CN114573500A

CN114573500A - Preparation method of lefenacin intermediate

Info

Publication number: CN114573500A
Application number: CN202210397728.7A
Authority: CN
Inventors: 王许鹏; 张广明; 时冬林; 韩晓秋; 郭晓东; 裴章宏
Original assignee: Yangzhou Zhongbao Pharmaceutical Co Ltd
Current assignee: Yangzhou Zhongbao Pharmaceutical Co Ltd
Priority date: 2021-04-20
Filing date: 2022-04-15
Publication date: 2022-06-03
Anticipated expiration: 2042-04-15
Also published as: CN113121412A; CN114573500B

Abstract

The invention discloses a preparation method of a lefenacin intermediate, which comprises the following steps: (1) performing a protection reaction on methylamino acetaldehyde dimethyl acetal shown in the formula I and a protecting group compound to obtain a compound shown in the formula II; (2) carrying out hydrolysis reaction on the compound shown in the formula II and a hydrochloric acid solution to obtain a compound shown in a formula III; (3) carrying out reductive amination reaction on a compound shown in a formula III, piperidine-4-yl [1, 1-biphenyl ] -2-carbamate shown in a formula IV and sodium triacetoxyborohydride to obtain a compound shown in a formula V; (4) and carrying out deprotection reaction on the compound shown in the formula V to obtain the leflufenacin intermediate shown in the formula VI. The invention adopts Fmoc-Cl as an amino protecting group, avoids the Pd/C hydrogenation high-pressure protecting group removing process, and has the advantages of milder and safer reaction conditions, lower production cost, less environmental pollution and the like.

Description

Preparation method of lefenacin intermediate

Technical Field

The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a lefenacin intermediate.

Background

Rifanapine was first developed by Ireland Theravance biopharmaceutical corporation, Kulanin Schke (GSK) pharmaceutical group, U.K. 2004, to obtain approval for the global development of the product; the 2009, month 2 GSK company returned the license to Theravance biopharmaceutical company due to the incompatibility of the proprietary inhaler devices of that company; in 1 month of 2015, the theavance biopharmaceutical company and the Mylan pharmaceutical company in the U.S. jointly develop rafenicin, a new drug marketing application is proposed to the Food and Drug Administration (FDA) in 13 months of 2017, and the new drug is approved to be marketed in 11 months of 2018 and 9 days of 2018, and the preparation is named Yupelri. Rafenine is LAMA, also commonly referred to as an anticholinergic drug. In the airway, the drug acts by inhibiting smooth muscle muscarinic M3 receptor to dilate the bronchus. Is suitable for the maintenance treatment of patients with Chronic Obstructive Pulmonary Disease (COPD).

Currently, there are two main synthetic routes for rafenicin.

The synthetic route of the original patent CN1930125A is as follows: biphenyl-2-isocyanate and 4-hydroxy-N-benzyl piperidine are used as initial raw materials, biphenyl-2-yl carbamic acid piperidine-4-yl ester is generated through condensation and debenzylation, and biphenyl-2-yl carbamic acid 1- [2- (benzyl methylamino) ethyl ] piperidine-4-yl ester is obtained through reduction and ammoniation; then obtaining biphenyl-2-yl carbamic acid 1- (2-methylamino ethyl) piperidine-4-yl ester (formula VI) through debenzylation, then condensing with 4-carboxylic acid benzaldehyde to obtain biphenyl-2-yl carbamic acid 1- {2- [ (4-formyl benzoyl) methylamino ] ethyl } piperidine-4-yl ester, and finally obtaining the ralfinacin through reduction and ammoniation reaction with the isopiperidine formamide. The biphenyl-2-yl carbamic acid 1- (2-methylaminoethyl) piperidin-4-yl ester (formula VI) is prepared by adopting high-pressure hydrogenation debenzylation, belongs to high-risk reaction and is not beneficial to large-scale production. The overall molar yield of this route is about 45%.

A synthesis process route is disclosed in U.S. Pat. No. 2012/0016130a1, and the route uses biphenyl-2-isocyanate and 4-hydroxy-N-benzylpiperidine as starting materials, and generates biphenyl-2-yl carbamic acid piperidine-4-yl ester through condensation and debenzylation, and biphenyl-2-yl carbamic acid 1- [2- (N-benzyloxycarbonyl-N-methylamino) ethyl ] piperidine-4-yl ester is obtained through reduction and ammoniation; then obtaining biphenyl-2-yl carbamic acid 1- (2-methylamino ethyl) piperidine-4-yl ester (formula VI) by debenzylation, then condensing with 4-carboxylic acid benzaldehyde to obtain biphenyl-2-yl carbamic acid 1- {2- [ (4-formyl benzoyl) methylamino ] ethyl } piperidine-4-yl ester, and finally carrying out reduction and ammoniation reaction with isopiperidine formamide to obtain the lefenacin. The biphenyl-2-yl carbamic acid 1- (2-methylaminoethyl) piperidin-4-yl ester (formula VI) prepared by the method adopts high-pressure hydrogenation to remove benzyloxycarbonyl, belongs to high-risk reaction, and is not beneficial to large-scale production. The overall yield of this route is about 40%.

The synthetic routes reported in the two patents are the same and different, and the defects of a highly toxic reagent, Pd/C hydrogenation high-risk high-pressure reaction and the like are mostly used in the synthetic process.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to solve the technical problem of providing a preparation method of a lefenacin intermediate aiming at the defects of the prior art.

In order to solve the technical problem, the invention discloses a preparation method of a lefenacin intermediate (the reaction path is shown in figure 1), which comprises the following steps:

(1) performing a protection reaction on methylamino acetaldehyde dimethyl acetal shown in the formula I and a protecting group compound to obtain a compound shown in the formula II;

(2) carrying out hydrolysis reaction on the compound shown in the formula II and a hydrochloric acid solution to obtain a compound shown in a formula III;

(3) carrying out reductive amination reaction on a compound shown in a formula III, piperidine-4-yl [1, 1-biphenyl ] -2-carbamate shown in a formula IV and sodium triacetoxyborohydride to obtain a compound shown in a formula V;

(4) carrying out deprotection reaction on the compound shown in the formula V to obtain a leflufenacin intermediate shown in the formula VI;

wherein, R is shown as the following structural formula;

in the step (1), the protecting group compound is chloroformic acid-9-fluorenylmethyl ester (Fmoc-Cl).

In the step (1), the molar ratio of the methylamino acetaldehyde dimethyl acetal shown in the formula I to the protecting group compound is 1.5-2: 1; preferably, the molar ratio of the methylamino acetaldehyde dimethyl acetal shown in the formula I to the protecting group compound is 1.75: 1.

in the step (1), the protection reaction is carried out under the alkaline condition provided by inorganic base.

Wherein the inorganic base is any one or combination of potassium carbonate, sodium hydroxide, sodium carbonate and sodium acetate; preferably, the inorganic base is sodium hydroxide or sodium carbonate.

Wherein the inorganic base participates in the reaction in the form of a solution, such as an aqueous solution; among them, the concentration of the alkali solution is not particularly required in the present invention.

Wherein the molar ratio of the inorganic base to the protecting group compound is 1.5-2.5: 1; preferably, the molar ratio of the inorganic base to the protecting group compound is 1.8: 1.

in the step (1), the solvent for the protection reaction is any one or a combination of more of 2-methyltetrahydrofuran, methanol, ethyl acetate and dichloromethane; preferably, the solvent for the protection reaction is 2-methyltetrahydrofuran.

In the step (1), the concentration of the methylamino acetaldehyde dimethyl acetal is 1: 3-9 g/mL; preferably, the concentration of the methylaminoacetaldehyde dimethyl acetal is 1: 6 g/mL.

In the step (1), methylamino acetaldehyde dimethyl acetal shown in the formula I and a solvent are added into an inorganic alkali solution; then adding a protecting group compound for protection reaction to obtain the product.

Wherein, the temperature of the methylamino acetaldehyde dimethyl acetal shown in the formula I and the protective group compound is kept at 0 ℃ in the adding process.

Wherein, the protective group compound is added in a feeding or dropping manner; preferably, the addition is completed within 1-2 h.

In the step (1), the protection reaction is a reaction under stirring.

In the step (1), the temperature of the protection reaction is 15-25 ℃; preferably, the temperature of the protection reaction is 20 ℃.

In the step (1), the protection reaction time is 4-8 h; preferably, the time of the protection reaction is 5 h.

In the step (2), the hydrochloric acid solution is a hydrochloric acid aqueous solution.

In the step (2), the concentration of the hydrochloric acid solution is 1-6 mol/L; preferably, the concentration of the hydrochloric acid solution is 3 mol/L.

In the step (2), the mass-to-volume ratio of the methylamino acetaldehyde dimethyl acetal to the hydrochloric acid solution is 1: 3-9 g/mL; preferably, the mass-volume ratio of the methylamino acetaldehyde dimethyl acetal to the hydrochloric acid solution is 1: 6 g/mL.

In the step (2), the hydrolysis reaction is a reaction under stirring.

In the step (2), the temperature of the hydrolysis reaction is 15-25 ℃; preferably, the temperature of the hydrolysis reaction is 20 ℃.

In the step (2), the hydrolysis reaction time is 6-10 h; preferably, the time of the hydrolysis reaction is 8 h.

In the step (3), the reductive amination reaction is that the compound shown in the formula III firstly reacts with piperidine-4-yl [1, 1-biphenyl ] -2-carbamate shown in the formula IV for the first reaction, and then sodium triacetoxyborohydride is added for the second reaction.

Wherein, in the first reaction, the molar ratio of the compound shown in the formula III to the piperidine-4-yl [1, 1-biphenyl ] -2-carbamate shown in the formula IV is 1: 1-2; preferably, the molar ratio of the compound of formula III to the piperidin-4-yl [1, 1-biphenyl ] -2-carbamate of formula IV is 1: 1.

wherein, in the first reaction, the concentration of the compound shown as the formula III is 1: 8-12 g/mL; preferably, the concentration of the compound of formula iii is 1: 10 g/mL.

In the first reaction, the solvent of the reductive amination reaction is any one or combination of tetrahydrofuran, methanol, ethyl acetate and dichloromethane; preferably, the solvent is tetrahydrofuran.

Wherein the first reaction is a reaction under stirring.

Wherein the temperature of the first reaction is 20-30 ℃; preferably, the temperature of the first reaction is 25 ℃.

Wherein the time of the first reaction is 1-3 h; preferably, the time of the first reaction is 1 h.

Wherein, in the second reaction, sodium triacetoxyborohydride is added at 0-5 ℃; preferably, the sodium triacetoxyborohydride is added at 0 ℃.

In the second reaction, the molar ratio of the compound shown in the formula III to sodium triacetoxyborohydride is 1: 1-1.5; preferably, the molar ratio of the compound shown in the formula III to sodium triacetoxyborohydride is 1: 1.2.

wherein the second reaction is a reaction under stirring.

Wherein the temperature of the second reaction is 20-30 ℃; preferably, the temperature of the second reaction is 25 ℃.

Wherein the time of the second reaction is 1-3 h; preferably, the time of the second reaction is 2 h.

In the step (4), the solvent for deprotection reaction is any one or combination of tetrahydrofuran, methanol, ethyl acetate and dichloromethane; preferably, the solvent for the deprotection reaction is tetrahydrofuran.

In the step (4), the concentration of the compound represented by the formula V is 1: 3-9 g/mL; preferably, the concentration of the compound of formula V is 1: 6 g/mL.

In the step (4), the compound shown in the formula V and morpholine are subjected to deprotection reaction.

Wherein the molar ratio of the compound shown in the formula V to morpholine is 1: 1-3; preferably, the molar ratio of the compound of formula V to morpholine is 1: 2.

in the step (4), the deprotection reaction is a reaction under stirring.

In the step (4), the temperature of the deprotection reaction is 25-35 ℃; preferably, the deprotection reaction temperature is 30 ℃.

In the step (4), the deprotection reaction time is 3-8 h; preferably, the deprotection reaction time is 4 h.

The rate of agitation is not particularly critical in the present invention.

Has the advantages that: compared with the prior art, the invention has the following advantages:

(1) the method takes Fmoc-Cl as an amino protecting group, avoids the Pd/C hydrogenation high-pressure protecting group removing process, and has the advantages of milder and safer reaction conditions, lower production cost, less environmental pollution and the like.

(2) The materials selected in the route are all bulk materials sold in the market and are easy to purchase.

Drawings

The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.

Figure 1 is a scheme showing the synthesis scheme of a rafenicin intermediate.

FIG. 2 is a nuclear magnetic spectrum of formula III.

FIG. 3 is a mass spectrum of formula III.

FIG. 4 is a nuclear magnetic spectrum of formula V.

FIG. 5 is a mass spectrum of formula V.

FIG. 6 is a nuclear magnetic spectrum of formula VI.

FIG. 7 is a mass spectrum of formula VI.

Detailed Description

The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1: synthesis of Leinaxine intermediates (FIG. 1)

(1) Adding 76.32g of sodium carbonate into a 2L reaction bottle, stirring with 600mL of water, dissolving, and cooling to 0 ℃; weighing 82.5g of methylamino acetaldehyde dimethyl acetal material, adding 600mL of 2-methyl tetrahydrofuran to prepare a mixed solution, adding the mixed solution into a reaction bottle, and keeping the temperature at 0 ℃; weighing 102.3g of Fmoc-Cl, dropwise adding into a reaction bottle, and keeping the temperature at 0 ℃ in the dropwise adding process; after the dropwise addition is finished within 1 hour, heating to 20 ℃, carrying out heat preservation reaction for 5 hours, standing for layering, and keeping an organic phase to obtain a formula II, wherein the organic phase is directly used for feeding in the next step.

(2) The organic phase in the step (1) is stirred and reacted for 8 hours at 20 ℃ by 600mL of 3mol/L hydrochloric acid aqueous solution; after the reaction is finished, standing and layering the reaction solution, adding 600mL of saturated salt aqueous solution into the organic phase, washing once, and standing and layering; mixing the water phases, adding 600mL of EA, stirring and extracting, standing and layering; the organic phases were combined, dried over anhydrous sodium sulfate and the filtrate was concentrated to dryness at 40 ℃ to give 112g of an oil of formula III in 96% yield. The nuclear magnetic spectrum and the mass spectrum of the formula III are respectively shown in FIG. 2 and FIG. 3.

(3) 1100mL of THF is added into a 2L reaction flask, 110g of formula III is added, and the mixture is stirred to be dissolved; weighing 110g of piperidine-4-yl [1, 1-biphenyl ] -2-carbamate and adding the mixture into a reaction bottle, weighing 110g of anhydrous sodium sulfate and adding the mixture into the reaction bottle, and stirring the mixture for 1 hour at normal temperature; cooling to 0 ℃, adding 94.4g of sodium triacetoxyborohydride in batches, heating to room temperature, keeping the temperature at 25 ℃, and reacting for 2 hours; dropwise adding 1000mL of 1mol/L hydrochloric acid into a reaction bottle, stirring for 10min after dropwise adding is finished, and standing for layering; adding 500mL of ethyl acetate into the water phase for extraction, standing for layering, combining an organic phase and the organic phase in the previous step, and discarding the water phase; washing the combined organic phase with 500mL of 1mol/L potassium carbonate solution, stirring for 5min, and standing for layering; adding 500mL of ethyl acetate into the water phase, stirring for 5min, and standing for layering; the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness to give 203g of oil of formula V in 95% yield. The nuclear magnetic spectrum and mass spectrum of formula V are shown in FIG. 4 and FIG. 5, respectively.

(4) Adding 1200mL of tetrahydrofuran into a 2L reaction bottle, adding 200g of formula V, stirring to dissolve, adding 60.53g of morpholine into the reaction bottle, and stirring; heating the reaction to 30 ℃, and keeping the temperature for reaction for 4 hours; filtering the materials, concentrating the filtrate to dryness, adding 1200mL of DCM, and stirring for dissolving; washing the organic phase twice with 600mL of 10% potassium carbonate aqueous solution, and washing once with 600mL of water; combining the water phases washed for three times, extracting twice by 600mL of DCM, standing and layering; the organic phases are combined, dried by anhydrous sodium sulfate and concentrated to obtain oily matter; adding 600mL of isopropyl acetate into the oily matter, and stirring for crystallization for 2 h; filtering, leaching a filter cake by using 100mL of isopropyl acetate, and drying the filter cake to obtain 105.60g with the yield of 86%. The nuclear magnetic spectrum and mass spectrum of formula VI are shown in FIGS. 6 and 7, respectively.

Example 2:

the synthesis route of the leflufenacin intermediate is fully optimized by parameters, and the parameter optimization result is as follows:

1. fmoc protection of amino groups

(1) The optimization results of the types of solvents for Fmoc protection of amino groups are shown below (Table 1), and other parameters are the same as those in step (1) of example 1:

TABLE 1

The above results show that: when 2-methyltetrahydrofuran was used as the Fmoc-protected reaction solvent for the amino group, Fmoc-Cl could be reacted to completion, while the other three solvents, Fmoc-Cl, remained.

(2) The optimization of the solvent ratio for Fmoc protection of amino groups was as follows (Table 2), with the other parameters being as in step (1) of example 1:

TABLE 2

The above results show that: when 2-methyltetrahydrofuran is used, the volume ratio is 6: 1, 5h can enable Fmoc-Cl reaction to be complete, 3: 1 and 9: Fmoc-Cl can not completely react at 1 or can completely react but the using amount of the solvent is large, so that the volume ratio of 2-methyltetrahydrofuran is preferably 6: 1.

(3) Fmoc-Cl protection of amino groups Methylaminoacetaldehyde dimethyl acetal equivalent optimization results are as follows (Table 3), and other parameters are the same as in example 1, step (1):

TABLE 3

The above results show that: the Fmoc-Cl reaction is incomplete when the molar equivalent of the methylaminoacetaldehyde dimethyl acetal is 1.5, while the Fmoc-Cl reaction is complete and the reaction time is not greatly different between 1.75 and 2.0 equivalents, so that 1.75 equivalents is preferred.

2. Hydrolysis reaction

(1) The concentration of hydrochloric acid in the hydrolysis reaction was optimized as follows (Table 4), and the other parameters were the same as in step (2) of example 1:

TABLE 4

The above results show that: 1mol/L hydrochloric acid is not completely reacted, and 3mol/L hydrochloric acid and 6mol/L hydrochloric acid can be completely reacted, so 3mol/L hydrochloric acid is preferred.

(2) The optimization of the hydrochloric acid ratio in the hydrolysis reaction was as follows (Table 5), and the other parameters were the same as in step (2) of example 1:

TABLE 5

The above results show that: 3: incomplete reaction at 1 time, 6: 1 and 9: 1, the reaction is complete, so the ratio of the hydrochloric acid solution to the methylamino acetaldehyde dimethyl acetal is preferably 6: 1 (mL/g).

3. Reductive amination reaction

(1) The solvent type in the reductive amination reaction was optimized as follows (Table 6), and other parameters were the same as in step (3) in example 1:

TABLE 6

The above results show that: in the reductive amination reaction, tetrahydrofuran and ethyl acetate are used as solvents, the reaction is relatively complete, but when ethyl acetate is used as a solvent, the content of impurities is increased, and when methanol and dichloromethane are used as solvents, the reaction is not complete, so that tetrahydrofuran is preferably used as a solvent for the reaction.

(2) The solvent ratio in the reductive amination reaction was optimized as follows (Table 7), and the other parameters were the same as in step (3) in example 1:

TABLE 7

The above results show that: when tetrahydrofuran is used, the volume ratio is 10: 1, 5h can be completely reacted, 8: 1 and 12: 1 or can be completely reacted but the amount of solvent is large, so the volume ratio of tetrahydrofuran to the compound of formula III is preferably 10: 1.

(3) the sodium triacetoxyborohydride equivalent in the reductive amination reaction was optimized as follows (table 8), and other parameters were the same as in step (3) in example 1:

TABLE 8

The above results show that: in the reductive amination reaction, sodium triacetoxyborohydride equivalent of 1.0 is preferably 1.2, since sodium triacetoxyborohydride equivalent is not completely reacted for 2 hours, and is completely reacted for 1.2 and 1.5 equivalents.

(4) The piperidin-4-yl [1, 1-biphenyl ] -2-carbamate equivalent weight in the reductive amination reaction was optimized as follows (Table 9), and other parameters were the same as in step (3) in example 1:

TABLE 9

The above results show that: in the reductive amination reaction, the reaction is completed when the piperidine-4-yl [1, 1-biphenyl ] -2-carbamate equivalent is 1.0, so that the piperidine-4-yl [1, 1-biphenyl ] -2-carbamate equivalent is preferably 1.0.

4. Deprotection reaction of Fmoc

(1) The solvent type for the Fmoc deprotection reaction was optimized as follows (Table 10), and other parameters were the same as in step (4) of example 1:

watch 10

The above results show that: tetrahydrofuran is preferably used as the solvent for the Fmoc deprotection reaction because the reaction is completed in 4h and the other three solvents are not completely reacted when tetrahydrofuran is used as the solvent for the Fmoc deprotection reaction.

(2) The solvent ratio in the Fmoc deprotection reaction was optimized as follows (Table 11), with the other parameters being as in step (4) of example 1:

TABLE 11

The above results show that: when tetrahydrofuran is used, the volume ratio is 6: 1, 4h can be completely reacted, 3: 1 and 9: 1 or can be completely reacted but the solvent is used in a large amount, so that the volume ratio of the tetrahydrofuran compound of the formula V is preferably 6: 1.

(3) the morpholine equivalents in the Fmoc deprotection reactions were optimized as follows (Table 12), with the other parameters being as in step (4) of example 1:

TABLE 12

The above results show that: when morpholine equivalent is 1: 1 hour, 4 hours are not completely reacted, 2: 1 and 3: 1, the reaction is complete, so the preferred ratio of compound of formula V to morpholine is 2: 1.

the invention provides a method and a thought of a method for synthesizing a lefenacin intermediate, and a plurality of methods and ways for realizing the technical scheme, and the above description is only a preferred embodiment of the invention, and it should be noted that, for a person skilled in the art, a plurality of improvements and decorations can be made without departing from the principle of the invention, and these improvements and decorations should also be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.

Claims

1. A preparation method of a lefenacin intermediate is characterized by comprising the following steps:

wherein, R is shown as the following structural formula;

2. the method according to claim 1, wherein in the step (1), the protecting group compound is chloroformate-9-fluorenylmethyl ester.

3. The process according to claim 1, wherein in the step (1), the molar ratio of the methylaminoacetaldehyde dimethyl acetal represented by the formula I to the protecting group compound is 1.5 to 2: 1.

4. the preparation method according to claim 1, wherein in the step (1), the protection reaction is carried out under alkaline conditions provided by an inorganic base; the molar ratio of the inorganic base to the protecting group compound is 1.5-2.5: 1.

5. the preparation method according to claim 1, wherein in the step (1), the solvent for the protection reaction is any one or a combination of several of 2-methyltetrahydrofuran, methanol, ethyl acetate and dichloromethane; the concentration of the methylamino acetaldehyde dimethyl acetal is 1: 3-9 g/mL.

6. The method according to claim 1, wherein in the step (2), the concentration of the hydrochloric acid solution is 1 to 6mol/L, and the mass-to-volume ratio of the methylamino acetaldehyde dimethyl acetal to the hydrochloric acid solution is 1: 3-9 g/mL.

7. The process according to claim 1, wherein in the step (3), the molar ratio of the compound represented by the formula III to the piperidin-4-yl [1, 1-biphenyl ] -2-carbamate represented by the formula IV is 1: 1-2.

8. The method according to claim 1, wherein in the step (3), the molar ratio of the compound represented by the formula III to sodium triacetoxyborohydride is 1: 1-1.5.

9. The preparation method according to claim 1, wherein in the step (4), the solvent for the deprotection reaction is any one or a combination of several of tetrahydrofuran, methanol, ethyl acetate and dichloromethane; the concentration of the compound of formula V is 1: 3-9 g/mL.

10. The method according to claim 1, wherein in step (4), the compound represented by formula V is subjected to deprotection reaction with morpholine; preferably, the molar ratio of the compound of formula V to morpholine is 1: 1-3.