CN103992277A - Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor - Google Patents
Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor Download PDFInfo
- Publication number
- CN103992277A CN103992277A CN201410207032.9A CN201410207032A CN103992277A CN 103992277 A CN103992277 A CN 103992277A CN 201410207032 A CN201410207032 A CN 201410207032A CN 103992277 A CN103992277 A CN 103992277A
- Authority
- CN
- China
- Prior art keywords
- rosickyite
- pyrimidines
- chloro
- bis
- amino
- 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.)
- Pending
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
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for preparing an intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor. The method is characterized by comprising the steps of dissolving 4,6-dichloro-5-nitro-2-propylthiouracil into a solvent; adding a dechlorinating inhibitor and a metal catalyst, and introducing hydrogen for reduction reaction so as to obtain 4,6-dichloro-5-amino-2-propylthiouracil; and recrystallizing by an organic solvent so as to obtain the product meeting the requirement of preparation of bulk drug. The preparation method has the advantages of environment protection, simple and convenient operation and low cost, overcomes the defects in the prior art, lowers the production cost and reduces environment pollution.
Description
Technical field
The invention belongs to technical field of organic synthesis, particularly a kind of ADZ6140 intermediate 4, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines.
Background technology
ADZ6140 (foreign language title: Ticagrelor, has another name called: ticagrelor) be U.S.'s AstraZeneca (AstraZeneca) company research and development a kind of novel, there is optionally small molecules anticoagulant.This medicine is the purine 2 acceptors (Purinoceptor 2 on vasoactive smooth muscle cell (VSMC) reversibly, P2) hypotype P2Y12, do not need metabolic activation, the platelet aggregation that adenosine diphosphate (ADP) (ADP) is caused has obvious restraining effect, and it is rapid to orally use rear onset, can effectively improve acute coronary patient's symptom.Different from Thienopyridines medicine, ADZ6140 is reversible inhibitor to P2Y12 acceptor, so for those need after carrying out anticoagulant therapy in advance, the patient of row operation be particularly applicable again.This medicine was ratified it in 2010 by drug administration of European Union (the English EMEA that is called for short) and is gone on the market in European Union, within 2011, ratifying it by FDA (Food and Drug Adminstration) (the English FDA that is called for short) goes on the market in the U.S., within 2012, passed through the approval of medicine control general bureau of India (the English DCGI of abbreviation) and state food and drug administration (the English SFDA of abbreviation), its preparation will be in India and Discussion on Chinese Listed.
The key intermediate of ADZ6140 is the chloro-5-amino-2-of 4,6-bis-rosickyite yl pyrimidines, and the method for preparing at present this intermediate mainly contains following two kinds:
Route 1:
Patent WO2007093368, WO2005095358, WO0192263 and document Bioorganic & Medicinal Chemistry Letters, 22 (11), 3598-3602,2012 adopt be route 1 preparation method, midbody compound is stable in process of production, process conditions is gentle for the method, but operational path is long, the low final cost of product that makes of yield is high, three industrial wastes are also many, are unfavorable for the large-scale industrial production of this product.
Wherein WO2005095358 uses expensive platinum carbon, platinum carbon vanadium or platinum carbon and other transition-metal catalysts, and the drawback of this catalyzer or the cost of product are high and be unfavorable for market competition;
WO0192263 uses expensive platinum carbon molybdenum catalyst, even if this catalyzer repeats to recycle, the cost of product is also higher and be unfavorable for market competition;
WO2007093368 and Bioorganic & Medicinal Chemistry Letters, 22 (11), 3598-3602, the two keys of 2012 use zinc powder/ammonium acetate reduction system azo-compound are singly-bound, then hydrazine class intermediate is reduced to amino with Raney's nickel, this preparation technology produces a lot containing the environmental pollution of zinc acetate solid waste deposits yields, and product cost is also higher;
Route 2:
That patent US20110071290, WO2005095358, CN102659691, WO2012138981, CN103130726 adopt is route 2 preparation methods, the method has with respect to route 1 easy, the clean environment firendly of production, meet the modernization industry pharmacy theory of environmental protection, but also have aborning weak point.
Wherein US20110071290 uses expensive platinum carbon molybdenum catalyst, even if this catalyzer repeats to recycle, the cost of product is also higher and be unfavorable for market competition;
WO2005095358 uses expensive platinum carbon, platinum carbon vanadium or platinum carbon and other transition-metal catalysts, and the drawback of this catalyzer or the cost of product are high and be unfavorable for market competition;
WO2012138981 and CN102659691 use reduced iron powder and glacial acetic acid as reductive agent, and this preparation technology produces the environmental pollution of a lot of iron mud solid waste deposits yields, and product cost is also higher;
CN103130726 uses V-Brite B as reductive agent, we carry out verification experimental verification to patent and find that 5 times of ability reduction that use equivalent to be at least substrate are complete, the product cost that this preparation technology produces is relatively cheap, but a large amount of has brought very large pressure containing V-Brite B waste water to environmental protection, environmental pollution is large especially, is unfavorable for very much suitability for industrialized production.
Summary of the invention
The invention provides a kind of ADZ6140 intermediate 4, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, its object is to solve current intermediate 4, the problem that product cost is high and environmental pollution is heavy that the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines exists.
For achieving the above object, the technical solution used in the present invention is: a kind of ADZ6140 intermediate 4, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, comprises the following steps:
The first step, by 4 shown in formula (6), the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines is dissolved in reaction solvent, adds dechlorination inhibitor and metal catalyst, passes into reduction reaction under hydrogen;
Wherein, described reaction solvent is selected from toluene, tetrahydrofuran (THF), N, dinethylformamide, N, any one in N-diethylformamide, dimethyl sulfoxide (DMSO), dioxane, methyl tertiary butyl ether, methyl alcohol, ethanol, propyl alcohol, Virahol and water or at least two kinds are mixed into the mixture of homogeneous phase with arbitrary proportion; Described 4, the mass volume ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and reaction solvent is 1:1 ~ 20, and unit is g/mL;
Described dechlorination inhibitor is selected from any one or at least two kinds of mixtures with arbitrary proportion in triethylene tetramine, hexahydroaniline, Dyhard RU 100, thanomin and thiazolamine; Described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and dechlorination inhibitor is 100:0.1 ~ 15;
Described metal catalyst is palladium carbon or Raney's nickel; Described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and metal catalyst is 100:0.1 ~ 20;
Second step, filters after to be restored reacting completely, washs, is dried, and obtains the ADZ6140 intermediate 4 shown in formula (1), the crude product of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, and reaction formula is as follows:
The 3rd step, the crude product more described second step being obtained obtains the ADZ6140 intermediate 4 shown in formula (1) by organic solvent recrystallization, the sterling of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, wherein, described 4, the mass volume ratio of 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines and organic solvent is 1:1 ~ 30, and unit is g/mL.
Related content in technique scheme is explained as follows:
1,, in such scheme, described mass volume ratio refers to such an extent that be quality: volume, i.e. W:V.
2, in such scheme, preferably scheme is described 4, and the mass volume ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and reaction solvent is 1:3 ~ 6, and unit is g/mL.
3, in such scheme, preferably scheme is described 4, and the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and dechlorination inhibitor is 100:1 ~ 3.
4, in such scheme, preferably scheme is described 4, and the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and metal catalyst is 100:1 ~ 2.5.
5,, in such scheme, preferably scheme is that under the hydrogen of the described the first step, the condition of reduction reaction is: reaction pressure is 0.03MPa ~ 10MPa, and temperature of reaction is 0 DEG C ~ 150 DEG C; More preferred scheme is that reaction pressure is 0.15 ~ 5MPa, and temperature of reaction is 20 ~ 50 DEG C.
6,, in such scheme, preferably scheme is that the organic solvent of described the 3rd step is selected from any one or at least two kinds of mixtures with arbitrary proportion in hexanaphthene, normal hexane, hexane, heptane, butyl ether, isopropyl ether, methyl tertiary butyl ether, sherwood oil.These organic solvents of selecting carry out recrystallization, and in the product finally obtaining, impurity is low.
7, in such scheme, preferably scheme is described 4, and the mass volume ratio of 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines and organic solvent is 1:6 ~ 9.
8,, in such scheme, preferably scheme is that the recrystallization temperature of described the 3rd step is-30 DEG C ~ 5 DEG C.The recrystallization temperature that more preferred scheme is described the 3rd step is-5 ~-15 DEG C.
The principle of the invention and beneficial effect are: in preparation method of the present invention, reaction solvent used is conducive to the dissolving of hydrogen and substrate, can also reduce the amino generation that waits by product; The effect of dechlorination inhibitor used is to prevent that the chlorine atom on reactant from removing; Metal catalyst used and dechlorination inhibitor are used in conjunction with, to ensure that catalyzed reaction carries out smoothly.The catalyzer using in preparation method of the present invention is cheap, organic solvent used in recrystallization process is safer, 4, the rate of recovery high (reaching more than 80%) of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, purity reaches more than 99%, meets the requirement of raw materials medicine, simple to operate, environmental protection, cost is low, is applicable to large-scale industrial production.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
Embodiment 1:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g), ethanol (400mL) and Virahol (400mL) mixing solutions add in the autoclave of inflated with nitrogen; under nitrogen protection, dechlorination inhibitor Dyhard RU 100 (0.5g), palladium catalyst charcoal (8.0g, 10%W/W) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL washed with isopropyl alcohol catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 147.4g crude product.
Embodiment 2:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g) and methyl alcohol (800mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor thanomin (4.0g), catalyzer Raney's nickel (4.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL methanol wash catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 154.1g crude product.
Embodiment 3:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g) and methyl alcohol (800mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor thanomin (3.0g), Dyhard RU 100 (1.0g) and catalyzer Raney's nickel (4.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL methanol wash catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 153.9g crude product.
Embodiment 4:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g), ethanol (400mL) and methyl alcohol (400mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor thanomin (4.0g), catalyzer Raney's nickel (4.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL methanol wash catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 153.9g crude product.
Embodiment 5:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g) and propyl alcohol (800mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor thiazolamine (4.0g), catalyzer Raney's nickel (6.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL propyl alcohol washing catalyst.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 148.3g crude product.
Embodiment 6:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g), deionized water (200mL) and ethanol (600mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor hexahydroaniline (4.0g), catalyzer Raney's nickel (4.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL washing with alcohol catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 147.1g crude product.
Embodiment 7:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g), N; dinethylformamide (500mL) and tetrahydrofuran (THF) (300mL) mixing solutions add in the autoclave of inflated with nitrogen; under nitrogen protection, dechlorination inhibitor triethylene tetramine (1.0g), palladium catalyst charcoal (8.0g, 10%W/W) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL washed with isopropyl alcohol catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 146.5g crude product.
Embodiment 8:
By 4; 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (150.0g) and methyl alcohol (800mL) mixing solutions add in the autoclave of inflated with nitrogen, under nitrogen protection, dechlorination inhibitor Dyhard RU 100 (0.5g), catalyzer Raney's nickel (4.0g) are added in autoclave.Nitrogen 2 times in unlatching stirring displacement still, then use hydrogen exchange nitrogen 3 times.Pressurized with hydrogen to 1.9 for autoclave ~ 2.0Mpa, is slowly warming up to 35 ~ 40 DEG C of reactions.Sampling analysis is cooled to room temperature after raw material disappears, and filtering catalyst under nitrogen, with 40mL methanol wash catalyzer.Merging filtrate and washing lotion, under 40 DEG C of water-baths, vacuum concentration, to dry, obtains brown oil 153.8g crude product.
Embodiment 9:
Under nitrogen protection by 4; 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines (100.0g) crude product, hexanaphthene (800mL) and gac (5.0g) add in 2000mL flask; stirring and dissolving, filtration; after be cooled to-5 DEG C ~-10 DEG C; be incubated 30 minutes; filter, with cooling hexanaphthene 30mL washing, vacuum-drying obtains 85.7g off-white color crystal.Be 99.8%(area normalization method by HPLC purity assay).
Embodiment 10:
Under nitrogen protection by 4; 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines (100.0g) crude product, butyl ether (750mL) and gac (5.0g) add in 2000mL flask; stirring and dissolving, filtration; after be cooled to-5 DEG C ~-10 DEG C; be incubated 30 minutes; filter, with cooling butyl ether 30mL washing, vacuum-drying obtains 83.4g off-white color crystal.Be 99.7%(area normalization method by HPLC purity assay).
Embodiment 11:
Under nitrogen protection by 4; 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines (100.0g) crude product, isopropyl ether (300mL), butyl ether (450mL) and gac (5.0g) add in 2000mL flask; stirring and dissolving, filtration; after be cooled to-5 DEG C ~-10 DEG C; be incubated 30 minutes; filter, with cooling butyl ether 30mL washing, vacuum-drying obtains 84.9g off-white color crystal.Be 99.8%(area normalization method by HPLC purity assay).
In above-described embodiment, described reaction solvent can also be selected toluene, tetrahydrofuran (THF), N, dinethylformamide, N, any one in N-diethylformamide, dimethyl sulfoxide (DMSO), dioxane, methyl tertiary butyl ether, propyl alcohol and water or at least two kinds are mixed into the mixture of homogeneous phase with arbitrary proportion; Described dechlorination inhibitor can also be selected any one or at least two kinds of mixtures with arbitrary proportion in triethylene tetramine, hexahydroaniline and thiazolamine; Organic solvent in recrystallization process can also be selected any one or at least two kinds of mixtures with arbitrary proportion in normal hexane, hexane, heptane, methyl tertiary butyl ether, sherwood oil.
Above-described embodiment is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (10)
1. an ADZ6140 intermediate 4, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: described preparation method comprises the following steps:
The first step, by 4 shown in formula (6), the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines is dissolved in reaction solvent, adds dechlorination inhibitor and metal catalyst, passes into reduction reaction under hydrogen;
Wherein, described reaction solvent is selected from toluene, tetrahydrofuran (THF), N, dinethylformamide, N, any one in N-diethylformamide, dimethyl sulfoxide (DMSO), dioxane, methyl tertiary butyl ether, methyl alcohol, ethanol, propyl alcohol, Virahol and water or at least two kinds are mixed into the mixture of homogeneous phase with arbitrary proportion; Described 4, the mass volume ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and reaction solvent is 1:1 ~ 20, and unit is g/mL;
Described dechlorination inhibitor is selected from any one or at least two kinds of mixtures with arbitrary proportion in triethylene tetramine, hexahydroaniline, Dyhard RU 100, thanomin and thiazolamine; Described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and dechlorination inhibitor is 100:0.1 ~ 15;
Described metal catalyst is palladium carbon or Raney's nickel; Described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and metal catalyst is 100:0.1 ~ 20;
Second step, filters after to be restored reacting completely, washs, is dried, and obtains the ADZ6140 intermediate 4 shown in formula (1), the crude product of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, and reaction formula is as follows:
；
The 3rd step, the crude product more described second step being obtained obtains the ADZ6140 intermediate 4 shown in formula (1) by organic solvent recrystallization, the sterling of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, wherein, described 4, the mass volume ratio of 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines and organic solvent is 1:1 ~ 30, and unit is g/mL.
2. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, it is characterized in that: described 4, the mass volume ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and reaction solvent is 1:3 ~ 6, and unit is g/mL.
3. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and dechlorination inhibitor is 100:1 ~ 3.
4. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: described 4, the mass ratio of 6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines and metal catalyst is 100:1 ~ 2.5.
5. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, it is characterized in that: under the hydrogen of the described the first step, the condition of reduction reaction is: reaction pressure is 0.03MPa ~ 10MPa, temperature of reaction is 0 DEG C ~ 150 DEG C.
6. ADZ6140 intermediate 4 according to claim 5, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, it is characterized in that: under the hydrogen of the described the first step, the condition of reduction reaction is: reaction pressure is 0.15 ~ 5MPa, temperature of reaction is 20 ~ 50 DEG C.
7. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: the organic solvent of described the 3rd step is selected from any one or at least two kinds of mixtures with arbitrary proportion in hexanaphthene, normal hexane, hexane, heptane, butyl ether, isopropyl ether, methyl tertiary butyl ether, sherwood oil.
8. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: described 4, the mass volume ratio of 6-bis-chloro-5-amino-2-rosickyite yl pyrimidines and organic solvent is 1:6 ~ 9.
9. ADZ6140 intermediate 4 according to claim 1, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: the recrystallization temperature of described the 3rd step is-30 DEG C ~ 5 DEG C.
10. ADZ6140 intermediate 4 according to claim 9, the preparation method of the chloro-5-amino-2-of 6-bis-rosickyite yl pyrimidines, is characterized in that: the recrystallization temperature of described the 3rd step is-5 ~-15 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410207032.9A CN103992277A (en) | 2014-05-16 | 2014-05-16 | Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410207032.9A CN103992277A (en) | 2014-05-16 | 2014-05-16 | Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103992277A true CN103992277A (en) | 2014-08-20 |
Family
ID=51306645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410207032.9A Pending CN103992277A (en) | 2014-05-16 | 2014-05-16 | Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103992277A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218729A (en) * | 2018-02-28 | 2018-06-29 | 江苏优普生物化学科技股份有限公司 | The method that hydrogenating reduction synthesizes 2,4,4 '-three chloro- 2 '-amino-diphenylethers |
| CN111253321A (en) * | 2019-09-12 | 2020-06-09 | 大连大学 | Preparation method of 2-methoxy-5-amino-4-methylpyrimidine |
| CN111763175A (en) * | 2020-07-23 | 2020-10-13 | 广州康瑞泰药业有限公司 | Purification method of 4, 6-dichloro-2- (thiopropyl) -5-aminopyrimidine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005095358A2 (en) * | 2004-03-31 | 2005-10-13 | Astrazeneca Ab | Process for the preparation of aminopyrimidines |
| CN101774930A (en) * | 2010-02-10 | 2010-07-14 | 江苏康恒化工有限公司 | Method for preparing m-chloro aniline |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| CN103130726A (en) * | 2013-02-07 | 2013-06-05 | 许学农 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine |
| CN103288748A (en) * | 2013-06-21 | 2013-09-11 | 四川铂瑞生物医药有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
-
2014
- 2014-05-16 CN CN201410207032.9A patent/CN103992277A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005095358A2 (en) * | 2004-03-31 | 2005-10-13 | Astrazeneca Ab | Process for the preparation of aminopyrimidines |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| CN101774930A (en) * | 2010-02-10 | 2010-07-14 | 江苏康恒化工有限公司 | Method for preparing m-chloro aniline |
| CN103130726A (en) * | 2013-02-07 | 2013-06-05 | 许学农 | Preparation method of Ticagrelor intermediate 4,6-dichloro-2-(pyridinecarboxylic)-5- aminopyrimidine |
| CN103288748A (en) * | 2013-06-21 | 2013-09-11 | 四川铂瑞生物医药有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
Non-Patent Citations (2)
| Title |
|---|
| 吴倩倩，等: "2-丙硫基-4,6-二氯-5-氨基嘧啶的合成", 《中国医药工业杂志》 * |
| 强根荣，等: "《综合化学实验》", 31 August 2010, 化学工业出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218729A (en) * | 2018-02-28 | 2018-06-29 | 江苏优普生物化学科技股份有限公司 | The method that hydrogenating reduction synthesizes 2,4,4 '-three chloro- 2 '-amino-diphenylethers |
| CN111253321A (en) * | 2019-09-12 | 2020-06-09 | 大连大学 | Preparation method of 2-methoxy-5-amino-4-methylpyrimidine |
| CN111763175A (en) * | 2020-07-23 | 2020-10-13 | 广州康瑞泰药业有限公司 | Purification method of 4, 6-dichloro-2- (thiopropyl) -5-aminopyrimidine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102295638B (en) | Novel method for preparing lapatinib | |
| CN104892623B (en) | A kind of preparation method of 5 Isosorbide Mononitrate | |
| CN103992277A (en) | Method for preparing intermediate 4,6-dichloro-5-amino-2-propylthiouracil of ticagrelor | |
| CN110885985B (en) | Preparation method of deuterated chemical | |
| CN106881085A (en) | The catalyst and preparation method and process for selective hydrogenation of hydroquinones hydrogenation | |
| CN106543017B (en) | A kind of preparation method of 4 aminocyclohexyl acetic acid | |
| Gong et al. | Sulfonic acid functionalized covalent organic frameworks as efficient catalyst for the one-pot tandem reactions | |
| Cui et al. | Direct Iodosulfonylation of Alkylynones with Sulfonylhydrazides and Iodine Pentoxide Leading to Multisubstituted α, β-Enones | |
| CN103638949B (en) | A kind of preparation of nano nickel/silver/copper composite catalyst and application thereof | |
| CN107304177B (en) | Chemical preparation method of benzoyl peroxide micronization | |
| CN113024385A (en) | Preparation method of 2,2 '-bis (trifluoromethyl) -4, 4' -diaminobiphenyl | |
| CN102172528A (en) | 1,5-dinitronaphthalene hydrogenation catalyst, and preparation method and application thereof | |
| CN103113288A (en) | Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative | |
| CN109574797A (en) | A kind of preparation method of chirality benzylalcohol | |
| CN113173953B (en) | Purification method of high-purity lobaplatin trihydrate for preparing antitumor drugs | |
| CN108558758A (en) | A kind of synthetic method of 4- fluorine isoquinolin -5- amine | |
| CN104910095B (en) | The preparation method of 4-replacement-thiazolamine compound | |
| CN103570619B (en) | A kind of preparation method of montelukast sodium derivative | |
| CN104402830A (en) | Synthesis method of 2-chloropyrimidine | |
| CN104861032A (en) | Glycyrrhetinic acid 11-site carbonyl structure modification method | |
| CN109704955A (en) | Deuterated Rhein and its preparation method and application | |
| CN104086452A (en) | Method for preparing high-purity (3,4-diaminophenyl)(4-fluorophenyl) ketone by virtue of catalytic hydrogenation | |
| CN108863900A (en) | A kind of preparation method of 5- fluoro indole -2- ketone | |
| CN105348278B (en) | A kind of preparation method of butanedioic acid Solifenacin impurity | |
| CN103450284B (en) | One prepares 3-methyl isophthalic acid, the method for 3-diferrocenyl propylene-1-ketone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140820 |