Asymmetric syntheses method and correlated intermediate of (R)-3-aminopiperidine (I)

Abstract

The invention relates to an asymmetric syntheses method of (R)-3-aminopiperidine (I). The method comprises: reducing a formula (III) compound to obtain a formula (II) compound, and then removing a chiral prosthetic group and an amino protective group from the formula (II) compound to obtain (R)-3-aminopiperidine (I), wherein R is the amino protective group, and specially is C1-4 alkoxycarbonyl or benzyl removable by hydrolysis or hydrogenation. Preferably, the formula (III) compound is obtained by performing a dehydration reaction on 3-piperidone and a chiral amine (R)-1-phenylethylamine. The invention also relates to a new compound (II). The asymmetric syntheses method of (R)-3-aminopiperidine (I) is reasonable in technology and concise in route, the needed product with relatively high ee value is obtained by utilizing chiral induction, the raw material is cheap and does not need resolving, no waste isomer is discharged, and the asymmetric synthesis method is applicable to large-scale industrial production.

Description

technical field

[0001] The present invention relates to the technical field of (R)-3-aminopiperidine, more specifically, to the technical field of chemical synthesis of (R)-3-aminopiperidine, in particular to a kind of (R)-3-aminopiperidine (I ) asymmetric synthesis method and related intermediates. Background technique

[0002] (R)-3-aminopiperidine (I) is an important pharmaceutical intermediate, mainly used to synthesize dipeptidyl peptidase-IV (DPP-IV) inhibitors, such as alogliptin (Alogliptin), which is used to Antihyperglycemic drugs such as Linagliptin. So far, there are many reports on the synthesis of (R)-3-aminopiperidine (I).

[0003]

[0004] In PCT patent application publications WO2007075630 and WO2008028654, 3-aminopyridine is used as a starting material to obtain (R)-3-aminopiperidine dihydrochloride through catalytic oxidation, resolution and salification, as shown in reaction scheme 1 . Although this method has a simple route, the catalytic hydrogen...

Examples

Embodiment 1

[0034] Example 1: Preparation of (R)-3-((R)-1-phenylethyl)aminopiperidine-1-carboxylic acid tert-butyl ester (1-3)

[0035]

[0036] Under nitrogen protection, 10.0 g of 1-tert-butoxycarbonylpiperidin-3-one (1-1) (Changzhou Daou Chemical Co., Ltd.) and R-(+)-α-methylbenzylamine (1-2 ) (Guangde Keyuan Chemical Co., Ltd.) 7.3g was added to 60mL ethanol, and refluxed at 80°C for 3 hours. After the reaction is completed, the temperature is lowered to room temperature, 1.0 g of Ranny-Ni (Raney nickel) is added to the system, and the reaction is carried out at room temperature under a pressure of 30 kg for 48 hours. After the reaction is completed, filter with a sand core funnel with diatomaceous earth, spin the filtrate, and purify by column chromatography to obtain a light yellow liquid (R)-3-((R)-1-phenylethyl)aminopiperidine-1 - tert-butyl carboxylate (1-3) 12.4 g, de value: 93.2%. The obtained compound (1-3) was salted and crystallized with oxalic acid to obtain 13.7 g of ...

Embodiment 2

[0037] Example 2: Preparation of (R)-1-benzyl-N-((R)-1-phenylethyl)piperidin-3-amine (2-2)

[0038]

[0039]Under nitrogen protection, 5.0 g of 1-benzylpiperidin-3-one (2-1) (Changzhou Daou Chemical Co., Ltd.) and R-(+)-α-methylbenzylamine (1-2) ( Guangde Keyuan Chemical Co., Ltd.) 4.0g was added to 50mL benzene, refluxed at 80°C for 3 hours to separate water. After the reaction was completed, the temperature was lowered to room temperature, 1.0 g of palladium carbon was added to the system, and 40 kg of pressure was reacted at room temperature for 48 hours. After the reaction is completed, filter with a sand core funnel lined with diatomaceous earth, spin the filtrate, and purify by column chromatography to obtain a light yellow liquid (R)-1-benzyl-N-((R)-1-phenylethyl) Piperidin-3-amine (2-2) 6.4 g, de value: 35%. The obtained compound (2-2) was salted and crystallized with oxalic acid to obtain 4.5 g of white oxalate crystals, the total yield: 44.3%, de value: 98.4%. ...

Embodiment 3

[0040] Example 3: Preparation of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (3-1)

[0041]

[0042] Add (R)-3-((R)-1-phenylethyl)aminopiperidine-1-carboxylate tert-butyl ester (1-3) 10.0g and Pd / C 1.0g to 40mL ethanol and 40mL acetic acid In the mixed solution, 30 kilograms of pressures were reacted at room temperature for 48 hours. After the reaction was completed, filter with a sand core funnel lined with diatomaceous earth, and spin the filtrate to obtain 5.4 g of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (3-1) as a light yellow viscous liquid. Yield: 82.1%, the product is directly used in the next step. 1 H NMR (400MHz, CDCl 3 )δ7.96(s,6H),4.03(d,J=11.6Hz,1H),3.74(d,J=6.7Hz,1H),3.12(s,1H),3.04-2.84(m,2H), 1.73(s,1H),1.56(dd,J=24.6,11.9Hz,2H),1.45(s,9H),1.36-1.16(m,2H).MS(ESI)m / z=201(M + +1).

technical field

[0001] The present invention relates to the technical field of (R)-3-aminopiperidine, more specifically, to the technical field of chemical synthesis of (R)-3-aminopiperidine, in particular to a kind of (R)-3-aminopiperidine (I ) asymmetric synthesis method and related intermediates. Background technique

[0002] (R)-3-aminopiperidine (I) is an important pharmaceutical intermediate, mainly used to synthesize dipeptidyl peptidase-IV (DPP-IV) inhibitors, such as alogliptin (Alogliptin), which is used to Antihyperglycemic drugs such as Linagliptin. So far, there are many reports on the synthesis of (R)-3-aminopiperidine (I).

[0003]

[0004] In PCT patent application publications WO2007075630 and WO2008028654, 3-aminopyridine is used as a starting material to obtain (R)-3-aminopiperidine dihydrochloride through catalytic oxidation, resolution and salification, as shown in reaction scheme 1 . Although this method has a simple route, the catalytic hydrogen...

Examples

Embodiment 1

[0034] Example 1: Preparation of (R)-3-((R)-1-phenylethyl)aminopiperidine-1-carboxylic acid tert-butyl ester (1-3)

[0035]

[0036] Under nitrogen protection, 10.0 g of 1-tert-butoxycarbonylpiperidin-3-one (1-1) (Changzhou Daou Chemical Co., Ltd.) and R-(+)-α-methylbenzylamine (1-2 ) (Guangde Keyuan Chemical Co., Ltd.) 7.3g was added to 60mL ethanol, and refluxed at 80°C for 3 hours. After the reaction is completed, the temperature is lowered to room temperature, 1.0 g of Ranny-Ni (Raney nickel) is added to the system, and the reaction is carried out at room temperature under a pressure of 30 kg for 48 hours. After the reaction is completed, filter with a sand core funnel with diatomaceous earth, spin the filtrate, and purify by column chromatography to obtain a light yellow liquid (R)-3-((R)-1-phenylethyl)aminopiperidine-1 - tert-butyl carboxylate (1-3) 12.4 g, de value: 93.2%. The obtained compound (1-3) was salted and crystallized with oxalic acid to obtain 13.7 g of ...

Embodiment 2

[0037] Example 2: Preparation of (R)-1-benzyl-N-((R)-1-phenylethyl)piperidin-3-amine (2-2)

[0038]

[0039]Under nitrogen protection, 5.0 g of 1-benzylpiperidin-3-one (2-1) (Changzhou Daou Chemical Co., Ltd.) and R-(+)-α-methylbenzylamine (1-2) ( Guangde Keyuan Chemical Co., Ltd.) 4.0g was added to 50mL benzene, refluxed at 80°C for 3 hours to separate water. After the reaction was completed, the temperature was lowered to room temperature, 1.0 g of palladium carbon was added to the system, and 40 kg of pressure was reacted at room temperature for 48 hours. After the reaction is completed, filter with a sand core funnel lined with diatomaceous earth, spin the filtrate, and purify by column chromatography to obtain a light yellow liquid (R)-1-benzyl-N-((R)-1-phenylethyl) Piperidin-3-amine (2-2) 6.4 g, de value: 35%. The obtained compound (2-2) was salted and crystallized with oxalic acid to obtain 4.5 g of white oxalate crystals, the total yield: 44.3%, de value: 98.4%. ...

Embodiment 3

[0040] Example 3: Preparation of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (3-1)

[0041]

[0042] Add (R)-3-((R)-1-phenylethyl)aminopiperidine-1-carboxylate tert-butyl ester (1-3) 10.0g and Pd / C 1.0g to 40mL ethanol and 40mL acetic acid In the mixed solution, 30 kilograms of pressures were reacted at room temperature for 48 hours. After the reaction was completed, filter with a sand core funnel lined with diatomaceous earth, and spin the filtrate to obtain 5.4 g of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (3-1) as a light yellow viscous liquid. Yield: 82.1%, the product is directly used in the next step. 1 H NMR (400MHz, CDCl 3 )δ7.96(s,6H),4.03(d,J=11.6Hz,1H),3.74(d,J=6.7Hz,1H),3.12(s,1H),3.04-2.84(m,2H), 1.73(s,1H),1.56(dd,J=24.6,11.9Hz,2H),1.45(s,9H),1.36-1.16(m,2H).MS(ESI)m / z=201(M + +1).

Images