Preparation method of L-vinyl glycine hydrochloride
A cost-effective synthesis of L-vinylglycine hydrochloride is achieved through a six-step process using L-serine as a starting material, addressing the high cost and accessibility issues of previous methods, with efficient and scalable production.
Patent Information
- Application Number
- CN202411313025.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-20
- Publication Date
- 2024-12-27
AI Technical Summary
Existing methods for synthesizing L-vinylglycine hydrochloride rely on expensive and difficult-to-obtain raw materials, leading to high costs and inefficiencies.
A synthesis method using L-serine as a raw material, involving methyl esterification, ketal exchange, hydrolysis, hydroxylamine reaction, red aluminum reduction, Wittig reaction, and final oxidation/deprotection steps to produce L-vinylglycine hydrochloride, utilizing easily accessible and cost-effective reagents and conditions.
The method achieves a high yield with low equipment requirements, safe operations, and is suitable for large-scale production without racemization, using common organic synthesis techniques.
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Figure CN119192008A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a synthesis method of L-vinylglycine hydrochloride and belongs to the field of organic synthesis. Background Art
[0002] L-vinylglycine hydrochloride, also known as (S)-2-aminobut-3-enoic acid hydrochloride, CAS: 75266-38-5, is a derivative of the peptide compound glycine. It can be used as a precursor of chiral catalysts, used in chiral organic synthesis reactions, and can also be used to synthesize biologically active compounds.
[0003] The literature [Tetrahedron, 1985, 41, 4347-4358] reported that (S)-3-benzyloxycarbonyl-5-oxo-4-vinyltetrahydro-1,3-oxazole was heated in an acidic solution to obtain L-vinylglycine hydrochloride with a yield of 52%. The raw materials for this reaction are expensive.
[0004] The literature [Chimia, 1998, 52, 272-283] reported that (S)-N-phthalylvinylglycine methyl ester was heated in hydrochloric acid to obtain L-vinylglycine hydrochloride with a yield of 88%. The raw materials in this process are expensive and difficult to obtain.
[0005] The literature [Journal of Organic Chemistry, 1980, 45, 4817-4820] reported that (S)-2-(benzyloxycarbonylamino)-3-butyric acid methyl ester was used as a raw material and the target product was synthesized by hydrolysis with hydrochloric acid with a yield of 88%. However, the raw material is difficult to synthesize and is expensive, and Cbz-L-methionine methyl ester needs to be obtained through multiple steps.
[0006] In summary, it is crucial to develop a synthetic route with cheap raw materials, easy access and high yield. Summary of the invention
[0007] In order to solve the problems existing in the above-mentioned prior art, the present invention provides a method for preparing L-vinylglycine hydrochloride, so as to overcome the problems that the raw materials are expensive and difficult to obtain in the prior art. Using L-serine as a raw material, methyl esterification / Boc protection obtains Boc-L-serine methyl ester, and then ketal exchange generates (R)-N-Boc-2,2-dimethyloxazolidine-4-methyl carboxylate, followed by hydrolysis / N,O-dimethylhydroxylamine reaction / red aluminum reduction to obtain (R)-4-formyl-2,2-dimethyl-3-oxazoline carboxylic acid tert-butyl ester, followed by Wittg reaction / p-toluenesulfonic acid hydrolysis to obtain (S)-2-(Boc amino)-2-vinylethanol, and finally oxidation / deprotection of Boc to obtain L-vinylglycine hydrochloride. The synthesis method provided by the present invention has easy raw materials, low requirements on equipment, easy monitoring, low cost and relatively safe.
[0008] The preparation method of L-vinylglycine hydrochloride of the present invention is represented by the following reaction equation:
[0009]
[0010] The steps include:
[0011] Step 1: L-serine reacts with thionyl chloride in methanol for esterification, followed by reaction with Boc2O / 2,2-dimethoxypropane exchange to generate intermediate A;
[0012] Step 2: hydrolysis / acidification of intermediate A, followed by reaction with N,O-dimethylhydroxylamine hydrochloride in the presence of n-butylphosphoric anhydride and triethylamine to produce intermediate B;
[0013] Step 3: Intermediate B reacts in the presence of red aluminum, and then reacts with methyltriphenylphosphonium bromide in the presence of a base to obtain intermediate C;
[0014] Step 4: Intermediate C is hydrolyzed under acid catalysis, then reacted with sodium chlorite under TEMPO catalysis, and finally deprotected with hydrochloric acid or hydrogen chloride to obtain L-vinylglycine hydrochloride.
[0015] Furthermore, in the first step of the above technical solution, the molar ratio of L-serine to thionyl chloride is 1:1.1-1.2.
[0016] Furthermore, in the second step of the above technical solution, the hydrolysis uses sodium hydroxide, potassium hydroxide or lithium hydroxide.
[0017] Furthermore, in the second step of the above technical solution, the molar ratio of intermediate A, N,O-dimethylhydroxylamine hydrochloride and n-butyl phosphoric anhydride is 1:1-1.2:1-1.2.
[0018] Furthermore, in the third step of the above technical solution, red aluminum is selected from 70% toluene solution; and the base is selected from potassium tert-butoxide or LDA.
[0019] Furthermore, in the third step of the above technical solution, the molar ratio of intermediate B to methyltriphenylphosphonium bromide is 1:1-2.
[0020] Furthermore, in the fourth step of the above technical solution, the acid is selected from p-toluenesulfonic acid or PPTS.
[0021] Furthermore, in the fourth step of the above technical solution, the molar ratio of intermediate C, TEMPO and sodium chlorite is 1:0.01-0.05:2.0.
[0022] Furthermore, as the most preferred technical solution, it can be decomposed into a more detailed six-step reaction operation, and the specific operation steps are as follows:
[0023] Step 1: L-serine reacts with thionyl chloride in methanol to obtain L-serine methyl ester hydrochloride, which is then dissolved in water and reacted with Boc anhydride through triethylamine acid binding to synthesize Boc-L-serine methyl ester, which is then cyclized with 2,2-dimethoxypropane to generate (R)-N-BOC-2,2-dimethyloxazolidine-4-carboxylic acid methyl ester;
[0024] Step 2, (R)-N-Boc-2,2-dimethyloxazolidine-4-carboxylic acid methyl ester is hydrolyzed in lithium hydroxide hydrate, followed by acidification to obtain the intermediate (R)-N-Boc-2,2-dimethyloxazolidine-4-carboxylic acid, which is then reacted with n-butyl phosphoric anhydride, triethylamine, and N,O-dimethylhydroxylamine hydrochloride to generate (R)-3-Boc-N-methoxy-N,2,2-trimethyloxazolidine-4-carboxamide;
[0025] Step 3, (R)-3-Boc-N-methoxy-N,2,2-trimethyloxazolidine-4-carboxamide is subjected to reduction reaction with red aluminum to obtain (R)-4-formyl-2,2-dimethyl-3-oxazolinecarboxylic acid tert-butyl ester;
[0026] Step 4, (R)-3-Boc-2,2-dimethyloxazolidine-4-carboxaldehyde, methyltriphenylphosphonium bromide and LDA react to obtain (S)-2,2-dimethyl-4-vinyloxazolidine-3-carboxylic acid tert-butyl ester;
[0027] Step 5, (S)-2,2-dimethyl-4-vinyloxazolidine-3-carboxylic acid tert-butyl ester is hydrolyzed under the action of p-toluenesulfonic acid to obtain (S)-2-(Boc-amino)-2-vinyl-ethanol;
[0028] Step 6, (S)-2-(Boc-amino)-2-vinyl-ethanol reacts with sodium chlorite under TEMPO catalysis to obtain Boc-L-vinylglycine, and then hydrogen chloride is added to remove Boc to obtain L-vinylglycine hydrochloride.
[0029] The reaction equation is expressed as:
[0030]
[0031] The raw materials of the invention are simple and easy to obtain, and the product is smoothly obtained after four-step reaction through common unit operations in organic synthesis. No racemization occurs during the reaction, the reaction conditions are mild, and the process is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1This is the HNMR spectrum of L-vinylglycine hydrochloride obtained in Example 9. DETAILED DESCRIPTION
[0033] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to these specific embodiments.
[0034] Example 1
[0035]
[0036] Dissolve L-serine (50g, 0.47mol) in methanol (250mL), and add thionyl chloride (67.9g, 0.57mol) at a temperature below 30℃. After the thionyl chloride is added, react at 45℃ for 2h and then at 60℃ for 2h. After the reaction is completed by TLC monitoring, add water (126mL) and triethylamine (120.4g, 1.18mol) after the methanol is dried, and measure pH = 8.5-9.0, then add ethyl acetate (100mL); start to add Boc anhydride (98.7g, 0.45mol), and react at room temperature for 5 hours after the addition is completed. After the reaction is completed by TLC monitoring, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and dry the filtrate to obtain 88.8g of oil.
[0037] Add 2,2-dimethoxypropane (168.5 g, 1.62 mol) and acetone (100 mL) to the oil and stir evenly. Then add boron trifluoride-ether (5.74 g, 0.04 mol) and heat to 50 ° C for 4 hours. After the reaction is completed by TLC monitoring, the (R)-N-BOC-2,2-dimethyloxazolidine-4-carboxylic acid methyl ester 105.73 g is obtained by vacuum distillation as an oily liquid with a total yield of 85.7%. 1 HNMR (400MHz, CDCl3): 4.44(dd,1H),4.20-4.10(m,1H),4.09-4.01(m,1H),3.77(s,3H),7.68(d,6H),1.43(s,9H).
[0038]
[0039] Example 4
[0040]
[0041] In an ice-water bath, add the product from the previous step (50 g, 0.19 mol), methanol (50 mL) and water (100 mL) at a temperature of 5°C to 10°C, and mix and stir. Add a mixed solution of lithium hydroxide hydrate (9.3 g, 0.22 mol) and 85 g of water, stir and react at 15°C overnight, and monitor the reaction by TLC. Add MTBE for extraction, add 3N hydrochloric acid at 10 to 15°C to adjust the pH to 2-3, and stand to separate. MTBE is evaporated under reduced pressure to obtain 43 g of the intermediate.
[0042] Then, under nitrogen protection, dichloromethane (360mL) and 50% n-butylphosphonic anhydride-ethyl acetate solution (151.4g, 0.2102mol) were added to the reactor and stirred for 20min. The dichloromethane solution (43mL) of the intermediate was slowly added dropwise, and the temperature was controlled at 30-35℃ for 2h. After the reaction was completed by TLC monitoring, N,O-dimethylhydroxylamine hydrochloride (20.5g, 0.21mol) was added in batches at a temperature of 5-10℃. The temperature was controlled to be less than 15℃, and triethylamine (23g, 0.2275mol) was added dropwise. The temperature was raised to 22-28℃ overnight, and the reaction was completed by TLC monitoring. After cooling to 5-10°C and adjusting pH to 2-3 with hydrochloric acid, the mixture was separated and washed with water. The dichloromethane phase was evaporated under reduced pressure and petroleum ether (20 mL) was added once. Petroleum ether (230 mL) was added and the temperature was lowered to 20°C. The mixture was kept for 30 min and then cooled to -15°C and stirred overnight. The filter cake was rinsed once with -15°C petroleum ether and dried to obtain 38 g of an off-white solid (R)-3-Boc-N-methoxy-N,2,2-trimethyloxazolidine-4-carboxamide with a yield of 68.4%. 1 HNMR(400MHz,DMSO-d6):4.72-4.68(m,1H),4.21-4.14(m,1H),3.85-3.79(m,1H), 3.68-3.66(m,3H),3.133.11(m,3H),1.54(s,3H),1.45-1.41(m,3H),1.38(s,9H).
[0043]
[0044] Example 6
[0045]
[0046] Under nitrogen protection, add (R)-3-Boc-N-methoxy-N,2,2-trimethyloxazolidine-4-carboxamide (20g, 0.0694mol) and tetrahydrofuran (60mL) into the reaction bottle, stir and dissolve. Control the temperature at 0-5℃ and add 70% red aluminum toluene solution (30g). TLC monitoring the next day shows that there is no residual raw material. Control the temperature at 5-10℃, add ethyl acetate (110mL) dropwise, and stir at 0℃ for 1h after dripping. Add ethyl acetate (50mL), then slowly add saturated ammonium chloride aqueous solution (80g), stir for 30min and filter. Wash the filter cake twice with ethyl acetate (20mL) to obtain 15.05g of (R)-4-formyl-2,2-dimethyl-3-oxazolinecarboxylic acid tert-butyl ester, with a yield of 94.6%. 1 HNMR(400MHz, CDCl3):9.72(d,1H),4.49-3.95(m,3H),1.74-1.57(m,3H),1.43(s,9H).
[0047] Example 7
[0048]
[0049] Under nitrogen protection, tetrahydrofuran (160mL) and methyltriphenylphosphonium bromide (29.7g, 0.083mol) were added and stirred at room temperature. Cooled to -10°C, 2.0mol / L LDA (43.5mL) solution was slowly added dropwise. The reaction solution was further cooled to -35°C, and a solution consisting of the product from the previous step (13.3g, 0.058mol) and tetrahydrofuran (18mL) was added dropwise at a temperature not exceeding -30°C. The reaction was allowed to react overnight at room temperature, and the reaction was monitored by TLC. Saturated ammonium chloride solution (35mL) was added dropwise to quench, stirred for 20min, and separated. The aqueous phase was extracted with MTBE, washed, dried, and spin-dried, and the (S)-2,2-dimethyl-4-vinyloxazolidine-3-carboxylic acid tert-butyl ester was obtained by oil pump distillation to obtain 12g of tert-butyl ester with a yield of 90.8%. 1 HNMR(400MHz, CDCl3):5.83-5.81(m,1H),5.19-5.15(m,2H),4.10-4.04(m,1H),3.75-3.51(m,2H),1.59(s,6H),1.48(d,9H).
[0050] Example 8
[0051]
[0052] Add the product obtained in Example 7 (4.95g, 0.0218mol) and methanol (25mL), cool to 10℃-15℃, add p-toluenesulfonic acid (1.88g, 0.0109mol), then heat to room temperature and stir to react, and monitor the reaction by TLC. Dry to obtain a yellow oil. Add 30mL of MTBE and saturated sodium bicarbonate solution to adjust pH to 6.8-7.5, stir and separate. Extract the aqueous phase with MTBE, wash the combined organic phases with saturated brine, and rotary evaporate to obtain 3.57g of a yellow oil (S)-2-(BOC-amino)-2-vinyl-ethanol, with a yield of 87.55%. 1 HNMR (400MHz, CDCl3): 7.66(s,1H),5.83-5.81(m,1H),5.23-5.19(m,2H),4.94(s,1H),4.28-4.24(m,1H),3.92-3.67(q,2H),1.44(s,9H).
[0053] Example 9
[0054]
[0055] The product obtained in Example 8 (3.57 g, 0.019 mol), water (36 mL), sodium dihydrogen phosphate (2.29 g, 0.019 mol) and sodium hydrogen phosphate (1.78 g, 0.0126 mol, 0.66 eq) were added, and the temperature was raised to 35°C. Then TEMPO (0.6 g, 3.817 mmol, 0.2 eq) was added, and then sodium chlorite solid (3.45 g, 0.038 mol) was added in batches to 13% sodium hypochlorite aqueous solution (0.11 g, 0.1895 mmol, 0.01 eq) and dripped into the reaction solution. The temperature was raised to 40-45°C for 2 h, and the reaction was completed by TLC monitoring.
[0056] Cool to 5-10°C, adjust pH to 2-3 with dilute sulfuric acid. Extract the product with MTBE, combine the organic phases, wash with saturated brine, spin dry, add MTBE (10 mL), and extract with saturated sodium bicarbonate. Combine the aqueous phases and wash impurities with MTBE. Adjust the pH of the aqueous phase to 2-3 with dilute sulfuric acid, and extract the product with MTBE. Wash with saturated brine, dry and filter with anhydrous sodium sulfate, spin dry to obtain 3.69 g of the product as an oil, then add 30 mL of dichloromethane and stir at room temperature to dissolve, cool to 3-5°C, pass HCl to remove Boc, and solid precipitate. After the reaction is completed by TLC monitoring, concentrate under reduced pressure, add 30 mL of MTBE, solid precipitate, filter and dry to obtain 2.28 g of L-vinylglycine hydrochloride, with a yield of 86.78%. 1HNMR(400MHz,CD3OD):6.09-6.00(m,1H),5.64-5.57(m,2H),4.63-4.60(m,1H).
[0057] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for preparing L-vinylglycine hydrochloride, characterized in that: The steps include: Step 1: L-serine reacts with thionyl chloride in methanol for esterification, followed by reaction with Boc2O / 2,2-dimethoxypropane exchange to generate intermediate A; Step 2: hydrolysis / acidification of intermediate A, followed by reaction with N,O-dimethylhydroxylamine hydrochloride in the presence of n-butylphosphoric anhydride and triethylamine to produce intermediate B; Step 3: Intermediate B reacts in the presence of red aluminum, and then reacts with methyltriphenylphosphonium bromide in the presence of a base to obtain intermediate C; Step 4: Intermediate C is hydrolyzed under acid catalysis, then reacted with sodium chlorite under TEMPO catalysis, and finally deprotected with hydrochloric acid or hydrogen chloride to obtain L-vinylglycine hydrochloride.
2. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the first step, the molar ratio of L-serine to thionyl chloride is 1:1.1-1.
2.
3. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the second step, the hydrolysis uses sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the second step, the molar ratio of intermediate A, N,O-dimethylhydroxylamine hydrochloride and n-butyl phosphoric anhydride is 1:1-1.2:1-1.
2.
5. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the third step, red aluminum is selected from 70% toluene solution; and the base is selected from potassium tert-butoxide or LDA.
6. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the third step, the molar ratio of the intermediate B to methyltriphenylphosphonium bromide is 1:1-2.
7. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the fourth step, the acid is selected from p-toluenesulfonic acid or PPTS.
8. The method for preparing L-vinylglycine hydrochloride according to claim 1, characterized in that: In the fourth step, the molar ratio of intermediate C, TEMPO and sodium chlorite is 1:0.01-0.05:2.0.