CN107857743B - A kind of method for preparing roxatidine hydrochloride acetate and intermediate - Google Patents

Abstract

The invention relates to a method for preparing roxatidine hydrochloride acetate and an intermediate thereof, comprising the following steps: dissolving m-hydroxybenzaldehyde in a solvent, adding piperidine dropwise, then adding sodium borohydride, and after post-processing , make 3-(1-piperidine methyl) phenol; In 3-(1-piperidine methyl) phenol, add the standby liquid of 3-chloropropylamine hydrochloride, prepare intermediate 3-[3-(1 -Piperidinylmethyl)phenoxy]propylamine; After the reaction is completed, add acetoxyacetyl chloride and carry out the reaction to obtain the final product Roxatidine hydrochloride acetate. The preparation method of roxatidine hydrochloride and its intermediate of the present invention has the characteristics of stable yield and quality, controllable quality, environmental friendliness and low cost, and is beneficial to industrialized production.

Description

A kind of method for preparing roxatidine hydrochloride acetate and intermediate

technical field

The invention relates to the technical field of compound preparation, in particular to a new preparation method of roxatidine hydrochloride acetate and an intermediate thereof.

Background technique

Roxatidine acetate hydrochloride (roxatidineacetatehydrochloride), chemical name is 2-acetoxy- N- [3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide hydrochloride, Histamine _H2 -receptor blocker developed by Imperial Organ Pharmaceutical Co., Ltd. First listed in Japan in 1986, it is clinically used to treat upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, etc., and is used for pre-anesthetic administration to prevent aspiration pneumonia.

The preparation method of roxatidine hydrochloride acetate has been reported in the literature:

Document 1 (Chen Fen'er, "Organic Drug Synthesis Method", pp. 772-775, 1999) reported the preparation method of roxatidine hydrochloride as shown below (see reaction scheme 1).

Reaction Scheme 1

In the method, m-nitrobenzaldehyde is used as the starting material, and in an aqueous solution, calcium carbonate is used as a carrier to reflux, and the intermediate (A1) is obtained by reduction of ferrous sulfate and sodium bisulfite, and the intermediate (A1) is purified by diazonium After calcination, it was hydrolyzed to obtain m-hydroxybenzaldehyde (A), and the total yield of two steps was 24%; the intermediate (A) was reacted with piperidine in ethanol solution under the action of sodium borohydride to obtain the intermediate (B) ), the yield was 74.5%; the intermediate (B) was in N,N-dimethylformamide solution, and under the action of sodium hydride, and N-bromophthalamide into ether to obtain the intermediate ( C), the yield was 78%; the intermediate (C) was amidated with glycolic acid at 200 °C to obtain the intermediate (C ₁ ), and the yield of the crude product was 91%; the intermediate (C ₁ ) and the Acetic anhydride was esterified at 100°C, purified by silica gel column, and passed into the chloroform solution to form a salt with dry hydrogen chloride gas to obtain roxatidine hydrochloride acetate.

The preparation method of roxatidine hydrochloride disclosed in document 2 (US4293557A) is basically the same as that in document 1, directly using m-hydroxybenzaldehyde (A) as the starting material, and preparing roxatidine hydrochloride by the same route and method as in document 1 titanate acetate. The preparation methods disclosed in documents 1-2 have long synthetic routes, many steps, and low total yield; the steps of preparing intermediate (B) are not completely reacted; when preparing intermediate C, expensive sodium hydride is used, and the cost is high And the reaction conditions are severe; when preparing the intermediate C1, it needs to be melted and reacted at high temperature (200 ° C), the operation is difficult, and the product is complex; after the intermediate (C1) is reacted, it needs to be purified by column chromatography, and the salt-forming step is passed through hydrogen chloride Step, hydrogen chloride itself has hygroscopicity, it is not easy to control absolute drying conditions, the product is easy to decompose, has strong corrosiveness, and requires high process equipment. Therefore, it is not easy to industrialize production.

Document 3 (US5317026A) discloses the preparation method of roxatidine acetate (F) shown below (see Reaction Scheme 2).

Reaction Scheme 2

The method takes m-hydroxybenzaldehyde (A) as the starting material, reacts with piperidine and sodium borohydride in methanol solution to obtain intermediate (B), and the yield is 84.7%; Under the action, it forms ether with 3-chloropropylamine hydrochloride in a mixed solution of dimethyl sulfoxide and benzene to obtain intermediate (C) with a yield of 86%; intermediate (C) and acetoxyacetyl chloride (E) Amidation in anhydrous benzene and triethylamine system, and then purified by silica gel column to obtain roxatidine acetate (F), the yield is higher than 95%. The solvent methanol used in the method step 1 of document 3 is highly toxic, and the reaction is not complete, the product yield and quality are unstable, and the purification step requires column chromatography, the highly toxic solvent benzene is used in steps 2-3, and industrial production is not used. .

Document 4 (CN102993121A) improves the preparation method of document 3, using m-hydroxybenzaldehyde and hexahydropyridine as starting materials, sodium borohydride as reducing agent, and performing condensation reaction in ethanol as solvent to obtain 3-(1-piperidine) pyridinemethyl)phenol (Intermediate B); Intermediate B reacts with 3-chloropropylamine hydrochloride in N,N-dimethylformamide (DMF) solution under the alkaline condition of sodium hydride/sodium hydroxide. 3-(3-(1-piperidinylmethyl)phenoxy)propylamine (Intermediate C) was obtained; Intermediate C was acylated with chloroacetyl chloride dropwise in dichloromethane solvent at low temperature to prepare 2-chloro-N-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide (Intermediate D) was obtained; Intermediate D was dissolved in tetrahydrofuran solution, added without Water potassium acetate powder, after the heating reaction is completed, HCl/tetrahydrofuran solution is added to obtain roxatidine acetate hydrochloride (white solid). The method of document 4 uses expensive sodium hydride in the preparation of intermediate B, which has problems such as higher cost and difficult reaction control, and the product yield is not high; the salt-forming step needs to prepare a hydrogen chloride solution, and hydrogen chloride itself has hygroscopicity and does not. It is easy to control absolute drying conditions, the product is easy to decompose, has strong corrosiveness, and requires high process equipment.

The preparation methods disclosed in documents 1-4 all need to go through multi-step reactions to obtain the final product, and there are harsh reaction conditions, complicated preparation process and operation, long production cycle, many three wastes, which are not conducive to environmental protection, and the preparation cost is high. It is well applied to defects such as industrial production.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide a method for preparing roxatidine hydrochloride acetate which is suitable for industrial production with stable process conditions, high yield, few reaction steps, mild reaction conditions, environmental friendliness, low cost and easy operation. .

One aspect of the present invention provides a method for preparing roxatidine hydrochloride acetate, the method comprising the steps of: 3-[3-(1-piperidinemethyl)phenoxy]propylamine and acetoxyethyl The acid chloride is reacted in a solvent to prepare roxatidine hydrochloride acetate, which is characterized in that the amidation and salt-forming steps are completed in one step, and HCl gas needs to be introduced into the salt-forming step.

The preparation method is as follows: dissolving the intermediate C3-[3-(1-piperidinylmethyl)phenoxy]propylamine in a reaction solvent, dripping acyloxyacetyl chloride under low temperature conditions, and completing the stirring reaction after dripping. After the reaction was completed, it was concentrated under reduced pressure, and the solid residue was slurried with acetonitrile, filtered, and dried in vacuo to obtain rosatidine hydrochloride acetate. Wherein, the molar ratio of the 3-[3-(1-piperidinylmethyl)phenoxy]propylamine:acetoxyacetyl chloride is 1~5:5~1, preferably 1:1-1:1.5, The specific ratio can be 1; 1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5; the reaction solvent is benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, dioxane, Any one of ethyl acetate and anhydrous ether or a combination thereof, preferably toluene, xylene, dichloromethane and ethyl acetate; the reaction temperature is -20~30°C, more preferably -10~25°C. Specifically, acetoxyacetyl chloride was added dropwise at -10 to 0°C. After the dropping is completed, the reaction is carried out at -10~10°C, and then the temperature is raised to 20~30°C and the reaction is continued with stirring.

Optionally, the acetoxyacetyl chloride can be purchased directly, or prepared by the following method:

According to the preparation method of the present invention, it further comprises the following steps: adding 3-chloropropylamine solution to 3-(1-piperidinylmethyl)phenol to obtain the intermediate 3-[3-(1-piperidinylmethyl) phenoxy]propylamine;

Wherein, described standby solution is to dissolve 3-chloropropylamine hydrochloride in alkaline solution, after extraction with organic solvent, obtain; wherein organic solvent is selected from toluene, xylene, carbon tetrachloride, chloroform, dichloromethane Any one of methyl chloride, dioxane or a combination thereof; the base is selected from any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or a combination thereof; the 3 The molar ratio of -(1-piperidinylmethyl)phenol and base can be 1-5:5-1, preferably 1:1; the reaction solvent is selected from ethanol, isopropanol, tetrahydrofuran, N,N-dimethyl Any one of formamide, dimethyl sulfoxide, toluene, xylene, and dioxane or a combination thereof; the reaction temperature is 0-150°C, preferably 100-150°C, more preferably 110-130°C; the reaction time 0.5-10 hours, preferably 1-5 hours; after the reaction is complete, the product is concentrated under reduced pressure and distilled under reduced pressure to obtain 3-[3-(1-piperidinylmethyl)phenoxy]propylamine.

According to the preparation method of the present invention, it further comprises the following steps: dissolving m-hydroxybenzaldehyde in a solvent, adding piperidine dropwise, then adding sodium borohydride, and after completion of the reaction, after post-treatment, the preparation of 3-(1-piperidinemethyl) )phenol;

Wherein, in the step, sodium borohydride is added in stages after m-hydroxybenzaldehyde and piperidine are fully mixed for a period of time (for example, 2-5 hours, preferably 3-4 hours); the classification can be 3 ~4 times, wherein the sodium borohydride is added by an equal amount, or the sodium borohydride is added by a gradient decreasing method, and the first addition at this time does not exceed 50% of the total amount. The molar ratio between the m-hydroxybenzaldehyde, piperidine and sodium borohydride is 1~3:1~5:1~3, preferably 1:3:1; the reaction solvent is selected from polar solvents, preferably N, Any one of N-dimethylformamide, dimethyl sulfoxide, ethanol, isopropanol, tetrahydrofuran or a combination thereof; the reaction temperature is 0~100°C, preferably 25~75°C, more preferably 25~40°C ; The reaction time is 0.5-10 hours, preferably 1-5 hours; the post-processing method is successively through acid washing, alkalization, filtration, water washing, refining and purification of the filter cake.

Compared with the prior art, the present invention has the following beneficial effects:

1. Roxatidine hydrochloride acetate is prepared by reacting (3-[3-(1-piperidinylmethyl)phenoxy]propylamine) with acetoxyacetyl chloride in the absence of an acid binding agent One-step coupling to form salt without subsequent introduction of HCl, the intermediates in each step in the reaction process are not converted into oxalate for purification, which reduces impurities due to the introduction of oxalate, and also shortens the reaction steps. The subsequent treatment procedure is simplified, the reaction cost is reduced, and the hygroscopicity and corrosiveness of hydrogen chloride are avoided. It has the advantages of environmental friendliness, low cost and simple operation.

2. In the method of the present invention, in step 1, before adding sodium borohydride for reduction, the raw material (A) and piperidine are fully reacted in ethanol for a period of time, and then the reducing agent is added in stages, which effectively solves the problem. The raw material reaction is incomplete and the product yield is low, so that the yield can be stabilized to more than 90%.

3. The preparation method of the present invention does not use expensive reagents, and does not require high temperature melting reaction, the reaction conditions are mild, the environment is friendly, the production cost is low, the operation is simple, and is suitable for industrial production.

Detailed ways

The present invention will be specifically described below with reference to the embodiments, and the embodiments are only used to illustrate the technical solutions of the present invention, but do not limit the essence of the present invention.

Example 1 Preparation of 3-(1-piperidinylmethyl)phenol (B)

In a 2L three-necked flask, add 160 g (1.311 mol) of m-hydroxybenzaldehyde, absolute ethanol, stir to dissolve, add 380 ml (3.889 mol) of piperidine dropwise at room temperature, continue stirring for 3 hours, and then cool in ice water Then, 50 g (1.315 mol) of sodium borohydride was added into the reaction flask in stages, and the addition was completed, and the reaction was carried out at room temperature. After the reaction was completed, most of the solvent was concentrated under reduced pressure, cooled, water was added, concentrated hydrochloric acid was added dropwise under stirring and cooling to make the system acidic, and washed with ethyl acetate. The aqueous layer was collected, and under ice-water cooling, the alkalized reaction solution was precipitated as a white solid, filtered, washed with water, drained, and the filter cake was purified and purified. 230 g of intermediate (B) was obtained as white crystalline powder, yield: 91.6%, mp: 135-138°C.

Example 2 Preparation of 3-(1-piperidinylmethyl)phenol (B)

In a 2L three-necked flask, add 160 g (1.311 mol) of m-hydroxybenzaldehyde, anhydrous ethanol, stir to dissolve, add 255 ml (2.60 mol) of piperidine dropwise at room temperature, continue stirring for 3 hours, and then cool in ice water Then, 50 g (1.315 mol) of sodium borohydride was added into the reaction flask in stages, and the addition was completed, and the reaction was carried out at room temperature. After the reaction was completed, most of the solvent was concentrated under reduced pressure, cooled, water was added, concentrated hydrochloric acid was added dropwise under stirring and cooling to make the system acidic, and washed with ethyl acetate. The aqueous layer was collected, and under ice-water cooling, the alkalized reaction solution was precipitated as a white solid, filtered, washed with water, drained, and the filter cake was purified and purified. 226.7 g of intermediate (B) was obtained as white crystalline powder, yield: 90.3%, mp: 135-138°C.

Example 3 Preparation of 3-(1-piperidinylmethyl)phenol (B)

In a 2L three-necked flask, add 160 g (1.311 mol) of m-hydroxybenzaldehyde, anhydrous ethanol, stir to dissolve, and add 380 ml (3.889 mol) of piperidine dropwise at room temperature. After the dripping is completed, the hydroboration is then cooled in ice water. Sodium 50g (1.315mol) was added into the reaction flask in stages, the addition was completed, and the reaction was carried out at room temperature. After the reaction was completed, most of the solvent was concentrated under reduced pressure, cooled, water was added, concentrated hydrochloric acid was added dropwise under stirring and cooling to make the system acidic, and washed with ethyl acetate. The aqueous layer was collected, and under ice-water cooling, the alkalized reaction solution was precipitated as a white solid, filtered, washed with water, drained, and the filter cake was purified and purified. 203.9 g of intermediate (B) was obtained as white crystalline powder, yield: 81.2%, mp: 133-138°C.

Example 4 Preparation of 3-(1-Piperidinylmethyl)phenol (B)

In a 2L three-necked flask, add 160 g (1.311 mol) of m-hydroxybenzaldehyde, anhydrous ethanol, stir to dissolve, add 254 ml (2.60 mol) of piperidine dropwise at room temperature, and after the dripping is completed, then under ice-water cooling, hydrogenate the hydroboration Sodium 50g (1.315mol) was added into the reaction flask in stages, the addition was completed, and the reaction was carried out at room temperature. After the reaction was completed, most of the solvent was concentrated under reduced pressure, cooled, water was added, concentrated hydrochloric acid was added dropwise under stirring and cooling to make the system acidic, and washed with ethyl acetate. The aqueous layer was collected, and under ice-water cooling, the alkalized reaction solution was precipitated as a white solid, filtered, washed with water, drained, and the filter cake was purified and purified. 208.9 g of intermediate (B) was obtained as white crystalline powder, yield: 83.2%, mp: 132-137°C.

Example 5 Preparation of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (C):

In a dry 5L three-necked flask equipped with a water separator, add 220g (1.152mol) of intermediate (B), 580ml of dimethyl sulfoxide, 400ml of toluene, 60g (1.500mol) of sodium hydroxide, heat under reflux to separate water, then The 3-chloropropylamine solution was added dropwise. After dripping, the reflux reaction was continued overnight. Then, cooled to room temperature, filtered, washed with a small amount of toluene, collected the filtrate, concentrated under reduced pressure, recovered the solvent, and distilled under reduced pressure to obtain 231 g of intermediate (C), which was a light yellow thick transparent oil, yield: 81.0%.

Example 6 Preparation of Roxatidine Hydrochloride Acetate:

190g (0.765mol) of intermediate C was dissolved in xylene, and 157g (1.148mol) of acetoxyacetyl chloride was added dropwise at -10~0°C. - After dropping, react at -10~10℃, then heat up to 20~30℃ and continue to stir the reaction. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was slurried with acetonitrile, filtered, and dried under vacuum at 50-60 °C to obtain rosatidine hydrochloride acetate, yield: 90%.

Example 7 Preparation of Roxatidine Hydrochloride Acetate:

190g (0.765mol) of intermediate C was dissolved in dichloromethane, and 157g (1.148mol) of acetoxyacetyl chloride was added dropwise at -10~0°C. After the dropping is completed, the reaction is carried out at -10~10°C, and then the temperature is raised to 20~30°C and the reaction is continued with stirring. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was slurried with acetonitrile, filtered, and dried under vacuum at 50-60 °C to obtain rosatidine hydrochloride acetate, yield: 88.6%.

Example 8 Preparation of Roxatidine Hydrochloride Acetate:

190g (0.765mol) of Intermediate C was dissolved in ethyl acetate, and 157g (1.148mol) of acetoxyacetyl chloride was added dropwise at -10~0°C. After the dropping is completed, the reaction is carried out at -10~10°C, and then the temperature is raised to 20~30°C and the reaction is continued with stirring. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was slurried with acetonitrile, filtered, and dried under vacuum at 50-60 °C to obtain rosatidine hydrochloride acetate, yield: 77.9%.

Example 9 Preparation of Roxatidine Hydrochloride Acetate:

190g (0.765mol) of Intermediate C was dissolved in chloroform, and 157g (1.148mol) of acetoxyacetyl chloride was added dropwise at -10~0°C. After the dropping is completed, the reaction is carried out at -10~10°C, and then the temperature is raised to 20~30°C and the reaction is continued with stirring. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was slurried with acetonitrile, filtered, and dried under vacuum at 50-60 °C to obtain rosatidine hydrochloride acetate, yield: 86.7%.

Example 10 Preparation of Roxatidine Hydrochloride Acetate:

190g (0.765mol) of intermediate C was dissolved in xylene, and 125.3g (0.918mol) of acetoxyacetyl chloride was added dropwise at -10~0°C. After the dropping is completed, the reaction is carried out at -10~10°C, and then the temperature is raised to 20~30°C and the reaction is continued with stirring. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was slurried with acetonitrile, filtered, and dried under vacuum at 50-60 °C to obtain rosatidine hydrochloride acetate, yield: 85.3%.

Claims (11)

1. A method for preparing roxatidine acetate hydrochloride, which comprises the following steps: 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine reacts with acetoxyacetyl chloride in a solvent to prepare roxatidine acetate hydrochloride, and the method is characterized by comprising the following steps: the amidation and salification steps are completed in one step, and HCl gas does not need to be introduced in the salification step; wherein the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine: the molar ratio of acetoxyacetyl chloride is 1-5: 5-1; the reaction solvent is any one or the combination of benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, ethyl acetate, dioxane and anhydrous ether; the reaction temperature is-20 to 30 ℃.

2. The process according to claim 1, wherein the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine: the molar ratio of acetoxyacetyl chloride is 1: 1-1: 1.5; the reaction solvent is toluene, xylene, dichloromethane or ethyl acetate; the reaction temperature is-10 to 25 ℃.

3. The method for preparing the compound of any one of claims 1 to 2, wherein the intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine is dissolved in a reaction solvent, acetoxyacetyl chloride is added dropwise at-10 to 0 ℃ to react at-10 to 10 ℃, and then the temperature is raised to 20 to 30 ℃ to continue the reaction with stirring.

4. The method of manufacturing according to claim 3, further comprising the steps of: adding 3-chloropropylamine solution into 3- (1-piperidinylmethyl) phenol to prepare an intermediate 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine, wherein the 3-chloropropylamine solution is prepared by dissolving 3-chloropropylamine hydrochloride in alkaline solution and extracting by using an organic solvent.

5. The method according to claim 4, wherein the molar ratio of the 3- (1-piperidinylmethyl) phenol to the base is 1-5: 5-1; the reaction solvent is selected from any one or combination of ethanol, isopropanol, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene, xylene and dioxane; the reaction temperature is 0-150 ℃; the reaction time is 0.5 to 10 hours; after the reaction is completed, the product is subjected to reduced pressure concentration and reduced pressure distillation to prepare the 3- [3- (1-piperidinylmethyl) phenoxy ] propylamine.

6. The method as claimed in claim 5, wherein the reaction temperature is 100-150 ℃ and the reaction time is 1-5 hours.

7. The method as claimed in claim 6, wherein the reaction temperature is 110-130 ℃.

8. The process according to any one of claims 4 to 7, which further comprises a step of preparing an intermediate compound, 3- (1-piperidinylmethyl) phenol: dissolving m-hydroxybenzaldehyde in a solvent, dropwise adding piperidine, then adding sodium borohydride, and after the reaction is finished, carrying out post-treatment to prepare the 3- (1-piperidinemethyl) phenol, wherein the sodium borohydride is added in several times after the m-hydroxybenzaldehyde and the piperidine are fully mixed for 2-5 hours.

9. The preparation method according to claim 8, wherein the molar ratio of m-hydroxybenzaldehyde, piperidine and sodium borohydride is 1-3: 1-5: 1-3; the reaction solvent is selected from polar solvents; the reaction temperature is 0-100 ℃; the reaction time is 0.5-10 hours.

10. The preparation method according to claim 9, wherein the molar ratio of m-hydroxybenzaldehyde, piperidine and sodium borohydride is 1:3: 1; the reaction solvent is selected from any one or combination of N, N-dimethylformamide, dimethyl sulfoxide, ethanol, isopropanol and tetrahydrofuran; the reaction temperature is 25-75 ℃.

11. The method according to claim 10, wherein the reaction temperature is 25 to 40 ℃.