Preparation method of S-4-chloro-3-hydroxybutyronitrile

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly discloses a preparation method of S-4-chloro-3-hydroxybutyronitrile. According to the method, 1, 3-dichloropropanol is used as a raw material and reacts with a chiral catalyst 9-trimethylsilylquinine to generate quaternary ammonium salt, the quaternary ammonium salt and hydrocyanic acid are subjected to a substitution reaction, and then heating is performed to remove the chiral catalyst, so that the S-4-chloro-3-hydroxybutyronitrile is prepared with high yield and high enantioselectivity. The method is simple and convenient to operate, the yield of the product S-4-chloro-3-hydroxybutyronitrile is high, the chiral catalyst is adopted instead of a chiral raw material, the chiral catalyst can be repeatedly used, and the cost is low.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry technology, specifically relating to a method for preparing S-4-chloro-3-hydroxybutyronitrile. Background Technology

[0002] S-4-chloro-3-hydroxybutyronitrile is an important organic intermediate with multifunctional groups in its molecule. It is a promising and important chiral building block, and can also be used to introduce other groups through chlorine group substitution and reduction reactions to generate desired chiral drug intermediates. Therefore, its synthesis has become a hot research topic.

[0003] The preparation of S-4-chloro-3-hydroxybutyronitrile (S-4-chloro-3-hydroxybutyronitrile) currently mostly uses S-epimylochloropropane as a starting material, selectively ring-opening it through reaction with cyanide salts to obtain the corresponding chiral product (Synthesis, 2004, 16, 2629-2632; WO200587715A1; Tetrahedron, 1994, 50, 118121-11826). However, this method requires a chiral substrate, and chiral S-epimylochloropropane is obtained by resolution of racemic epichlorochloropropane, so the yield of S-4-chloro-3-hydroxybutyronitrile is at most 50%. The EE value of the substrate greatly affects the chiral purity of S-4-chloro-3-hydroxybutyronitrile. Therefore, the requirement for high chiral purity of the substrate leads to high product cost, significantly affecting the product's market competitiveness.

[0004] S-4-chloro-3-hydroxybutyronitrile can also be obtained by using 1,3-dichloropropanol via bio-enzyme catalysis (ChemCatChem, 2025, vol 7, 2446-2450; Tetrohedron, 1994, vol 50, 11821-11826). Although the EE is greater than 99%, the yield is no more than 80%, and the bio-enzyme catalyst cannot be reused, which increases the production cost.

[0005] No S-4-chloro-3-hydroxybutyronitrile has been prepared using an organic chiral catalyst.

[0006] Therefore, in order to solve the above problems, it is urgent to develop a low-cost, simple and efficient method for preparing S-4-chloro-3-hydroxybutyronitrile. Summary of the Invention

[0007] To address the shortcomings of the existing technology, the present invention aims to provide a method for preparing S-4-chloro-3-hydroxybutyronitrile. The method involves reacting 1,3-dichloropropanol with a chiral catalyst, 9-trimethylsilylquinine, to generate a quaternary ammonium salt. The quaternary ammonium salt then undergoes a selective substitution reaction with hydrogen cyanide. The substituted product is then heated to remove the chiral catalyst, thereby producing S-4-chloro-3-hydroxybutyronitrile in high yield and with high enantioselectivity. This method is simple to operate, yields S-4-chloro-3-hydroxybutyronitrile in over 90% of the product, uses a chiral catalyst instead of a chiral raw material, is reusable, and has low cost.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing S-4-chloro-3-hydroxybutyronitrile includes the following steps: (1) Add 1,3-dichloropropanol and chiral catalyst 9-trimethylsilylquinine to an organic solvent and stir for 1-2 h to obtain a quaternary ammonium salt; (2) Control the temperature at 0-20℃, slowly add the freshly prepared hydrocyanic acid solution to (1), maintain the temperature and stir to carry out the asymmetric induced substitution reaction for 3-8 h. After the reaction is completed, separate the liquid and take the organic layer. (3) Remove the organic solvent by atmospheric distillation of the organic layer, and then perform vacuum distillation. The distillate is S-4-chloro-3-hydroxybutyronitrile product, and the remaining solid is 9-trimethylsilylquinine.

[0009] The molar ratio of 1,3-dichloropropanol to 9-trimethylsilylquinine is 1:1-1.5.

[0010] The molar ratio of the hydrogen cyanide to the 1,3-dichloropropanol in step (1) is 1.2-2:1, preferably 1.2-1.5:1. If the molar ratio of hydrogen cyanide to 1,3-dichloropropanol in step (1) is less than 1.2:1, the substitution reaction of hydrogen cyanide will be incomplete, resulting in a significant decrease in the yield of the final S-4-chloro-3-hydroxybutyronitrile product, which will be less than 90%.

[0011] The organic solvent in step (1) is any one of dichloromethane, chloroform, and carbon tetrachloride.

[0012] In step (1), the concentration of 1,3-dichloropropanol is 0.1-0.2 mol / L.

[0013] The reaction temperature in step (1) is 0-30℃.

[0014] In step (2), the concentration of the hydrogen cyanide solution is 0.1-0.5 mol / L. Freshly prepared hydrogen cyanide solution can be obtained by adding sodium cyanide solid to hydrochloric acid solution.

[0015] The reaction temperature in step (2) is 0-5℃.

[0016] The vacuum degree of the reduced pressure distillation in step (3) is 0.1 mmHg.

[0017] The reaction formula for preparing S-4-chloro-3-hydroxybutyronitrile according to this invention is as follows: 9-Trimethylsilylquinine reacts with 1,3-dichloropropanol to form a quaternary ammonium salt; HCN undergoes an asymmetric induced substitution reaction with the chlorinated derivative of the quaternary ammonium salt to selectively obtain a cyano-substituted chiral quaternary ammonium salt; the above chiral quaternary ammonium salt is decomposed by heating to obtain S-4-chloro-3-hydroxybutyronitrile and 9-trimethylsilylquinine.

[0018] Compared with the prior art, the present invention has the following advantages and beneficial effects: (1) This invention uses 1,3-dichloropropanol as raw material instead of chiral epichlorohydrin, resulting in high yield and significantly reduced cost, which is conducive to industrialization.

[0019] (2) The present invention utilizes the chiral catalyst 9-trimethylsilylquinine to carry out an asymmetric induced reaction of 1,3-dichloropropanol and hydrogen cyanide, thereby obtaining S-4-chloro-3-hydroxybutyronitrile with high yield (over 90%) and high enantioselectivity (over 99%), which greatly improves the efficiency of preparing chiral substances. In addition, the chiral catalyst used can be separated during the synthesis of the target product, and the catalyst recovery does not require additional separation steps, which is highly efficient. Detailed Implementation

[0020] To make the objectives and technical solutions of the embodiments of the present invention clearer, the technical solutions 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 some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] In the following examples, the chiral catalyst 9-trimethylsilylquinine was prepared according to the literature Michael, AC, "Catalytic, Asymmetric Dimerization of Methylketene", J. Org. Chem. 1996, 61, 8006. It was obtained by purifying quinine with trimethylchlorosilane, and its structural formula is as follows: TMS refers to trimethylsilyl group. The NMR characterization is as follows:1 H NMR (CDCl3, 400 MHz): 8.78(d, 1 H, J = 4.3 Hz), 8.02(d, 1 H, J = 9.2 Hz), 7.66 (br s, 1 H), 7.50 (d, 1 H, J = 4.4 Hz), 7.41(dd, 1H, J= 9.1 and 1.6 Hz), 6.70.(br s, 1 H), 5.59 (ddd, 1 H, J= 17.2, 10.1, and7.3 Hz), 5.06(d, 1 H, J = 16.3 Hz), 5.04 (d, 1 H, J = 10.8 Hz), 4.17 (s, 3H), 4.05 (t, 1 H, J = 9.0Hz), 3.45 (t, 1 H, J = 11.9 Hz), 3.25 (t, 1 H, J =8.9 Hz), 3.19-3.04 (m, 2 H), 2.78-2.72 (m, 1 H), 2.22 (dd, 1 H, J = 12.5,7.9), 2.18-2.08 (m, 2H), 1.98-1.88 (m, 1H), 1.41(t, 1H, J = 11.5 Hz), 0.14(s, 9 H); 13 C NMR (CDCl3, 100.578 MHz): 159.2, 146.5, 144.2, 137.5, 131.8,125.5, 123.1, 118.6, 117.2, 100.6, 68.2, 60.3, 57.8, 54.6, 43.0, 37.2, 27.0,24.6, 18.4, 0.3.

[0022] The 1,3-dichloropropanol used was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., with a purity of 99.5%.

[0023] Example 1: A method for preparing S-4-chloro-3-hydroxybutyronitrile, comprising the following steps: (1) In a reaction flask containing 50 mL of dichloromethane, add 1.29 g (0.01 mol) of 1,3-dichloropropanol and 3.97 g (0.01 mol) of chiral catalyst 9-trimethylsilylquinine, and stir at 5 °C for 1 hour.

[0024] (2) Keep the reaction system temperature at 5℃, slowly add 50mL of freshly prepared 0.3mol / L hydrocyanic acid solution (take 0.735g (0.015mol) sodium cyanide, add 50mL of 0.3mol / L hydrochloric acid solution to it, stir to obtain hydrocyanic acid solution) to the reaction flask, stir the reaction at 5℃ for 4 hours, separate the liquid, discard the aqueous layer and take the organic layer.

[0025] (3) Dichloromethane was removed by atmospheric distillation of the organic layer, followed by vacuum distillation (vacuum degree of 0.1 mmHg: product distillation temperature of about 76-80°C) to obtain 1.14 g of colorless S-4-chloro-3-hydroxybutyronitrile product with a yield of 95%, a purity of 99.4%, and an EE value of 99.5%. During vacuum distillation, a white solid precipitated. The remaining solid after distillation is the chiral catalyst 9-trimethylsilylquinine. After dissolving it in an appropriate amount of dichloromethane, no further treatment is required before it can be reused for catalysis.

[0026] Purity was determined by gas chromatography, using product standards for comparison and external standard method for quantification. The detection column was HP-5 (30m × 0.32mm, 0.25μm), with a flame ionization detector. Nitrogen was used as the carrier gas at a flow rate of 1.2 mL / min (constant flow mode) and a split ratio of 30:1. The injector temperature and detector temperature were both 290℃. The column temperature was programmed: 60℃ for 4 min, ramped to 200℃ at a rate of 20℃ / min, and held at 200℃ for 2 min. The retention time of S-4-chloro-3-hydroxybutyronitrile was 8.5 min.

[0027] The EE value was determined by gas chromatography using an Astec CHIRALDEX G-TA column (30m × 0.25mm, 0.12μm) and a flame ionization detector. Nitrogen was used as the carrier gas at a flow rate of 1.2 mL / min (constant flow mode) and a split ratio of 30:1. The injector and detector temperatures were both 290℃. The column temperature was programmed: 100℃ for 10 min, ramped to 120℃ at a rate of 2℃ / min, and held at 120℃ for 30 min. The retention time of S-4-chloro-3-hydroxybutyronitrile was 40.0 min, and the retention time of R-4-chloro-3-hydroxybutyronitrile was 41.8 min.

[0028] The product was characterized by NMR: 1H NMR (600 MHz, CDCl3): δ = 4.25-4.17 (m, 1H), 3.70 (dd, J = 11.5, 4.8 Hz, 1H), 3.67 (dd, J = 11.5, 5.6 Hz, 1H), 2.76-2.66(m, 2H), 2.58 (d, J = 5.8 Hz, 1H). 13 C NMR (151 MHz, CDCl3): δ = 116.3, 67.5, 47.6, 23.2. Example 2: A method for preparing S-4-chloro-3-hydroxybutyronitrile Unlike Example 1, in Example 2, the concentration and volume of the added hydrogen cyanide solution and the reaction time are different in step (2). Specifically, the reaction system temperature is maintained at 5°C, and 60 mL of freshly prepared 0.2 mol / L hydrogen cyanide solution is slowly added dropwise to the reaction flask. The reaction is carried out at 5°C for 6 hours. The liquid is separated, the aqueous layer is discarded, and the organic layer is taken. The other steps are exactly the same as in Example 1.

[0029] This example yielded 1.08 g of colorless S-4-chloro-3-hydroxybutyronitrile product, with a yield of 90%, a purity of 99.1%, and an EE value of 99.2%. The purity and EE value testing conditions were exactly the same as in Example 1.

[0030] Comparative Example 1: Unlike Example 1, in Comparative Example 1, the chiral catalyst added in step (1) was quinine, and the amount used was 3.24 g (0.01 mol). The other steps were exactly the same as in Example 1.

[0031] The comparative example ultimately yielded 1.10 g of S-4-chloro-3-hydroxybutyronitrile product, with a yield of 92%, a purity of 99.1%, and an EE value of 64.5%.

[0032] As can be seen from Comparative Example 1 and Example 1, the steric hindrance of the catalyst is greatly increased after the hydroxyl group is protected by a large group. The comparison results show that the reaction can proceed smoothly, but the catalyst in Example 1 has increased steric hindrance and better chirality control, so the EE value is higher.

[0033] The above are merely embodiments of the present invention, described in a relatively specific and detailed manner, but should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing S-4-chloro-3-hydroxybutyronitrile, characterized in that, Includes the following steps: (1) Add 1,3-dichloropropanol and chiral catalyst 9-trimethylsilylquinine to an organic solvent and stir for 1-2 h to obtain a quaternary ammonium salt; (2) Control the temperature at 0-20℃, slowly add the freshly prepared hydrocyanic acid solution to (1), maintain the temperature and stir to carry out the asymmetric induced substitution reaction for 3-8 h. After the reaction is completed, separate the liquid and take the organic layer. (3) Remove the organic solvent by atmospheric distillation of the organic layer, and then perform vacuum distillation. The distillate is S-4-chloro-3-hydroxybutyronitrile product, and the remaining solid is 9-trimethylsilylquinine.

2. The preparation method according to claim 1, characterized in that, The reaction formula is as follows: 。 3. The preparation method according to claim 1, characterized in that, The molar ratio of 1,3-dichloropropanol to 9-trimethylsilylquinine is 1:1-1.5; and / or The molar ratio of the hydrogen cyanide to the 1,3-dichloropropanol is 1.2-2:

1.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the hydrogen cyanide to the molar ratio of 1,3-dichloropropanol is 1.2-1.5:

1.

5. The preparation method according to claim 1, characterized in that, The organic solvent in step (1) is any one of dichloromethane, chloroform, and carbon tetrachloride.

6. The preparation method according to claim 1, characterized in that, In step (1), the concentration of 1,3-dichloropropanol is 0.1-0.2 mol / L.

7. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is 0-30℃.

8. The preparation method according to claim 1, characterized in that, The concentration of the hydrogen cyanide solution in step (2) is 0.1-0.5 mol / L.

9. The preparation method according to claim 1, characterized in that, The reaction temperature in step (2) is 0-5℃.

10. The preparation method according to claim 1, characterized in that, The vacuum degree of the reduced pressure distillation in step (3) is 0.1 mmHg.

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