SK5692001A3 - 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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- SK5692001A3 SK5692001A3 SK569-2001A SK5692001A SK5692001A3 SK 5692001 A3 SK5692001 A3 SK 5692001A3 SK 5692001 A SK5692001 A SK 5692001A SK 5692001 A3 SK5692001 A3 SK 5692001A3
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- diamino
- amino
- cyclopent
- enylmethanols
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 8
- UXKZFJDNFBNQHE-UHFFFAOYSA-N (4-aminocyclopent-2-en-1-yl)methanol Chemical compound NC1CC(CO)C=C1 UXKZFJDNFBNQHE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000003586 protic polar solvent Substances 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- -1 alkaline earth metal carbonate Chemical class 0.000 claims description 12
- LMYOLOWXQDLHKQ-UHFFFAOYSA-N cyclopent-2-en-1-ylmethanol Chemical class OCC1CCC=C1 LMYOLOWXQDLHKQ-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- ZXWGHENZKVQKPX-UHFFFAOYSA-N 4,6-dichloropyrimidine-2,5-diamine Chemical compound NC1=NC(Cl)=C(N)C(Cl)=N1 ZXWGHENZKVQKPX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BMHFIBKQNGTAER-FBCCYDICSA-M Cl.N[C@H]1C=C[C@H](C1)CO.C(O)([O-])=O.[Na+] Chemical compound Cl.N[C@H]1C=C[C@H](C1)CO.C(O)([O-])=O.[Na+] BMHFIBKQNGTAER-FBCCYDICSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- JVSLVBYLHIRGJQ-UHFFFAOYSA-N n-[4-(hydroxymethyl)cyclopent-2-en-1-yl]acetamide Chemical compound CC(=O)NC1CC(CO)C=C1 JVSLVBYLHIRGJQ-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
Oblasť technikyTechnical field
Predložený vynález sa týka nového spôsobu výroby 4-[(2',5'-diamino-6'-halogónpyrimidín-4'-yl)amino]cyklopent-2-enylmetanolov. 4-[(2',5’-Diamino-6’-halogénpyrimidín-4'-yl)amino]cyklopent-2-enylmetanoly sú dôležité medziprodukty na výrobu antivirálnych derivátov nukleotidov (WO 91/01310).The present invention relates to a novel process for the preparation of 4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanols. 4 - [(2 ', 5'-Diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanols are important intermediates for the production of antiviral nucleotide derivatives (WO 91/01310).
Doterajší stav technikyBACKGROUND OF THE INVENTION
Známa je 3-stupňová syntéza 4-[2'I5'-diamino-6'-halogénpyrimidín-4'-yl)amino]cyklopent-2-enylmetanolu zo 4-acetamidocyklopent-2-enylmetanolu reakciou s 2-amino-4,6-dichlórpyrimidínu v butanole pomocou diizopropyletylamínu ako zásady. Pri tom sa najprv vytvorí [(2'-amino-6'-chlórpyrimidín-4'-yl)amino]cyklopent-2-enylmetanol, ktorý sa potom diazotáciou v nasledujúcom stupni premení na zodpovedajúci amín, ktorý sa potom hydrolyzuje na konečný produkt (J. Chem. Soc. Perkin. Trans., 1, 1992). Nedostatkom tohto spôsobu je nadmerná nákladovosť a menšie výťažky požadovaného konečného produktu.The known 3-step synthesis of 4- [2 'I, 5'-diamino-6'-halopyrimidine-4-yl) amino] cyclopent-2-enylmethanol of 4-Acetamidocyclopent-2-enylmethanol by reaction with 2-amino-4, 6-dichloropyrimidine in butanol using diisopropylethylamine as the base. In this case, [(2'-amino-6'-chloropyrimidin-4'-yl) amino] cyclopent-2-enylmethanol is formed first, which is then diazotized to the corresponding amine in the next step, which is then hydrolyzed to the final product ( J. Chem. Soc. Perkin Trans., 1, 1992). The disadvantage of this method is the excessive cost and lower yields of the desired end product.
Úlohou predloženého vynálezu je poskytnúť jednostupňový a tým lacnejší spôsob výroby 4-[(2',5'-diamino-6'-halogénpyrimidín-4'-yl)amino]cyklopent-2-enylmetanolov, pri ktorej sa požadované produkty získajú v dobrom výťažku.It is an object of the present invention to provide a one-step and thus cheaper process for the production of 4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-enylmethanols in which the desired products are obtained in good yield .
Táto úloha sa rieši spôsobom podľa nároku 1.This object is solved by the method of claim 1.
Podstata vynálezuSUMMARY OF THE INVENTION
Pri spôsobe výroby 4-[(2',5'-diamino-6'-halogénpyrimidín-4'-yl)amino]cyklopent-2enylmetanolov všeobecného vzorca IIn the process for preparing 4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-phenylmethanols of formula I
kde X znamená atóm halogénu ako F, Cl, Br alebo I, prekvapením bolo zistenie nasledujúcej skutočnosti. Ak sa namiesto 2-amino-4,6-dichlórpyrimidínu ako východiskového materiálu použije 2,5-diamino-4,6-diľialogénpyrimidín všeobecného vzorca IIwhere X represents a halogen atom such as F, Cl, Br or I, the following was surprising. When 2,5-diamino-4,6-di-di-pyrimidine (II) is used as the starting material in place of 2-amino-4,6-dichloropyrimidine
XX
(II) a ten sa v prítomnosti zásady v polárnom protickom rozpúšťadle nechá reagovať so 4-aminocyklopent-2-enylmetanolom vzorca III(II) and this is reacted with 4-aminocyclopent-2-enylmethanol of formula III in the presence of a base in a polar protic solvent
HOHO
NH2 (III) alebo s jeho soľou, získa sa požadovaný konečný produkt všeobecného vzorca I niekoľkonásobne lacnejšie a v dobrom výťažku.NH 2 (III) or a salt thereof, yielding the desired end product of formula I several times cheaper and in good yield.
2,5-Diamino-4,6-dihalogénpyrimidíny ako je 2,5-diamino-4,6-dichlórpyrimidín sa môžu vyrobiť podľa EP-A-0 684 326.2,5-Diamino-4,6-dihalopyrimidines such as 2,5-diamino-4,6-dichloropyrimidine can be prepared according to EP-A-0 684 326.
Ako 4-aminocyklopent-2-enylmetanoly sa môžu použiť ako racemické, tak aj opticky aktívne zlúčeniny, ako (1R,4S)-, (1S.4R)-, (1R.4R)-, alebo (1 S,4S)-4-aminocyklopent-2-enylmetanoly. Vhodné soli sú adičné soli kyselín, najmä hydro3Both racemic and optically active compounds such as (1R, 4S) -, (1S, 4R) -, (1R, 4R) -, or (1S, 4S) - can be used as 4-aminocyclopent-2-enylmethanols. 4-amino-cyclopent-2-enylmethanols. Suitable salts are acid addition salts, especially hydro3
halogenidové soli, napríklad hydrochloridy alebo hydrobromidy. 4-Aminocyklopent-2enylmetanoly, najmä (1R,4S)-, alebo (1S,4R)-enantioméry sa môžu vyrobiť podľa WO 97/45529.halide salts such as hydrochlorides or hydrobromides. 4-Aminocyclopent-2-phenylmethanol, especially the (1R, 4S) - or (1S, 4R) -enantiomers can be prepared according to WO 97/45529.
Účelne sa reakcia uskutočňuje v prítomnosti uhličitanu alkalického kovu alebo uhličitanu kovu alkalickej zeminy, hydrogénuhličitanu alkalického kovu alebo hydrogénuhličitanu kovu alkalickej zeminy alebo v prítomnosti dusíkatých zásad, ako napríklad terc. amínov, ako zásady. Ako uhličitan alkalického kovu alebo hydrogénuhličitan alkalického kovu sa môže použiť uhličitan sodný, uhličitan draselný alebo hydrogénuhličitan sodný alebo hydrogénuhličitan draselný. Ako uhličitan kovu alkalickej zeminy, prípadne hydrogénuhličitan kovu alkalickej zeminy sa môže použiť uhličitan vápenatý alebo uhličitan horečnatý alebo hydrogénuhličitan vápenatý. Ako terc. amíny sú vhodné napríklad trietylamín a diizopropyletylamín. Výhodne sa reakcia uskutočňuje v prítomnosti hydrogénuhličitanu alkalického kovu ako je hydrogénuhličitan sodný alebo v prítomnosti terc. amínu ako je diizopropyletylamín.Conveniently, the reaction is carried out in the presence of an alkali metal or alkaline earth metal carbonate, an alkali metal bicarbonate or an alkaline earth metal bicarbonate, or in the presence of nitrogenous bases such as tert. amines as bases. As the alkali metal carbonate or alkali metal bicarbonate, sodium carbonate, potassium carbonate or sodium bicarbonate or potassium bicarbonate may be used. As the alkaline earth metal carbonate or alkaline earth metal bicarbonate, calcium carbonate or magnesium carbonate or calcium bicarbonate may be used. Ako terc. amines are, for example, triethylamine and diisopropylethylamine. Preferably, the reaction is carried out in the presence of an alkali metal hydrogencarbonate such as sodium hydrogencarbonate or in the presence of tert. an amine such as diisopropylethylamine.
Zásada sa účelne použije v prebytku, vzťažené na 2,5-diamino-4,6-dihalogénpyrimidín, výhodne sa použijú 1 až 4 móly zásady na mól 2,5-diamino-4,6-dihalogénpyrimidínu.The base is conveniently used in excess based on 2,5-diamino-4,6-dihalopyrimidine, preferably 1 to 4 moles of base per mole of 2,5-diamino-4,6-dihalopyrimidine are used.
Ako poláme protické rozpúšťadlo sú vhodné najmä (^alkoholy, ako metanol, etanol, propanol a jeho izoméry a butanol a jeho izoméry.Particularly suitable as polar protic solvents are alcohols such as methanol, ethanol, propanol and its isomers and butanol and its isomers.
Reakcia sa účelne uskutočňuje pri teplote od 20 °C po teplotu spätného toku zodpovedajúceho rozpúšťadla, výhodne od 50 °C po teplotu spätného toku. Účelne sa 4-aminocyklopent-2-enylmetanol a 2,5-diamino-4,6-dihalogénpyrimidín použijú v ekvimolárnom množstve.The reaction is conveniently carried out at a temperature of from 20 ° C to the reflux temperature of the corresponding solvent, preferably from 50 ° C to reflux temperature. Suitably, 4-aminocyclopent-2-enylmethanol and 2,5-diamino-4,6-dihalopyrimidine are used in equimolar amounts.
Po zvyčajnej reakčnej dobe 2 až 20 hodín sa môžu konečné produkty vzorca I, výhodne (1S,4R)-4-[(2',5'-diamino-6'-halogénpyrimidín-4'-yl)amino]cyklopent-2enylmetanol, získať zvyčajnými metódami spracovania.After a usual reaction time of 2 to 20 hours, the end products of formula I, preferably (1S, 4R) -4 - [(2 ', 5'-diamino-6'-halopyrimidin-4'-yl) amino] cyclopent-2-phenylmethanol, obtained by the usual processing methods.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Výroba 4-[(2',5'-diamino-6'-chlórpyrimidín-4'-yl)amino]cyklopent-2-enylmetanolu v prítomnosti hydrogénuhličitanu sodného (1S,4R)-4-Aminocyklopent-2-enylmetanolhydrochlorid (0,14 mólov, 23,25 g), etanol (3 móly, 138,12 g, 176 ml), 2,5-diamino-4,6-dichlórpyrimidín (0,14 mólov, 25 g) a hydrogénuhličitan sodný (0,34 mólov, 28,68 g) sa vnieslo do suchého reaktora. Táto zmes sa zohrievala až po teplotu spätného toku (cca 80 °C) 16 hodín. Reakčné pomery (rýchlosť) sa testovali pomocou TLC s 13/1 metylénchloridom: metanol ako vyvíjači prostriedok. Reakčná zmes sa ochladila na teplotu miestnosti a miešala sa 45 minút. Soli sa odstránili filtráciou a filtračný koláč sa premyl 2-krát etanolom (0,86 mólov, 39,5 g, 50 ml).Preparation of 4 - [(2 ', 5'-diamino-6'-chloropyrimidin-4'-yl) amino] cyclopent-2-enylmethanol in the presence of sodium bicarbonate (1S, 4R) -4-Aminocyclopent-2-enylmethanol hydrochloride 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 moles, 28.68 g) was charged to a dry reactor. This mixture was heated to reflux (ca. 80 ° C) for 16 hours. Reaction rates (rate) were tested by TLC with 13/1 methylene chloride: methanol as a developing agent. The reaction mixture was cooled to room temperature and stirred for 45 minutes. The salts were removed by filtration and the filter cake was washed 2 times with ethanol (0.86 mol, 39.5 g, 50 mL).
Po tom, čo sa vákuovou destiláciou odstránili 2/3 organickej fázy, sa po kvapkách pridával hexán (150 ml). Suspenzia sa ochladila pod 10 °C. Po filtrácii sa sušila vákuové pri 50 °C.After 2/3 of the organic phase was removed by vacuum distillation, hexane (150 mL) was added dropwise. The suspension was cooled below 10 ° C. After filtration, it was dried under vacuum at 50 ° C.
Získalo sa 21,5 g (0,08 mólov) konečného produktu, čo zodpovedá 60% výťažku.21.5 g (0.08 mol) of the final product was obtained, corresponding to a 60% yield.
Príklad 2Example 2
Výroba 4-[(2',5'-diamino-6'-chlórpyrimidín-4'-yl)amino]cyklopent-2-enylmetanolu v prítomnosti diizopropyletylamínu (1S,4R)-4-Aminocyklopent-2-enylmetanolhydrochlorid (0,14 mólov, 23,18 g), butanol (1,26 mólov, 93,39 g, 115,3 ml), 2,5-diamino-4,6-dichlórpyrimidín (0,14 mólov, 25,67Preparation 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 mole, 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) a diizopropyletylamín (0,29 mólov, 37,09 g, 49,99 ml) sa vnieslo do suchého reaktora. Táto zmes sa zohrievala cez noc až po teplotu spätného toku (cca 115 °C).g) and diisopropylethylamine (0.29 mol, 37.09 g, 49.99 mL) was charged to a dry reactor. The mixture was heated overnight to reflux (ca. 115 ° C).
Reakčné pomery (rýchlosť) sa testovali pomocou TLC s 13/1 metylénchloridom:Reaction rates (rate) were tested by TLC with 13/1 methylene chloride:
metanol ako vyvíjači prostriedok. Reakčná zmes sa ochladila na teplotu miestnosti. Potom sa pridala voda s následným dvojnásobným extrahovaním s etylacetátom.methanol as developing agent. The reaction mixture was cooled to room temperature. Water was then added followed by extraction twice with ethyl acetate.
Organická fáza sa 2-krát premyla vodou a potom sa organická fáza filtrovala cez Celíte. Po tom, čo sa vákuovou destiláciou odstránili 2/3 organickej fázy, sa po kvapkách pridával hexán. Suspenzia sa ochladila pod 10 °C. Po filtrácii sa vákuovo sušila pri 50 °C.The organic phase was washed twice with water and then the organic phase was filtered through Celite. After 2/3 of the organic phase was removed by vacuum distillation, hexane was added dropwise. The suspension was cooled below 10 ° C. After filtration, it was vacuum dried at 50 ° C.
Získalo sa 21,47 g (0,08 molov) konečného produktu, čo zodpovedá 60% výťažku.21.47 g (0.08 mol) of the final product was obtained, corresponding to a 60% yield.
Claims (3)
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 |
|---|---|
| SK5692001A3 true SK5692001A3 (en) | 2001-12-03 |
| SK285271B6 SK285271B6 (en) | 2006-10-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK569-2001A SK285271B6 (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 |
|---|---|---|---|---|
| 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 |
| 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 |
| IL142760A (en) | 2005-12-18 |
| 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 |
|---|---|---|---|
| MM4A | Patent lapsed due to non-payment of maintenance fees |
Effective date: 20131029 |