CN115073422A - Method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salt thereof - Google Patents

Method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salt thereof Download PDF

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CN115073422A
CN115073422A CN202210901377.9A CN202210901377A CN115073422A CN 115073422 A CN115073422 A CN 115073422A CN 202210901377 A CN202210901377 A CN 202210901377A CN 115073422 A CN115073422 A CN 115073422A
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罗建业
李海叶
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Chengdu Purexi Pharmaceutical Co ltd
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    • C07D401/00—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
    • C07D401/02—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
    • 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 method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salts thereof, belonging to the field of chemical medicines. The preparation method provided by the invention has the advantages of easily available raw materials, short steps, low cost, convenient and safe process operation, high total yield, environmental friendliness and suitability for industrial production.

Description

Method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salt thereof
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salts thereof.
Background
4- (1-methyl-1H-pyrazol-5-yl) piperidine (structure shown below), CAS number: 640270-01-5, is an important chemical synthesis intermediate. For example, patent publication No. US9593106B2 discloses that 4- (1-methyl-1H-pyrazol-5-yl) piperidine may be used as an intermediate in the preparation of muscarinic M4 receptor agonists, which M4 receptor agonists can be used for the treatment of schizophrenia, alzheimer's disease and the respective cognitive disorders as well as for pain relief. Therefore, the development of a method suitable for industrial production to prepare the 4- (1-methyl-1H-pyrazol-5-yl) piperidine and the salt thereof has important significance.
Figure BDA0003771027350000011
However, no reports have been made on the preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salts thereof.
Disclosure of Invention
The object of the present invention is to provide a process for the preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salts thereof.
The invention provides a method for preparing a salt of 4- (1-methyl-1H-pyrazol-5-yl) piperidine, which is characterized by comprising the following steps: the method comprises the following steps:
(1) reacting the compound A with the compound B in the presence of a lithiation reagent to obtain a compound C;
Figure BDA0003771027350000012
wherein R is 1 Is an amino protecting group;
(2) carrying out dehydration reaction on the compound C to obtain a compound D;
Figure BDA0003771027350000013
(3) carrying out hydrogenation reaction on the compound D in a hydrogen atmosphere to obtain a compound E;
Figure BDA0003771027350000021
(4) reacting the compound E in an acid solution to obtain a target compound F;
Figure BDA0003771027350000022
wherein n is selected from 1,2 and 3, and X is acid.
Further, in the step (1), the amino protecting group is tert-butyloxycarbonyl; the lithiation reagent is n-butyllithium, and the molar ratio of the compound A to the compound B to the lithiation reagent is 1 (1.0-1.2) to 1.1-1.3; the solvent of the reaction is an organic solvent; the reaction temperature is-90 to-50 ℃, and the reaction time is 1-4 h.
Further, in the step (1), the molar ratio of the compound A to the compound B to the lithiation reagent is 1:1.1: 1.2; the organic solvent is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether and diethyl ether, and tetrahydrofuran is preferred; the reaction temperature is-70 ℃ and the reaction time is 2-3 h;
preferably, the feeding mode of the step (1) is as follows: firstly, the solution of a lithiation reagent is dripped into the solution of the compound A at the temperature of between 50 ℃ below zero and 70 ℃ below zero, and then the solution of the compound B is dripped into the solution of the compound A at the temperature of between 50 ℃ below zero and 70 ℃ below zero; the solvent in the solution is the solvent for the reaction.
Further, in the step (2), the dehydration reaction is carried out under the action of acid; the molar ratio of the compound C to the acid is 1 (4-6); the solvent of the reaction is an organic solvent; the reaction temperature is 20-40 ℃ and the reaction time is 8-14 h.
Further, in the step (2), the acid is one or a mixture of more than two of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and methanesulfonic acid, and is preferably hydrochloric acid; the molar ratio of the compound C to the acid is 1: 5; the organic solvent is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene and methyl tert-butyl ether, preferably tetrahydrofuran; the reaction temperature is room temperature, and the reaction time is 10-12 h.
Further, in the step (3), the reaction is carried out under the action of a catalyst, wherein the catalyst is one or a mixture of more than two of palladium carbon, rhodium carbon and ruthenium carbon; the mass ratio of the compound D to the catalyst is 1: 0.03-0.05; the solvent for the reaction is an organic solvent; the reaction temperature is 40-60 ℃, the reaction time is 2-6h, and the reaction pressure is 0.5-2.5 MPa.
Further, in the step (3), the catalyst is palladium carbon; the mass ratio of the compound D to the catalyst is 1: 0.04; the organic solvent is one or a mixture of more than two of tetrahydrofuran, methanol, ethanol, methyl tert-butyl ether and toluene, preferably ethanol; the reaction temperature is 50 ℃, the reaction time is 3-4h, and the reaction pressure is 1-2 MPa.
Further, in the step (4), the reaction is carried out under an inert gas atmosphere; the acid is one or a mixture of more than two of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and methanesulfonic acid; a solvent organic solvent for the reaction; the molar ratio of the compound E to the acid is 1: (4-6); the reaction temperature is 20-40 ℃ and the reaction time is 2-6 h.
Further, in the step (4), the acid is hydrochloric acid; the organic solvent is one or a mixture of more than two of methanol, ethanol, isopropanol, ethyl acetate and methyl tert-butyl ether, preferably a mixture of ethanol and methyl tert-butyl ether; the molar ratio of the compound E to the acid is 1: 5; the reaction temperature is 30 ℃ and the reaction time is 3-4 h.
The present invention also provides a process for the preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine, comprising the steps of: the salt of 4- (1-methyl-1H-pyrazol-5-yl) piperidine is prepared according to the method, and is added with alkali to react to obtain the 4- (1-methyl-1H-pyrazol-5-yl) piperidine.
Further, the pH value of the reaction after the addition of the base is 8 to 10, preferably 9.
In the present invention, "room temperature" means 25. + -. 5 ℃.
The invention takes 1-methylpyrazole and N-tert-butyloxycarbonyl-4-piperidone as starting materials, and obtains 4- (1-methyl-1H-pyrazol-5-yl) piperidine or 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride through 4 steps of reaction. The preparation method provided by the invention has the advantages of easily available raw materials, short steps, low cost, convenient and safe process operation, high total yield, environmental friendliness and suitability for industrial production.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
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FIG. 1 shows a nuclear magnetic spectrum of 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine.
FIG. 2 shows the nuclear magnetic spectrum of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine.
FIG. 3 shows a nuclear magnetic spectrum of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine.
FIG. 4 is a nuclear magnetic spectrum of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1: preparation method of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
The preparation method of the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride comprises four steps as follows:
Figure BDA0003771027350000031
(1) preparation of 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-methylpyrazole (41.2g, 1.0eq) and tetrahydrofuran (300g) are added into a three-necked flask, N-butyllithium solution (240ml, 2.5mol/L, 1.2eq) is dropwise added at-70 ℃, the reaction is kept for 3 hours after the dropwise addition is finished, then tetrahydrofuran (100g) solution of N-tert-butoxycarbonyl-4-piperidone (110g, 1.1eq) is dropwise added into the reaction system, and the reaction is carried out for 3 hours at-70 ℃ after the dropwise addition is finished. After the reaction is finished, slowly adding the reaction system into water, separating an organic phase, extracting the product from an aqueous phase by using ethyl acetate (500g), combining the organic phases, concentrating until the organic phase is dry, and performing column chromatography (an eluent is a mixed solution of PE: EA (10: 1) in volume ratio) to obtain 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine, wherein the yield is as follows: 90 percent.
Nuclear magnetic detection: 1 H-NMR (400MHz in DMSO) < delta > 7.26(1H, d),6.11(1H, d),5.37(1H, d), 3.95(2H, d), 3.78(3H, s),3.15(2H, d), 1.87(2H, d),1.74(2H, d),1.40(9H, s). The nuclear magnetic spectrum is shown in FIG. 1.
(2) Preparation of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine
Dissolving 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine (100g, 1.0eq) prepared in the step (1) in tetrahydrofuran (200g), cooling to 0 ℃, slowly adding concentrated hydrochloric acid (177g, 5eq) with the concentration of 36% into a reaction system, returning to room temperature for reaction for 10 hours after dropwise addition is finished, adding a potassium carbonate solution to adjust the pH of the system to be 8 after the reaction is finished, then adding di-tert-butyl dicarbonate (93g, 1.2eq), reacting at room temperature for 2 hours, adding ethyl acetate (250g) to extract an organic phase after the reaction is finished, concentrating the organic phase to dryness to obtain 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine, yield: 90 percent.
Nuclear magnetic detection: 1 h NMR (400MHz, DMSO): δ 7.35(1H, d),6.23(1H, d),5.96(1H, d), 4.01(2H, d), 3.81(3H, s),3.51(2H, d), 2.35(2H, d),1.42(9H, s). The nuclear magnetic spectrum is shown in FIG. 2.
(3) Preparation of 1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine (80g, 1.0eq) obtained in step (2) was dissolved in ethanol (240g), and palladium on carbon (3.2g) was added. Pressurizing hydrogen to 2MPa, raising the temperature of the system to 50 ℃, reacting for 4H, cooling to room temperature after the reaction of the raw materials is finished, filtering the system, and concentrating an organic phase to dryness to obtain the 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine. Yield: 100 percent.
Nuclear magnetic detection: 1 h NMR (400MHz in DMSO) < delta > 7.27(1H, d),6.05(1H, d),4.04(2H, d), 3.76(3H, s),2.90(2H, d),2.84(1H, t),1.83(2H, d),1.41(9H, s),1.35(2H, d). The nuclear magnetic spectrum is shown in FIG. 3.
(4) Preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
Dissolving 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine (50g, 1.0eq) obtained in step (3) in methyl tert-butyl ether (300g), and adding a hydrogen chloride ethanol solution (23g, 5.0eq) dropwise. Under the protection of nitrogen, the temperature of the system is raised to 30 ℃, the reaction is carried out for 4 hours, after the reaction of the raw materials is finished, the temperature is reduced to room temperature, a large amount of solid is separated out, the mixture is stirred for a plurality of minutes, filtered and dried, and the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride is obtained. Yield: 85% and 98% HPLC purity.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO+D 2 o). delta.7.66 (1H, d),6.27(1H, d),3.89(3H, s),3.35(2H, d),3.17(1H, t),3.03(2H, d),2.02(2H, d),1.85(2H, d). The nuclear magnetic spectrum is shown in FIG. 4.
Example 2: preparation method of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
The preparation method of the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride comprises four steps as follows:
Figure BDA0003771027350000051
(1) preparation of 1-tert-butyloxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-methylpyrazole (41.2g, 1.0eq) and tetrahydrofuran (300g) are added into a three-necked flask, N-butyllithium solution (240ml, 2.5mol/L, 1.2eq) is dropwise added at-50 ℃, the reaction is kept for 3 hours after the dropwise addition is finished, then tetrahydrofuran (100g) solution of N-tert-butoxycarbonyl-4-piperidone (110g, 1.1eq) is dropwise added into the reaction system, and the reaction is carried out for 3 hours at-70 ℃ after the dropwise addition is finished. After the reaction is finished, slowly adding the reaction system into water, separating an organic phase, extracting the product from an aqueous phase by using ethyl acetate (500g), combining the organic phases, concentrating until the organic phase is dry, and performing column chromatography (an eluent is a mixed solution of PE: EA (10: 1) in volume ratio) to obtain 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine, wherein the yield is as follows: 80 percent.
Nuclear magnetic detection: 1 H-NMR(400MHz,DMSO):δ7.26(1H,d),6.11(1H,d),5.37(1H,d)，3.95(2H,d)，3.78(3H,s),3.15(2H,d)，1.87(2H,d),1.74(2H,d),1.40(9H,s)。
(2) preparation of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine
Dissolving 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine (100g, 1.0eq) prepared in the step (1) in tetrahydrofuran (200g), cooling to 0 ℃, slowly adding concentrated hydrochloric acid (177g, 5eq) with the concentration of 36% into a reaction system, reacting at 0 ℃ for 10 hours, adding a potassium carbonate solution to adjust the pH of the system to 8 after the reaction is finished, adding di-tert-butyl dicarbonate (93g, 1.2eq) to react at room temperature for 2 hours, adding ethyl acetate (250g) to extract an organic phase after the reaction is finished, concentrating the organic phase to dryness to obtain 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine, yield: 70 percent.
Nuclear magnetic detection: 1 H NMR(400MHz,DMSO)：δ7.35(1H,d),6.23(1H,d),5.96(1H,d)，4.01(2H,d)，3.81(3H,s),3.51(2H,d)，2.35(2H,d),1.42(9H,s)。
(3) preparation of 1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine (80g, 1.0eq) obtained in step (2) was dissolved in ethanol (240g), and palladium on carbon (3.2g) was added. Pressurizing hydrogen to 2MPa, raising the temperature of the system to 30 ℃, reacting for 4H, cooling to room temperature after the reaction of the raw materials is finished, filtering the system, and concentrating an organic phase to dryness to obtain the 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine. Yield: 95 percent.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO):δ7.27(1H,d),6.05(1H,d),4.04(2H,d)，3.76(3H,s),2.90(2H,d),2.84(1H,t),1.83(2H,d),1.41(9H,s),1.35(2H,d)。
(4) preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
Dissolving 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine (50g, 1.0eq) obtained in step (3) in methyl tert-butyl ether (300g), and dropwise adding a hydrogen chloride ethanol solution (23g, 5.0 eq). Under the protection of nitrogen, the temperature of the system is raised to 50 ℃, the reaction is carried out for 4 hours, after the reaction of the raw materials is finished, the temperature is reduced to room temperature, a large amount of solid is separated out, the mixture is stirred for a plurality of minutes, filtered and dried, and the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride is obtained. Yield: 80% and 98% HPLC purity.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO+D 2 O):δ7.66(1H,d),6.27(1H,d),3.89(3H,s),3.35(2H,d),3.17(1H,t),3.03(2H,d),2.02(2H,d),1.85(2H,d)。
example 3: preparation method of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
The preparation method of the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride comprises four steps as follows:
Figure BDA0003771027350000061
(1) preparation of 1-tert-butyloxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-methylpyrazole (41.2g, 1.0eq) and tetrahydrofuran (300g) are added into a three-necked flask, an N-butyllithium solution (220ml,2.5mol/L,1.1eq) is dropwise added at-70 ℃, after the dropwise addition is finished, the reaction is kept for 3 hours, then an N-tert-butoxycarbonyl-4-piperidone (110g, 1.1eq) tetrahydrofuran (100g) solution is dropwise added into the reaction system, and after the dropwise addition is finished, the reaction is carried out for 3 hours at-70 ℃. After the reaction is finished, slowly adding the reaction system into water, separating an organic phase, extracting the product from an aqueous phase by using ethyl acetate (500g), combining the organic phases, concentrating until the organic phase is dry, and performing column chromatography (an eluent is a mixed solution of PE: EA (10: 1) in volume ratio) to obtain 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine, wherein the yield is as follows: 85 percent.
Nuclear magnetic detection: 1 H-NMR(400MHz,DMSO):δ7.26(1H,d),6.11(1H,d),5.37(1H,d)，3.95(2H,d)，3.78(3H,s),3.15(2H,d)，1.87(2H,d),1.74(2H,d),1.40(9H,s)。
(2) preparation of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine
Dissolving 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine (100g, 1.0eq) prepared in the step (1) in tetrahydrofuran (200g), cooling to 0 ℃, slowly adding concentrated hydrochloric acid (106g, 3eq) with the concentration of 36% into a reaction system, returning to room temperature for reaction for 10 hours after dropwise addition is finished, adding a potassium carbonate solution to adjust the pH of the system to be 8 after the reaction is finished, then adding di-tert-butyl dicarbonate (93g, 1.2eq), reacting at room temperature for 2 hours, adding ethyl acetate (250g) to extract an organic phase after the reaction is finished, concentrating the organic phase to dryness to obtain 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine, yield: 65 percent.
Nuclear magnetic detection: 1 H NMR(400MHz,DMSO)：δ7.35(1H,d),6.23(1H,d),5.96(1H,d)，4.01(2H,d)，3.81(3H,s),3.51(2H,d)，2.35(2H,d),1.42(9H,s)。
(3) preparation of 1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine (80g, 1.0eq) obtained in step (2) was dissolved in ethanol (240g), and palladium on carbon (1.0g) was added. Pressurizing hydrogen to 2MPa, raising the temperature of the system to 50 ℃, reacting for 4H, cooling to room temperature after the reaction of the raw materials is finished, filtering the system, and concentrating an organic phase to dryness to obtain the 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine. Yield: 85 percent.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO):δ7.27(1H,d),6.05(1H,d),4.04(2H,d)，3.76(3H,s),2.90(2H,d),2.84(1H,t),1.83(2H,d),1.41(9H,s),1.35(2H,d)。
(4) preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride
1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine (50g, 1.0eq) obtained in step (3) was dissolved in methyl tert-butyl ether (300g), and a hydrogen chloride ethanol solution (13.8g, 3.0eq) was added dropwise. Under the protection of nitrogen, the temperature of the system is raised to 30 ℃, the reaction is carried out for 4 hours, after the reaction of the raw materials is finished, the temperature is reduced to room temperature, a large amount of solid is separated out, the mixture is stirred for a plurality of minutes, filtered and dried, and the 4- (1-methyl-1H-pyrazol-5-yl) piperidine hydrochloride is obtained. Yield: 70% and 98% HPLC purity.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO+D 2 O):δ7.66(1H,d),6.27(1H,d),3.89(3H,s),3.35(2H,d),3.17(1H,t),3.03(2H,d),2.02(2H,d),1.85(2H,d)。
example 4: preparation method of 4- (1-methyl-1H-pyrazol-5-yl) piperidine
The preparation method of the 4- (1-methyl-1H-pyrazol-5-yl) piperidine comprises four steps as follows:
Figure BDA0003771027350000071
(1) preparation of 1-tert-butyloxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-methylpyrazole (41.2g, 1.0eq) and tetrahydrofuran (300g) are added into a three-necked flask, an N-butyllithium solution (220ml,2.5mol/L,1.1eq) is dropwise added at-70 ℃, after the dropwise addition is finished, the reaction is kept for 3 hours, then an N-tert-butoxycarbonyl-4-piperidone (110g, 1.1eq) tetrahydrofuran (100g) solution is dropwise added into the reaction system, and after the dropwise addition is finished, the reaction is carried out for 3 hours at-70 ℃. After the reaction is finished, slowly adding the reaction system into water, separating an organic phase, extracting the product from an aqueous phase by using ethyl acetate (500g), combining the organic phases, concentrating until the organic phase is dry, and performing column chromatography (an eluent is a mixed solution of PE: EA (10: 1) in volume ratio) to obtain 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine, wherein the yield is as follows: 85 percent.
Nuclear magnetic detection: 1 H-NMR(400MHz,DMSO):δ7.26(1H,d),6.11(1H,d),5.37(1H,d)，3.95(2H,d)，3.78(3H,s),3.15(2H,d)，1.87(2H,d),1.74(2H,d),1.40(9H,s)。
(2) preparation of 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine
Dissolving 1-tert-butoxycarbonyl-4-hydroxy-4- (1-methyl-1H-pyrazol-5-yl) piperidine (100g, 1.0eq) prepared in the step (1) in tetrahydrofuran (200g), cooling to 0 ℃, slowly adding concentrated hydrochloric acid (106g, 3eq) with the concentration of 36% into a reaction system, returning to room temperature for reaction for 10 hours after dropwise addition is finished, adding a potassium carbonate solution to adjust the pH of the system to be 8 after the reaction is finished, then adding di-tert-butyl dicarbonate (93g, 1.2eq), reacting at room temperature for 2 hours, adding ethyl acetate (250g) to extract an organic phase after the reaction is finished, concentrating the organic phase to dryness to obtain 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine, yield: 65 percent.
Nuclear magnetic detection: 1 H NMR(400MHz,DMSO)：δ7.35(1H,d),6.23(1H,d),5.96(1H,d)，4.01(2H,d)，3.81(3H,s),3.51(2H,d)，2.35(2H,d),1.42(9H,s)。
(3) preparation of 1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-tert-Butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) -1,2,3, 6-tetrahydropyridine (80g, 1.0eq) obtained in step (2) was dissolved in ethanol (240g), and palladium on carbon (1.0g) was added. Pressurizing hydrogen to 2MPa, raising the temperature of the system to 50 ℃, reacting for 4H, cooling to room temperature after the reaction of the raw materials is finished, filtering the system, and concentrating an organic phase to dryness to obtain the 1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine. Yield: 85 percent.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO):δ7.27(1H,d),6.05(1H,d),4.04(2H,d)，3.76(3H,s),2.90(2H,d),2.84(1H,t),1.83(2H,d),1.41(9H,s),1.35(2H,d)。
(4) preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine
1-tert-butoxycarbonyl-4- (1-methyl-1H-pyrazol-5-yl) piperidine (50g, 1.0eq) obtained in step (3) was dissolved in methyl tert-butyl ether (300g), and a hydrogen chloride ethanol solution (13.8g, 3.0eq) was added dropwise. Under the protection of nitrogen, raising the temperature of the system to 30 ℃, reacting for 4H, after the reaction of the raw materials is finished, cooling to room temperature, adding a potassium carbonate solution to adjust the pH of the system to be 9, extracting the product by using ethyl acetate (500g), concentrating an organic phase to be dry, and carrying out column chromatography (an eluent is a mixed solution of PE: EA with a volume ratio of 5: 1) to obtain 4- (1-methyl-1H-pyrazol-5-yl) piperidine. Yield: 70% and 98% HPLC purity.
Nuclear magnetic detection: 1 H NMR(400MHz，DMSO+D 2 O):δ7.66(1H,d),6.27(1H,d),3.89(3H,s),3.35(2H,d),3.17(1H,t),3.03(2H,d),2.02(2H,d),1.85(2H,d)。
in conclusion, the invention provides a novel method for preparing the salt of 4- (1-methyl-1H-pyrazol-5-yl) piperidine, the method adopts common reagents as raw materials, has the advantages of low raw material cost, short synthesis process, high yield, no harsh reaction conditions, safety, convenient operation, environmental friendliness and suitability for large-scale industrial production.

Claims (10)

1. A process for preparing a salt of 4- (1-methyl-1H-pyrazol-5-yl) piperidine, characterized in that: the method comprises the following steps:
(1) reacting the compound A with the compound B in the presence of a lithiation reagent to obtain a compound C;
Figure FDA0003771027340000011
wherein R is 1 Is an amino protecting group;
(2) carrying out dehydration reaction on the compound C to obtain a compound D;
Figure FDA0003771027340000012
(3) carrying out hydrogenation reaction on the compound D in a hydrogen atmosphere to obtain a compound E;
Figure FDA0003771027340000013
(4) reacting the compound E in an acid solution to obtain a target compound F;
Figure FDA0003771027340000014
wherein n is selected from 1,2 and 3, and X is acid.
2. The method of claim 1, wherein: in the step (1), the amino protecting group is tert-butyloxycarbonyl; the lithiation reagent is n-butyl lithium, and the molar ratio of the compound A to the compound B to the lithiation reagent is 1 (1.0-1.2) to 1.1-1.3; the solvent of the reaction is an organic solvent; the reaction temperature is-90 to-50 ℃ and the reaction time is 1 to 4 hours.
3. The method of claim 2, wherein: in the step (1), the molar ratio of the compound A to the compound B to the lithiation reagent is 1:1.1: 1.2; the organic solvent is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether and diethyl ether, and tetrahydrofuran is preferred; the reaction temperature is-70 ℃ and the reaction time is 2-3 h;
preferably, the feeding mode of the step (1) is as follows: firstly, the solution of a lithiation reagent is dripped into the solution of the compound A at the temperature of between 50 ℃ below zero and 70 ℃ below zero, and then the solution of the compound B is dripped into the solution of the compound A at the temperature of between 50 ℃ below zero and 70 ℃ below zero; the solvent in the solution is the solvent for the reaction.
4. The method of claim 1, wherein: in the step (2), the dehydration reaction is carried out under the action of acid; the molar ratio of the compound C to the acid is 1 (4-6); the solvent for the reaction is an organic solvent; the reaction temperature is 20-40 ℃ and the reaction time is 8-14 h.
5. The method of claim 4, wherein: in the step (2), the acid is one or a mixture of more than two of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and methanesulfonic acid, and hydrochloric acid is preferred; the molar ratio of the compound C to the acid is 1: 5; the organic solvent is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene and methyl tert-butyl ether, preferably tetrahydrofuran; the reaction temperature is room temperature, and the reaction time is 10-12 h.
6. The method of claim 1, wherein: in the step (3), the reaction is carried out under the action of a catalyst, wherein the catalyst is one or a mixture of more than two of palladium carbon, rhodium carbon and ruthenium carbon; the mass ratio of the compound D to the catalyst is 1: 0.03-0.05; the solvent of the reaction is an organic solvent; the reaction temperature is 40-60 ℃, the reaction time is 2-6h, and the reaction pressure is 0.5-2.5 MPa.
7. The method of claim 6, wherein: in the step (3), the catalyst is palladium carbon; the mass ratio of the compound D to the catalyst is 1: 0.04; the organic solvent is one or a mixture of more than two of tetrahydrofuran, methanol, ethanol, methyl tert-butyl ether and toluene, preferably ethanol; the reaction temperature is 50 ℃, the reaction time is 3-4h, and the reaction pressure is 1-2 MPa.
8. The method of claim 1, wherein: in the step (4), the reaction is carried out under an inert gas atmosphere; the acid is one or a mixture of more than two of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and methanesulfonic acid; a solvent organic solvent for the reaction; the molar ratio of the compound E to the acid is 1: (4-6); the reaction temperature is 20-40 ℃ and the reaction time is 2-6 h.
9. The method of claim 8, wherein: in the step (4), the acid is hydrochloric acid; the organic solvent is one or a mixture of more than two of methanol, ethanol, isopropanol, ethyl acetate and methyl tert-butyl ether, preferably a mixture of ethanol and methyl tert-butyl ether; the molar ratio of the compound E to the acid is 1: 5; the reaction temperature is 30 ℃ and the reaction time is 3-4 h.
10. A process for the preparation of 4- (1-methyl-1H-pyrazol-5-yl) piperidine, characterized in that: the method comprises the following steps: a salt of 4- (1-methyl-1H-pyrazol-5-yl) piperidine prepared according to the process of any one of claims 1 to 9 is reacted with a base to give 4- (1-methyl-1H-pyrazol-5-yl) piperidine.
CN202210901377.9A 2022-07-28 2022-07-28 Method for preparing 4- (1-methyl-1H-pyrazol-5-yl) piperidine and salt thereof Pending CN115073422A (en)

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US20040002504A1 (en) * 2002-04-18 2004-01-01 Chambers Mark Stuart N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
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CN105121425A (en) * 2013-03-15 2015-12-02 安吉奥斯医药品有限公司 Therapeutic compounds and compositions
CN105189482A (en) * 2013-02-07 2015-12-23 武田药品工业株式会社 Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040002504A1 (en) * 2002-04-18 2004-01-01 Chambers Mark Stuart N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
CN102947295A (en) * 2010-04-29 2013-02-27 爱丁堡大学 3,3-disubstituted-(8-aza-bicyclo [3.2.1]oct-8-y)-[5-(1 -pyrazol-4-yl)-thiophe-3-yl] methanones as inhibitors of 11[beta]-HSD1
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