IL142760A - Method for producing 4-Ä(2',5'-diamino-6'- halopyrimidine-4' -yl) aminoÜ-cyclopent -2- enyl-methanols - Google Patents
Method for producing 4-Ä(2',5'-diamino-6'- halopyrimidine-4' -yl) aminoÜ-cyclopent -2- enyl-methanolsInfo
- Publication number
- IL142760A IL142760A IL14276099A IL14276099A IL142760A IL 142760 A IL142760 A IL 142760A IL 14276099 A IL14276099 A IL 14276099A IL 14276099 A IL14276099 A IL 14276099A IL 142760 A IL142760 A IL 142760A
- Authority
- IL
- Israel
- Prior art keywords
- diamino
- cyclopent
- amino
- general formula
- halopyrimidine
- Prior art date
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention relates to a novel method for producing 4- [(2',5'-diamino- 6'-halopyrimidine- 4'-yl)amino]- cyclopent- 2-enylmethanols of general formula (I), wherein X represents a halogen atom. According to the inventive method, a 2,5-diamino-4,6-halopyrimidine of general formula (II), wherein X has the aforementioned meaning, is reacted with a 4- aminocyclopent-2- enylmethanol of formula (III) or with a salt thereof in the presence of a base in a polar protic solvent.
Description
13076/01 Ο^Ι.ΠΤ] - O - 2 - Β]9Τ?ΡΊ3 -ΓΙΓΠ ΝΡ1 - '4 - rTTTTEJOn - '6 - lrrWT - '5/2)] - 4 mH11l7 Πϋ-'ίϋ METHOD FOR PRODUCING 4-[(2',5'-DIAMINO-6'-HALOPYRIMIDINE-4'-YL)AMINO]- CYCLOPENT-2-ENYL-METHANOLS Method for producing 4- [( 2 ' , 5 ' -Diamino-6 ' -halopyrimidin-A'-yl) amino] cyclopent:-2-enylmethanols Description The present invention relates to a novel . process for _ preparing 4- [ (2 ' , 5 ' -diamino-6' -halo- pyrimidin- ' -yl) amino] cyclopent - 2 -enylmethanols of the general formula 4- ( (2' , 5' -diamino-6' -halopyrimidin-4 ' -yl) - amino] cyclopen -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] cyclopen - 2 -enylmethanol starting from 4 -acetamidocyclopent -2 -enylmethanol by reaction with 2 -amino-4 , 6 -dichloropyrimidine in butanol using diisopropylethylamine as base is known. Here, the [ (2 ' -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 . Perkin 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- ' -yl ) amino ] cyclopent - 2 - enylme hanol s in which che desired products are obtained in good yield.
This object is achieved with the process according to Claim 1.
Surprisingly, it has been found that, if instead of 2 -amino- , 6-dichloropyrimidine , a 2,5- diamino-4 , 6-dihalopyrimidine of the general formula 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 f its salts, the desired end product of the general famula is obtained much more cos -efficiently and in good yield .
The substituent X is a halogen atom, such as F, CI , Br or I .
The 2 , -diamino-4 , 6 -dihalopyrimidines , 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)-, (1R,4R)-, or ( IS , S) - -amino-cyclopent -2 -enylmethanols .
Suitable salts thereof are the acid addition salts, in particular the hydrohalide salts, for example the Hydrochlorides or hydrobromides . These 4-aminocyclopent-2-enylmethanols , in particular the (1R,4S)- or the ( IS ( 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 , b -dihalopyrimidine .
Suitabe polar protic solvents are, in partictular 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 -amino-cyclopent -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 (iS, R)-4-[(2',5' -diamino-6 ' -halopyrimidin- ' -yl ) -amino ] cyclopent - 2 -enylmethanol , can then be obtained by customary work-up methods.
Examples Example 1 Preparation of 4- [ (2' , 5' -diamino-6' -chloropyrimidin- ' - 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 ml), 2 , 5-diamino-4, 6-dichloropyrimidine (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 13/1 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 10CC. 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 60%.
Example 2 Preparation of 4 -[ (2 ', 5 ' -diamino- 6 ' -chloropyrimidin-4 ' -yl) amino] cyclopent-2 -enylmethanol in the presence of diisopropylethylamine (IS, 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 celite. 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)
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, characterized in that 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 an alkali metal bicarbonate or alkali earth metal bicarbonate or in the presence of an alkali metal carbonate or 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 , characterized in that the polar protic solvent used is a Ci-4-alcohol.
3. Process according to Claims 1 or 2, characterized in that the reaction is carried out at a temperature of from 20 °C to the reflux temperature of the solvent in question. ΙΖΖΑΤΤΟ & LUZZATTO
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98120529 | 1998-10-30 | ||
| US14610599P | 1999-07-29 | 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 |
|---|---|
| IL142760A0 IL142760A0 (en) | 2002-03-10 |
| IL142760A true IL142760A (en) | 2005-12-18 |
Family
ID=56289961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL14276099A IL142760A (en) | 1998-10-30 | 1999-10-29 | Method for producing 4-Ä(2',5'-diamino-6'- halopyrimidine-4' -yl) aminoÜ-cyclopent -2- enyl-methanols |
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 |
|---|---|---|---|---|
| US6433170B1 (en) | 1998-10-30 | 2002-08-13 | Lonza Group | Method for producing 4-[2',5'-diamino-6'-halopyrimidine-4'-yl)amino]- 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 |
| AU2009203598B2 (en) | 2008-01-08 | 2013-09-26 | Merck Sharp & Dohme Llc | Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3- yl]phenyl} -2H-indazole-7-carboxamide |
| 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 |
|---|---|---|---|---|
| AT397801B (en) * | 1988-01-20 | 1994-07-25 | Univ Minnesota | DIDESOXYDEHYDROCARBOCYCLIC NUCLEOSIDES AND THEIR USE |
| 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 |
| CA2253977C (en) * | 1996-05-30 | 2009-08-04 | Lonza Ag | Process for the preparation of amino alcohols and derivatives thereof |
-
1999
- 1999-10-29 AU AU11580/00A patent/AU1158000A/en not_active Abandoned
- 1999-10-29 JP JP2000579582A patent/JP4457496B2/en not_active Expired - Fee Related
- 1999-10-29 ES ES99971416T patent/ES2200594T3/en not_active Expired - Lifetime
- 1999-10-29 SK SK569-2001A patent/SK285271B6/en not_active IP Right Cessation
- 1999-10-29 IL IL14276099A patent/IL142760A/en not_active IP Right Cessation
- 1999-10-29 CN CN99812845A patent/CN1115338C/en not_active Expired - Fee Related
- 1999-10-29 EP EP99971416A patent/EP1124805B1/en not_active Expired - Lifetime
- 1999-10-29 CZ CZ20011486A patent/CZ300155B6/en not_active IP Right Cessation
- 1999-10-29 CA CA002348374A patent/CA2348374C/en not_active Expired - Fee Related
- 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 PL PL347503A patent/PL198180B1/en unknown
- 1999-10-29 WO PCT/EP1999/008270 patent/WO2000026193A1/en active IP Right Grant
- 1999-10-29 DK DK99971416T patent/DK1124805T3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ES2200594T3 (en) | 2004-03-01 |
| CN1325386A (en) | 2001-12-05 |
| CN1115338C (en) | 2003-07-23 |
| IL142760A0 (en) | 2002-03-10 |
| HU227559B1 (en) | 2011-08-29 |
| CZ20011486A3 (en) | 2001-10-17 |
| EP1124805B1 (en) | 2003-05-21 |
| AU1158000A (en) | 2000-05-22 |
| WO2000026193A1 (en) | 2000-05-11 |
| SK5692001A3 (en) | 2001-12-03 |
| ATE240945T1 (en) | 2003-06-15 |
| EP1124805A1 (en) | 2001-08-22 |
| CZ300155B6 (en) | 2009-02-25 |
| CA2348374C (en) | 2009-04-07 |
| JP4457496B2 (en) | 2010-04-28 |
| DK1124805T3 (en) | 2003-09-15 |
| JP2003500333A (en) | 2003-01-07 |
| HUP0104045A2 (en) | 2002-05-29 |
| PL198180B1 (en) | 2008-06-30 |
| CA2348374A1 (en) | 2000-05-11 |
| PL347503A1 (en) | 2002-04-08 |
| HUP0104045A3 (en) | 2002-07-29 |
| SK285271B6 (en) | 2006-10-05 |
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Legal Events
| Date | Code | Title | Description |
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| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |