CN107021916B - Preparation method of trans-3-methyl-5-benzylaminopiperidine - Google Patents
Preparation method of trans-3-methyl-5-benzylaminopiperidine Download PDFInfo
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- CN107021916B CN107021916B CN201610077103.7A CN201610077103A CN107021916B CN 107021916 B CN107021916 B CN 107021916B CN 201610077103 A CN201610077103 A CN 201610077103A CN 107021916 B CN107021916 B CN 107021916B
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a preparation method of trans-3-methyl-5-benzylaminopiperidine, which comprises the following steps of preparing an intermediate compound shown in formula (e), and carrying out chiral turnover substitution reaction to obtain trans-3-methyl-5-benzylaminopiperidine; wherein, the definition of each group is described in the specification. The invention has the advantages of simple and easily obtained raw materials, simple process, convenient operation, mild reaction conditions and the like.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of trans-3-methyl-5-benzylaminopiperidine.
Background
(3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid is a quinolone antibiotic and is useful in the treatment of a variety of bacterial infections. The antibiotic is synthesized by nucleophilic substitution reaction on aromatic ring and some subsequent conversions by using side chain (N protected 3-amino-5-methyl piperidine) and mother nucleus (7-fluoro-1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid) as raw materials.
The parent nucleus of the quinolone antibiotics is basically the same, and the synthesis process of the parent nucleus is mature. Since the antibiotic side chain 3-amino-5-methylpiperidine has two chiral centers, the relative configuration of methyl and amino groups is trans. The difficulty of synthesis is high. At present, the side chain is synthesized by taking (S) -2-aminoadipic acid as a raw material through the following process route (shown in the following reaction formula): firstly, diacid is converted into dimethyl ester under the acidic condition; secondly, protecting amino with tert-butyloxycarbonyl (Boc); under the chiral induction of amino, LiHMDS is used as alkali, methyl iodide is used as a methylating agent, and methyl is introduced; the diester is first LiAlH4Reducing to obtain diol; the diol is subjected to Swern oxidation to obtain dialdehyde; the resulting dialdehyde and NH3Reacting and reusing NaBH4Reducing to obtain 3-tert-butyloxycarboryl amino-5-methylpiperidine, and obtaining the (3S,5S) -3-tert-butyloxycarboryl amino-5-methylpiperidine with high optical purity after chiral resolution.
Another synthesis method of (3S,5S) -3-tert-butoxycarbonylamino-5-methylpiperazine is based on the intermediate product of the above method, namely 2-methyl-4-tert-butoxycarbonylamino adipic acid dimethyl ester, and the synthesis method is shown as the following reaction formula: firstly, dimethyl ester is converted into diamide, and then amide is dehydrated to obtain dinitrile; in the presence of benzylamine, nitrile is catalytically hydrogenated to obtain the required piperidine structure, and the optically pure (3S,5S) -3-tert-butoxycarbonylamino-5-methylpiperidine is obtained after manual resolution.
The disadvantages of both synthetic methods are: (1) when methyl is introduced, expensive LiHMDS is used as a base and MeI is used as a methylating agent; (2) boc was used in the synthesis2Protection of O on amino group with Boc, Boc2The price of the O protecting group is high. Both of these reasons lead to high cost of synthesis of the side chain.
In conclusion, the art lacks a method for preparing a side chain of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, which has low cost, easily available raw materials and reaction reagents and good selectivity.
Disclosure of Invention
The invention provides a preparation method of a (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid side chain, which has low cost, easily obtained raw materials and reaction reagents and good selectivity.
In a first aspect of the present invention, there is provided a process for the preparation of a compound of formula (a), said process comprising the steps of:
(1) reacting the compound of the formula (b) with a benzyl halide Bn-X in an organic solvent to obtain a compound of the formula (c);
(2) carrying out catalytic hydrogenation on the compound (quaternary ammonium salt) in the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound in the formula (d);
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e);
(4) with compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
(5) hydrolyzing with a compound of formula (f) in an organic solvent in the presence of an acid to obtain a compound of formula (a);
wherein, X is selected from the following group: cl, Br;
said R1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl and p-tolyl.
In another preferred embodiment, after the step (2) is finished, the obtained product is subjected to chiral resolution to obtain the compound of the formula (d).
In another preferred embodiment, R1Is Me; r is Me, or p-methylphenyl.
In another preferred embodiment, in the step (1), the organic solvent is selected from the group consisting of: toluene, xylene, or combinations thereof.
In another preferred embodiment, in the step (1), the reaction temperature is 80-120 ℃.
In another preferred example, in the step (2), the catalyst is Ru-C or Pd-C.
In another preferred embodiment, in the step (2), the alcohol solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination thereof.
In another preferred example, in the step (2), the amount of the catalyst is 5-15% of the mass of the quaternary ammonium salt (c).
In another preferred embodiment, in the step (2), the catalytically hydrogenated H2The pressure of (A) is 5-10 MPa.
In another preferred example, in the step (2), the reaction temperature is 80-120 ℃.
In another preferred example, in the step (2), the reaction time is 10 to 24 hours.
In another preferred embodiment, in the step (3), the sulfonylation reagent is selected from the group consisting of: C1-C4 alkylsulfonyl chloride, C1-C4 alkylsulfonate, p-toluenesulfonyl chloride, or p-toluenesulfonate.
In another preferred embodiment, in the step (3), the sulfonating agent is selected from the group consisting of: methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, or combinations thereof.
In another preferred embodiment, in the step (3), the reaction solvent is a non-polar solvent, preferably a non-polar solvent selected from the group consisting of: dichloromethane, cyclohexane, toluene, carbon tetrachloride and petroleum ether.
In another preferred embodiment, in the step (3), the temperature of the reaction is room temperature (10-40 ℃).
In another preferred embodiment, in the step (3), the base is an organic base or a carbonate, preferably selected from the group consisting of: triethylamine, ethylenediamine, pyridine, sodium carbonate, sodium bicarbonate, or a combination thereof.
In another preferred embodiment, in the step (3), the molar ratio of the sulfonylating agent to the compound of formula (d) is 2.0 to 6.0: 1.
in another preferred embodiment, in the step (3), the molar ratio of the base to the compound of formula (d) is 2.0-8.0: 1.
in another preferred example, in the step (5), the acid is acetic acid and/or concentrated hydrochloric acid; preferably, the acid is a mixed acid of acetic acid and concentrated hydrochloric acid, and the volume ratio of the two is 1.5-2: 2.
In another preferred embodiment, the concentrated hydrochloric acid is commercially available concentrated hydrochloric acid.
In another preferred embodiment, in the step (4), the compound of formula (e) and Bn-NH2In a molar ratio of 1: 2.0-4.0.
In another preferred embodiment, in the step (4), the temperature of the reaction is 160-200 ℃.
In another preferred embodiment, in the step (4), the reaction time is 5 to 10 hours.
In another preferred embodiment, in the step (5), the molar/volume ratio of the compound of formula (f) to the acid is 1mmol:2-8 mL.
In another preferred embodiment, in the step (5), the temperature of the reaction is 90-120 ℃.
In a second aspect of the present invention, there is provided a compound represented by the following formula (e):
wherein, R is1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl and p-tolyl.
In a third aspect of the invention, there is provided a process for the preparation of a compound of formula (e) as described in the second aspect of the invention, said process comprising the steps of:
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e).
In another preferred embodiment, the method further comprises the steps of:
(2) and (c) carrying out catalytic hydrogenation on the compound of the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound of the formula (d).
In another preferred embodiment, the method further comprises the steps of:
(1) reacting the compound of formula (b) with a benzyl halide Bn-X in an organic solvent to obtain the compound of formula (c).
In a fourth aspect of the present invention, there is provided a process for the preparation of a compound of formula (f), said process comprising the steps of:
(4) with compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
wherein, R is1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl and p-tolyl.
In a fifth aspect of the present invention, there is provided a process for the preparation of a compound of formula (a), said process comprising the steps of:
(4) with compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
said R1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl and p-tolyl.
(5) Hydrolyzing with a compound of formula (f) in an organic solvent in the presence of an acid to obtain a compound of formula (a).
In another preferred example, the method further comprises the steps of:
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e).
In another preferred embodiment, the method further comprises the steps of:
(2) and (c) carrying out catalytic hydrogenation on the compound of the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound of the formula (d).
In another preferred embodiment, the method further comprises the steps of:
(1) reacting the compound of formula (b) with a benzyl halide Bn-X in an organic solvent to obtain the compound of formula (c).
In a sixth aspect of the present invention, there is provided a process for the preparation of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, which comprises:
preparing a compound of formula (a) by a process according to the first aspect of the invention or according to the fifth aspect of the invention, and;
preparation of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid from a compound of formula (a).
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has long and intensive research and developed a method for preparing a side chain intermediate of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, wherein the method comprises the steps of constructing a (3S,5R) chiral center through catalytic hydrogenation and chiral resolution reaction of an intermediate shown as a formula (e), and obtaining a chiral reversed product through SN2 substitution reaction, so that the intermediate compound with (3S,5S) stereo configuration, namely the compound shown as the formula (I), is prepared. Based on the above findings, the inventors have completed the present invention.
Preparation of Compounds of formula (a)
The present invention provides a process for the preparation of a compound of formula (a), said process comprising the steps of:
wherein, X is selected from the following group: cl, Br; said R1Selected from the group consisting of: C1-C4 alkyl; the R is selected from the following group: C1-C4 alkyl and p-tolyl.
In another preferred embodiment, R1Is Me; r is Me, or p-methylphenyl.
(1) Reacting the compound of the formula (b) with a benzyl halide Bn-X in an organic solvent to obtain a compound of the formula (c);
the organic solvent and the reaction temperature are not particularly limited and may be selected according to actual needs, and in a preferred embodiment, the organic solvent is selected from the group consisting of: toluene, xylene, or combinations thereof; the reaction temperature is 80-120 ℃.
(2) Carrying out catalytic hydrogenation on the compound (quaternary ammonium salt) in the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound in the formula (d);
the catalytic hydrogenation may employ a catalytic hydrogenation system commonly used in the art, for example, in a preferred embodiment of the present invention, the catalyst is Ru-C or Pd-C.
In this step, by catalytic hydrogenation, a hydrogenation product having a chiral center configuration of (3S,5R) can be obtained. The proportions of the reactants are not particularly limited, and in another preferred embodiment, the amount of the catalyst is 5 to 15% by mass of the quaternary ammonium salt (c), and the pressure of the catalytically hydrogenated H2 is 5 to 10 MPa.
In this step, the reaction solvent, reaction temperature, reaction time, etc. may be selected according to the specific reactants, for example, in a preferred embodiment, the alcohol solvent is selected from the following group: methanol, ethanol, isopropanol, or a combination thereof, wherein the reaction temperature is 80-120 ℃, and the reaction time is 10-24 hours.
After the step (2) is finished, carrying out chiral resolution on the obtained product to obtain the compound of the formula (d) with the chiral center configuration of (3S,5S) for subsequent preparation.
(3) Reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e);
in another preferred embodiment, in the step (3), the sulfonylation reagent is selected from the group consisting of: C1-C4 alkylsulfonyl chloride, C1-C4 alkylsulfonate, p-toluenesulfonyl chloride, or p-toluenesulfonate; preferably, the sulfonating agent is selected from the group consisting of: methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, or combinations thereof.
In the step (3), the base is an organic base or a carbonate, and is preferably selected from the following group: triethylamine, ethylenediamine, pyridine, sodium carbonate and sodium bicarbonate. In another preferred embodiment, in the step (3), the molar ratio of the sulfonylating agent to the compound of formula (d) is 2.0 to 6.0: 1.
in another preferred embodiment, in the step (3), the molar ratio of the base to the compound of formula (d) is 2.0-8.0: 1.
in this step, the reaction solvent, the reaction temperature, the reaction time, and the like may be selected according to specific reactants, for example, in a preferred embodiment, the reaction solvent is a non-polar solvent, preferably a non-polar solvent selected from the group consisting of: dichloromethane, cyclohexane, toluene, carbon tetrachloride and petroleum ether, wherein the reaction temperature is room temperature (10-40 ℃).
(4) With compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
in another preferred embodiment, the compound of formula (e) and Bn-NH2In a molar ratio of 1: 2.0-4.0; the temperature of the reaction is preferably 160-200 ℃; the reaction time is preferably 5 to 10 hours.
(5) Hydrolyzing with a compound of formula (f) in an organic solvent in the presence of an acid to obtain a compound of formula (a);
the acid may be any organic or inorganic acid capable of providing an acidic environment, preferably a concentrated acid, such as acetic acid and/or concentrated hydrochloric acid; preferably, the acid is a mixed acid of acetic acid and concentrated hydrochloric acid, the volume ratio of the two is 1.5-2:2, and the concentrated hydrochloric acid is preferably commercial concentrated hydrochloric acid (for example, 36.5% concentrated hydrochloric acid).
In the step (5), the mol/volume ratio of the compound of the formula (f) to the acid is preferably 1mmol:2-8 mL; the temperature of the reaction is preferably 90 to 120 ℃.
Compounds of formula (e) and their preparation
The present invention also provides a compound represented by the following formula (e):
wherein, R is1Selected from the group consisting of: C1-C4 alkyl; the R is selected from the following group: C1-C4 alkyl, p-methylA phenyl group.
The compound of formula (e) may be prepared by:
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e).
In another preferred embodiment, the method further comprises the steps of:
(2) and (c) carrying out catalytic hydrogenation on the compound of the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound of the formula (d).
In another preferred embodiment, the method further comprises the steps of:
(1) reacting the compound of formula (b) with a benzyl halide Bn-X in an organic solvent to obtain the compound of formula (c).
The compounds of formula (e) may be used for the preparation of intermediates in the synthesis of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, for example by:
(4) with compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f); wherein, R1 is selected from the following group: C1-C4 alkyl; the R is selected from the following group: C1-C4 alkyl and p-tolyl.
Wherein this step can be inverted by hand to give compounds of formula (f) to build intermediates of (S, R) configuration. The above intermediate (f) can be used for the preparation of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.
Preparation of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid
The process for the preparation of the compound of formula (c) provided by the present invention can also be used for the preparation of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. Wherein the compound of formula (c) can be converted to (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid using methods known in the art.
Preparation of trans-3-methyl-5-benzylaminopiperidine
The starting material used in the invention is 3-methyl-5-hydroxypyridine, and racemic trans-3-methyl-5-benzylaminopiperidine is obtained through the steps of quaternization, catalytic hydrogenation, sulfonylation, nucleophilic substitution, sulfonamide hydrolysis and the like. The method comprises the following steps:
(1) 3-methyl-5-hydroxypyridine (II) and benzyl halide react in an organic solvent to obtain quaternary ammonium salt (III).
(2) In an alcohol solvent, in the presence of a catalyst, carrying out catalytic hydrogenation on the quaternary ammonium salt (III) to obtain cis-3-methyl-5-hydroxypiperidine (IV).
(3) Reacting 3-methyl-5-hydroxypiperidine (IV) with a sulfonylating agent in an organic solvent in the presence of a base to give a sulfonic acid ester (V).
(4) Carrying out nucleophilic substitution reaction on the sulfonic acid ester (V) and an amine compound to obtain trans-3-methyl-5-benzylamino-1-sulfonyl piperidine (VI).
(5) Hydrolyzing with trans-3-methyl-5-benzylamino-1-sulfonylpiperidine (VI) in an organic solvent in the presence of an acid to give-3-methyl-5-benzylaminopiperidine (I).
Each reaction step is described in detail below:
the first step is as follows: a method for preparing quaternary ammonium salt shown in formula (II) comprises the following steps:
heating and refluxing 3-methyl-5-hydroxypyridine shown in formula (II) and benzyl halide in an organic solvent to obtain quaternary ammonium salt shown in formula (III), wherein the reaction formula is as follows:
preferably, the organic solvent is toluene or xylene.
Preferably, the reaction temperature is 80-120 ℃.
Preferably, the benzyl halide is benzyl bromide or benzyl chloride.
Preferably, the molar amount of the benzyl halide used is 1.1 to 1.3 times the molar amount of the 3-methyl-5-hydroxypyridine (II).
Preferably, the second reaction step is carried out after the reaction is completed by filtration, washing with ethyl acetate, and vacuum drying to obtain the desired quaternary ammonium salt.
Specifically, a certain amount of 3-methyl-5-hydroxypyridine is weighed and added into a round-bottom flask, 5-10 times of solvent toluene or xylene and 1.1-1.3 times of benzyl halide are sequentially added, the round-bottom flask is connected with a condenser tube and then heated and refluxed for 3-5 hours, and after cooling reaction liquid, the reaction liquid is filtered, washed by ethyl acetate and dried in vacuum to obtain the quaternary ammonium salt.
The second step is that: a process for the preparation of racemic cis 3-methyl-5-hydroxy-piperidine of formula (IV) which comprises:
in an alcohol solvent, Pd-C or Ru-C is used as a catalyst, the quaternary ammonium salt (III) is catalyzed and hydrogenated under certain hydrogen pressure and certain temperature to obtain the racemic cis-3-methyl-5-hydroxy-piperidine (IV), and the reaction formula is as follows:
preferably, the catalyst is Pd-C or Ru-C.
Preferably, the alcohol solvent is methanol, ethanol or isopropanol.
Preferably, the reaction temperature is 80-120 ℃.
Preferably, the mass of the catalyst is 5 to 15% of the mass of the quaternary ammonium salt (III).
Preferably, after the completion of the reaction, the reaction mixture is filtered through a sand-core funnel, the catalyst is washed with a reaction solvent, and the combined filtrates are concentrated under reduced pressure to obtain the catalytic hydrogenation product (IV).
Specifically, a certain mass of quaternary ammonium salt (III) is weighed in a reaction kettle, then 0.05-0.15 mass time of Pd-C or Ru-C is added, 5-10 mass times of solvent is added, hydrogenation is carried out, the pressure of hydrogen is 5-10MPa, the reaction is carried out for 10-24 hours at the temperature of 80-120 ℃, the catalyst is removed by filtration, the catalyst is washed by the solvent, the filtrate is combined, and then reduced pressure concentration is carried out to obtain white or light yellow solid, namely the racemic cis-3-methyl-5-hydroxy-piperidine (IV).
The racemic cis-3-methyl-5-hydroxy-piperidine obtained by the invention can be subjected to manual resolution to obtain optically pure (3S,5S) -3-methyl-5-hydroxy-piperidine for subsequent reaction.
The third step: a synthetic method for preparing racemic trans-3-methyl-5-sulfonyloxy-1-sulfonylpiperidine shown as a formula (V) comprises the following steps:
adding a certain amount of the catalytic hydrogenation product (IV), triethylamine, a sulfonylating reagent (sulfonating reagent) and 4-N, N-Dimethylaminopyridine (DMAP) into a nonpolar solvent in sequence, stirring the reaction mixed solution at room temperature until the reaction is completed, and adding water and NaOH aqueous solution to stop the reaction. Light yellow solid is obtained through operations such as extraction, column chromatography and the like, and the reaction equation is as follows:
preferably, the nonpolar solvent is dichloromethane.
Preferably, the reaction temperature is room temperature.
Preferably, the sulfonylation reagent is methanesulfonyl chloride, a mesylate, p-toluenesulfonyl chloride or p-toluenesulfonate.
Preferably, the amount of triethylamine and sulfonylating agent and 4-N, N-Dimethylaminopyridine (DMAP) are 3-4 times, 2.4-3 times and 0.2-0.5 times the amount of the catalytic hydrogenation product (IV) respectively.
Preferably, water and aqueous NaOH are added after the reaction is completed, extraction is carried out with dichloromethane, and the organic phase is passed over anhydrous Na2SO4Drying, concentrating under reduced pressure, and performing column chromatography to obtain a light yellow solid product.
Specifically, a certain mass of catalytic hydrogenation product (IV) is weighed in a round-bottom flask, then 30-60 times of solvent and 3-4 times of triethylamine are added, after the reaction bottle is cooled by an ice-water bath, 2.4-3 times of sulfonylation reagent and 0.2-0.5 time of DMAP are added, and the mixture is stirred at room temperature until the reaction is complete. Adding water and NaOH aqueous solution into the reaction solution, extracting the water phase with dichloromethane, combining the organic phases, and passing through anhydrous Na2SO4Drying, concentrating under reduced pressure, and performing column chromatography to obtain light yellow solid. The obtained racemic compound shown as the formula (V) is resolved by a chiral column to obtain the (3S,5R) configuration required by the next SN2 substitution reaction, which is shown as the formula (Va).
The fourth step: a synthetic method for preparing trans-3-methyl-5-benzylamino-1-sulfonyl piperidine shown in formula (VI) comprises the following steps:
sequentially adding a certain amount of benzene sulfonate and benzylamine into a round-bottom flask, stirring at a certain temperature until the reaction is complete, carrying out reduced pressure distillation to remove excessive benzylamine, carrying out column chromatography on residual liquid to obtain benzylamine (VI), wherein the reaction equation is as follows
Preferably, the amount of benzylamine substance is 2 to 4 times that of the sulfonic acid ester.
Preferably, the reaction temperature is 160-200 ℃.
Preferably, the reduced pressure distillation can recover the excessive benzylamine.
Specifically, in a pressure-resistant reaction test tube, a certain amount of sulfonate is weighed, benzylamine with 2-4 times of the amount of the sulfonate is added, the mixture is heated in an oil bath at the temperature of 160-200 ℃ for reaction for 5-10 hours, and the reaction is completely detected by TLC. Adding a certain amount of EtOAc into the reaction liquid to generate white solid, filtering to obtain filtrate, and concentrating the filtrate for column chromatography to obtain a white solid product.
The fifth step: a synthetic method for preparing racemic trans-3-methyl-5-benzylaminopiperidine as shown in formula (I) comprises the following steps:
a certain amount of sulfamide (VI), acetic acid and 37 percent concentrated hydrochloric acid are added into a pressure-resistant reaction tube, and the reaction mixture is stirred at a certain temperature until the reaction is completed. Cooling the reaction liquid, concentrating under reduced pressure, adding water and methyl tert-butyl ether, adjusting the pH value to 13 by NaOH, extracting by using methyl tert-butyl ether and ethyl acetate, filtering and concentrating by using alkaline alumina to obtain a crude product of trans-3-methyl-5-benzylaminopiperidine, wherein the reaction equation is as follows:
preferably, the volume ratio of AcOH to concentrated HCl is 1.5-1.8: 2.
preferably, the reaction temperature is 90-120 ℃.
Preferably, after the reaction is completed, the pH of the reaction solution is adjusted to 13 with an aqueous NaOH solution.
Specifically, a certain amount of sulfonamide (VI) is weighed in a pressure-resistant reaction tube, then a certain amount of AcOH and 37% concentrated hydrochloric acid are added, and the reaction mixed solution is stirred at 90-120 ℃ until the reaction is completed. Concentrating the reaction solution under reduced pressure, adding a certain amount of hydrated methyl tert-butyl ether, adding NaOH aqueous solution until the pH value reaches 13, extracting the aqueous phase with ethyl acetate, combining the organic phases, filtering with alkaline alumina, and concentrating to obtain a crude product of racemic trans-3-methyl-5-benzylaminopiperidine.
Compared with the prior art, the invention has the main advantages that:
(1) a process for the preparation of trans-3-methyl-5-benzylaminopiperidine which enables the preparation of a product having the (3S,5S) configuration is provided.
(2) An intermediate represented by formula (e) and a preparation method thereof are provided, wherein the intermediate can be used for preparing a series of compounds which can be used as intermediates for preparing (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid side chains.
(3) Compared with the prior art, the preparation method of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid has low cost and easily available raw materials, thereby being suitable for industrial production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Synthesis of quaternary ammonium salt: in a 100mL round-bottom flask, 3-hydroxy-5-methylpyridine (4.36g) and benzyl chloride (5mL) were added sequentially to toluene (30 mL). The reaction mixture was heated to reflux at 110 ℃ for 3.5 hours and then cooled to room temperature. The solid product was filtered through a sand core, washed with EtOAc and dried by oil pump to give light brown quaternary ammonium salt (III) (9.04g, 96% yield) which was then filtered through a frit1H-NMR(D2O) products, structures and methods of identifying high purity1The H-NMR data are as follows:
1H-NMR(400MHz,D2O)ppmδ8.04(s,1H),8.02(s,1H),7.52(s,1H),7.26(s,5H),5.42(s,2H),2.21(s,3H).
example 2
Catalytic hydrogenation: methanol (30mL) and quaternary ammonium salt (5g) are sequentially added into a 100mL high-pressure hydrogenation reaction kettle, and the mixture is stirred until the quaternary ammonium salt is dissolved, and then Ru-C catalyst (the Ru content is 5 wt%, 0.8g and 16 wt%) is added. After hydrogen (7MPa) was charged into the reactor, the reaction was carried out in an oil bath at 110 ℃ for 24 hours (when the hydrogen pressure was lowered to 4MPa, hydrogen was again charged to 7 MPa). The reaction solution is filtered by a sand core to recover the catalyst, the catalyst and the reaction kettle are washed by methanol, the filtrate is filtered and combined by the sand core, and the filtrate is decompressed, concentrated and dried in vacuum to obtain a white solid crude product (2.5g) to carry out the next reaction. The structural and mass spectral data are as follows:
MS(+ESI):m/z(％)＝116(34)[M+H]+,212(35)[2M-H2O]+.
example 3
Sulfonylation reaction: in an ice-water bath, the catalytic hydrogenation product (346mg, 3mmol), dichloromethane (30mL), Et were added sequentially to a 100mL round-bottomed flask3N (1.67mL, 12mmol), TsCl (1.7g, 9mmol, added directly in four times) and DMAP (219mg, 1.8mmol) were reacted and stirred overnight, water and aqueous NaOH were added, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with anhydrous Na2SO4After drying, concentration under reduced pressure and column chromatography gave a pale yellow solid (671mg) with a yield of 71.4% in both steps.
The racemic compound shown in the formula (V) obtained by the method is subjected to chiral column resolution to obtain the (3S,5R) configuration required by the next SN2 substitution reaction, which is shown in the formula (Va).
The structure of the product,1H-NMR and13C-NMR data are as follows:
1H-NMR(400MHz,CDCl3)ppmδ7.79(d,J＝8.4Hz,2H),7.57(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),4.45-4.37(m,1H),3.89-3.85(m,1H),3.64(d,J＝7.6Hz,1H),2.48(s,3H),2.44(s,3H),2.09(dd,J＝10.8,10.8Hz,1H),2.03(d,J＝13.2Hz,1H),1.78-1.70(m,2H),1.06-0.97(m,1H),0.87(d,J＝6.4Hz,3H).
13C-NMR(400MHz,CDCl3)ppmδ145.2,143.9,133.4,133.0,130.1(×2),129.8(×2),127.8(×2),127.5(×2),75.4,52.1,49.2,38.8,29.6,21.7,21.6,18.3.
MS(+ESI):m/z(％)＝424(100)[M+H]+,446(19)[M+Na]+.
example 4
BnNH2Nucleophilic substitution: a10 mL pressure-resistant reaction tube was charged with the above-mentioned compound of formula (Va) (950mg, 2.24mmol) and benzylamine (3mL), and the reaction mixture was heated in an oil bath at 180 ℃ for 7 hours and checked for completion by TLC. Addition of EtOAc (50mL) to the reaction appeared as a white solid (537mg) insoluble in EtOAc as determined by H-NMR to be p-MePhSO2NHBn, filtered to give a filtrate, concentrated and subjected to column chromatography (EA: PE ═ 1:2) to give the product as a white solid (500mg, yield 62%), structure of the product1H-NMR、13C-NMR and mass spectral data are as follows:
1H-NMR(400MHz,CDCl3)ppmδ7.67(d,J＝6.4Hz,2H),7.39(d,J＝6.0Hz,2H),7.36-7.32(m,4H),7.28-7.25(m,1H),3.93and 3.76(AB q,J＝10.8,10.0Hz,2H),3.57(d,J＝8.4Hz,1H),3.49(d,J＝6.8Hz,1H),2.93-2.92(m,1H),2.52(d,J＝9.2Hz,1H),2.45(s,3H),2.11(dd,J＝8.8,7.6Hz,1H),2.06-2.02(m,1H),1.86-1.82(m,1H),1.77-1.74(m,1H),1.16-1.11(m,1H),0.91(d,J＝5.2Hz,3H).
13C-NMR(400MHz,CDCl3)ppmδ143.4,140.2,133.5,129.6(×2),128.4(×2),128.3(×2),127.6(×2),127.0,53.0,50.9,50.2,48.9,37.6,26.3,21.5,18.8.
MS(+ESI):m/z(％)＝359(100)[M+H]+,717(35)[2M+H]+.
example 5
Hydrolysis deprotection of sulfonamide N-Ts: the starting compound of formula (VI) (300mg, 0.84mmol), AcOH (1.8mL) and 37% concentrated hydrochloric acid (2mL) were sequentially added to a 5mL pressure-resistant reaction tube, and the mixture was heated in an oil bath at 115 ℃ for 16 hours and checked for completion by TLC. Transferring the reaction solution to round bottom flask, concentrating by rotary evaporation under reduced pressure (25mbar, 40 deg.C), addingAdding water (5mL) and methyl tert-butyl ether (MTBE, (10mL), slowly adding 40 wt% NaOH aqueous solution dropwise into the reaction solution until the pH value reaches 13 (about 1mL), separating with a separating funnel, extracting the aqueous phase twice with MTBE and three times with EtOAc, filtering the organic phase with basic alumina (200-300 mesh), and concentrating to obtain oily crude product (135mg), the structure of the product, the concentration,1H-NMR and mass spectral data are as follows:
1H-NMR(400MHz,CDCl3)ppmδ7.34-7.29(m,5H),3.79and 3.74(AB q,J＝13.6,12.8Hz,2H),2.95-2.88(m,2H),2.77-2.76(m,1H),2.66(dd,J＝12.4,2.0Hz,1H),2.25-2.20(m,1H),1.87-1.84(m,1H),1.81-1.76(m,1H),1.33-1.25(m,2H),0.86(d,J＝6.4Hz,1H),0.82(d,J＝6.8Hz,3H).
MS(+ESI):m/z(％)＝205(100)[M+H]+.
all documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (9)
1. A process for the preparation of a compound of formula (a), comprising the steps of:
(1) reacting the compound of the formula (b) with a benzyl halide Bn-X in an organic solvent to obtain a compound of the formula (c);
(2) carrying out catalytic hydrogenation on the compound of the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound of a formula (d);
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e);
(4) with compounds of formula (e) and Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
(5) hydrolyzing with a compound of formula (f) in an organic solvent in the presence of an acid to obtain a compound of formula (a);
wherein, X is selected from the following group: cl, Br;
said R1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl and p-tolyl.
2. The method of claim 1, wherein R is1Is Me; r is Me, or p-methylphenyl.
3. The method of claim 1, wherein in step (2), the catalyst is Ru-C or Pd-C.
4. The method of claim 1, wherein in step (3), the sulfonylating agent is selected from the group consisting of: C1-C4 alkylsulfonyl chloride, C1-C4 alkylsulfonate, p-toluenesulfonyl chloride, or p-toluenesulfonate.
5. The method of claim 1, wherein in step (3), the base is an organic base or a carbonate.
6. The method of claim 1, wherein in step (3), the base is selected from the group consisting of: triethylamine, ethylenediamine, pyridine, sodium carbonate, sodium bicarbonate, or a combination thereof.
7. A process for the preparation of a compound of formula (a), comprising the steps of:
(4) by usingA compound of formula (e) with Bn-NH2Carrying out nucleophilic substitution reaction to obtain a compound shown as a formula (f);
said R1Selected from the group consisting of: C1-C4 alkyl;
the R is selected from the following group: C1-C4 alkyl, p-tolyl; and
(5) hydrolyzing with a compound of formula (f) in an organic solvent in the presence of an acid to obtain a compound of formula (a).
8. The method of claim 7, wherein the method further comprises the steps of:
(3) reacting a compound of formula (d) with a sulfonylating agent in an organic solvent in the presence of a base to provide a compound of formula (e).
9. The method of claim 8, wherein said method further comprises the steps of:
(2) and (c) carrying out catalytic hydrogenation on the compound of the formula (c) in an alcohol solvent in the presence of a catalyst to obtain a compound of the formula (d).
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