CN109516998B

CN109516998B - Synthesis method of Barosavir intermediate

Info

Publication number: CN109516998B
Application number: CN201811598135.7A
Authority: CN
Inventors: 费安杰; 叶伟平; 周章涛; 黄志宁; 陈润林; 崔锦栋
Original assignee: Shenzhen Hwagen Pharmaceutical Co ltd
Current assignee: Shenzhen Hwagen Pharmaceutical Co ltd
Priority date: 2018-12-25
Filing date: 2018-12-25
Publication date: 2021-06-25
Anticipated expiration: 2038-12-25
Also published as: CN109516998A

Abstract

The invention discloses a synthesis method of a baloxavir intermediate; belongs to the field of organic chemical synthesis. The method starts from pyridone, and obtains a key intermediate of the baloxavir through deprotection, condensation and chiral reduction. The method has the advantages of short process route and mild conditions, can obtain higher chiral purity without chiral resolution, is easy to industrialize, and further reduces the production cost of the baroxavir.

Description

Synthesis method of Barosavir intermediate

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of a Barosavir intermediate.

Background

The balosavir is a Cap-dependent endonuclease inhibitor developed by salt wild-sense pharmacy, is also a few new drugs capable of inhibiting the proliferation of influenza viruses in the world, does not affect host cells, has small side effects, and is expected to replace oseltamivir to become a Wang drug in the field of influenza lead.

At present, few reports are provided on the synthesis method of the breusavir, and especially, the synthesis of a key intermediate is only reported by salt wild pharmacy of the original manufacturers.

According to the first reporting route, phthalic acylamino ethanol is used as a starting material to perform substitution reaction with bromoacetaldehyde dimethyl acetal, primary amine is obtained after deprotection, condensation reaction is performed on the primary amine and a pyridinone compound protected by Boc under an acidic condition to obtain a racemate, and further chemical resolution is performed through chiral furoic acid to obtain a chiral pure intermediate.

The method is unstable under the alkaline condition of phthalimidyl ethanol used in the previous step, and has poor process repeatability; meanwhile, in the condensation process, the obtained racemate needs to be further resolved, and the chiral pure intermediate can be obtained only by losing about 60% of yield. Therefore, the production cost of the route is high, the reproducibility is poor, and the method is not suitable for industrialization.

And a second reporting route, replacing a condensation strategy, constructing a leaving group by using morpholone as a raw material through amide protection, carbonyl reduction and methylation, then carrying out a condensation reaction with pyridinone subjected to Boc protection removal, and finally carrying out chemical resolution to obtain a chiral pure intermediate.

The route is simpler and more convenient in a strategy of condensation on a closed loop, but the construction of the morpholone fragment uses a low-temperature condition of-78 ℃, and uses n-BuLi and DIBAL reagents which are sensitive to water and air, so that a larger safety risk is generated in the amplification process; in addition, the obtained racemate after condensation does not bypass the chiral resolution problem, more than half of materials are consumed to obtain a chiral pure intermediate, and the production cost is high. Therefore, the route is still not optimistic in terms of industrialization, whether from a safety or economic standpoint.

In conclusion, the existing process of the intermediate of the baroxavir still has the defects of high cost and poor safety and repeatability, and is not beneficial to large-scale production, so that the industrialization of the baroxavir is restricted, the production cost of the raw material medicine is increased, and the medication burden of patients is increased.

Disclosure of Invention

In order to overcome the defects of harsh reaction conditions, low process safety, difficult production amplification, high production cost and the like of the Barosavir intermediate, the invention develops a new process route. The method specifically comprises the following reaction steps:

step 1, removing a Boc protecting group of a compound shown as a formula A under an acidic condition to generate a compound shown as a formula B;

step 2, carrying out substitution reaction on the compound shown in the formula B and the compound shown in the formula C, and then condensing to obtain a compound shown in a formula D;

step 3, selectively reducing the compound shown in the formula D under the action of a chiral catalyst to obtain a baroxavir intermediate;

wherein, formula A

Formula B

Formula C

Formula D

In the formula C, R represents alkyl.

The synthetic route of the invention is as follows:

the acid in the step 1 comprises trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrogen chloride and the like; trifluoroacetic acid is preferred.

Further, R in the formula C in the step 2 represents methyl, ethyl, propyl and the like; methyl is preferred.

The solvent used for the substitution reaction in step 2 includes acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N-dimethylacetamide, tetrahydrofuran, toluene, xylene, etc., preferably acetonitrile.

The reaction temperature of the substitution reaction in the step 2 is 30-120 ℃; preferably 60 ℃ to 100 ℃; optimally 80-90 ℃.

The chiral catalyst used in the reaction in the step 3 is a ruthenium catalyst and has the following structure:

wherein Ar is₁Is aryl or alkyl substituted aryl, preferably p-methylphenyl; ar (Ar)₂Is a benzene ring or an alkyl substituted benzene ring, preferably 1,3, 5-trimethylbenzene or p-methylisopropylbenzene.

The reducing agent used in the selective reduction reaction of step 3 includes hydrogen, formic acid and salts of amines, preferably triethylamine formate.

The synthesis method for producing the intermediate of the baroxavir is short in process route and mild in conditions, can obtain high chiral purity without chiral resolution, is easy to industrialize, and further reduces the production cost of the baroxavir.

Detailed Description

Example 1: the synthesis method of the baroxavir intermediate in this example is completed according to the following reaction steps:

2.0g of the compound represented by the formula A, 2.0g of trifluoroacetic acid and 10mL of dichloromethane were added to a three-necked flask, the mixture was stirred and reacted at room temperature for 3 hours, the TLC detection was carried out until the starting material was consumed, the solvent was distilled off under reduced pressure, and the residue was added to toluene and distilled over once. The residue was dissolved in dichloromethane, added to saturated aqueous sodium bicarbonate and stirred, the organic phase separated and the aqueous phase extracted with dichloromethane (3 × 50 mL). The organic phases were combined, and the solvent was distilled off under reduced pressure to obtain 1.40g of the compound represented by the formula B in a yield of 95%.

a three-necked flask was charged with 1.0g of the compound represented by formula B, 5- (methylmercapto) -3, 6-dihydro-2H-1, 4-oxazine and 20ml of acetonitrile, and then refluxed for 3 hours under nitrogen atmosphere. TLC detection raw material reaction is finished, decompression concentration is carried out until 5vol, cooling is carried out until the temperature is between 30 and 40 ℃, 30ml of water is dripped, cooling is carried out until the temperature is reduced to room temperature, filtration is carried out, filter cake is washed by 10ml of water, and vacuum drying is carried out, so that 1.08g of compound shown in formula D is obtained, and the yield is 91%.

1.0g of the compound represented by the formula D and 10ml of dichloromethane are added into a three-necked flask, the mixture is cooled to 0 ℃ under the protection of nitrogen, 0.43g of formic acid is added dropwise, then 0.93g of triethylamine is added dropwise, finally 0.05% eq (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride is added, the temperature is slowly raised to the room temperature, and the reaction is carried out until the consumption of the compound represented by the formula D is detected by TLC. The reaction solution was filtered through a small amount of silica gel, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was crystallized from methyl tert-butyl ether to give 0.85g of the intermediate baroxavir, in 84.5% yield, 99.2% HPLC purity, and 98.7% ee.

Example 2: the synthesis method of the baroxavir intermediate in this example is completed according to the following reaction steps:

2.0g of the compound represented by the formula A and 6ml of 20% ethanol hydrogen chloride solution were added to a three-necked flask, the mixture was stirred at room temperature for 1 hour, TLC was carried out to detect the completion of the consumption of the starting material, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane, added to saturated aqueous sodium bicarbonate and stirred, the organic phase separated and the aqueous phase extracted with dichloromethane (3 × 50 mL). The organic phases were combined, and the solvent was distilled off under reduced pressure to obtain 1.23g of the compound represented by formula B in a yield of 84%.

a three-necked flask was charged with 1.0g of the compound represented by formula B, 5- (methylthio) -3, 6-dihydro-2H-1, 4-oxazine (0.53 g), and 20ml of toluene, and then heated to 100 ℃ under nitrogen atmosphere for reaction for 3 hours. TLC detection of the completion of the reaction of the raw materials, cooling to 0-10 ℃, stirring for crystallization for 1h, filtering, washing the filter cake with a small amount of precooled toluene, and vacuum drying to obtain 0.97g of the compound represented by formula D with a yield of 81.8%.

And 3, selectively reducing the compound shown in the formula D under the action of a chiral catalyst to obtain a baroxavir intermediate, wherein the specific operation is shown in step 3 of example 1.

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

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

and 3, selectively reducing the compound shown in the formula D under the action of a chiral catalyst to obtain a baroxavir intermediate with the structure of

Wherein, formula A is

Formula B is

Formula C is

Formula D is

In the formula C, R represents alkyl;

wherein the content of the first and second substances,

the solvent used in the substitution reaction in the step 2 is one of acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N-dimethylacetamide, tetrahydrofuran, toluene and xylene;

the reaction temperature of the substitution reaction in the step 2 is 60-100 ℃;

the chiral catalyst used in the reaction in the step 3 is (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride;

the reducing agent used in the selective reduction in the step 3 is hydrogen gas, formic acid or a salt of formic acid and amine, and the salt of formic acid and amine is a triethylamine formate salt.

2. The method according to claim 1, wherein the acid in step 1 is one of trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and hydrogen chloride.

3. The synthesis process according to claim 1, wherein R in the formula C represents methyl, ethyl or propyl.