Preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester

Abstract

The invention relates to the technical field of synthesis of organic compounds, and discloses a preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester, which comprises the following steps: step 1, synthesis of (2S, 4R)-4-p-toluenesulfonyloxy-1, 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester (2): (2S, 4R)-4-hydroxy-1, 2, 4-triazole-2-methyl ester (3) is prepared from (2S, 4R)-4-hydroxy-1, 2, 4-triazole-2-methyl ester and (2S, 4R)-4-p-toluenesulfonyloxy-1, 2-pyrroline dicarboxylic acid-1- The preparation method comprises the following steps: dissolving 1-tert-butyl-2-methyl 2-pyrroline dicarboxylic acid-1-tert-butyl ester-2-methyl ester in dichloromethane; according to the method, (2S, 4R)-4-hydroxy-1, 2-pyrroline dicarboxylic acid-1-tert-butyl-2-methyl ester which is cheap and easy to obtain in the market is adopted as a raw material, after p-benzoylation and acetylation are performed, hydroxyl of the raw material is converted from trans form to cis form, chiral conversion is performed, and finally the target product is synthesized. The used acetate replaces benzoate, the raw materials are cheaper, and the generated by-product acetic acid is more environment-friendly than benzoic acid, so that the method is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, in particular to a method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester. Background Art

[0002] N-Boc-cis-4-hydroxy-L-proline methyl ester is an important chemical substance with wide applications in the fields of medicine and biochemistry. It can be used as a pharmaceutical intermediate, biochemical reagent, and chiral pharmaceutical chemical intermediate, and can be used in the synthesis of antibody-drug conjugates (ADCs).

[0003] Torino, Domenica (Bioorganic & Medicinal Chemistry 2009, 17 (1), 251-259) et al. studied the use of Mitsunobu reaction to carry out cis-trans isomerization of hydroxyl groups. The reagent used was an azo compound (diethyl azodicarboxylate). The reagent cost of this method was relatively high, and more by-products were generated. The post-processing was relatively troublesome. In addition, the azo compound was unstable and easily exploded after friction or collision. Wang Yongcan et al. (CN 101863817 A) used benzoate as a reagent to synthesize the target product. Each step of the reaction was simple, the cost was low, and the product yield and purity were both ideal. However, the by-products generated in the synthesis steps were not environmentally friendly. Summary of the invention

[0004] The purpose of the present invention is to solve the problems existing in the prior art and to propose a method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] The preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester comprises the following steps:

[0007] Step 1, synthesis of (2S, 4R)-4-p-toluenesulfonyloxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (2): dissolving (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester in dichloromethane, maintaining the temperature below 5°C, adding triethylamine and p-toluenesulfonyl chloride, maintaining the temperature and continuing the reaction to obtain a reaction mixture, and sequentially washing, drying, distilling and recrystallizing the reaction mixture to obtain intermediate product No. 2;

[0008] Step 2, synthesis of (2S, 4R)-4-acetoxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (3): Mix the intermediate product No. 2 and sodium acetate, add dimethyl sulfoxide dropwise, heat and stir to react, then cool to room temperature, dilute the reaction mixture, wash, dry and distill in sequence to obtain an oily substance, and recrystallize the oily substance to obtain the intermediate product No. 3;

[0009] Step 3, synthesis of N-Boc-cis-4-hydroxy-L-proline methyl ester (4): the intermediate product No. 3 is mixed with methanol, potassium carbonate is added, and the reaction is stirred at room temperature. The reaction solution is adjusted from alkaline to neutral, and then the methanol is evaporated. Extraction, drying and distillation are performed in sequence to obtain an oily substance, which is recrystallized to obtain the intermediate product No. 4.

[0010] Preferably, in the step 1, the molar ratio of (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester, triethylamine and p-toluenesulfonyl chloride is 1:1.10-1.15:1.0-1.5, and the reaction is continued for 3 hours.

[0011] Preferably, the reaction mixture is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is recrystallized with n-hexane to obtain intermediate product No. 2.

[0012] Preferably, the dilute hydrochloric acid is 5% dilute hydrochloric acid.

[0013] Preferably, in the step 2, the molar ratio of the intermediate product No. 2 to sodium acetate is 1:2; the mixture is heated to 90° C. and stirred for a reaction time of 6-7 hours.

[0014] Preferably, the reaction mixture is diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase is dried over anhydrous sodium sulfate, the solvent is distilled off to obtain an oily substance, and the intermediate product No. 3 is obtained by recrystallization with n-hexane.

[0015] Preferably, in step three, the molar ratio of intermediate product No. 3 to potassium carbonate is 1:1; and the reaction time under stirring at room temperature is 0.5-3 hours.

[0016] Preferably, after stirring the reaction at room temperature, first adjust the pH value to neutral with hydrochloric acid, distill off the methanol, add ethyl acetate to dilute, and wash with water; the organic phase is washed with saturated brine, the aqueous phase is extracted with chloroform, and washed with saturated brine, the combined organic phases are dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain an oily substance, which is recrystallized from n-hexane to obtain intermediate product No. 4.

[0017] Preferably, the stirring reaction time at room temperature is 1 hour.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The invention adopts (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester which is cheap and easily available on the market as a raw material, and after benzoylation and acetylation, the hydroxyl group of the raw material is converted from trans to cis, and the chirality is converted, and finally the target product is synthesized. Compared with the prior art, the invention has simple synthesis steps, and the product yield and purity are ideal. Acetate is used instead of benzoate, the raw material is cheaper, and the generated byproduct acetic acid is more environmentally friendly than benzoic acid, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The present invention provides a schematic diagram of the synthetic route of the method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0022] The preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester, the synthetic route is as follows:

[0023]

[0024] The first step is to synthesize (2S, 4R)-4-p-toluenesulfonyloxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (2): dissolve (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester in dichloromethane and keep the temperature below 5°C;

[0025] Add triethylamine and p-toluenesulfonyl chloride, keep warm and continue the reaction for 3 hours. The reaction mixture is washed with 5% dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is recrystallized with n-hexane to obtain intermediate product No. 2;

[0026] Step 2: Synthesis of (2S, 4R)-4-acetoxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (3): Mix the intermediate product No. 2 and sodium acetate, add dimethyl sulfoxide dropwise, heat to 90° C. and stir for 7 hours, then cool to room temperature, dilute the reaction mixture with ethyl acetate, wash with water and saturated brine in sequence, dry the organic phase with anhydrous sodium sulfate, distill off the solvent to obtain an oily substance, and recrystallize from n-hexane to obtain the intermediate product No. 3;

[0027] The third step is to synthesize N-Boc-cis-4-hydroxy-L-proline methyl ester (4): the intermediate product No. 3 is mixed with methanol, potassium carbonate is added, stirred at room temperature for 1 hour, the pH value is adjusted to neutral with hydrochloric acid, the methanol is distilled off, ethyl acetate is added to dilute, and washed with water; the organic phase is washed with saturated brine, the aqueous phase is extracted with chloroform, and washed with saturated brine, the combined organic phases are dried with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain an oily substance, and the intermediate product No. 4 is recrystallized from n-hexane.

[0028] In order to verify the effect of the preparation method of N-Boc-cis-4-hydroxy-L-proline methyl ester proposed by the present invention, the following implementation process is now carried out:

[0029] Example

[0030] The first step is to synthesize (2S, 4R)-4-p-toluenesulfonyloxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (2): Intermediate product No. 3 (21.4 g, 0.096 mol) is dissolved in dichloromethane (220 ml), cooled to below 5 degrees in an ice-water bath, triethylamine (10.2 g, 0.102 mol) and p-toluenesulfonyl chloride (12.9 g, 0.113 mol) are added, and the reaction is continued at the same temperature for 3 hours. The reaction mixture is washed with 5% dilute hydrochloric acid (200 ml), water (200 ml), saturated sodium bicarbonate solution (200 ml) and saturated brine (200 ml) in sequence, and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue is shaken with n-hexane (60 ml) and frozen to crystallize to obtain intermediate product No. 4; product: white solid, 24.6 g, purity 92%, yield 87.9%.

[0031] Step 2: Synthesis of (2S, 4R)-4-acetoxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (3): A solution of intermediate No. 2 (5.7 g, 0.017 mol) and sodium acetate (5.1 g, 0.035 mol) in dimethyl sulfoxide 7 (57 ml) was heated to 90°C and stirred for 7 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (110 ml), washed with water (170 ml) and saturated brine (110 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation to obtain an oily substance. Slowly add n-hexane (20 ml) and shake to crystallize to obtain intermediate No. 5; product: white solid, weighing 4.7 g, purity 94%, yield 76%;

[0032] Step 3: Synthesis of N-Boc-cis-4-hydroxy-L-proline methyl ester (4): Potassium carbonate (1.6 g, 0.011 mol) was added to a solution of intermediate product No. 3 (4.0 g, 0.011 mol) in methanol (60 ml), stirred at room temperature for 1 hour, adjusted the pH to neutral with concentrated hydrochloric acid, distilled off methanol, added ethyl acetate (13 ml) to dilute, and washed with water (70 ml); the organic phase was washed with saturated brine (70 ml), the aqueous phase was saturated with sodium chloride, extracted with chloroform (100 ml), and washed with saturated brine (100 ml). The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily substance. Intermediate product No. 6 was crystallized from n-hexane; product: white solid, weighing 24.6 g, yield 77.6%, purity 98%.

[0033] It can be clearly seen from the above examples that:

[0034] The preparation process proposed in the present invention has ideal product yield and purity. Acetate is used instead of benzoate. Based on the existing market, the raw material is cheaper, and the generated by-product acetic acid is more environmentally friendly than benzoic acid. Breakthroughs have been made in the cost control of raw materials and the impact of by-products on the environment, and the invention is suitable for large-scale production.

[0035] 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 N-Boc-cis-4-hydroxy-L-proline methyl ester, characterized in that: The following steps are involved: Step 1, synthesis of (2S, 4R)-4-p-toluenesulfonyloxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (2): dissolving (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester in dichloromethane, maintaining the temperature below 5°C, adding triethylamine and p-toluenesulfonyl chloride, maintaining the temperature and continuing the reaction to obtain a reaction mixture, and sequentially washing, drying, distilling and recrystallizing the reaction mixture to obtain intermediate product No. 2; Step 2, synthesis of (2S, 4R)-4-acetoxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester (3): Mix the intermediate product No. 2 and sodium acetate, add dimethyl sulfoxide dropwise, heat and stir to react, then cool to room temperature, dilute the reaction mixture, wash, dry and distill in sequence to obtain an oily substance, and recrystallize the oily substance to obtain the intermediate product No. 3; Step 3, synthesis of N-Boc-cis-4-hydroxy-L-proline methyl ester (4): the intermediate product No. 3 is mixed with methanol, potassium carbonate is added, and the reaction is stirred at room temperature. The reaction solution is adjusted from alkaline to neutral, and then the methanol is evaporated. Extraction, drying and distillation are performed in sequence to obtain an oily substance, which is recrystallized to obtain the intermediate product No.

4.

2. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 1, characterized in that: In the step 1, the molar ratio of (2S, 4R)-4-hydroxy-1,2-pyrrolinedicarboxylic acid-1-tert-butyl-2-methyl ester, triethylamine and p-toluenesulfonyl chloride is 1:1.10-1.15:1.0-1.5, and the reaction is continued for 3 hours.

3. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 2, characterized in that: The reaction mixture was washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was recrystallized with n-hexane to obtain intermediate product No.

2.

4. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 3, characterized in that: The dilute hydrochloric acid used is 5% dilute hydrochloric acid.

5. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 1, characterized in that: In the step 2, the molar ratio of the intermediate product No. 2 to sodium acetate is 1:2; the mixture is heated to 90° C. and stirred for reaction for 6-7 hours.

6. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 5, characterized in that: The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain an oily substance, and the intermediate product No. 3 was obtained by recrystallization using n-hexane.

7. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 1, characterized in that: In the step 3, the molar ratio of intermediate product No. 3 to potassium carbonate is 1:1; the reaction time is 0.5-3 hours under stirring at room temperature.

8. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 7, characterized in that: After stirring the reaction at room temperature, the pH value was first adjusted to neutral with hydrochloric acid, methanol was distilled off, ethyl acetate was added to dilute, and the mixture was washed with water; the organic phase was washed with saturated brine, the aqueous phase was extracted with chloroform, and washed with saturated brine, the combined organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an oily substance, and the intermediate product No. 4 was obtained by recrystallization from n-hexane.

9. The method for preparing N-Boc-cis-4-hydroxy-L-proline methyl ester according to claim 7, characterized in that: The reaction time at room temperature was 1 hour.

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