# US 8,772,497 B2 · Method for producing 1, 2-dihydropyridine-2-one compound

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- Number: US 8,772,497 B2
- Document ID: US8772497B2
- Status: Granted
- Kind: B2
- Application number: 12/870,507
- Filed: 2010-08-27
- Published: 2010-12-23
- Granted: 2014-07-08
- Earliest claimed: 2004-07-06
- Assignees: Eisai R&D Management Co., Ltd.
- Applicants: Itaru Arimoto; Satoshi Nagato; Yukiko Sugaya; Yoshio Urawa; Koichi Ito; Hiroyuki Naka; Takao Omae; Akio Kayano; Katsutoshi Nishiura
- Inventors: Itaru Arimoto; Satoshi Nagato; Yukiko Sugaya; Yoshio Urawa; Koichi Ito; Hiroyuki Naka; Takao Omae; Akio Kayano; Katsutoshi Nishiura
- Web page: https://patentgrep.com/patent/US8772497B2

## CPC

- C07D 213/64: attached in position 2 or 6
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present inventions provide a method for commercially producing a 1,2-dihydropyridine-2-one compound represented by the following formula (III-a) wherein the ring A represents an optionally substituted 2-pyridyl group, the ring B represents an optionally substituted phenyl group, and the ring C represents an optionally substituted phenyl group. Further, the invention provides crystals of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one and production processes therefore.

## Claims

### Claim 1

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a diffraction peak at a diffraction angle (2θ±0.2°) of 8.7° in a powder X-ray diffraction.

### Claim 2

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a diffraction peak at a diffraction angle (2θ±0.2°) of 12.5° in a powder X-ray diffraction.

### Claim 3

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 8.7° and 12.5° in a powder X-ray diffraction.

### Claim 4

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having an absorption peak at a wavenumber of 1588±1 cm−1 in an infrared absorption spectrum (KBr method).

### Claim 5

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 1588±1 cm−1 and 751±1 cm−1 in an infrared absorption spectrum (KBr method).

### Claim 6

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 146.7 ppm and around 123.3 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.

### Claim 7

A process for producing a crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate, the process comprising the step of crystallizing 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one with an aid of one or two crystallization solvents selected from the group consisting of an alcoholic solvent, an alkylketone solvent, and water, wherein the 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate has (a) a diffraction peak at a diffraction angle (2θ±0.2°) of 8.7° in a powder X-ray diffraction, (b) a diffraction peak at a diffraction angle (2θ±0.2°) of 12.5° in a powder X-ray diffraction, (c) diffraction peaks at diffraction angles (2θ±0.2°) of 8.7° and 12.5° in a powder X-ray diffraction, (d) an absorption peak at a wavenumber of 1588±1 cm−1 in an infrared absorption spectrum (KBr method), (e) absorption peaks at wavenumbers of 1588±1 cm−1 and 751±1 cm−1 in an infrared absorption spectrum (KBr method) or, (f) peaks at chemical shifts of around 146.7 ppm and around 123.3 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum, (g) diffraction peaks at diffraction angles (20±0.2°) of 7.78°, 8.70° and 24.19° in a powder X-ray diffraction, (h) diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45° and 24.19° in a powder X-ray diffraction, (i) diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45°, 15.24°, 17.54°, 23.26°, 24.19°, 25.44° and 26.43° in a powder X-ray diffraction, (j) diffraction peaks at diffraction angles (2θ±0.2° of 7.78°, 8.70°, 9.52°, 12.45°, 14.59°, 15.24°, 15.60°, 16.18°, 17.54°, 19.98°, 21.04°, 21.42°, 23.26°, 24.19°, 25.44°, 25.82°, 26.43°, 27.31°, 27.86° and 28.87° in a powder X-ray diffraction, (k) absorption peaks at wavenumbers of 1661.37±1 cm−1, 1482.03±1 cm−1, 1282.43±1 cm−1, 899.63±1 cm−1 and 784.89±1 cm−1 in an infrared absorption spectrum (KBr method), (l) absorption peaks at wavenumbers of 3406.64±1 cm−1, 2217.74±1 cm−1, 1661.37±1 cm−1, 1619.91±1 cm−1, 1588.09±1 cm−1, 1566.88±1 cm−1, 1550.49±1 cm−1, 1482.03±1 cm−1, 1434.78±1 cm−1, 1369.21±1 cm−1, 1318.11±1 cm−1, 1282.43±1 cm−1, 1249.65±1 cm−1, 1157.08±1 cm−1, 1099.23±1 cm−1, 899.63±1 cm−1, 879.38±1 cm−1, 784.89±1 cm−1, 751.14±1 cm−1, 730.89±1 cm−1, 697.14±1 cm−1, 606.50±1 cm−1, 557.33±1 cm−1 and 505.26±1 cm−1 in an infrared absorption spectrum (KBr method), (m) peaks at chemical shifts of around 146.7 ppm, around 139.4 ppm, around 132.7 ppm, around 123.3 ppm, around 120.8 ppm and around 118.4 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum, (n) peaks at chemical shifts of around 159.8 ppm, around 150.8 ppm, around 146.7 ppm, around 139.4 ppm, around 136.6 ppm, around 134.9 ppm, around 132.7 ppm, around 129.0 ppm, around 127.8 ppm, around 126.5 ppm, around 125.8 ppm, around 123.3 ppm, around 120.8 ppm, around 118.4 ppm, around 114.6 ppm and around 108.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum, (o) a powder X-ray diffraction pattern shown in FIG. 4, (p) an infrared spectrum (KBr method) shown in FIG. 1 or (q) a 13C Solid State NMR spectrum shown in FIG. 8.

### Claim 8 (depends on 7)

The process according to claim 7, wherein the crystallization solvent is a mixed solvent of acetone and water.

### Claim 9 (depends on 7)

The process according to claim 7, wherein the crystallization solvent is a mixed solvent of acetone and water with a volume ratio of 37:3 to 24:16.

### Claim 10 (depends on 7)

The process according to claim 7, wherein the crystallization is carried out at a temperature of 60 to −30° C.

### Claim 11 (depends on 7)

The process according to claim 7 comprising the steps of heating a solution of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one dissolved in the crystallization solvent at a temperature of 50° C. or more and thereafter cooling the solution to a temperature of 10 to −20° C. at a cooling rate of 40 to 5° C. per hour.

### Claim 12 (depends on 7)

The process according to claim 7, wherein the crystallization solvent is used in a volume ratio of 10- to 50-fold (v/w) based on the weight of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one.

### Claim 13 (depends on 7)

The process according to claim 7, wherein seed crystals are added at 60° C. or less.

### Claim 14 (depends on 7)

The process according to claim 7, wherein the crystals are dried under reduced pressure after the crystallization.

### Claim 15 (depends on 7)

The process according to claim 7, wherein the crystals are allowed to stand in the atmosphere after the crystallization and the drying under reduced pressure.

### Claim 16

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70° and 24.19° in a powder X-ray diffraction.

### Claim 17

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45° and 24.19° in a powder X-ray diffraction.

### Claim 18

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45°, 15.24°, 17.54°, 23.26°, 24.19°, 25.44° and 26.43° in a powder X-ray diffraction.

### Claim 19

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45°, 14.59°, 15.24°, 15.60°, 16.18°, 17.54°, 19.98°, 21.04°, 21.42°, 23.26°, 24.19°, 25.44°, 25.82°, 26.43°, 27.31°, 27.86° and 28.87° in a powder X-ray diffraction.

### Claim 20

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 1661.37±1 cm−1, 1482.03±1 cm−1, 1282.43±1 cm−1, 899.63±1 cm−1 and 784.89±1 cm−1 in an infrared absorption spectrum (KBr method).

### Claim 21

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 3406.64±1 cm−1, 2217.74±1 cm−1, 1661.37±1 cm−1, 1619.91±1 cm−1, 1588.09±1 cm−1, 1566.88±1 cm−1, 1550.49±1 cm−1, 1482.03±1 cm−1, 1434.78±1 cm−1, 1369.21±1 cm−1, 1318.11±1 cm−1, 1282.43±1 cm−1, 1249.65±1 cm−1, 1157.08±1 cm−1, 1099.23±1 cm−1, 899.63±1 cm−1, 879.38±1 cm−1, 784.89±1 cm−1, 751.14±1 cm−1, 730.89±1 cm−1, 697.14±1 cm−1, 606.50±1 cm−1, 557.33±1 cm−1 and 505.26±1 cm−1 in an infrared absorption spectrum (KBr method).

### Claim 22

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 146.7 ppm, around 139.4 ppm, around 132.7 ppm, around 123.3 ppm, around 120.8 ppm and around 118.4 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.

### Claim 23

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 159.8 ppm, around 150.8 ppm, around 146.7 ppm, around 139.4 ppm, around 136.6 ppm, around 134.9 ppm, around 132.7 ppm, around 129.0 ppm, around 127.8 ppm, around 126.5 ppm, around 125.8 ppm, around 123.3 ppm, around 120.8 ppm, around 118.4 ppm, around 114.6 ppm and around 108.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.

### Claim 24

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a powder X-ray diffraction pattern shown in FIG. 4.

### Claim 25

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having an infrared spectrum (KBr method) shown in FIG. 1.

### Claim 26

A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a 13C Solid State NMR spectrum shown in FIG. 8.