Process for the preparation of (s)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid and intermediate compounds thereof

Abstract

The application discloses a preparation method of a Ledipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid and an intermediate compound thereof, and belongs to the technical field of synthesis of pharmaceutical intermediates. The method uses N-tert-butoxycarbonyl glycine and (R)-alpha-methyl benzylamine as starting materials, and generates a diastereoisomer mixture of (S)-3A and (R)-3B through amide condensation and intramolecular N-alkylation ring closure reaction, and obtains the target configuration intermediate compound (S)-3A through solvent recrystallization and mother liquor racemization reaction and recrystallization. Further, (S)-3A is further subjected to one-pot deprotection of double protection groups and amino protection to obtain the target product. The yield of the target intermediate configuration obtained by the application can reach 86.7%, the chiral purity of the product is greater than 99%, the operation is simple, the conditions are mild, the reaction stability is high, the recycling of non-target configuration compounds is realized, and the industrialized production is easy.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to the preparation method of leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid and its intermediate compounds. Background Technology

[0002] Hepatitis C, or HCV for short, is a viral hepatitis caused by infection with the hepatitis C virus (HCV). HCV infection leads to liver inflammation, resulting in decreased liver function or even liver failure. The pathological manifestations are mainly hepatocellular necrosis and lymphocyte infiltration.

[0003] Ledipasvir, formerly known as GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. It is used in combination with Gilead's other blockbuster hepatitis C treatment, sofosbuvir (Sovaldi), under the brand name Harvoni. It was approved by the US FDA on October 10, 2014, and received marketing authorization from the European Union on November 21 of the same year. It is an all-oral, once-daily tablet used to treat genotype 1 hepatitis C virus infection, exhibiting excellent therapeutic efficacy and relatively few side effects.

[0004] The development of the synthesis process and raw material cost of the chiral compound (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid is of great significance as a key intermediate of ledipasvir.

[0005]

[0006] The usual method for preparing chiral compounds is to use chiral reagents to resolve the desired product, with a yield of around 30%. The remaining configurations are typically discarded as byproducts, resulting in higher product costs. The reported methods for synthesizing the chiral intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid mainly include the following: Method 1: US2013324496A1. This patent reports a method for preparing the chiral intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. A racemic mixture of 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid is prepared from 1,1-cyclopropanediethanol as the starting material. This mixture is then reacted with the chiral resolving agent (1S,2R)-1-amino-2-indanol in 2-methyltetrahydrofuran to obtain the (1S,2R)-1-amino-2-indanol salt of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. Finally, under acidic conditions, (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid is released.

[0007] The disadvantages of this route are: the chiral resolution operation is complicated, the resolution reagent (1S,2R)-1-amino-2-indanol is expensive, and the yield is only 33%, resulting in high costs and making it unsuitable for industrial production.

[0008]

[0009] Method 2: CN104788361A. This patent reports a chiral resolution method. The racemic mixture of 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid is reacted with the chiral resolving agent (R)-α-methylbenzylamine in isopropyl acetate and isopropanol to give a salt, which is then released under acidic conditions to give (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid.

[0010] Compared to Method 1, this route uses a cheaper chiral resolution reagent, but the resolution yield is still low, resulting in a large waste of resources and hindering industrial production.

[0011]

[0012] Method 3: CN107216278A. This patent reports a method for resolution by crystallization-induced asymmetric transformation. In the presence of an aldehyde racemic reagent and a chiral resolving reagent such as tartaric acid, the racemic mixture of 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid is converted to the corresponding salt, and then released under acidic conditions to obtain (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid.

[0013] This route improves the yield of chiral separation, but it is prone to yielding racemic byproducts.

[0014]

[0015] As can be seen from the above literature on the preparation of chiral intermediates of leadipasvir, chiral resolution is a key step in the synthesis of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. Current methods all use acid and resolving reagents to form salts for precipitation. However, the salts are highly hygroscopic and the salt formation rate is not high, resulting in low resolving yields. On the other hand, the product of the other configuration after resolving is treated as a byproduct and not recycled, which also leads to the high market cost of this compound. Summary of the Invention

[0016] The purpose of this invention is to provide a method for preparing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid and its intermediate compounds, in order to solve the problems of low chiral resolution yield, waste of non-target configurations, and high production costs in the prior art. This method first introduces a chiral cofactor to achieve asymmetric synthesis of the target configuration, and then combines multiple solvent recrystallization and mother liquor racemization reactions to achieve efficient preparation of the target configuration and recycling of non-target configurations. The raw material utilization rate is high, the reaction conditions are mild, and stable industrial production can be achieved.

[0017] This invention provides a method for preparing compound (S)-3A, comprising the following steps: N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine undergo an amide condensation reaction to obtain compound 2; compound 2 undergoes an intramolecular N-alkylation ring-closure reaction with an alkylating agent to obtain a mixture of (S)-3A and (R)-3B; the mixture of (S)-3A and (R)-3B is recrystallized to obtain compound (S)-3A. The synthetic route is as follows: .

[0018] Furthermore, in the step of preparing compound 2 from N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine, the organic base is one of N,N-diisopropylethylamine and triethylamine, preferably N,N-diisopropylethylamine, which can reduce the side reactions of the condensing agent; The condensing agent is one or more of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-carbonyldiimidazole, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, which has high reactivity and few byproducts; The reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably N,N-dimethylformamide.

[0019] Furthermore, in the step of preparing compound 2 from N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine, the molar ratio of N-tert-butoxycarbonylglycine:(R)-α-methylbenzylamine:organic base:condensing agent is 1:1~1.2:2.5~3:1.5~1.8, preferably 1:1:3:1.5.

[0020] Furthermore, in the step of preparing a mixture of (S)-3A and (R)-3B with compound 2 and an alkylating agent, the alkylating agent is a 1,1-cyclopropane dimethyl dialkylating agent, wherein the R group in the alkylating agent is a leaveable group selected from iodine, bromine, chlorine, methanesulfonyloxy, and p-toluenesulfonyloxy, preferably 1,1-bis(iodomethyl)cyclopropane, which has high reactivity; The alkali is selected from sodium hydride, lithium diisopropylamino, and potassium tert-butoxide, and the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably N,N-dimethylformamide; The molar ratio of compound 2: alkylating agent: base is 1:1~1.1:2.5~4.

[0021] Furthermore, the recrystallization step for preparing compound (S)-3A from a mixture of (S)-3A and (R)-3B includes: Step 1: The mixture containing (S)-3A and (R)-3B was recrystallized for the first time, filtered to obtain filter cake I and mother liquor I, and filter cake I was dried to obtain compound (S)-3A; Step 2: Concentrate the mother liquor I obtained in Step 1, recrystallize it a second time, filter it to obtain filter cake II and mother liquor II, and dry filter cake II to obtain compound (S)-3A; Step 3: Concentrate the mother liquor II obtained in Step 2, racemate it under alkaline conditions, and then recrystallize and filter it to obtain filter cake III. Filter cake III is dried to obtain compound (S)-3A. Preferably, step two can be repeated multiple times until no target product precipitates out of the mother liquor.

[0022] The solvent used for recrystallization in steps one, two, and three is one or more of ethyl acetate, n-heptane, petroleum ether, and isopropanol, preferably ethyl acetate and n-heptane.

[0023] The base used in the racemization reaction in step three is sodium hydride, which is low in cost and has strong controllability; the reaction solvent is one of tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably tetrahydrofuran.

[0024] This invention provides a method for preparing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid, comprising the following steps: N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine undergo an amide condensation reaction to obtain compound 2; compound 2 undergoes an intramolecular N-alkylation ring-closure reaction with an alkylating agent to obtain a mixture of (S)-3A and (R)-3B; the mixture of (S)-3A and (R)-3B is recrystallized to obtain compound (S)-3A; (S)-3A is deprotected to obtain compound 4; compound 4 is reacted with ditert-butyl dicarbonate to obtain compound 1. The synthetic route is as follows: .

[0025] Furthermore, in the step of preparing compound 4 from compound (S)-3A, the deprotection system is a hydrochloric acid-toluene system, and (R)-α-methylbenzylamine is recovered simultaneously during the deprotection reaction.

[0026] Furthermore, in the step of preparing compound 1 from compound 4, the base is selected from sodium hydroxide and potassium hydroxide, the catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium bisulfate, the reaction solvent is dichloromethane, tetrahydrofuran, and 1,4-dioxane, and the molar ratio of compound 4: ditert-butyl dicarbonate: base: catalyst is 1:1.2~1.3:2.2~2.5:0.009~0.01.

[0027] Beneficial effects: This invention provides a method for synthesizing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid and its intermediate compounds. The method uses N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine as starting materials, and generates a diastereomeric mixture of intermediates (S)-3A and (R)-3B through amide condensation and intramolecular N-alkylation ring-closure reaction. After multiple recrystallizations and racemic reactions in the mother liquor, high-optical-purity intermediate compound (S)-3A is obtained by recrystallization. Further, using N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine as starting materials, intermediate compound (S)-3A is first prepared according to the above synthetic route, and then deprotected and amino-protected in a one-pot process to obtain (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid.

[0028] The synthesis method provided by this invention significantly improves the utilization rate of raw materials, has a simple process, and is highly adaptable to industrial applications. Specifically, it is manifested in the following aspects: (1) The introduction of the chiral cofactor (R)-α-methylbenzylamine achieves the asymmetric synthesis of the target configuration. The proportion of (S)-3A in the diastereomeric mixture of (S)-3A and (R)-3B can reach 86%; (2) The traditional resolution mode of salting out by acid and resolving reagent is abandoned. Instead, a solvent recrystallization resolution process is adopted, which avoids the problem of easy moisture absorption and decomposition of the product after salting. This makes the crystallization process stable and controllable, and the chiral purity of the product is >99%; (3) Through multiple recrystallization and recrystallization after racemic reaction of the mother liquor, the yield of the target configuration is effectively improved. The yield of compound (S)-3A after the first recrystallization can reach 70%, and the yield of the second recrystallization can reach 70%. The filtrate after the first recrystallization filtration was subjected to a second recrystallization. The cumulative yield of compound (S)-3A after the two recrystallizations was 80.79%. The filtrate after the second recrystallization filtration was racemized and recrystallized again to obtain compound (S)-3A. The cumulative yield reached 86.7%, which further realized the recycling and reuse of non-target configurations and solved the problem that non-target configurations were directly discarded as by-products in the existing technology, resulting in raw material waste. (4) At the same time, the raw material (R)-α-methylbenzylamine was recovered, which greatly improved the raw material utilization rate and reduced the production cost. (5) The preparation process route is simple and mild, and the operation is safe and controllable. The Boc and benzyl protecting groups are removed simultaneously in one pot, which reduces intermediate operation links and reagent consumption and is suitable for large-scale industrial scale-up production. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments, but these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0030] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0031] The abbreviations for the reaction reagents mentioned in the instructions are as follows: HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate.

[0032] Example 1: Preparation of intermediate compound (S)-3A:

[0033] Synthesis of Compound 2

[0034]

[0035] N-tert-butoxycarbonylglycine (87.59 g, 0.5 mol) and N,N-dimethylformamide (500 mL) were added to a reaction flask and stirred until completely dissolved. HATU (285.18 g, 0.75 mol) and N,N-diisopropylethylamine (193.86 g, 1.5 mol) were added sequentially, and the mixture was stirred at room temperature for 20 min. Then (R)-α-methylbenzylamine (60.59 g, 0.5 mol) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was complete under LC control, the reaction solution was concentrated by rotary evaporation under reduced pressure to remove the solvent. Dichloromethane (1000 mL) was added and stirred to dilute the solution. The solution was washed with saturated sodium carbonate solution (250 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product (R)-2-((tert-butoxycarbonyl)amino)-N-(1-phenylethyl)acetamide (compound 2, yellow oily liquid, 137.78 g / mL). g (yield 99%), the crude product is used directly in the next reaction step.

[0036] Synthesis of a mixture of intermediates (S)-3A and (R)-3B

[0037]

[0038] Sodium hydride (60%, 40 g, 1 mol) and N,N-dimethylformamide (100 mL) were added to a reaction flask. Under argon protection, the mixture was cooled to 0°C. While stirring, a solution of 1,1-bis(iodomethyl)cyclopropane (128.77 g, 0.4 mol) and compound 2 (111.34 g, 0.4 mol) in N,N-dimethylformamide (400 mL) was slowly added dropwise. The mixture was stirred at 0–5°C for 2 h. After the reaction was complete under LC control, ethyl acetate (1110 mL) and process water (600 mL) were slowly added dropwise to the reaction solution. The mixture was stirred for 10 min, allowed to stand, and allowed to separate into layers. The aqueous phase was back-extracted once with ethyl acetate (500 mL). The organic phases were combined and washed with saturated sodium chloride solution (250 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture of compounds (S)-3A and (R)-3B (oily solid, 117.39 g / mL). g, yield 85.2%, (S)-3A:(R)-3B=86:14).

[0039] Synthesis of intermediate compound (S)-3A

[0040]

[0041] Ethyl acetate (300 mL) was added to a mixture of (S)-3A and (R)-3B (88.46 g, 0.257 mol), the mixture was heated to 60 °C and refluxed until the material was completely dissolved, the temperature was slowly lowered to 40 °C, and n-heptane (600 mL) was added dropwise. After the addition was complete, the temperature was restored to 20 °C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain intermediate compound (S)-3A (61.92 g, chiral purity 99.2%, yield 70%).

[0042] The filtrate obtained from the first filtration was transferred to a vacuum concentration apparatus, and the temperature was set to 30°C. The mixture of (S)-3A and (R)-3B (26.54 g, 0.077 mol, (S)-3A:(R)-3B=51:49) was recovered by vacuum concentration. Ethyl acetate (100 mL) was added to the recovered mixture, and the temperature was raised to 60°C and heated under reflux until the material was completely dissolved. The temperature was then slowly lowered to 40°C, and n-heptane (200 mL) was added dropwise. After the addition was complete, the temperature was restored to 20°C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40-50°C to obtain the second batch of intermediate compound (S)-3A (9.55 g, chiral purity 99.1%, yield 36%, based on the recovered mixture).

[0043] The filtrate obtained from the second filtration was transferred to a vacuum concentration apparatus. The temperature was set to 30°C, and the mixture was concentrated under reduced pressure to recover compounds (S)-3A and (R)-3B (16.99 g, 0.049 mol, (S)-3A:(R)-3B = 15:49). Tetrahydrofuran (150 mL) was added to the recovered mixture, and the temperature was lowered to 0°C. Sodium hydride (60%, 8 g, 0.2 mol) was slowly added, and the temperature was raised to room temperature. The reaction was stirred for 4 h. Acetic acid (5 mL) was slowly added dropwise to quench the reaction, and the mixture was stirred for 1 h at 0°C. Ethyl acetate (170 mL) and process water (100 mL) were added, and the mixture was allowed to stand for separation. The organic phase was separated, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compounds (S)-3A and (R)-3B (16.99 g, 0.049 mol). g, (S)-3A:(R)-3B=52:48); Ethyl acetate (60 mL) was added to the recovered mixture, the temperature was raised to 60°C and heated under reflux until the material was completely dissolved, the temperature was slowly lowered to 40°C, n-heptane (120 mL) was added dropwise, and after the addition was complete, the temperature was restored to 20°C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40~50°C to obtain the third batch of intermediate compound (S)-3A (5.2 g, chiral purity 99.3%, yield 30.7%, based on the recovered mixture).

[0044] After three recrystallizations, 76.67 g of (S)-3A with high chiral purity was obtained from the initial mixture of (S)-3A and (R)-3B (88.46 g), with an overall yield of 86.7%.

[0045] Example 2: Preparation of compound 1 ((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid)

[0046]

[0047] Synthesis of Compound 2

[0048]

[0049] N-tert-butoxycarbonylglycine (87.59 g, 0.5 mol) and N-methylpyrrolidone (500 mL) were added to a reaction flask and stirred until completely dissolved. HATU (342.21 g, 0.9 mol) and triethylamine (126.49 g, 1.25 mol) were added sequentially, and the mixture was stirred at room temperature for 20 min. Then (R)-α-methylbenzylamine (72.71 g, 0.6 mol) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was complete under LC control, the reaction solution was concentrated by rotary evaporation under reduced pressure to remove the solvent. Dichloromethane (1000 mL) was added and stirred to dilute the solution. The solution was washed with saturated sodium carbonate solution (250 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product (R)-2-((tert-butoxycarbonyl)amino)-N-(1-phenylethyl)acetamide (compound 2, yellow oily liquid, 130.02 g / mL). g, yield 93.42%), the crude product was used directly in the next reaction.

[0050] Synthesis of a mixture of intermediates (S)-3A and (R)-3B

[0051]

[0052] Potassium tert-butoxide (179.54 g, 1.6 mol) and N,N-dimethylacetamide (100 mL) were added to the reaction flask. Under argon protection, the temperature was lowered to 0 °C. While stirring, a solution of cyclopropane-1,1-dimethylbis(methylene)dimethylsulfonate (113.66 g, 0.44 mol) and compound 2 (111.34 g, 0.4 mol) in N,N-dimethylacetamide (400 mL) was slowly added dropwise. The mixture was stirred at 0–5 °C for 2 h. After the reactants had reacted completely under LC control, ethyl acetate (1110 mL) and process water (600 mL) were slowly added dropwise to the reaction solution. The mixture was stirred for 10 min, allowed to stand, and allowed to separate into layers. The aqueous phase was back-extracted once with ethyl acetate (500 mL). The organic phases were combined and washed with saturated sodium chloride solution (250 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture of compounds (S)-3A and (R)-3B (oily solid, 112.4 g). g, yield 81.58%, (S)-3A:(R)-3B=86:14).

[0053] Synthesis of intermediate compound (S)-3A

[0054]

[0055] Ethyl acetate (300 mL) was added to a mixture of (S)-3A and (R)-3B (88.46 g, 0.257 mol), the mixture was heated to 60 °C and refluxed until the material was completely dissolved, the temperature was slowly lowered to 40 °C, and n-heptane (600 mL) was added dropwise. After the addition was complete, the temperature was restored to 20 °C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40-50 °C to obtain intermediate compound (S)-3A (61.92 g, chiral purity 99.2%, yield 70%).

[0056] The filtrate obtained from the first filtration was transferred to a vacuum concentration apparatus, and the temperature was set to 30°C. The mixture of (S)-3A and (R)-3B (26.54 g, 0.077 mol, (S)-3A:(R)-3B=51:49) was recovered by vacuum concentration. Ethyl acetate (100 mL) was added to the recovered mixture, and the temperature was raised to 60°C and heated under reflux until the material was completely dissolved. The temperature was then slowly lowered to 40°C, and n-heptane (200 mL) was added dropwise. After the addition was completed, the temperature was restored to 20°C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40-50°C to obtain the second batch of intermediate compound (S)-3A (9.55 g, chiral purity 99.1%, yield 36%, based on the recovered mixture).

[0057] The filtrate obtained from the second filtration was transferred to a vacuum concentration apparatus. The temperature was set to 30°C, and the mixture was concentrated under reduced pressure to recover compounds (S)-3A and (R)-3B (16.99 g, 0.049 mol, (S)-3A:(R)-3B = 15:49). N,N-dimethylformamide (150 mL) was added to the recovered mixture, and the temperature was lowered to 0°C. Sodium hydride (60%, 8 g, 0.2 mol) was slowly added, and the temperature was raised to room temperature. The reaction was stirred for 4 h. Acetic acid (5 mL) was slowly added dropwise to quench the reaction, and the mixture was stirred for 1 h at 0°C. Ethyl acetate (170 mL) and process water (100 mL) were added. The mixture was allowed to stand and separate into layers. The organic phase was separated, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compounds (S)-3A and (R)-3B (16.99 g, 0.049 mol, (S)-3A:(R)-3B = 15:49). g, (S)-3A:(R)-3B=52:48); Ethyl acetate (60 mL) was added to the recovered mixture, the temperature was raised to 60°C and heated under reflux until the material was completely dissolved, the temperature was slowly lowered to 40°C, n-heptane (120 mL) was added dropwise, and after the addition was complete, the temperature was restored to 20°C and stirred for 2 h. The mixture was filtered, and the filter cake was dried under vacuum at 40~50°C to obtain the third batch of intermediate (S)-3A (4.8 g, chiral purity 99.3%, yield 28.3%, based on the recovered mixture).

[0058] After three recrystallizations, 76.27 g of (S)-3A with high chiral purity was obtained from the initial mixture of (S)-3A and (R)-3B (88.46 g), with an overall yield of 86.2%.

[0059] Synthesis of Compound 4

[0060]

[0061] Intermediate compound (S)-3A (68.89 g, 0.2 mol), toluene (350 mL), and hydrochloric acid (69 mL, 36%) were added to the reaction flask. The mixture was heated to 90-100 °C and stirred for 8 h. After the reaction was completed by TLC, the mixture was cooled to room temperature, and process water (345 mL) was added and stirred for 30 min. The mixture was allowed to stand and separate into layers. The lower aqueous phase was separated, and the pH was adjusted to 10-11 by adding 30% sodium hydroxide solution. Toluene (300 mL × 2) was added and extracted twice. The upper organic phase was concentrated under reduced pressure at 40-60 °C to recover (R)-α-methylbenzylamine (21.81 g, 90% yield). Dilute hydrochloric acid (1M) was added dropwise to the aqueous phase to adjust the pH to 6-7. Ethyl acetate (350 mL × 3) was added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4 (24.68 g, 87.4% yield).

[0062] Synthesis of Compound 1 ((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid)

[0063]

[0064] Add intermediate 4 (14.12 g, 0.1 mol), tetrahydrofuran (150 mL), and tetrabutylammonium bromide (0.3 g, 0.93 mmol) to the reaction flask and stir until dissolved. Maintain the temperature at 0–10 °C and slowly add 30% sodium hydroxide solution (29.33 g, 0.22 mol) dropwise to the reaction solution, stirring for 10 min after each addition. Slowly add di-tert-butyl dicarbonate (26.19 g, 0.12 mol) and tetrahydrofuran solution (50 mL) dropwise at room temperature, stirring for 4 h after each addition. Monitor the reaction progress by TLC. Add process water (30 mL) to the reaction solution, adjust the pH to 4–5 by adding dilute hydrochloric acid (1 M), and extract twice with ethyl acetate (150 mL × 2). Combine the organic phases, dry under anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude target product. The crude product is then treated with ethyl acetate (30 mL × 1 ... Heating (60 mL) to 60 °C and stirring to dissolve, cooling to 40 °C, adding n-heptane (60 mL) dropwise, slowly cooling to 10~15 °C and stirring to crystallize for 2 h, filtering, and drying to obtain the target product (compound 1, off-white solid, 22.28 g, yield 92.34%). 1 H NMR (400 MHz, CDCl3) δ: 11.3(s, 1H), 4.22(m, 1H), 3.30-3.20(m, 2H), 1.84(m, 2H), 1.42(m,9H), 0.48-0.42(m, 4H).

[0065] Example 3: Preparation of compound 1 ((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid)

[0066]

[0067] Synthesis of Compound 4

[0068]

[0069] Intermediate compound (S)-3A (68.89 g, 0.2 mol), toluene (350 mL), and hydrochloric acid (69 mL, 36%) were added to the reaction flask. The mixture was heated to 90-100 °C and stirred for 8 h. After the reaction was completed by TLC, the mixture was cooled to room temperature, and process water (345 mL) was added and stirred for 30 min. The mixture was allowed to stand and separate into layers. The lower aqueous phase was separated, and the pH was adjusted to 10-11 by adding 30% sodium hydroxide solution. Toluene (300 mL × 2) was added and extracted twice. The upper organic phase was concentrated under reduced pressure at 40-60 °C to recover (R)-α-methylbenzylamine (21.81 g, 90% yield). Dilute hydrochloric acid (1M) was added dropwise to the aqueous phase to adjust the pH to 6-7. Ethyl acetate (350 mL × 3) was added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4 (24.68 g, 87.4% yield).

[0070] Synthesis of Compound 1

[0071]

[0072] Compound 4 (14.12 g, 0.1 mol), 1,4-dioxane (150 mL), and tetrabutylammonium hydrogen sulfate (0.34 g, 1 mmol) were added to the reaction flask and stirred until dissolved. The temperature was maintained at 0–10 °C. A 30% sodium hydroxide solution (33.33 g, 0.25 mol) was slowly added dropwise to the reaction solution, and stirring was continued for 10 min after the addition was complete. Di-tert-butyl dicarbonate (28.37 g, 0.13 mol) and a 1,4-dioxane solution (50 mL) were slowly added dropwise at room temperature, and the reaction was stirred at room temperature for 4 h after the addition was complete. The reaction was monitored by TLC until the reactants were fully reacted. Process water (30 mL) was added to the reaction solution, and the pH was adjusted to 4–5 by adding dilute hydrochloric acid (1 M). Ethyl acetate (150 mL × 2) was added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target product. The crude product was then treated with ethyl acetate (30 mL × 1 mmol). Heating (60 mL) to 60 °C and stirring to dissolve, cooling to 40 °C, adding n-heptane (60 mL) dropwise, slowly cooling to 10~15 °C and stirring to crystallize for 2 h, filtering, and drying to obtain the target product (off-white solid, 21.68 g, yield 89.85%).

[0073] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing compound (S)-3A, characterized in that, The synthetic route includes the following steps: N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine undergo an amide condensation reaction to obtain compound 2; compound 2 undergoes an intramolecular N-alkylation ring-closure reaction with an alkylating agent to obtain a mixture of (S)-3A and (R)-3B; the mixture of (S)-3A and (R)-3B is recrystallized to obtain compound (S)-3A. 。 2. The method for preparing compound (S)-3A according to claim 1, characterized in that, In the step of preparing compound 2 from N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine, the organic base is one of N,N-diisopropylethylamine and triethylamine; the condensing agent is one or more of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-carbonyldiimidazole; the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; and the molar ratio of N-tert-butoxycarbonylglycine:(R)-α-methylbenzylamine:organic base:condensing agent is 1:1~1.2:2.5~3:1.5~1.

8.

3. The method for preparing compound (S)-3A according to claim 1, characterized in that, In the step of preparing a mixture of (S)-3A and (R)-3B with compound 2 and an alkylating agent, the alkylating agent is a 1,1-cyclopropanedimethyldialkylating agent, and the R group in the alkylating agent is a leaveable group selected from iodine, bromine, chlorine, methanesulfonyloxy, and p-toluenesulfonyloxy.

4. The method for preparing compound (S)-3A according to claim 1, characterized in that, In the step of preparing a mixture of (S)-3A and (R)-3B with compound 2 and an alkylating agent, the base is selected from sodium hydride, lithium diisopropylamino, and potassium tert-butoxide, the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and the molar ratio of compound 2: alkylating agent: base is 1:1~1.1:2.5~4.

5. The method for preparing compound (S)-3A according to any one of claims 1 to 4, characterized in that, The recrystallization of compound (S)-3A from a mixture of (S)-3A and (R)-3B comprises the following steps: Step 1: The mixture containing (S)-3A and (R)-3B was recrystallized for the first time, filtered to obtain filter cake I and mother liquor I, and filter cake I was dried to obtain compound (S)-3A; Step 2: Concentrate the mother liquor I obtained in Step 1, recrystallize it a second time, filter it to obtain filter cake II and mother liquor II, and dry filter cake II to obtain compound (S)-3A; Step 3: Concentrate the mother liquor II obtained in Step 2, racemate it under alkaline conditions, and then recrystallize and filter it to obtain filter cake III. Filter cake III is dried to obtain compound (S)-3A. Preferably, step two can be repeated multiple times until no target product precipitates out of the mother liquor.

6. The method for preparing compound (S)-3A according to claim 5, characterized in that, The solvents used for recrystallization in steps one, two, and three are one or more of ethyl acetate, n-heptane, petroleum ether, and isopropanol.

7. The method for preparing compound (S)-3A according to claim 5, characterized in that, The base used in the racemic reaction in step three is sodium hydride, and the reaction solvent is one of tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

8. A method for preparing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid, characterized in that, The synthetic route includes the following steps: N-tert-butoxycarbonylglycine and (R)-α-methylbenzylamine undergo an amide condensation reaction to obtain compound 2; compound 2 undergoes an intramolecular N-alkylation ring-closure reaction with an alkylating agent to obtain a mixture of (S)-3A and (R)-3B; the mixture of (S)-3A and (R)-3B is recrystallized to obtain compound (S)-3A; (S)-3A is deprotected to obtain compound 4; compound 4 reacts with di-tert-butyl dicarbonate to obtain compound 1. The synthetic route is as follows: 。 9. The method for preparing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid according to claim 8, characterized in that, In the step of preparing compound 4 from compound (S)-3A, the deprotection system is a hydrochloric acid-toluene system, and (R)-α-methylbenzylamine is recovered simultaneously during the deprotection reaction.

10. The method for preparing the leadipasvir intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid according to claim 8, characterized in that, In the step of preparing compound 1 from compound 4, the base is selected from sodium hydroxide and potassium hydroxide, the catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium bisulfate, the reaction solvent is dichloromethane, tetrahydrofuran, and 1,4-dioxane, and the molar ratio of compound 4: ditert-butyl dicarbonate: base: catalyst is 1:1.2~1.3:2.2~2.5:0.009~0.01.

Images