A method for preparing S-epoxychloropropane

Abstract

This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a method for preparing S-epimachloropropane. The method uses racemic epichlorohydrin as a raw material, which is converted into an epoxide quaternary ammonium salt under a chiral thiourea-tertiary amine catalyst. This epoxide quaternary ammonium salt catalyzes an asymmetric nucleophilic ring-opening reaction between ECH and a saturated sodium chloride aqueous solution, producing S-epimachloropropane and 1,3-dichloro-2-propanol with high enantioselectivity. The byproduct 1,3-dichloro-2-propanol is cyclized under alkaline conditions to generate ECH. This invention achieves a closed-loop cycle of catalyst and raw material, resulting in low cost, simple operation, and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and specifically relates to a method for preparing S-epoxychloropropane. Background Technology

[0002] S-epoxychloropropane (S-ECH), as an important chiral building block, is widely used in the synthesis of drugs such as β-receptor blockers and HIV protease inhibitors (e.g., atorvastatin prodrugs). The core challenge in its preparation lies in the highly enantioselective resolution of inexpensive and readily available racemic ECH. Currently, the main industrial method is hydrolytic kinetic resolution (HKR), which uses a (Salen)Co complex to catalyze the reaction of racemic ECH with water to obtain S-ECH and the byproduct chloropropanediol. This method, developed by Eric Jacobsen and T. Katsuki et al. (Furrow, ME; Schaus, SE; Jacobsen, ENJOrg. Chem. 1998, 63(19), 6776-6777.), utilizes water as a nucleophile. Under the catalysis of a chiral Salen-Co(III) catalyst (such as the Jacobsen catalyst), it preferentially reacts with one enantiomer of racemic ECH to generate chiral chloropropanediol, thereby separating the other enantiomer, S-ECH, with high optical purity. However, this method has the following problems: (1) The preparation of Salen-Co(III) catalyst is complex, contains the precious metal cobalt, and is difficult to recover, resulting in high production costs; (2) The byproduct is chloropropanediol, which has low value, and the theoretical maximum yield of ECH is only 50%; (3) Pharmaceutical intermediates have strict requirements for metal residues, and the removal of metal catalysts increases the purification burden. Summary of the Invention

[0003] To address the shortcomings of the existing technology, the present invention aims to provide a low-cost, simple-to-operate, and industrially suitable method for preparing S-epoxychloropropane. The method of the present invention achieves a green synthesis process through chiral phase transfer catalytic resolution, enabling catalyst recovery and feedstock recycling.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing S-epoxychloropropane includes the following steps: (1) Mix racemic epichlorohydrin, chiral thiourea-tertiary amine catalyst and anhydrous organic solvent, stir (monitor by thin layer chromatography) until the chiral thiourea-tertiary amine catalyst is completely converted into epoxide quaternary ammonium salt; cool the reaction system to 0-5℃, then add saturated sodium chloride aqueous solution at 0-5℃ to the system, maintain the reaction at 0-5℃, and stop the reaction when the conversion rate of ECH is 48%-50% as monitored by gas chromatography. Transfer the reaction solution to a separatory funnel, let it stand to separate into layers, and collect the lower organic phase; distill the organic phase at atmospheric pressure to obtain organic solvent (recovered), S-epiochlorohydrin and 1,3-dichloro-2-propanol in sequence.

[0005] A saturated sodium chloride solution is used to provide a high concentration of Cl. - To avoid hydrolysis side reactions; selecting a low-temperature reaction of 0-5°C can improve the selectivity of chiral recognition.

[0006] The structural formula of the chiral thiourea-tertiary amine catalyst is as follows: .

[0007] The epoxide quaternary ammonium salt, abbreviated as active ingredient B, has the following structural formula: .

[0008] The molar ratio of racemic epichlorohydrin to chiral thiourea-tertiary amine catalyst is 1:0.01-0.1, preferably 1:0.01.

[0009] The organic solvent is dichloromethane and / or toluene.

[0010] The ratio of racemic epichlorohydrin to organic solvent is 1 mol: 200-300 mL.

[0011] The volume ratio of the saturated sodium chloride aqueous solution to the organic solvent is 1-2:1, preferably 1:1.

[0012] In step (1) of the method of the present invention, the reaction mechanism is as follows: First, the tertiary amine site in the chiral thiourea-tertiary amine catalyst undergoes an SN2 ring-opening quaternization reaction with racemic epichlorohydrin to generate a ring-opening quaternary ammonium salt (intermediate A). This intermediate is unstable, and its alkoxide anion immediately attacks the adjacent carbon atom, undergoing an intramolecular SN2 reaction and releasing a Cl- ion. - This process generates an epoxide quaternary ammonium salt (active compound B). The structural diagram is shown below: Next, the epoxide quaternary ammonium salt (active compound B) becomes the truly active catalyst in the subsequent catalytic cycle. The epoxide quaternary ammonium salt (active compound B) acts as a phase transfer catalyst, balancing the anion (Cl... -The epoxide quaternary ammonium salt (active compound B) is introduced into the organic phase from the aqueous phase (saturated sodium chloride solution). Simultaneously, the epoxide quaternary ammonium salt (active compound B), within its rigid chiral framework and the chiral cavity constructed in conjunction with the thiourea group, specifically recognizes and activates the epoxy groups of the R-ECH molecule through the thiourea group. The principle of this specific recognition is as follows: the epoxide quaternary ammonium salt (active compound B) constructs a chiral cavity with a specific shape and size. The stereoconfiguration of the R-ECH perfectly matches this cavity and forms a double hydrogen bond with the thiourea. However, the S-ECH, due to its mismatched configuration, cannot simultaneously form an effective double hydrogen bond with the thiourea, resulting in a weak binding affinity.

[0013] Finally, Cl was introduced into the organic phase. - Under the electrostatic attraction of the epoxide quaternary ammonium salt (active ingredient B) cation, it attacks the epoxide carbon of the stereochemically matched R-ECH molecule, which is activated by thiourea hydrogen bonds, from the back side, undergoing a highly stereoselective SN2 ring-opening reaction to generate 1,3-dichloro-2-propanol and regenerate the epoxide quaternary ammonium salt (active ingredient B), thus maintaining the catalytic cycle. However, due to the poor matching degree between the S-ECH and the chiral cavity of the epoxide quaternary ammonium salt (active ingredient B), it is affected by Cl... - The attack has an extremely slow reaction rate, which allows it to accumulate and be retained in the reaction system.

[0014] Furthermore, this method can recover the catalyst and also includes step (2): adding alkaline solution to the residue after distillation in (1), stirring at 0-5°C for 15-30 minutes to induce Hofmann elimination reaction, and after purification, obtaining a chiral thiourea-tertiary amine catalyst, which is then reused in step (1).

[0015] The alkaline solution is a sodium hydroxide solution, potassium hydroxide solution, etc. The concentration of the alkaline solution is 1-2 mol / L.

[0016] Furthermore, this method can recover raw materials and also includes step (3): heating the 1,3-dichloro-2-propanol obtained by distillation in (1) to 60-70°C, then adding alkaline solution, stirring, separating the liquid, washing the organic phase with dilute hydrochloric acid until neutral, and after purification treatment, obtaining racemic epichlorohydrin, which is reused in step (1).

[0017] The alkaline solution is sodium hydroxide solution, lime milk, etc.

[0018] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: (1) Using a thiourea-quaternary ammonium salt bifunctional catalyst, the ee value reaches over 99% through hydrogen bond activation and chiral control.

[0019] (2) Using inexpensive NaCl instead of water as a nucleophile, racemic ECH is converted into S-ECH and 1,3-dichloro-2-propanol. The by-products can be recycled as raw materials, with a theoretical raw material utilization rate of 100%.

[0020] (3) Use recyclable organic small molecule catalysts to replace metal catalysts to reduce costs and environmental burden. Attached Figure Description

[0021] Figure 1 Gas chromatogram of S-epoxychloropropane in Example 1.

[0022] Figure 2 Gas chromatogram of S-epoxychloropropane in Comparative Example 1. Detailed Implementation

[0023] 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.

[0024] The chiral thiourea-tertiary amine catalyst used in this invention was purchased from Alpha-ISA Reagents, CAS No. 890044-38-9, and its structural formula is as follows: .

[0025] The chiral thiourea-tertiary amine catalyst of the present invention contains a tertiary amine group and reacts with ECH in situ to form an epoxide quaternary ammonium salt. The in-situ formed epoxide quaternary ammonium salt has phase transfer capability, and the epoxide quaternary ammonium salt cation can transfer Cl in the aqueous phase. - The chiral thiourea-tertiary amine catalyst is introduced into the organic phase in the form of ion pairs. The rigid chiral framework (quinoline) and thiourea groups of the entire catalyst synergistically provide chiral recognition of R-ECH. The rigid framework (quinoline) provides a differentiated binding pocket for R-ECH / S-ECH, while the double hydrogen bonds of thiourea enhance this differentiation, resulting in stronger binding to R-ECH. The phase transfer center (quaternary ammonium salt), the hydrogen bond activation center (thiourea), and the chiral recognition unit (rigid framework) work closely together within the same molecule, thus achieving chiral phase transfer catalysis. Cl- is introduced into the organic phase. - Under the electrostatic interaction of the epoxide quaternary ammonium salt cation, the epoxide carbon of the R-ECH molecule, which is activated by the hydrogen bond of thiourea and has a matching stereoconfiguration, is attacked from the back side, resulting in a highly stereoselective SN2 ring-opening reaction to generate 1,3-dichloro-2-propanol; at the same time, the S-ECH retains its configuration in the reaction system, thereby achieving configuration resolution.

[0026] The racemic epichlorohydrin (ECH) used in this invention was purchased from Aladdin Reagent (Shanghai) Co., Ltd., with a purity ≥99.0%.

[0027] Example 1: Preparation and recycling of S-epoxychloropropane (1) Generation of active catalyst and resolution reaction: In a 500 mL three-necked flask, 200 mL of anhydrous dichloromethane, racemic epichlorohydrin (92.5 g, 1.0 mol), and chiral thiourea-tertiary amine catalyst (4.0 g, approximately 0.01 mol) were added. The mixture was stirred at room temperature (25±2℃) for 2 hours. Thin-layer chromatography (TLC) was used to monitor the disappearance of the original spots of the chiral thiourea-tertiary amine catalyst, indicating that the chiral thiourea-tertiary amine catalyst had been completely converted to the epoxide quaternary ammonium salt (active substance B). Subsequently, the reaction system was cooled to 0-5℃ in an ice-water bath. Under vigorous stirring (800 rpm), 200 mL of saturated sodium chloride aqueous solution pre-cooled to 0℃ was slowly added. The reaction was maintained at a low temperature (0-5℃), and the conversion rate of ECH was monitored by gas chromatography (GC). GC monitoring conditions: HP-5 column (30 m × 0.32 mm × 0.25 μm), temperature program: 60°C for 2 minutes, then increased to 120°C at 10°C / min, FID detector, injection volume 1 μL. The reaction was stopped when GC showed an ECH conversion ≥ 48% (approximately 6 hours). The reaction solution was transferred to a separatory funnel, allowed to stand for phase separation, and the lower organic phase was collected.

[0028] (2) Product separation and purity determination: The above organic phase was subjected to atmospheric distillation. The oil bath temperature was controlled to be ≤80℃, and the fraction at 39-41℃ was collected to recover dichloromethane (>95%). Heating was continued, and the main fraction at 115-117℃ was collected to obtain 46.2 g of colorless and transparent liquid S-epoxychloropropane. Its chemical purity was determined by GC under the following conditions: HP-5 column (30 m×0.32 mm×0.25 μm), temperature program: 60°C for 2 minutes, then increased to 120°C at 10°C / min, FID detector, and the chemical purity was determined to be 99.5%. The enantiomeric excess (ee) was determined by chiral GC under the following conditions: SH-βDEX chiral column (30 m × 0.25 mm × 0.25 μm), isothermal at 100°C, carrier gas nitrogen, flow rate 1.0 mL / min, FID detector temperature 250°C, and the measured ee value was 99.9% (corresponding to...). Figure 1 The temperature was further increased, and the fraction collected at 175-180℃ was used to obtain 63.0 g of colorless liquid 1,3-dichloro-2-propanol. The yield was 97.7%.

[0029] (3) Catalyst regeneration: Add 50 mL of 1M sodium hydroxide aqueous solution to the residue after distillation in step (2), and stir in an ice bath at 0-5℃ for 30 minutes to allow the epoxide quaternary ammonium salt (active substance B) to undergo Hofmann elimination. Extract the aqueous phase with dichloromethane (3×20 mL), combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the recovered catalyst. The recovery rate is 92% (average of three parallel experiments), which can be directly used for the next batch.

[0030] (4) Raw material recovery: 63.0 g (0.49 mol) of 1,3-dichloro-2-propanol obtained in step (2) was added to the reaction flask and preheated to 65°C. Freshly prepared lime milk (made from 42 g of calcium hydroxide and 100 mL of water) was rapidly added dropwise under vigorous stirring, and the dropping rate was controlled so that the total reaction time was completed within 5 minutes. After the addition was completed, stirring was continued for 30 seconds, and the mixture was immediately cooled. The mixture was transferred to a separatory funnel and the upper organic phase (crude ECH) was separated. The organic phase was washed with dilute hydrochloric acid until neutral and dried with anhydrous sodium sulfate. The dried crude product was distilled at atmospheric pressure, and the fraction at 115-117°C was collected to obtain about 40.8 g (90% yield) of racemic epichlorohydrin, which was recycled to step (1).

[0031] Example 2: Effect of catalyst recycling The catalyst recovered in Example 1 was used in a new round of separation reaction. After five consecutive cycles, the ee value of S-ECH remained above 99%, and the catalyst activity did not decrease significantly.

[0032] Comparative Example 1: Chiral catalyst Tetrabutylammonium chloride (TBACl) was used instead of the chiral thiourea-tertiary amine catalyst in Example 1. TBACl is a commonly used achiral phase transfer catalyst, lacking a chiral center and thiourea hydrogen bond donor, and was used for comparison to highlight the hydrogen bond activation and chiral recognition effects of the chiral thiourea in the catalyst of this invention. The molar amount added was the same as that of the chiral catalyst, and other conditions were the same as in Example 1. The resulting ECH was a racemic mixture (ee≈0), with no resolving effect (corresponding to...). Figure 2 ).

[0033] Comparative Example 2: Using Takemoto catalyst (CAS: 620960-26-1) The chiral thiourea-tertiary amine catalyst in Example 1 was replaced with Takemoto catalyst (CAS: 620960-26-1), and the molar amount added was the same as in Example 1 (0.01 mol), with other conditions being the same as in Example 1. After the reaction was completed, separation and determination were performed in the same manner as in Example 1. The resulting racemic epichlorohydrin was a racemic mixture (ee≈0), showing no resolution effect.

[0034] Although the Takemoto catalyst contains bifunctional groups of thiourea and tertiary amine, possessing two chiral centers on its cyclohexane skeleton, which together constitute the chiral environment of the molecule, the overall molecular structure is flexible and lacks rigidity, failing to form stable chiral cavities to effectively distinguish R-ECH and S-ECH substrate configurations. In contrast, the chiral thiourea-tertiary amine catalyst in Example 1 possesses a rigid skeleton such as quinoline, providing a significantly different recognition environment for the R / S enantiomers of epichlorohydrin, thereby achieving high enantioselective resolution (ee ≥ 99%). This comparison demonstrates that the rigidity of the catalyst's chiral skeleton and its spatial matching with the substrate are key factors for achieving efficient asymmetric induction; simply containing a thiourea-tertiary amine structure is insufficient to guarantee high enantioselectivity.

[0035] 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 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 scope of protection of the present invention.

Claims

1. A method for preparing S-epoxychloropropane, characterized in that, Includes the following steps: (1) Mix racemic epichlorohydrin, chiral thiourea-tertiary amine catalyst and anhydrous organic solvent, stir until the chiral thiourea-tertiary amine catalyst is completely converted into epoxide quaternary ammonium salt; cool the reaction system to 0-5℃, then add saturated sodium chloride aqueous solution at 0-5℃ to the system, maintain the reaction at 0-5℃, and stop the reaction when the conversion rate of ECH is 48%-50% as monitored by gas chromatography. Transfer the reaction solution to a separatory funnel, let it stand to separate the layers, and collect the lower organic phase; distill the organic phase at atmospheric pressure to obtain S-epoxychlorohydrin and 1,3-dichloro-2-propanol in sequence. The structural formulas of the chiral thiourea-tertiary amine catalyst and the epoxide quaternary ammonium salt are as follows: 、 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of the racemic epichlorohydrin and the chiral thiourea-tertiary amine catalyst is 1:0.01-0.

1.

3. The preparation method according to claim 1, characterized in that, The organic solvent is dichloromethane and / or toluene.

4. The preparation method according to claim 1, characterized in that, The ratio of racemic epichlorohydrin to organic solvent is 1 mol: 200-300 mL; and / or The volume ratio of the saturated sodium chloride aqueous solution to the organic solvent is 1-2:

1.

5. The preparation method according to any one of claims 1 to 4, characterized in that, It also includes step (2): adding alkaline solution to the residue after distillation in (1), stirring at 0-5°C for 15-30 minutes to induce Hofmann elimination reaction, and after purification, obtaining a chiral thiourea-tertiary amine catalyst, which is then reused in step (1).

6. The preparation method according to claim 5, characterized in that, The alkaline solution is a sodium hydroxide solution and / or a potassium hydroxide solution; and / or the concentration of the alkaline solution is 1-2 mol / L.

7. The preparation method according to any one of claims 1 to 4, characterized in that, It also includes step (3): heating the 1,3-dichloro-2-propanol obtained by distillation in (1) to 60-70°C, adding alkaline solution, stirring, separating the liquid, washing the organic phase with dilute hydrochloric acid until neutral, and after purification treatment, obtaining racemic epichlorohydrin, which is reused in step (1).

8. The preparation method according to claim 7, characterized in that, The alkaline solution is either sodium hydroxide solution or lime milk.

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