CN112094224B - Preparation method of 3-substituted-5-aminopiperidine with protecting group - Google Patents
Preparation method of 3-substituted-5-aminopiperidine with protecting group Download PDFInfo
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- CN112094224B CN112094224B CN201910527792.0A CN201910527792A CN112094224B CN 112094224 B CN112094224 B CN 112094224B CN 201910527792 A CN201910527792 A CN 201910527792A CN 112094224 B CN112094224 B CN 112094224B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention provides a preparation method of 3-substituted-5-aminopiperidine with a protecting group, in particular a preparation method of 3-substituted-5-aminopiperidine with a protecting group, which has low cost and easily obtained raw materials and reaction reagents.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of 3-substituted-5-aminopiperidine with a protecting group.
Background
N-protected 3-amino-5-methylpiperidine, which is an intermediate for use in pharmaceutical syntheses, for example as side chain in the synthesis of (3S,5S) -7- [ 3-amino-5-methyl-piperidine ] -1-cyclopropyl-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, a quinolone antibiotic. The existing main preparation method comprises the following steps:
the first method (shown in the following formula) uses (S) -2-aminoadipic acid as raw material, firstly converts diacid into dimethyl ester under acidic condition, secondly protects amino with tert-butyloxycarbonyl (Boc), secondly introduces methyl with LiHMDS as base and iodomethane as methylating agent, and then uses LiAlH 4 Reducing to obtain diol, and then conducting Swern oxidation to obtain dialdehyde; finally dialdehyde and NH 3 Reacting and then using NaBH 4 Reduction to give 3-tert-butoxycarbonylamino-5-methylpiperidine (US 2010/152452);
in the third method (shown in the following formula), 5-methylpiperidine-3-alcohol is used as a raw material, firstly, the raw material reacts with benzyl halide to obtain quaternary ammonium salt, then, the quaternary ammonium salt is subjected to catalytic hydrogenation, then, the quaternary ammonium salt reacts with a sulfonylation reagent in the presence of alkali, the nucleophilic substitution is carried out on the quaternary ammonium salt and benzylamine, and finally, the quaternary ammonium salt is hydrolyzed in the presence of acid to obtain the required piperidine structure (CN 107021916A).
Among the three methods, the method I and the method II for synthesizing the 2-methyl-4-tert-butoxycarbonylamino adipic acid dimethyl ester need to react at a low temperature of-78 ℃, and have the disadvantages of harsh conditions, large energy consumption and high equipment requirement; the method has the advantages of reaction in the third step and the fourth step, easy elimination of side reaction and low yield.
The 3-methyl-5-aminopiperidine with a protective group can be synthesized by simple transformation as shown in the following formula
The above N-protected 3-amino-5-methylpiperidine. In addition, it can be used for the synthesis of a specific kinase inhibitor (Journal of Medicinal Chemistry; vol.60; nb.5; (2017); p.1971-1993).
Therefore, it would be valuable to develop a low-cost, readily available chemical process for the preparation of protected 3-methyl-5-aminopiperidine.
Disclosure of Invention
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:
in the formula, the Acid is inorganic Acid or organic Acid;
R 1 is C1-C4 alkyl;
r is an amino protecting group;
(i) reducing the compound of formula (b) in an organic solvent to obtain a compound of formula (c);
(ii) reacting a compound of formula (c) with an amino protecting reagent in the presence of a base, optionally in an organic solvent, to give a compound of formula (d);
(iii) reacting the compound of formula (d) with halogen and base to obtain the compound of formula (a).
In another preferred embodiment, the inorganic acid or organic acid is selected from the group consisting of: HCl, HBr, HF, H 3 PO 4 、H 2 SO 4 、CH 3 COOH、CF 3 COOH, oxalic acid, malic acid, citric acid, or a combination thereof.
In another preferred embodiment, the Acid is HCl, HBr, HF, H 3 PO 4 Preferably selected from the group consisting of: HCl and HBr.
In another preferred embodiment, R is an amino protecting group selected from the group consisting of: benzyloxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, p-toluenesulfonyl, trifluoroacetyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, o- (p) -nitrobenzenesulfonyl, trityl.
In another preferred embodiment, R is selected from the group consisting of: benzyloxycarbonyl, tert-butoxycarbonyl, phthaloyl, benzyl.
In another preferred embodiment, R is benzyloxycarbonyl.
In another preferred example, in the step (i), the catalytic hydrogenation is carried out in the presence of a noble metal catalyst; the catalytic hydrogenation comprises the following steps: in the hydrogenation of H 2 Carrying out catalytic hydrogenation under the pressure of 1-10 MPa; the reaction is carried out at a reaction temperature of 40-80 ℃.
In another preferred embodiment, in step (i), the catalysis is catalytic hydrogenation in the presence of Pd-C or Ru-C.
In another preferred embodiment, in the step (i), the organic solvent is an alcohol solvent.
In another preferred embodiment, in the step (i), the organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, propanol, butanol, ethylene glycol, or combinations thereof; more preferably selected from: methanol, ethanol, isopropanol, or a combination thereof.
In another preferred embodiment, in the step (i), the amount of the noble metal catalyst is 5-10% of the amount of the compound of the formula (b).
In another preferred embodiment, in step (ii), the amino protecting reagent is benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, 9-fluorenylmethyl chloroformate, allyl chloroformate; the base is an organic base, a carbonate, a bicarbonate, or a combination thereof; the reaction is carried out at a temperature of-10 to 25 ℃.
In another preferred embodiment, in step (ii), the amino group protecting reagent is benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, or benzyl chloride.
In another preferred embodiment, in the step (ii), the molar ratio of the amino protecting agent to the compound of formula (c) is 1.0-1.5: 1.
In another preferred embodiment, in the step (ii), the base is selected from the group consisting of: sodium bicarbonate, triethylamine, pyridine, sodium carbonate, potassium bicarbonate, or a combination thereof, preferably selected from: sodium bicarbonate, triethylamine, or a combination thereof.
In another preferred embodiment, in the step (ii), the molar ratio of the base to the compound of formula (c) is 2.0-8.0: 1.
In another preferred embodiment, in the step (ii), the organic solvent is selected from the group consisting of: tetrahydrofuran, methanol, ethanol, acetonitrile, toluene, chloroform, dichloromethane, 1, 4-dioxane, or a combination thereof, preferably selected from: tetrahydrofuran, methanol, ethanol, acetonitrile, or combinations thereof.
In another preferred embodiment, in step (iii), the halogen is selected from the group consisting of: liquid bromine, chlorine; and/or the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, cesium hydroxide, or combinations thereof.
In another preferred embodiment, the alkali is sodium hydroxide.
In another preferred embodiment, the molar ratio of halogen to compound of formula (d) is 1.0-1.5: 1.
In another preferred embodiment, the molar ratio of the base to the compound of formula (d) is 2.0-8.0: 1.
In another preferred embodiment, the reaction is divided into two stages, wherein the temperature of the first stage is-10-10 ℃, and the temperature of the second stage is 55-85 ℃.
In a second aspect of the present invention, there is provided a process for the preparation of an N-protected 3-amino-5-substituted piperidine, said process comprising the steps of:
(1) preparing a compound of formula (a) using a compound of formula (d); and
(2) reacting a compound of formula (a) to produce an N-protected 3-amino-5-substituted piperidine;
wherein R is 1 Is C1-4 alkyl;
r is an amino protecting group.
In another preferred example, the step (2) includes: with compounds of formula (a) and (Boc) 2 And O reaction, and then removing the R protecting group to obtain the N-protected 3-amino-5-substituted piperidine.
In another preferred embodiment, R 1 Is methyl.
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 invention develops a method for preparing 3-substituted-5-aminopiperidine with protecting groups and an intermediate thereof through long-term intensive research, and the method obtains a compound shown in a formula (a) through the intermediate shown in a formula (b) and sequentially through catalytic hydrogenation, amino protection and rearrangement reaction. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the "amino protecting agent" used in the present invention is not particularly limited, and amino protecting agents well known in the art can be used. The terms "amino protecting agent" and "amino protecting group" are mainly divided into three categories: an alkoxycarbonyl amino protecting group, an acyl amino protecting group, and an alkyl amino protecting group. Examples of the alkoxycarbonyl amino-protecting group include benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilethoxycarbonyl (Teoc), and methyl (or ethyl) oxycarbonyl; examples of the acyl amino-protecting group include phthaloyl (Pht), p-toluenesulfonyl (Tos), and trifluoroacetyl (Tfa); examples of the alkyl-amino protecting group include trityl (Trt), benzyl (Bn), and p-methoxybenzyl (PMB).
The term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having, for example, 1 to 6 (preferably 1 to 4) carbon atoms, and attached to the rest of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, and the like. For example, in the present invention, the C1-C4 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
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, the Acid is an inorganic Acid or an organic Acid, such as: HCl, HBr, HF, H 3 PO 4 、H 2 SO 4 、CH 3 COOH、CF 3 COOH, oxalic acid, malic acid, citric acid; r 1 Is C1-C4 alkyl; r is benzyloxycarbonyl, tert-butoxycarbonyl, phthaloyl, or benzyl.
(1) Catalytically hydrogenating the compound of formula (b) in an organic solvent in the presence of a catalyst to obtain a compound of formula (c);
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 Pd-C or Ru-C.
In this step, the proportions of the respective reaction materials are not particularly limited, and for example, the catalyst may be used in an amount of 5% to 10% by mass based on the compound of the formula (b) to catalytically hydrogenate H 2 The pressure is 1-10 MPa.
In this step, the reaction solvent, reaction temperature, reaction time, etc. may be selected according to specific reactants, for example, the organic solvent may be selected from the following group: methanol, ethanol, isopropanol, propanol, butanol, ethylene glycol, or a combination thereof, the reaction temperature may be 40-80 ℃, and the reaction time may be 10-20 hours.
(2) Reacting a compound of formula (c) with an amino protecting reagent in an organic solvent in the presence of a base to obtain a compound of formula (d);
in this step, the ratio of each reaction material is not particularly limited. For example, the amino protecting agent may be any known amino protecting agent, for example selected from the group consisting of: benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, chlorobenzyl, triphenylchloromethane, 9-fluorenylmethyl chloroformate and allyl chloroformate; the molar ratio of the amino protecting reagent to the compound of formula (c) may be 1.0-1.5: 1; the base may be an organic base, or a carbonate, or a combination thereof, such as: sodium bicarbonate, triethylamine, pyridine, sodium carbonate, potassium bicarbonate, or a combination thereof; the molar ratio of base to compound of formula (c) may be 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 the specific reactants, and for example, the reaction solvent may be: tetrahydrofuran, methanol, ethanol, acetonitrile, toluene, chloroform, dichloromethane, 1, 4-dioxane, or their combination, and the reaction temperature is-10-25 deg.c.
(3) Reacting a compound of formula (d) with a halogen and a base to obtain a compound of formula (a);
in this step, the ratio of each reaction material is not particularly limited. The halogen is selected from the group consisting of: the molar ratio of liquid bromine, chlorine, halogen and compound of formula (d) may be 1.0-1.5:1, the base is sodium hydroxide, and the molar ratio of base and compound of formula (d) may be 2.0-8.0: 1.
In this step, the reaction solvent, reaction temperature, reaction time, etc. may be selected according to the specific reactants, for example, the reaction may be divided into two stages, the first stage temperature being-10 to 10 ℃ and the second stage temperature being 55 to 85 ℃.
Preparation of N-protected 3-amino-5-methylpiperidines
The preparation method of the compound of the formula (a) provided by the invention can be used for preparing N-protected 3-amino-5-methylpiperidine. Wherein the compound of formula (a) can be converted to an N-protected 3-amino-5-methylpiperidine using methods known in the art.
Preparation of 3-methyl-5-aminopiperidine with protecting group
The starting material used by the invention is 5-methylnicotinamide hydrochloride, and the 3-methyl-5-aminopiperidine with a protecting group is obtained by the steps of catalytic hydrogenation, amino protection, rearrangement reaction and the like, wherein the method comprises the following steps:
(1) in an organic solvent, in the presence of a catalyst, carrying out catalytic hydrogenation on 5-methylnicotinamide hydrochloride (II) to obtain 5-methylpiperidine-3-formamide hydrochloride (III);
(2) reacting 5-methylpiperidine-3-formamide hydrochloride (III) with an amino protective reagent in an organic solvent in the presence of alkali to obtain 5-methylpiperidine-3-formamide (IV) with a protective group;
(3) reacting 5-methylpiperidine-3-formamide (IV) with a protecting group with halogen and alkali to obtain 3-methyl-5-aminopiperidine (I) with a protecting group;
each reaction is detailed below:
the first step is as follows: a method for preparing 5-methylpiperidine-3-formamide hydrochloride shown in the formula (III) comprises the following steps:
in an organic solvent, Pd-C or Ru-C is used as a catalyst, the 5-methylnicotinamide hydrochloride (II) is catalytically hydrogenated under certain hydrogen pressure and certain temperature to obtain 5-methylpiperidine-3-formamide hydrochloride (III), and the reaction formula is as follows:
preferably, the catalyst is Pd-C or Ru-C.
Preferably, the organic solvent is methanol, ethanol or isopropanol.
Preferably, the reaction temperature is 40-80 ℃.
Preferably, the mass of the catalyst is 5-10% of the mass of the 5-methylnicotinamide hydrochloride (II).
Preferably, after the reaction is completed, 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 (III).
Specifically, in a reaction kettle, weighing a certain mass of 5-methylnicotinamide hydrochloride (II), then adding 0.05-0.15 times of Pd-C or Ru-C, then adding 5-10 times of solvent, introducing hydrogenation, reacting for 10-20 hours at the temperature of 40-80 ℃ under the pressure of hydrogen of 1-10MPa, filtering to remove the catalyst, washing the catalyst with the solvent, combining the filtrates, and concentrating under reduced pressure to obtain a white or light yellow solid, namely 5-methylpiperidine-3-formamide hydrochloride (III), which is used for the subsequent reaction.
The second step is that: a synthetic method for preparing 5-methylpiperidine-3-formamide with a protecting group as shown in formula (IV) comprises the following steps:
sequentially adding a certain amount of catalytic hydrogenation product (III) and a sodium bicarbonate aqueous solution into an organic solvent, slowly dropwise adding an amino protection reagent at a certain temperature, keeping the temperature until the reaction is complete, adding ethyl acetate and water, separating, extracting, washing with water, drying, concentrating under reduced pressure to obtain a light yellow solid, and finally pulping with petroleum ether to obtain a white or light yellow solid, wherein the reaction equation is as follows:
preferably, the organic solvent is tetrahydrofuran, methanol, ethanol or acetonitrile.
Preferably, the reaction temperature is-10-25 ℃.
Preferably, the amino protecting reagent is benzyl chloroformate.
Preferably, the amounts of the base and the amino protecting agent are 2.0 to 8.0 times and 1.0 to 1.5 times the amount of the catalytic hydrogenation product (III) substance, respectively.
Preferably, after the reaction is completed, ethyl acetate and water are added for liquid separation, the organic phase is washed by water, dried by anhydrous sodium sulfate and then concentrated under reduced pressure, and finally, petroleum ether is used for pulping to obtain white or light yellow solid.
Specifically, a certain amount of compound (III) is weighed in a round-bottom flask, then a certain amount of solvent and a certain amount of 15% sodium bicarbonate aqueous solution are added, wherein the mass ratio of the solvent to the compound (III) is 5-10:1, the molar ratio of the sodium bicarbonate to the compound (III) is 2.0-8.0:1, the temperature in the flask is controlled to be-10-25 ℃ in an ice-water bath, the temperature is kept, a certain amount of amino protecting reagent is dropwise added, the molar ratio of the amino protecting reagent to the compound (III) is 1.0-1.5:1, and the temperature is kept until the reaction is complete. Adding ethyl acetate and water, separating, extracting the water phase with ethyl acetate, combining the organic phases, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and pulping with petroleum ether to obtain white or light yellow solid. The obtained 5-methylpiperidine-3-formamide with a protecting group is shown as a formula (IV).
The third step: a synthetic method for preparing 3-methyl-5-aminopiperidine with protecting groups as shown in formula (I) comprises the following steps:
adding a certain amount of sodium hydroxide and water into a round-bottom flask in sequence, dropwise adding halogen at a certain temperature, keeping the temperature after dropwise adding, adding a certain amount of 5-methylpiperidine-3-formamide (IV) with a protecting group in batches, keeping the temperature until the raw materials disappear, raising the temperature, adding ethyl acetate and water after complete reaction, separating to obtain an organic phase, washing the organic phase with dilute hydrochloric acid to obtain an aqueous phase, adjusting the pH with an aqueous solution of sodium hydroxide, adding ethyl acetate, separating, washing with water, drying, and concentrating under reduced pressure to obtain a yellow oily substance (I), wherein the reaction equation is as follows:
preferably, the halogen is liquid bromine or chlorine.
Preferably, the amount of the halogen and the sodium hydroxide is 1.0 to 1.5 times and 2.0 to 8.0 times, respectively, the amount of the 5-methylpiperidine-3-carboxamide substance having a protecting group.
Preferably, the reaction is divided into two stages, wherein the temperature of the first stage is-10-10 ℃, and the temperature of the second stage is 55-85 ℃.
Specifically, a round-bottom flask is firstly added with a certain amount of sodium hydroxide and water, an ice-water bath is used for controlling the temperature in the flask to be-10-10 ℃, the temperature is kept and a certain amount of halogen is dropwise added, the temperature is kept and a certain amount of 5-methylpiperidine-3-formamide with a protecting group is added in batches, wherein the molar ratio of the sodium hydroxide to the halogen to the 5-methylpiperidine-3-formamide (IV) with the protecting group is respectively 2.0-8.0:1 and 1.0-1.5:1, the mass ratio of the water to the 5-methylpiperidine-3-formamide with the protecting group is 6-10:1, the temperature is kept until the raw materials disappear, the temperature is increased to 55-85 ℃ for reaction, ethyl acetate and water are added after the reaction, liquid separation is carried out to obtain an organic phase, the organic phase is washed twice by 1N hydrochloric acid to obtain an aqueous phase, the pH is adjusted to be 10 by 1N sodium hydroxide solution, adding ethyl acetate, separating liquid, washing, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain yellow oily substance, i.e. 3-methyl-5-aminopiperidine with protecting group.
Compared with the prior art, the invention has the main advantages that:
(1) provides a preparation method of 3-substituted-5-aminopiperidine with protecting groups.
(2) Provided is a method for preparing a compound represented by formula (a), which can be used for preparing N-protected 3-amino-5-substituted piperidine.
(3) Compared with the prior art, the method has low cost and easily obtained 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 following examples are experimental procedures without specific conditions noted, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.
Experimental procedures for the synthesis of N-protected 3-amino-5-methylpiperidine using a protected 3-methyl-5-aminopiperidine are described in the following examples.
EXAMPLE 1 Synthesis of 5-methylpiperidine-3-carboxamide hydrochloride
In a 1L hydrogenation reactor, 5-methyl nicotinamide hydrochloride 50.00g (289.67mmol), 10% Pd-C11.32g (wet weight, water content 55.83%) and methanol 395.50g were put and stirred; pressurizing to 2.07MPa, heating to 60 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-methylpiperidine-3-carboxamide hydrochloride (51.23g, yield 99%, white or pale yellow solid).
EXAMPLE 2 Synthesis of 5-methylpiperidine-3-carboxamide with a protecting group
In a 2L three-necked flask, 50.00g (279.86mmol) of 5-methylpiperidine-3-carboxamide hydrochloride, 552.94g of a 15% aqueous solution of sodium hydrogencarbonate (82.94 g of sodium hydrogencarbonate mixed with 470.00g of water) and 208.45g of tetrahydrofuran were put and stirred; cooling to 0 ℃, controlling the temperature at 0 ℃, and dropwise adding 50.12g (293.80mmol) of benzyl chloroformate; keeping the temperature at 0 ℃ until the reaction is complete; 225.50g of ethyl acetate and 250.00g of water are added; separating, extracting water layer with 112.75g ethyl acetate, and combining organic layers; concentrating the organic layer under reduced pressure to dryness; 76.05g of petroleum ether is added for pulping; the resulting mixture was filtered under suction and dried to give 5-methylpiperidine-3-carboxamide (71.92g, 93% yield, white or pale yellow solid) with a protecting group.
Of the product 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.46-7.21(m,5H),6.65(s,1H),5.80(s,1H),5.25-5.02(m,2H),4.05(s,1H),3.79(s,1H),3.32(s,1H),2.82(s,1H),2.56(s,1H),2.27(s,1H),2.04-1.51(m,1H),1.50-1.20(m,1H),0.90(d,J＝6.6Hz,3H)。
EXAMPLE 3 Synthesis of protected 3-methyl-5-aminopiperidine
Putting 18.35g (458.75mmol) of sodium hydroxide and 157.25g of water into a 1L three-necked flask, stirring, and cooling to 0 ℃; slowly adding 15.41g (96.41mmol) of liquid bromine dropwise at the temperature of 0 ℃, and reacting for 0.5h after dropwise addition; adding 20.00g (72.38mmol) of 5-methylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at 0 ℃ until the raw materials disappear; heating to 70 ℃, and reacting for 2 h; adding 120.51g of ethyl acetate, and separating to obtain an organic phase; washing twice with 1mol/L hydrochloric acid, 66.8mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 72.16g of ethyl acetate, separating, taking an organic phase, extracting a water layer by 72.16g of ethyl acetate, combining the organic phases, and washing by 40.00g of water; the solvent was removed by concentration under reduced pressure to give 3-methyl-5-aminopiperidine (14.56g, yield 81%, yellow oil) with a protecting group.
Product of 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.43-7.18(m,5H),5.24-5.01(m,2H),3.75(d,J＝47.0Hz,1H),3.59-3.38(m,1H),3.37-3.15(m,1H),3.14-2.94(m,1H),2.76(d,J＝50.3Hz,1H),2.37-2.00(m,1H),1.68-1.48(m,1H),1.45-1.29(m,1H),0.88(d,J＝6.8Hz,3H)。
EXAMPLE 4 Synthesis of N-protected 3-amino-5-methylpiperidine
In a 250mL three-necked flask, 20.00g (80.54mmol) of 3-methyl-5-aminopiperidine with a protecting group and 88.70g of tetrahydrofuran were put and cooled to 0 ℃; 12.23g (120.86mmol) of triethylamine and di-tert-butyl dicarbonate ((Boc) 2 O)18.50g (84.77mmol) are sequentially added into the reaction solution, and the mixture is stirred at room temperature until the reaction is completed; adding 1.21g (13.73mmol) of N, N-dimethylethylenediamine, and stirring to react until no di-tert-butyl dicarbonate remains; adding ethyl acetate and water, separating to obtain an organic phase, washing with 1mol/L hydrochloric acid, washing with saturated sodium bicarbonate, washing with water, drying, and spin-drying; 2.7g of 10 percent Pd-C (wet weight, water content of 55.83 percent) and 79.1mL of methanol are added and reacted under hydrogen gas till the reaction is completed; carrying out suction filtration and rotary evaporation to remove the solvent; ethyl acetate and water were added and the organic phase was separated, washed 2 times with 1mol/L hydrochloric acid, adjusted to pH 10 with 1mol/L sodium hydroxide solution, added with ethyl acetate, separated, washed with water and dried to give N-protected 3-amino-5-methylpiperidine (14.70g, 86% yield, white solid).
Of the product 1 H-NMR data were as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ4.54(dd,J＝3.1,9.5Hz,1H),3.7(s,3H),2.58-2.50(m,1H),2.41(ddd,J＝17.6,9.5,3.7Hz,1H),2.30-2.23(m,1H),1.98-1.93(m,1H),1.40(s,9H),0.85(d,J＝6.8Hz,3H)。
EXAMPLE 5 Synthesis of N-protected (3S,5S) -3-amino-5-methylpiperidine
In a 1000mL single-neck bottle, 20.00g (93.32mmol) of N-protected 3-amino-5-methylpiperidine and 179.56g of acetone are put into the bottle; dissolving 4.20g (46.65mmol) of oxalic acid in 227mL of solution prepared from acetone and water according to the volume ratio of 10:1, and slowly dropping the solution into a reaction bottle; stirring at room temperature for 0.5h, cooling to 0 deg.C, stirring for 1h, and vacuum filtering to obtain solid; adding ethyl acetate and water, adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution, separating, washing with water, drying and spin-drying; adding 111.56g of acetonitrile, adding 8.67g (57.00mmol) of D-mandelic acid in batches, separating out solids, stirring for 1h at room temperature, cooling to 0 ℃, stirring for 1h, and performing suction filtration to obtain solids; ethyl acetate and water were added, the pH was adjusted to 10 with 1mol/L sodium hydroxide solution, and the mixture was separated, washed with water, dried, and spun to give N-protected (3S,5S) -3-amino-5-methylpiperidine (5.50g, yield 28%, white solid).
The structure of the product, 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ5.69-5.68(m,1H),3.77(s,1H),2.96-2.93(m,1H),2.88(d,J＝12.0Hz,1H),2.70(dd,J＝11.9,2.5Hz,1H),2.21(t,J＝10.8,1.0Hz,1H),1.82-1.74(m,2H),1.44(s,9H),1.23-1.16(m,1H),0.85(d,J＝6.5Hz,3H)。
EXAMPLE 6 Synthesis of 5-ethylpiperidine-3-carboxamide hydrochloride
In 500mL hydrogenation reactor, add 5-ethyl nicotinamide hydrochloride 20.00g (107.16mmol), 10% Pd-C4.53 g (wet weight, water content 55.83%) and methanol 158.20g, stir; pressurizing to 2.07MPa, heating to 60 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-ethylpiperidine-3-carboxamide hydrochloride (20.24g, yield 98%, white or pale yellow solid).
1 H-NMR(400MHz,CDCl 3 )ppmδ7.03(s,2H),3.14–3.01(m,3H),3.01–2.93(m,1H),2.85-2.80(m,1H),2.67-2.62(m,1H),1.95–1.81(m,3H),1.43–1.31(m,1H),1.31–1.20(m,1H),0.93-0.89(m,3H).
EXAMPLE 7 Synthesis of 5-ethylpiperidine-3-carboxamide with a protecting group
In a 1L three-necked flask, 20.00g (103.80mmol) of 5-ethylpiperidine-3-carboxamide hydrochloride, 221.18g of a 15% aqueous sodium hydrogencarbonate solution and 83.38g of tetrahydrofuran were charged and stirred; cooling to 0 deg.C, controlling temperature at 0 deg.C and adding 18.59g (108.99mmol) of benzyl chloroformate dropwise; keeping the temperature at 0 ℃ until the reaction is complete; adding 90.20g of ethyl acetate and 100.00g of water; separating, extracting water layer with 45.10g ethyl acetate, and combining organic layers; concentrating the organic layer under reduced pressure to dryness; 30.43g of petroleum ether is added for pulping; the resulting mixture was filtered with suction and dried to give 5-ethylpiperidine-3-carboxamide (27.73g, 92% yield, white or pale yellow solid) with a protecting group.
Of the product 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.34(s,3H),7.37–7.29(m,2H),6.92(d,J＝7.5Hz,1H),6.79(d,J＝7.5Hz,1H),5.23–5.18(m,1H),5.15(d,J＝12.4Hz,1H),3.58(dd,J＝12.4,7.0Hz,1H),3.54–3.45(m,3H),2.84-2.78(m,1H),2.16–2.06(m,1H),2.04–1.95(m,2H),1.45-1.37(m,1H),1.34-1.26(m,1H),0.91-0.88(m,3H)。
EXAMPLE 8 Synthesis of protected 3-Ethyl-5-aminopiperidine
Putting 18.35g (458.75mmol) of sodium hydroxide and 157.25g of water into a 1L three-necked flask, stirring, and cooling to 0 ℃; slowly adding 15.41g (96.41mmol) of liquid bromine dropwise at the temperature of 0 ℃, and reacting for 0.5h after dropwise addition; adding 20.00g (68.88mmol) of 5-ethylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at 0 ℃ until the raw materials disappear; heating to 70 ℃, and reacting for 2 h; adding 120.51g of ethyl acetate, and separating to obtain an organic phase; washing twice with 1mol/L hydrochloric acid, 66.8mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 72.16g of ethyl acetate, separating, taking an organic phase, extracting a water layer by 72.16g of ethyl acetate, combining the organic phases, and washing by 40.00g of water; the solvent was removed by concentration under reduced pressure to give 3-ethyl-5-aminopiperidine (14.82g, yield 82%, yellow oil) with a protecting group.
Product of 1 H-NMR data were as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.39–7.27(m,5H),5.21-5.17(m,1H),5.17-5.14(m,1H),4.27(d,J＝8.1Hz,2H),3.56(dd,J＝12.5,7.2Hz,1H),3.55–3.48(m,2H),3.51–3.44(m,1H),3.14-3.06(m,1H),2.07-2.01(m,1H),1.68(t,J＝7.0Hz,2H),1.43-1.34(m,1H),1.34–1.22(m,1H),0.93-0.90(m,3H)。
EXAMPLE 9 Synthesis of 5-methylpiperidine-3-carboxamide hydrochloride
In a 250mL hydrogenation vessel, 10.00g (57.93mmol) of 5-methylnicotinamide hydrochloride, 2.26g (wet weight, water content 55.83%) of 10% Pd-C and 79.10g of methanol were charged and stirred; pressurizing to 1.00MPa, heating to 40 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-methylpiperidine-3-carboxamide hydrochloride (10.04g, yield 97%, white or pale yellow solid).
EXAMPLE 10 Synthesis of 5-methylpiperidine-3-carboxamide hydrochloride
In a 250mL hydrogenation vessel, 10.00g (57.93mmol) of 5-methylnicotinamide hydrochloride, 2.26g (wet weight, water content 55.83%) of 10% Pd-C and 79.10g of methanol were charged and stirred; pressurizing to 1.00MPa, heating to 80 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-methylpiperidine-3-carboxamide hydrochloride (10.14g, yield 98%, white or pale yellow solid).
EXAMPLE 11 Synthesis of 5-methylpiperidine-3-carboxamide hydrochloride
In a 250mL hydrogenation vessel, 10.00g (57.93mmol) of 5-methylnicotinamide hydrochloride, 2.26g (wet weight, water content 55.83%) of 10% Pd-C and 79.10g of methanol were charged and stirred; pressurizing to 10.00MPa, heating to 40 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-methylpiperidine-3-carboxamide hydrochloride (10.21g, yield 99%, white or pale yellow solid).
EXAMPLE 12 Synthesis of 5-methylpiperidine-3-carboxamide hydrochloride
In a 250mL hydrogenation vessel, 10.00g (57.93mmol) of 5-methylnicotinamide hydrochloride, 2.26g (wet weight, water content 55.83%) of 10% Pd-C and 79.10g of methanol were charged and stirred; pressurizing to 10.00MPa, heating to 80 ℃, and reacting for 15 h; after suction filtration, the filtrate was concentrated under reduced pressure to dryness to give 5-methylpiperidine-3-carboxamide hydrochloride (10.25g, yield 99%, white or pale yellow solid).
EXAMPLE 13 Synthesis of 5-methylpiperidine-3-carboxamide with protecting group
In a 500mL three-necked flask, 10.00g (55.97mmol) of 5-methylpiperidine-3-carboxamide hydrochloride, 110.59g of a 15% aqueous solution of sodium hydrogencarbonate and 41.69g of tetrahydrofuran were put and stirred; cooling to-10 deg.C, controlling temperature to-10 deg.C, and dropwise adding 10.02g (58.76mmol) of benzyl chloroformate; keeping the temperature of minus 10 ℃ until the reaction is complete; 45.10g of ethyl acetate and 50.00g of water are added; separating, extracting water layer with ethyl acetate 22.55g, and combining organic layers; concentrating the organic layer under reduced pressure to dryness; adding 15.21g of petroleum ether for pulping; the resulting mixture was filtered under suction and dried to give 5-methylpiperidine-3-carboxamide (14.69g, 95% yield, white or pale yellow solid) with a protecting group.
Of the product 1 H-NMR data were as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.46-7.21(m,5H),6.65(s,1H),5.80(s,1H),5.25-5.02(m,2H),4.05(s,1H),3.79(s,1H),3.32(s,1H),2.82(s,1H),2.56(s,1H),2.27(s,1H),2.04-1.51(m,1H),1.50-1.20(m,1H),0.90(d,J＝6.6Hz,3H)。
EXAMPLE 14 Synthesis of 5-methylpiperidine-3-carboxamide with a protecting group
In a 500mL three-necked flask, 10.00g (55.97mmol) of 5-methylpiperidine-3-carboxamide hydrochloride, 110.59g of a 15% aqueous solution of sodium hydrogencarbonate and 41.69g of tetrahydrofuran were put and stirred; controlling the temperature to be 25 ℃, and dropwise adding 10.02g (58.76mmol) of benzyl chloroformate; keeping the temperature at 25 ℃ until the reaction is complete; 45.10g of ethyl acetate and 50.00g of water are added; separating, extracting the water layer with 22.55g of ethyl acetate, and combining the organic layers; concentrating the organic layer under reduced pressure to dryness; adding 15.21g of petroleum ether for pulping; the resulting mixture was filtered under suction and dried to give 5-methylpiperidine-3-carboxamide (14.08g, 91% yield, white or pale yellow solid) with a protecting group.
Of the product 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.46-7.21(m,5H),6.65(s,1H),5.80(s,1H),5.25-5.02(m,2H),4.05(s,1H),3.79(s,1H),3.32(s,1H),2.82(s,1H),2.56(s,1H),2.27(s,1H),2.04-1.51(m,1H),1.50-1.20(m,1H),0.90(d,J＝6.6Hz,3H)。
EXAMPLE 15 Synthesis of protected 3-methyl-5-aminopiperidine
Putting 9.18g (229.38mmol) of sodium hydroxide and 78.63g of water into a 500mL three-necked flask, stirring, and cooling to-10 ℃; slowly adding 7.70g (48.21mmol) of liquid bromine dropwise at the temperature of minus 10 ℃, and reacting for 0.5h after dropwise addition; adding 10.00g (36.19mmol) of 5-methylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at-10 ℃ until the raw materials disappear; heating to 55 ℃, and reacting for 2 h; adding 60.26g of ethyl acetate, and separating to obtain an organic phase; washing twice with hydrochloric acid of 1mol/L, 33.4mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 36.08g of ethyl acetate, separating, taking an organic phase, extracting a water layer by using 36.08g of ethyl acetate, combining the organic phases, and washing by using 20.00g of water; the solvent was removed by concentration under reduced pressure to give 3-methyl-5-aminopiperidine (7.37g, yield 82%, yellow oil) with a protecting group.
Product of 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.43-7.18(m,5H),5.24-5.01(m,2H),3.75(d,J＝47.0Hz,1H),3.59-3.38(m,1H),3.37-3.15(m,1H),3.14-2.94(m,1H),2.76(d,J＝50.3Hz,1H),2.37-2.00(m,1H),1.68-1.48(m,1H),1.45-1.29(m,1H),0.88(d,J＝6.8Hz,3H)。
EXAMPLE 16 Synthesis of protected 3-methyl-5-aminopiperidine
Putting 9.18g (229.38mmol) of sodium hydroxide and 78.63g of water into a 500mL three-necked flask, stirring, and cooling to-10 ℃; controlling the temperature to be minus 10 ℃, slowly adding 7.70g (48.21mmol) of liquid bromine dropwise, and reacting for 0.5h after dropwise adding; adding 10.00g (36.19mmol) of 5-methylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at-10 ℃ until the raw materials disappear; heating to 85 ℃, and reacting for 2 h; adding 60.26g of ethyl acetate, and separating to obtain an organic phase; washing twice with hydrochloric acid of 1mol/L, 33.4mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 36.08g of ethyl acetate, separating, taking an organic phase, extracting a water layer by using 36.08g of ethyl acetate, combining the organic phases, and washing by using 20.00g of water; the solvent was removed by concentration under reduced pressure to give 3-methyl-5-aminopiperidine (7.10g, yield 79%, yellow oil) with a protecting group.
Product of 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.43-7.18(m,5H),5.24-5.01(m,2H),3.75(d,J＝47.0Hz,1H),3.59-3.38(m,1H),3.37-3.15(m,1H),3.14-2.94(m,1H),2.76(d,J＝50.3Hz,1H),2.37-2.00(m,1H),1.68-1.48(m,1H),1.45-1.29(m,1H),0.88(d,J＝6.8Hz,3H)。
EXAMPLE 17 Synthesis of protected 3-methyl-5-aminopiperidine
Putting 9.18g (229.38mmol) of sodium hydroxide and 78.63g of water into a 500mL three-neck flask, and stirring; slowly adding 7.70g (48.21mmol) of liquid bromine dropwise at the temperature of 10 ℃, and reacting for 0.5h after dropwise addition; adding 10.00g (36.19mmol) of 5-methylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at 10 ℃ until the raw materials disappear; heating to 55 ℃, and reacting for 2 h; adding 60.26g of ethyl acetate, and separating to obtain an organic phase; washing twice with hydrochloric acid of 1mol/L, 33.4mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 36.08g of ethyl acetate, separating, taking an organic phase, extracting a water layer by using 36.08g of ethyl acetate, combining the organic phases, and washing by using 20.00g of water; the solvent was removed by concentration under reduced pressure to give 3-methyl-5-aminopiperidine (6.83g, yield 76%, yellow oil) with a protecting group.
Product of 1 The H-NMR data are as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.43-7.18(m,5H),5.24-5.01(m,2H),3.75(d,J＝47.0Hz,1H),3.59-3.38(m,1H),3.37-3.15(m,1H),3.14-2.94(m,1H),2.76(d,J＝50.3Hz,1H),2.37-2.00(m,1H),1.68-1.48(m,1H),1.45-1.29(m,1H),0.88(d,J＝6.8Hz,3H)。
EXAMPLE 18 Synthesis of protected 3-methyl-5-aminopiperidine
Putting 9.18g (229.38mmol) of sodium hydroxide and 78.63g of water into a 500mL three-neck flask, and stirring; slowly adding 7.70g (48.21mmol) of liquid bromine dropwise at the temperature of 10 ℃, and reacting for 0.5h after dropwise addition; adding 10.00g (36.19mmol) of 5-methylpiperidine-3-formamide with a protecting group in batches, and keeping the temperature at 10 ℃ until the raw materials disappear; heating to 85 ℃, and reacting for 2 h; adding 60.26g of ethyl acetate, and separating to obtain an organic phase; washing twice with hydrochloric acid of 1mol/L, 33.4mL each time, and obtaining a water phase; adjusting the pH value to 10 by using 1mol/L sodium hydroxide solution; adding 36.08g of ethyl acetate, separating, taking an organic phase, extracting a water layer by using 36.08g of ethyl acetate, combining the organic phases, and washing by using 20.00g of water; the solvent was removed by concentration under reduced pressure to give 3-methyl-5-aminopiperidine (6.74g, yield 75%, yellow oil) with a protecting group.
Product of 1 H-NMR data were as follows:
1 H-NMR(400MHz,CDCl 3 )ppmδ7.43-7.18(m,5H),5.24-5.01(m,2H),3.75(d,J＝47.0Hz,1H),3.59-3.38(m,1H),3.37-3.15(m,1H),3.14-2.94(m,1H),2.76(d,J＝50.3Hz,1H),2.37-2.00(m,1H),1.68-1.48(m,1H),1.45-1.29(m,1H),0.88(d,J＝6.8Hz,3H)。
all documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or 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 appended claims of the present application.
Claims (10)
1. A process for the preparation of a compound of formula (a), said process comprising the steps of:
wherein, the Acid is HCl, HBr or the combination thereof;
R 1 is C1-C4 alkyl;
r is an amino protecting group;
(i) carrying out catalytic hydrogenation on the compound of the formula (b) in an organic solvent in the presence of a catalyst to obtain a compound of the formula (C), wherein the catalyst is Pd-C or Ru-C; the organic solvent is an alcohol solvent; the reaction temperature is 40-80 ℃;
(ii) reacting a compound of formula (c) with an amino protecting reagent in the presence of a base, optionally in an organic solvent, to give a compound of formula (d);
(iii) reacting the compound of the formula (d) with halogen and a base to obtain the compound of the formula (a).
2. The method of claim 1, wherein the Acid is HCl.
3. The method of claim 1, wherein R is benzyloxycarbonyl or tert-butoxycarbonyl.
4. The method of claim 1, wherein R is 1 Is methyl.
5. The process of claim 1, wherein in step (i), said catalytic hydrogenation comprises: in the hydrogenation of H 2 The catalytic hydrogenation is carried out under the pressure of 1-10 MPa.
6. The process of claim 1, wherein in step (i), the catalysis is catalytic hydrogenation in the presence of Pd-C.
7. The method of claim 1, wherein in step (i), the organic solvent is methanol, ethanol, isopropanol, propanol, butanol, ethylene glycol, or a combination thereof.
8. The method of claim 1, wherein in step (ii), the amino protecting reagent is benzyl chloroformate, di-tert-butyl dicarbonate; the base is an organic base, a carbonate, a bicarbonate, or a combination thereof; the reaction is carried out at a temperature of-10 to 25 ℃.
9. The method of claim 1, wherein in step (iii), said halogen is selected from the group consisting of: liquid bromine, chlorine; and/or the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, cesium hydroxide, or combinations thereof.
10. A process for the preparation of an N-protected 3-amino-5-substituted piperidine, said process comprising the steps of:
(1) preparing a compound of formula (a) using a compound of formula (d); and
(2) reacting a compound of formula (a) to produce an N-protected 3-amino-5-substituted piperidine;
wherein R is 1 Is C1-4 alkyl;
r is an amino protecting group;
and, the method further comprises the steps of: a compound of formula (d) is prepared using the process of claim 1.
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