# US 12,180,224 B2 · Thienopyrimidine derivatives and production methods thereof

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- Number: US 12,180,224 B2
- Document ID: US12180224B2
- Status: Granted
- Kind: B2
- Application number: 18/121,886
- Filed: 2023-03-15
- Published: 2023-07-06
- Granted: 2024-12-31
- Earliest claimed: 2012-09-28
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Koichiro Fukuoka; Kazuhiro Miwa
- Web page: https://patentgrep.com/patent/US12180224B2

## CPC

- C07D 495/04: Ortho-condensed systems
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a production method of a thienopyrimidine derivative or a salt thereof which has a gonadotropin releasing hormone (GnRH) antagonistic action with high quality in high yield. The present invention provides a method of producing a thienopyrimidine derivative, which comprises reacting 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or salt thereof, 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof, and the like.

## Claims

### Claim 1

A compound represented by the formula (I)
or a salt thereof, wherein R1 is a C1-6 alkoxy group.

### Claim 2 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is a methoxy group.

### Claim 3 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is an ethoxy group.

### Claim 4 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is a C3 alkoxy group.

### Claim 5 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is a C4 alkoxy group.

### Claim 6 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is a C5 alkoxy group.

### Claim 7 (depends on 1)

The compound of claim 1 or salt thereof, wherein R1 is a C6 alkoxy group.

### Claim 8 (depends on 3)

A method of producing the compound of claim 3, or a salt thereof, which comprises reacting ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate, or a salt thereof, with N-bromosuccinimide and a radical initiator, and reacting the obtained ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate, or salt thereof, with dimethylamine or a salt thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the N-bromosuccinimide is used in an amount in the range of 1.0 to 1.5 molar equivalents per molar equivalent of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.

### Claim 10 (depends on 8)

The method of claim 8, wherein the reaction of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with N-bromosuccinimide and the radical initiator is performed in the presence of trifluoromethylbenzene.

### Claim 11 (depends on 10)

The method of claim 10, wherein the trifluoromethylbenzene is used in an amount in the range of 0.1 mL to 1.0 mL per 1 mmol of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.

### Claim 12 (depends on 8)

The method of claim 8, wherein the radical initiator is 2,2′-azobis (2,4-dimethylvaleronitrile).

### Claim 13 (depends on 12)

The method of claim 12, wherein the 2,2′-azobis(2,4-dimethylvaleronitrile) is used in an amount in the range of 0.01 to 0.2 molar equivalents per molar equivalent of the ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.

### Claim 14 (depends on 8)

The method of claim 8, wherein the radical initiator is 2,2′-azobisisobutyronitrile.

### Claim 15 (depends on 8)

The method of claim 8, wherein the reaction of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with N-bromosuccinimide and the radical initiator is performed in a solvent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the solvent comprises ethyl acetate, carbon tetrachloride, dichloromethane, dichloroethane, chlorobenzene, or acetonitrile.

### Claim 17 (depends on 8)

The method of claim 8, wherein the dimethylamine is used in an amount in the range of 1.0 to 3.0 molar equivalents per molar equivalent of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.

### Claim 18 (depends on 8)

The method of claim 8, wherein the dimethylamine is used in an amount in the range of 1.2 to 1.8 molar equivalents per molar equivalent of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof.

### Claim 19 (depends on 8)

The method of claim 8, wherein the reaction of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with dimethylamine or salt thereof is performed in the presence of a solvent.

### Claim 20 (depends on 19)

The method of claim 19, wherein the solvent comprises dimethylformamide, dimethylacetamide, or tetrahydrofuran.

### Claim 21 (depends on 8)

The method of claim 8, wherein the reaction of the ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]-5-(4-nitrophenyl)thiophene-3-carboxylate or salt thereof with dimethylamine or salt thereof is performed in the presence of a base.

### Claim 22 (depends on 21)

The method of claim 21, wherein the base is triethylamine or diisopropylethylamine.