CN111943805A - Preparation method of (R) -3-chloro-1, 2-propanediol - Google Patents

Abstract

The invention discloses a preparation method of (R)-3-chloro-1,2-propanediol, and belongs to the technical field of chiral material preparation. The method firstly adds chloroform to a reaction vessel under nitrogen protection, successively adds tetraisopropyltitanium oxide and L(-)-diethyl tartrate, fully stirs and then adds chloropropene dropwise, and then adds tert-butyl After the reaction was completed, (S)-3-chloro-1,2-epoxy propylene was obtained by distillation under reduced pressure, and (S)-3-chloro-1,2-epoxy After the propane was dissolved in distilled water and fully dissolved, a phase transfer catalyst was added dropwise to it, and heated to 90°C with stirring. After 24 hours of reaction, the lye solution was added to the mixed solution after the reaction, and the pH value was adjusted to 7. The reaction mixture was decompressed. Fractional distillation to obtain the target product (R)-3-chloro-1,2-propanediol. The raw materials required by the invention are cheap and easy to obtain, and the preparation cost is low; the method of the invention has simple process flow, simple and convenient operation, high product yield, and is favorable for industrialization promotion.

Description

A kind of preparation method of (R)-3-chloro-1,2-propanediol

Technical field:

The invention belongs to the technical field of preparation of chiral materials, in particular to a preparation method of (R)-3-chloro-1,2-propanediol.

Background technique:

(R)-3-Chloro-1,2-propanediol is an important pharmaceutical intermediate, which can be used to synthesize the antitussive drug L-hydroxypropanediol. Levodropopizine, with the chemical name of S-(-)-3-(4-phenyl-1-piperazinyl)-1,2-propanediol, is a new antitussive. The racemate R-(-)-3-(4-phenyl-1-piperazinyl)-1,2-propanediol has the same effect in antitussive, but the side effects are larger, especially the central nervous system. reaction. If the pair of racemates can be separated, the pair of optically active enantiomer products will have better medicinal effects, but the cost of industrially separating the racemates is very high, and it is difficult to achieve industrialization. promotion. With (R)-3-chloro-1,2-propanediol, the reaction process of synthesizing L-Hydroxypropanediol is as follows:

The current method for producing (R)-3-chloro-1,2-propanediol is as follows:

The method has low production efficiency and high cost, and uses a Salen-Co catalyst ((R,R')-(-)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2 - Cyclohexyldiamine acetate cobalt(III)), (R)-3-chloro-1,2-propanediol in heavy metal ions are seriously exceeding the standard. The heavy metals exceed the standard and fail to meet the standard requirements of food and pharmaceutical grade additives. If the heavy metal ions are removed by recrystallization of levothyroxine again, the production cost will also be greatly increased accordingly.

Invention content:

Aiming at the above-mentioned problems in the prior art, the present invention provides a preparation method of (R)-3-chloro-1,2-propanediol. The method is simple and practical, without the pollution of heavy metal cobalt ions, and the obtained (R)-3-chloro-1,2-propanediol has high yield, high chiral purity and low water content, and has good industrialization value.

The concrete steps of the preparation method of a kind of (R)-3-chloro-1,2-propanediol provided by the invention are as follows:

(1) Synthesis of (S)-3-chloro-1,2-epoxypropane:

Under nitrogen protection, a certain amount of reaction solvent was added to the reaction vessel, and at -10°C to 0°C, tetraisopropyl titanium oxide and L(-)-diethyl tartrate ((-)DET were added successively to it ), add chloropropene dropwise to it after fully stirring, add tert-butyl hydroperoxide to it after fully mixing after the dropwise addition, stir the gained mixed solution for 12 hours, use TLC (thin layer chromatography) or HPLC (high performance liquid phase) Chromatography) to monitor the reaction progress, after the reaction is complete, the product is distilled under reduced pressure and fractionated to obtain (S)-3-chloro-1,2-epoxypropane.

The reaction solvent is chloroform, and the molar ratio of the allyl chloride, tetraisopropyl titanium oxide, L(-)-diethyl tartrate and the tert-butyl hydroperoxide is: allyl chloride: tetraisopropyl oxygen Titanium: L(-)-diethyl tartrate: tert-butyl hydroperoxide=1:1:1:1.5～2.5; vacuum distillation temperature is 60～65℃, pressure is -0.08MPa; Sharpless is asymmetric in this step The epoxidation reaction solvent is chloroform, and the oxidant used is tert-butyl hydroperoxide.

(2) Synthesis of (R)-3-chloro-1,2-propanediol:

Under nitrogen protection, (S)-3-chloro-1,2-epoxypropane obtained in step (1) was dissolved in a certain amount of distilled water, and after fully dissolving, an aqueous solution of phase transfer catalyst was added dropwise thereto, and heated with stirring. to 90°C, react for 24 hours, monitor the reaction progress by TLC or HPLC, after the reaction is completed, add the lye solution to the mixed solution after the reaction, adjust the pH value to 7, stop the reaction after the adjustment, and pass the reaction mixture through fractional distillation under reduced pressure, Moisture and product (R)-3-chloro-1,2-propanediol were separated off.

The phase transfer catalyst is tetra-n-butyl ammonium hydrogen sulfate. In water, hydrogen sulfate can ionize H ⁺ to participate in the catalytic reaction, and the quaternary ammonium salt cation can cause phase transfer between the organic phase and the anions in the water to speed up the reaction rate; the reactants Molar ratio: (S)-3-chloro-1,2-epoxypropane: tetra-n-butylammonium hydrogen sulfate=100: 1～3; the vacuum distillation temperature is 60～65℃, and the pressure is -0.08MPa .

The reaction process is as follows:

The present invention has the following technical characteristics:

1. Using cheap and readily available chloropropene as the starting material, the production cost is lower.

2. By making full use of Sharpless asymmetric epoxidation, high-yield levorotatory or dextrorotatory enantiomer products can be obtained. In this aspect, dextrorotatory intermediate products are mainly synthesized.

3. Compared with the traditional catalyst Salen-Co, the use of an acidic phase transfer catalyst, on the one hand, has a phase transfer catalytic effect, on the other hand, the conversion rate is high in an acidic medium, and the problem of excessive heavy metal ion content in the product is solved.

4. High yield, easy separation and purification, high chiral purity and high added value.

Detailed ways:

Embodiment 1: the specific steps of the preparation method of (R)-3-chloro-1,2-propanediol provided by the invention are as follows:

(1) Preparation of (S)-3-chloro-1,2-epoxypropane:

At -10°C, 30 mL of chloroform was added to a 100 mL three-necked round-bottomed flask, followed by 0.344 mL (0.412 g, 2 mmol) of L(-) diethyl tartrate, 0.594 mL (2 mmol) of tetrapropyl titanium oxide , after fully stirring, add 0.153g (2mmol) chloropropene, stir for 10min, add 0.391mL (0.36g, 4mmol) tert-butyl hydroperoxide, stir the resulting mixed solution in a refrigerator at -10～0℃ for 12 hours During the reaction, the reaction progress was monitored by TLC or HPLC. After the reaction was completed, the product was fractionated at 65°C (-0.08MPa) to obtain pure product. Yield 90.4%, purity: 99.3%, chiral purity: 99.5% e.e.

(2) Preparation of (R)-3-chloro-1,2-propanediol:

In a 50 mL three-necked flask, add 20 mL of distilled water and 0.78 mL (0.92 g, 10 mmol) of pure (S)-3-chloro-1,2-epoxypropane, and after thorough mixing, add 3.4 mg of tetra-n-butyl sulfuric acid to the mixed solution Ammonium hydrogen, heated to 90°C with stirring, and reacted for 24 hours. TLC or HPLC was used to monitor the reaction progress. After the reaction was completed, 0.1N sodium hydroxide was added to the mixed solution after the reaction, and the pH was adjusted to 7. After the adjustment, the reaction was stopped, and 60 Excess water was distilled at °C (-0.08MPa), then the product (R)-3-chloro-1,2-propanediol was distilled at high vacuum -0.1MPa. Yield 96.4%, purity: 99.5%, chiral purity: 99.7% e.e.

Embodiment 2: the specific steps of the preparation method of (R)-3-chloro-1,2-propanediol provided by the invention are as follows:

(1) Preparation of (S)-3-chloro-1,2-epoxypropane

At -10 °C, 60 mL of chloroform was added to a 250 mL three-necked round-bottomed flask, followed by 34.4 mL (41.2 g, 0.2 mol) of L(-) diethyl tartrate and 59.4 mL (0.2 mol) of tetrapropyl tartrate. Titanium oxide, after fully stirring, add 15.3g (0.2mol) chloropropene, stir for 10min, add 39.1mL (36g, 0.4mol) tert-butyl hydroperoxide, put the resulting mixed solution in a refrigerator at -10～0℃ Stir for 12 hours. During the reaction, monitor the reaction progress by TLC or HPLC. After the reaction is complete, fractionate the product at 65°C (-0.08MPa) to obtain pure product. Yield 90.1%, purity: 98.8%, chiral purity: 99.3% e.e.

(2) Preparation of (R)-3-chloro-1,2-propanediol

Add 50 mL of distilled water and 78 mL (92 g, 1 mol) of pure (S)-3-chloro-1,2-epoxypropane to a 250 mL three-necked flask, mix thoroughly, and add 0.35 g of tetra-n-butyl hydrogen sulfate dropwise to the mixed solution Aqueous ammonium solution, heated to 90°C with stirring, and reacted for 24 hours. TLC or HPLC monitored the reaction progress. After the reaction was completed, 0.1N sodium hydroxide was added to the mixed solution after the reaction, and the pH was adjusted to 7. After the adjustment, the reaction was stopped, and 60 Excess water was distilled at °C (-0.08MPa), then the product (R)-3-chloro-1,2-propanediol was distilled at high vacuum -0.1MPa. Yield 95.9%, purity: 98.5%, chiral purity: 99.6% e.e.

Claims (1)

1. A preparation method of (R) -3-chloro-1, 2-propanediol is characterized by comprising the following steps:

(1) synthesis of (S) -3-chloro-1, 2-epoxypropane:

under the protection of nitrogen, adding a certain amount of reaction solvent into a reaction container, sequentially adding tetraisopropyl titanyl and L (-) -diethyl tartrate into the reaction container at the temperature of between 10 ℃ below zero and 0 ℃, fully stirring, dropwise adding chloropropene into the mixture, after the dropwise adding and the full mixing are completed, adding tert-butyl hydroperoxide into the mixture, stirring the obtained mixed solution for 12 hours, monitoring the reaction process by TLC or HPLC, after the reaction is completed, carrying out reduced pressure distillation and fractionating to obtain (S) -3-chloro-1, 2-epoxypropane; the reaction solvent is chloroform, and the mol ratio of chloropropene, tetraisopropyloxytitanium, L (-) -diethyl tartrate and tert-butyl hydroperoxide is as follows: chloropropene, tetraisopropyltitanyl, L (-) -diethyl tartrate and tert-butyl hydroperoxide are 1: 1.5-2.5; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08 MPa;

(2) synthesis of (R) -3-chloro-1, 2-propanediol:

under the protection of nitrogen, dissolving (S) -3-chloro-1, 2-epoxypropane obtained in the step (1) in a certain amount of distilled water, after full dissolution, dropwise adding an aqueous solution of a phase transfer catalyst, stirring and heating to 90 ℃, reacting for 24h, monitoring the reaction process by TLC or HPLC, after the reaction is completed, adding an alkali liquor into the mixed solution after the reaction, adjusting the pH value to 7, stopping the reaction after the adjustment is completed, and separating water and a product (R) -3-chloro-1, 2-propanediol from the reaction mixture by reduced pressure fractionation; the phase transfer catalyst is tetra-n-butyl ammonium hydrogen sulfate; the molar ratio of the (S) -3-chloro-1, 2-epoxypropane to the tetra-n-butyl ammonium hydrogen sulfate is as follows: (S) -3-chloro-1, 2-epoxypropane and tetra-n-butyl ammonium hydrogen sulfate are respectively 100: 1-3; the reduced pressure distillation temperature is 60-65 ℃, and the pressure is-0.08 MPa.