CN105198864B - A kind of non-solvent preparation of cyclopenta pyrimidine compound - Google Patents

A kind of non-solvent preparation of cyclopenta pyrimidine compound Download PDF

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Publication number
CN105198864B
CN105198864B CN201510687681.8A CN201510687681A CN105198864B CN 105198864 B CN105198864 B CN 105198864B CN 201510687681 A CN201510687681 A CN 201510687681A CN 105198864 B CN105198864 B CN 105198864B
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reaction
solvent
pyrimidine compound
cyclopenta pyrimidine
improves
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CN105198864A (en
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冯新光
李学超
李伟
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Huaren Pharmaceutical Co Ltd
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Huaren Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to a kind of non-solvent preparations of cyclopenta pyrimidine compound, belong to chemical preparation process field.The non-solvent preparation of the cyclopenta pyrimidine compound (SM-C) generates SM-C with SM-B solvent-free reactions under alkaline condition using SM-A.This method avoids the uses of organic solvent, reduce production cost, reduce environmental pollution, and post-processing simplifies without removing organic solvent；Due to being solvent-free reaction, reaction volume substantially reduces, and improves equipment capacity；Due to being solvent-free reaction, reactant concentration improves, and reaction raw materials conversion ratio improves, and reaction rate improves, and the reaction time substantially shortens；Meanwhile reaction can produce in atmospheric conditions, be not necessarily to autoclave, be conducive to produce.

Description

A kind of non-solvent preparation of cyclopenta pyrimidine compound
Technical field
The present invention relates to a kind of non-solvent preparations of cyclopenta pyrimidine compound, belong to chemical preparation process field.
Background technology
Ticagrelor is a kind of novel, selective of Britain's AstraZeneca (AstraZeneca) company research and development Small molecule anticoagulant.The medicine can reversibly on vasoactive smooth muscle cell (VSMC) 2 receptor of purine (purinoceptor 2, P2) hypotype P2Y12, does not need metabolic activation, to platelet aggregation caused by adenosine diphosphate (ADP) (ADP) There is apparent inhibiting effect, and it is rapid to work after being administered orally, and can effectively improve the symptom of acute coronary patient.
Cyclopenta pyrimidine compound (SM-C) is the important intermediate of ticagrelor, and preparation method is as follows：
SM-A or its salt under alkaline condition, react with SM-B generate SM-C in organic solvent.
SM-A salts are mostly white solid powder, and fusing point is higher, therefore when it is reacted with SM-B, need to add solvent, make Reaction is smoothed out.Patent WO 2001092263 is salt compressive reaction life in alkaline condition, organic solvent with SM-B of SM-A At SM-C；Patent WO 2010030224 is salt compressive reaction generation in alkaline hypoxia condition, organic solvent with SM-B of SM-A SM-C；Patent CN103626745 is that the synthesis under normal pressure in alkaline condition, high boiling organic solvent generates with SM-B for SM-A or its salt SM-C is conducive to produce this method avoid the use of autoclave.The prior art is made a general survey of, the reaction is all organic It is reacted under solvent condition, although the use of high boiling organic solvent can be to avoid the use later stage higher boiling of autoclave Eliminating for organic solvent is more difficult.
Invention content
The object of the present invention is to provide a kind of non-solvent preparation of cyclopenta pyrimidine compound, the preparation method with SM-A and SM-B under alkaline condition, is not added with organic solvent, and heating reaction prepares cyclopenta pyrimidine compound SM-C；This method is kept away The use of organic solvent is exempted from, post-processing simplifies without removing organic solvent, and reaction can produce in atmospheric conditions, is not necessarily to high pressure Reaction kettle, reaction volume substantially reduce, and the reaction time substantially shortens, and are conducive to produce.
The technical scheme is that：
A kind of non-solvent preparation of cyclopenta pyrimidine compound (SM-C) using following reaction formula be condensed anti- It answers：
Wherein：SM-A generates SM-C with SM-B solvent-free reactions under alkaline condition.
Further, the alkali is triethylamine or n,N-diisopropylethylamine, particularly preferred n,N-diisopropylethylamine.
Further, the reaction temperature is 90-140 DEG C, preferably 120-130 DEG C.
Further, the reaction time is 5-50 hours, preferably 8-12 hours.
Further, the reactant molar ratio is SM-A:SM-B：Alkali=1：1：1-10, preferably SM-A:SM-B： Alkali=1：1：1.5-2.5.
Compared with prior art, beneficial effects of the present invention are：
(1) SM-A fusing points are relatively low in the present invention, are solution under heating condition, and organic solvent, drop can not be used in reaction Low production cost, reduces environmental pollution, and post-processing simplifies without removing organic solvent.
(2) due to being solvent-free reaction, reaction volume substantially reduces, and improves equipment capacity.
(3) due to being solvent-free reaction, reactant concentration improves, and reaction raw materials conversion ratio improves, and reaction rate improves, instead Substantially shorten between seasonable.
(4) simultaneously, reaction can produce in atmospheric conditions, be not necessarily to autoclave, be conducive to produce.
Specific implementation mode
The present invention is explained in detail with reference to embodiments.
Embodiment 1
500ml three-necked flasks are taken, are protected equipped with condensing reflux pipe and nitrogen ball, 2- [[(3AR, 4S, 6R, 6AS) -6- are added Amino tetrahydrochysene -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygroup] ethyl alcohol (88.7g, 408.3mmol, 1.0eq), 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines (98.0g, 408.3mmol, 1.0eq), N, N- bis- Wopropyl ethyl amine (79.1g, 612.5mmol, 1.5eq), (HPLC is detected 120-125 DEG C of heating stirring, peak area percentage within 10 hours Than 4,6-, bis- chloro- 2- (rosickyite base) -5- aminopyrimidines < 1.0%), stop heating and be cooled to 60 DEG C of <, be added ethyl acetate and Water washing extracts.It is concentrated under reduced pressure into ethyl acetate residue 200ml, petroleum ether recrystallization is added, obtains off-white powder 160g, yield 93.5%, HPLC peak area percent SM-C >=98.5%.
Embodiment 2
500ml three-necked flasks are taken, are protected equipped with condensing reflux pipe and nitrogen ball, 2- [[(3AR, 4S, 6R, 6AS) -6- are added Amino tetrahydrochysene -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygroup] ethyl alcohol (88.7g, 408.3mmol, 1.0eq), 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines (98.0g, 408.3mmol, 1.0eq), N, N- bis- Wopropyl ethyl amine (105.5g, 816.6mmol, 2.0eq), (HPLC is detected 120-125 DEG C of heating stirring, peak area hundred within 10 hours Divide ratio 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines < 1.0%), stop heating and is cooled to 60 DEG C of <, ethyl acetate is added It is extracted with water washing.It is concentrated under reduced pressure into ethyl acetate residue 200ml, petroleum ether recrystallization is added, obtains off-white powder 152.7g, Yield 89%, HPLC peak area percent SM-C >=98.5%.
Embodiment 3
500ml three-necked flasks are taken, are protected equipped with condensing reflux pipe and nitrogen ball, 2- [[(3AR, 4S, 6R, 6AS) -6- are added Amino tetrahydrochysene -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygroup] ethyl alcohol (88.7g, 408.3mmol, 1.0eq), 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines (98.0g, 408.3mmol, 1.0eq), N, N- bis- Wopropyl ethyl amine (131.9g, 1020.75mmol, 2.5eq), (HPLC is detected 125-130 DEG C of heating stirring, peak area hundred within 8 hours Divide ratio 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines < 1.0%), stop heating and is cooled to 60 DEG C of <, ethyl acetate is added It is extracted with water washing.It is concentrated under reduced pressure into ethyl acetate residue 200ml, petroleum ether recrystallization is added, obtains off-white powder 150.5g, Yield 88%, HPLC peak area percent SM-C >=98.5%.
Embodiment 4
500ml three-necked flasks are taken, are protected equipped with condensing reflux pipe and nitrogen ball, 2- [[(3AR, 4S, 6R, 6AS) -6- are added Amino tetrahydrochysene -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygroup] ethyl alcohol (88.7g, 408.3mmol, 1.0eq), 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines (98.0g, 408.3mmol, 1.0eq), N, N- bis- Wopropyl ethyl amine (79.1g, 612.5mmol, 1.5eq), (HPLC is detected 110-115 DEG C of heating stirring, peak area within 20-30 hours Percentage 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines < 1.0%), stop heating and be cooled to 60 DEG C of <, acetic acid second is added Ester and water washing extraction.It is concentrated under reduced pressure into ethyl acetate residue 200ml, petroleum ether recrystallization is added, obtains off-white powder 158.7g, yield 92.5%, HPLC peak area percent SM-C >=98.5%.
Embodiment 5
500ml three-necked flasks are taken, are protected equipped with condensing reflux pipe and nitrogen ball, 2- [[(3AR, 4S, 6R, 6AS) -6- are added Amino tetrahydrochysene -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygroup] ethyl alcohol (88.7g, 408.3mmol, 1.0eq), 4,6- bis- chloro- 2- (rosickyite base) -5- aminopyrimidines (98.0g, 408.3mmol, 1.0eq), triethylamine (124g, 1226mmol, 3.0eq), being heated to return stirring 48 hours, (HPLC is detected, peak area percent 4, bis- chloro- 2- of 6- (rosickyite base) -5- aminopyrimidines < 8.0%), stop heating and be cooled to 60 DEG C of <, ethyl acetate and water washing extraction is added.Subtract Pressure is concentrated into ethyl acetate residue 200ml, and petroleum ether recrystallization is added, obtains off-white powder 154.8g, yield 90.5%, HPLC Peak area percent SM-C >=98.5%.

Claims (5)

1. a kind of non-solvent preparation of cyclopenta pyrimidine compound, which is characterized in that be condensed using following reaction formula Reaction：
Wherein：SM-A generates SM-C with SM-B solvent-free reactions under alkaline condition；
The reactant molar ratio is SM-A:SM-B：Alkali=1：1：1.5-2.5；
The alkali is triethylamine or N, N- diisopropylethylamine；
Reaction temperature is 110-130 DEG C.
2. the non-solvent preparation of cyclopenta pyrimidine compound according to claim 1, which is characterized in that the alkali For N, N- diisopropylethylamine.
3. the non-solvent preparation of cyclopenta pyrimidine compound according to claim 1, it is characterised in that：The reaction Temperature is 120-130 DEG C.
4. the non-solvent preparation of cyclopenta pyrimidine compound according to claim 1, it is characterised in that：The reaction Time is 5-50 hours.
5. the non-solvent preparation of cyclopenta pyrimidine compound according to claim 4, it is characterised in that：The reaction Time is 8-12 hours.
CN201510687681.8A 2015-10-21 2015-10-21 A kind of non-solvent preparation of cyclopenta pyrimidine compound Active CN105198864B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110862382A (en) * 2019-12-06 2020-03-06 华中药业股份有限公司 Improved preparation method of ticagrelor intermediate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (en) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 Preparation method for ticagrelor intermediate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (en) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 Preparation method for ticagrelor intermediate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
An efficient and simple methodology for the synthesis of 2-amino-4-(N-alkyl/arylamino)-6-chloropyrimidines;Khalid Mohammed Khan, et al.;《Tetrahedron Letters》;20150128;第56卷;1179-1182 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110862382A (en) * 2019-12-06 2020-03-06 华中药业股份有限公司 Improved preparation method of ticagrelor intermediate
CN110862382B (en) * 2019-12-06 2021-11-23 华中药业股份有限公司 Preparation method of ticagrelor intermediate

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