CN108017599B

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Publication number: CN108017599B
Application number: CN201610972580.XA
Authority: CN
Inventors: 许庆; 彭程; 骆玉美; 姚二东; 冯二龙
Original assignee: Shanghai Ark Biosciences Co Ltd
Current assignee: Shanghai Aike Baifa Biomedical Technology Co.,Ltd.
Priority date: 2016-11-04
Filing date: 2016-11-04
Publication date: 2020-03-03
Anticipated expiration: 2036-11-04
Also published as: CN108017599A

Abstract

The invention provides a [3- (aminomethyl) -oxetaneAlk-3-yl]The synthesis method of p-methoxybenzyl carbamate and p-chlorobenzoate is characterized by comprising the following steps: a. substituting bromine group of the compound 1 with a cyclic imide group to generate a compound 2, wherein the cyclic imide group is one of phthalimide, succinimide and maleimide; b. carrying out amination reaction on the primary amine and the compound 2 to generate a compound 3; c. reacting the compound 3 with p-chlorobenzoic acid to obtain a compound 4; the reaction route is as follows:

the synthesis method provided by the invention is more environment-friendly and is suitable for large-scale industrial production.

Description

Synthesis method of [3- (aminomethyl) -oxetane-3-yl ] carbamic acid p-methoxybenzyl ester p-chlorobenzoate

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing [3- (aminomethyl) -oxetane-3-yl ] carbamic acid p-methoxybenzyl ester p-chlorobenzoate.

Background

Patent WO2015110446A1 discloses a synthetic method of p-methoxybenzyl [3- (aminomethyl) -oxetan-3-yl ] carbamate. In the synthetic route disclosed in the patent, liquid ammonia is used for substitution reaction to introduce primary amino group into molecular fragments, but the liquid ammonia pollutes the environment and is difficult to post-treat, and the substitution reaction needs to be carried out in a high-pressure reaction kettle at 25-30 ℃ with explosion risk, so the synthetic route is not suitable for industrial scale-up production.

Disclosure of Invention

Aiming at the technical defects in the prior art, the invention provides a synthesis method of [3- (aminomethyl) -oxetane-3-yl ] carbamic acid p-methoxybenzyl ester p-chlorobenzoate, which comprises the following steps:

a. substituting bromine group of compound 1 with cyclic imide group A to generate compound 2, wherein the imide group A is any one of phthalimide, succinimide and maleimide;

b. performing an amination reaction with said compound 2 using a primary amine to produce said compound 3;

c. reacting the compound 3 with p-chlorobenzoic acid to obtain a compound 4;

the reaction route is as follows:

preferably, the step a is completed in an organic solvent, the organic solvent in the step a is any one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and the reaction temperature in the step a is 40-100 ℃.

Preferably, the step b is completed in any one system of a methanol system, an ethanol system, a propanol system, an isopropanol system and a butanol system, and the reaction temperature of the step b is 0-60 ℃.

Preferably, the step c is performed in an organic solvent, and the organic solvent in the step c is any one or more of 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, isopropyl ether and chloroform.

Preferably, the step a comprises the steps of:

a1. mixing N, N-dimethylformamide, a potassium salt of cyclic imide and an organic phase of the compound 1, heating to 40-100 ℃, and stirring to react completely to obtain a first system;

a2. cooling the first system to 0-30 ℃, adding water to obtain a second system, and keeping the second system at 20-25 ℃ for continuous stirring;

a3. filtering the second system to obtain a filter cake of the compound 2, and drying the filter cake of the compound 2 to obtain the compound 2.

Preferably, in the step a1, heating to 55-65 ℃ and stirring for reaction for 3 hours;

in the step a2, the first system is cooled to 10 ℃, water is added, and the second system is continuously stirred for 2 hours at 20-25 ℃;

in the step a3, after the filter cake of the compound 2 is washed by water, the filter cake is dried for 12 hours in vacuum at 60 ℃ to obtain the compound 2.

Preferably, the step b comprises the steps of:

b1. mixing the compound 2 with methanol to obtain a third system;

b2. keeping the third system at 5-15 ℃, adding primary amine, and stirring at 0-60 ℃ to react completely to obtain a fourth system;

b3. the fourth system was washed with water and extracted with organic solvent, the organic phases were combined and washed with brine to give a crude solution of compound 3.

Preferably, in the step b2, the third system is cooled to 5 ℃, primary amine is added, and the third system is stirred for 3 hours at 20-25 ℃ to obtain the fourth system;

in the step b3, the fourth system is washed with a mixture of water and brine for 1 hour, and the organic solvent in the step b3 is any one of ethyl acetate, dichloromethane, tert-butyl methyl ether and n-heptane.

Preferably, the step c includes the steps of:

c1. concentrating the crude product solution of the compound 3, replacing the organic solvent in the crude product solution with a replacement solvent, fixing the volume to obtain a fifth system, adding p-chlorobenzoic acid into the fifth system, and stirring to react completely;

c2. and (3) pulping the fifth system by using an organic solvent, filtering to obtain a filter cake of the compound 4, and drying the filter cake of the compound 4 to obtain the compound 4.

Preferably, in the step c1, the substitution solvent is any one of 2-methyltetrahydrofuran, tetrahydrofuran and acetonitrile, p-chlorobenzoic acid is added into the fifth system, and then the fifth system is heated to 45-50 ℃ to be stirred and reacted for 1 hour;

the organic solvent for pulping in the step c2 is any one of tert-butyl methyl ether, ethyl acetate, dichloromethane and n-heptane, the pulping in the step c2 lasts for 2 hours at 20-25 ℃, and the filter cake of the compound 4 is dried in vacuum at 40 ℃ to obtain the compound 4.

The invention uses primary amine to complete amination reaction, and overcomes the defect that liquid ammonia is used to complete industrial production in the prior art. Meanwhile, there is also a scheme for accomplishing amination reaction by using hydrazine hydrate, but hydrazine hydrate has genetic toxicity and is easy to remain in the product, so that it is not suitable for synthesis in the pharmaceutical field.

Drawings

FIG. 1 shows the NMR spectrum of Compound 4 according to an embodiment of the present invention.

Detailed Description

The invention provides a synthesis method of [3- (aminomethyl) -oxetane-3-yl ] carbamic acid p-methoxybenzyl ester p-chlorobenzoate, which comprises the following specific reaction route:

combining the reaction route, the method specifically comprises the following steps:

step a is first performed to substitute the bromo group of compound 1 with a cyclic imide group, which is any one of salts of phthalimide, succinimide, and maleimide, to generate compound 2. In particular, the aim of this step is to convert the bromoalkyl group on compound 1, which belongs to an intermediate in the synthesis process, into a protective imide group, which can be obtained in combination with the technical solution presented in patent WO2015110446a 1. More specifically, phthalimide, succinimide, and maleimide may be formed into potassium salts by potassium carbonate, and applied to actual reactions. The person skilled in the art understands that said step a is carried out in an organic solvent, and in particular the selection of the organic solvent in this step requires the following considerations: firstly, reactants and products can be dissolved; secondly, the reaction can not be participated in by the self; thirdly, the separation from the reactants and products is convenient; fourthly, the organic solvent in the step a is as low as possible toxic or non-toxic, correspondingly, the organic solvent in the step a can be any one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and the reaction temperature in the step a is 40-100 ℃.

Further, step b is performed, and the compound 2 is subjected to amination reaction using primary amine to produce a compound 3. It will be appreciated by those skilled in the art that the purpose of this step is to remove the imide-protecting group from compound 2 using a primary amine, and thus to obtain compound 3 for the subsequent salt formation step. In particular, the primary amine may be selected from primary amines or primary diamines. For example, the primary amine may be selected from C_1-6One or a mixture of two or more of alkyl-substituted primary amines, C_1-6Alkyl represents a saturated, linear-or branched alkyl group containing 1 to 6 (preferably 1 to 4) carbon atoms, and includes methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl and the like, preferably methyl, ethyl, isopropyl, tert-butyl. For example, the primary diamine may be selected from aliphatic primary diamines, such as one or a mixture of two or more of ethylenediamine, 1, 3-propanediamine, 1, 2-propanediamine, 1, 4-butanediamine, 1, 3-butanediamine, 1, 2-butanediamine, 1, 5-pentanediamine, 1, 6-hexanediamine, 1, 7-heptanediamine, 1, 8-octanediamine, 1, 10-decanediamine, and 1, 12-dodecyldiamine; the primary diamine can also be alicyclic primary diamine, such as one of 1, 2-cyclohexanediamine, 1, 3-cyclohexanediamine and 1, 4-cyclohexanediamine, or a mixture of two or more of them; the primary diamine may also be aromatic, and may be one of p-phenylenediamine, m-phenylenediamine and o-phenylenediamine, or a mixture of two or more thereof. The skilled person understands that the step b is completed in any system of a methanol system, an ethanol system, a propanol system, an isopropanol system and a butanol system, and the reaction temperature of the step b is 0-60 ℃.

Further, step c is performed on the basis of step b, the compound 3 reacts with p-chlorobenzoic acid to obtain a compound 4, and the skilled person understands that the step c is a salt formation step, the step c is performed in an organic solvent, and the organic solvent in the step c is any one or more of 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, isopropyl ether and chloroform

As an example of the present invention, a complete synthetic route is shown below:

in conjunction with the above reaction scheme, this embodiment includes the following steps:

step S1 is executed firstly, pure water and sodium hydroxide are added into a reaction kettle, then the compound 5 is added into the reaction kettle, the temperature is heated to 40-100 ℃, the reaction liquid of step S1 is obtained after the stirring is carried out till the reaction is completed, and the reaction liquid of step S1 is cooled to 10-15 ℃, so that the crude product solution of the compound 6 can be obtained.

Further, step S2 is performed, acetonitrile and tetramethylpiperidine nitroxide are added to the crude solution of compound 6, and potassium phosphate and sodium hypochlorite are added while stirring at 0-30 ℃, and then stirring is continued until the reaction is completed to obtain the reaction solution of step S2. And S2, extracting the reaction solution for the first time by using an organic solvent, adjusting the pH value of the water phase after the first extraction to 6-8 by using hydrochloric acid, then adding a sodium bisulfite water solution, then continuously adjusting the pH value of the water phase after the first extraction to 3-4 by using hydrochloric acid, and then extracting for the second time by using the organic solvent. Adjusting pH value of the water phase of the second extraction to 1-2 with hydrochloric acid, and extracting with organic solvent for the third time. And combining the organic phases, concentrating, pulping and washing the residual liquid by using an organic solvent, filtering and drying to obtain the compound 7.

Further, step S3 is performed, compound 7 and toluene are added into the reaction kettle, the mixture is heated to 40-100 ℃, methylmorpholine and diphenylphosphoryl azide are added, stirring is performed for 15 minutes after the addition, then p-methoxybenzyl alcohol is added, and the reaction solution of step S3 is obtained after the stirring is performed until the reaction is completed. Cooling the reaction liquid of the step S3 to 0-40 ℃, quenching the reaction liquid by water, stirring and standing the reaction liquid, extracting the reaction liquid by an organic solvent, and respectively washing the extracted organic phase by sodium carbonate and water to obtain a solution of a compound 1.

Further, step S4 is executed, the solution of N, N-dimethylformamide and compound 1 is added into the reaction kettle, the potassium phthalimide salt is added, the temperature is heated to 40-100 ℃, and the reaction solution of step S4 is obtained after the reaction is completed. And (3) cooling the reaction liquid obtained in the step S4 to 0-30 ℃, adding water, stirring at 20-25 ℃, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound 2.

Further, step S5 is performed, compound 2 and methanol are added into the reaction kettle, cooled to 5 ℃, primary amine is added, the reaction solution is stirred at 0-60 ℃ until the reaction is completed to obtain the reaction solution of step S5, water is added into the reaction solution of step S5 for washing, then organic solvent is used for multiple extraction, organic phases are combined, brine is used for washing, and concentration is performed to obtain a crude solution of compound 3. Further, step S6 is performed, and 2-methyltetrahydrofuran, the crude solution of compound 3 and p-chlorobenzoic acid are added to the reaction kettle, heated to 45-50 ℃ and stirred for 1 hour. And (3) dropwise adding an organic solvent, cooling to 20-25 ℃, filtering, pulping by using the organic solvent, and drying in vacuum to obtain the compound 4.

More specifically, as a specific implementation manner of this embodiment, the method includes the following steps:

first, step R1 was performed by adding 810kg of pure water and 54.0kg of sodium hydroxide to a 2000L reactor, stirring until it became clear, and cooling to an internal temperature of less than 25 ℃. 270kg of Compound 5 was charged into a reaction vessel, heated to an internal temperature of 48 to 53 ℃ and stirred at 48 to 53 ℃ for 4 hours to obtain a reaction liquid of step R1. The reaction solution of step R1 was cooled to an internal temperature of 10-15 ℃ to give a crude solution of compound 6. Further, step R2 was carried out by adding 270L of acetonitrile and 25.8kg of tetramethylpiperidine nitroxide to the crude solution of Compound 6, stirring at 10-15 ℃ for 0.5 hour, adding 189kg of potassium phosphate and 1701kg of an aqueous sodium hypochlorite solution (8.4% concentration) at 10-20 ℃ while maintaining the pH at 10-13, and stirring at 10-20 ℃ for 2 hours to obtain a reaction solution of step R2. The reaction solution of step R2 was extracted twice with 540L of ethyl acetate, the pH of the aqueous phase of the extraction was adjusted to 6-8 with 24kg of hydrochloric acid (18% strength), and 1.51kg of sodium bisulfite solution (0.6% strength) were added. The pH of the aqueous phase thus extracted was adjusted to 3 to 4 with 24kg of hydrochloric acid (18% strength), and the aqueous phase was extracted three times with 540L of methylene chloride. The extracted aqueous phase is then brought to pH 1-2 with 24kg of hydrochloric acid (18% strength) and extracted three times with 540L of ethyl acetate. The organic phases are combined and the concentration step is carried out while maintaining the internal temperature of the organic phase at 45-55 ℃. The organic phase remaining after the concentration was charged into a new reaction vessel, and then 135L of n-hexane and 30L of ethyl acetate were added and stirred at room temperature for 12 hours, filtered to obtain a cake, and washed with n-hexane. The washed cake was dried under vacuum at 45 ℃ for 16 hours to give 70.5kg of Compound 7. (purity: 99.4%, moisture: 0.04%, content: 95.3%, total yield of steps R1 and R2: 35%).

Further, step R3 was performed by adding 60kg of compound 7 and 480kg of toluene to a 1000L reaction kettle and heating to 77 ℃. 36kg of methylmorpholine was slowly added while controlling the internal temperature at 77-80 ℃ and 88.2kg of diphenylphosphorylazide was slowly added while controlling the internal temperature at 77-83 ℃ and stirred for 15 minutes after the addition was completed. Then, 36.1kg of p-methoxybenzyl alcohol was slowly added while controlling the internal temperature at 77 to 80 ℃ and then stirred for 60 minutes to obtain a reaction liquid of step R3. The reaction solution of step R3 was cooled to 30-35 ℃ and quenched with 300Kg of water, stirred for 60 minutes, left to stand for 30 minutes, and the organic phase was separated and washed with 310Kg of sodium carbonate solution (concentration: 4%) and 144Kg of water, respectively, to give 552Kg of an organic phase of Compound 1 (content: 9.7%, yield: 60.3%).

Further, step R4 was carried out by charging 156kg of N, N-dimethylformamide and 470kg of a compound 1 solution into a 1000L reactor, followed by further addition of 145.7kg of potassium phthalimide salt to obtain a reaction liquid of step R4. The reaction solution of step R4 was heated to 55-65 ℃ and stirred for 3 hours, then cooled to 10 ℃, and then 988kg of water was added to the reaction solution of step R4, stirred for 2 hours at 20-25 ℃, filtered to obtain a filter cake, and the filter cake was washed with 518kg of water. The washed cake was vacuum-dried at 60 ℃ for 12 hours to obtain 126.7kg of Compound 2 (purity: 97.8%, yield: 94%).

Further, step R5 was carried out by charging 76.4kg of Compound 2 and 184kg of methanol into a 1000L reactor to obtain a reaction liquid of step R5 and cooling to 5 ℃. 232kg of ethylenediamine was added dropwise to the reaction solution of the step R5, and the temperature of the reaction solution of the step R5 was controlled at 5 to 15 ℃ during the addition. Thereafter, the mixture was stirred at 20 to 25 ℃ for 3 hours, and 306kg of ethyl acetate, 153kg of water and 92kg of brine were sequentially added to the reaction solution of step R5, followed by stirring for 1 hour. The mixture was allowed to stand for liquid separation, and the aqueous phase obtained after liquid separation was extracted three times with 230kg of ethyl acetate. The multiply extracted organic phases were combined and washed four times with 268kg brine, filtered and concentrated to 214L to give the concentrate of step R5.

Further, step R6 was performed by replacing the solvent in the concentrate of step R5 twice with 150kg of 2-methyltetrahydrofuran and metering to obtain 214L of crude compound 3 solution. To the crude solution of the compound 3, 24.1kg of p-chlorobenzoic acid was added, heated to 45 to 50 ℃ and stirred for 1 hour to obtain a reaction solution of step R6. 230kg of t-butyl methyl ether was added dropwise to the reaction liquid of step R6, followed by slow cooling to 20-25 ℃ and stirring for 2 hours to complete the beating step, filtration was conducted to obtain a filter cake, which was washed with 115kg of t-butyl methyl ether, and the washed filter cake was dried under vacuum at 45 ℃ to obtain 55kg of Compound 4(HPLC purity: 98.7%, total yield of steps R5 and R6: 68%).

Compound 4 can also be obtained (HPLC purity: 97%, total yield of steps R5 and R6: 56%) by reacting compound 2 with methylamine in methanol according to a similar method to that in steps R5 and R6.

Further, FIG. 1 shows the NMR spectra of Compound 4 obtained according to steps R1 to R6, as can be seen from FIG. 1,¹H NMR(400MHz，DMSO)δ：7.89(dd，J＝2.0，6.8Hz，2H)，7.44(dd，J＝2.0，6.8Hz，2H)，7.29(d，J＝8.4Hz，2H)，6.91(d，J＝2.0，6.8Hz，2H)，4.95(s，2H)，4.55(d，J＝6.4Hz，2H)，4.44(d，J＝6.0Hz，2H)，3.75(s，3H)，3.16(s，2H)。

the foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims

A process for the preparation of p-methoxybenzyl [3- (aminomethyl) -oxetan-3-yl ] carbamate, p-chlorobenzoate, which comprises the steps of:
a. substituting the bromo group of compound 1 with a cyclic imide group to generate compound 2, wherein the cyclic imide group is any one of phthalimide, succinimide and maleimide;
b. performing amination reaction on primary amine and the compound 2 to generate a compound 3, wherein the primary amine is primary diamine, and the primary diamine is one of or a mixture of two or more of ethylene diamine, 1, 3-propylene diamine, 1, 2-propylene diamine, 1, 4-butylene diamine, 1, 3-butylene diamine and 1, 2-butylene diamine;
c. reacting the compound 3 with p-chlorobenzoic acid to obtain a compound 4;
the reaction route is as follows:
2. the preparation method according to claim 1, wherein the step a is carried out in an organic solvent, the organic solvent in the step a is any one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and the reaction temperature in the step a is 40-100 ℃.
3. The preparation method according to claim 1, wherein the step b is performed in any one of a methanol system, an ethanol system, a propanol system, an isopropanol system and a butanol system, and the reaction temperature of the step b is 0-60 ℃.
4. The method of claim 1, wherein the step c is performed in an organic solvent, and the organic solvent in the step c is any one or more of 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, isopropyl ether and chloroform.
5. The method for preparing according to any one of claims 1 to 4, wherein the step a comprises the steps of:
a1. mixing N, N-dimethylformamide, a potassium salt of cyclic imide and an organic phase of the compound 1, heating to 40-100 ℃, and stirring to react completely to obtain a first system;
a2. cooling the first system to 0-30 ℃, adding water to obtain a second system, and keeping the second system at 20-25 ℃ for continuous stirring;
a3. filtering the second system to obtain a filter cake of the compound 2, and drying the filter cake of the compound 2 to obtain the compound 2.
6. The preparation method according to claim 5, wherein the step a1 is carried out by heating to 55-65 ℃ and stirring for reaction for 3 hours;
in the step a2, the first system is cooled to 10 ℃, water is added, and the second system is continuously stirred for 2 hours at 20-25 ℃;
in the step a3, after the filter cake of the compound 2 is washed by water, the filter cake is dried for 12 hours in vacuum at 60 ℃ to obtain the compound 2.
7. The method for preparing a composite material according to claim 5, wherein the step b comprises the steps of:
b1. mixing the compound 2 with methanol to obtain a third system;
b2. keeping the third system at 5-15 ℃, adding primary amine, and stirring at 0-60 ℃ to react completely to obtain a fourth system;
b3. the fourth system was washed with water and extracted with organic solvent, the organic phases were combined and washed with brine to give a crude solution of compound 3.
8. The preparation method according to claim 7, wherein in the step b2, the third system is cooled to 5 ℃, primary amine is added, and the mixture is stirred for 3 hours at 20-25 ℃ to obtain the fourth system;
in the step b3, the fourth system is washed with a mixture of water and brine for 1 hour, and the organic solvent in the step b3 is any one of ethyl acetate, dichloromethane, tert-butyl methyl ether and n-heptane.
9. The method for preparing a composite material according to claim 6, 7 or 8, wherein the step c comprises the steps of:
c1. concentrating the crude product solution of the compound 3, replacing the organic solvent in the crude product solution with a replacement solvent, fixing the volume to obtain a fifth system, adding p-chlorobenzoic acid into the fifth system, and stirring to react completely;
c2. and (3) pulping the fifth system by using an organic solvent, filtering to obtain a filter cake of the compound 4, and drying the filter cake of the compound 4 to obtain the compound 4.
10. The preparation method according to claim 9, wherein in the step c1, the substitution solvent is any one of 2-methyltetrahydrofuran, tetrahydrofuran and acetonitrile, p-chlorobenzoic acid is added into the fifth system, and the fifth system is heated to 45-50 ℃ for stirring reaction for 1 hour;
the organic solvent for pulping in the step c2 is any one of tert-butyl methyl ether, ethyl acetate, dichloromethane and n-heptane, the pulping in the step c2 lasts for 2 hours at 20-25 ℃, and the filter cake of the compound 4 is dried in vacuum at 40 ℃ to obtain the compound 4.