Preparation method of 4-amino-5-hexenoic acid hydrochloride
Through a new seven-step reaction route, 4-amino-5-hexenoic acid hydrochloride was successfully prepared using 1,4-butanediol as raw material, which solved the problems of cumbersome steps, low yield and high cost in the prior art, and achieved high purity and high yield preparation effects, which were suitable for industrial production.
Patent Information
- Application Number
- CN202411884006.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-20
- Publication Date
- 2025-03-28
AI Technical Summary
In the prior art, the preparation steps of 4-amino-5-hexenoic acid hydrochloride are complicated, the yield is low, the cost is high, and it is not suitable for industrial production.
Using 1,4-butanediol as raw material, 4-amino-5-hexenoic acid hydrochloride is obtained through seven-step reactions including tert-butyldimethylchlorosilane monoprotection, Swern oxidation reaction, condensation reaction, deprotection, oxidation and hydrogen chloride deprotection.
This method is easy to obtain raw materials, cheap, simple process, few purification steps, can reach 99% purity, and is suitable for industrial production.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing 4-amino-5-hexenoic acid hydrochloride, and belongs to the technical field of pharmaceutical intermediate synthesis. Background Art
[0002] γ-Aminobutyric acid (GABA) is a key inhibitory neurotransmitter in the central nervous system that maintains the balance of excitation and inhibition in mammals. The release of GABA into the synaptic cleft activates ion channels, resulting in inhibition of nerve impulses. Vigabatrin hydrochloride is a derivative of γ-aminobutyric acid and a selective, irreversible GABA transaminase inhibitor. It is often used as a drug for the treatment of various mental and central nervous system diseases, such as epilepsy and infantile spasms. Vigabatrin has a higher bioavailability and a longer half-life, and the effective duration of action of vigabatrin is significantly longer than the half-life. Vigabatrin plays an important role in the treatment of epilepsy that is ineffective with other anti-epileptic drugs.
[0003] At present, there are few reports on the synthesis route of 4-amino-5-hexenoic acid hydrochloride in the literature. Among them, the literature [Organic and Biomolecular Chemistry, 2024, 22, 1027-1033] uses 2-vinylcyclopropane-1,1-dicarboxylic acid dimethyl ester as raw material, and obtains 4-amino-5-hexenoic acid hydrochloride by decarboxylation and ring opening. The raw materials of this method are not easy to obtain, the price is high, and it is not suitable for industrial production. The reaction equation is expressed as follows:
[0004]
[0005] The document [Tetrahedron Letters, 1994, 35, 3049-3050] uses 6-formyloxy-4-hexenoic acid ethyl ester as a raw material and obtains 4-amino-5-hexenoic acid hydrochloride through three steps. The raw materials of this method are not easy to obtain, trichloroacetonitrile is a dangerous substance with strong irritation, and the product needs to be purified by column chromatography after each step. The total yield is low, the steps are cumbersome, the cost is high, and it is not convenient for industrial scale-up. The reaction equation is as follows:
[0006]
[0007] In order to solve the defects of the prior art in preparing the non-natural amino acid, such as complicated steps, low yield and high cost, the present invention provides a method for preparing the non-natural amino acid. The method of the present invention has a higher yield and a simpler process when preparing the target product. Summary of the invention
[0008] In order to overcome the defects of the above-mentioned technology, the present invention discloses a preparation method of 4-amino-5-hexenoic acid hydrochloride. The method uses 1,4-butanediol as a raw material, adopts tert-butyldimethylsilyl chloride to monoprotect to obtain 4-(tert-butyldimethylsilyl) oxo-1-butanol, and obtains 4-(tert-butyldimethylsilyloxy) n-butyraldehyde by Swern oxidation reaction, and obtains 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide by Schiff base with p-toluenesulfonamide, and reacts with vinyl Grignard reagent, followed by deprotection / Boc protection to obtain (6-hydroxyhex-1-ene-3-yl) tert-butyl carbamate, and oxidizes in the presence of catalyst TEMPO to obtain Boc-4-amino-4-vinylbutyric acid, and finally deprotects with hydrogen chloride to obtain 4-amino-5-hexenoic acid hydrochloride. The raw materials of the present invention are easy to obtain and cheap, the equipment requirements are not high, the process is coherent, the purification steps are few, the product quality is high, and it meets the industrial production standards.
[0009] The preparation method of 4-amino-5-hexenoic acid hydrochloride of the present invention has a reaction route as follows:
[0010]
[0011] The method for preparing 4-amino-5-hexenoic acid hydrochloride of the present invention comprises the following steps:
[0012] Step A: using 1,4-butanediol and tert-butyldimethylsilyl chloride as raw materials, reacting in an organic solvent in the presence of a non-nucleophilic base to obtain 4-(tert-butyldimethylsilyl)oxy-1-butanol;
[0013] Step B: oxidizing 4-(tert-butyldimethylsilyl)oxy-1-butanol in the presence of oxalyl chloride and dimethyl sulfoxide to obtain 4-(tert-butyldimethylsilyloxy)-n-butyraldehyde;
[0014] Step C: condensing 4-(tert-butyldimethylsilyloxy)-butylaldehyde and p-toluenesulfonamide in the presence of anhydrous ferric chloride to obtain 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide;
[0015] Step D: reacting 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide with a vinyl Grignard reagent, then adding acid for deprotection and adjusting to alkalinity, and reacting with di-tert-butyl dicarbonate to obtain tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate;
[0016] Step E: reacting tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate with sodium hypochlorite solution under TEMPO catalysis to obtain Boc-4-amino-4-vinylbutyric acid;
[0017] Step F: Boc-4-amino-4-vinylbutyric acid is treated in an organic solvent by passing hydrogen chloride gas to obtain 4-amino-5-hexenoic acid hydrochloride.
[0018] Furthermore, in the above preferred embodiment, the non-nucleophilic base in step A is selected from sodium tert-butoxide, potassium tert-butoxide or 60% NaH. The organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
[0019] Furthermore, in the above preferred embodiment, the molar ratio of 1,4-butanediol, tert-butyldimethylchlorosilane and non-nucleophilic base in step A is 1.4-1.5:1.0:1.0-1.05.
[0020] Furthermore, in the above preferred embodiment, the molar ratio of 4-(tert-butyldimethylsilyl)oxy-1-butanol, oxalyl chloride and dimethyl sulfoxide in step B is 1:1-1.2:2-2.4.
[0021] Furthermore, in the above preferred embodiment, the molar ratio of 4-(tert-butyldimethylsilyloxy)butyraldehyde, anhydrous ferric chloride and p-toluenesulfonamide in step C is 1:0.05:1.2-1.25.
[0022] Furthermore, in the above preferred embodiment, the vinyl Grignard reagent in step D is selected from vinyl magnesium chloride or vinyl magnesium bromide.
[0023] Furthermore, in the above preferred embodiment, the molar ratio of 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide, vinyl Grignard reagent and di-tert-butyl dicarbonate in step D is 1:1.1-1.2:0.9-0.95.
[0024] Furthermore, in the above preferred embodiment, the molar ratio of (6-hydroxyhex-1-en-3-yl)carbamic acid tert-butyl ester, TEMPO and sodium hypochlorite in step E is 1:0.005-0.01:2.5-3.0; and the concentration of sodium hypochlorite is selected to be greater than 8.0%.
[0025] Furthermore, in the above preferred embodiment, the molar ratio of Boc-4-amino-4-vinylbutyric acid to hydrogen chloride in step F is 1:2.0-9.0. The organic solvent is selected from MTBE, ethyl acetate or acetone.
[0026] Advantageous Effects of the Invention
[0027] The present invention uses low-cost raw materials and synthesizes in seven consecutive steps without column chromatography purification. The target product with high purity and high yield can be obtained through specific purification steps such as alkali washing, back extraction and acid salt formation, and the purity can eventually reach more than 99%. The whole process has higher operability, stronger practicality and lower cost in the actual scale-up production process. DETAILED DESCRIPTION
[0028] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0029] Example 1
[0030]
[0031] Add 126.2 g (1.4 mol) of 1,4-butanediol and 800 mL of tetrahydrofuran to the reaction bottle, cool to 0°C, add 96.1 g (1 mol) of sodium tert-butoxide in batches, stir for 30 minutes, slowly add 150.7 g (1 mol) of tert-butyldimethylsilyl chloride dropwise, add saturated aqueous ammonium chloride solution to quench, let stand and separate, extract the aqueous phase with MTBE, combine the organic phases, add saturated brine to wash the organic phase, and concentrate in vacuo to obtain 4-(tert-butyldimethylsilyl)oxy-1-butanol, which is used directly in the next step without purification. 1 H NMR(400MHz, CDCl3):3.64-3.54(m,4H),1.63-1.51(m,4H),0.83(s,9H),-0.00(s,6H).
[0032] Example 2
[0033]
[0034] Add 126.2 g (1.4 mol) of 1,4-butanediol and 800 mL of tetrahydrofuran to the reaction bottle, cool to 0°C, add 40 g (1 mol) of 60% NaH in batches, stir for 30 minutes, slowly add 150.7 g (1 mol) of tert-butyldimethylsilyl chloride dropwise, add saturated aqueous ammonium chloride solution to quench, let stand and separate, extract the aqueous phase with MTBE, combine the organic phases, wash the organic phase with saturated brine, and concentrate in vacuo to obtain 204.4 g of 4-(tert-butyldimethylsilyl)oxo-1-butanol, which is used directly in the next step without purification.
[0035] Example 3
[0036]
[0037] Under nitrogen protection, oxalyl chloride 152.3g (1.2mol) and dichloromethane 1000mL were added to the reaction bottle, the temperature was lowered to -50°C, DMSO 156.3g (2.0mol) and dichloromethane 100mL mixed solvent were added dropwise, followed by the mixed solution of 4-(tert-butyldimethylsilyl)oxo-1-butanol 204.4g (1mol) and dichloromethane 200mL obtained in Example 2, -40 to -50°C for 1 hour, triethylamine 222.6g (2.2mol) was added dropwise, the temperature was slowly raised to room temperature for 2 hours, saturated ammonium chloride was added for quenching, the organic phase was washed with 5% potassium bicarbonate aqueous solution and water, respectively, and concentrated in vacuo, dichloromethane was dehydrated to a moisture content of <0.1% to obtain 4-(tert-butyldimethylsilyloxy)butyraldehyde 198.3g, a yield of 98%, which was directly used in the next step reaction. 1 H NMR (400MHz, CDCl3): 9.75 (s, 1H), 3.61 (t, 2H), 2.46 (td, 2H), 1.87-1.72 (m, 2H), 0.84 (s, 9H), -0.00 (s, 6H).
[0038] Example 4
[0039]
[0040] 198.3 g (0.98 mol) of 4-(tert-butyldimethylsilyloxy)-butyraldehyde obtained in Example 3 and 1200 mL of dichloromethane were added to the reaction flask, and 8 g of anhydrous ferric chloride, 312.8 g of anhydrous copper sulfate and 118 g of anhydrous magnesium sulfate were added in sequence. 400 mL of a solution of p-toluenesulfonamide (1.18 mol) mixed with dichloromethane was added dropwise at room temperature, the temperature was raised to 40°C, the reaction was performed for 6 hours, the temperature was lowered to room temperature, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated in vacuo to remove dichloromethane, replaced with MTBE, and washed with sodium bicarbonate aqueous solution. The precipitated solid was filtered out, the organic phase was concentrated in vacuo, and n-heptane was added for recrystallization to obtain 327.6 g of 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide, HPLC normal phase column 99.3%, yield 94%. 1 HNMR(400MHz, CDCl3):7.47-7.43(m,2H),7.25-7.21(m,2H),3.81-3.77(m,2H) ,2.46(s,3H),2.39-2.44(m,2H),1.97-1.91(m,2H),0.89(s,9H),0.09(s,6H).
[0041] Example 5
[0042]
[0043] Under nitrogen protection, 163.6 g (0.46 mol) of 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide and 1200 mL of tetrahydrofuran were added to the reaction bottle, the temperature was lowered to -50°C, 66.7 g (0.47 mol) of boron trifluoride-ether was added dropwise, 575 mL (0.575 mol) of 1.0 M vinylmagnesium bromide was added dropwise, the temperature was slowly raised to 10°C, the reaction was carried out for 2 hours, saturated ammonium chloride was added to quench, the layers were separated at rest, the aqueous phase was extracted with MTBE, the organic phases were combined, washed with saturated brine, the temperature was raised to 45°C, 6 M hydrogen chloride / trifluoroethanol solution was added dropwise, and the reaction was kept warm for 2 hours. The mixture was cooled to 0°C and filtered. The filter cake was put into a reaction bottle. An aqueous sodium carbonate solution was added to adjust the pH to 10-12. A mixed solution of 94.9 g (0.435 mol) of di-tert-butyl dicarbonate and MTBE was added dropwise. The pH was adjusted to 10-12 with an aqueous sodium carbonate solution. After reacting at room temperature for 6 hours, the mixture was allowed to stand and the layers were separated. The aqueous phase was extracted with MTBE. The organic phases were combined and washed with saturated brine. The organic phase was concentrated in vacuo to obtain 79.8 g of tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate, which was used directly in the next step with a yield of 80.6%. 1 H NMR(400MHz, CDCl3):5.77-7.68(m,1H),5.16-5.06(m,2H),4.63(t,1H),4.08 (d,1H),3.64-3.60(m,2H),2.41-2.37(m,1H),1.61-1.47(m,4H),1.41(s,9H).
[0044] Example 6
[0045]
[0046] Under nitrogen protection, 163.6 g (0.46 mol) of 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide and 1200 mL of 2-methyltetrahydrofuran were added to the reaction bottle, the temperature was lowered to -50°C, 66.7 g (0.47 mol) of boron trifluoride-ether was added dropwise, 288 mL (0.575 mol) of 2.0 M vinyl magnesium chloride was added dropwise, the temperature was slowly raised to 10°C, the reaction was carried out for 2 hours, saturated ammonium chloride was added to quench, the layers were separated at rest, the aqueous phase was extracted with 2-methyltetrahydrofuran, the organic phases were combined, washed with saturated brine, the temperature was raised to 45°C, 6 M hydrogen chloride / trifluoroethanol solution was added dropwise, and the reaction was kept warm for 2 hours. The mixture was cooled to 0°C and filtered. The filter cake was put into a reaction bottle. An aqueous sodium carbonate solution was added to adjust the pH to 10-12. A mixed solution of 94.9 g (0.435 mol) of di-tert-butyl dicarbonate and 2-methyltetrahydrofuran was added dropwise. The pH was adjusted to 10-12 with an aqueous sodium carbonate solution. After reacting at room temperature for 6 hours, the mixture was allowed to stand and the layers were separated. The aqueous phase was extracted with MTBE. The organic phases were combined and washed with saturated brine. The organic phase was concentrated in vacuo to obtain 81.5 g of tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate, which was used directly in the next step with a yield of 82.3%.
[0047] Example 7
[0048]
[0049] Under nitrogen protection, add 75.4g (0.35mol) of tert-butyl (6-hydroxyhex-1-ene-3-yl)carbamate and 600mL of dichloromethane to the reaction bottle, add sodium acetate and acetic acid to adjust pH=6.0, add 919.6g (1.05mol) of 8.5% sodium hypochlorite aqueous solution dropwise, during which sodium hydroxide or acetic acid is used to maintain pH=5.5-6.5. Let stand for stratification, wash with water and saturated salt water, and concentrate the organic phase in vacuo to obtain 74.9g of Boc-4-amino-4-vinylbutyric acid with a yield of 93.4%. 1 H NMR (400MHz, CDCl3): 11.64(s,1H),5.74(ddd,1H),5.15(dd,2H),4.71-4.67(m,1H),4.08(d,1H),2.41(t,2H),1.91-1.85(m,2H),1.43(s,9H).
[0050] Example 8
[0051]
[0052] To the reaction flask, 74.9 g (0.327 mol) of Boc-4-amino-4-vinylbutyric acid and 600 mL of dichloromethane were added, the temperature was lowered to 0°C, hydrogen chloride was introduced, and no Boc-4-amino-4-vinylbutyric acid remained after TLC detection. The reaction was concentrated in vacuo, MTBE was added for replacement, MTBE was added for pulping, the reaction mixture was filtered, and the filter cake was rinsed with MTBE to obtain 48.8 g of 4-amino-5-hexenoic acid hydrochloride, HPLC (CAD) 99.1%, and a yield of 90.1%. 1 H NMR(400MHz,DMSO-d6):11.63(s,1H),8.48(s,3H),5.75(ddd,1H),5.33-5.24 (m,2H),3.60(s,1H),2.29-2.19(m,2H),1.99-1.88(m,1H),1.79-1.68(m,1H).
[0053] The description of the above embodiments is only used to help understand the method of the present invention and its core idea. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will conform to the widest range consistent with the principles and novel features disclosed herein.
Claims
1. A method for preparing 4-amino-5-hexenoic acid hydrochloride, characterized in that: The steps include: Step A: using 1,4-butanediol and tert-butyldimethylsilyl chloride as raw materials, reacting in an organic solvent in the presence of a non-nucleophilic base to obtain 4-(tert-butyldimethylsilyl)oxy-1-butanol; Step B: oxidizing 4-(tert-butyldimethylsilyl)oxy-1-butanol in the presence of oxalyl chloride and dimethyl sulfoxide to obtain 4-(tert-butyldimethylsilyloxy)-n-butyraldehyde; Step C: condensing 4-(tert-butyldimethylsilyloxy)-butylaldehyde and p-toluenesulfonamide in the presence of anhydrous ferric chloride to obtain 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide; Step D: reacting 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide with a vinyl Grignard reagent, then adding acid for deprotection and adjusting to alkalinity, and reacting with di-tert-butyl dicarbonate to obtain tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate; Step E: reacting tert-butyl (6-hydroxyhex-1-en-3-yl)carbamate with sodium hypochlorite solution under TEMPO catalysis to obtain Boc-4-amino-4-vinylbutyric acid; Step F: Boc-4-amino-4-vinylbutyric acid is treated in an organic solvent by passing hydrogen chloride gas to obtain 4-amino-5-hexenoic acid hydrochloride.
2. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, wherein: In step A, the non-nucleophilic base is selected from sodium tert-butoxide, potassium tert-butoxide or 60% NaH.
3. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step A, the molar ratio of 1,4-butanediol, tert-butyldimethylchlorosilane and non-nucleophilic base is 1.4-1.5:1.0:1.0-1.
05.
4. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step B, the molar ratio of 4-(tert-butyldimethylsilyl)oxy-1-butanol, oxalyl chloride and dimethyl sulfoxide is 1:1-1.2:2-2.
4.
5. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step C, the molar ratio of 4-(tert-butyldimethylsilyloxy)butyraldehyde, anhydrous ferric chloride and p-toluenesulfonamide is 1:0.05:1.2-1.
25.
6. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step D, the vinyl Grignard reagent is selected from vinyl magnesium chloride or vinyl magnesium bromide.
7. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step D, the molar ratio of 4-(tert-butyldimethylsilyloxy)-butyl-methylbenzenesulfonamide, vinyl Grignard reagent and di-tert-butyl dicarbonate is 1:1.1-1.2:0.9-0.
95.
8. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step E, the molar ratio of (6-hydroxyhex-1-en-3-yl)carbamic acid tert-butyl ester, TEMPO and sodium hypochlorite is 1:0.005-0.01:2.5-3.0; and the concentration of sodium hypochlorite is selected to be greater than 8.0%.
9. The method for preparing 4-amino-5-hexenoic acid hydrochloride according to claim 1, characterized in that: In step F, the molar ratio of Boc-4-amino-4-vinylbutyric acid to hydrogen chloride is 1:2.0-9.0.