WO1994007892A1 - Process for the preparation of 2-amino-6-chloropurine - Google Patents

Process for the preparation of 2-amino-6-chloropurine Download PDF

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Publication number
WO1994007892A1
WO1994007892A1 PCT/GB1993/002027 GB9302027W WO9407892A1 WO 1994007892 A1 WO1994007892 A1 WO 1994007892A1 GB 9302027 W GB9302027 W GB 9302027W WO 9407892 A1 WO9407892 A1 WO 9407892A1
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Prior art keywords
preparation
chloropurine
amino
triamino
process according
Prior art date
Application number
PCT/GB1993/002027
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French (fr)
Inventor
John Christopher Hanson
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP6508838A priority Critical patent/JPH08502055A/en
Priority to EP93921023A priority patent/EP0662970A1/en
Publication of WO1994007892A1 publication Critical patent/WO1994007892A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • This invention relates to a process for the preparation of a compound useful as an intermediate in the preparation of pharmaceutical compounds.
  • nucleoside analogue antiviral agents such as penciclovir and famciclovir, described in EP-A- 141927 (Example 1) and
  • EP-A- 182024 (Example 2).
  • the intermediate is 9-substituted with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
  • EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a compound of formula (I) as hereinbefore defined, which process comprises reacting guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions.
  • a new process has now been discovered, which obviates the need for using guanine as an intermediate, and avoids other possible routes from pyrimidines which react irreversibly with ACP, which new process utilises a condensation reaction to form the purine from a 2,4,5-triaminopyrimidine.
  • the present invention provides a process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of
  • Appropriate reagents for imidazole ring closure include suitable carbanion generating condensation agents, such as diethoxymethylacetate and triethyl orthoformate.
  • the reaction preferably takes place at elevated temperature, above 80°C, in the absence of any additional solvent or in the presence of a suitable inert solvent.
  • 2,4,5-Triamino-6-chloropyrimidine is a known compound which may be prepared as described in EP-A-335355, or from 2,5-diamino-4,6-dichloropyrimidine or 2,4,5-triamino-6-hydroxypyrimidine. The invention may be illustrated with reference to the following scheme and examples.
  • reaction mixture was poured into water ice to maintain a temperature of approx. 60°C to complete hydrolysis. Some water/HCl was stripped off and KOH added to cause crystallisation of either monohydrochloride or free base at different pH's.
  • the solid and liquors were made basic to pH 11.8 charcoaled with carbon 0.4g at 50°C in 80 ml (total solution filtered), acetone 8 ml added and the pH adjusted with 4N HC1 to 7.5 (while hot), allowing the product to crystallise. The product was filtered, washed and dried.
  • ACP may also be prepared directly from 2,4,5-triamino-6-hydroxypyrimidine by treatment with POCI3 in dimethylformamide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of 2,4,5-triamino-6-chloropyrimidine.

Description

PROCESS FOR THE PREPARATION OF 2-AMIN0-6-CHL0R0PURINE
This invention relates to a process for the preparation of a compound useful as an intermediate in the preparation of pharmaceutical compounds.
The compound 2-amino-6-chloropurine (ACP) of formula (I):
Figure imgf000003_0001
(I)
is a useful intermediate in the preparation of nucleoside analogue antiviral agents, such as penciclovir and famciclovir, described in EP-A- 141927 (Example 1) and
EP-A- 182024 (Example 2). The intermediate is 9-substituted with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a compound of formula (I) as hereinbefore defined, which process comprises reacting guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions. A new process has now been discovered, which obviates the need for using guanine as an intermediate, and avoids other possible routes from pyrimidines which react irreversibly with ACP, which new process utilises a condensation reaction to form the purine from a 2,4,5-triaminopyrimidine.
Accordingly, the present invention provides a process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of
2,4,5-triamino-6-chloropyrimidine.
Appropriate reagents for imidazole ring closure include suitable carbanion generating condensation agents, such as diethoxymethylacetate and triethyl orthoformate. The reaction preferably takes place at elevated temperature, above 80°C, in the absence of any additional solvent or in the presence of a suitable inert solvent. 2,4,5-Triamino-6-chloropyrimidine is a known compound which may be prepared as described in EP-A-335355, or from 2,5-diamino-4,6-dichloropyrimidine or 2,4,5-triamino-6-hydroxypyrimidine. The invention may be illustrated with reference to the following scheme and examples.
Scheme
Figure imgf000004_0001
Figure imgf000004_0002
Examples of 2-Amino-6-chloropurine (ACP) Preparation
2,4,5-Triamino-6-chloropyrimidine intermediate
A. 2,5-Diamino 4,6-dichloropyrimidine (prepared as in WO 91/01310) (10.8g) and concentrated aqueous ammonia (30 ml) were heated together in a sealed vessel at 105°C for 18 hrs., then cooled. 2.34g NaOH in water (10 ml) was added and the excess ammonia striped out by concentrating to a low volume - 25 ml at 20°C. Dilute HC1 2N 35 ml and water 10 ml were added and heated to dissolve, charcoaled with carbon, filtered hot, cooled to crystallize, then filtered to give 2,4,5-triamino-6- chloropyrimidine hydrochloride 8.93g and a second crop on concentrating of 1.28g total 87% yield. [Higher acid concentration gives the dihydrochloride monohydrate.]
B. 2,4,5-Triamino-6-hydroxypyrimidine free base (2.82g), triethylmethylammonium chloride (20g) and phosphorus oxychloride (25 ml) (41g) were stirred and heated to 105° for 24-48 hrs. The reaction was shown by h.p.l.c. to be almost complete. Some excess phosphorus oxychloride was distilled out at a temperature of 130°C over a period of one hour.
The reaction mixture was poured into water ice to maintain a temperature of approx. 60°C to complete hydrolysis. Some water/HCl was stripped off and KOH added to cause crystallisation of either monohydrochloride or free base at different pH's.
ACP Preparation
A. 2,4,5-Triamino-6-chloropyrimidine hydrochloride (3.92g, 0.02M) and diethoxymethyl acetate (32g) were heated for 10 hrs. at 95°C, allowing the ethanol to distill off. Two products were formed, ACP and formyl ACP. After checking that the reaction was complete by h.p.l.c, the reaction mixture was cooled to (20°C) and 2N HC1 20ml added to give a solution which slowly crystallised. After stirring for 2 hrs., the mixture was filtered to give 2-amino-6-chloropurine hydrochloride (2.16g). A second crop was obtained from the concentration of the liquors (0.5g). Total yield 64%. Ig of hydrochloride was suspended in water (20 ml), 0.38g NaOH added to pH 12 and the solution warmed to 50°C. The solution was filtered over charcoal, acetone (8 ml) added and the pH adjusted to 7.5 (while hot) to give 2-amino-6-chloropurine (0.84g 98%).
B. 2,4,5-Triamino-6-chloropurine hydrochloride and triethyl orthoformate (26 ml) were heated overnight at 105°C allowing the ethanol produced to distill off.
After checking the reaction was complete by h.p.l.c, it was cooled and 2N Hydrochloric acid (20 ml) added to give a solution which crystallised slowly.
The solid and liquors were made basic to pH 11.8 charcoaled with carbon 0.4g at 50°C in 80 ml (total solution filtered), acetone 8 ml added and the pH adjusted with 4N HC1 to 7.5 (while hot), allowing the product to crystallise. The product was filtered, washed and dried.
Yield 2.12g ACP 62.5% 13C n.m.r., δ = 159.8, 155.2, 148.9, 141.2, 123.0 ppm in D6DMSO, identical to ACP.
ACP may also be prepared directly from 2,4,5-triamino-6-hydroxypyrimidine by treatment with POCI3 in dimethylformamide.

Claims

Claims
1. A process for the preparation of 2-amino-6-chloropurine, which process comprises imidazole ring closure of 2,4,5-triamino-6-chloropyrimidine.
2. A process according to claim 1 wherein the carbanion generating condensation agent for imidazole ring closure is diethoxymethylacetate or triethyl orthoformate.
3. A process according to claim lor 2 wherein the reaction takes place at elevated temperature, above 80°C, in the absence of any additional solvent or in the presence of a suitable inert solvent.
4. A process for the preparation of a nucleoside analogue antiviral agent which process comprises the preparation of 2-amino-6-chloropurine according to the process of any one of claims 1 to 3, and thereafter reacting 2-amino-6-chloropurine with a side chain precursor at the 9-position of the purine and optionally converting the 6-chloro substituent.
5. A process according to claim 4, for the preparation of famciclovir.
6. A process according to claim 4, for the preparation of penciclovir.
PCT/GB1993/002027 1992-09-30 1993-09-28 Process for the preparation of 2-amino-6-chloropurine WO1994007892A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6508838A JPH08502055A (en) 1992-09-30 1993-09-28 Method for producing 2-amino-6-chloropurine
EP93921023A EP0662970A1 (en) 1992-09-30 1993-09-28 Process for the preparation of 2-amino-6-chloropurine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929220585A GB9220585D0 (en) 1992-09-30 1992-09-30 Pharmaceuticals
GB9220585.5 1992-09-30

Publications (1)

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EP (1) EP0662970A1 (en)
JP (1) JPH08502055A (en)
GB (1) GB9220585D0 (en)
WO (1) WO1994007892A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996021664A1 (en) * 1995-01-09 1996-07-18 Lonza Ag Process for producing 2-amino-6-chloropurine and intermediates therefor
EP0773220A1 (en) * 1995-11-09 1997-05-14 SUMIKA FINE CHEMICALS Co., Ltd. 2-Amino-6-chloropurine and method for preparing the same
US5750694A (en) * 1994-04-26 1998-05-12 Zeneca Limited Process for the preparation of 4,6-dichloropyrimidine
US6018045A (en) * 1995-01-30 2000-01-25 Zeneca Limited Process for preparing 4,6-dichloro-pyrimidine
WO2004110343A2 (en) * 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same
CN110627729A (en) * 2019-10-28 2019-12-31 南京红杉生物科技有限公司 2-amino-6-chloropurine, and synthesis method, intermediate and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2844576A (en) * 1955-11-22 1958-07-22 American Cyanamid Co Preparation of purines
EP0335355A2 (en) * 1988-03-30 1989-10-04 E.R. Squibb & Sons, Inc. Bis-(hydroxymethyl) cyclobutyl purines and pyrimidines
EP0548640A2 (en) * 1991-12-21 1993-06-30 BASF Aktiengesellschaft Process for the preparation of 2,4,5-triamino-6-halopyrimidines and 2-amino-6-halopurines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2844576A (en) * 1955-11-22 1958-07-22 American Cyanamid Co Preparation of purines
EP0335355A2 (en) * 1988-03-30 1989-10-04 E.R. Squibb & Sons, Inc. Bis-(hydroxymethyl) cyclobutyl purines and pyrimidines
EP0548640A2 (en) * 1991-12-21 1993-06-30 BASF Aktiengesellschaft Process for the preparation of 2,4,5-triamino-6-halopyrimidines and 2-amino-6-halopurines

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HOWARD J. SCHAEFFER ET. AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 15, no. 5, May 1972 (1972-05-01), WASHINGTON, pages 456 - 458 *
HOWARD J. SCHAEFFER ET. AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 17, no. 1, January 1974 (1974-01-01), WASHINGTON, pages 6 - 8 *
JOHN A. MONTGOMERY ET. AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 80, no. 2, 25 January 1958 (1958-01-25), WASHINGTON, pages 409 - 411 *
JOHN A. MONTGOMERY ET. AL., THE JOURNAL OF ORGANIC CHEMISTRY, vol. 25, no. 3, 11 April 1960 (1960-04-11), WASHINGTON, pages 395 - 399 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750694A (en) * 1994-04-26 1998-05-12 Zeneca Limited Process for the preparation of 4,6-dichloropyrimidine
WO1996021664A1 (en) * 1995-01-09 1996-07-18 Lonza Ag Process for producing 2-amino-6-chloropurine and intermediates therefor
US6018045A (en) * 1995-01-30 2000-01-25 Zeneca Limited Process for preparing 4,6-dichloro-pyrimidine
EP0773220A1 (en) * 1995-11-09 1997-05-14 SUMIKA FINE CHEMICALS Co., Ltd. 2-Amino-6-chloropurine and method for preparing the same
US5789590A (en) * 1995-11-09 1998-08-04 Sumika Fine Chemicals Co., Ltd. Double cone-like crystal form of 2-amino-6-chloropurine and preparation
AU717952B2 (en) * 1995-11-09 2000-04-06 Sumitomo Chemical Company, Limited 2-amino-6-chloropurine and method for preparing the same
US6187921B1 (en) 1995-11-09 2001-02-13 Sumika Fine Chemicals Co., Ltd. 2-amino-6-chloropurine and method for preparing the same
KR100455241B1 (en) * 1995-11-09 2004-12-31 스미또모 가가꾸 고오교오 가부시끼가이샤 2-amino-6-chloropurine having double conical crystal form and preparation method thereof
WO2004110343A2 (en) * 2003-06-13 2004-12-23 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same
WO2004110343A3 (en) * 2003-06-13 2005-09-01 Kyungdong Pharm Co Ltd 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same
AU2004246958B2 (en) * 2003-06-13 2010-09-16 Kyungdong Pharm. Co., Ltd. 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9-(4-acetoxy-3-(acetoxymethyl)but-1-yl)- 2- aminopurine using the same
CN110627729A (en) * 2019-10-28 2019-12-31 南京红杉生物科技有限公司 2-amino-6-chloropurine, and synthesis method, intermediate and application thereof

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GB9220585D0 (en) 1992-11-11
EP0662970A1 (en) 1995-07-19
JPH08502055A (en) 1996-03-05

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