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CN114957087A - Preparation method of intermediate of palovaried - Google Patents

Preparation method of intermediate of palovaried Download PDF

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Publication number
CN114957087A
CN114957087A CN202210389855.2A CN202210389855A CN114957087A CN 114957087 A CN114957087 A CN 114957087A CN 202210389855 A CN202210389855 A CN 202210389855A CN 114957087 A CN114957087 A CN 114957087A
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鲁光英
罗志希
苏位东
周跃辉
谭密
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Hunan Furui Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a preparation method of a paroxetine intermediate, which comprises the following steps of carrying out carbene reaction on a compound 3 cis-1, 2-dimethylol ethylene and a reaction material to form a ring to obtain a compound 4; chloridizing the hydroxyl of a compound 4 to obtain a compound 5, and condensing the compound 5 and benzylamine to obtain a compound 6; after the compound 6 is converted into hydrochloride compound 7, the carboxyl on the compound 7 obtains a racemic compound 8; racemizing a by-product obtained after chiral resolution of the compound 8, and then resolving the by-product by adopting D-DTTA to obtain a compound 9, and esterifying the obtained compound with methanol to obtain a compound 2 of the intermediate of the Parovirid. In order to realize low-pollution large-scale production of the compound 2, the technical scheme for solving the problems is to obtain a key intermediate by starting from cheap 1, 2-dimethylolethylene and performing cyclization reaction and carboxylation reaction. The method has the advantages of cheap raw materials and simple synthesis steps, and is suitable for industrial production.

Description

Preparation method of intermediate of palovaried
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of a palovir intermediate.
Background
Parovirids (Paxlovid) consist of the novel coronavirus 3CL protease inhibitor nemadevir (Nirmatrelvir) (PF-07321332) and the antiviral therapy ritonavir (ritonavir). The medicine is taken as an oral medicine which is on the market at present and has the best curative effect, and clinical tests prove that the death risk related to the new crown can be reduced by 89%. Due to the effectiveness of the drug, parevir has been approved by a plurality of countries such as inn, de, day, new, etc. within more than 50 days after receiving FDA approval for emergency use.
The structure of the nemadefovir is shown as a compound 1.
Figure RE-GDA0003724974590000011
Figure RE-GDA0003724974590000021
In the synthetic process of the nemadevir, the compound 2 and the hydrochloride thereof are key intermediates, which are also key points of the main technical difficulty in synthesis and the restriction on the control of the product cost, and in the prior art, the synthetic method of the compound is as follows:
the method comprises the following steps: the pyroglutamic acid derivative B-1 is subjected to oxidation-elimination reaction under the action of phenylselenochloride and hydrogen peroxide to obtain alpha, beta-unsaturated lactam B-2, B-2 is subjected to cyclopropanation reaction with isopropyl phosphorus ylide under the action of butyllithium to obtain B-3, then the reduction-debenzylation-protection 3 steps are carried out to obtain prolinol derivative B-4, the hydroxyl of B-4 is oxidized into carboxylic acid-methyl esterification-deprotection-salt formation 3 steps to obtain B-5. In the first 2 steps of the reaction in the route, ultralow temperature (-78 ℃) is required, and a toxic phenylselenochloride reagent is used, so that the method is not suitable for industrial production.
Figure RE-GDA0003724974590000022
The second method comprises the following steps: ethyl chrysanthemate B-6 is oxidized by potassium permanganate to obtain a carboxylic acid compound B-7, B-7 generates anhydride B-8 under the action of acetic anhydride, B-8 obtains carboxylic acid through ring opening of allyl alcohol, B-9 is obtained through resolution of (R) - (+) -alpha-methylbenzylamine, then the carboxylic acid is converted into amide B-10 under the action of ammonium bicarbonate and anhydride, B-10 is reduced by lithium aluminum hydride to obtain B-11, then amino is protected to obtain B-12, the carboxylic acid is oxidized into aldehyde B-13, B-13 is subjected to ring closing-addition reaction under the action of sodium thiosulfate and acetic acid to obtain B-14, B-15 is obtained through cyanation reaction, B-15 is hydrolyzed into ester to obtain a carbomethoxy B-16, and finally deprotection is carried out to obtain B-5. The steps of the route are as long as 11 steps, and the synthetic reagent has high danger and is not suitable for industrial production.
Figure RE-GDA0003724974590000031
The third method comprises the following steps: reacting anhydride B-8 with benzylamine to obtain B-17, removing benzyl to obtain B-18, reducing B-18 with lithium aluminium hydride to obtain amine B-19, oxidizing with potassium persulfate to obtain imine compound B-20, adding B-20 and potassium cyanide to obtain B-21, hydrolyzing cyano group to obtain ester, separating B-22 and D- (+) -di-p-methylbenzoyl tartaric acid (D-DTTA) to obtain B-23, and replacing with hydrochloric acid to obtain B-5. The route has 8 steps of reaction, the total yield is low (15%), the chiral control strategy is the resolution of D-DTTA, and in addition, a virulent reagent potassium cyanide is used, so the method is not suitable for industrial production.
Figure RE-GDA0003724974590000041
The method four comprises the following steps: the method comprises the following steps of carrying out salt forming resolution on cis-dichlorochrysanthemic acid B-24 and (R) - (+) -alpha-methylbenzylamine to obtain chiral pure B-25, converting the B-25 into amide B-26 under the action of thionyl chloride and ammonia water, carrying out elimination-ring closure reaction on the B-26 under an alkaline condition to obtain B-27, carrying out reduction and substitution reaction on the B-27 to obtain alcohol B-28, protecting amino to obtain B-29, and oxidizing hydroxyl of the B-29 by sodium hypochlorite and tetramethyl piperidine oxide (TEMPO) to obtain aldehyde B-30. The aldehyde group of B-30 is firstly subjected to potassium carbonate-methanol action to obtain aldehyde with reversed configuration, then iodine simple substance is added for oxidation to obtain methyl ester B-31, and finally deprotection is carried out to form salt to obtain B-5. The route has 8 reaction steps in total, the total yield is low (12%), the chiral control strategy is the resolution of (R) - (+) -alpha-methylbenzylamine, compared with the second route and the third route, the resolution step is more economical in the step 1, but the starting materials are expensive and are not suitable for industrial production.
Figure RE-GDA0003724974590000051
The method five comprises the following steps: b-19 is oxidized into chiral imine compound B-32 by oxygen under the action of monoamine oxidase MAON401, B-32 and sodium bisulfite are subjected to addition reaction to obtain B-33, then the addition reaction is carried out with sodium cyanide to obtain cyanide B-34, and finally, the cyanide B-34 is hydrolyzed and esterified under the action of hydrochloric acid/methanol to obtain B-5. The route only has 4 steps, the total yield is 56 percent, the chiral purity is very high (>99.9 percent), the chiral control strategy is stereoselective enzyme catalysis, and the defect is that a virulent reagent sodium cyanide is used.
Figure RE-GDA0003724974590000052
Disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of a paroxetine intermediate.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a paroxetine intermediate comprises the following steps:
step one, a compound 3 cis-1, 2-dimethylolethylene and a reaction material are subjected to carbene reaction cyclization to obtain a compound 4, and the reaction material is one of 2, 2-dichloropropane, 2-dibromopropane or 2, 2-diiodopropane;
step two, chloridizing the hydroxyl of the compound 4 to obtain a compound 5, and condensing the compound 5 and benzylamine to obtain a compound 6;
step three, after the compound 6 is converted into a hydrochloride compound 7, a racemic compound 8 is obtained from carboxyl on the compound 7; racemizing a by-product obtained after chiral resolution of the compound 8, and then resolving by adopting D-DTTA to obtain a compound 9;
and step four, esterifying the intermediate with methanol to obtain a compound 2 of the intermediate of the paluvirde.
In the technical scheme, in the first step, a zinc-copper coupling agent, cis-1, 2-dimethylolethylene and zinc bromide are respectively added into anhydrous tetrahydrofuran, after stirring for half an hour at 25 ℃, 10.6g of 2, 2-dichloropropane is slowly dropped, after that, stirring is carried out at 25 ℃ until the detection reaction is complete, ice water is added, liquid separation is carried out by filtration, water phase ethyl acetate is used for extraction, organic phases are combined, drying and concentrating are carried out, and a compound 4 is obtained by column chromatography.
In the technical scheme, in the second step, the compound 4 is added into dichloromethane, methanol and pyridine are added under stirring, the temperature is reduced to 0 ℃, thionyl chloride is dropwise added at the temperature of 0-5 ℃, the temperature is kept at 20 ℃ for reaction for 8 hours after the dripping is finished, and then the reaction solution is subjected to reduced pressure concentration and column purification to obtain a compound 5; adding the compound 5 and benzylamine into DMF, stirring uniformly, adding potassium carbonate, stirring for dissolving, heating to 100 ℃, keeping the temperature for reaction for 6 hours, concentrating, and purifying by a column to obtain a compound 6.
In the technical scheme, in the third step, the compound 6 is dissolved in absolute methanol, concentrated hydrochloric acid is added, the reaction is stirred until the reaction is completed, the reaction product is filtered, concentrated to be dry, and the compound 7 is obtained through column chromatography; dissolving a compound 7 in tetrahydrofuran, adding 3, 7-dipropyl-3, 7-diazabicyclo [3.3.1] nonane, cooling to-60 ℃, dropwise adding sec-butyl lithium, cooling to-68 ℃, adding dry ice, uniformly stirring, heating to-45 ℃, keeping the temperature and stirring for 1h, adding water to stop the reaction, concentrating at 40 ℃ under reduced pressure, adding methyl tert-butyl ether to extract for 2 times, adding a combined extract, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain a compound 8; dissolving the compound 8 in methanol, adding D-di-p-methylbenzoyl tartaric acid, 2-formyl pyridine and glacial acetic acid, heating to 70 ℃, preserving heat for reaction for 3 hours, cooling to 5 ℃ after the reaction is finished, stirring and crystallizing for 1 hour to obtain a white solid, drying, adding the solid into isopropanol, adding concentrated hydrochloric acid l, heating to 40 ℃, stirring for 2 hours, adding water, stirring uniformly, adding ethyl acetate, extracting for 2 times, combining organic phases, and concentrating to dryness to obtain a compound 9.
In the above technical scheme, in the fourth step, the compound 9 is dissolved in anhydrous methanol, concentrated hydrochloric acid is added and stirred until the reaction is completed, and the reaction product is filtered and concentrated to dryness to obtain the compound 2.
In the above technical scheme, in the second step, nitrobenzene is used to replace benzylamine.
In the above technical solution, in the third step, the compound 8 is subjected to chiral resolution to obtain a byproduct compound 10, and after racemization of the compound 10, the compound is subjected to resolution by D-DTTA to obtain a compound 9.
In order to realize low-pollution large-scale production of the compound 2, the technical scheme for solving the problems is to obtain a key intermediate by starting from cheap 1, 2-dimethylolethylene and performing cyclization reaction and carboxylation reaction. The method has the advantages of cheap raw materials and simple synthesis steps, and is suitable for industrial production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
A preparation method of a paroxetine intermediate comprises the following steps:
step one, performing carbene reaction on a compound 3 cis-1, 2-dimethylolethylene and a reaction material to form a ring to obtain a compound 4, wherein the reaction material is one of 2, 2-dichloropropane, 2-dibromopropane or 2, 2-diiodopropane;
step two, chloridizing the hydroxyl of the compound 4 to obtain a compound 5, and condensing the compound 5 and benzylamine to obtain a compound 6;
step three, after the compound 6 is converted into a hydrochloride compound 7, a racemic compound 8 is obtained from carboxyl on the compound 7; racemizing a by-product obtained after chiral resolution of the compound 8, and then resolving by adopting D-DTTA to obtain a compound 9;
and step four, esterifying the intermediate with methanol to obtain a compound 2 of the intermediate of the paluvirde.
The specific synthetic route is shown as the following formula:
Figure RE-GDA0003724974590000091
specific example 1:
4.6g of zinc-copper coupling agent, 32.8g of cis-1, 2-dimethylolethylene, 8.12g of zinc powder and 10.64g of zinc bromide are respectively added into 100ml of anhydrous tetrahydrofuran, stirred for half an hour at 25 ℃, then 10.6g of 2, 2-dichloropropane is slowly dripped in, after the addition is finished, stirred at 25 ℃ until the detection reaction is complete, ice water is added, the liquid is filtered and separated, the water phase and ethyl acetate are extracted, the organic phases are combined, dried and concentrated, and the column chromatography is carried out to obtain 21.06g of compound 4.
Adding 21.06g of the compound 4 into 150ml of dichloromethane, adding 40ml of methanol and 25ml of pyridine while stirring, cooling to 0 ℃, dropwise adding 40ml of thionyl chloride at the temperature of 0-5 ℃, keeping the temperature at 20 ℃ for reacting for 8 hours after the dropwise adding is finished, and then concentrating under reduced pressure and purifying by a column to obtain 20.3g of the compound 5.
Adding 20.3g of compound 5 and 25.1g of benzylamine into 200ml of DMF, stirring uniformly, adding 24.6g of potassium carbonate, stirring to dissolve, heating to 100 ℃, keeping the temperature for reaction for 6 hours, concentrating, and purifying by a column to obtain 26.4g of compound 6.
26.4g of compound 6 is dissolved in 200ml of anhydrous methanol, 30g of concentrated hydrochloric acid is added, the reaction is stirred until the reaction is completed, the filtration, the concentration to be dry and the column chromatography are carried out, so as to obtain 20.6g of compound 7.
Dissolving 20.6g of compound 7 in 250ml of tetrahydrofuran, adding 21.4g of 3, 7-dipropyl-3, 7-diazabicyclo [3.3.1] nonane, cooling to-60 ℃, dropwise adding 60ml of sec-butyl lithium, cooling to-68 ℃, adding 8g of dry ice, uniformly stirring, heating to-45 ℃, keeping the temperature and stirring for 1h, adding 200ml of water to terminate the reaction, concentrating at 40 ℃ under reduced pressure, adding 100ml of methyl tert-butyl ether to extract for 2 times, adding the combined extract, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain 16.9g of compound 8.
Dissolving 16.9g of compound 8 in 150ml of methanol, adding 28.6g D-di-p-methylbenzoyl tartaric acid (D-DTTA), 10g of 2-formyl pyridine and 40ml of glacial acetic acid, heating to 70 ℃, preserving heat for reaction for 3h, cooling to 5 ℃, stirring and crystallizing for 1h after the reaction is finished, drying, adding the solid into 100ml of isopropanol, adding 15ml of concentrated hydrochloric acid, heating to 40 ℃, stirring for 2h, adding 100ml of water, uniformly stirring, adding 100ml of ethyl acetate, extracting for 2 times, combining organic phases, and concentrating to dryness to obtain 7.4g of compound 9.
7.4g of Compound 9 was dissolved in 50ml of anhydrous methanol, and 6g of concentrated hydrochloric acid was added thereto, and the mixture was stirred until the reaction was completed, filtered, and concentrated to dryness to obtain 6.2g of Compound 2.
Specific example 2:
the compound 9 obtained after chiral resolution of the compound 8 also has a byproduct compound 10, and after racemization of the compound 10, the compound 9 is obtained by resolution of D-DTTA, so that the utilization rate of raw materials can be further improved.
Figure RE-GDA0003724974590000111
Taking 10g of compound 10, adding 120ml of DMF for dissolving, adding 25ml of 2mol/L sodium hydroxide solution, heating to 80 ℃, keeping the temperature for 2 hours, cooling to room temperature after the reaction is finished, and concentrating to a small volume to obtain a compound 8.
Dissolving the obtained compound 8 in 130ml of methanol, adding 20.4g D-di-p-methylbenzoyl tartaric acid (D-DTTA), 10g of 2-formyl pyridine and 40ml of glacial acetic acid, heating to 70 ℃, preserving heat for reaction for 3h, cooling to 5 ℃, stirring and crystallizing for 1h after the reaction is finished, drying, adding the solid into 90ml of isopropanol, adding 13ml of concentrated hydrochloric acid, heating to 40 ℃, stirring for 2h, adding 80ml of water, uniformly stirring, adding 70ml of ethyl acetate, extracting for 2 times, combining organic phases, and concentrating to dryness to obtain 3.6g of a compound 9.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (7)

1. A preparation method of a paroxetine intermediate is characterized by comprising the following steps: the method comprises the following steps:
step one, performing carbene reaction on a compound 3 cis-1, 2-dimethylolethylene and a reaction material to form a ring to obtain a compound 4, wherein the reaction material is one of 2, 2-dichloropropane, 2-dibromopropane or 2, 2-diiodopropane;
step two, chloridizing the hydroxyl of the compound 4 to obtain a compound 5, and condensing the compound 5 and benzylamine to obtain a compound 6;
step three, forming the compound 6 into hydrochloride to obtain a compound 7; the carboxyl on the compound 7 can obtain a racemic compound 8; chiral resolution is carried out on the compound 8 to obtain a compound 9;
and step four, esterifying the compound 9 with methanol to obtain a compound 2 of the intermediate of the paluvirde.
2. The process for preparing a paroxetine intermediate as claimed in claim 1, wherein: in the first step, a zinc-copper coupling agent, cis-1, 2-dimethylolethylene and zinc bromide are respectively added into anhydrous tetrahydrofuran, after stirring for half an hour at 25 ℃, 10.6g of 2, 2-dichloropropane is slowly dripped, after that, stirring is carried out at 25 ℃ until the detection reaction is complete, ice water is added, liquid separation is carried out by filtration, water phase ethyl acetate is used for extraction, organic phases are combined, drying and concentrating are carried out, and a compound 4 is obtained by column chromatography.
3. The process for preparing a paroxetine intermediate as claimed in claim 1, wherein: in the second step, adding the compound 4 into dichloromethane, adding methanol and pyridine while stirring, cooling to 0 ℃, dropwise adding thionyl chloride at the temperature of 0-5 ℃, keeping the temperature at 20 ℃ for reaction for 8 hours after the dropwise adding is finished, and then carrying out reduced pressure concentration and column purification to obtain a compound 5; adding the compound 5 and benzylamine into DMF, stirring uniformly, adding potassium carbonate, stirring for dissolving, heating to 100 ℃, keeping the temperature for reaction for 6 hours, concentrating, and purifying by a column to obtain a compound 6.
4. The process for preparing a paroxetine intermediate as claimed in claim 1, wherein: in the third step, the compound 6 is dissolved in absolute methanol, concentrated hydrochloric acid is added, the mixture is stirred until the reaction is completed, filtered, concentrated to be dry, and subjected to column chromatography to obtain a compound 7; dissolving a compound 7 in tetrahydrofuran, adding 3, 7-dipropyl-3, 7-diazabicyclo [3.3.1] nonane, cooling to-60 ℃, dropwise adding sec-butyl lithium, cooling to-68 ℃, adding dry ice, uniformly stirring, heating to-45 ℃, keeping the temperature and stirring for 1h, adding water to stop the reaction, concentrating at 40 ℃ under reduced pressure, adding methyl tert-butyl ether to extract for 2 times, adding a combined extract, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain a compound 8; dissolving the compound 8 in methanol, adding D-di-p-methylbenzoyl tartaric acid, 2-formyl pyridine and glacial acetic acid, heating to 70 ℃, preserving heat for reaction for 3 hours, cooling to 5 ℃ after the reaction is finished, stirring and crystallizing for 1 hour to obtain a white solid, drying, adding the solid into isopropanol, adding concentrated hydrochloric acid l, heating to 40 ℃, stirring for 2 hours, adding water, stirring uniformly, adding ethyl acetate, extracting for 2 times, combining organic phases, and concentrating to dryness to obtain a compound 9.
5. The process for preparing a paroxetine intermediate as claimed in claim 1, wherein: in the fourth step, the compound 9 is dissolved in absolute methanol, concentrated hydrochloric acid is added, the mixture is stirred until the reaction is completed, and the mixture is filtered and concentrated to be dry, so that the compound 2 is obtained.
6. The process for preparing a paroxetine intermediate as claimed in claim 1, wherein: in the second step, nitrobenzene is used instead of benzylamine.
7. The process for preparing intermediate of parecoxib according to claim 1, wherein: in the third step, the compound 8 is subjected to chiral resolution to obtain a byproduct compound 10, and after the compound 10 is racemized, the compound is subjected to resolution by using D-DTTA to obtain a compound 9.
CN202210389855.2A 2022-04-13 2022-04-13 Preparation method of intermediate of palovaried Pending CN114957087A (en)

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