AU669874B2 - Preparation of 2-amino-6-chloropurine - Google Patents
Preparation of 2-amino-6-chloropurineInfo
- Publication number
- AU669874B2 AU669874B2 AU33654/93A AU3365493A AU669874B2 AU 669874 B2 AU669874 B2 AU 669874B2 AU 33654/93 A AU33654/93 A AU 33654/93A AU 3365493 A AU3365493 A AU 3365493A AU 669874 B2 AU669874 B2 AU 669874B2
- Authority
- AU
- Australia
- Prior art keywords
- process according
- guanine
- chloropurine
- amino
- phase transfer
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Preparation of 2-am1 no-6-chloropurine
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 of formula (I):
(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. EP-A-433846 (Hoechst Aktiengesellschaft) describes a corresponding process for preparing the 2-acylated derivative, involving chlorination of 2,9-diacylguanine and subsequent removal of the 9- acyl group by hydrolysis.
The reaction is preferably carried out in a polar inert organic solvent such as acetonitrile, tetrahydrofuran, dioxan, nitromethane, diglyme, dimethoxyethane, ordichloromethane. Acetonitrile is highly preferred.
Suitable phase transfer catalysts include tetrasubstituted ammonium chlorides. Examples of ammonium substituents include C2-12 aik i, usually C2-4 alkyl, or phenyl or benzyl. Other possible phase transfer catalysts include tetra-substituted phosphonium chlorides wherein examples of the substitutents are as defined above for ammonium chlorides. Preferably the phase transfer catalyst is tetraethylammonium chloride.
The phase-transfer catalyst is preferably present in an amount of from 1 to 3 equivalents of the compound of formula (II) and preferably from 1 to 2 equivalents.
A preferred chlorinating agent is phosphorus oxychloride.
Preferably the chlorinating agent is present in an amount of from 2-10 preferably from 3-6 molar equivalents of the guanine derivative.
The reaction may be effected in the presence of a weak base, such as a tertiary amine, for example N,N-dimethylaniliπe or diethylaniline or triethylamine- The base is usually present in an approximately molar equivalent amount with respect to the guanine derivative. Alternatively, a catalytic amount of water may be added to the reaction mixture. When acetonitrile is the solvent, added base may not be necessary, but is preferred.
The reaction is preferably carried out at an elevated temperature of from 30-100°C, most preferably under reflux and/or with ultrasonication at 50-70°C.
Preferably the reaction is allowed to proceed for a period of greater than half an hour, usually less than 30 hours.
We have now discovered that the compound of formula (I) may be prepared from 2,9-diacylguanine.
Accordingly, the present invention provides a process for preparing 2-amino- 6-chloropurine, which process comprises reacting a 2,9-diacylated derivative of guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions, and thereafter removing the 9-acyl group and the 2-acyl group by hydrolysis.
The reaction is described in EP-A-203685 and EP-A-433846, which are incorporated herein by reference, except that methyltriethylammonium chloride is a preferred phase transfer catalyst; the amount of phosphorus oxychioride may be reduced to 2-4 equivalents, and the reaction time can be reduced.
If the removal of the 9-acyl group generally occurs at ambient temperature (below 30°C), but higher temperatures and reaction times (80-100°C, 1 -2 hours) are needed for removal of the 2-acyl group. Aqueous sodium hydroxide is a suitable basic medium for the hydrolysis.
The following example illustrates the invention.
Example
Diacetyl guanine (8.0g, 0.034 moles), triethyimethylammonium chloride (15.45g, 0.102 moles), and triethylamine (4.74 mis, 0.034 moles) were heated together with stirring in acetonitrile (70mls) to 50°C. Phosphorus oxychioride (6.34 mis, 0.068 moles) was then added and stirring continued for 4 hours. The reaction mixture was cooled and then added to aqueous sodium hydroxide solution (20g in 300mls water). The reaction mixture was heated to 80°C for 2 hours and then the volume made up to 300 mis with water. The mixture was cooled to 25°C and the pH adjuster to 7 using 10% hydrochloric acid. The resulting slurry was stirred for fifteen minutes and the product filtered off and washed with water 30 mis and then dried at 80°C under vacuum to give a cream/off white coloured product.
Weight 2-amino-6-chioropurine 4.69 g (74.6% yield).
Claims (6)
1. A process for preparing 2-amino-6-chloropurine, which process comprises reacting a 2,9-diacylated derivative of guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions, and thereafter removing the 9-acyl group and the 2-acyl group by hydrolysis.
2. A process according to claim 1 , as described in EP-A-203685 and EP-A-433846.
3. A process according to claim 2, wherein the chlorinating agent is phosphorus oxychioride and the phase transfer catalyst is methyltriethyiammonium chloride.
4. A process according to in claim 3, wherein the amount of phosphorus oxychioride is 2-4 equivalents with respect to the 2,9-acylated guanine.
5. A process according to claim 1 , wherein aqueous sodium hydroxide is used as the basic medium for the hydrolysis.
6. A process according to claim 1 , substantially as described herein with reference to the Example.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9201961 | 1992-01-30 | ||
GB929201961A GB9201961D0 (en) | 1992-01-30 | 1992-01-30 | Pharmaceuticals |
PCT/GB1993/000185 WO1993015075A1 (en) | 1992-01-30 | 1993-01-28 | Preparation of 2-amino-6-chloropurine |
Publications (2)
Publication Number | Publication Date |
---|---|
AU3365493A AU3365493A (en) | 1993-09-01 |
AU669874B2 true AU669874B2 (en) | 1996-06-27 |
Family
ID=10709516
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU33654/93A Ceased AU669874B2 (en) | 1992-01-30 | 1993-01-28 | Preparation of 2-amino-6-chloropurine |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0625154A1 (en) |
JP (1) | JPH07503246A (en) |
KR (1) | KR950700299A (en) |
AU (1) | AU669874B2 (en) |
CA (1) | CA2117435A1 (en) |
GB (1) | GB9201961D0 (en) |
MX (1) | MX9300482A (en) |
NZ (1) | NZ246677A (en) |
WO (1) | WO1993015075A1 (en) |
ZA (1) | ZA93615B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4231036A1 (en) * | 1992-09-17 | 1994-03-24 | Basf Ag | Process for the preparation of 2-amino-6-halopurines |
JPH07133276A (en) * | 1993-09-17 | 1995-05-23 | Jiyuuzen Kagaku Kk | Production of 2-acetylamono-6-chloropurine |
DE4415196C1 (en) * | 1994-04-30 | 1995-04-27 | Boehringer Ingelheim Kg | Improved process for the preparation of 2-amino-6-chloropurine and 2-acylamino-6-chloropurines |
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 |
AU2003226448A1 (en) * | 2002-04-04 | 2003-10-20 | Sumitomo Chemical Company, Limited | Production method of 2,6-dihalopurine |
CN102336755B (en) * | 2011-09-30 | 2013-03-27 | 浙江工业大学 | Chemical synthesis method of 6-chloropurine |
CN113214260B (en) * | 2021-05-10 | 2022-04-01 | 上海凌凯医药科技有限公司 | Synthesis method of 2-acetamido-9-acetyl purine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203685A2 (en) * | 1985-03-23 | 1986-12-03 | Beecham Group Plc | Process for the preparation of 2-amino-6-chloro-purine |
EP0433846A1 (en) * | 1989-12-16 | 1991-06-26 | Hoechst Aktiengesellschaft | Process for the preparation of 2-acylamino-6-halogeno-purine from 2,9-diacylguanine |
AU655002B2 (en) * | 1991-01-31 | 1994-12-01 | Novartis International Pharmaceutical Ltd | Process for the preparation of 2-amino-6-chloropurine or a 2-acylated derivative thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0141927B1 (en) | 1983-08-18 | 1991-10-30 | Beecham Group Plc | Antiviral guanine derivatives |
EP0182024B1 (en) | 1984-09-20 | 1991-04-03 | Beecham Group Plc | Purine derivatives and their pharmaceutical use |
DE3941658A1 (en) * | 1989-12-16 | 1991-06-20 | Hoechst Ag | METHOD FOR PRODUCING 2-ACYLAMINO-9-ACYL-6-HALOGEN PURIN |
-
1992
- 1992-01-30 GB GB929201961A patent/GB9201961D0/en active Pending
-
1993
- 1993-01-28 AU AU33654/93A patent/AU669874B2/en not_active Ceased
- 1993-01-28 WO PCT/GB1993/000185 patent/WO1993015075A1/en not_active Application Discontinuation
- 1993-01-28 NZ NZ246677A patent/NZ246677A/en unknown
- 1993-01-28 KR KR1019940702650A patent/KR950700299A/en not_active Application Discontinuation
- 1993-01-28 CA CA002117435A patent/CA2117435A1/en not_active Abandoned
- 1993-01-28 EP EP93902481A patent/EP0625154A1/en not_active Withdrawn
- 1993-01-28 ZA ZA93615A patent/ZA93615B/en unknown
- 1993-01-28 JP JP5513055A patent/JPH07503246A/en active Pending
- 1993-01-28 MX MX9300482A patent/MX9300482A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203685A2 (en) * | 1985-03-23 | 1986-12-03 | Beecham Group Plc | Process for the preparation of 2-amino-6-chloro-purine |
EP0433846A1 (en) * | 1989-12-16 | 1991-06-26 | Hoechst Aktiengesellschaft | Process for the preparation of 2-acylamino-6-halogeno-purine from 2,9-diacylguanine |
AU655002B2 (en) * | 1991-01-31 | 1994-12-01 | Novartis International Pharmaceutical Ltd | Process for the preparation of 2-amino-6-chloropurine or a 2-acylated derivative thereof |
Also Published As
Publication number | Publication date |
---|---|
GB9201961D0 (en) | 1992-03-18 |
JPH07503246A (en) | 1995-04-06 |
CA2117435A1 (en) | 1993-08-05 |
MX9300482A (en) | 1994-07-29 |
NZ246677A (en) | 1996-02-27 |
WO1993015075A1 (en) | 1993-08-05 |
ZA93615B (en) | 1993-11-26 |
KR950700299A (en) | 1995-01-16 |
AU3365493A (en) | 1993-09-01 |
EP0625154A1 (en) | 1994-11-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6870053B2 (en) | Chloropyrimidine intermediates | |
EP0569421B1 (en) | Process for the preparation of 2-amino-6-chloropurine and derivatives | |
GB1595337A (en) | Synthesis of methotrexate | |
AU669874B2 (en) | Preparation of 2-amino-6-chloropurine | |
EP0203685B1 (en) | Process for the preparation of 2-amino-6-chloro-purine | |
AU634564B2 (en) | Process for preparing 2,5-diamino-4,6-dichloropyrimidine | |
JP2672874B2 (en) | Manufacturing method of cytosine | |
JPH0645620B2 (en) | Method for methylating xanthines | |
JP2724881B2 (en) | Improved method for precipitating cytosine from alkaline solution with sulfuric acid | |
GB2160204A (en) | Preparation of N-methyl-1-alkylthio-2-nitroethenamines | |
JPH07300480A (en) | Improved process for producing 2-amino-6-chloropurine and 2-acylamino-6-chloro-purine | |
JPH0578358A (en) | New method for preparing and purififying compound | |
JP2002069050A (en) | Method for producing hydrazocarbonamide |