# US 2019/0169200 A1 · Novel method of manufacturing 4-chloro-7h-pyrrolo[2,3-d]pyrimidine

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- Number: US 2019/0169200 A1
- Document ID: US20190169200A1
- Status: Published application
- Kind: A1
- Application number: 16/324,475
- Filed: 2017-08-11
- Published: 2019-06-06
- Earliest claimed: 2016-08-11
- Assignees: Siegfried (Nantong) Pharmaceuticals Co. Ltd.
- Applicants: Siegfried (Nantong) Pharmaceuticals Co. Ltd.
- Inventors: Ben Pan; Jiang Chen; Bernhard Berger; Beat Weber
- Web page: https://patentgrep.com/patent/US20190169200A1

## CPC

- C07D 487/04: Ortho-condensed systems
- B01D 9/005: {Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)

## Abstract

The present invention discloses a method of manufacturing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine comprising the steps: a) Preparing ethyl 2-cyano-4,4-dimethoxybutanoate by coupling ethyl 2-cyanoacetate and 2-bromo-1,1-dimethoxyethane; b) Preparing 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol by adding formamidine to ethyl 2-cyano-4,4-dimethoxybutanoate; c) Converting 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol to 7H-pyrrolo[2,3-d]pyrimidin-4-ol; and d) Converting the 7H-pyrrolo[2,3-d]pyrimidin-4-ol to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The method offers increased yield, less by-products and a decrease in waste compared to methods known as being state of the art.

## Claims

### Claim 1

A method of preparing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine comprising the steps:
a) Preparing ethyl 2-cyano-4,4-dimethoxybutanoate by coupling ethyl 2-cyanoacetate and 2-bromo-1,1-dimethoxyethane;
b) Preparing 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol by adding formamidine to ethyl 2-cyano-4,4-dimethoxybutanoate;
c) Converting 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol to 7H-pyrrolo[2,3-d]pyrimidin-4-ol; and
d) Converting the 7H-pyrrolo[2,3-d]pyrimidin-4-ol to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the ethyl 2-cyano-acetate in step a) is added in excess to the 2-bromo-1,1-dimethoxyethane at a molar ratio between 1.5:1.0 to 10.0:1.0.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the excess of ethyl 2-cyano-acetate used in step a) is recycled.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the yield of step a) exceeds 80% of the theoretically reachable conversion rate.

### Claim 5 (depends on 1)

The method according to claim 1, further comprising adding carbonate in step a).

### Claim 6 (depends on 1)

The method according to claim 1, wherein the purity of ethyl 2-cyano-4,4-dimethoxybutanoate in step a) is above 70 area-% as measured by HPLC.

### Claim 7 (depends on 1)

The method according to claim 1, wherein conditions in reaction step d) are at pH levels 8.0 or above.

### Claim 8 (depends on 7)

The method according to claim 7, wherein potassium hydroxide is used to adjust the pH level in step d) to a value of 8.0 or above.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the product 4-chloro-7H-pyrrolo[2,3-d]pyrimidine is directly isolated from the reaction mixture by precipitation.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the purity of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine after step d) is higher than 99.5 area-%.

### Claim 11 (depends on 1)

The method according to claim 1, further comprising adding tosyl to the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine to prepare 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine.

### Claim 12 (depends on 2)

The method according to claim 2, wherein the ethyl 2-cyano-acetate in step a) is added in excess to the 2-bromo-1,1-dimethoxyethane at a molar ratio between 2.0:1.0 to 5.0:1.0.

### Claim 13 (depends on 5)

The method according to claim 5, wherein the carbonate is added in at least in three portions.

### Claim 14 (depends on 7)

The method according to claim 7, wherein conditions in reaction step d) are at pH levels between 8.0 and 9.0.

### Claim 15 (depends on 8)

The method according to claim 8, wherein potassium hydroxide is used to adjust the pH level in step d) to a value of between 8.0 and 9.0.

### Claim 16 (depends on 10)

The method according to claim 10, wherein the purity of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine after step d) is higher than 99.7 area-% as measured by HPLC.

### Claim 17 (depends on 10)

The method according to claim 10, wherein the purity of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine after step d) is higher than 99.9 area-% as measured by HPLC.