CA2348374C - Method for producing 4- [(2',5'- diamino-6'- halopyrimidine- 4'-yl)amino]- cyclopent- 2-enylmethanols - Google Patents
Method for producing 4- [(2',5'- diamino-6'- halopyrimidine- 4'-yl)amino]- cyclopent- 2-enylmethanols Download PDFInfo
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- CA2348374C CA2348374C CA002348374A CA2348374A CA2348374C CA 2348374 C CA2348374 C CA 2348374C CA 002348374 A CA002348374 A CA 002348374A CA 2348374 A CA2348374 A CA 2348374A CA 2348374 C CA2348374 C CA 2348374C
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- Canada
- Prior art keywords
- diamino
- amino
- cyclopent
- enylmethanols
- general formula
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- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
Abstract
A novel process for preparing 4-[(2',5'-diamino-6'--halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of the general formula (see formula I) in which X is a halogen atom, is described. According to this process, a 2,5-diamino-4,6-dihalopyrimidine of the general formula (see formula II) in which X is as defined above, is reacted with a 4-aminocyclopent-2-enylmethanol of the formula (see formula III) or one of its salts, in the presence of a base in a polar protic solvent.
Description
Method for producing 4-[(2',5'-Diamino-61-halopyrimidin-4'-yl)amino] cyclopent-2-enylmethanols Description The present invention relates to a novel process for preparing 4-[(2',5'-diamino-61-halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of the general formula X
H,N N
HO ~ . I
HI~ NIi2 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)-amino]cyclopent-2-enylmethanols are important intermediates for preparing antiviral nucleotide derivatives (WO 91/01310).
The 3-step synthesis of 4-[(2',5'-diamino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol starting from 4-acetamidocyclopent-2-enylmethanol by reaction with 2-amino-4,6dichloropyrimidine in butanol using diisopropylethylamine as base is known. Here, the [(21-amino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol is initially formed, which is then converted in a subsequent step by diazotization into the corresponding amine which is then hydrolysed to give the end product (J. Chem. Soc. Perkins Trans, 1, 1992).
This process has the disadvantage that it is too costly and that the desired end product is obtained in only moderate yield.
It is the object of the present invention to provide a 1-step and thus more cost-efficient process for preparing 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols in which the desired products are obtained in good yield.
H,N N
HO ~ . I
HI~ NIi2 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)-amino]cyclopent-2-enylmethanols are important intermediates for preparing antiviral nucleotide derivatives (WO 91/01310).
The 3-step synthesis of 4-[(2',5'-diamino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol starting from 4-acetamidocyclopent-2-enylmethanol by reaction with 2-amino-4,6dichloropyrimidine in butanol using diisopropylethylamine as base is known. Here, the [(21-amino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol is initially formed, which is then converted in a subsequent step by diazotization into the corresponding amine which is then hydrolysed to give the end product (J. Chem. Soc. Perkins Trans, 1, 1992).
This process has the disadvantage that it is too costly and that the desired end product is obtained in only moderate yield.
It is the object of the present invention to provide a 1-step and thus more cost-efficient process for preparing 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols in which the desired products are obtained in good yield.
According to the invention, there is provided a process for preparing 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of the general formula x H2 O'l HO H~,=~N/~NH2 in which X is a halogen atom, wherein a 2,5-diamino-4,6-dihalopyrimidine of the general formula x H2N / N lI
in which X is defined as above, is reacted with a 4-aminocyclopent-2-enylmethanol of the formula ~-I U NHl I I I
or one of its salts, in the presence of a base selected from the group consisting of an alkali metal bicarbonate, an alkali earth metal bicarbonate, an alkali metal carbonate and an alkali earth metal carbonate, in a polar protic solvent to give the end product of the general formula I.
in which X is defined as above, is reacted with a 4-aminocyclopent-2-enylmethanol of the formula ~-I U NHl I I I
or one of its salts, in the presence of a base selected from the group consisting of an alkali metal bicarbonate, an alkali earth metal bicarbonate, an alkali metal carbonate and an alkali earth metal carbonate, in a polar protic solvent to give the end product of the general formula I.
Surprisingly, it has been found that, if instead of 2-amino-4,6-dichloropyri.midine, a 2,5-diamino-4,6-dihalopyrimidine of the general formula x NzN ~
~ N II
X N NHI
is used as starting material, and this is allowed to react in the presence of a base in a polar protic solvent with a 4-aminocyclopent-2-enylmethanol of the formula HO NH2 z1t or one of its salts, the desired eiid product of the general formula x F{0 ~u i ~t N Nl~
is obtained much more cost-efficiently and in good yield.
The substituent X is a halogen atom, such as F, Cl, Br or I.
The 2,5-diamino-4,6-dihalopyrimdines, such as the 2,5-diamino-4,6-dichloropyrimidine, can be prepared in accordance with EP-A 0 684 326.
The 4-aminocyclopent-2-enylmethanols used can be both the racemic and the optically active compounds, such as (1R,4S)-, (1S,4R)-, (lR,4R)-, or (iS,4S)-4-aminocyclopent-2-enylmethanols.
~ N II
X N NHI
is used as starting material, and this is allowed to react in the presence of a base in a polar protic solvent with a 4-aminocyclopent-2-enylmethanol of the formula HO NH2 z1t or one of its salts, the desired eiid product of the general formula x F{0 ~u i ~t N Nl~
is obtained much more cost-efficiently and in good yield.
The substituent X is a halogen atom, such as F, Cl, Br or I.
The 2,5-diamino-4,6-dihalopyrimdines, such as the 2,5-diamino-4,6-dichloropyrimidine, can be prepared in accordance with EP-A 0 684 326.
The 4-aminocyclopent-2-enylmethanols used can be both the racemic and the optically active compounds, such as (1R,4S)-, (1S,4R)-, (lR,4R)-, or (iS,4S)-4-aminocyclopent-2-enylmethanols.
Suitable salts thereof are the acid addition salts, in particular the hydrobalide salts, for example the hydrochlorides or hydrobromides. These 4-aminocyclopent-2-enylmethanols, in particular the (1R,4S)- or the (1S,4R)-enantiomers, can be prepared in accordance with WO 97/45529.
The reaction is advantageously carried out in the presence of an alkali metal carbonate or alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate or in the presence of nitrogen bases, such as, for example, tert. amines, as base. The alkali metal carbonate or alkali metal bicarbonate used can be sodium carbonate, potassium carbonate or sodium bicarbonate or potassium bicarbonate. The alkaline earth metal carbonate or alkaline earth metal bicarbonate used can be calcium carbonate or magnesium carbonate or calcium bicarbonate.
Suitable tert. amines are, for example, triethylamine and diisopropylethylamine. The reaction is preferably carried out in the presence of an alkali metal bicarbonate such as sodium bicarbonate or in the presence of a tert. amine such as diisopropylethylamine.
The base is advantageously employed in excess, based on the 2,5-diamino-4,6-dihalopyrimidine; preferably, 1 to 4 mol of base are employed per mole of 2,5-diamino-4,6-dihalopyrimidine.
Suitable polar protic solvents are, in particular, C1_4-alcohols, such as methanol, ethanol, propanol and its isomers, and butanol and its isomers.
The reaction is advantageously carried out at a temperature of from 20 C to the reflux temperature of the solvent in question, preferably from 50 C to the reflux temperature.
Advantageously, the 4-aminocyclopent-2-enylmethanol and the 2,5-diamino-4,6-dihalopyrimidine are employed in equimolar amounts.
After a customary reaction time of from 2 to 20 h, the end products of formula I, preferably the (1S,4R)-4-[(2',-5'-diamino-6'-halopyrimidin-4'-yl)-amino]cyclopent-2-enylmethanol, can then be obtained by customary work-up methods.
The reaction is advantageously carried out in the presence of an alkali metal carbonate or alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate or in the presence of nitrogen bases, such as, for example, tert. amines, as base. The alkali metal carbonate or alkali metal bicarbonate used can be sodium carbonate, potassium carbonate or sodium bicarbonate or potassium bicarbonate. The alkaline earth metal carbonate or alkaline earth metal bicarbonate used can be calcium carbonate or magnesium carbonate or calcium bicarbonate.
Suitable tert. amines are, for example, triethylamine and diisopropylethylamine. The reaction is preferably carried out in the presence of an alkali metal bicarbonate such as sodium bicarbonate or in the presence of a tert. amine such as diisopropylethylamine.
The base is advantageously employed in excess, based on the 2,5-diamino-4,6-dihalopyrimidine; preferably, 1 to 4 mol of base are employed per mole of 2,5-diamino-4,6-dihalopyrimidine.
Suitable polar protic solvents are, in particular, C1_4-alcohols, such as methanol, ethanol, propanol and its isomers, and butanol and its isomers.
The reaction is advantageously carried out at a temperature of from 20 C to the reflux temperature of the solvent in question, preferably from 50 C to the reflux temperature.
Advantageously, the 4-aminocyclopent-2-enylmethanol and the 2,5-diamino-4,6-dihalopyrimidine are employed in equimolar amounts.
After a customary reaction time of from 2 to 20 h, the end products of formula I, preferably the (1S,4R)-4-[(2',-5'-diamino-6'-halopyrimidin-4'-yl)-amino]cyclopent-2-enylmethanol, can then be obtained by customary work-up methods.
Examples Example 1 Preparation of 4-[(21,51 -diamino-61 -chloropyrimidin-4'-yl)amino]cyclopent-2--enylmethanol in the presence of sodium bicarbonate.
(1S,4R) -4-aminocyclopent-2-enylmethanol hydrochloride (0.14 mol, 23.25 g) , ethanol (3 mol, 138.12 g, 176 m:l), 2,5-diamino-4,6-dichloropyri.midine (0.14 mol, 25 g) and. sodium bicarbonate (0.34 mol, 28.68 g) were added to a dry reactor. This mixture was heated at reflux temperature (about 80 C) for 16 h.
The rate of conversion was tested by TLC using 13/i methylene chloride:methanol as mobile phase. The reaction mixture was cooled to room temperature and stirred for 45 min. The salts were removed by filtration and the filter cake was washed twice with ethanol (0.86 mol, 39.5 g, 50 ml).
2/3 of the organic phase were removed by distillation under reduced pressure, and hexane (150 ml) was then added dropwise. The suspension was cooled to below 10 C. After filtration, the product was dried under reduced pressure at 50 C.
This gave 21.5 g (0.08 mol) of end product, corresponding to a yield of 601.
Example 2 Preparation of 4-[(2',5'-diamino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol in the presence of diisopropylethylamine.
(1S,4R) -4-aminocyclopent-2-enylmethanol hydrochloride (0.14 mol, 23.25 g) , ethanol (3 mol, 138.12 g, 176 m:l), 2,5-diamino-4,6-dichloropyri.midine (0.14 mol, 25 g) and. sodium bicarbonate (0.34 mol, 28.68 g) were added to a dry reactor. This mixture was heated at reflux temperature (about 80 C) for 16 h.
The rate of conversion was tested by TLC using 13/i methylene chloride:methanol as mobile phase. The reaction mixture was cooled to room temperature and stirred for 45 min. The salts were removed by filtration and the filter cake was washed twice with ethanol (0.86 mol, 39.5 g, 50 ml).
2/3 of the organic phase were removed by distillation under reduced pressure, and hexane (150 ml) was then added dropwise. The suspension was cooled to below 10 C. After filtration, the product was dried under reduced pressure at 50 C.
This gave 21.5 g (0.08 mol) of end product, corresponding to a yield of 601.
Example 2 Preparation of 4-[(2',5'-diamino-6'-chloropyrimidin-4'-yl)amino]cyclopent-2-enylmethanol in the presence of diisopropylethylamine.
(1S,4R)-4-aminocyclopent-2-enylmethanol hydrochloride (0.14 mol, 23.18 g), butanol (1.26 mol, 93.39 g, 115.3 ml), 2,5-diamino-4,6-dichloropyrimidine (0.14 mol, 25.67 g) and diisopropylethylamine (0.29 mol, 37.09 g, 49.99 ml) were added to a dry reactor. This mixture was heated at reflux temperature (about 115 C) overnight. The rate of conversion was tested by TLC using 13/1 methylene chloride:methanol as mobile phase. The reaction mixture was cooled to room temperature. Water was then added, and the mixture was subsequently extracted twice with ethyl acetate.
The organic phase was washed twice with water, and then filtered through celiteTM. 2/3 of the organic phase were removed by distillation under reduced pressure, and hexane was then added dropwise. The suspension was cooled to below 10 C. After filtration, the product was dried under reduced pressure at 50 C.
This gave 21.47 g (0.08 mol) of end product, corresponding to a yield of 60%.
The organic phase was washed twice with water, and then filtered through celiteTM. 2/3 of the organic phase were removed by distillation under reduced pressure, and hexane was then added dropwise. The suspension was cooled to below 10 C. After filtration, the product was dried under reduced pressure at 50 C.
This gave 21.47 g (0.08 mol) of end product, corresponding to a yield of 60%.
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for preparing 4-[(2',5'-diamino-6'-halopyrimidin-4'-yl)amino]cyclopent-2-enylmethanols of the general formula in which X is a halogen atom, wherein a 2,5-diamino-4,6-dihalopyrimidine of the general formula in which X is defined as above, is reacted with a 4-aminocyclopent-2-enylmethanol of the formula or one of its salts, in the presence of a base selected from the group consisting of an alkali metal bicarbonate, an alkali earth metal bicarbonate, an alkali metal carbonate and an alkali earth metal carbonate, in a polar protic solvent to give the end product of the general formula I.
2. Process according to claim 1, wherein the polar protic solvent used is a C1-4-alcohol.
3. Process according to Claim 1 or 2, wherein the reaction is carried out at a temperature of from 20°C to the reflux temperature of the solvent in question.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98120529.7 | 1998-10-30 | ||
| EP98120529 | 1998-10-30 | ||
| US14610599P | 1999-07-29 | 1999-07-29 | |
| US60/146,105 | 1999-07-29 | ||
| PCT/EP1999/008270 WO2000026193A1 (en) | 1998-10-30 | 1999-10-29 | Method for producing 4- [(2',5'- diamino-6'- halopyrimidine- 4'-yl)amino]- cyclopent- 2-enylmethanols |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2348374A1 CA2348374A1 (en) | 2000-05-11 |
| CA2348374C true CA2348374C (en) | 2009-04-07 |
Family
ID=56289961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002348374A Expired - Fee Related CA2348374C (en) | 1998-10-30 | 1999-10-29 | Method for producing 4- [(2',5'- diamino-6'- halopyrimidine- 4'-yl)amino]- cyclopent- 2-enylmethanols |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1124805B1 (en) |
| JP (1) | JP4457496B2 (en) |
| CN (1) | CN1115338C (en) |
| AT (1) | ATE240945T1 (en) |
| AU (1) | AU1158000A (en) |
| CA (1) | CA2348374C (en) |
| CZ (1) | CZ300155B6 (en) |
| DK (1) | DK1124805T3 (en) |
| ES (1) | ES2200594T3 (en) |
| HU (1) | HU227559B1 (en) |
| IL (1) | IL142760A (en) |
| PL (1) | PL198180B1 (en) |
| SK (1) | SK285271B6 (en) |
| WO (1) | WO2000026193A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100606625B1 (en) | 1998-10-30 | 2006-07-28 | 론자 아게 | Method for producing 4-[2',5'-diamino-6'-halopyrimidine-4'-ylamino]-cyclopent-2-enylmethanols |
| AU2008204380B2 (en) | 2007-01-10 | 2013-08-15 | Msd Italia S.R.L. | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
| CN101932572A (en) | 2008-01-08 | 2010-12-29 | 默沙东有限公司 | 2-{4-[(3S)-and piperidines-3-yl] phenyl }-pharmacologically acceptable salts of 2H-indazole-7-carboxylic acid amides |
| CN103626745B (en) * | 2013-12-04 | 2016-02-24 | 青岛黄海制药有限责任公司 | A kind of preparation method of ticagrelor midbody |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE505213C2 (en) * | 1988-01-20 | 1997-07-14 | Univ Minnesota | Dideoxycarbocyclic nucleoside analogues, pharmaceutical preparations thereof and intermediates |
| GB8916698D0 (en) * | 1989-07-21 | 1989-09-06 | Beecham Group Plc | Novel process |
| MY104575A (en) * | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
| CA2145928C (en) * | 1994-04-27 | 2007-10-09 | Gerhard Stucky | N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide, and a process for its preparation |
| KR100577891B1 (en) * | 1996-05-30 | 2006-05-10 | 론자 아게 | Enzymes having n-acylamino-alcohol hydrolase activity |
-
1999
- 1999-10-29 EP EP99971416A patent/EP1124805B1/en not_active Expired - Lifetime
- 1999-10-29 PL PL347503A patent/PL198180B1/en unknown
- 1999-10-29 CA CA002348374A patent/CA2348374C/en not_active Expired - Fee Related
- 1999-10-29 IL IL14276099A patent/IL142760A/en not_active IP Right Cessation
- 1999-10-29 SK SK569-2001A patent/SK285271B6/en not_active IP Right Cessation
- 1999-10-29 AT AT99971416T patent/ATE240945T1/en active
- 1999-10-29 HU HU0104045A patent/HU227559B1/en not_active IP Right Cessation
- 1999-10-29 AU AU11580/00A patent/AU1158000A/en not_active Abandoned
- 1999-10-29 DK DK99971416T patent/DK1124805T3/en active
- 1999-10-29 CN CN99812845A patent/CN1115338C/en not_active Expired - Fee Related
- 1999-10-29 CZ CZ20011486A patent/CZ300155B6/en not_active IP Right Cessation
- 1999-10-29 JP JP2000579582A patent/JP4457496B2/en not_active Expired - Fee Related
- 1999-10-29 WO PCT/EP1999/008270 patent/WO2000026193A1/en active IP Right Grant
- 1999-10-29 ES ES99971416T patent/ES2200594T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20011486A3 (en) | 2001-10-17 |
| PL198180B1 (en) | 2008-06-30 |
| DK1124805T3 (en) | 2003-09-15 |
| EP1124805A1 (en) | 2001-08-22 |
| WO2000026193A1 (en) | 2000-05-11 |
| CZ300155B6 (en) | 2009-02-25 |
| JP2003500333A (en) | 2003-01-07 |
| SK5692001A3 (en) | 2001-12-03 |
| SK285271B6 (en) | 2006-10-05 |
| PL347503A1 (en) | 2002-04-08 |
| AU1158000A (en) | 2000-05-22 |
| CN1325386A (en) | 2001-12-05 |
| ATE240945T1 (en) | 2003-06-15 |
| IL142760A0 (en) | 2002-03-10 |
| EP1124805B1 (en) | 2003-05-21 |
| CN1115338C (en) | 2003-07-23 |
| HUP0104045A2 (en) | 2002-05-29 |
| IL142760A (en) | 2005-12-18 |
| ES2200594T3 (en) | 2004-03-01 |
| HU227559B1 (en) | 2011-08-29 |
| JP4457496B2 (en) | 2010-04-28 |
| HUP0104045A3 (en) | 2002-07-29 |
| CA2348374A1 (en) | 2000-05-11 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141029 |