Synthesis method of (S)-2, 2, 4-trimethylpyrrolidine hydrochloride

Abstract

The invention relates to a synthesis method of (S)-2, 2, 4-trimethyl pyrrolidine hydrochloride, which comprises the following steps: step a, carrying out Michael addition reaction on a compound 10 and a compound 11 in the presence of a solvent to prepare a compound 12; b, the compound 12 and ethyl bromoacetate are subjected to an affinity substitution reaction under the alkaline and solvent conditions, and a compound 13 is prepared; c, carrying out condensation ring closing reaction on the compound 13 under alkaline and solvent conditions to prepare a compound 14; step d, the compound 14 is subjected to a decarboxylation reaction under the acidic condition, and a compound 15 is prepared; e, the compound 15 is subjected to Wittig reaction under the alkaline condition, and a compound 16 is prepared; and step f, carrying out asymmetric hydrogenation reaction on the compound 16 to prepare a target compound 1, namely (S)-2, 2, 4-trimethylpyrrolidine hydrochloride. According to the synthetic method of the (S)-2, 2, 4-trimethylpyrrolidine hydrochloride, the reaction type of the whole synthetic route is safe, the yield of each step is relatively high, and industrial production is convenient to realize.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride. BACKGROUND

[0002] Cystic fibrosis (CF) is a common autosomal recessive genetic disease in the West. The pathogenic gene CFTR is located on chromosome 7q31.2. Loss of function mutations in CFTR gene lead to reduced or defective CFTR protein, resulting in abnormal epithelial cell ion transport, causing mucus accumulation and mucociliary clearance disorders, which is the cause of CF. Patients are rare in China, and were included in the first batch of rare disease list in China in 2018. The treatment of CF in China has been mainly symptomatic treatment such as airway clearance, and lacks specific treatment. Currently, a variety of small molecule modulators have been developed internationally, mainly divided into five categories: potentiators, correctors, amplifiers, stabilizers and read-through agents, which can target CFTR protein and improve lung function, increase body weight and improve quality of life in patients. However, due to the large differences in genotype between Chinese CF patients and European and American populations, there is currently a lack of drug effectiveness verification for Chinese patients, and such drugs have not been used in China.

[0003] International reports show that about 90% of CF patients have at least one p.Phe508del (referred to as F508del) mutation. This mutation site is the focus of western drug development and belongs to class II mutations. Corrector lumacaftor (VX-809, LUM) can be used to improve the folding, processing and transport of CFTR protein. However, the efficacy of lumacaftor alone for F508del homozygous patients is very small, because even if the protein folding is corrected, there are still gating defects in the transport of CFTR protein to PM, and the combination of potentiators is needed to further help the channel opening. Therefore, there is currently no marketed corrector monotherapy, and combination therapy is mainly used. For example, lumacaftor-ivacaftor combination (referred to as LUM / IVA) was approved for marketing in 2015, which is suitable for F508del homozygous (referred to as F / F) patients.

[0004] Due to the adverse effects of Ivacaftor on the F508del-CFTR protein corrected by Lumacaftor, and the adverse reactions such as bronchospasm and respiratory difficulty, a second-generation corrector, Tezacaftor (VX-661, TEZ), with better pharmacokinetics and fewer side effects, was developed. The combination of Tezacaftor-Ivacaftor for F / F or F508del compound heterozygous patients with G551D as the second allele can improve lung function and reduce sweat Cl-concentration, so the drug (TEZ / IVA for short) was approved by FDA and EMA in 2018. Elexacaftor (VX-445, ELE) is a second-generation corrector with a different mechanism of action than the first-generation corrector, and the combination has an additive effect, which is now mainly used as a triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ELE / TEZ / IVA for short).

[0005] Elexacaftor and Tezacaftor bind to different sites on the CFTR protein and have an additive effect in promoting the cellular processing and transport of F508del-CFTR, which can increase the amount of CFTR protein transported to the cell surface compared to using either molecule alone.

[0006] Ivacaftor can enhance the probability of CFTR protein channel opening (or gating) on the cell surface. The overall effect is to increase the number and function of F508del-CFTR on the cell surface, resulting in increased CFTR activity (measured by CFTR-mediated chloride transport).

[0007] (S)-2,2,4-trimethylpyrrolidine hydrochloride is an important intermediate for the synthesis of Elexacaftor, and there are currently two main synthesis routes: 1) Michael addition reaction occurs under basic conditions to obtain compound 4, followed by enzymatic resolution to obtain compound 3 in s configuration, reduction to close the ring to obtain compound 2, and finally reduction of the amide with lithium aluminum hydride and salt formation to obtain the target intermediate compound 1. This route uses dangerous raw materials such as Raney Ni and lithium aluminum hydride. The reaction route is as follows: 2) Compound 8 undergoes ring-closing reaction with chloroform under basic conditions in the presence of a phase transfer catalyst to obtain a five-membered lactam 9, which is then subjected to asymmetric hydrogenation under the action of a metal catalyst to obtain a chiral lactam 2, and finally lithium aluminum hydride is used to reduce the lactam and salt to obtain the target intermediate 1. This route still uses the dangerous raw material lithium aluminum hydride, which limits industrialization. The reaction route is as follows: Therefore, in order to industrial production, popularization and economic benefits, it is urgent to develop a synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride which is safer in synthesis steps and has higher overall yield. SUMMARY

[0008] The purpose of the present application is to provide a synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, which aims to solve the problems existing in the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the prior art, the reaction type of the whole synthesis route is safe, the yield of each step is higher, and the industrial production is easy to realize, and the application prospect is wide.

[0009] The purpose of the present application is achieved by the following technical scheme: A synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, the synthesis route of which is as follows: Synthesis according to the following steps: Step a: Compound 10 and compound 11 are subjected to Michael addition reaction under solvent conditions to prepare compound 12; Step b: Compound 12 and ethyl bromoacetate are subjected to affinity substitution reaction under alkaline and solvent conditions to prepare compound 13; Step c: Compound 13 is subjected to condensation ring-closing reaction under alkaline and solvent conditions to prepare compound 14; Step d: Compound 14 is subjected to decarboxylation reaction under acidic conditions to prepare compound 15; Step e: Compound 15 is subjected to Wittig reaction under alkaline conditions to prepare compound 16; Step f: Compound 16 is subjected to asymmetric hydrogenation reaction to prepare the target compound 1, i.e. (S)-2,2,4-trimethylpyrrolidine hydrochloride.

[0010] The synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride described in the present application is reasonable in design and includes six steps: step a: Michael addition reaction to obtain compound 12, i.e. secondary amine; step b: affinity substitution reaction of secondary amine and ethyl bromoacetate to construct C-N bond; step c: condensation ring-closing reaction under alkaline conditions to construct five-membered ring skeleton; step d: acid-catalyzed decarboxylation reaction; step e: Wittig reaction to construct exocyclic double bond; and step f: asymmetric hydrogenation reaction.

[0011] The above synthesis method has the following advantages: 1) all the materials used are commercial raw materials, which are cheap and easy to obtain; 2) harsh reaction conditions are not used in the synthesis process; 3) dangerous materials such as lithium aluminum hydride are not used in the reaction process.

[0012] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step a, the molar ratio of compound 10 to compound 11 is 1:1.1-1.2; the solvent selected is an alcohol solvent.

[0013] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step a, the reaction temperature is heated to reflux; the solvent selected includes but is not limited to one of methanol, ethanol.

[0014] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step b, the molar ratio of compound 12 to ethyl bromoacetate is 1:1.1-1.2; the base selected is an inorganic base; the molar ratio of compound 12 to the base is 1:2.0-2.5; the solvent selected is a polar solvent.

[0015] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step b, the reaction temperature is room temperature; the base selected includes but is not limited to potassium carbonate; the solvent selected includes but is not limited to one of DMF, acetonitrile.

[0016] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step c, the base selected includes but is not limited to one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide; the molar ratio of compound 13 to the base is 1:1.1-1.5; the solvent selected includes but is not limited to one of toluene, xylene; the reaction temperature is room temperature.

[0017] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step d, compound 14 is prepared into compound 15 by decarboxylation reaction under acidic conditions by heating; the acid selected includes but is not limited to one of acetic acid, sulfuric acid, hydrochloric acid; the ratio of compound 14 to the acid is 1 mmol / 1 mL, and the reaction temperature is heated to reflux.

[0018] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step d, the reaction temperature is 100°C.

[0019] Further, the above-mentioned synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride, in step e, the base selected includes one of potassium tert-butoxide, sodium tert-butoxide; the molar ratio of compound 13 to the base is 1:1.5; the reaction temperature is initially -20°C, and then slowly rises to room temperature.

[0020] Further, the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the above, the step f, the target compound 1 is prepared by asymmetric hydrogenation reaction of compound 16 under the action of metal catalyst; the metal catalyst includes but is not limited to one of Pd, Ru, Rh.The amount of metal catalyst is usually one thousandth or less of the molar amount of substrate.

[0021] Compared with the prior art, the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride has the following beneficial effects: the compound 10 and the compound 11 are subjected to Michael addition reaction to obtain the compound 12, then the compound 13 is obtained by reacting with ethyl bromoacetate, then the compound 14 is obtained by condensation reaction under alkaline conditions, then the compound 15 is obtained by heating decarboxylation, then the compound 16 is obtained by Wittig reaction, and finally the target compound 1 is obtained by asymmetric hydrogenation and salification, in the whole synthesis route, the starting materials used are commercial raw materials, the relative price is low, there is no harsh reaction condition, no dangerous material such as lithium aluminum hydride is used, the yield of each step is high, the industrialized production is easy to realize, good economic benefits are obtained, and the application prospect is wide. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The product prepared in step a of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 2 The product prepared in step b of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 3 The product prepared in step c of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 4 The product prepared in step d of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 5 The product prepared in step e of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 6 The product prepared in step f of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride in the application has 1 H NMR spectrum; Figure 7 The product prepared in step f of the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride described in the present application 13 C NMR spectrum. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be described below in combination with examples, accompanying drawings Figure 1 , 2 , 3, 4, 5, 6, 7 and specific experimental data, apparently, the described embodiments are only part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the present application. Unless otherwise specified, the materials, methods and equipment used in the embodiments of the present application are conventional materials, methods and equipment in the technical field.

[0024] The synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride described in the present application has the following synthesis route: Synthesized according to the following steps: Step a: Example 1: In a 500 ml reaction bottle, compound 10 (53.6 g, 0.5 mol) was added and dissolved in 100 mL of ethanol, then compound 11 (96.2 g, 0.75 mol) was added and heated to reflux. The reaction was monitored by TLC. After the reaction was completed, the low boiling point substances were removed under reduced pressure, and the remaining material was column chromatographed. PE / EA=6:1 column chromatography obtained 82.37 g of colorless oily liquid, with a molar yield of 70%. 1 H NMR (400 MHz, DMSO-d6) δ 7.37-7.27 (m, 4H), 7.25-7.18 (m, 1H),4.07 (q,J = 7.1 Hz, 2H), 3.67 (s, 2H),2.47 (s, 2H), 1.20 (t,J = 7.1 Hz, 3H),1.17 (s, 6H). 1 The H NMR spectrum is shown in Figure 1 .

[0025] Example 2: In a 50 ml reaction flask, add compound 10 (1.07 g, 10.0 mmol), dissolve in 15 mL ethanol, after stirring evenly, add compound 11 (1.41 g, 11.0 mmol), heat to reflux reaction. TLC monitoring reaction. After the reaction is completed, the low boiling point material is removed under reduced pressure, and the residue is column chromatography. PE / EA=6:1 column chromatography to get colorless oily liquid 1.53 g, molar yield 65%.

[0026] Example 3: In a 50 ml reaction flask, add compound 10 (1.07 g, 10.0 mmol), dissolve in 15 mL methanol, after stirring evenly, add compound 11 (1.41 g, 11.0 mmol), heat to reflux reaction. TLC monitoring reaction. After the reaction is completed, the low boiling point material is removed under reduced pressure, and the residue is column chromatography. PE / EA=6:1 column chromatography to get colorless oily liquid 1.29 g, molar yield 55%.

[0027] Step b: Example 1: In a 1L reaction flask, add compound 12 (40.11 g, 170.4 mmol), dissolve in 400 ml DMF, add potassium carbonate (70.65 g, 511.2 mmol). After stirring evenly, add ethyl bromoacetate (56.91 g, 340.8 mmol), stir vigorously, react at room temperature for 36 hours. After the reaction is completed, quench the reaction with water until the remaining solid is dissolved. Extract with ethyl acetate for 3 times, combine the organic phase, dry with anhydrous sodium sulfate, concentrate column chromatography, PE / EA=15:1 column chromatography to get colorless oily liquid 35.6 g, molar yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 7.41-7.35 (m, 2H),7.32-7.24 (m, 2H), 7.23-7.16 (m, 1H), 4.08 (q,J = 7.2 Hz,2H), 3.95 (q,J = 7.2Hz, 2H), 3.84 (s, 2H), 3.29 (s, 2H), 2.54 (s, 2H), 1.22 (s, 6H), 1.19 (t,J =7.2 Hz, 3H), 1.11 (t,J = 7.1 Hz, 3H). 1 H NMR spectrum as Figure 2

[0028] ​Example 2: In a 250 mL reaction flask, compound 12 (4.71 g, 20.0 mmol) was dissolved in 40 ml DMF, potassium carbonate (8.29 g, 60.0 mmol) was added. After stirring uniformly, ethyl bromoacetate (6.68 g, 40.0 mmol) was added, and stirred vigorously, and reacted at room temperature for 36 hours. After the reaction was completed, the reaction was quenched with water until the remaining solid was dissolved. Ethyl acetate was extracted 3 times, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed with PE / EA = 15:1 to obtain 3.92 g of colorless oily liquid, with a molar yield of 61%.

[0029] Example 3: In a 250 mL reaction flask, compound 12 (4.71 g, 20.0 mmol) was dissolved in 40 ml acetonitrile, potassium carbonate (8.29 g, 60.0 mmol) was added. After stirring uniformly, ethyl bromoacetate (6.68 g, 40.0 mmol) was added, and stirred vigorously, and reacted at room temperature for 36 hours. After the reaction was completed, the reaction was filtered, the solid was washed with ethyl acetate 3 times, the filtrate was combined, concentrated, and column chromatography was performed with PE / EA = 15:1 to obtain 3.34 g of colorless oily liquid, with a molar yield of 52%.

[0030] Step c: Example 1: In a 500 ml three-necked reaction flask, potassium tert-butoxide (8.01 g, 71.4 mmol) was added, and nitrogen was exchanged, and toluene 200 ml was added and stirred uniformly. It was cooled to 0 oC, and compound 13 in toluene (15.30 g, 47.6 mmol, in 40 ml toluene) was slowly added dropwise, and after the dropwise addition was completed, it was kept at 0 oC for 1 h, and then the temperature was increased to room temperature and reacted. After TLC showed that the reaction was complete, it was cooled to 0 oC, and aqueous acetic acid was added, and the pH was adjusted to about 5, and EA was added for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed with PE / EA = 10:1 to obtain the target compound as a colorless liquid, 12.58 g, with a molar yield of 96%. 1 H NMR (400MHz, CDCl3) δ 7.44 – 7.24 (m, 5H), 4.27 (q,J = 7.1 Hz, 2H), 3.99 (d,J = 13.2Hz, 1H), 3.47 (d,J = 13.2 Hz, 1H), 3.31 (s, 1H), 3.20 (d,J = 18.2Hz, 1H),3.03 (d,J = 18.3 Hz, 1H), 1.52 (s, 3H), 1.34 (t,J = 7.2 Hz, 3H), 1.23 (s,3H)。 1 H NMR spectrum is shown in Figure 3 .

[0031] Example 2: In a 50ml three-necked flask, potassium tert-butoxide (337 mg, 3.0 mmol) was added, and the flask was purged with nitrogen. Toluene (10 ml) was added and stirred uniformly. The flask was cooled to 0°C, and a toluene solution of compound 13 (643 mg, 2.0 mmol, in 2 ml toluene) was added dropwise slowly. After the addition was completed, the reaction was maintained at 0°C for 1 h and then the temperature was raised to room temperature. TLC showed that the reaction was complete. The reaction mixture was cooled to 0°C, and an aqueous acetic acid solution was added to adjust the pH to about 5. EA was added for extraction, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 10:1) to obtain the target compound as a colorless liquid, 501 mg, with a molar yield of 91%.

[0032] Example 3: In a 50ml three-necked flask, sodium tert-butoxide (288 mg, 3.0 mmol) was added, and the flask was purged with nitrogen. Toluene (10 ml) was added and stirred uniformly. The flask was cooled to 0°C, and a toluene solution of compound 13 (643 mg, 2.0 mmol, in 2 ml toluene) was added dropwise slowly. After the addition was completed, the reaction was maintained at 0°C for 1 h and then the temperature was raised to room temperature. TLC showed that the reaction was complete. The reaction mixture was cooled to 0°C, and an aqueous acetic acid solution was added to adjust the pH to about 5. EA was added for extraction, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 10:1) to obtain the target compound as a colorless liquid, 468 mg, with a molar yield of 85%.

[0033] Example 4: In a 50ml three-necked flask, potassium tert-butoxide (337 mg, 3.0 mmol) was added, and the flask was purged with nitrogen. Xylene (10 ml) was added and stirred uniformly. The flask was cooled to 0°C, and a xylene solution of compound 13 (643 mg, 2.0 mmol, in 2 ml xylene) was added dropwise slowly. After the addition was completed, the reaction was maintained at 0°C for 1 h and then the temperature was raised to room temperature. TLC showed that the reaction was complete. The reaction mixture was cooled to 0°C, and an aqueous acetic acid solution was added to adjust the pH to about 5. EA was added for extraction, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 10:1) to obtain the target compound as a colorless liquid, 512 mg, with a molar yield of 93%.

[0034] Step d: Example 1: In a 100ml flask, compound 14 (5.5g, 20.0mmol) was added, and AcOH / H2O (15ml / 15ml) was added to dissolve. The reaction was heated to reflux. TLC was used to monitor the reaction. After the raw material was completely reacted, 50ml of water was added, followed by EA extraction three times. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 20:1) to obtain the target compound as a yellow liquid, 3.63g, with a molar yield of 90%. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.32 (m, 5H), 3.70 (s, 2H), 3.05 (s, 2H), 2.39 (s, 2H), 1.32 (s, 6H). 1 H NMR spectrum as Figure 4 shown.

[0035] Example 2: In a 25ml reaction flask, add compound 14 (551mg, 2.0mmol), add AcOH / H20 (2ml / 2ml) to dissolve, heat to reflux reaction. TLC monitor reaction, after the raw material reaction is complete, add 5ml water, followed by EA extraction 3 times, the organic phase is combined, the organic phase is dried with anhydrous sodium sulfate, concentrated column chromatography. PE / EA=20:1 column chromatography to obtain the target compound as a yellow liquid, 349mg, molar yield 86%.

[0036] Step e: Example 1: In a 50ml reaction flask, add methyl triphenyl phosphonium bromide (957mg, 2.68mmol), add tetrahydrofuran to dissolve, and protect with nitrogen gas exchange. Cool to 0oC, add potassium tert-butoxide (321mg, 2.86mmol), after adding, rise to room temperature reaction 1h. Then cool to -20oC, drop compound 15 tetrahydrofuran solution (363mg, 1.79mmol, in 2ml THF), after dropwise addition, keep the existing temperature reaction 30min, then rise to room temperature reaction. After the reaction is complete, quench the reaction by adding water, extract with EA 3 times, combine the organic phase, dry with anhydrous sodium sulfate, concentrate column chromatography, PE / EA=20:1 column chromatography to obtain the target compound as a colorless liquid, 338mg, molar yield 94%. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.32 (m,4H), 7.31-7.23 (m, 1H),4.88 (s, 1H), 4.83 (s, 1H), 3.59 (s, 2H), 3.27 (s, 2H), 2.43 (s, 2H), 1.18 (s, 6H). 1 H NMR spectrum as Figure 5 shown.

[0037] Example 2: In a 50ml reaction flask, add methyltriphenylphosphonium bromide (1.07 g, 3.0mmol), add tetrahydrofuran to dissolve, and protect with nitrogen replacement. Cool to 0oC, add potassium tert-butoxide (360mg, 3.2 mmol), after adding, rise to room temperature and react for 1h. Then cool to -20oC, drop tetrahydrofuran solution of compound 15 (406mg, 2.0 mmol, in 2ml THF), after dropping, keep the existing temperature for 30min, then rise to room temperature and react. After the reaction is complete, quench the reaction with water, extract with EA for 3 times, combine the organic phase, dry with anhydrous sodium sulfate, concentrate and column chromatography, PE / EA=20:1 column chromatography to obtain the target compound as a colorless liquid, 382 mg, molar yield 95%.

[0038] Example 3: In a 50ml reaction flask, add methyltriphenylphosphonium bromide (1.07 g, 3.0mmol), add tetrahydrofuran to dissolve, and protect with nitrogen replacement. Cool to 0oC, add sodium tert-butoxide (308 mg, 3.2 mmol), after adding, rise to room temperature and react for 1h. Then cool to -20oC, drop tetrahydrofuran solution of compound 15 (406 mg, 2.0 mmol, in 2ml THF), after dropping, keep the existing temperature for 30min, then rise to room temperature and react. After the reaction is complete, quench the reaction with water, extract with EA for 3 times, combine the organic phase, dry with anhydrous sodium sulfate, concentrate and column chromatography, PE / EA=20:1 column chromatography to obtain the target compound as a colorless liquid, 365 mg, molar yield 91%.

[0039] Step f: Example 1: In a 20ml reaction flask, deaerate tetrahydrofuran (1ml) with argon flow. Add Mandyphos ligand (10.5mg) and [Rh(nbd)Cl]2(98%, 4.6mg) (chloro norbornadiene rhodium(I) dimer). Stir the resulting orange catalyst solution at room temperature for 30min to form a catalyst solution. In a 250ml reaction flask, add compound 16 (2.01g, 10.0mmol), add tetrahydrofuran to dissolve, and replace with argon. Add the catalyst solution from the previous step to the reaction flask, replace with hydrogen, and react at room temperature overnight. After the reaction is complete, filter, remove low boiling point substances from the resulting solution under reduced pressure, and crystallize the resulting crude product with hydrochloric acid to obtain the target compound 1.29g, molar yield 86%. 1H NMR (400 MHz, DMSO-d6) δ 9.15-8.55 (m, 1H),2.85 – 2.72 (m, 1H), 2.52 –2.42 (m, 2H), 2.00 (dd, J = 12.9, 7.7 Hz, 1H),1.41(s, 3H), 1.40-1.34 (m, 1H), 1.32(s, 3H), 1.06 (d, J = 6.6 Hz, 3H)。 13 C NMR(151 MHz, DMSO-d6) δ 63.78, 49.32, 45.68, 30.69, 25.74, 24.89, 18.00。 1 H NMR spectrum as Figure 6 shown, 13 C NMR spectrum as Figure 7 shown.

[0040] Example 2: Compound 16 (2.01 g, 10.0 mmol) was dissolved in THF (20 ml) in a vessel. In a separate vessel, a solution of [RuCl(p-cymene){(R)-segphos]}Cl (3.0 mg) in THF (2 ml) was prepared. The solution of catalyst was added to the reaction flask containing compound 16 and the reaction was carried out under hydrogen gas displacement. After the reaction was completed, the filtrate was obtained by filtration, the solvent was removed by concentration, and the resulting crude product was salted with hydrochloric acid and crystallized to obtain the target compound 1.20 g with a molar yield of 80%.

[0041] In summary, the synthesis method of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to the present application can solve the problems in the prior art synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride. The reaction type of the entire synthesis route is safe, the yield of each step is high, and industrialized production can be easily realized.

[0042] The present application has many specific application approaches, and the above description is only a preferred embodiment of the present application. It should be noted that the above examples are only used to illustrate the present application and are not used to limit the protection scope of the present application. For ordinary skilled persons in the art, several improvements can be made without departing from the principles of the present application, and these improvements should also be considered as the protection scope of the present application.

Claims

1. A process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride, characterized in that, The synthetic route is as follows: Synthesis is carried out according to the following steps: Step a: Compound 10 and compound 11 are subjected to Michael addition reaction under solvent conditions to prepare compound 12; Step b: Compound 12 and ethyl bromoacetate are subjected to affinity substitution reaction under alkaline and solvent conditions to prepare compound 13; Step c: Compound 13 is subjected to condensation ring-closing reaction under alkaline and solvent conditions to prepare compound 14; Step d: Compound 14 is subjected to decarboxylation reaction under acidic conditions to prepare compound 15; Step e: Compound 15 is subjected to Wittig reaction under alkaline conditions to prepare compound 16; Step f: Compound 16 is subjected to asymmetric hydrogenation reaction to prepare target compound 1, i.e. (S)-2,2,4-trimethylpyrrolidine hydrochloride.

2. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized in that, In step a, the molar ratio of compound 10 to compound 11 is 1:1.1-1.2; the solvent used is an alcohol solvent.

3. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 2, characterized in that, In step a, the reaction temperature is heating reflux; the solvent used includes one of methanol and ethanol.

4. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized in that, In step b, the molar ratio of compound 12 to ethyl bromoacetate is 1:1.1-1.2; the base used is an inorganic base; the molar ratio of compound 12 to the base is 1:2.0-2.5; the solvent used is a polar solvent.

5. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 2, characterized by, In step b, the reaction temperature is room temperature; the base used is potassium carbonate; the solvent used is one of DMF and acetonitrile.

6. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized in that, In step c, the base used includes one of potassium tert-butoxide, sodium tert-butoxide and sodium methoxide; the molar ratio of compound 13 to the base is 1:1.1-1.5; the solvent used includes one of toluene and xylene; the reaction temperature is room temperature.

7. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized by, In step d, compound 14 is subjected to decarboxylation reaction under acidic conditions by heating to prepare compound 15; the acid used includes one of acetic acid, sulfuric acid and hydrochloric acid; the ratio of compound 14 to the acid is 1 mmol / 1 ml; the reaction temperature is heating reflux.

8. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 7, characterized by, In step d, the reaction temperature is 100°C.

9. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized by, In step e, the base used includes one of potassium tert-butoxide and sodium tert-butoxide; the molar ratio of compound 13 to the base is 1:1.5; the reaction temperature is initial temperature of -20°C, and then slowly rises to room temperature.

10. The process for the synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride according to claim 1, characterized in that, In step f, compound 16 is subjected to asymmetric hydrogenation reaction under the action of a metal catalyst to prepare target compound 1; the metal catalyst includes one of Pd, Ru and Rh.

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