaction solution was cooled to 10-20° C. for crystallization for about 4-6 hours. When the internal temperature reaches 10-20°C, filter, and wash the filter cake with water (30 mL×1) and acetonitrile (50 mL×1) successively. Compound 1 was obtained after drying 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 sulfite were added, and the temperature was raised to 80 degrees Celsius to dissolve, kept for 5 minutes, and then cooled to room temperature naturally to obtain rod-shaped crystals.

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

表3單晶掌性解析結果

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

Table 3 Results of single crystal chiral analysis

和

。實施例 2 Using the same method as above, after dissolving the residue in the concentration kettle with acetonitrile, respectively, p-toluenesulfonic acid or methanesulfonic acid is prepared into a solution, added dropwise to the acetonitrile solution, and after the reaction is completed, the following products are obtained respectively through post-processing :

and

. Example 2

tert-butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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: tertiary butyl 2-(tricyclo[4.2.1.0 ^3,8 ]nonyl-2-ylidene) acetate (1R,3S,6R,8R and 1S,3R,6S,8S elimination Rotary 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)

1,8-Diazabicycloundec-7-ene (288 g, 1.90 mol) and tert-butyl dimethoxyphosphonoacetate (197 g, 0.88 mol) were added to the reaction at room temperature bottle, add and continue to stir for 20 minutes. 1D (100 g, 0.73 mol) was added to the reaction overnight and the addition was complete. The temperature was raised to 40°C for 6 hours. A yellow liquid was obtained, which was carried directly to the next reaction 1E (172 g).

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

The second step: tertiary butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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)

1E reaction solution (172 g, 0.73 mol), nitromethane (224 g, 3.67 mol), 1,8-diazabicycloundec-7-ene (134 g, 0.88 mol) were successively added to the 2L reactor ) and dimethylsulfoxide (500 mL). Heated to 80°C-85°C, and the reaction was continued 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 brown liquid IF (193 g, yield: 90%).

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

tert-butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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: tertiary butyl 2-(tricyclo[4.2.1.0 ^3,8 ]nonyl-2-ylidene) acetate (1R,3S,6R,8R and 1S,3R,6S,8S elimination Rotary 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 tertiary butoxide (9.06 g, 80.76 mmol) and tetrahydrofuran (150 mL) were added to a 1 L reaction kettle. The temperature was lowered to 5°C, and tert-butyl dimethoxyphosphonoacetate (18.11 g, 80.76 mmol, 1.1 eq) was added dropwise to the reaction solution, and the reaction temperature was controlled to 10°C-15°C, and the dropwise addition was completed in about 20 minutes. Continue stirring for 0.5 hours, and control the temperature to 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 reaction was naturally raised to room temperature for 2 hours. Saturated ammonium chloride (100.0 mL) was sequentially added to the reaction kettle, and purified water (100.0 mL) was quenched. After stirring for 20 minutes, the mixture was left to stand for layers, 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 yellow liquid 1E (17.5 g).

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

The second step: tertiary butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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)

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 dimethylsulfite (116 mL) sequentially. Then potassium tertiary butoxide (15.8 g, 0.14 mol, 2.0 eq) was added to the reaction solution. After the addition was completed, the mixture was heated to 80°C-85°C, and the reaction was continued 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

tert-butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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: tertiary butyl 2-(tricyclo[4.2.1.0 ^3,8 ]nonyl-2-ylidene) acetate (1R,3S,6R,8R and 1S,3R,6S,8S elimination Rotary 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 tertiary butoxide (1.23 kg, 11.0 mol) and tetrahydrofuran (10.0 L) were added to a 50 L reaction kettle. The temperature was lowered to 5°C, and tert-butyl dimethoxyphosphonoacetate (2.50 kg, 11.0 mol, 1.1 eq) was added dropwise to the reaction solution, and the reaction temperature was controlled to 10°C-15°C, and the dropwise addition was completed in about 40 minutes. Continue stirring for 0.5 hours, and control the temperature to 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 dropwise addition was completed within 0.5 hour. After the addition was completed, the reaction was naturally raised to room temperature for 2 hours. After the complete reaction of the raw materials detected by the central control, 5% ammonium chloride solution (6.0 L) was sequentially added to the reaction kettle to quench the reaction. After stirring for 20 minutes, the mixture was left to stand for layers, and the aqueous phase was extracted with dichloromethane (5.0 L×1). The organic phases were combined, washed with 5% brine (5.0L×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: tertiary butyl 2-(2-(nitromethyl)tricyclo[ ^4.2.1.03,8 ]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)

1E (2.34 kg, 10.0 mol, 1.0 eq), nitromethane (1.53 kg, 25.0 mol, 2.5 eq) and dimethylsulfite (2.34 L) were successively added to the 50 L reactor. Turn on stirring, and then add potassium tertiary butoxide (15.8 g, 0.14 mol, 2.0 eq) to the reaction solution. After the addition was completed, the mixture was heated to 85°C-90°C, and the reaction was continued for 10 hours. In the control, 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 successively with 0.5mol/L hydrochloric acid solution (2.0L×1), 0.5mol/L sodium hydroxide solution (2.0L×1) and 5% sodium chloride solution (2.0L×1). Filter, control the temperature of the filtrate and concentrate under reduced pressure below 35±5°C until no large amount of distillate flows out. The temperature was raised to 55±5°C, and the nitromethane was evaporated under reduced pressure. The sampling was controlled in the middle, and the content of nitromethane was controlled to be less than 5%. A brown liquid 1F (2.95 kg) was obtained.

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

tert-butyl 2-(2-(aminomethyl)tricyclo[ ^4.2.1.03,8 ]nonyl-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)

1F (90 g, 0.31 mol), methanol (900 mL), palladium carbon 10% (9.0 g) were successively added to the reaction flask, the hydrogen was purged three times, and the hydrogenation reaction was carried out 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

tert-butyl 2-(2-(aminomethyl)tricyclo[ ^4.2.1.03,8 ]nonyl-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)

1F (70 g, 0.24 mol), ethanol (360 mL) and water (120 mL) were added to the reaction flask, followed by iron powder (67.2 g, 1.2 mol) and ammonium chloride (38.5 g, 0.72 mol), and the addition was completed. 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[ ^4.2.1.03,8 ]nonyl-2-yl)acetate (S )-2-Acetyloxy-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 sequentially added to the reaction flask. The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. Cool to 20°C for crystallization, filter, wash the filter cake with isopropanol (0.40 L×1), and dry at 60-65°C for 4 hours. 60 g of 1H recrystallized product was obtained for the first time, yield: 75%), and the ee value was determined to be 97.22% after the solid was derivatized.

The second recrystallization: The first recrystallization product of 1H (137 g, 0.30 mol), isopropanol (1284 mL) and water (85.6 mL, v:v=15:1) were sequentially added to the reaction kettle. The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. Cool to 20°C for crystallization, filter, wash the filter cake with isopropanol (0.10 L×1), and dry at 60-65°C. A white solid 1H recrystallized product (112 g, yield: 82%) was obtained for the second time , and the ee value was determined to be 99.72% after derivatization of the solid.

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

Method Two:

The second recrystallization: the first recrystallization product of 1H (10.0g, 21.76 mmol, ee%=77%), isopropanol and water (290mL/10mL, v:v=29:1) were added to the reaction flask in turn . The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. Cool to 30°C for crystallization, filter, and wash the filter cake with isopropanol (10.0 mL × 1). The solids were combined and dried at 60-65°C. The second recrystallization product (6.1 g, yield: 61%) of 1H was obtained as a white solid, and the ee value was determined to be 97.3% after derivatization 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)

1H (10.0 g, 21.77 mol) and purified water (100.0 mL) were sequentially added to the reaction flask. Cool down to 0-10°C. When the internal temperature reached 0-10 °C, 25% aqueous ammonia solution (4.0 mL) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted to 9-10. The layers were left to stand, and 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 to decolorize and dried over anhydrous sodium sulfate. Filter, add benzenesulfonic acid monohydrate (8.06 g, 43.54 mmol) to the filtrate and finish the addition. Heat up to 80-85°C. Incubate the reaction for 4-6 hours, and the central control detects that the reaction of the raw materials is complete. Cool the ice water to 20-25°C for crystallization, about 2 hours. When the internal temperature reaches 20-25°C, filter, and wash the filter cake with isopropyl acetate (10 mL×1). Compound 1 (7.8 g, yield: 97.6%) was obtained as a white solid after drying. 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)

1H (4.59 g, 10.0 mmol) and purified water (40.0 mL) were sequentially added to the reaction flask. Cool down to 0-10°C. When the internal temperature reached 0-10 °C, 1.0 mol/L sodium hydroxide solution (11.0 mL) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted to 9-10. The layers were left to stand, and 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 to decolorize 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, and the addition was completed. Heating to 80°C. Incubate the reaction for 4-6 hours, and the central control detects that the reaction of the raw materials is complete. The ice water was cooled to 25°C for crystallization for about 2 hours. When the internal temperature reaches 25°C, filter, and wash the filter cake with acetonitrile (3.0 mL×2). Compound 1 (3.4 g, yield: 92.6%) was obtained as a white solid after drying. 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)

1H (150 g, 0.33 mol) and purified water (1500 mL) were added to the reaction flask sequentially. The temperature was lowered to 0-10°C, 1.0 mol/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. The layers were left to stand, and the aqueous phase was extracted with dichloromethane (800 mL×2). The organic phases were combined and washed successively with 1.0 mol/L sodium hydroxide solution (300.0 mL×1) and 10% brine (300.0 mL×1). Activated carbon (5.0 g) was added to the organic phase and stirred for decolorization. Celite was filtered, the filtrate was concentrated, and acetonitrile (328.0 mL), purified water (328.0 mL) and benzenesulfonic acid monohydrate (114 g, 0.66 mol) were added, and the addition was completed. Heating to 80°C. Incubate the reaction for 12 hours, and the central control detects that less than 0.2% of the raw material reacts completely. The ice water was cooled to 10±5°C, and the mixture was stirred for about 6 hours to crystallize. When the internal temperature reaches 10°C, filter, and the filter cake is washed successively with acetonitrile, 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 as a white solid (104 g, yield: 86.9%).

Compound 1 can be further purified by the following methods:

Method 1: Compound 1 (430.0 g, 1.17 mol) and N-methylpyrrolidone (2.15 L) were added to a 5 L reaction flask. After adding, heat to 80±5℃ and keep for 0.5 hours. After the solid was completely dissolved, activated carbon (10 g) was added and stirring was continued for 10 minutes. Filter while hot, and the filter cake is washed with N-methylpyrrolidone (400 mL×1) and dried by suction. Isopropyl acetate (7.5 L) was added dropwise to the filtrate, and after the addition was completed, stirring and crystallization were continued for 2 hours. After filtration, the filter cake was washed with isopropyl acetate (500.0 mL), dried by suction, 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 (410 g, 1.12 mol) and dimethyl sulfite (1230 mL) were added to a 5L reaction flask. After adding, heat to 50±5℃ and keep for 0.5 hours. After the solid was completely dissolved, purified water (2460 mL) was added dropwise, and after the addition was completed, the temperature was lowered to 15°C in a water bath and continued to stir and crystallize for 2 hours. After filtration, the filter cake was washed successively with purified water (400.0 mL×1) and dichloromethane (400.0 mL×2), suction-dried, 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 ]nonyl-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 was added 2A (44.45 g, 0.17 mol) followed by dichloromethane (150.0 mL). After stirring and cooling to 0°C-5°C, trifluoroacetic acid (60.0 mL) was added dropwise to the reaction solution. After the addition was completed, the reaction was carried out at 0°C to 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-5°C. The pH was adjusted to 7-8 with triethylamine (60.0 mL) and a white solid precipitated and was stirred for 1 hour. After filtration, the filter cake was washed with dichloromethane (50.0 mL), and the combined solids were dried to give 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[ ^4.2.1.03,8 ]nonane 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 were added 2B (6.32 g, 30.0 mmol), L-mandelic acid (8.86 g, 45.0 mmol), isopropanol (62.0 mL) and water (12.4 mL) sequentially. After the addition is completed, the temperature is heated to 82° C. to completely dissolve the solid, and the temperature is naturally lowered to 20° C. for crystallization after being kept for 0.5 hours for about 6 hours. When the internal temperature reached 20 °C, filter, and wash the filter cake with isopropanol (5.0 mL×2). The solid was dried for 1 hour to give a white solid (3.2 g, yield: 24.2%).

The first crystallization: white solid salt (3.2 g), isopropanol (32 mL) and water (5.2 mL) were sequentially added to a 100 mL reaction flask. Heating, program the temperature to 82° C. to completely dissolve the solid, and keep the temperature for 0.5 hours, then lower the temperature to 20° C. for crystallization, for about 6 hours. When the internal temperature reached 20 °C, filter, and wash the filter cake with isopropanol (5.0 mL×2). The solids were combined and dried for 1 hour to obtain the first crystal (2.0 g, yield: 62.5%), and the ee value after derivatization was determined to be 53%.

The 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. The temperature was heated to 82°C to completely dissolve the solid, and the temperature was lowered to 20°C for about 4.5 hours after the temperature was maintained for 0.5 hours. When the internal temperature reaches 30 °C, filter, and wash the filter cake 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%), and the ee value was determined to be 72% after derivatization.

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

The 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 1-hydroxybenzotriazole (4.32 kg, 32.02 mol, 1.2eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.11 kg, 32.02 mol, 1.2eq), added 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, the addition was completed, and 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 obtain a brown oily substance 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)

2A (1.0 g, 3.77 mmol) was dissolved in 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 addition was stirred at room temperature for 4 hours. After filtering, the filter cake was washed with acetonitrile (2.0 mL×1), and dried to obtain a white solid compound 3 crude product (0.48 g, yield: 37%). The ee value was determined to be 41.9% after derivatization of the solid.

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

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

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

Figure 3 is the absolute configuration of compound 1.

Claims (20)

A method for preparing a compound represented by formula (I), wherein the method comprises the steps of: using the compound of formula (IV) as a raw material to obtain a compound of formula (III) through reaction, and then using the compound of formula (III) as a raw material for reaction preparation to obtain a compound of formula (I),

A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid; R ¹ is selected from H or -C(=O)R ¹¹ ; R ² is selected from tert-butyl group; R ¹¹ is selected from methyl group. The preparation method according to claim 1, wherein the preparation of the compound of the formula (III) comprises preparing the compound of the formula (III) by using the compound of the formula (IV) and a chiral acid as raw materials; the chiral acid is selected from the group of the formula (XI) compound, R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid or d-quinic acid;

R ¹ definition is the same as claim item 1. A method for preparing a compound represented by formula (I), wherein the method comprises using the compound of formula (IV) as a raw material to obtain a compound of formula (III) through reaction, and then using the compound of formula (III) as a raw material to first prepare a compound of formula (II) ) compound, and then use the compound of formula (II) as a raw material to prepare the compound of formula (I):

The definitions of A, R ¹ and R ² are the same as in claim 1. The preparation method according to claim 3, wherein the compound of formula (II) is reacted with acid A in a solvent compatible with the compound of formula (II) to obtain the compound of formula (I), and the solvent is selected from acetonitrile, Methyl chloride, ethanol, methanol, isopropyl acetate, water, toluene, dioxane or a combination thereof, the molar ratio of acid A to the compound of formula (II) is 1.1:1~5:1, at 70-90°C next reaction. The preparation method according to claim 1 or 3, wherein the method further comprises a method for purifying the compound of formula (III), which is to recrystallize the compound of formula (III) in a recrystallization solvent;

R ¹ is selected from H or -C(=O)R ¹¹ ; R ² is selected from tert-butyl group; R ¹¹ is selected from methyl group; the mass volume ratio of the compound of formula (III) to the recrystallization solvent is 1:10-1 : 30, and the recrystallization was repeated 1-2 times; wherein the recrystallization solvent was isopropanol and water. The preparation method according to any one of claim 1 or 2, wherein the method further comprises the step of preparing the compound of formula (IV) by using the compound of formula (V) as a raw material, in the presence of a catalyst/reducing agent, at 0 The compound of formula (IV) is prepared at -40°C, and the catalyst/reducing agent is selected from nickel chloride hexahydrate/sodium borohydride or 10% palladium on carbon/hydrogen,

The definition of R ² is the same as that of claim 1. The preparation method according to claim 6, wherein the method further comprises the preparation of the compound of formula (V): comprising preparing the compound of formula (V) by using the compound of formula (VI) as a raw material, in cesium carbonate, potassium tertiary butoxide Or in the presence of 1,8-diazabicycloundec-7-ene, compound (VI) reacts with nitromethane, and the temperature of the reaction is 60° C. ~ reflux to generate compound (V); alternatively, you can In the presence of a solvent, the solvent is selected from dimethylsulfoxide or N,N-dimethylformamide,

The definition of R ² is the same as that of claim 1. The preparation method according to claim 7, wherein the method further comprises the preparation of the compound of formula (VI): including preparing the compound of formula (VI) by using the compound of formula (VII) as a raw material, in the third potassium butoxide, 1, In the presence of 8-diazabicycloundec-7-ene, lithium diisopropylamide or potassium carbonate or lithium hydride, the compound of formula (VII) is combined with tert-butyl dimethoxyphosphinoacetic acid selected from the group consisting of ester, 3-butyl diethoxyphosphoryl acetate, 3-butyl bromoacetate, 3-butyl chloroacetate or 3-butyl acetoacetate react to generate the compound of formula (VI),

A preparation method of a compound represented by formula (VII), wherein the method comprises using the compound of formula (VIII) as a raw material to prepare the compound of formula (VII),

^R3 and ^R4 together with the carbon atom to which they are attached form a ring. The preparation method according to claim 9, wherein the method comprises the following steps: (1) adding the compound of formula (VIII) in acid anhydride and 2,4,6-collidine, 2,6-lutidine or The reaction occurs in the presence of pyridine; (2) the pH of the reaction solution obtained in the step (1) is adjusted to 8-11 with an inorganic base; (3) the mixture obtained in the step (2) is acidified with an inorganic acid to obtain the compound of formula (VII) . The preparation method according to claim 9 or 10, wherein the method further comprises that the compound of formula (IX) and the secondary amine NH(R ³ )(R ⁴ ) are in oxalic chloride, dichlorosulfite, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N,N'-carbonyldiimidazole is reacted to prepare the compound of formula (VIII) in the presence of,

The preparation method according to claim 11, wherein the method further comprises the step of preparing the compound of formula (IX) by using the compound of formula (X) as a raw material,

A preparation method of a compound shown in formula (VII), wherein the method comprises the following steps:

(1) The compound of formula (X) reacts with cyclo()isopropyl malonate to form the compound of formula (IX); (2) the compound of formula (IX) reacts with 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); R ³ and R ⁴ together with the carbon atom to which they are attached form a ring. The preparation method according to claim 13, wherein the method comprises the following steps: (1) under the catalysis of triethylamine formate, the compound of formula (X) is reacted with cyclo()isopropyl malonate to generate compound of formula (IX); (2) compound of formula (IX) reacts with secondary amine NH(R ³ )(R ⁴ ) to generate compound of formula (VIII); (3) dichloromethane or 1,2-dichloroethane As a solvent, in the presence of a pyridine base, after the formula (VIII) is reacted with trifluoromethanesulfonic anhydride, the pH of the reaction solution is adjusted to alkaline with an inorganic base, and the compound of formula (VII) is prepared under acidic conditions. The preparation method according to claim 9 or 13, wherein the preparation method comprises a method for purifying the compound represented by formula (VII):

The method includes adding the compound of formula (VII) and sodium bisulfite to salt at room temperature, extracting impurities with ethyl acetate, dichloromethane or methyl tertiary butyl ether, and then adding hydrochloric acid or sulfuric acid or hydrogen at room temperature. After the sodium oxide reaction is completed, it can be obtained by post-treatment. A method for preparing a compound represented by formula (I), wherein the method comprises the following steps: (1) using compound (VII) as a raw material to prepare the compound of formula (VI); (2) compounding the compound of formula (VI) with Nitromethane reacts to generate the compound of formula (V); (3) the compound of formula (V) undergoes a reduction reaction to obtain (IV), and then reacts with the compound of formula (XI) to obtain the compound of formula (III); (4) formula (III) The compound obtains the compound of formula (II) by reacting, and then reacts with acid A to obtain the compound of formula (I);

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

The definitions of A, R ¹ and R ² are the same as in claim 1. The preparation method according to claim 16, wherein the method comprises the following steps: (1) in the presence of potassium 3-butoxide or 1,8-diazabicycloundec-7-ene, compound ( VII) Reaction with tert-butyl dimethoxyphosphinoacetate at 10°C to 40°C to generate compound (VI); (2) cesium carbonate, potassium tert-butoxide or 1,8-diazabicyclodeca In the presence of monocarbon-7-ene, compound (VI) React with nitromethane at 80 ℃ ~ 100 ℃ to generate compound (V); (3) in methanol solvent, nickel chloride hexahydrate is used as catalyst, sodium borohydride is used as reducing agent, after compound (V) undergoes reduction reaction, Reaction with the chiral acid compound (XI) 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 A compound of formula (I) is obtained. A preparation method of a compound represented by formula (I), wherein the method comprises the steps: (1) the compound of formula (X) reacts with cyclo()isopropyl malonate to generate the compound of formula (IX); ( 2) The compound of formula (IX) reacts with 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) to Compound (VII) is prepared as a raw material to obtain the compound of formula (VI); (5) the compound of formula (VI) reacts with nitromethane to generate the compound of formula (V); (6) after the compound of formula (V) undergoes a reduction reaction, it is reacted with palm The compound of formula (XI) is reacted to obtain the compound of formula (III); (7) the compound of formula (III) is reacted to obtain the compound of formula (II), which is then reacted with acid A to generate the compound of formula (I);

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

The definitions of A, R ¹ and R ² are the same as those of claim 1; the definitions of R ³ and R ⁴ are the same as those of claim 9. A compound of formula (III), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable salts thereof,

R ¹ is selected from H, a hydroxyl protecting group or -C(=O)R ¹¹ ; R ² is selected from a carboxyl protecting group or a C _1-6 alkyl group; R ³ and R ⁴ form a ring. The preparation method according to any one of claims 1, 3, 16 and 18, wherein the preparation method comprises a method for purifying the compound represented by formula (I), wherein the compound of formula (I) is prepared in N - Heat to dissolve in methylpyrrolidone or dimethyl sulfite, add isopropyl acetate and/or water, stir for crystallization, filter, and dry under reduced pressure to obtain:

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

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