A kind of synthesis process of 4-morpholine-1-phenylmercapto-2-butanone

Abstract

The invention belongs to the field of pharmaceutical chemicals, and specifically relates to a synthesis process of 4-morpholine-1-phenylmercapto-2-butanone. In synthesis step 1, a starting material morpholine hydrochloride is subjected to a Mannich reaction to prepare a compound 01; in synthesis step 2, compound 01 is subjected to a bromination reaction to prepare a compound 02; in synthesis step 3, compound 02 is subjected to a substitution reaction to prepare a target compound 00. The process has high reaction yield, low material cost, good product purity, simple operation, good safety, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and specifically relates to a synthesis process of 4-morpholine-1-phenylmercapto-2-butanone. Background Art

[0002] Potassium channels are transmembrane proteins commonly found on the cell membranes of both excited and unexcited cells. They are tetramers composed of four β subunits, forming a tiny hydrophilic pore that penetrates the lipid bilayer membrane. There are three types of potassium channels in airway smooth muscle: calcium-activated potassium channel (Kca), delayed rectifier potassium channel (Kdr), and ATP-sensitive potassium channel (K ATP), among which K ATP is the main one. When the potassium channel is open, K + Move to the outside of the cell membrane, causing hyperpolarization of airway smooth muscle, resulting in a decrease in spontaneous electrical activity, preventing the opening of voltage-dependent calcium channels, and allowing Ca 2+ Inflow is reduced, resulting in relaxation of airway smooth muscle.

[0003] The synthesis of 4-morpholine-1-phenylmercapto-2-butanone, a key intermediate fragment of the potassium channel open innovative drug under development, has not been reported in the literature. Summary of the invention

[0004] In order to overcome the deficiencies in the above-mentioned prior art, the purpose of the present invention is to design a route and method suitable for the industrial synthesis of 4-morpholine-1-phenylmercapto-2-butanone, so as to provide a stable supply of the intermediate for the second phase clinical trial of innovative drugs and subsequent new drug research, and even for the raw materials after listing. The present invention designs a new and easy-to-implement method using morpholine as the starting material through Mannich reaction, bromination reaction and substitution reaction, and obtains 4-morpholine-1-phenylmercapto-2-butanone safely, conveniently and in high yield, and this method has not been reported in the literature.

[0005] The technical solution of the present invention to solve the above technical problems is as follows:

[0006] A new synthesis method of 4-morpholine-1-phenylmercapto-2-butanone, the specific steps are as follows:

[0007] 1) In the synthesis step 1, the starting material morpholine hydrochloride is subjected to a Mannich reaction to prepare compound 01;

[0008] 2) In the synthesis step 2, compound 01 is subjected to a bromination reaction to prepare compound 02;

[0009] 3) In the synthesis step 3, compound 02 is subjected to a substitution reaction to obtain the target compound 00; the specific route is as follows:

[0010]

[0011] Furthermore, the molecular formula and molecular weight of the compound in each step are as follows:

[0012]

[0013] Furthermore, in step 1, in the Mannich reaction, morpholine hydrochloride, acetone and paraformaldehyde are used in the presence of an acidic catalyst at a suitable temperature and in a solvent to synthesize intermediate 01;

[0014] Further, in step 1, in the Mannich reaction, the ratio of morpholine hydrochloride: acetone: formaldehyde: acidic catalyst: solvent is a molar or volume or weight ratio, and the ratio is 1mol: 0.6-2mol: 1-3mol: 0.1-1%wt (0.1-1% of the mass of 1mol morpholine hydrochloride): 2.5-10vol (2.5-10 times the volume of the mass value of 1mol morpholine hydrochloride, ml, the same below), preferably: 1mol: 1.3mol: 1.6mol: 0.5%wt: 6v (6 times the volume, ml); the acidic catalyst is concentrated hydrochloric acid.

[0015] Further, in step 1, in the Mannich reaction, the reaction solvent is one or more of the alcohol solvents of methanol, ethanol, isopropanol, and n-butanol, preferably methanol; the reaction temperature is 50°C-reflux, preferably 55°C; the reaction time is 20-30 hours, preferably 24 hours;

[0016] Furthermore, in step 2, in the bromination reaction, the intermediate 01 reacts with bromine in a solvent to obtain the intermediate 02;

[0017] Furthermore, in step 2, the molar or volume ratio of the intermediate 01: bromine: solvent is 1 mol: 1-3 mol: 1-15 vol (1-15 times volume, ml), preferably: 1 mol: 2 mol: 1 vol (1 times volume, ml);

[0018] Furthermore, in step 2, the molar or volume ratio of the intermediate 01: bromine: solvent is 1 mol: 1-3 mol: 6-15 vol (6-15 times volume, ml), preferably 1 mol: 2 mol: 8 vol (8 times volume, ml);

[0019] Furthermore, in step 2, the solvent is methanol or acetic acid, preferably methanol; the reaction temperature is -5-30°C, preferably 10°C; the reaction time is 2-6 hours, preferably 4 hours;

[0020] Furthermore, in step 3, in the substitution reaction, the intermediate 02 and sodium thiophenolate react in a solvent to obtain the target compound 00;

[0021] Furthermore, in step 3, the molar ratio of the intermediate 02: sodium thiophenolate: solvent is 1 mol: 1-3 mol: 8-20 vol (8-20 times volume, ml), preferably 1 mol: 1.2 mol: 10 vol (10 times volume, ml);

[0022] Furthermore, in step 3, the solvent is one or more alcohol solvents such as methanol, ethanol, isopropanol, etc., preferably methanol; the reaction temperature is -5-50°C, preferably 40°C; the reaction time is 1-5 hours, preferably 3 hours.

[0023] If there is a conflict between the Chinese name and the structural formula of the compound in the present invention, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0024] The beneficial effects of the present invention are as follows: the inventors have designed a novel synthesis method of 4-morpholine-1-phenylmercapto-2-butanone and studied its synthesis process. The method has high reaction yield, low material cost, good product purity, simple operation, good safety, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0025] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0026] Embodiment 1:

[0027] Synthesis of compound 01: In a three-necked reaction flask, add 100 g of morpholine hydrochloride, 61 g of paraformaldehyde, 38.9 g of acetone, 0.5 g of hydrochloric acid, and 600 ml of ethanol; after nitrogen replacement, heat the system to 55°C and keep the reaction for 24 hours; concentrate the ethanol (6v), then cool to room temperature, precipitate the solid, filter, and rinse the solid twice with 10 ml of ethanol each time to obtain 95.7 g of white solid with a purity of 98.3%.

[0028] 1 H-NMR (400MHz, CDCl3) δppm 2.18 (s, 3H), 2.40-2.49 (m, 4H), 2.58-2.69 (m, 4H), 3.66-3.73 (m, 4H).

[0029] Embodiment 2:

[0030] Synthesis of compound 02: In a three-necked reaction flask, add 100g of intermediate 01 and 100ml of methanol, cool the system to 5°C, start adding bromine, add 20g and keep warm and stir for 1 hour until the red color disappears, then slowly add the remaining 180g of bromine, after the decrease is complete, keep warm and stir for 1.5 hours, slowly add saturated sodium sulfite until the color disappears, then keep warm and stir for 20 minutes, filter, concentrate the filtrate to about 300ml, precipitate solid, filter, rinse the solid twice with 30ml / time methanol to obtain the product, and the solid is directly put into the next step to absorb moisture.

[0031] Embodiment 3:

[0032] Synthesis of compound 00: Add 30g of compound 02 and 240ml of methanol to a reaction bottle and replace with nitrogen; cool the material to 10-15°C, add 60ml of methanol dissolved in 12.5g of methanol solution of sodium thiophenolate, and after the addition is complete, keep warm and react for 2 hours; filter, rinse the solid with 15ml / time of methanol twice, add 200ml of water to the solid, stir, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, extract with 150ml / time of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate to dryness, add 60ml of petroleum ether for pulping, filter, and dry under reduced pressure to obtain 19.6g of the product with a purity of 99.1%.

[0033] 1 H-NMR (400MHz, CDCl3) δppm 2.48 (s, 4H), 2.70 (dd, 2H), 2.83 (dd, 2H), 3.63-3.71 (m, 6H), 7.17-7.37 (m, 5H),

[0034] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A synthesis process for 4-morpholine-1-phenylmercapto-2-butanone, characterized in that: The specific steps are as follows: 1) In the synthesis step 1, the starting material morpholine hydrochloride is subjected to a Mannich reaction to prepare compound 01; in the step 1, in the Mannich reaction, morpholine hydrochloride, acetone and paraformaldehyde are used to synthesize intermediate 01 under the action of an acidic catalyst at a suitable temperature and in a solvent; 2) In the synthesis step 2, compound 01 is subjected to a bromination reaction to obtain compound 02; in the step 2, the bromination reaction is performed by reacting intermediate 01 with bromine in a solvent to obtain intermediate 02; 3) In the synthesis step 3, compound 02 is subjected to a substitution reaction to obtain the target compound 00; in the step 3, in the substitution reaction, intermediate 02 and sodium thiophenolate react in a solvent to obtain the target compound 00; the specific route is as follows:

2. The synthesis process according to claim 1, characterized in that In the step 1, in the Mannich reaction, the molar or volume ratio of morpholine hydrochloride: acetone: paraformaldehyde: acidic catalyst: solvent is 1 mol: 0.6-2 mol: 1-3 mol: 0.1-1% wt: 2.5-10 vol, and the acidic catalyst is concentrated hydrochloric acid.

3. The synthesis process according to claim 2, characterized in that: In the step 1, in the Mannich reaction, the reaction solvent is one or more of methanol, ethanol, isopropanol, and n-butanol, the reaction temperature is 50° C.-reflux, and the reaction time is 20-30 hours.

4. The synthesis process according to claim 1, characterized in that In the step 2, the molar or volume ratio of the intermediate 01: bromine: solvent is 1 mol: 1-3 mol: 1-15 vol.

5. The synthesis process according to claim 1, characterized in that: In step 2, the solvent is methanol or acetic acid, the reaction temperature is -5-30°C, and the reaction time is 2-6 hours.

6. The synthesis process according to claim 1, characterized in that: In the step 3, the molar or volume ratio of the intermediate 02: sodium thiophenolate: solvent is 1 mol: 1-3 mol: 8-20 vol.

7. The synthesis process according to claim 1, characterized in that: In step 3, the solvent is one or more of methanol, ethanol, and isopropanol, the reaction temperature is -5-50° C., and the reaction time is 1-5 hours.

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