CN114276384A - Synthetic method of desmethyl olopatadine and its intermediates - Google Patents

Abstract

The application relates to the field of drug synthesis, and discloses a synthetic method of demethyl olopatadine and an intermediate thereof, wherein the synthetic method of the demethyl olopatadine intermediate comprises the following steps: adding a solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere; distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry; recrystallizing, filtering to obtain white solid, and drying the white solid to constant weight; the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide. In the application, the first raw material is introduced to react with triphenylphosphine respectively, and hydrogen bromide molecules of an intermediate are directly neutralized and removed, so that the consumption of a metal reducing agent is reduced in the subsequent synthesis of demethylolopatadine, and the purposes of high efficiency and safety risk reduction are achieved.

Description

Synthetic method of desmethyl olopatadine and its intermediates

technical field

The application relates to the field of pharmaceutical synthesis, and mainly relates to a method for synthesizing desmethyl olopatadine and an intermediate thereof.

Background technique

N-desmethyl olopatadine and N,N-desmethyl olopatadine are commonly used to demarcate the impurities in olopatadine hydrochloride, a novel H ₁ receptor antagonist, to determine the purity of olopatadine hydrochloride . N-DesMethylOlopatadine (N-DesMethylOlopatadine) chemical name: (Z)-11-[3-(methylamino)propylene]-6,11-dihydrodibenzo[ b,e ]oxy Hetero-2-acetic acid, 2-[(11Z)-11-[3-(methylamino)

propylidene]-6H-benzo[c][1]benzoxepin-2-yl]acetic acid, CAS: 113835-92-0. N,N-Didesmethyl Olopatadine (N,N-Didesmethyl Olopatadine) Chemical name: (Z)-11-[3-(amino)propylene]-6,11-dihydrodibenzo[ b,e ]oxazepin-2-acetic acid, 2-[(11Z)-11-[3-(amino)propylidene]-6H-benzo[c][1]benzoxepin-2-yl]acetic acid, CAS: 113835-94-2. The structural formulas of N-desmethyl olopatadine, N,N-desmethyl olopatadine and olopatadine are as follows:

。

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There are few methods to obtain N-desmethyl olopatadine and N,N-desmethyl olopatadine. By referring to the synthesis method of olopatadine, the compound containing tertiary amine structure can be replaced during the synthesis process into a compound containing a primary or secondary amine structure, and then according to the olopatadine synthesis method to synthesize the target product.

For example, EP0235796 reported the synthesis of (3-methylaminopropyl) triphenylphosphonium bromide hydrobromide and (3- Aminopropyl) triphenylphosphonium bromide hydrobromide, the two kinds of hydrobromide and isokic acid synthesize trans-N-desmethyl olopatadine methyl ester, N-desmethyl olopatadine methyl ester, trans-N,N-desmethyl olopatadine methyl ester and N,N-desmethyl olopatadine methyl ester, N-desmethyl olopatadine obtained by column chromatography methyl ester and N,N-desdimethylolopatadine methyl ester. N-desmethyl olopatadine methyl ester and N,N-desmethyl olopatadine methyl ester are then hydrolyzed to obtain N-desmethyl olopatadine and N,N-desmethyl olopatadine Certainly. In the synthesis method, the synthesis process requires a high temperature reaction, involving dangerous chemicals such as n-butyllithium, which increases the reaction risk, and the lengthy reaction steps lead to a serious decrease in the overall yield. Its synthetic route is shown as follows:

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Therefore, the existing technology still needs to be improved and developed.

SUMMARY OF THE INVENTION

In view of the deficiencies of the above-mentioned prior art, the purpose of this application is to provide a kind of synthetic method of desmethyl olopatadine and intermediate thereof, is intended to solve existing N-desmethyl olopatadine and N,N- The problems of complex synthetic route and low yield of dimethyl olopatadine are eliminated.

The technical solution of this application is as follows:

A kind of synthetic method of the intermediate of desmethyl olopatadine, wherein, the intermediate of described desmethyl olopatadine is (3-methylaminopropyl) triphenylphosphine bromide or (3-amino propyl) triphenylphosphine bromide, comprising the following steps:

Add the first solvent, triphenylphosphine and the first raw material, and heat and stir under a protective gas atmosphere;

Distill under reduced pressure to dryness, add water, add extraction solvent, separate the organic phase to retain the organic phase, stir and wash the organic phase with a neutralized alkaline solution, separate the organic phase to retain the organic phase, and dry the organic phase with a desiccant and then distill to dryness;

Add recrystallization solvent, recrystallization, suction filtration to obtain white solid, and the white solid is dried to constant weight;

Described first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide;

When the first raw material is the (3-bromopropyl)(N-methyl)amine hydrobromide, the prepared product is (3-methylaminopropyl)triphenylphosphine bromide; when When the first raw material is the 3-bromopropylamine hydrobromide, the prepared product is (3-aminopropyl) triphenylphosphine bromide.

In this application, by introducing (3-bromopropyl) (N-methyl) amine hydrobromide and 3-bromopropylamine hydrobromide, respectively react with triphenylphosphine, and then directly neutralize and remove the intermediate Hydrogen bromide molecule, in order to reduce the amount of metal reducing agent in the subsequent synthesis of N-desmethyl olopatadine and N,N-desmethyl olopatadine, to achieve the purpose of high efficiency but reduced safety risk.

The synthetic method of the intermediate of described desmethyl olopatadine, wherein, the molar ratio of described triphenylphosphine and described (3-bromopropyl) (N-methyl) amine hydrobromide is 1 : (1.1~2.3);

The molar ratio of the triphenylphosphine to the 3-bromopropylamine hydrobromide is 1: (1.1 to 2.4).

Too much triphenylphosphine is not conducive to removing unreacted triphenylphosphine during post-processing. Therefore, triphenylphosphine is compared to another core raw material (3-bromopropyl)(N-methyl)amine hydrogen Bromate or 3-bromopropylamine hydrobromide should be less.

The synthetic method of the intermediate of described desmethyl olopatadine, wherein, described protective gas is argon or nitrogen;

The first solvent is one of isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio of the first solvent to the triphenylphosphine The range is (4~7): 1;

The extraction solvent is one of dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, ethyl acetate, toluene or benzene; the The mass ratio range of water to the triphenylphosphine is (5~7):1, and the mass ratio range of the extraction solvent to the triphenylphosphine is (10~15):1;

Described neutralization alkali is a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammoniacal liquor, diethylamine or triethylamine; The quality of described neutralization alkali solution The concentration range is 10% to 30%, and the mass ratio of the content of the neutralized alkali in the neutralized alkali solution to the triphenylphosphine is in the range of (0.2 to 0.6): 1;

The desiccant is one of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieve, and the mass ratio of the desiccant to triphenylphosphine ranges from (0.5 to 1): 1;

The recrystallization solvent is one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether; the mass ratio of the recrystallization solvent to the triphenylphosphine ranges from (1 to 2):1.

The synthetic method of the intermediate of described desmethyl olopatadine, wherein, the first solvent is isopropanol;

The extraction solvent is dichloromethane;

Described neutralization alkali is sodium hydroxide;

Described desiccant is anhydrous sodium sulfate;

The recrystallization solvent is tetrahydrofuran.

The synthetic method of the described intermediate of desmethyloclopatadine, wherein, the process of heating and stirring is specifically heated to 75～82° C. and stirred for 10～16 hours;

The process of described recrystallization is warming up to the temperature range of material dissolving, the temperature range of described material dissolving is 60～66 ℃, and then cooling down to the temperature range of material crystallization, the temperature range of described material crystallization is-5～5 ℃ ;

During the drying process, the temperature is controlled at 55-65°C.

A kind of synthetic method of desmethyl olopatadine, desmethyl olopatadine is N-desmethyl olopatadine or N,N-desmethyl olopatadine, wherein, comprises the following steps:

Adopt the above-mentioned synthetic method of the intermediate of desmethyl olopatadine to prepare the second raw material, and the second raw material is (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) ) triphenylphosphine bromide;

Add the second raw material and the second solvent, start stirring, control the temperature, add a metal reducing agent, control the temperature after adding, and react for several hours;

Add isoxocic acid, control the temperature and stir for several hours, then lower the temperature, add the first quenching solvent, then add the second quenching solvent, and finally add water to quench the reaction;

Add acid to adjust pH value, distill to dryness under reduced pressure, and separate the dry product by column chromatography;

When the second raw material is (3-methylaminopropyl) triphenylphosphine bromide, the prepared product is N-desmethyl olopatadine; when the second raw material is (3-aminopropyl) base) triphenylphosphine bromide, the prepared product is N,N-desdimethylolopatadine.

The synthetic method of the described desmethyl olopatadine, wherein, the mass ratio range of the second raw material to the isoxocic acid is (1.5-2.5): 1;

When the second raw material is (3-methylaminopropyl) triphenylphosphine bromide, the pH value is adjusted to 7.2~7.8; when the second raw material is (3-aminopropyl) ) triphenylphosphine bromide, the pH value is adjusted to 8.0~8.4.

The synthetic method of described desmethyl olopatadine, wherein, described second solvent is a kind of in tetrahydrofuran, chloroform or toluene, and the mass ratio scope of described solvent and described isoxocic acid is (5～5～1. 15): 1;

The metal reducing agent is one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, and the mass concentration range of the metal reducing agent is 30% to 35%. The content of the metal reducing agent in the metal reducing agent and the isokic acid mass ratio range is (0.4~0.8): 1;

The first quenching solvent is anhydrous methanol or anhydrous ethanol, the mass ratio of the first quenching solvent to the isokic acid is (0.2~0.4): 1, and the second quenching solvent is Tetrahydrofuran aqueous solution, the mass concentration of the tetrahydrofuran aqueous solution is 40~60%, and the content of the tetrahydrofuran in the tetrahydrofuran aqueous solution and the isoxic acid mass ratio range is (1.5~2.5): 1; The mass ratio range of isoxocic acid is (10~20): 1;

Described acid is a kind of in hydrochloric acid, sulfuric acid or acetic acid;

During the separation process of the column chromatography, the eluent is a system of ethyl acetate and methanol, a system of ethyl acetate and ethanol, or a system of ethyl acetate and acetone, and the fillers in the chromatography column are silica gel and basic alumina.

The synthetic method of described desmethyl olopatadine, wherein, the second solvent is tetrahydrofuran;

Described metal reducing agent is potassium hydride;

The first quenching solvent is anhydrous methanol;

Described acid is concentrated hydrochloric acid, and the mass concentration of described concentrated hydrochloric acid is 20%～38%;

The eluent is an ethyl acetate and methanol system, and the ratio of the ethyl acetate to the methanol is (6-10):1.

The method for synthesizing desmethyl olopatadine, wherein, the temperature control, the process of adding a metal reducing agent is specifically controlling the temperature at 18-25° C., adding a metal reducing agent;

The described temperature control after adding, and the process of reacting for several hours is specifically that the temperature is controlled at 58～66 ℃ after adding, and the reaction is performed for 1～2 hours;

The process of adding isoxocic acid, controlling the temperature and stirring for several hours, and then cooling down is specifically adding isoxocic acid, stirring at 58-66° C. for 1.5-3.5 hours under temperature control, and then cooling to 5-10° C.

Beneficial effect: the synthetic method of desmethyl olopatadine provided by the application, on the basis of the prior art, has carried out upgrading and transformation to the key steps, has the following advantages: 1, the intermediate removes unnecessary molecules, reduces the lower One-step reaction risk; 2. Reduce reaction steps, reduce loss, and improve production efficiency; 3. Replace metal reducing agent, reduce reaction and post-processing risks; 4. Post-processing is concise and direct separation; 5. The reaction conditions are mild, and the The equipment requirements are not high; 6. The yield is high and the quality is good.

Description of drawings

Fig. 1 is the HPLC detection result figure of the product N-desmethylolopatadine obtained in Example 1 of the application.

Fig. 2 is the HPLC detection result diagram of the product obtained in the embodiment 2 of the application, N,N-desdimethyloclopatadine.

Fig. 3 is the HPLC detection result diagram of the product obtained in Example 3 of the application, N-desmethylolopatadine.

Fig. 4 is the HPLC detection result figure of the product obtained in the embodiment 4 of the application, N,N-desdimethylolopatadine.

Detailed ways

The present application provides a synthetic method of desmethyl olopatadine and a synthetic method of its intermediates. In order to make the purpose, technical scheme and effect of the present application more clear and definite, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application, but not to limit the present application.

In this application, the intermediate of desmethylolopatadine is (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) triphenylphosphine bromide, and desmethylolopatadine He was designated as N-desmethyl olopatadine or N,N-desmethyl olopatadine.

In this application, the compounds involved include: triphenylphosphine (CAS:603-35-0), (3-bromopropyl)(N-methyl)amine hydrobromide (CAS:60035-88-3) , 3-bromopropylamine hydrobromide (CAS: 5003-71-4), (3-methylaminopropyl) triphenylphosphine bromide (CAS: 145126-87-0), (3-aminopropyl) Triphenylphosphine bromide (CAS: 89996-01-0) and isokic acid (CAS: 55453-87-7), the molecular structures are as follows:

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The application provides a kind of synthetic method of the intermediate of desmethyl olopatadine, by introducing (3-bromopropyl) (N-methyl) amine hydrobromide and 3-bromopropylamine hydrobromide respectively with Triphenylphosphine reaction, and then directly neutralize and remove the hydrogen bromide molecule of the intermediate, so as to reduce the metal reducing agent in the subsequent synthesis of N-desmethyl olopatadine and N,N-desmethyl olopatadine Dosage to achieve high efficiency but reduce safety risks.

Specifically, the synthetic method of the intermediate of desmethyl olopatadine, the intermediate of desmethyl olopatadine is (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) Triphenylphosphine bromide, comprising the following steps:

Add the first solvent, triphenylphosphine and the first raw material, and heat and stir under a protective gas atmosphere;

Distill under reduced pressure to dryness, add water, add extraction solvent, separate the organic phase to retain the organic phase, stir and wash the organic phase with a neutralized alkaline solution, separate the organic phase to retain the organic phase, and dry the organic phase with a desiccant and then distill to dryness;

Add a recrystallization solvent, recrystallize, and suction filtration to obtain a white solid, which is dried to constant weight to obtain (3-methylaminopropyl)triphenylphosphine bromide or (3-aminopropyl)triphenylene Phosphine bromide.

The first raw material is (3-bromopropyl) (N-methyl)amine hydrobromide or 3-bromopropylamine hydrobromide. When the first raw material is (3-bromopropyl)(N-methyl)amine hydrobromide, the prepared product is (3-methylaminopropyl)triphenylphosphine bromide; when the first raw material is When 3-bromopropylamine hydrobromide is used, the prepared product is (3-aminopropyl) triphenylphosphine bromide.

As the core raw material of chemical reaction, triphenylphosphine participates in the construction of chemical structure, and too much triphenylphosphine is not conducive to removing unreacted triphenylphosphine during post-processing. Therefore, triphenylphosphine is compared with another core raw material. (3-bromopropyl)(N-methyl)amine hydrobromide or 3-bromopropylamine hydrobromide is less. Therefore, in this application, the molar ratio of triphenylphosphine to (3-bromopropyl)(N-methyl)amine hydrobromide is 1:(1.1~2.3); triphenylphosphine to 3-bromopropylamine The molar ratio of hydrobromide is 1:(1.1~2.4).

The first solvent can be a kind of in isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio scope of the first solvent and triphenylphosphine can be (4 ~7): 1. In the embodiment of the present application, using isopropanol as the first solvent can reach the temperature required for the reaction and dissolve the two products. If it is replaced with other alternative solvents, the same effect can also be achieved, but the reaction time is only a matter of time. Alternative solvents are n-propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol and isobutanol.

The shielding gas can be argon or nitrogen. The process of heating and stirring is specifically heating to 75-82° C. and stirring for 10-16 hours.

In the embodiments of the present application, the first solvent and the subsequent extraction solvent have a certain mutual solubility, so the first solvent is selected to be distilled to dryness to remove the first solvent, and then the extraction is performed. After distillation, choose to dissolve in water and then extract with the extraction solvent, instead of directly using the extraction solvent for filtration, because both phases are liquid phases, which can more completely extract the product and improve the yield. In actual production, the organic phase and the water phase are separated. The liquid is simpler than filtration, and the undissolved solid of the extraction solvent is also likely to form large pieces of solid. In actual production, it is not conducive to discharge and filter from the bottom valve of the production kettle. The unreacted raw material (3-bromopropyl) (N- Methyl)amine hydrobromide or 3-bromopropylamine hydrobromide can also be dissolved under anhydrous conditions and part of it exists as an impurity in dichloromethane.

The extraction solvent can be one of dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, ethyl acetate, toluene or benzene. After distillation under reduced pressure to dryness, the range of the mass ratio of the added amount of water to triphenylphosphine can be (5~7): 1, and the range of the added amount of the extraction solvent to the mass ratio of triphenylphosphine can be (10~15). ):1. In the embodiments of the present application, dichloromethane is selected as the extraction solvent, because it has strong mutual solubility with the product, low toxicity, low price, low boiling point and easy distillation, and is immiscible with water and good for liquid separation. Other alternative extraction solvents may be chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, ethyl acetate, toluene or benzene.

The neutralizing base can be one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine. In this step, the mass concentration range of the neutralized alkali solution can be 10%-30%, and the mass ratio of the neutralized alkali content to triphenylphosphine in the neutralized alkali solution can be (0.2-0.6):1. In the embodiment of the present application, the organic phase selects sodium hydroxide solution as the neutralized alkali solution to stir and wash, and its main purpose is to remove (3-methylaminopropyl) triphenylphosphonium bromide hydrobromide or (3 -aminopropyl) triphenylphosphine bromide hydrobromide molecule in hydrobromide to obtain the free state product (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) Triphenylphosphine bromide, and at the same time, sodium hydroxide is convenient and easy to obtain and low in price, which is beneficial to industrial production. In addition to sodium hydroxide solution, the neutralized alkali solution can also be a solution prepared by potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine, and these solutions also have the same Effect.

In the process of drying the organic phase with a desiccant, the desiccant can be one of anhydrous sodium sulfate, anhydrous magnesium sulfate or molecular sieve, and the amount of the desiccant added to the mass ratio of triphenylphosphine can range from (0.5 to 1 ):1.

The organic phase is dried with a desiccant, distilled to dryness, and then recrystallized with a recrystallization solvent, which can effectively dissolve the product and then cool down to separate the product, and can well remove impurities to achieve the purpose of purification. The recrystallization solvent can be one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether. The process of recrystallization is to heat up and then cool down, heat up to the temperature range of 60~66°C where the material dissolves, and cool down to the temperature range of -5~5°C for the material to crystallize. The range of the added amount of the recrystallization solvent to the mass ratio of triphenylphosphine can be (1~2):1. In the embodiments of the present application, the recrystallization solvent is tetrahydrofuran, and the alternative solvent is dioxane, acetonitrile, ethyl acetate or diethyl ether.

During the drying process, the temperature is controlled at 55~65℃, and hot air circulation oven, vacuum oven, double cone dryer or fluidized bed can be used.

The present application also provides a synthetic method of desmethyl olopatadine, and desmethyl olopatadine is N-desmethyl olopatadine or N,N-desmethyl olopatadine, wherein The intermediate of desmethyl olopatadine synthesized by the above synthesis method is the second raw material, which can reduce the amount of metal reducing agent. At the same time, in the subsequent post-processing, the isomers are directly separated to obtain the target product, and the ester separation is discarded. The hydrolysis step is reduced, the reaction step is reduced, the synthetic route of desmethyloclopatadine is simplified, and the yield is improved.

Specifically, the synthetic method of desmethyl olopatadine, comprises the following steps:

Add the second raw material and the second solvent, start stirring, control the temperature at 18-25°C, add a metal reducing agent, control the temperature at 58-66°C after adding, and react for 1-2 hours;

Add isokic acid, control the temperature at 58-66 °C and stir for 1.5-3.5 hours, then cool down to 5-10 °C, slowly add the first quenching solvent, then add the second quenching solvent, and finally add water to quench the reaction;

The pH of the reaction solution is adjusted with acid, and then distilled under reduced pressure to dryness, and the dry product is separated by column chromatography to obtain the finished product N-desmethylolopatadine or N,N-desmethylolopatadine.

The second raw material is (3-methylaminopropyl) triphenylphosphine bromide or (3-aminopropyl) triphenylphosphine bromide, and the mass ratio of the second raw material to isokic acid is in the range of (1.5~2.5) :1. When the second raw material is (3-methylaminopropyl) triphenylphosphine bromide, the prepared product is N-desmethyl olopatadine; when the second raw material is (3-aminopropyl) triphenyl bromide When phosphine bromide is used, the prepared product is N,N-desdimethylolopatadine. (3-Methylaminopropyl)triphenylphosphine bromide or (3-aminopropyl)triphenylphosphine bromide is a uniform free base, which can effectively reduce the amount of metal reducing agent used, and can reduce production risks. The second raw material is the core raw material of the synthetic finished product, which participates in the construction of the product structure, and there is no other alternative raw material.

Isokic acid is the core raw material for synthetic finished products and participates in the construction of product structure. Although methyl isoxocate can be used instead of isoxocic acid, it has to be hydrolyzed into a product after the reaction, and the number of reaction steps is increased to reduce the yield. Therefore, in this application, isoxocic acid is selected as one of the core raw materials.

The second solvent can be one of tetrahydrofuran, chloroform or toluene, and the mass ratio of the second solvent to isokic acid is in the range of (5-15):1. In the embodiment scheme of the present application, tetrahydrofuran is selected as the second solvent, which can reach the temperature required for the reaction and dissolve the two products. If it is replaced with other alternative solvents, the same effect can be achieved, but the reaction time is a problem. Other alternative solvents are chloroform or toluene.

The metal reducing agent can be one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, and the mass concentration range of the metal reducing agent can be 30% to 35%. The ratio of the content of the metal reducing agent to the mass of isokic acid is in the range of (0.4~0.8):1. In the embodiment scheme of this application, potassium hydride is selected as the metal reducing agent, which can effectively pull out the oxygen atom of the ketone carbonyl group in isokic acid to activate it, and at the same time, it can also pull out (3-methylaminopropyl) three The bromine atom in phenylphosphine bromide or (3-aminopropyl) triphenylphosphine bromide achieves the purpose of activation and promotes the reaction. Potassium hydride is milder than other metal reducing agents, which can reduce production risks and is beneficial to industrialization. If synthesis efficiency and safety are not considered, it can be replaced by sodium hydride, calcium hydride, n-butyllithium, tert-butyllithium or lithium aluminum hydride.

In this application, the first quenching solvent is anhydrous methanol or anhydrous ethanol, the mass ratio of the first quenching solvent to isokic acid is (0.2~0.4): 1, and the second quenching solvent is an aqueous solution of tetrahydrofuran, The mass concentration of the tetrahydrofuran aqueous solution is 40-60%, and the ratio of the content of tetrahydrofuran in the tetrahydrofuran aqueous solution to the mass ratio of isokic acid is (1.5-2.5):1. In the embodiment scheme of the present application, the combination of anhydrous methanol and tetrahydrofuran aqueous solution is selected as the quenching solvent, because the quenching is usually methanol or water, and the direct reaction between water and unreacted potassium hydride in the system is more violent, so in the present application The aqueous solution of anhydrous methanol and tetrahydrofuran is selected for quenching step by step, thereby reducing the safety risk and effectively controlling the temperature to improve the quenching efficiency.

In the present application, during the final addition of water to quench the reaction process, the mass ratio of water to isokic acid is in the range of (10-20):1.

In this application, the acid may be one of hydrochloric acid, sulfuric acid or acetic acid. In the embodiment scheme of the present application, concentrated hydrochloric acid is selected to adjust pH, and the mass concentration of concentrated hydrochloric acid is 20% to 38%. Because concentrated hydrochloric acid is cheaper and commonly used than other acids, hydrochloric acid, sulfuric acid or acetic acid can also be used as substitutes. When the second raw material is (3-methylaminopropyl)triphenylphosphine bromide, adjust the pH to 7.2~7.8; when the second raw material is (3-aminopropyl)triphenylphosphine bromide, adjust the pH to 8.0~8.4.

In this application, the eluent used in the separation process of column chromatography can be ethyl acetate and methanol system, ethyl acetate and ethanol system or ethyl acetate and acetone system; the filler in the column can be silica gel and Basic alumina. In the embodiments of the present application, the system of ethyl acetate and methanol is selected, and the ratio of ethyl acetate to methanol is (6~10): 1. Because both ethyl acetate and methanol are cheap and easy to obtain, the system of ethyl acetate and ethanol or ethyl acetate and acetone system instead.

The synthetic method of desmethyl olopatadine provided by the present application, on the basis of the prior art, has carried out upgrading and transformation to key steps, and has the following advantages:

1. By replacing the initial raw materials, the overall reaction steps are reduced from 4 steps to 2 steps, and the synthesis of intermediates and the synthesis of desmethyl olopatadine. The synthetic route is shown in the following formula, which saves materials and effectively improves the total yield:

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;

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2. Improve the reaction conditions, effectively reduce the generation of impurities and isomers, and improve the yield of the target product;

3. Reduce the difficulty of post-processing while ensuring quality and yield;

4. The post-processing conditions are optimized, ultra-high temperature harsh reactions are eliminated, and the dependence on equipment is reduced;

5. The overall reaction is simple and easy to operate, and there are no special requirements for stable synthesis, which is suitable for industrial production.

The present invention will be further described below through specific embodiments.

Example 1

1. Synthesis of (3-methylaminopropyl) triphenylphosphine bromide

Add 150 g of isopropanol, 26.2 g of triphenylphosphine and 28.0 g of (3-bromopropyl) (N-methyl)amine hydrobromide to the four-necked flask. Under nitrogen protection, the mixture was stirred at 80°C for 15 hours. Vacuum distillation to dryness, add 150 g of water, add 300 g of dichloromethane, separate the organic phase to retain the organic phase, stir and wash the organic phase with 50 g of 20% sodium hydroxide solution, separate the organic phase to retain the organic phase, and dry the organic phase with 20 g of anhydrous sodium sulfate. Distilled to dryness, 50 g of tetrahydrofuran was added, the temperature was raised to 65° C., then cooled to 0° C., and a white solid was obtained by suction filtration. The solid was dried in an oven at 60° C. to constant weight. 27.1 g of (3-methylaminopropyl) triphenylphosphine bromide was obtained, and the yield in this step was 65.5%.

2. Synthesis of N-desmethyl olopatadine

Add 20.7g of (3-methylaminopropyl) triphenylphosphine bromide in the there-necked flask, then add 100g of anhydrous tetrahydrofuran, turn on stirring, control the temperature to 20°C, add 17g of 30% potassium hydride, be warming up to 65°C after adding , the reaction is 1h. Then add 10.7g of isokic acid, stir at 65°C for 2 hours, then cool down to 8°C, slowly add 3g of anhydrous methanol, then add 40g of 50% tetrahydrofuran aqueous solution, and finally add 160g of water to quench the reaction. The reaction solution was adjusted to pH=7.5 with concentrated hydrochloric acid (30% by mass), then distilled under reduced pressure to dryness, and the dry product was subjected to column chromatography (ethyl acetate:methanol=9:1) (200~300 mesh column chromatography on silica gel) ) to obtain the finished product N-desmethylolopatadine, the HPLC detection results are shown in Figure 1 and Table 1, the purity is 99.78% (Z/E=99.78:0.22), the yield is 7.9g, and the yield in this step is 61.3%.

Table 1

Example 2

1. Synthesis of (3-aminopropyl)triphenylphosphine bromide

Add 150g of isopropanol, 26.2g of triphenylphosphine and 26.3g of 3-bromopropylamine hydrobromide to the four-necked bottle. Under nitrogen protection, the mixture was stirred at 80°C for 15 hours. Vacuum distillation to dryness, add 150 g of water, add 300 g of dichloromethane, separate the organic phase to retain the organic phase, stir and wash the organic phase with 50 g of 20% sodium hydroxide solution, separate the organic phase to retain the organic phase, and dry the organic phase with 20 g of anhydrous sodium sulfate. Distilled to dryness, 50 g of tetrahydrofuran was added, the temperature was raised to 65° C., then cooled to 0° C., and a white solid was obtained by suction filtration. The solid was dried in an oven at 60° C. to constant weight. 20.1 g of (3-aminopropyl) triphenylphosphine bromide was obtained, and the yield in this step was 64.9%.

2. Synthesis of N,N-Desdimethylolopatadine

Add 20.0 g of (3-aminopropyl) triphenylphosphine bromide in the there-necked flask, then add 100 g of anhydrous tetrahydrofuran, turn on stirring, control the temperature to 20 ° C, add 17 g of 30% potassium hydride, be warming up to 65 ° C after adding, Reaction for 1h. Then add 10.7g of isokic acid, stir at 65°C for 2 hours, then cool down to 8°C, slowly add 3g of anhydrous methanol, then add 40g of 50% tetrahydrofuran aqueous solution, and finally add 160g of water to quench the reaction. The reaction solution was adjusted to pH=8.0 with concentrated hydrochloric acid (30% by mass), then distilled under reduced pressure to dryness, and the dry product was subjected to column chromatography (ethyl acetate:methanol=9:1) (200~300 mesh column chromatography on silica gel) ) to obtain the finished product N,N-desmethyl olopatadine, the HPLC detection results are shown in Figure 2 and Table 2, the purity is 99.71% (Z/E=99.76:0.18), the output is 7.8g, and the yield in this step is 60.5% .

Table 2

Example 3

1. Synthesis of (3-methylaminopropyl) triphenylphosphine bromide

Add 200 g of isopropanol, 34.1 g of triphenylphosphine and 36.4 g of (3-bromopropyl) (N-methyl)amine hydrobromide to the four-necked flask. Under nitrogen protection, the mixture was stirred at 76°C for 13 hours. Vacuum distillation to dryness, add 200 g of water, add 400 g of dichloromethane, separate the organic phase to retain the organic phase, stir and wash the organic phase with 70 g of 20% sodium hydroxide solution, separate the organic phase to retain the organic phase, and dry the organic phase with 30 g of anhydrous sodium sulfate. Distilled to dryness, added 65 g of tetrahydrofuran, heated to 60°C, then cooled to 2°C, suction filtered to obtain a white solid, which was dried in an oven at 65°C to constant weight. 35.1 g of (3-methylaminopropyl) triphenylphosphine bromide was obtained, and the yield in this step was 65.2%.

2. Synthesis of N-desmethyl olopatadine

Add (3-methylaminopropyl) triphenylphosphine bromide 26.9g in the there-necked flask, then add 150g of anhydrous tetrahydrofuran, turn on stirring, control temperature to 22°C, add 19g of 35% potassium hydride, be warming up to 62°C after adding , the reaction 2h. Then add 13.9g isoxocic acid, stir at 62°C for 3 hours, then cool to 6°C, slowly add 4g of anhydrous methanol, then add 65g of tetrahydrofuran aqueous solution with a mass concentration of 40%, and finally add 200g of water to quench the reaction. The reaction solution was adjusted to pH=7.2 with concentrated hydrochloric acid (30% by mass), then distilled under reduced pressure to dryness, and the dry product was subjected to column chromatography (ethyl acetate:methanol=7:1) (200~300 mesh column chromatography on silica gel) ) to obtain the finished product N-desmethylolopatadine, the HPLC detection results are shown in Figure 3 and Table 3, the purity is 99.76% (Z/E=99.71:0.22), the yield is 10.1 g, and the yield in this step is 60.1%.

table 3

Example 4

1. Synthesis of (3-aminopropyl)triphenylphosphine bromide

Add 200g of isopropanol, 34.1g of triphenylphosphine and 34.2g of 3-bromopropylamine hydrobromide to the four-necked bottle. Under nitrogen protection, the mixture was stirred at 77°C for 14 hours. Vacuum distillation to dryness, add 200 g of water, add 400 g of dichloromethane, separate the organic phase and retain the organic phase, stir and wash the organic phase with 72 g of 20% sodium hydroxide solution, separate the organic phase and retain the organic phase, after the organic phase is dried with 30 g of anhydrous sodium sulfate Distilled to dryness, 65 g of tetrahydrofuran was added, the temperature was raised to 61° C., then cooled to 1° C., and a white solid was obtained by suction filtration, which was dried in an oven at 63° C. to constant weight. 26.2 g of (3-aminopropyl) triphenylphosphine bromide was obtained, and the yield in this step was 64.8%.

2. Synthesis of N,N-Desdimethylolopatadine

In the there-necked flask, add 26.0 g of (3-aminopropyl) triphenylphosphine bromide, then add 160 g of anhydrous tetrahydrofuran, start stirring, control the temperature to 23 ° C, add 20 g of 35% potassium hydride, be warming up to 62 ° C after adding, The reaction was carried out for 1.5h. Then 13.9 g of isokic acid was added, stirred at 64 °C for 2.5 hours, then cooled to 7 °C, slowly added with 4 g of anhydrous methanol, then added with 44 g of an aqueous solution of tetrahydrofuran with a mass concentration of 60%, and finally added 200 g of water to quench the reaction. The reaction solution was adjusted to pH=8.2 with concentrated hydrochloric acid (30% by mass), then distilled under reduced pressure to dryness, and the dry product was subjected to column chromatography (ethyl acetate:methanol=8:1) (200~300 mesh column chromatography on silica gel) ) to obtain finished product N,N-desmethyl olopatadine, purity 99.83% (Z/E=99.83:0.17), HPLC detection result is shown in Figure 4 and Table 4, output 9.8g, this step yield 61.3% .

Table 4

It can be seen from the above examples that the method of the present application has successfully synthesized N-desmethyl olopatadine and N,N-desmethyl olopatadine by reducing the reaction steps, and the total yield reaches 39.2%, which has a high yield. Good industrial application value. 99.7% of N-desmethyl olopatadine and N,N-desdimethyl olopatadine prepared by the method of the present application can be used for chemical analysis, biological property research or further as a pharmaceutical intermediate synthesis.

It should be understood that the application of the present application is not limited to the above examples. For those of ordinary skill in the art, improvements or transformations can be made according to the above descriptions, and all these improvements and transformations should belong to the protection scope of the appended claims of the present application.

Claims (10)

1. A synthetic method of an intermediate of demethyl olopatadine is characterized in that the intermediate of demethyl olopatadine is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide, and comprises the following steps:

adding a first solvent, triphenylphosphine and a first raw material, and heating and stirring under a protective gas atmosphere;

distilling under reduced pressure until the organic phase is dry, adding water, adding an extraction solvent, separating the liquid and keeping an organic phase, washing the organic phase by using a neutralizing alkali solution, separating the liquid and keeping the organic phase, drying the organic phase by using a drying agent, and distilling until the organic phase is dry;

adding a recrystallization solvent, recrystallizing, performing suction filtration to obtain a white solid, and drying the white solid to constant weight;

the first raw material is (3-bromopropyl) (N-methyl) amine hydrobromide or 3-bromopropylamine hydrobromide;

when the first raw material is the (3-bromopropyl) (N-methyl) amine hydrobromide, the prepared product is (3-methylaminopropyl) triphenyl phosphonium bromide; when the first raw material is the 3-bromopropylamine hydrobromide, the product prepared is (3-aminopropyl) triphenyl phosphonium bromide.

2. The process for the synthesis of an intermediate of demethylolopatadine according to claim 1, wherein the molar ratio of triphenylphosphine to the (3-bromopropyl) (N-methyl) amine hydrobromide is 1: (1.1-2.3);

the molar ratio of the triphenylphosphine to the 3-bromopropylamine hydrobromide is 1: (1.1-2.4).

3. The method for synthesizing an intermediate of demethylolopatadine according to claim 1, wherein the protective gas is argon or nitrogen;

the first solvent is one of isopropanol, propanol, mixed propanol, acetonitrile, n-butanol, tert-butanol or isobutanol, and the mass ratio of the first solvent to the triphenylphosphine is (4-7): 1;

the extraction solvent is one of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane, ethyl acetate, toluene or benzene; the mass ratio of the water to the triphenylphosphine is (5-7): 1, the mass ratio of the extraction solvent to the triphenylphosphine is (10-15): 1;

the neutralizing alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water, diethylamine or triethylamine; the mass concentration range of the neutralizing alkali solution is 10-30%, and the mass ratio of the content of the neutralizing alkali in the neutralizing alkali solution to the triphenylphosphine is (0.2-0.6): 1;

the drying agent is one of anhydrous sodium sulfate, anhydrous magnesium sulfate or a molecular sieve, and the mass ratio of the drying agent to triphenylphosphine is (0.5-1): 1;

the recrystallization solvent is one of tetrahydrofuran, dioxane, acetonitrile, ethyl acetate or diethyl ether; the mass ratio of the recrystallization solvent to the triphenylphosphine is (1-2): 1.

4. the method for synthesizing an intermediate of demethylolopatadine according to claim 3, wherein the first solvent is isopropanol;

the extraction solvent is dichloromethane;

the neutralizing alkali is sodium hydroxide;

the drying agent is anhydrous sodium sulfate;

the recrystallization solvent is tetrahydrofuran.

5. The method for synthesizing an intermediate of demethylolopatadine according to claim 1, wherein the heating and stirring process is specifically heating to 75-82 ℃ and stirring for 10-16 hours;

the recrystallization process comprises the steps of heating to a material dissolution temperature range of 60-66 ℃, and then cooling to a material crystallization temperature range of-5 ℃;

and the temperature is controlled to be 55-65 ℃ in the drying process.

6. A method for synthesizing demethylolopatadine, wherein the demethylolopatadine is N-demethylolopatadine or N, N-dedimethylamolopatadine, which is characterized by comprising the following steps:

preparing a second starting material by the synthesis method of the intermediate of demethylolopatadine according to any one of claims 1 to 5, wherein the second starting material is (3-methylaminopropyl) triphenyl phosphonium bromide or (3-aminopropyl) triphenyl phosphonium bromide;

adding the second raw material and a second solvent, starting stirring, controlling the temperature, adding a metal reducing agent, controlling the temperature after the addition, and reacting for a plurality of hours;

adding isoxofenac, stirring for a plurality of hours at a controlled temperature, cooling, adding a first quenching solvent, adding a second quenching solvent, and finally adding water to quench and react;

adding acid to adjust pH value, distilling under reduced pressure to dryness, and separating by column chromatography;

when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, the prepared product is N-demethylolopatadine; when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, the prepared product is N, N-dedimethyl olopatadine.

7. The method for synthesizing demethylolopatadine according to claim 6, wherein the mass ratio of the second starting material to isoxeloxolone ranges from (1.5-2.5): 1;

when the second raw material is (3-methylaminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 7.2-7.8; and when the second raw material is (3-aminopropyl) triphenyl phosphonium bromide, adjusting the pH value to 8.0-8.4.

8. The method for synthesizing demethylolopatadine according to claim 6, wherein the second solvent is one of tetrahydrofuran, chloroform or toluene, and the mass ratio of the second solvent to isoxeloxolone ranges from (5-15): 1;

the metal reducing agent is one of potassium hydride, sodium hydride, calcium hydride, n-butyl lithium, tert-butyl lithium or lithium aluminum hydride, the mass concentration range of the metal reducing agent is 30-35%, and the mass ratio of the content of the metal reducing agent in the metal reducing agent to the isoxofenac is (0.4-0.8): 1;

the first quenching solvent is absolute methanol or absolute ethanol, and the mass ratio of the first quenching solvent to the isoxepac is (0.2-0.4): 1, the second quenching solvent is a tetrahydrofuran aqueous solution, the mass concentration of the tetrahydrofuran aqueous solution is 40-60%, and the mass ratio of the tetrahydrofuran content in the tetrahydrofuran aqueous solution to the isoxepac is (1.5-2.5): 1; the mass ratio range of the water to the isoxepac is (10-20): 1;

the acid is one of hydrochloric acid, sulfuric acid or acetic acid;

in the column chromatography separation process, the eluent is an ethyl acetate and methanol system, an ethyl acetate and ethanol system or an ethyl acetate and acetone system, and the filler in the chromatographic column is silica gel and alkaline alumina.

9. The method of synthesizing demethylolopatadine according to claim 8, wherein the second solvent is tetrahydrofuran;

the metal reducing agent is potassium hydride;

the first quenching solvent is absolute methanol;

the acid is concentrated hydrochloric acid, and the mass concentration of the concentrated hydrochloric acid is 20-38%;

the eluent is an ethyl acetate and methanol system, and the proportion of ethyl acetate to methanol is (6-10): 1.

10. the method for synthesizing demethylolopatadine according to claim 6, wherein the temperature is controlled, and the metal reducing agent is added at a temperature of 18-25 ℃;

controlling the temperature after the addition, wherein the reaction is carried out for a plurality of hours, specifically controlling the temperature to be 58-66 ℃ after the addition, and reacting for 1-2 hours;

the process of adding the isoxaglic acid, stirring for a plurality of hours at a controlled temperature and then cooling specifically comprises the steps of adding the isoxaglic acid, stirring for 1.5-3.5 hours at a controlled temperature of 58-66 ℃, and then cooling to 5-10 ℃.

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