CN115466214B - Preparation method of valicarb intermediate - Google Patents

Preparation method of valicarb intermediate Download PDF

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CN115466214B
CN115466214B CN202211086027.8A CN202211086027A CN115466214B CN 115466214 B CN115466214 B CN 115466214B CN 202211086027 A CN202211086027 A CN 202211086027A CN 115466214 B CN115466214 B CN 115466214B
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formula
preparation
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reaction
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CN115466214A (en
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朱晓峰
夏伊健
陈文坤
王子坤
金飞敏
杨绍波
郑保富
高强
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Medchemexpress China Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems

Abstract

The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a valicarb intermediate.The method comprises the following steps: 1) In a proper organic solvent A, carrying out reductive amination reaction on the compound 4 and triethylamine under the action of a reducing agent to obtain a compound 3; 2) In CO 2 Under the environment, carrying out oxidation reaction on the compound 3 and an oxidant, and separating and purifying to obtain a compound 2; 3) In a proper solvent C, the compound 2 is subjected to nitration reaction with a nitrating agent under the action of a catalyst, and the compound 1 is obtained by separation. The method uses the 2, 2-trifluoroethylamine for reductive amination, has novel route, simple steps, good atomic economy and high yield, has market value and is suitable for industrial production.

Description

Preparation method of valicarb intermediate
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a valicarb intermediate.
Background
The valicarb isopropyl tartrate is mainly used as a drug for stopping smoking of adults. Valicarb selectively binds to the α4β2 nicotinic acetylcholine receptor, with high affinity for that receptor, subtype binding producing agonism, while blocking nicotine binding to that receptor, giving rise to smoking cessation.
The key intermediate 2,3,4, 5-tetrahydro-7, 8-dinitro-3- (trifluoroacetyl) -1, 5-methyl bridge-1H-3-benzazepine (CAS: 230615-59-5) of valicarb has the structure shown in the following formula 1:
the prior art discloses a preparation method of a key intermediate 2,3,4, 5-tetrahydro-7, 8-dinitro-3- (trifluoroacetyl) -1, 5-methyl bridge-1H-3-benzazepine of valicarb, which is mainly shown in a route 1:
the preparation method of the compound shown in the formula 1 in the scheme 1 has the problems of complicated steps, low atom utilization rate, high cost, high risk, low efficiency and difficult industrial production by carrying out reductive amination on the compound shown in the formula 1 through benzylamine and trifluoroacetic anhydride, purifying the hydrochloride, carrying out hydrogenation to remove benzyl, and carrying out N protection and nitration on the compound through trifluoroacetyl.
Disclosure of Invention
The technical problem to be solved by the application is to provide a novel and improved method for preparing the valicarb intermediate represented by the compound shown in the formula 1, wherein 2, 2-trifluoroethylamine is used for reductive amination, the route is novel, the steps are simple, the atom economy is good, and the yield is high; in addition, the application does not use trifluoroacetic anhydride which is corrosive, sensitive to moisture and capable of being severely hydrolyzed when meeting water, is safer and more environment-friendly, and saves cost; therefore, the preparation method of the key intermediate of valicarb provided by the invention has market value and is suitable for industrial production.
In a first aspect the present invention provides a novel compound of formula 3 having the structure shown below:
in a second aspect the present invention provides a process for the preparation of a compound of formula 3,
the synthetic route is shown in the following formula I:
comprises the following steps:
in a proper organic solvent A, the compound 4 is subjected to reductive amination reaction with triethylamine under the action of a reducing agent to obtain a compound 3.
As a further improvement of the invention, in the amination and reduction, the molar ratio of the compound 4 to the trifluoroethylamine is 1 (0.5-1.5), preferably 1:1.
As a further improvement of the invention, in the amination reduction, the reaction temperature is 5-25 ℃, preferably room temperature.
As a further improvement of the present invention, in the amination and reduction, the organic solvent a is selected from an alcohol solvent or a chlorinated hydrocarbon solvent.
As a further improvement of the invention, in the amination and reduction, the alcohol solvent is selected from one of methanol, ethanol, n-propanol, isopropanol or n-butanol; the chlorinated hydrocarbon solvent is selected from one of chloroform, dichloromethane or dichloroethane; preferably dichloromethane.
As a further improvement of the present invention, in the amination reduction, the reducing agent is selected from one of sodium borohydride, 2-methylpyridine borane, sodium cyanoborohydride or sodium borohydride acetate; sodium borohydride acetate is preferred.
As a further improvement of the present invention, in the amination and reduction, the molar ratio of the compound 4 to the reducing agent is 1 (0.5 to 1.5), preferably 1 (0.5 to 1).
As a further improvement of the present invention, in the amination reduction, the reducing agent: compound 4: the mass volume ratio (g: g: mL) of the organic solvent A is (0.1-1): 0.1-2): 1, preferably (0.1-0.5): 0.5-1): 1.
As a further improvement of the present invention, in the amination reduction, an isolation step is optionally included: regulating pH with alkali, standing for layering, concentrating, vacuum filtering, and leaching.
As a further improvement of the invention, in the amination and reduction, the alkali is 5-40% of strong alkali, preferably 30% NaOH, and the pH is more than or equal to 10.
The compounds of formula 4 according to the invention are obtained by methods conventional in the art, for example according to journal literature (Chemical Communications (Cambridge) (1999), (9), 819-820).
In a third aspect, the present invention provides a method for preparing a compound of formula 2, wherein the synthetic route is shown in formula ii below:
comprises the following steps:
in CO 2 Under the environment, carrying out oxidation reaction on the compound 3 and an oxidant, and separating and purifying to obtain a compound 2;
or the reaction formula is shown in the following formula III:
comprising preparing a compound of formula 3 from a compound of formula 4 by amination reduction, and obtaining a compound 2 from compound 3 by:
in CO 2 And (3) under the environment, carrying out oxidation reaction on the compound 3 and an oxidant, and separating and purifying to obtain the compound 2.
As a further development of the invention, in the oxidation reaction, the compound 3 is dissolved in an organic solvent B selected from polar solvents, preferably acetonitrile.
As a further development of the invention, the oxidizing agent is selected from chlorous acid or chlorite, preferably sodium chlorite, more preferably an aqueous solution of sodium chlorite, in the oxidation reaction.
As a further improvement of the present invention, the molar ratio of the compound 3 to the oxidizing agent in the oxidation reaction is 1 (1.5 to 3.5), preferably 1 (2 to 3).
As a further improvement of the invention, in the oxidation reaction, the oxidation reaction temperature is 25-55 ℃, preferably 50 ℃.
As a further improvement of the present invention, in the oxidation reaction, the separation and purification step includes: quenching, extracting, concentrating, and recrystallizing.
In a fourth aspect, the present invention provides a method for preparing a compound of formula 1, wherein the synthetic route is as shown in formula v below:
the method comprises the following steps:
in a proper solvent C, performing nitration reaction on the compound 2 and a nitrating agent under the action of a catalyst, and separating to obtain a compound 1;
or the synthetic route is shown in the following formula IV:
comprising preparing a compound of formula 2 from a compound of formula 4 by amination reduction, oxidation, and obtaining a compound 1 from a compound 2 by:
in a proper solvent C, the compound 2 is subjected to nitration reaction with a nitrating agent under the action of a catalyst, and the compound 1 is obtained by separation.
As a further improvement of the present invention, in the nitration reaction, the solvent C is selected from one of alcohols, nitriles, chlorine solvents, ketones, ethers, aliphatic or aromatic hydrocarbons, esters, preferably one of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, butyronitrile, acrylonitrile, dichloromethane, dichloroethane, chloroform, chlorobenzene, acetone, propane, butanone, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene, benzene, ethyl acetate, propyl acetate or butyl acetate, more preferably dichloromethane.
As a further improvement of the invention, the volume amount of the solvent C in the nitration reaction is 5 to 15 times, preferably 8 to 10 times, the mass amount of the compound 2.
As a further improvement of the present invention, in the nitration reaction, the catalyst is selected from one of phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride diethyl ether, perchloric acid or phosphomolybdic acid, preferably trifluoromethanesulfonic acid.
As a further development of the invention, the molar ratio of the compound 2 to the catalyst in the nitration reaction is 1 (3-6), preferably 1:5.
As a further improvement of the present invention, in the nitration reaction, the nitrating agent is selected from one of nitric acid and fuming nitric acid, preferably fuming nitric acid.
As a further improvement of the invention, in the nitration reaction, the mass ratio of the compound 2 to the nitrating agent is 1 (0.1-1), preferably 1:0.6.
As a further improvement of the present invention, in the nitration reaction, the separation step includes: quenching, separating liquid, extracting, washing, concentrating, pulping, filtering and drying.
In a fifth aspect the invention provides the use of the aforementioned preparation route and a compound of formula 3 for the preparation of valicarb.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention uses 2, 2-trifluoroethylamine for reductive amination and introduces trifluoroacetyl through methylene oxidation, and has novel route, simple steps, good atom economy and high yield.
2. The invention does not use trifluoroacetic anhydride which has corrosiveness, is sensitive to moisture and can be severely hydrolyzed when meeting water, is safer and more environment-friendly, saves cost, has market value and is suitable for industrial production.
Drawings
FIG. 1 shows the compounds of formula 3 prepared in examples 1 to 3 1 H-NMR spectrum;
FIG. 2 shows the compounds of formula 2 obtained by the preparation of examples 4 to 7 1 H-NMR spectrum;
FIG. 3 shows the compounds of formula 1 obtained by the preparation of examples 8 to 9 1 H-NMR spectrum.
Detailed Description
In order to facilitate understanding of the present disclosure by those skilled in the art, the following describes the technical scheme of the present disclosure in conjunction with specific embodiments. It should be understood that the following examples are not intended to limit the scope and spirit of the invention as claimed. The raw materials, reagents or solvents used in the present invention are commercially available without any particular description, and experimental methods under specific conditions not specifically described are carried out by routine procedures in the art.
Example 1:
657.2g of sodium borohydride acetate was dissolved in 5.3L of dichloromethane at room temperature and stirred under nitrogen. After 500g of trifluoroethylamine was added thereto at 25℃and 879.4g of a DCM solution of Compound 4 (1.2L) was added dropwise thereto, the mixture was stirred for 2.5 hours, and the reaction was completed. Controlling the temperature to 25 ℃, dropwise adding 2L of 30% sodium hydroxide solution, and adjusting the pH to be more than or equal to 10. Standing and layering the water phase, discarding the water phase, controlling the temperature of the organic phase to 30 ℃, and concentrating; n-heptane was added thereto at 20℃and the temperature was lowered to 5℃and stirred for 2h. Suction filtration, leaching the filter cake with n-heptane to obtain about 898.7g of off-white solid with the yield of 74%, 1 H-NMR is shown in FIG. 1.
Example 2:
650g of sodium cyanoborohydride were dissolved in 4.8L of dichloromethane at room temperature and stirred under nitrogen. After 522.5g of trifluoroethylamine was added thereto at 25℃and 837.6g of a DCM solution of Compound 4 (1.1L) was added dropwise thereto, the mixture was stirred for 2.5 hours, and the reaction was completed. Controlling the temperature to 25 ℃, dropwise adding 2L of 15% sodium hydroxide solution, and adjusting the pH to be more than or equal to 10. Standing and layering the water phase, discarding the water phase, controlling the temperature of the organic phase to 30 ℃, and concentrating; n-heptane was added thereto at 20℃and the temperature was lowered to 5℃and stirred for 3 hours. Suction filtration, leaching the filter cake with n-heptane to obtain about 810g of off-white solid with the yield of 69.8%, 1 H-NMR is shown in FIG. 1.
Example 3:
635.6g of sodium borohydride acetate was dissolved in 5.6L of chloroform at room temperature, and the mixture was stirred under nitrogen. After 515.6g of trifluoroethylamine was added thereto, 710.5g of a chloroform solution of Compound 4 (1.1L) was added dropwise thereto, and the mixture was stirred for 2.5 hours, whereby the reaction was completed. Controlling the temperature to 20 ℃, dropwise adding 2L of 20% sodium hydroxide solution, and adjusting the pH to be more than or equal to 10. Standing and layering the water phase, discarding the water phase, controlling the temperature of the organic phase to 40 ℃, and concentrating; n-heptane was added at 15℃and the temperature was lowered to 5℃and stirred for 3h. Suction filtration, leaching the filter cake with n-heptane to obtain about 710.6g of off-white solid with a yield of 72.2%, 1 H-NMR is shown in FIG. 1.
Example 4:
500g of Compound 3 (2 mmol) was dissolved in 2L of acetonitrile at 50℃and stirred for 20min under carbon dioxide. Adding into the reaction solution1L of an aqueous solution of 80% sodium chlorite (542.7 g,6 mmol) was stirred until the reaction was complete. Quench the reaction with saturated aqueous sodium sulfite solution, extract with DCM (3 x 3 l); the combined organic phases were concentrated, ethyl acetate: recrystallizing n-heptane=1:1 system, purifying to obtain compound of formula 2 380.8g, yield 72%, HPLC purity 99.6%, 1 H-NMR is shown in FIG. 2.
Example 5:
500g of Compound 3 (2 mmol) was dissolved in 2L of acetonitrile at 30℃and stirred for 20min under carbon dioxide. To the reaction mixture was added 1L of an aqueous solution of 80% sodium chlorite (561.3 g,6.2 mmol), and the mixture was stirred until the reaction was completed. Quench the reaction with saturated aqueous sodium sulfite solution, extract with DCM (3 x 3 l); the combined organic phases were concentrated, ethyl acetate: recrystallizing n-heptane=1:1 system, purifying to obtain 375.6g of the compound of formula 2, yield 71%, HPLC purity 99.2%, 1 H-NMR is shown in FIG. 2.
Example 6:
500g of Compound 3 (2 mmol) was dissolved in 2L of ethanol at 50℃and stirred for 20min under carbon dioxide. To the reaction mixture was added 1L of an aqueous solution of 80% sodium chlorite (545.8 g,6 mmol), and the mixture was stirred until the reaction was completed. Quench the reaction with saturated aqueous sodium sulfite solution, extract with DCM (3 x 3 l); the combined organic phases were concentrated, ethyl acetate: recrystallizing n-heptane=1:1 system, purifying to obtain 373.1g of the compound of formula 2, with yield of 70.5%, HPLC purity of 99.3%, 1 H-NMR is shown in FIG. 2.
Example 7:
500g of Compound 3 (2 mmol) was dissolved in 2L of acetonitrile at 35℃and stirred for 20min under carbon dioxide. To the reaction mixture was added 1L of an aqueous solution of 80% calcium chlorite (540.6 g,3.1 mmol), and the mixture was stirred until the reaction was completed. Quench the reaction with saturated aqueous sodium sulfite solution, extract with DCM (3 x 3 l); the combined organic phases were concentrated, ethyl acetate: recrystallizing n-heptane=1:1 system, purifying to obtain 369.2g of the compound of formula 2, with yield of 69.8%, HPLC purity of 98.8%, 1 H-NMR is shown in FIG. 2.
Example 8:
179.9g of trifluoromethanesulfonic acid is cooled to 5 ℃, 37g of fuming nitric acid is dropwise added at the temperature of 5+/-5 ℃, a DCM solution (60 g dissolved in 600mL of dichloromethane) of the compound 2 is dropwise added, and the temperature is 23+/-2 ℃ for reaction for 6 hours; after the reaction, 1200mL of water was added dropwise to quench the reaction. Separating, extracting the water phase with 600mL of dichloromethane, merging organic phases, washing with 600mL of saturated sodium bicarbonate solution, concentrating the organic phases, adding 500mL of n-heptane, carrying out hot pulping at 50 ℃, filtering and drying to obtain 55.2g of white solid, and obtaining the yield: 68%, HPLC purity 99.7%, 1 H-NMR is shown in FIG. 3.
Example 9:
165.8g of trifluoromethanesulfonic acid is cooled to 0 ℃, 35g of fuming nitric acid is dropwise added at the temperature of 5+/-5 ℃, a DCM solution (68 g dissolved in 610mL of dichloromethane) of the compound 2 is dropwise added, and the temperature is 23+/-2 ℃ for reaction for 6 hours; after the reaction, 1200mL of water was added dropwise to quench the reaction. Separating, extracting the water phase with 610mL of dichloromethane, merging organic phases, washing with 600mL of saturated sodium bicarbonate solution, concentrating the organic phases, adding 500mL of n-heptane, carrying out hot pulping at 50 ℃, filtering and drying to obtain 59.6g of white solid, and obtaining the yield: 64.8%, HPLC purity 99.5%, 1 H-NMR is shown in FIG. 3.

Claims (16)

1. A method for preparing a compound of formula 3, wherein the reaction formula is shown as formula i:
(formula I);
comprises the following steps:
in a proper organic solvent A, the compound 4 is subjected to reductive amination reaction with triethylamine under the action of a reducing agent to obtain a compound 3.
2. The preparation method according to claim 1, wherein the molar ratio of the compound 4 to the trifluoroethylamine is 1 (0.5-1.5);
or the organic solvent A is selected from alcohol solvents or chlorinated hydrocarbon solvents; the alcohol solvent is selected from one of methanol, ethanol, n-propanol, isopropanol or n-butanol; the chlorinated hydrocarbon solvent is selected from one of chloroform, dichloromethane or dichloroethane;
or the reducing agent is selected from one of sodium borohydride, 2-picoline borane, sodium cyanoborohydride or sodium borohydride acetate.
3. The preparation method according to claim 2, wherein the molar ratio of the compound 4 to the trifluoroethylamine is 1:1; or the chlorinated hydrocarbon solvent is selected from dichloromethane; or the reducing agent is sodium borohydride acetate.
4. The preparation method according to claim 1, wherein the molar ratio of the compound 4 to the reducing agent is 1 (0.5-1.5).
5. The method according to claim 4, wherein the molar ratio of the compound 4 to the reducing agent is 1 (0.5-1).
6. A compound of formula 3, characterized by the structure shown below:
。
7. a method for preparing a compound of formula 2, which is characterized by the following formula II:
(formula II);
comprises the following steps:
in CO 2 Under the environment, carrying out oxidation reaction on the compound 3 and an oxidant, and separating and purifying to obtain a compound 2, wherein the oxidant is selected from chlorous acid or chlorite;
or the reaction formula is shown in the following formula III:
(formula III);
comprising synthesizing a compound of formula 3 according to the preparation method of any one of claims 1 to 5, and obtaining a compound 2 from the compound 3 by the following steps and operations:
in CO 2 And (3) under the environment, carrying out oxidation reaction on the compound 3 and an oxidant, and separating and purifying to obtain the compound 2, wherein the oxidant is selected from chlorous acid or chlorite.
8. The method of claim 7, wherein the oxidizing agent is selected from sodium chlorite;
or the molar ratio of the compound 3 to the oxidant is 1 (1.5-3.5).
9. The preparation method of claim 8, wherein the molar ratio of the compound 3 to the oxidizing agent is 1 (2-3).
10. A method for preparing a compound of formula 1, which is characterized by the following formula IV:
(formula IV);
comprising synthesizing a compound of formula 2 according to the preparation method of claim 7, wherein compound 1 is obtained from compound 2 by the steps and operations of:
in a proper solvent C, the compound 2 is subjected to nitration reaction with a nitrating agent under the action of a catalyst, and the compound 1 is obtained by separation.
11. The preparation method according to claim 10, wherein the solvent C is one selected from the group consisting of alcohols, nitriles, ketones, ethers, aliphatic or aromatic hydrocarbons, esters;
the catalyst is selected from one of phosphoric acid, polyphosphoric acid, methane sulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride diethyl ether, perchloric acid or phosphomolybdic acid;
the nitrifying agent is selected from one of nitric acid and fuming nitric acid.
12. The preparation method according to claim 10, wherein the solvent C is one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, butyronitrile, acrylonitrile, dichloromethane, dichloroethane, chloroform, chlorobenzene, acetone, propane, butanone, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene, benzene, ethyl acetate, propyl acetate, and butyl acetate; the catalyst is trifluoromethanesulfonic acid; the nitrifying agent is fuming nitric acid.
13. The preparation method according to claim 10, wherein the molar ratio of the compound 2 to the catalyst is 1 (3-6); or the mass ratio of the compound 2 to the nitrating agent is 1 (0.1-1).
14. The preparation method according to claim 13, wherein the molar ratio of the compound 2 to the catalyst is 1:5; the mass ratio of the compound 2 to the nitrating agent is 1:0.6.
15. Application of preparation method according to any one of claims 1-5 and 7-14 in preparation of valicarb intermediate compound of formula 1。
16. Use of a compound of formula 3 according to claim 6 for the preparation of a compound of formula 1 valicarb intermediate。
CN202211086027.8A 2022-09-06 2022-09-06 Preparation method of valicarb intermediate Active CN115466214B (en)

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WO2009155403A2 (en) * 2008-06-19 2009-12-23 Teva Pharmaceutical Industries Ltd. Processes for the preparation of varenicline and intermediates thereof
CN104478803A (en) * 2014-12-19 2015-04-01 连云港恒运医药科技有限公司 Preparation method of varenicline intermediate and nitroreduction impurity thereof
CN114685497A (en) * 2020-12-25 2022-07-01 江苏嘉逸医药有限公司 Intermediate impurity of varenicline tartrate and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11602537B2 (en) * 2022-03-11 2023-03-14 Par Pharmaceutical, Inc. Varenicline compound and process of manufacture thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009155403A2 (en) * 2008-06-19 2009-12-23 Teva Pharmaceutical Industries Ltd. Processes for the preparation of varenicline and intermediates thereof
CN104478803A (en) * 2014-12-19 2015-04-01 连云港恒运医药科技有限公司 Preparation method of varenicline intermediate and nitroreduction impurity thereof
CN114685497A (en) * 2020-12-25 2022-07-01 江苏嘉逸医药有限公司 Intermediate impurity of varenicline tartrate and preparation method thereof

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