阅读说明：本技术 一种盐酸奥洛他定的制备方法 (Preparation method of olopatadine hydrochloride ) 是由 李昌华 于 2021-08-26 设计创作，主要内容包括：本发明涉及药物合成领域,尤其涉及一种盐酸奥洛他定的制备方法,其包括如下步骤：将[3-(二甲基氨基)丙基]三苯基磷溴化物氢溴酸盐加入四氢呋喃、氢化钠与二甲基亚砜中,保温搅拌加入11-氧代-6,11-二氢二苯并[b,e]氧杂卓-2-乙酸,搅拌至反应体系成黑褐色浊液反应结束；反应液经纯化水和四氢呋喃的混合液淬灭,水相用盐酸和正丁醇的混合溶剂后处理,后处理得水溶液在经过减压浓缩,浓缩液经正丁醇析晶、过滤、干燥即得盐酸奥洛他定粗品,接着在水和氢氧化钠溶液中,析出固体物,经过滤、干燥得奥洛他定；奥洛他定经丙酮搅拌加入盐酸,成白色浊液,继续搅拌后过滤、干燥得盐酸奥洛他定,本发明制备得到的盐酸奥洛他定其收率高,反应路线短。(The invention relates to the field of drug synthesis, in particular to a preparation method of olopatadine hydrochloride, which comprises the following steps: adding [3- (dimethylamino) propyl ] triphenyl phosphonium bromide hydrobromide into tetrahydrofuran, sodium hydride and dimethyl sulfoxide, keeping the temperature, stirring, adding 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid, and stirring until a reaction system becomes black brown turbid liquid to react; quenching the reaction liquid by mixed liquid of purified water and tetrahydrofuran, post-treating the water phase by using mixed solvent of hydrochloric acid and n-butyl alcohol, carrying out reduced pressure concentration on the obtained water solution, carrying out crystallization on the concentrated solution by using n-butyl alcohol, filtering and drying to obtain crude olopatadine hydrochloride, then separating out solids in water and sodium hydroxide solution, filtering and drying to obtain olopatadine; the olopatadine hydrochloride is prepared by adding the olopatadine into hydrochloric acid through stirring by acetone to form white turbid liquid, continuously stirring, filtering and drying to obtain the olopatadine hydrochloride.)

1. The preparation method of olopatadine hydrochloride is characterized by comprising the following steps:

A. under the protection of nitrogen, firstly adding [3- (dimethylamino) propyl ] triphenyl phosphonium bromide hydrobromide into tetrahydrofuran, controlling the temperature to be 10-20 ℃, then adding sodium hydride solution and dimethyl sulfoxide, keeping the temperature at 20-30 ℃ and stirring for 1-2 h, heating to 45-50 ℃, continuing stirring for 2-3 h, finally adding 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid, continuing stirring for 15-20 h until the reaction system becomes black brown turbid liquid, ending the reaction, quenching the reaction liquid by mixed liquid of purified water and tetrahydrofuran, treating the water phase by using mixed solvent of hydrochloric acid and n-butyl alcohol, decompressing and concentrating the obtained water solution, and crystallizing, filtering and drying the concentrated solution by using the n-butyl alcohol to obtain crude olopatadine hydrochloride;

B. adding a sodium hydroxide solution into the olopatadine hydrochloride crude product obtained in the step A to adjust the pH value to 6.8-7.2, separating out a solid, filtering and drying to obtain olopatadine;

C. and D, adding acetone into the olopatadine obtained in the step B, adding hydrochloric acid while stirring until the mixture becomes white turbid liquid, continuously stirring for 10-15 h, filtering and drying to obtain the olopatadine hydrochloride.

2. The method for preparing olopatadine hydrochloride according to claim 1, wherein the mass fraction of the sodium hydride solution in the step A is 60%.

3. The method for preparing olopatadine hydrochloride according to claim 1, wherein the tetrahydrofuran is 10% by weight in the step A.

4. The method for preparing olopatadine hydrochloride according to claim 1, wherein the mass fraction of the dimethyl sulfoxide in the step A is 0.66%.

5. The method for preparing olopatadine hydrochloride according to claim 1, wherein in the step A, the molar ratio of the [3- (dimethylamino) propyl ] triphenyl phosphonium bromide hydrobromide to the 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid is (2-3): 1.

6. the method for preparing olopatadine hydrochloride according to claim 1, wherein in step A, the molar ratio of the [3- (dimethylamino) propyl ] triphenylphosphonium bromide hydrobromide to sodium hydride is 2.7: (6.5-7).

7. The method for preparing olopatadine hydrochloride according to claim 1, wherein in the step B, the molar ratio of the crude olopatadine hydrochloride to the sodium hydroxide is 1: (1-1.5).

8. The method for preparing olopatadine hydrochloride according to claim 1, wherein in the step C, the molar ratio of olopatadine to hydrochloric acid is 1: (1-3).

Technical Field

The invention relates to the field of drug synthesis, in particular to a preparation method of olopatadine hydrochloride.

Background

Olopatadine hydrochloride with molecular formula C₂₁H₂₃NO₃HCl, molecular weight 373.87, chemical name (Z) -11- [3- (dimethylamino) propylidene]-6, 11-dihydrodibenzo [ b, e ]]Oxepin-2-acetic acid hydrochloride, CAS: 140462-76-6. The structural formula is as follows:

olopatadine hydrochloride is an antiallergic drug developed and marketed by Japan cooperative and fermentation companies, is successively marketed in Europe, America, Japan and other countries, belongs to an h1 receptor antagonist, has main clinical effects and efficacies of antihistaminic and antiallergic, and is used for treating various diseases closely related to allergic reactions, such as allergic rhinitis, allergic conjunctivitis, allergic asthma, insect bite dermatitis, dermatosis (eczema, dermatitis, prurigo, cutaneous pruritus, psoriasis vulgaris, erythema exudativum multiforme) accompanied with pruritus atopic dermatitis, urticaria and the like.

In the prior art, p-hydroxyphenylacetic acid and phthalide are used as raw materials, and olopatadine hydrochloride is prepared through nucleophilic substitution, dehydration cyclization, Wittig reaction and salification, so that the yield is low and the reaction route is long.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of olopatadine hydrochloride, which has high yield and short reaction route and is suitable for large-scale production.

The invention takes 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid as an initial raw material 1, takes [3- (dimethylamino) propyl ] triphenyl phosphorus bromide hydrobromide as an initial raw material 2, and finally obtains olopatadine hydrochloride through a series of reactions, wherein the process flow is as follows:

specifically, the invention provides a preparation method of olopatadine hydrochloride, which comprises the following steps:

A. under the protection of nitrogen, firstly adding [3- (dimethylamino) propyl ] triphenyl phosphonium bromide hydrobromide into tetrahydrofuran, controlling the temperature to be 10-20 ℃, then adding sodium hydride solution and dimethyl sulfoxide, keeping the temperature at 20-30 ℃ and stirring for 1-2 h, heating to 45-50 ℃, continuing stirring for 2-3 h, finally adding 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid, continuing stirring for 15-20 h until the reaction system becomes black brown turbid liquid, ending the reaction, quenching the reaction liquid by mixed liquid of purified water and tetrahydrofuran, treating the water phase by using mixed solvent of hydrochloric acid and n-butyl alcohol, decompressing and concentrating the obtained water solution, and crystallizing, filtering and drying the concentrated solution by using the n-butyl alcohol to obtain crude olopatadine hydrochloride;

B. adding a sodium hydroxide solution into the olopatadine hydrochloride crude product obtained in the step A to adjust the pH value to 6.8-7.2, separating out a solid, filtering and drying to obtain olopatadine;

C. and D, adding acetone into the olopatadine obtained in the step B, adding hydrochloric acid while stirring until the mixture becomes white turbid liquid, continuously stirring for 10-15 h, filtering and drying to obtain the olopatadine hydrochloride.

The invention has the beneficial effects that: the olopatadine hydrochloride prepared by the method has high yield and short reaction route, and is suitable for large-scale production.

Optionally, in step a, the mass fraction of the sodium hydride solution is 60%.

Optionally, in step a, the mass fraction of tetrahydrofuran is 10%.

Optionally, in step a, the mass fraction of dimethyl sulfoxide is 0.66%.

Alternatively, in step a, the molar ratio of [3- (dimethylamino) propyl ] triphenylphosphonium bromide hydrobromide to 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid is (2-3): 1.

alternatively, in step a, the molar ratio of [3- (dimethylamino) propyl ] triphenylphosphonium bromide hydrobromide to sodium hydride is 2.7: (6.5-7).

Optionally, in step B, the molar ratio of the crude olopatadine hydrochloride to sodium hydroxide is 1: (1-1.5).

Optionally, in step C, the molar ratio of olopatadine to hydrochloric acid is 1: (1-3).

Detailed Description

The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.

Example 1

A. Under the protection of nitrogen, firstly, adding 30.76kg (60.40mol) of [3- (dimethylamino) propyl ] triphenyl phosphorus bromide hydrobromide into 60.0kg of tetrahydrofuran with the mass fraction of 10%, controlling the temperature to be 10 ℃, then adding 3.65kg (152.12mol) of sodium hydride solution with the mass fraction of 60% and 3.96kg of dimethyl sulfoxide with the mass fraction of 0.66%, keeping the temperature and stirring for 1h at the temperature of 20 ℃, then heating to 45 ℃, continuing to stir for 2h, finally adding 6.00kg (22.37mol) of 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid, continuing to stir for 15h until the reaction system becomes black brown turbid liquid, quenching the reaction liquid by 77.94kg of a mixed liquid of purified water and 2.44kg of tetrahydrofuran with the mass fraction of 10%, treating the water phase by using a mixed solvent of 5kg of hydrochloric acid and 87.4kg of n-butyl alcohol, concentrating the obtained water solution under reduced pressure, crystallizing the concentrated solution by n-butanol, filtering, and drying to obtain 3.48kg crude olopatadine hydrochloride;

B. adding 412.40g (10.31mol) of sodium hydroxide solution into the olopatadine hydrochloride crude product obtained in the step A to adjust the pH value to 6.8, separating out a solid, filtering and drying to obtain 2.60kg (7.71mol) of olopatadine;

C. and C, adding 38.71kg of acetone into the olopatadine obtained in the step B, adding 0.29kg (7.94mol) of hydrochloric acid while stirring to form a white turbid solution, continuously stirring for 10 hours, filtering and drying to obtain 2.88kg of olopatadine hydrochloride, wherein the total yield is 24% and the purity is 96%.

m.p.248℃(dec)[24.3％，248℃(dec)[7]]；1HNMRδ：2.72(s，6H)，2.79(q,J＝7.2Hz，2H)3.24(t，J＝8.0Hz，2H)3.57(s，2H)，5.17(br，2H)5.65(t，J＝7.2Hz，1H)，6.79～7.39(m，7H)；IRν：2682，1718，1622，1491，1225cm^-1；MSm/Z：337(M⁺)。

Example 2

A. Under the protection of nitrogen, firstly, 52.34kg of 10% tetrahydrofuran is added with 18.31kg (44.74mol) of [3- (dimethylamino) propyl ] triphenyl phosphorus bromide hydrobromide, the temperature is controlled to be 15 ℃, then 2.59kg (107.71mol) of 60% sodium hydride solution and 3.12kg of 0.66% dimethyl sulfoxide are added, the mixture is kept at 23 ℃ and stirred for 2h, then the temperature is raised to 48 ℃, the mixture is continuously stirred for 2h, finally 6.00kg (22.37mol) of 11-oxo-6, 11-dibenzo [ b, e ] oxepin-2-acetic acid is added, the stirring is continuously carried out for 18h until the reaction system becomes brown turbid liquid, the reaction liquid is quenched by a mixed solution of 62.41kg of purified water and 1.83kg of 10% tetrahydrofuran, the water phase is treated by a mixed solvent of 3.1kg of hydrochloric acid and 64.23kg of n-butyl alcohol, concentrating the obtained water solution under reduced pressure, crystallizing the concentrated solution by n-butanol, filtering, and drying to obtain 2.74kg crude olopatadine hydrochloride;

B. adding 293.15g (7.33mol) of sodium hydroxide solution into the olopatadine hydrochloride crude product obtained in the step A to adjust the pH value to 7.1, separating out a solid, filtering and drying to obtain 2.12kg (6.28mol) of olopatadine;

C. and D, adding 25.87kg of acetone into the olopatadine obtained in the step B, adding 0.46kg (12.57mol) of hydrochloric acid while stirring to form a white turbid solution, continuously stirring for 11h, filtering and drying to obtain 2.35kg of olopatadine hydrochloride, wherein the total yield is 21 percent, and the purity is 98 percent.

m.p.248℃(dec)[24.3％，248℃(dec)[7]]；1HNMRδ：2.72(s，6H)，2.79(q,J＝7.2Hz，2H)3.24(t，J＝8.0Hz，2H)3.57(s，2H)，5.17(br，2H)5.65(t，J＝7.2Hz，1H)6.79～7.39(m，7H)；IRν：2682，1718，1622，1491，1225cm^-1；MSm/Z：337(M⁺)。

Example 3

A. Under the protection of nitrogen, firstly adding 34.17kg (67.11mol) of [3- (dimethylamino) propyl ] triphenyl phosphorus bromide hydrobromide into 68.25kg of tetrahydrofuran with the mass fraction of 10%, controlling the temperature to be 20 ℃, then adding 4.118kg (173.99mol) of sodium hydride solution with the mass fraction of 60% and 5.12kg of dimethyl sulfoxide with the mass fraction of 0.66%, keeping the temperature and stirring for 2h at 30 ℃, then heating to 48 ℃, continuing to stir for 2h, finally adding 6.00kg (22.37mol) of 11-oxo-6, 11-dihydrodibenzo [ b, e ] oxepin-2-acetic acid, continuing to stir for 20h until the reaction system becomes black brown turbid liquid, quenching the reaction liquid by a mixed solution of 93.12kg of purified water and 3.67kg of tetrahydrofuran with the mass fraction of 10%, treating the water phase by a mixed solvent of 8kg of hydrochloric acid and 98.12kg of n-butanol, concentrating the obtained water solution under reduced pressure, crystallizing the concentrated solution by n-butanol, filtering, and drying to obtain 5.24kg crude olopatadine hydrochloride;

B. adding 840.71g (21.02mol) of sodium hydroxide solution into the olopatadine hydrochloride crude product obtained in the step A to adjust the pH value to 7.2, separating out a solid, filtering and drying to obtain 4.13kg (12.24mol) of olopatadine;

C. and C, adding 52.13kg of acetone into the olopatadine obtained in the step B, adding 1.34kg (36.72mol) of hydrochloric acid while stirring to form a white turbid solution, continuously stirring for 15 hours, filtering and drying to obtain 4.58kg of olopatadine hydrochloride, wherein the total yield is 25 percent, and the purity is 99 percent.

m.p.248℃(dec)[24.3％，248℃(dec)[7]]；1HNMRδ：2.72(s，6H)，2.79(q,J＝7.2Hz，2H)3.24(t，J＝8.0Hz，2H)3.57(s，2H)，5.17(br，2H)5.65(t，J＝7.2Hz，1H)6.79～7.39(m，7H)；IRν：2682，1718，1622，1491，1225cm^-1；MSm/Z：337(M⁺)。

Comparative example

The olopatadine hydrochloride is prepared by taking p-hydroxyphenylacetic acid and phthalide as raw materials through nucleophilic substitution, dehydration cyclization, Wittig reaction and salification, and the process flow is as follows:

the preparation process comprises the following steps:

(1) preparation of 4- (2-carboxybenzyloxy) phenylacetic acid (4): adding 10.0g (0.06mol) of p-hydroxyphenylacetic acid, 8.1g (0.06mol) of phthalide and 60mL into a 250mL three-necked bottle, stirring for dissolving, dropwise adding 7.0g (0.13mol) of potassium hydroxide methanol solution, performing reflux reaction for 1h after the dropwise adding is finished, evaporating the methanol, heating for reflux reaction for 3h, cooling, pouring the reaction solution into 50mL of water, adjusting the pH to be 2 by using 4mol/L of hydrochloric acid solution, generating a large amount of white precipitates, standing for 1h, performing suction filtration to obtain a white solid, washing with water, drying, and recrystallizing ethanol to obtain 14.1g of the white solid with the yield of 78%;

(2) preparation of Ethyl 6, 11-dihydrobenzo [ b, e ] oxa-11-one-2-acetate (5): adding 25g of phosphorus pentoxide into a 100mL three-necked bottle, slowly dropwise adding 22.7mL of absolute ethanol at room temperature, heating to 110 ℃ for reaction for 1h, adding 10.0g (33mmol) of 4- (2-carboxybenzyloxy) phenylacetic acid, reacting at 110 ℃ for 2h, cooling, pouring into ice water, extracting with ethyl acetate (30mL multiplied by 3), combining ethyl acetate layers, washing with water until the pH value is 7, drying with anhydrous sodium sulfate, and evaporating the solvent to dryness to obtain 9.4g of brown oily matter with the yield of 90%;

(3) preparation of 6, 11-dihydrobenzo [ b, e ] oxa-11-one-2-acetic acid (6): placing the brown oily substance prepared in the previous step into a 100mL eggplant-shaped bottle, adding 20mL of 4mol/L sodium hydroxide solution, carrying out reflux reaction for 1h, cooling, adjusting the pH to 5 with 2mol/L hydrochloric acid solution, extracting with ethyl acetate (20mL multiplied by 3), combining the ethyl acetate, washing with water until the pH is 7, drying with anhydrous sodium sulfate, evaporating the solvent to obtain yellow sticky substance, recrystallizing with ethyl acetate and diethyl ether, and decolorizing with activated carbon to obtain 7.1g of light yellow crystal, wherein the yield is 83%;

(4) preparation of cis) -11- [ 3-dimethylaminopropenyl ] -6, 11-dihydrobenzo [ b, e ] oxa-2-acetic acid (7): in a 250mL three-necked flask, 14.4g (28mmol) of 3-dimethylaminopropyltriphenylphosphonium hydrobromide and 40mL of a 1.92mol/L n-hexane solution of n-butyllithium were added slowly while cooling in an ice salt bath, and after completion of the addition, the reaction was stirred at 0 ℃ or lower for 1 hour, a 20mL THF solution of 4g (14mmol) of Compound 6 was added, the reaction was refluxed for 12 hours, cooled, THF was evaporated, the residue was dissolved in 20mL water, extracted with diethyl ether (15 mL. times.2), the aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid, extracted with ethyl acetate (15 mL. times.2), the aqueous solution was neutralized with 4mol/L sodium hydroxide solution to pH 7, and the water was removed by concentration to obtain 3.1g of crude Compound 7 with a yield of 65%. Recrystallizing the crude product with isopropanol for 2 times to obtain (Z) -70.97g with yield of 31.2%;

(5) preparation of olopatadine hydrochloride (1): dissolving 0.45g of olopatadine prepared above in 2mL of isopropanol, introducing hydrogen chloride gas, stirring at room temperature for 1h, concentrating, and recrystallizing the residue with acetone to obtain 0.25g of white powdery solid with the yield of 50% and the total yield of 9.09%.

From the above examples 1, 2 and 3, it is clear that the total yield of the present application is between 21% and 25%, which is higher than the total yield of the comparative example of 9.09%. Meanwhile, the reaction route of the application is shorter than that of the comparative example.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.