CN112266381B

CN112266381B - Novel synthesis method of Barosavir intermediate

Info

Publication number: CN112266381B
Application number: CN202011148975.0A
Authority: CN
Inventors: 陈桂平
Original assignee: Nanjing Anhuai Innovative Drug Research Institute Co ltd
Current assignee: Nanjing Anhuai Innovative Drug Research Institute Co ltd
Priority date: 2020-10-23
Filing date: 2020-10-23
Publication date: 2022-03-04
Anticipated expiration: 2040-10-23
Also published as: CN112266381A

Abstract

The invention relates to the technical field of synthesis of organic compounds, in particular to a synthesis method of a Barosavir intermediate, which comprises the following steps: condensing cheap and easily-obtained morpholine and allyl chloroformate serving as initial raw materials under the action of alkali to obtain a compound 3, reacting the compound 3 with formic acid and methanol in the presence of an NBS catalyst to obtain a compound 4, and then reacting the compound 4 with Boc hydrazine under the heating condition to obtain a compound 5; resolving the compound 5 to obtain a target compound 6, and finally reacting with the compound 7 to obtain a target product; the method has the advantages of simple reaction, short route, early resolution, less three wastes, environment friendliness, higher yield of each step and less waste of raw materials and reagents.

Description

Novel synthesis method of Barosavir intermediate

Technical Field

The invention relates to the technical field of synthesis of organic compounds, and particularly relates to a novel synthesis method of a Barosavir intermediate.

Background

Barosavir is a novel Cap-dependent endonuclease inhibitor anti-influenza drug discovered by Japan salt wild-sense pharmacy and developed together with Swiss, and has been developed for the treatment of influenza A or B. Unlike neuraminidase inhibitors, which inhibit the release of the virus from infected host cells, baroxavir blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In 11 months 2018, the U.S. Food and Drug Administration (FDA) announced approval of the new anti-influenza drug baroxavir disoproxil for marketing for the treatment of acute influenza patients with no complications, 12 years old and older, for no more than 48 hours. The drug is the first anti-influenza drug approved by the FDA and having a novel action mechanism in recent 20 years, and has a great market prospect. In japan, baloxavir is also in the preclinical study stage of influenza a virus subtype H5N 1.

At present, the synthesis method of the Barosavir intermediate is mainly to synthesize a morpholine ring in the last step of ring closure and then carry out chiral resolution, so that the yield is low, the raw material waste is serious, and the cost is increased (WO 2017221869A 1).

。

CN110105372 reports a method for preparing racemic hydrazino morpholine, which uses allyl-3-oxomorpholine-4-carboxylic ester as raw material, and obtains intermediate 1 through hydrazine hydrate reaction, and then hydrazine is obtained through sodium borohydride reduction. The reaction formula is as follows:

。

the method has the advantages of easily obtained raw materials, high cost and poor safety because a large amount of sodium borohydride is used.

Patent CN 111018803A used 3-morpholinone and 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid as starting materials to prepare (R) -7-benzyloxy-3, 4, 12, 12A-tetrahydro-1H- [1, 4] diaza [3, 4-C ] pyrido [2, 1-F ] [1, 2, 4] triazine-6, 8-dione.

。

The method needs column chromatography, the used raw materials and the catalyst are expensive, the key steps need special equipment for hydrogenation reaction, and the method is high in cost and not suitable for industrial production.

Disclosure of Invention

Aiming at the defects of the prior art, the synthesis method which has simple steps, mild conditions and relatively friendly environment is provided; more importantly, the raw materials are cheap and easy to obtain, the supply is stable, favorable conditions are created for reducing the cost of the raw materials of the Barosavir, and the method is suitable for industrial production.

In order to achieve the purpose, the invention provides the following technical scheme:

a novel synthesis method of a baroxavir intermediate comprises the following steps:

step 1: reacting the compound 2 with an amino protective agent and triethylamine to obtain a compound 3;

step 2: dissolving the compound 3 in methanol and formic acid, heating to reflux, adding NBS, and reacting to obtain a compound 4;

and step 3: reacting the compound 4 with Boc hydrazine under the action of a catalyst 1 to obtain a compound 5;

and 4, step 4: resolving the compound 5 by using D-tartaric acid, and reacting to obtain a compound 6;

and 5: reacting the compound 6 with the compound 7 under the action of a catalyst 2 to obtain a baroxavir intermediate compound 1;

。

further, the reaction solvent in step 1, step 2, step 3 and step 4 is one or more of methanol, formic acid, acetic acid, dichloromethane, dichloroethane, ethanol, isopropanol, n-butanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, toluene, benzene and chloroform.

Further, the amino protecting group of the amino protecting agent in the step 1 is one of allyl formyl, acetyl, Boc, benzyl and benzyloxycarbonyl; in the step 1, the molar ratio of the compound 2 to the amino protective agent to the triethylamine is 1.0: 1.0-3.0.

Further, the reaction temperature in the step 1 is-20 ℃ to 50 ℃; the reaction time is 2-12 hours.

Preferably, the temperature of the reaction in the step 1 is 0-10 ℃; the reaction time is 6-8 hours.

Further, the molar ratio of the compound 3 to NBS to methanol to formic acid in the step 2 is 1.0: 1.0-3.0: 10-100: 1-5; the reaction time is 1-10 hours.

Further, the molar ratio of the compound 4 to Boc hydrazine to the catalyst 1 in the step 3 is 1.0: 1.0-3.0: 0.1-0.5; the catalyst 1 is one or more of stannic chloride, titanium tetrachloride, aluminum trichloride and zinc chloride.

Further, the reaction temperature in the step 3 is-50 ℃ to 40 ℃; the reaction time is 1-8 hours.

Further, the molar ratio of the compound 4 to the D-tartaric acid in the step 4 is 1.0: 1.0-3.0; the reaction temperature is 20-80 ℃; the reaction time is 1-5 hours; the solvent for the reaction is one or more of methanol, ethanol and isopropanol.

Further, the molar ratio of the compound 6 to the compound 7 to the catalyst 2 in the step 5 is 1.0: 1.0-3.0: 1.0-5.0; the catalyst 2 is one or more of p-toluenesulfonic acid, methanesulfonic acid, pyridine hydrochloride, pyridine p-toluenesulfonic acid salt and pyridine methanesulfonic acid salt.

Further, the reaction temperature in the step 5 is 20-80 ℃; the reaction time is 15-24 hours; the solvent for the reaction is one or more of ethanol, ethyl acetate, DMF, DME, DMSO, acetonitrile, toluene and isopropanol.

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

the synthesis method of the Barosavir intermediate has the advantages of simple steps, mild conditions, environment friendliness, low price, easy obtainment and stable supply of raw materials, low cost, creation of favorable conditions for reducing the cost of the raw materials of the Barosavir, high product yield and high purity; is suitable for industrial production.

Detailed Description

The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.

Example 1

Preparation of compound 3:

100.0g of morpholine, 348.45g of triethylamine and 700ml of tetrahydrofuran are added into a 2000ml four-neck flask, 207.53g of allyl chloroformate is dropwise added after the temperature is reduced to 0 ℃, the reaction is carried out overnight at 25 ℃ after the dropwise addition, the reaction is controlled by GC, the tetrahydrofuran is concentrated and recovered, 800ml of ethyl acetate and 400ml of 5% diluted hydrochloric acid are added for washing twice, the ethyl acetate is dried and concentrated by anhydrous sodium sulfate to obtain the compound 3, a light yellow oily liquid, and the yield is 94%.

Example 2

Preparation of compound 4:

1900ml of methanol, 100ml of formic acid and 100.00g of compound 3 were added to a 5000ml four-neck flask, the system was heated to reflux, 124.76g of NBS was added 5 times in 5 hours, after completion of the addition, refluxing was continued for 3 hours, the GC controlled disappearance of the starting material, the system was cooled, methanol was recovered by concentration, 1000ml of 5% sodium hydroxide solution was added, and then extraction was carried out three times with dichloromethane (1000 ml x 3), dichloromethane was combined, dried over anhydrous sodium sulfate, dichloromethane was recovered by concentration, and then the fraction was collected by vacuum distillation (top temperature 165 ℃,2 mmHg), yielding 61.6%.

Example 3

Preparation of compound 5:

80.01g of Compound 4 was dissolved in 600ml of acetonitrile under nitrogen protection, 105.05g of Boc hydrazine was added, the system was cooled to-25 ℃ with a dry ice ethanol bath, 51.80g of tin tetrachloride were slowly added dropwise and stirred at-25 ℃ for 90 minutes. After the completion of the control reaction, the reaction solution was poured into an ice aqueous sodium bicarbonate solution and quenched by quenching, 400ml of dichloromethane was added, stirring was performed at room temperature, celite was applied for filtration, the filtrate was separated into layers, and then the aqueous phase was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then dichloromethane was recovered by distillation under reduced pressure to give crude compound 5, which was recrystallized from 300ml of t-butyl methyl ether to give a pure product as a pale yellow solid with a yield of 64%.

Example 4

Preparation of compound 6:

32.37g of D-tartaric acid and 400ml of methanol were added to a 1000ml round bottom flask, and stirred magnetically, 50.00g of Compound 5 was added thereto at 55 ℃ and the mixture was refluxed for 1.5 hours. Naturally cooling, cooling to room temperature, precipitating, and vacuum filtering to obtain the D-tartrate crude product of the compound 1. The crude product was recrystallized from 180ml of methanol to obtain the D-tartrate salt of the purified compound 1 in a yield of 40.5%. The D-tartrate of Compound 1 obtained in the above step was dissolved in 200ml of water, and an aqueous ammonia solution was added dropwise to adjust the pH to 11, followed by extraction with dichloromethane (200 ml, 100ml, 100 ml) 3 times, the dichloromethane layers were combined, washed once with 100ml of water and once with 100ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Compound 1 in a yield of 37.0% and an ee value of 99.5%.

Example 5

Preparation of compound 1:

7.25g of Compound 6 was dissolved in 50ml of DMF, and 9.78g of Compound 7 and 21.69g of p-toluenesulfonic acid were added to react at 60 ℃ overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine and dried. Concentration under reduced pressure gave a yellow oil which was recrystallized by addition of methanol to give a white solid. The yield was 79.5%, and the ee value was 99.4%.

The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.

Claims

1. A novel synthesis method of a baroxavir intermediate is characterized by comprising the following steps:

。

2. the novel synthesis method of a baroxavir intermediate as claimed in claim 1, wherein the reaction solvent in step 1, step 2, step 3, step 4 is one or more of methanol, formic acid, acetic acid, dichloromethane, dichloroethane, ethanol, isopropanol, n-butanol, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, toluene, benzene, chloroform.

3. The novel process for synthesizing a baroxavir intermediate as claimed in claim 1, wherein the amino protecting group of the amino protecting agent in step 1 is one of allyl formyl, acetyl, Boc, benzyl and benzyloxycarbonyl; the molar ratio of the compound 2 to the amino protective agent to the triethylamine is 1.0: 1.0-3.0.

4. The novel synthesis method of the baroxavir intermediate as claimed in claim 1, wherein the reaction temperature in the step 1 is-20 ℃ to 50 ℃; the reaction time is 2-12 hours.

5. The novel synthesis method of a baroxavir intermediate as claimed in claim 1, wherein the molar ratio of the compound 3 to NBS to methanol to formic acid in step 2 is 1.0: 1.0-3.0: 10-100: 1-5; the reaction time is 1-10 hours.

6. The novel synthesis method of a baroxavir intermediate as claimed in claim 1, wherein the molar ratio of the compound 4 to Boc hydrazine to the catalyst 1 in the step 3 is 1.0: 1.0-3.0: 0.1-0.5; the catalyst 1 is one or more of stannic chloride, titanium tetrachloride, aluminum trichloride and zinc chloride.

7. The novel synthesis method of the baroxavir intermediate as claimed in claim 1, wherein the reaction temperature in the step 3 is-50 ℃ to 40 ℃; the reaction time is 1-8 hours.

8. The novel synthesis method of the baroxavir intermediate as claimed in claim 1, wherein the molar ratio of the compound 5 to the D-tartaric acid in the step 4 is 1.0: 1.0-3.0; the reaction temperature is 20-80 ℃; the reaction time is 1-5 hours; the solvent for the reaction is one or more of methanol, ethanol and isopropanol.

9. The novel synthesis method of the baroxavir intermediate as claimed in claim 1, wherein the molar ratio of the compound 6 to the compound 7 to the catalyst 2 in the step 5 is 1.0: 1.0-3.0: 1.0-5.0; the catalyst 2 is one or more of p-toluenesulfonic acid, methanesulfonic acid, pyridine hydrochloride, pyridine p-toluenesulfonic acid salt and pyridine methanesulfonic acid salt.

10. The novel synthesis method of the baroxavir intermediate as claimed in claim 1, wherein the reaction temperature in the step 5 is 20-80 ℃; the reaction time is 15-24 hours; the solvent for the reaction is one or more of ethanol, ethyl acetate, DMF, DME, DMSO, acetonitrile, toluene and isopropanol.