A method for synthesizing chiral epichlorohydrin

Abstract

The application belongs to the technical field of medicine and chemical industry, and particularly discloses a synthesis method of chiral epichlorohydrin.The chiral Salen Co(II) is in-situ oxidized, and then is reacted with TsOH or PhSO3H to obtain a catalyst Salen Co(III) OTs or Salen Co(III) SO3Ph, which is used to catalyze the asymmetric kinetic resolution of racemic epichlorohydrin and TsOH or PhSO3H at a certain temperature, and chiral epichlorohydrin is obtained at a high yield.In addition, the reaction raw material and the catalyst can be recycled and reused.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical and chemical industry, and particularly relates to a synthesis method of chiral epichlorohydrin. BACKGROUND

[0002] Chiral epichlorohydrin is an important three-carbon chiral synthon, and is widely applied in the fields of medicine, pesticide, chemical industry, material and the like. Chiral epichlorohydrin can be used as a starting material and a chiral source to synthesize many chiral drugs or intermediates with high optical purity. For example, in the synthesis processes of chiral drugs and intermediates such as aromatic propylamine drugs (timolol, bisoprolol, esmol and the like), L-carnitine, atorvastatin, radiosensitizers, heterocyclic compounds and the like, chiral epichlorohydrin is used as a chiral source.

[0003] The common method for preparing chiral epichlorohydrin at present is to use the chiral SalenCo(III)OAc catalyst invented by Eric N.Jacobsen to hydrolyze racemic epichlorohydrin by kinetics resolution with water as a nucleophile, so as to obtain chiral epichlorohydrin and 3-chloro-1,2-propanediol (US Patent No 5637739, 5663393, 5665890, 5929232, 6262278, 6448414, 6800766, International Patent Publication No WO9114694, 0009463). However, this method has some disadvantages: the reaction system is a homogeneous reaction, and after the reaction is completed, the catalyst is difficult to be conveniently recycled and reused, for example, if the catalyst is obtained after distillation of the product, the catalyst is easily deactivated at high temperature due to the high boiling point of the product; the by-product 3-chloro-1,2-propanediol is generally recycled and purified by vacuum distillation, and the recycling temperature is high (>170℃), so that a large amount of polymerization solid waste is generated; and a large amount of waste liquid is also generated in the whole process.

[0004]

[0005] How to solve the above problems, improve the utilization efficiency of the catalyst and the by-product, reduce the generation of waste residue and waste liquid, is conducive to environmental protection, and can reduce the cost and improve the benefit, which has become a difficult problem in the preparation process of chiral epichlorohydrin. SUMMARY

[0006] In order to solve the above problems in the prior art, the purpose of the present application is to provide a synthesis method of chiral epichlorohydrin.

[0007] The present application is: using Salen Co(II) in situ oxidation and then reacting with p-toluene sulfonic acid (TsOH) or benzene sulfonic acid (PhSO3H) to obtain catalyst Salen Co(III) OTs or Salen Co(III) SO3Ph, which catalyzes the asymmetric kinetic resolution of racemic epichlorohydrin and p-toluene sulfonic acid (TsOH) or benzene sulfonic acid (PhSO3H) at a certain temperature to obtain chiral epichlorohydrin and 1-chloro-2-p-toluenesulfonate-3-propanol or 1-chloro-2-benzenesulfonate-3-propanol. The latter undergoes ortho elimination reaction under the action of base to remove p-toluene sulfonic acid or benzene sulfonic acid to obtain racemic epichlorohydrin, which can be recycled as raw material. In addition, the catalyst Salen Co(III) OTs or Salen Co(III) SO3Ph, p-toluene sulfonic acid or benzene sulfonic acid can be recycled.

[0008] Among them, the structural formula of (R,R)-Salen Co(II) catalyst (referred to as Cat1) and (R,R)-Salen Co(III) OTs catalyst (referred to as Cat2) is as follows:

[0009]

[0010] In order to achieve the above technical purpose, the present application adopts the following technical scheme:

[0011] A synthesis method of chiral epichlorohydrin, comprising the following steps:

[0012] S1, under a certain temperature, (R,R)-Salen Co(II) and p-toluene sulfonic acid or benzene sulfonic acid are added to racemic epichlorohydrin, air is activated to obtain S-epichlorohydrin and R-1-chloro-2-p-toluenesulfonate-3-propanol or R-1-chloro-2-benzenesulfonate-3-propanol, the E.E. value of the target product is monitored to reach more than 99%, the reaction is stopped, and vacuum distillation is carried out to obtain chiral epichlorohydrin; or

[0013] Under a certain temperature, (S,S)-Salen Co(II) and p-toluene sulfonic acid or benzene sulfonic acid are added to racemic epichlorohydrin, air is activated to obtain R-epichlorohydrin and S-1-chloro-2-p-toluenesulfonate-3-propanol or S-1-chloro-2-benzenesulfonate-3-propanol, the E.E. value of the target product is monitored to reach more than 99%, the reaction is stopped, and vacuum distillation is carried out to obtain chiral epichlorohydrin;

[0014] In order to improve the recycling of by-products, the following steps are further included:

[0015] S2, water is added to the distillation residue obtained in step S1 and stirred to precipitate the catalyst Salen Co(III) OTs or Salen Co(III) SO3Ph, and the catalyst is filtered and recycled;

[0016] S3, solid base is added to the filtrate obtained in step S2, the pH is adjusted to 7-9, and the mixture is heated to reflux, and R(S)-1-chloro-2-p-toluenesulfonate-3-propanol or R(S)-1-chloro-2-benzenesulfonate-3-propanol undergoes ortho-elimination reaction under the action of base to remove p-toluenesulfonic acid or benzenesulfonic acid, to obtain racemic epichlorohydrin crude product, which is subjected to vacuum distillation, and the fractions are separated to obtain racemic epichlorohydrin, which can be recycled as raw material;

[0017] S4, the distillation residue obtained in step S3 is acidified with hydrochloric acid of a certain concentration to pH 4-7, and p-toluenesulfonic acid or benzenesulfonic acid is precipitated, which can be recycled after drying.

[0018] Further, the molar ratio of the catalyst in step S1: racemic epichlorohydrin: p-toluenesulfonic acid or benzenesulfonic acid is (0.01-0.05):2:(1.01-1.05).

[0019] Further, the reaction temperature in step S1 is 0-15℃, preferably 8-12℃.

[0020] Further, the air flow rate in step S1 is 3.5-7L / min.

[0021] Further, the base in step S3 is sodium hydroxide, sodium carbonate and / or sodium bicarbonate, preferably sodium bicarbonate.

[0022] Further, the concentration of hydrochloric acid in step S4 is 6-12mol / L, preferably 8-10mol / L.

[0023] Compared with the prior art, the advantages and beneficial effects of the present application are:

[0024] First, the present application uses sulfonic acid (p-toluenesulfonic acid, benzenesulfonic acid) to asymmetrically kinetically resolve racemic epichlorohydrin under the action of a catalyst, and the chiral epichlorohydrin obtained has high yield, and the catalyst can be recovered at mild conditions by precipitating solid at low temperature, and the catalyst activity does not change;

[0025] Second, the present application can effectively improve the recovery and reuse efficiency of by-products by allowing the by-products R(S)-1-chloro-2-p-toluenesulfonate-3-propanol and R(S)-1-chloro-2-benzenesulfonate-3-propanol to undergo elimination reaction under alkaline conditions to cyclize to obtain the main reaction raw material racemic epichlorohydrin;

[0026] Third, the catalyst of the present application can be used in an amount as low as 0.5% of the substrate, which greatly reduces the production cost while ensuring the quality of the resolution;

[0027] Fourth, the present application can achieve the recycling of catalysts and by-products through the design of the synthesis route, greatly reducing the generation of waste residues and waste liquids, being more environmentally friendly, and improving the overall utilization efficiency of the reaction. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The synthesis method of chiral epichlorohydrin in Example 1 is shown in the schematic diagram.

[0029] Figure 2 The gas chromatogram of chiral epichlorohydrin prepared in Example 1 is shown in the schematic diagram.

[0030] Figure 3 The gas chromatogram of chiral epichlorohydrin prepared in Example 2 is shown in the schematic diagram.

[0031] Figure 4 The gas chromatogram of chiral epichlorohydrin prepared in Example 3 is shown in the schematic diagram. DETAILED DESCRIPTION

[0032] In order to make the purpose and technical scheme of the present application clearer, the technical scheme of the present application will be described in detail below in combination with specific examples. Obviously, the described examples are part of the embodiments of the present application, rather than all the embodiments. Based on the described embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0033] In the following examples, (R,R)-Salen Co(II) was purchased from Shanghai Aladdin Reagent Co., Ltd.; and racemic epichlorohydrin was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0034] Example 1 Synthesis method of chiral epichlorohydrin

[0035] The synthesis method of chiral epichlorohydrin is shown in the schematic diagram Figure 1 . The specific steps are as follows:

[0036] The temperature was controlled at 10°C, 6.04g (0.01 mol) of (R,R)-Salen Co(II) catalyst (abbreviation Cat 1) was added into 185g (2 mol) of racemic epichlorohydrin, after stirring uniformly, 174g (1.02 mol) of p-toluene sulfonic acid was added in batches, air was blown in at a flow rate of 5L / min, the reaction was stopped by monitoring the E.E. value of S-epichlorohydrin reaching more than 99%, S-epichlorohydrin (product 1) was obtained by distillation at 60-70°C under reduced pressure, the yield was 95%, the content was 99.2%, and the E.E. value was 99.3%.

[0037] The remaining liquid was distilled into 200mL of water, stirred uniformly at room temperature, and filtered to obtain the recovered Cat 2: Salen Co(III) OTs catalyst, which was dried at 60°C under vacuum to obtain 7.36g, with a recovery rate of 95%.

[0038] About 9g of solid sodium bicarbonate was added into the filtrate to adjust the pH to 9, heated to 100°C to reflux for 2 hours, and distilled under reduced pressure to obtain a mixture of racemic epichlorohydrin and water, and the racemic epichlorohydrin (product 2) was obtained by liquid separation, with a yield of 92% and a content of more than 99%.

[0039] The remaining liquid was acidified with 10 mol / L hydrochloric acid to pH 5, a large amount of solid was precipitated, filtered, washed with a small amount of ice water, and dried to obtain 148g of p-toluene sulfonic acid, with a recovery rate of 85%.

[0040] The content of epichlorohydrin was determined by gas phase external standard method, the gas phase conditions were as follows: HP-5 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 120°C, vaporization chamber temperature: 160°C, detector temperature: 160°C; the enantiomeric excess percentage (E.E.) of epichlorohydrin was determined by gas phase, the gas phase conditions were as follows: Gamma DE 225 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 60°C, vaporization chamber temperature: 180°C, detector temperature: 180°C. TM The gas chromatogram of the chiral epichlorohydrin prepared in Example 1 is shown below, the peak time of S-epichlorohydrin was 10.6min, and the peak time of R-epichlorohydrin was 12.2min, and the peak area data were as follows. Figure 2

[0041]

[0042] Example 2: A method for synthesizing a chiral epichlorohydrin

[0043] ​The temperature was controlled at 10°C, 6.04g (0.01mol) of (R,R)-Salen Co(II) catalyst (abbreviation Catl) was added into 185g (2mol) of racemic epichlorohydrin, after stirring uniformly, 161g (1.02mol) of benzene sulfonic acid was added in batches, air was blown in at a flow rate of 5L / min, the reaction was stopped by monitoring the E.E. value of S-epichlorohydrin reaching more than 99%, S-epichlorohydrin (product 1) was obtained by distillation at 60-70°C under reduced pressure, the yield was 92%, the content was 99.3%, and the E.E. value was 99.1%.

[0044] The remaining liquid was distilled into 200ml of water, stirred uniformly at room temperature, and filtered to obtain the recovered Cat2: Salen Co(III) SO3Ph catalyst, which was dried at 60°C under vacuum to obtain 7.2g, with a recovery rate of 93%.

[0045] About 9g of solid sodium bicarbonate was added into the filtrate to adjust the pH to 9, heated to 100°C to reflux for 2 hours, and distilled under reduced pressure to obtain a mixture of racemic epichlorohydrin and water, and the racemic epichlorohydrin (product 2) was obtained by liquid separation, with a yield of 90% and a content of more than 99%.

[0046] The remaining liquid was acidified with 10mol / L hydrochloric acid to pH 5, a large amount of solid was precipitated, filtered, washed with a small amount of ice water, and dried to obtain 130g of benzene sulfonic acid, with a recovery rate of 81%.

[0047] The content of epichlorohydrin was determined by gas phase external standard method, the gas phase conditions were as follows: HP-5 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 120°C, vaporization chamber temperature: 160°C, detector temperature: 160°C; the enantiomeric excess percentage (E.E.) of epichlorohydrin was determined by gas phase, the gas phase conditions were as follows: Gamma DE 225 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 60°C, vaporization chamber temperature: 180°C, detector temperature: 180°C. TM 225 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 60°C, vaporization chamber temperature: 180°C, detector temperature: 180°C. Figure 3 The gas chromatogram of the chiral epichlorohydrin prepared in Example 2 is shown below, the peak time of S-epichlorohydrin was 10.7min, and the peak time of R-epichlorohydrin was 12.2min, and the peak area data is as follows.

[0048]

[0049] Example 3: Repeated use experiment of recovered catalyst Cat2

[0050] The temperature was controlled at 10°C, 7.75g (0.01mol) of Cat2: (R,R)-Salen Co(III) OTs catalyst recovered from Example 1 was added into 185g (2mol) of racemic epichlorohydrin, after stirring uniformly, the reaction was stopped by monitoring the E.E. value of S-epichlorohydrin reaching more than 99%, S-epichlorohydrin (product 1) was obtained by distillation under reduced pressure at 60-70°C, the yield was 97%, the content was more than 99%, the E.E. value was 99.0%.

[0051] The content of epichlorohydrin was determined by gas phase external standard method, the gas phase conditions were: HP-5 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 120°C, vaporization chamber temperature: 160°C, detector temperature: 160°C; the enantiomeric excess percentage (E.E.) of epichlorohydrin was determined by gas phase, the gas phase conditions were: Gamma DE TM 225 (30m x 0.25mm x 0.25um) was used as the detection column, hydrogen flame detector, column temperature: 60°C, vaporization chamber temperature: 180°C, detector temperature: 180°C. Figure 4 The gas chromatogram of the chiral epichlorohydrin prepared in Example 3 was shown as follows, the peak time of S-epichlorohydrin was 10.3min, the peak time of R-epichlorohydrin was 12.1min, and the peak area data were as follows.

[0052]

[0053] The above merely describes specific embodiments of the present application, which are specific and detailed, but should not be understood as limiting the protection scope of the claims of the present application. It should be noted that, for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the protection scope of the present application.

Claims

1. A method for the synthesis of chiral epichlorohydrin, characterized in that, The method comprises the following steps: S1. Adding (R, R)-Salen Co(II) or (S, S)-Salen Co(II) and p-toluene sulfonic acid or benzene sulfonic acid to racemic epichlorohydrin at a certain temperature, activating by passing air, monitoring the E.E. value of the target product to reach more than 99%, stopping the reaction, and distilling under reduced pressure to obtain chiral epichlorohydrin; S2. Adding water to the remaining liquid after distillation in step S1 to stir, precipitating catalyst Salen Co(III) OTs or Salen Co(III) SO3Ph, filtering to obtain the catalyst, and recycling; S3. Adding solid base to the filtrate obtained in step S2 to adjust the pH to 7-9, heating to reflux to obtain crude racemic epichlorohydrin, distilling under reduced pressure, and separating the fractions to obtain racemic epichlorohydrin, which is recycled as raw material; S4. Acidifying the remaining liquid after distillation in step S3 by hydrochloric acid to pH 4-7, precipitating to obtain p-toluene sulfonic acid or benzene sulfonic acid, and recycling after drying.

2. The method for synthesizing chiral epichlorohydrin according to claim 1, characterized in that, The reaction temperature in step S1 is 0-15℃.

3. The method of claim 1 or 2, wherein the method is characterized by, The molar ratio of catalyst: racemic epichlorohydrin: p-toluene sulfonic acid or benzene sulfonic acid in step S1 is (0.01-0.05):2:(1.01-1.05).

4. The method for synthesizing chiral epichlorohydrin according to claim 1, characterized in that, The base in step S3 is sodium hydroxide, sodium carbonate and / or sodium bicarbonate.

5. The method for synthesizing chiral epichlorohydrin according to claim 1, characterized in that, The concentration of hydrochloric acid in step S4 is 6-12 mol / L.

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