TW201730151A - Processes to produce brivaracetam - Google Patents

Abstract

The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.

Description

Preparation method of bovastamtam

This application relates to the field of pharmaceutical synthesis, and in particular to a method for the synthesis of bovistam (a compound of formula XII). Bovasistat is a third-generation anti-epileptic drug with very good prospects after levetiracetam.

Epilepsy is a common disease of the nervous system, and the incidence rate in the population is 0.6% to 1.1%. Among them, 60% to 70% of patients still have seizures when taking anti-epileptic drugs, causing some patients to stop taking drugs themselves. At present, there are about 6 million epilepsy patients in China, and the number of new epilepsy patients is 650,000 to 700,000 per year, and about 25% is refractory epilepsy. Although the current diagnosis and treatment of epilepsy has made great progress, the number of patients with refractory epilepsy is increasing. Generalized refractory epilepsy refers to the use of current anti-epileptic drugs (AEDs) to treat epilepsy and epilepsy syndrome that cannot be terminated or has been clinically proven to be refractory.

Brivaracetam (Brivaracetam) is a novel high-affinity synaptophysin 2A ligand that inhibits neuronal voltage-dependent sodium channels and is used to treat partial episodes of refractory epilepsy. Both Phase II and Phase III clinical trials of bovistam have good efficacy. The incidence of major adverse events was similar to that of the placebo group, with mild to moderate fatigue, headache, nasopharyngitis, nausea, lethargy, and dizziness. No patients discontinued treatment due to adverse events. . The results showed that bovistam tablets were effective and well tolerated in the adjuvant treatment of patients with refractory epilepsy with a prevalence of 16 to 65 years of age. Overall, bovistam is a third-generation anti-epileptic drug with very good prospects after levetiracetam.

So far, domestic patents on the synthesis of bovistam have not been reported. There are also a number of foreign related patent reports, such as the patents US 6,784,197, US 7,629,474, US 8,957,226, US 8,338,621, US 8,076,493, and related patents, which disclose the synthesis of bosiracetam, wherein US 6,784,197, US 7,629,474 report the following synthetic routes :

US 8,957,226 (Examples 1, 3) and US 8,338,621 (Examples 4, 11) report the following synthetic routes:

Kenda et al. (Journal of Medicinal Chemistry, 2004, 47, 530) reported the following synthetic pathways:

The above-mentioned several pathways have not constructed the palmar center of n-propylamine on butane, but the optical purity of bovistam is obtained by palm-purity high-performance liquid purification in the final product. The utilization of raw materials is not economical. .

Therefore, there is a need for a simple and cost effective method for preparing bovistam to obtain bovistam with high optical purity.

The present invention provides a method of synthesizing formula XII bovistam.

Another object of the present invention is to provide a compound of the formula IV and a process for the preparation thereof.

A further object of the invention is to provide the use of a compound of formula IV for the synthesis of bovistam of formula XII.

In one aspect, the invention provides a compound having the structure of Formula IV: Wherein R is a C _1-20 hydrocarbyl group.

The term "C _1-20 hydrocarbyl" includes C _1-20 alkyl, C _1-20 alkenyl, C _1-20 alkynyl and aryl, etc., and aryl may include phenyl, benzyl or other aryl groups. Preferably, the C _1-20 hydrocarbyl group is methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl or benzyl.

Moreover, it will be understood by those of ordinary skill in the art that the compound of formula IV requires only the 4-position n-propyl group to be in the (R) configuration, and there is no particular requirement for the configuration of the 3-position ester group, so that 3 The -ester group may be in the (R) or (S) configuration, or the 3-position ester group may be in both the (R) and (S) configurations.

In another aspect, the invention provides a process for the preparation of a compound of formula IV, which comprises the step of preparing a compound of formula IV from a compound of formula III: Wherein R is a C _1-20 hydrocarbyl group.

It will be understood by those of ordinary skill in the art that a compound of formula IV can be prepared from a compound of formula III by a ring opening process known in the art, such as reacting a compound of formula III with an ethyl metal reagent.

In a specific embodiment, the compound of formula III can be prepared by reacting a compound of formula III with an ethyl metal reagent in an aprotic organic solvent at a temperature of from -78 ° C to 200 ° C, wherein the use of the ethyl metal reagent The molar equivalent may be between 1 and 5, preferably, the ethyl metal reagent may be selected from one of ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium, and diethyl lead. Or more, more preferably, the ethyl metal reagent may be used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride in the reaction of cuprous iodide, cuprous cyanide or anhydrous zinc chloride. The molar equivalent weight may be between 0.01 and 2; preferably, the aprotic organic solvent may be selected from the group consisting of tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether and methyl tert-butyl ether. One or more.

In a further aspect, the invention provides the use of a compound of formula IV above for the synthesis of bovistam of formula XII .

In a specific embodiment, a compound of formula VI can be synthesized from a compound of formula IV, and then a compound of formula VI can be designed to synthesize formula XII bovistam: Wherein R is a C _1-20 hydrocarbyl group.

In a specific embodiment, the compound of the formula IV can be removed from the mixture of the water-soluble high-boiling organic solvent and water under the action of a salt or a base at a temperature ranging from 50 ° C to 200 ° C. The ester is reacted to give a compound of formula VI wherein the salt or base has a molar equivalent weight of between 0.01 and 10; preferably, the salt is selected from the group consisting of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and One or more of lithium bromide, the base being selected from one or more of lithium hydroxide, potassium hydroxide or sodium hydroxide, the water-soluble high-boiling organic solvent being selected from N-methylpyrrolidone , one or more of N,N-dimethylformamide, dimethylhydrazine, cyclobutanthene and 4-methyl-2-pentanol;

Alternatively, if R contains an unsaturated moiety, the compound of formula IV is first subjected to metal catalyzed removal of the R group, followed by decarboxylation at a temperature ranging from 25 ° C to 200 ° C to give a compound of formula VI; preferably, deacidification The reaction is carried out in one or more selected from the group consisting of toluene, methyl tert-butyl ether, N-methylpyrrolidone, N,N-dimethylformamide and dimethylhydrazine.

With regard to metal catalysis, it will be understood by those of ordinary skill in the art that it can be carried out by metal catalyzed methods known in the art, and the catalyst can be a metal catalyst such as Pd, Pt, Ni or triphenylphosphine palladium. Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter GM Wuts, 1999, John Wiley & Sons, Inc. Chapter V, etc.

In other aspects, the invention provides a method of synthesizing XIV bovistam, the method comprising the steps of: Wherein R is a C _1-20 hydrocarbyl group; preferably, R is methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl Or benzyl; more preferably, R is ethyl; R1 is H or _C1-20 hydrocarbyl; preferably, R1 is methyl, ethyl, propyl, allyl, n-butyl, isobutyl , isopropyl, n-pentyl, n-hexyl, tert-butyl or benzyl; more preferably, R1 is ethyl; and X is chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy or P-nitrophenylsulfonyloxy; preferably, X is bromine.

Those of ordinary skill in the art can reasonably select R, R1 or X depending on the type of reaction involved in the method. For example, R can be any C _1-20 hydrocarbyl group that does not interfere with the decarboxylation reaction; R 1 can be any C _1-6 alkyl group capable of forming a ring-opening ester, depending on the alcohol used for the ring opening reaction; Is any leaving group such as chlorine, bromine, iodine, methanesulfonyloxy or p-toluenesulfonyloxy.

In some embodiments, R can be methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl or benzyl.

In some embodiments, R and R1 can be ethyl and X can be bromine.

It will also be understood by those of ordinary skill in the art that, based on the synthetic routes described above, those of ordinary skill in the art are well able to rationally select materials and synthetic methods known in the art based on their technical common knowledge and common technical means. Obtain the desired product.

In a specific embodiment, the reaction conditions of each reaction step can be:

Preparation of a compound of formula IV from a compound of formula III:

The compound of the formula IV is prepared by reacting a compound of the formula III with an ethyl metal reagent in an aprotic organic solvent at a temperature of from -78 ° C to 200 ° C, wherein the molar equivalent of the ethyl metal reagent can be from 1 to 5 Preferably, the ethyl metal reagent may be selected from one or more of ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium, and diethyl lead; more preferably The ethyl metal reagent can be used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride. In the reaction, the molar equivalent of cuprous iodide, cuprous cyanide or anhydrous zinc chloride is 0.01- Preferably, the aprotic organic solvent may be selected from one or more of tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether and methyl tert-butyl ether.

Preparation of a compound of formula VI from a compound of formula IV:

The compound of the formula IV is subjected to a deesterification reaction in a mixture of a water-soluble high-boiling organic solvent and water under the action of a salt or a base at a temperature ranging from 50 ° C to 200 ° C to obtain a compound of the formula VI. Wherein the salt or base has a molar equivalent weight of between 0.01 and 10; preferably, the salt is selected from one or more of the group consisting of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide. The alkali is selected from one or more of lithium hydroxide, potassium hydroxide or sodium hydroxide, and the water-soluble high-boiling organic solvent is selected from the group consisting of N-methylpyrrolidone and N,N-dimethyl One or more of carbamide, dimethyl hydrazine, cyclobutyl hydrazine, and 4-methyl-2-pentanol;

Alternatively, if R contains an unsaturated moiety, the compound of formula IV is first subjected to metal catalyzed removal of the R group, followed by decarboxylation at a temperature ranging from 25 ° C to 200 ° C to give a compound of formula VI, preferably deacidified. The reaction is carried out in one or more solvents selected from the group consisting of toluene, methyl tert-butyl ether, N-methylpyrrolidone, N,N-dimethylformamide and dimethylhydrazine.

Preparation of a compound of formula VII from a compound of formula VI:

Ring-opening a compound of formula VI with trimethyl iododecane, trimethylbromodecane, hydrobromic acid, hydrochloric acid or hydroiodic acid in an organic solvent to give a compound of formula VII;

Alternatively, the compound of formula VI is hydrolyzed and opened under basic conditions, and then reacted with methanesulfonium chloride, p-toluenesulfonyl chloride or p-nitrophenylsulfonium chloride in an organic solvent to give a compound of formula VII; preferably, The organic solvent is one selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl hydrazine, cyclobutyl hydrazine, dichloromethane, acetonitrile or a C _1-20 hydrocarbon group. Or more, the alkaline condition of hydrolyzing ring opening is achieved by adding sodium hydroxide, potassium hydroxide or lithium hydroxide.

Preparation of a compound of formula IX from a compound of formula VII:

The compound of the formula VII is reacted with (S)-2-amino-butanamine or a salt thereof under basic conditions formed by a basic compound, in an organic solvent, and at a temperature of from 25 ° C to 200 ° C. A compound of the formula IX wherein the basic compound has a molar equivalent of between 1 and 5 and the (S)-2-aminobutyricamine or a salt thereof has a molar equivalent weight of between 0.5 and 5; preferably, The basic compound is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium t-butoxide, potassium t-butoxide, lithium diisopropylamide, bis(trimethyldecyl)amino group. One or more of lithium or sodium bis(trimethylsulfonyl)amide, the organic solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl hydrazine, and cyclobutyl hydrazine. One or more of them.

Preparation of a compound of formula XII from a compound of formula IX:

The compound of the formula IX is ring-closed in an organic solvent at a temperature of from 25 ° C to 200 ° C to obtain a compound of the formula XII; preferably, the ring closure reaction is carried out under the action of a guanamine bond promoter, and The guanamine forming accelerator is selected from the group consisting of HOBt or 2-hydroxypyridine, and the organic solvent is selected from one or more of toluene, methyl isobutyl ketone, xylene or chlorobenzene.

In a specific exemplary embodiment, the method may include the following steps: Wherein R is a C _1-20 hydrocarbyl group, a substituted or unsubstituted benzyl group or an aryl group, and preferably R is an ethyl group.

In the above or other embodiments, the compound of formula III can also be prepared in the following manner: Wherein R is a C _1-20 hydrocarbyl group, wherein the reaction temperature is from 0 ° C to 100 ° C, the molar equivalent of the base is between 1 and 3, and the molar equivalent of the compound II is between 1 and 3; Preferably, the base is selected from one or more of sodium metal and potassium metal. More preferably, the sodium metal is sodium methoxide, sodium ethoxide or sodium t-butoxide, and the potassium metal is tert-butyl. Potassium alkoxide; the organic solvent is selected from one or more of the group consisting of ethanol, methanol, propanol, and isopropanol.

Furthermore, in an embodiment of the invention, the compound of formula XII, bovistam, can also be synthesized by the following route:

Further, in an embodiment of the present invention, the compound of formula XII, bovastatin, may also be synthesized by the following route:

Compared with the prior art, the method for synthesizing bovistam of the invention has the following advantages: 1. The raw materials are easy to obtain and the price is low. 2. The separation and purification of the intermediates and products are easy, and even without purification, the direct series reaction can be carried out to prepare the basiracetam and the like in the next step, and the operation is simple. 3. Since the palmar center of n-propyl group on butanide is constructed from the beginning, bovistam with high optical purity can be obtained without expensive and toxic heavy metals and palm ligands. 4. The preparation of bovistam by the method of the invention avoids the occurrence of difficult-to-separate palm-isomers, avoids purification methods such as column chromatography purification, which are not conducive to industrial scale-up production, and the synthesis process does not involve expensive and toxic. Heavy metal and palm ligand, get high quality, high optical purity products (four kinds of optical isomers, bovistam ratio is more than 99.5%), the other single impurity high-performance liquid peak area is less than 0.1%, no need to use expensive The palmar high-performance liquid phase method avoids the waste of raw materials by palm division. The overall yield of bovistam from the compound of formula III is about 50% higher than the existing split path.

Example 1 Preparation of Compound III

Sodium methoxide (2.05 g, 38 mmol) was added to 80 ml of absolute ethanol to dissolve completely. The reaction flask was placed in an ice water bath and diethyl malonate was added. After stirring at this temperature for 10 minutes, the system was allowed to warm to room temperature, and (R)-epichlorohydrin (ee 98%) (2.7 ml, 35 mmol) (purchased from Angie Chemical) was slowly added to the reaction system. The system was reacted under reflux for 18 hours, the reaction was stopped, the system was cooled to room temperature, the solvent was evaporated, and 100 ml of water was added, and extracted three times with 100 ml of ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, dried, filtered, and then evaporated to give compound III. Compound III palm HPLC (ee 98%). The nuclear magnetic data of compound III are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.33 (1H, dd), 4.23 (2H, q), 4.16 (1H, d), 2.73-2.75 (1H, m), 2.05 (1H, dd), 1.35 (1H, t), 1.28 (3H, t).

Example 2 Preparation of Compound IV

The cuprous iodide (9.5 g, 50 mol) was added to 100 ml of dry tetrahydrofuran, and the reaction flask was placed in a -30 ° C low temperature reaction bath, and a solution of ethyl chloroprene reagent in tetrahydrofuran (1.0 M, was added to the reaction flask. The mixture was stirred for 1 hour, and a solution of the compound III (20 g, 117 mmol) obtained in the same manner as in Example 1 was added dropwise to the reaction mixture. After the dropwise addition was completed, the mixture was stirred at this temperature for 30 minutes, and then slowly heated to -15 °C. The reaction was quenched with saturated aq. EtOAc. EtOAc (EtOAc) The nuclear magnetic data of the purified compound IV obtained by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1) was as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.52 (1H, dd ), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H, t). Purification by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1) gave a specific optical rotation of compound IV: [α] ²³ _D = +22.6 (C=10, CHCl ₃ ) .

Example 3 Preparation of Compound VI

The crude product of Example IV, Compound IV (as 117 mmol) was added to DMSO/H ₂ O (400 mL / 20 mL) and LiCl (14.7 g, 350 mmol) was added to the reaction flask. After the reaction was carried out at 140 ° C for 18 hours, it was poured into 400 ml of water, extracted three times with 400 ml of ethyl acetate, and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, Distillation under reduced pressure gave Compound VI as a colorless liquid. The NMR data of compound VI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40 -1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound 5 was: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 4 Preparation of Compound VII

TMSBr (3.1 ml, 24 mmol) was added to a compound VI (1.1 g, 7.8 mmol), which was obtained by the method of Example 3, and a solution of 2.5 ml of anhydrous ethanol in 40 ml of dichloromethane under ice-water bath. The reaction was overnight. To the system, a sodium thiosulfate solution was added, and 50 ml of water was added thereto, and the system was extracted three times with ethyl acetate (50 ml × 3), and the organic phase was combined, washed twice with 20 ml of saturated sodium chloride and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate were purified by column chromatography (yield: EtOAc:EtOAc:EtOAc: The nuclear magnetic data of the compound VII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.16 (q, 2H), 3.58 (dd, 1H), 3.55 (dd, 1H), 2.51 (dd, 1H), 2.36 (dd , 1H), 2.15-2.30 (m, 1H), 1.25-1.51 (m, 7H), 0.94 (t, 3H). The specific optical rotation of Compound VII is: [α] ²³ _D = -3.8 (C = 10, CHCl ₃ ).

Example 5 Preparation of Compound IX

Compound (S)-2-Aminobutanamine hydrochloride (3.4 g, 24.5 mmol) (available from Beijing Co., Ltd.), Compound VII (2.83 g, 20.4 mmol) prepared by the method of Example 4, carbonic acid Sodium (7.78 g, 73.4 mmol) and sodium iodide (1.83 g, 12.2 mmol) were added to 60 ml of dimethylformamide solution and reacted at 90 ° C for 18 hours. The reaction was stopped, and the reaction mixture was combined with 100 ml of water and 50 ml of ethyl acetate. The organic phase was taken out, and the aqueous phase was extracted twice with ethyl acetate (50 ml × 2). The organic phase was combined, washed twice with 20 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography. (Eluent polar methylene chloride / methanol / triethylamine = 100 / 1 / 1) gave Compound IX, egg yellow liquid, yield 40%. The nuclear magnetic data of Compound IX are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (brs, 1H), 5.86 (brs, 1H), 4.13 (q, 2H), 2.96 (t, 1H), 2.54 (dd, 1H), 2.33 (dd, 1H), 1.78-2.10 (m, 1H), 1.56-1.75 (m, 2 H), 1.24-1.48 (m, 7 H), 0.85-1.03 (m, 6H).

Example 6 Preparation of Compound XII Buvaacetam

Compound IX (120 mg, 0.46 mmol), HOBt (63 mg, 0.46 mmol), which was obtained by the procedure of Example 5, was added to 1 ml of toluene. The system was warmed to 90 ° C for 3 hours. The reaction was stopped, and the reaction mixture was combined with 50 ml of saturated aqueous sodium hydrogen carbonate and 50 ml of ethyl acetate. The organic phase was taken out, the aqueous phase was extracted twice with ethyl acetate (50 ml × 2), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent ethyl acetate / triethyl Amine = 100/1) gave a white solid, i.e., basiacetam, yield 41%, palm HPLC 98% ee. The nucleus magnetic data of bosiracetam are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.42 (brs, 1H), 5.69 (brs, 1H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd , 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m , 4 H), 0.80-0.95 (m, 6H).

Example 7 Preparation of Compound XII Buvaacetam

Compound IX (435 mg, 1.73 mmol), 2-hydroxypyridine (82 mg, 0.86 mmol), which was obtained by the procedure of Example 5, was added to 4 ml of toluene. The system was warmed to 90 ° C for 3 hours. The reaction was stopped, and the reaction mixture was combined with 50 ml of saturated aqueous sodium hydrogen carbonate and 50 ml of ethyl acetate. The organic phase was taken, the aqueous phase was extracted twice with ethyl acetate (50 mL×2), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent petroleum ether / ethyl acetate /Triethylamine = 50/50/1) gave a white solid, ie, basiacetam, yield 58%, palm HPLC 98% ee. The nucleus magnetic data of bosiracetam are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.42 (brs, 1H), 5.69 (brs, 1H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd , 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m , 4 H), 0.80-0.95 (m, 6H).

Example 8 Preparation of Compound XII Buvaacetam

(S)-2-Aminobutanamine hydrochloride (4.35 g, 31.5 mmol) (available from Beijing Co., Ltd.), Compound VII (5.0 g, 21.0 mmol) prepared according to the method of Example 4, sodium carbonate (8.9 g, 84.0 mmol) and sodium iodide (1.57 g, 10.5 mmol) were added to 50 ml of dimethylformamide solution and reacted at 90 ° C for 18 hours. The reaction was stopped, and the reaction mixture was combined with 100 ml of water and 50 ml of ethyl acetate. The organic phase was taken out, the aqueous phase was extracted twice with ethyl acetate (50 ml × 2), and the organic phase was combined, washed twice with 20 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated and evaporated. 2-Hydroxypyridine (1.0 g, 10.5 mmol) was added and reacted at 90 ° C for 5 hours. The reaction mixture was combined with 100 ml of saturated aqueous sodium hydrogen sulfate and 100 ml of ethyl acetate. The organic phase was taken out, the aqueous phase was extracted twice with ethyl acetate (100 ml×2), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent petroleum ether / ethyl acetate /Triethylamine = 50/50/1) gave a white solid, ie, basiacetam, yield 50%, palm HPLC 98% ee. The nucleus magnetic data of bosiracetam are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.42 (brs, 1H), 5.69 (brs, 1H), 4.46 (dd, 1H), 3.50 (dd, 1H), 3.05 (dd , 1H), 2.57 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m , 4 H), 0.80-0.95 (m, 6H).

Example 9 Preparation of Compound X

Anhydrous zinc chloride (2.5 g, 18.3 mmol) was added to a reaction flask in 20 ml of dichlorohydrazine, and then compound VI (12.0 g, 93.7 mmol) was added. The reaction flask was placed in a 55 ° C oil bath for reaction. No gas residue was detected by gas chromatography. The reaction was stopped. The system was cooled to room temperature, and the dichlorohydrazine was spun off, and then distilled under reduced pressure to obtain a compound X of a pale yellow liquid. The yield was 68%. The NMR data of the compound X are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t). The specific optical rotation of Compound X is: [α] ²³ _D = +2.9 (C=10, CHCl ₃ ).

Example 10 Preparation of Compound X

Anhydrous zinc chloride (40 g, 0.29 mol) was added to a reaction flask in 400 ml of dichlorohydrazine, and Compound VI (188 g, 1.47 mol) was further added. The reaction flask was placed in an oil bath at 85 ° C, and the reaction was stopped by gas chromatography. The reaction was stopped, the system was cooled to room temperature, and the dichlorohydrazine was spun off, and then distilled under reduced pressure to obtain a compound X of a pale yellow liquid. The yield was 63.5%. The NMR data of the compound X are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t). The specific optical rotation of Compound X is: [α] ²³ _D = +2.9 (C=10, CHCl ₃ ).

Example 11 Preparation of Compound XI

(S)-2-Aminobutyramine hydrochloride (1.67 g, 12 mol) (available from Beijing Co., Ltd.) was added to 40 ml of dry dichloromethane, and triethylamine (2.43 g, 24 mmol) was added. After stirring for 30 minutes under temperature, the compound X (2.0 g, 10.8 mmol) was added dropwise, and the mixture was added dropwise, and the mixture was stirred at room temperature until TLC. Add 30 ml of water, 4 ml of ethanol, extract and separate the organic phase, extract twice with 40 ml of dichloromethane, combine the organic phase, dried over anhydrous sodium sulfate, dried, filtered, and filtrated to give the crude product of compound XI, yield 96.7%. Purification by column chromatography (developing agent polarity: ethyl acetate 100%) gave purified compound of formula XI with NMR data as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.20-6.45 (2H, m) , 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23 -1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t). The specific optical rotation of the compound XI is: [α] ²⁵ _D = -23.7 (C = 3, CH ₃ OH).

Example 12 Preparation of Buvaxitan XII

The crude product XI 10.0 g (as 40 mmol) of the compound obtained by the procedure of Example 11 was added to 150 ml of dry tetrahydrofuran, and potassium t-butoxide (5.6 g, 50 mmol) was added to the reaction flask. The system was reacted at -30 ° C until TLC to detect no residue of the starting material. The reaction was quenched with saturated ammonium chloride. The organic phase was separated and the aqueous phase was extracted three times with 50 ml of ethyl acetate. The organic phase was combined and washed with saturated sodium chloride solution. Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a crude product, isopropyl ether, and the obtained solid is bovastatin, yield 93%, and purified by further recrystallization to obtain high purity product, palmitic HPLC >99.5% product. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 13 Preparation of Buvaxitan XII

The crude product XI 10.0 g (as 40 mmol) of the compound obtained by the method of Example 11 was added to 150 ml of dry dichloromethane, tetrabutylammonium chloride (2.3 g, 10 mmol), anhydrous sodium sulfate (5.6 g, 40 mmol) was added to the reaction flask. Solid potassium hydroxide (4.2 g, 75 mmol) was added, and the system was reacted at -10 ° C until TLC to detect no residue of the material. The reaction was quenched with saturated ammonium chloride. The organic phase was separated and the aqueous phase was extracted three times with 50 ml of dichloromethane. The organic phase is combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give crude product, isopropyl ether, and the obtained solid is boisacetam, yield 96%, purified by further recrystallization. High purity product, palmitic HPLC >99.5% product. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 14 Preparation of Compound XI

(S)-2-Aminobutanamine hydrochloride (5.0 g, 36 mol) (available from Beijing Co., Ltd.) was added to 100 ml of dry tetrahydrofuran, and triethylamine (7.3 g, 72 mmol) was added at room temperature. After stirring for 30 minutes, the compound X (6.0 g, 32.5 mmol) was added dropwise, and the mixture was added dropwise, and the mixture was stirred at room temperature until TLC. After adding 100 ml of water, the organic phase was separated, and extracted with EtOAc (EtOAc m. Purification by column chromatography (developing agent polarity: ethyl acetate 100%) gave purified compound of formula XI with NMR data as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.20-6.45 (2H, m) , 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23 -1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t). The specific optical rotation of Compound IV is: [α] ²⁵ _D = -23.7 (C = 3, CH ₃ OH).

Example 15 Preparation of Bovastam XII

The crude product of compound XI (e.g., 36 mmol) obtained by the procedure of Example 14 was added to 100 ml of dry tetrahydrofuran, and potassium t-butoxide (4.8 g, 43.2 mmol) was added to the reaction flask. The system was reacted at 0 ° C until TLC. No raw material remained. The saturated ammonium chloride was quenched. The organic phase was separated. The aqueous phase was extracted three times with 50 ml of ethyl acetate. The organic phase was combined and washed with saturated sodium chloride solution. Drying over sodium sulfate, filtration, EtOAc (EtOAc) Palm purity HPLC >99.5%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 16 Preparation of Compound VI

Sodium methoxide (2.05 g, 38 mmol) was added to 80 ml of absolute ethanol to dissolve completely. The reaction flask was placed in an ice water bath and diethyl malonate was added. After stirring at this temperature for 10 minutes, the system was allowed to warm to room temperature, and (R)-epichlorohydrin (ee 98%) (2.7 ml, 35 mmol) (purchased from Angie Chemical) was slowly added to the reaction system. The reaction was carried out under reflux conditions for 18 hours, the reaction was stopped, the system was cooled to room temperature, the solvent was evaporated, and 100 ml of water was added, and the mixture was extracted three times with 100 ml of ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, dried, filtered, and then evaporated to give compound III. Compound III palm HPLC (ee 98%). The cuprous iodide (9.5 g, 50 mol) was added to 100 ml of dry tetrahydrofuran, and the reaction flask was placed in a -30 ° C low temperature reaction bath, and a solution of ethyl chloroprene reagent in tetrahydrofuran (1.0 M, was added to the reaction flask. After stirring for 1 hour, 300 ml of a solution of Compound III (20 g, 117 mmol) obtained in the above manner was added dropwise to a reaction flask. After the dropwise addition was completed, the mixture was stirred at this temperature for 30 minutes, and then slowly heated to -15 °C. The reaction was quenched with saturated aq. EtOAc. EtOAc (EtOAc) This was added to dimethyl hydrazine/water (400 ml / 20 ml), and lithium chloride (14.7 g, 350 mmol) was added to the reaction flask. After the reaction was carried out at 140 ° C for 18 hours, it was poured into 400 ml of water, extracted three times with 400 ml of ethyl acetate, and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, Distillation under reduced pressure gave Compound VI as a colorless liquid, yield 50%. The nuclear magnetic data of Compound VI are as follows: ¹ H NMR (400 MHz, CDCl3) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40- 1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound VI is: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 17 Preparation of Compound III

Sodium methoxide (2.0 kg, 37.03 mol) was added to 44.5 kg of absolute ethanol to dissolve completely, and diethyl malonate (6.0 kg, 37.46 mol) was added at an external temperature of 10 °C. After stirring at this temperature for 10 minutes, the system was allowed to warm to room temperature, and (R)-epichlorohydrin (ee >99%) (3.3 kg, 35.67 mol) (purchased from Angie Chemical) was slowly added to the reaction system. After the addition, the reaction was carried out under reflux conditions for 2 hours, the reaction was stopped, the system was cooled to room temperature, the solvent was evaporated, 19.03 kg of water was added, and the mixture was extracted twice with 17.0 kg and 12 kg of ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, dried, filtered, evaporated, evaporated, evaporated. Compound III palm HPLC (ee 98.5%). The nuclear magnetic data of compound III are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.33 (1H, dd), 4.23 (2H, q), 4.16 (1H, d), 2.73-2.75 (1H, m), 2.05 (1H, dd), 1.35 (1H, t), 1.28 (3H, t).

Example 18 Preparation of Compound IV

A solution of ethyl chloroprene reagent in 2-methyltetrahydrofuran (1.29 mol/kg, 2.44 kg, 3.14 mol) was added to the reaction vessel, and the internal temperature was controlled to -20 to -30 ° C, and copper iodide (108.3) was added. g, 0.57 mol) was added to the reaction system, and the mixture was stirred for 30 minutes, and a solution of the compound III (434 g, 2.55 mol) obtained in the method of Example 17 was added dropwise to dry 2-methyltetrahydrofuran. After completion of the dropwise addition, the mixture was stirred at this temperature for 30 minutes, and then quenched with saturated aqueous ammonium chloride to give a solution of Compound IV in 2-methyltetrahydrofuran, yield: 64%. The purified compound IV was obtained by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1). The NMR data was as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.52 (1H, Dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m) , 0.95 (3H, t). Purification by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1) gave a specific optical rotation of compound IV: [α] ²³ _D = +22.6 (C=10, CHCl ₃ ) .

Example 19 Preparation of Compound IV

A 2-methyltetrahydrofuran solution (1.29 kg/mol, 63.51 g, 81.93 mmol) of ethyl griner reagent was added to the reaction flask, and the reaction flask was placed in a low temperature reaction bath to control the internal temperature to -20~-30. The cuprous iodide (2.22 g, 11.70 mol) was added to the reaction flask at ° C for 0.5 hour, and the compound III (10.0 g, 58.52 mmol) obtained by the method described in Example 17 was added dropwise to the reaction flask. The solution of 2-methyltetrahydrofuran was dried. After completion of the dropwise addition, the mixture was stirred at this temperature for 30 minutes, and then quenched with saturated aqueous ammonium chloride to give a solution of Compound IV in 2-methyltetrahydrofuran, yield: 87%. The purified compound IV was obtained by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1). The NMR data was as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.52 (1H, Dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m), 1.49-1.56 (2H, m), 1.27-1.35 (5H, m) , 0.95 (3H, t). Purification by column chromatography (developing agent polarity: petroleum ether / ethyl acetate = 10/1) gave a specific optical rotation of compound IV: [α] ²³ _D = +22.6 (C=10, CHCl ₃ ) .

Example 20 Preparation of Compound V

The solution of the compound IV in 2-methyltetrahydrofuran obtained by the method described in Example 19 was added to sodium hydroxide/water (255 g / 640 ml), and the mixture was reacted at room temperature for 2 hours, and then separated to give an aqueous phase. It was washed once with 1 liter of ethyl acetate, adjusted to pH 1 with concentrated hydrochloric acid, and extracted twice with 1 liter of 2-methyltetrahydrofuran. The organic phase was combined, concentrated, and evaporated with toluene to give compound V, yield 99%. The nuclear magnetic data of the purified compound V was purified by column chromatography (developing solvent: ethyl acetate) as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.57 (1H, brs), 4.54 (1H, dd) , 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m), 1.27-1.35 (2H, m), 0.95 (3H, t).

Example 21 Preparation of Compound VI

The compound V obtained by the method described in Example 20 was placed in a reaction flask at an external temperature of 120 ° C, and after reacting for 2 hours, it was cooled to room temperature, and distilled under reduced pressure to give Compound VI, yield: 99%. The NMR data of compound VI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40 -1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound VI is: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 22 Preparation of Compound VI

The compound V prepared by the method described in Example 20 was added to a reaction flask, 2 volumes of toluene was added, the external temperature was 120 ° C, the reaction was allowed to fall to room temperature after 8 hours, and the compound VI was obtained by distillation under reduced pressure. : 95%. The NMR data of compound VI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40 -1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound VI is: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 23 Preparation of Compound X

Anhydrous zinc chloride (10.6 g, 0.078 mol) was added to a reaction flask containing Compound VI (100 g, 0.78 mol), and then 200 ml of dichlorohydrazine was added to the reaction. The reaction flask was placed in an oil bath at 85 ° C, and the reaction was stopped by gas chromatography. The reaction was stopped, the system was cooled to room temperature, and the dichlorohydrazine was spun off, and then distilled under reduced pressure to obtain a compound X of a pale yellow liquid. The yield was 79.7%. The NMR data of the compound X are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): 1H NMR (400 MHz, CDCl ₃ ): δ 3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t). The specific optical rotation of Compound X is: [α] ²³ _D = +2.9 (C=10, CHCl ₃ ).

Example 24 Preparation of Compound XI

(S)-2-Aminobutanamine hydrochloride (10 g, 72.5 mmol) (available from Beijing Co., Ltd.) was added to 150 ml of dry acetonitrile, and potassium carbonate (25 g, 181.3 mmol) was added at 0 ° C. After stirring for 30 minutes, the compound X (14.6 g, 79.71 mmol) was added dropwise, and the mixture was added dropwise, and the mixture was stirred at room temperature until TLC. The organic phase was extracted with 150 ml of dichloromethane, 150 ml of water and 10 ml of ethanol. The organic phase was extracted and extracted with 100 ml of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, dried, filtered and concentrated. Compound XI, yield 96%. Further purification by recrystallization gives high purity compound XI. The nuclear magnetic data of the purified compound XI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61 (2H, d ), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t ). The specific optical rotation of the compound XI is: [α] ²⁵ _D = -23.7 (C = 3, CH ₃ OH).

Example 25 Preparation of Buvasimtan XII

Compound XI (2.0 g, 8 mmol) obtained by the procedure described in Example 24 was added to 6 ml of dry dimethylformamide, and potassium hydroxide (670 mg, 12 mmol) was added to the reaction flask in five portions. The system was reacted at -15 to -10 °C until HPLC, no raw material remained, 1N hydrochloric acid was quenched, 12 times volume of saturated brine was added, methyl tert-butyl ether was extracted four times, and the organic phase was combined with saturated sodium chloride. The solution is washed once, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give the product. The obtained solid is boisacetam, yield 95%, and purified by further recrystallization to obtain a product of high purity, palmitic HPLC >99.5%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 26 Preparation of Buvaxitan XII

(S)-2-Aminobutanamine hydrochloride (8.0 g, 58 mmol) (available from Beijing Co., Ltd.) was added to 120 ml of dry dichloromethane, and PEG400 (3.5 g, 8.7 mmol) was added and reduced. After stirring at -10 ° C for 30 minutes, potassium hydroxide (17.9 g, 320 mmol) was added portionwise, during which the compound X (11.7 g, 64 mmol) was added dropwise, and the mixture was added dropwise, and stirred at -2 ° C until TLC was passed. Remaining. The reaction was quenched with a half-saturated ammonium chloride. The organic phase was extracted and extracted twice with 40 ml of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product. The yield was 92%, and the product was purified by further recrystallization to obtain a product of high purity, palmitic HPLC >99%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 27 Preparation of Buvaxitan XII

(S)-2-Aminobutyramine hydrochloride (2.5 g, 18 mmol) (available from Beijing Co., Ltd.) was added to 40 ml of dry dichloromethane, and tetrabutylammonium bromide (1.16 g, 3.6) was added. After stirring for 30 minutes at -10 ° C, potassium hydroxide (4.53 g, 81 mmol) was added portionwise, during which the compound X (3.66 g, 20 mmol) was added dropwise, and the mixture was stirred at -2 ° C. No residue of raw materials was detected by TLC. The reaction was quenched with a half-saturated ammonium chloride. The organic phase was extracted and extracted twice with 40 ml of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product. The yield was 83%, and the product was purified by further recrystallization to obtain a product of high purity, palmitic HPLC >99%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 28 Preparation of Buvaxitan XII

Compound XI (2.5 g, 10 mmol) was added to 20 mL of dry dichloromethane. EtOAc (EtOAc, EtOAc (EtOAc) . The system is reacted at -15 to -10 ° C until HPLC to detect the absence of the starting material, the saturated ammonium chloride is quenched, the dichloromethane is extracted three times, the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give the product. The yield was 68%, and the product was purified by further recrystallization to obtain a product of high purity, palmitic HPLC >99.5%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 29 Preparation of Buvaxitan XII

Compound XI (100 mg, 0.4 mmol) was added to 1 mL dry dichloromethane. EtOAc EtOAc EtOAc. The system is reacted at -15 to -10 ° C until HPLC to detect the absence of the starting material, the saturated ammonium chloride is quenched, the dichloromethane is extracted three times, the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give the product. For bovistam, the yield was 87%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 30 Preparation of Buvaxitan XII

Compound XI (100 mg, 0.4 mmol) was added to 1 mL of dry acetonitrile. EtOAc EtOAc EtOAc EtOAc EtOAc The system is reacted at -15 to -10 ° C until HPLC to detect the residue of the starting material. The reaction is quenched with saturated ammonium chloride. The organic solvent is evaporated, and the organic phase is extracted three times with dichloromethane. The product was obtained, and the obtained product was bovistam, and the yield was 86%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 31 Preparation of Buvaxitan XII

Compound XI (100 mg, 0.4 mmol) was added to 1 mL of dry EtOAc. EtOAc EtOAc EtOAc. The system is reacted at -15 to -10 ° C until HPLC to detect the residue of the starting material. The reaction is quenched with saturated ammonium chloride. The organic solvent is evaporated, and the organic phase is extracted three times with dichloromethane. The product was obtained, and the obtained product was bovistam, and the yield was 90%. The nuclear magnetic data of compound XII are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.45 (brs, 1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.80-0.95 (m, 6H).

Example 32 Preparation of Compound VI

Copper iodide (9.5 g, 50 mol) was added to 100 ml of dry tetrahydrofuran, and the reaction flask was placed in a -30 ° C low temperature reaction bath, and a solution of ethyl chloroprene reagent in tetrahydrofuran (1.0 M, 300) was added to the reaction flask. The mixture was stirred for 1 hour, and a solution of Compound III (20 g, 117 mmol) in dry tetrahydrofuran was added dropwise to the reaction mixture. After the dropwise addition was completed, the mixture was stirred at this temperature for 30 minutes, and then slowly heated to -15 °C. The reaction was quenched with saturated ammonium chloride. One liter of water was added and the mixture was extracted three times with 1 liter of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, dried and filtered and evaporated. This compound IV was added to DMSO/H ₂ O (400 mL / 20 mL), and LiCl (14.7 g, 350 mmol) was added to the reaction flask. After reacting the system at 140 ° C for 18 hours, it was poured into 400 ml of water and extracted three times with 400 ml of ethyl acetate. The combined organic phases were washed once with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The NMR data of compound VI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40 -1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound VI is: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 33 Preparation of Compound V

A solution of ethyl chloroprene reagent in 2-methyltetrahydrofuran (1.36 mol/kg, 64.85 g, 88.2 mmol) was added to the reaction flask, and the reaction flask was placed in a low temperature reaction bath to control the internal temperature to -20~-30. At ° C, copper iodide (2.24 g, 11.79 mmol) was added to the reaction flask and stirred for 0.5 hours, and then dried 2-methyltetrahydrofuran (10 ml) such as compound III (10.0 g, 58.52 mmol) was added dropwise to the reaction flask. ) solution. The reaction was quenched by the addition of 60 mL of 3N aqueous hydrochloric acid. The mixture was heated under reflux for 24 hours, and then partitioned to give a solution of Compound V in 2-methyltetrahydrofuran, yield: 74%. The nuclear magnetic data of the purified compound V was purified by column chromatography (developing solvent: ethyl acetate) as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.57 (1H, brs), 4.54 (1H, dd) , 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m), 1.27-1.35 (2H, m), 0.95 (3H, t).

Example 34 Preparation of Compound VI

A solution of ethyl chloroprene reagent in 2-methyltetrahydrofuran (1.36 mol/kg, 64.85 g, 88.2 mmol) was added to the reaction flask, and the reaction flask was placed in a low temperature reaction bath to control the internal temperature to -20~-30. At ° C, copper iodide (2.24 g, 11.79 mmol) was added to the reaction flask and stirred for 0.5 hours, and then compound III (10.0 g, 58.52 mmol) of dry 2-methyltetrahydrofuran (10 ml) was added dropwise to the reaction flask. ) solution. The reaction was quenched with 50 mL of a saturated aqueous solution of ammonium chloride. Sodium hydroxide/water (7 g / 18 ml) was added, and the mixture was stirred at room temperature for 2 hours, and the mixture was allowed to stand for liquid phase. The aqueous phase was washed once with 50 ml of 2-methyltetrahydrofuran. Concentrated hydrochloric acid was added to adjust the pH to 1, and 10 ml of 2-methyltetrahydrofuran was added, and the organic phase was separated. The aqueous phase was extracted once with 20 ml of 2-methyltetrahydrofuran. The organic phases were combined and concentrated to remove solvent. The residual liquid was heated to 105 ° C for 10 hours, and distilled under reduced pressure to give Compound VI, colorless or pale yellow liquid, yield 75%. The NMR data of compound VI are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (1H, dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40 -1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t). The specific optical rotation of Compound VI is: [α] ²³ _D = +3.9 (C = 10, CHCl ₃ ).

Example 35 Preparation of Compound XI-a

(S)-2-Aminobutyric acid methyl ester hydrochloride (5.0 g, 32.6 mmol) was added to 10 ml of dry acetone, potassium carbonate (11.2 g, 81.7 mmol) was added and stirred at 0 ° C for 30 minutes. Compound X (6.28 g, 34.3 mmol) was added dropwise, and the mixture was added dropwise, and the mixture was stirred at room temperature until TLC, and no material remained. The mixture was applied to a solution of XI-a (yield, 50 ml of dichloromethane, 50 ml of water), and the organic phase was extracted with 50 ml of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, dried and filtered. R = OMe), purified by petroleum ether / ethyl acetate = 20/1 column chromatography, yield 70%. The NMR data of the compound XI-a (R = OMe) are as follows: ¹ H NMR (400 MHz, CDCl3) δ 6.24 (1H, d), 4.54 (1H, ddd), 3.72 (3H, s), 3.61 (2H, d ), 2.23-2.42 (3H, m), 1.85-1.95 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.85-0.95 (6H, m).

Example 36 Preparation of Compound XII-a

Compound XI-a (R = OMe, 2.0 g, 7.6 mmol) was added to 6 mL dry dimethylformamide, and potassium hydroxide (670 mg, 12 mmol) was added to the reaction flask in five portions. The system was reacted at -15 to -10 °C until HPLC, no raw material remained, 1N hydrochloric acid was quenched, 12 times volume of saturated brine was added, methyl tert-butyl ether was extracted four times, and the organic phase was combined with saturated sodium chloride. The solution is washed once, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to give the product. The obtained solid is compound XII-a (R=OMe), purified by petroleum ether/ethyl acetate=15/1 column chromatography, yield 65 %. The NMR data of the compound XII-a (R=OMe) are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.67 (dd, 1H), 3.69 (s, 3H), 3.40 (dd, 1H), 3.12 (dd, 1H), 2.53 (dd, 1H), 2.32-2.40 (m, 1H), 2.05 (dd, 1H), 1.95-2.05 (m, 1H), 1.62-1.75 (m, 1H), 1.25-1.48 (m, 4 H), 0.85-0.95 (m, 6H).

The present invention includes, but is not limited to, the above embodiments, and any equivalent or partial modifications made by the spirit of the present invention are considered to be within the scope of the present invention.

no

The route shown in Figure 1 is a method for the synthesis of a key intermediate compound of formula VI using commercially available palmitic starting materials.

Figure 2 shows the method of the route A to synthesize a compound of the formula XII, bovistam, wherein the compound of the formula VII and the compound of the formula IX are novel compounds, and the Br in the compound of the formula VII can also be Cl, I, OMs, OTs or ONs. Replace. Et in the compound of formula VII, formula IX may also be H or a C _1-20 hydrocarbyl or benzyl group, a substituted benzyl or aryl group.

Figure 3 shows the method for synthesizing the compound of formula XII, bovistam, by the method of path B and path C in the examples of the present invention. The compound of formula X and the compound of formula XI are novel compounds. Path D is also possible at high temperatures and pressures.

Claims (24)

Method for preparing a compound of formula XII from a compound of formula IV Wherein R is a C _1-20 hydrocarbyl group, a substituted benzyl group or a substituted aryl group, the method comprising: synthesizing a compound of formula VI from a compound of formula IV by a deacidification reaction Synthesis of a compound of formula VII or a compound of formula X by ring opening reaction from a compound of formula VI Wherein R1 is a C _1-20 hydrocarbyl group, a substituted benzyl group or a substituted aryl group, and X is Cl, Br, I, OMs, OTs or ONs; then, a compound of formula VII or a compound of formula X is Synthesizing a compound of formula XII with S)-2-aminobutyricamine or a salt thereof or (S)-2-aminobutyrate; or a compound of formula VI with (S)-2-aminobutyricamine or a salt thereof Synthesizing a compound of formula XII in a one-step reaction; or synthesizing a compound of formula VI with (S)-2-aminobutyrate to form a compound of formula XII-a, followed by aminolysis to form a guanamine to synthesize a compound of formula XII Wherein R is a C _1-20 alkoxy group. The method of claim 1, wherein R is methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl or benzyl. The method of claim 2, wherein R is methyl, ethyl, tert-butyl or benzyl. A method of preparing a compound of formula VI from a compound of formula IV, comprising the steps of: 1. Conversion of a compound of formula IV to a compound of formula VI wherein R is a C _1-20 hydrocarbyl group in a solvent, and under the action of a salt or a base; or 2. converting a compound of formula IV to a compound of formula V, Synthesis of a compound of formula VI from a compound of formula V . The method of claim 4, wherein the salt is lithium chloride, sodium chloride, potassium chloride, magnesium chloride, magnesium bromide or a mixture of any two or more of the foregoing; the base is lithium hydroxide or potassium hydroxide. , sodium hydroxide or a mixture of any two or more of the foregoing; the solvent is N-methylpyrrolidone, N,N-dimethylformamide, dimethyl hydrazine, cyclobutyl hydrazine, 4-methyl-2-pentyl An alcohol or a mixture of any two or more of the foregoing. A method of preparing a compound of formula VII from a compound of formula VI, comprising the steps of: 1. Synthesis of a compound of formula VI in a solvent and TMSI, TMSBr, HBr, HCl or HI; or 2. ring opening of the compound of formula VI under solvent and basic conditions, and corresponding sulfonium chloride The reaction forms a compound of formula VII, wherein the sulfonium chloride can be MsCl, TsCl or NsCl; wherein R1 is a C _1-20 hydrocarbyl, substituted or unsubstituted benzyl group; X is Cl, Br, I, OMs, OTs or ONs . The method of claim 6, wherein the solvent is N-methylpyrrolidone, N,N-dimethylformamide, dimethyl hydrazine, cyclobutyl hydrazine, dichloromethane, acetonitrile, tetrahydrofuran, C _1-20 An alcohol or a mixture of any two or more of the foregoing. Method for preparing a compound of formula XII from a compound of formula VII Wherein R1 is a C _1-20 hydrocarbyl group, a substituted or unsubstituted benzyl group; X is Cl, Br, I, OMs, OTs or ONs; the method comprises: 1. in a solvent and under alkaline conditions, Preparation of a compound of formula IX or a compound of formula IX-a with a compound of formula VII and (S)-2-aminobutylimamine or a salt thereof or (S)-2-aminobutyrate 2. Preparation of a compound of formula XII by ring closure of a compound of formula IX Or a compound of formula IX-a can be subjected to ring closure reaction to prepare a compound of formula XII . The method of claim 8, wherein HOBt or 2-hydroxypyridine is added to promote a ring closure reaction. The method of claim 8, wherein the solvent is selected from the group consisting of toluene, methyl isobutyl ketone, xylene, chlorobenzene or a mixture of any two or more of the foregoing. A process for the preparation of a compound of formula X comprising synthesizing a compound of formula X with SOCl ₂ under the action of a Lewis acid catalyst . The method of claim 11, wherein the Lewis acid catalyst is ZnCl ₂ . Method for preparing compound of formula XII from compound of formula X The method comprises: synthesizing a compound of the formula X with (S)-2-aminobutylimine or a salt thereof to synthesize a compound of the formula XII; or synthesizing a compound of the formula X with (S)-2-aminobutyrate to synthesize the formula XII-a The compound is further subjected to aminolysis or first hydrolysis by a compound of the formula XII-a and then subjected to amidoximation to form a compound of the formula XII, wherein R is a hydrocarbon group of NH ₂ or C _1-20 , and when R is NH ₂ , XII-a is consistent with formula XII; Or synthesizing a compound of formula X with (S)-2-aminobutyricamine or a salt thereof to synthesize a compound of formula XI, and then synthesizing a compound of formula XII from a compound of formula XI; or a compound of formula X with (S)-2-aminobutyl Synthesis of a compound of formula XI-a with an acid ester, synthesis of a compound of formula XII-a from a compound of formula XI-a, and synthesis of a compound of formula XII from a compound of formula XII-a Wherein R is NH ₂ or a C _1-20 alkoxy group, and when R is NH ₂ , formula XII-a is identical to formula XII. The method of claim 13, wherein the compound of the formula X is reacted with (S)-2-aminobutyricamine or a salt thereof or (S)-2-aminobutyrate to synthesize a compound of the formula XI-a. Wherein R is a hydrocarbon group of NH ₂ or C _1-20 . The method of claim 13, wherein the compound of the formula XII-a is subjected to a ring closure reaction under the action of a base to synthesize a compound of the formula XII-a. Wherein R is a hydrocarbon group of NH ₂ or C _1-20 ; and X is Cl, Br, I, OMs, OTs or ONs. A method of preparing a compound of formula XII, comprising the steps of: . A method of preparing a compound of formula XII, comprising the steps of: . A process for the preparation of a compound of formula XII, which comprises reacting a compound of formula VI with (S)-2-aminobutanamine to synthesize a compound of formula XII . a compound having the structure of formula VII Wherein R1 is H, a C _1-20 hydrocarbyl group or a substituted or unsubstituted benzyl group; and X is Cl, Br, I, OMs, OTs or ONs. The compound of claim 19, wherein R1 is methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl or benzyl. The compound of claim 20, wherein R1 is ethyl and X is Br. a compound having the structure of formula IX Wherein R1 is H, a C _1-20 hydrocarbyl group or a substituted or unsubstituted benzyl group. a compound having the structure of formula X . a compound having the structure of formula XI-a Wherein R is NH ₂ or a C _1-20 alkoxy group; and X is Cl, Br, I, OMs, OTs or ONs.