CN102659691A - Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine - Google Patents

Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine Download PDF

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CN102659691A
CN102659691A CN2012101619236A CN201210161923A CN102659691A CN 102659691 A CN102659691 A CN 102659691A CN 2012101619236 A CN2012101619236 A CN 2012101619236A CN 201210161923 A CN201210161923 A CN 201210161923A CN 102659691 A CN102659691 A CN 102659691A
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rosickyite
pyrimidines
dihydroxyl
chloro
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CN102659691B (en
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宋文同
姚松芝
谢鸿霞
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Shandong Chengchuang Blue Sea Pharmaceutical Technology Co ltd
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SHANDONG CHENGCHUANG MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
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Abstract

The invention provides a method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine. The method comprises the following steps: 1, adding 4,6-dyhydroxy-2-mercaptopyrimidine into water, dripping a 10 percent sodium hydroxide solution, adding methanol and 1-bromopropane, reacting by keeping temperature, and acidifying to separate out crystals so as to obtain 4,6-dyhydroxy-2-(propylthio)pyrimidine; 2, adding fuming nitric acid into glacial acetic acid, adding the 4,6-dyhydroxy-2-(propylthio)pyrimidine, and adding water to separate out crystals so as to obtain 4,6-dyhydroxy-5-nitro-2-(propylthio)pyrimidine; 3, adding a chloro agent into dichloromethane, adding the 4,6-dyhydroxy-5-nitro-2-(propylthio)pyrimidine in batches, adding saturated brine, and postprocessing to obtain 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine; and 4, adding iron powder into an organic solvent, adding the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine in batches, adding dichloromethane and water to dissolve residue, demixing, evaporating an organic layer to dryness under reduced pressure obtain an oily product, and adding a crystallizing solvent to obtain the 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine. The method overcomes defects of the prior art, so that production cost is reduced.

Description

A kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines
Technical field
The present invention relates to medicine, is a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines.
Background technology
Gray is a kind of optionally anticoagulant for card; It also is first reversible mating type P2Y12 adp receptor antagonist; Purine 2 receptor subtype P2Y12 on the ability reversibility ground vasoactive smooth muscle cell; The platelet aggregation that ADP is caused has the obvious suppression effect, can effectively improve acute coronary patient's symptom.And replace the midbody of card Gray most critical is 4,6-two chloro-5-amino-2-rosickyite yl pyrimidines, and the method for preparing this midbody at present is generally two kinds, route 1:
Figure 276514DEST_PATH_IMAGE001
The deficiency of this method is: the 1-iodo propane prices of employing is expensive, and cost is higher; It is nitrated directly to adopt a large amount of nitrosonitric acids (midbody and nitrosonitric acid mol ratio are 1:21) to carry out, and nitrosonitric acid concentration is 98%, and it is directly nitrated not add any reagent; Not only consumption is big; And dangerous high, and can destroy 4,6-dihydroxyl-2-rosickyite yl pyrimidines; Side reaction increases, thereby causes productive rate to reduce; Carry out chloro with the POCl3 reflux, temperature of reaction is high, and side reaction is many, needs chromatographic purification, needs a large amount of solvents and the wash-out of long period, causes preparation cycle long, and workload is big, and yield is lower; Route 2:
Figure 661359DEST_PATH_IMAGE002
The deficiency of this method is: the 1-iodo propane of employing, and SL 1332 and platinum C catalyst cost an arm and a leg, and cost is higher; Reaction conditionss such as azoization and pressurization hydrogenating reduction require harsh, and productive rate and purity are difficult to also guarantee that the product postprocessing complicacy is unfavorable for large-scale commercial prodn.And above-mentioned two kinds of equal difficulties of method are applicable to suitability for industrialized production, and then cause the production cost height for card Gray, and price is reduced than difficult, bring heavier economical load to the patient.
Summary of the invention
The purpose of this invention is to provide a kind ofly 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines makes its solve the deficiency of prior art, and then reduces production costs.
The present invention realizes through following technical scheme for realizing above-mentioned purpose: a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines comprises the steps:
With 4,6-dihydroxyl-2-mercaptopyrimidine adds in the entry
Figure 54294DEST_PATH_IMAGE003
, drip 10% sodium hydroxide solution dissolving after; Add methyl alcohol and 1-bromo propane,, be cooled to room temperature at 40-45 ℃ of following insulation reaction 15-20 hour; The acidifying crystallization; Obtain 4,6-dihydroxyl-2-rosickyite yl pyrimidines, the mass ratio of sodium hydroxide solution and methyl alcohol is 1:1; 4; The mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and water is 0.14:2,4, and the mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and 1-bromo propane is 1:1.7-1.8;
Figure 360642DEST_PATH_IMAGE004
adds nitrosonitric acid in the glacial acetic acid, and low temperature adds 4 down, 6-dihydroxyl-2-rosickyite yl pyrimidines; After reaction finishes; Add the elutriation crystalline substance, obtain 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines; 4; The mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and glacial acetic acid is 1:1,4, and the mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and nitrosonitric acid is 1:1.3-1.4;
Under
Figure 127085DEST_PATH_IMAGE005
low temperature chlorinating agent is added in the methylene dichloride, add 4 in batches, 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines; After reaction finishes; Add saturated brine, aftertreatment obtains 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines; 4; The mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and methylene dichloride is 1:5,4, and the mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and chlorinating agent is 1:2.7-2.8;
Figure 366437DEST_PATH_IMAGE006
adds iron powder in the organic solvent, adds 4 in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines; After insulation reaction finishes, filter the filtrate decompression evaporate to dryness; Add methylene dichloride and water dissolution residue, separatory, organic layer evaporated under reduced pressure; Obtain oily matter, add the crystallization solvent, obtain 4; 6-two chloro-5-amino-2-rosickyite yl pyrimidines; Reductive agent and 4, the mass ratio of 6-two chloro-5-nitros-2-rosickyite yl pyrimidines is 1:1.6-1.7, the mass ratio of reductive agent and organic solvent is 1:3.
Temperature of reaction is 0～5 ℃ in the step of the present invention
Figure 664694DEST_PATH_IMAGE004
, and the reaction times is 3 hours.Chlorinating agent is a phosphorus pentachloride in the step
Figure 989496DEST_PATH_IMAGE005
.Temperature of reaction is-5～0 ℃ in the step
Figure 31401DEST_PATH_IMAGE005
, and the reaction times is 2 hours.Organic solvent is the mixed solvent of glacial acetic acid and methyl alcohol, and the mass ratio of glacial acetic acid and methyl alcohol is 2:1, and the crystallization solvent is a sherwood oil.Temperature of reaction is 60～65 ℃ in the step
Figure 390839DEST_PATH_IMAGE006
, and the reaction times is 2 hours.
Described a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines, its step is following:
With 700g 4,6-dihydroxyl-2-mercaptopyrimidine adds in the 10kg water
Figure 125576DEST_PATH_IMAGE003
, stirs to drip 10% sodium hydroxide solution 5kg down; Temperature control < 25 ℃ dropwise the back and add 5kg methyl alcohol, 1.19kg 1-bromo propane; Spend the night in 40 ~ 45 ℃ of stirring reactions, be cooled to room temperature, dripping Hydrogen chloride accent pH is 2～3; Stir 1h, filter, washing; 45 ℃ of drying under reduced pressure obtain 700g 4,6-dihydroxyl-2-rosickyite yl pyrimidines;
Figure 406516DEST_PATH_IMAGE004
adds the 910g nitrosonitric acid in the 700g glacial acetic acid; Be cooled to 0～5 ℃, add 700g 4 in batches, 6-dihydroxyl-2-rosickyite yl pyrimidines; Add back stirring reaction 3h; Add the elutriation crystalline substance, filter, washing; 45 ℃ of drying under reduced pressure obtain 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines;
Compound identification: MS m/z: theoretical value: 231.03 [M +], measured value: 254.1 [M+Na +];
Figure 520621DEST_PATH_IMAGE005
adds the 1.97kg phosphorus pentachloride in the 9.85kg methylene dichloride; Be cooled to-5～0 ℃; Add 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines adds afterreaction 2h in batches; Add the 5kg saturated brine; Separatory, the organic layer evaporated under reduced pressure obtains 798g 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines;
Figure 141090DEST_PATH_IMAGE006
The 500g reduced iron powder is added in 10kg glacial acetic acid and the 5kg methyl alcohol, add 798g 4 under stirring in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines add the back in 60～65 ℃ of reaction 2h; Filter, the filtrate decompression evaporate to dryness, resistates adds 5kg methylene dichloride and 2.5kg water stirring and dissolving resistates; Separatory adds 1.5kg sherwood oil crystallization and spends the night after the organic layer evaporated under reduced pressure, filter; Reduced pressure at room temperature obtains: 572g 4,6-two chloro-5-amino-2-rosickyite yl pyrimidines, purity; 99%, total recovery: 49.4%; Product is identified: MS m/z: theoretical value: 236.99 [M +], measured value: 237.1 [M +].
Advantage of the present invention: serve as to replace reagent with 1-bromo propane in the method for the present invention, methyl alcohol is solvent, and the reaction reagent price is low, and then reduces production costs; With the glacial acetic acid is solvent, has not only reduced the consumption of nitrosonitric acid, and makes the nitration reaction process be easy to control, has reduced danger, has reduced side reaction simultaneously, has improved productive rate; Replace POCl3 to carry out chloro with phosphorus pentachloride, reduced temperature of reaction, reduced side reaction; Reduce with iron powder, not only price is low, and production cost is low, and simple to operate; Side reaction is few etc., and with 4 of method preparation of the present invention, 6-two chloro-5-amino-2-rosickyite yl pyrimidines, total recovery is about 50%; Purity all improves a lot than prior art greater than 99%, has reaction conditions gentleness, simple to operate, need not chromatographic separation and purification; Shorten preparation cycle greatly, reduced cost effectively, improved productive rate, be suitable for suitability for industrialized production.
Embodiment
Of the present invention a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines comprises the steps:
With 4,6-dihydroxyl-2-mercaptopyrimidine adds in the entry
Figure 312308DEST_PATH_IMAGE003
, drip 10% sodium hydroxide solution dissolving after; Add methyl alcohol and 1-bromo propane,, be cooled to room temperature at 40-45 ℃ of following insulation reaction 15-20 hour; The acidifying crystallization; Obtain 4,6-dihydroxyl-2-rosickyite yl pyrimidines, the mass ratio of sodium hydroxide solution and methyl alcohol is 1:1; 4; The mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and water is 0.14:2,4, and the mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and 1-bromo propane is 1:1.7-1.8;
Figure 80544DEST_PATH_IMAGE007
chemical compounds I; compound ii;
Figure 798281DEST_PATH_IMAGE004
adds nitrosonitric acid in the glacial acetic acid, and low temperature adds 4 down, 6-dihydroxyl-2-rosickyite yl pyrimidines; After reaction finishes; Add the elutriation crystalline substance, obtain 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines; 4; The mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and glacial acetic acid is 1:1,4, and the mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and nitrosonitric acid is 1:1.3-1.4;
Figure 609242DEST_PATH_IMAGE009
compound III;
Under
Figure 393003DEST_PATH_IMAGE005
low temperature chlorinating agent is added in the methylene dichloride, add 4 in batches, 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines; After reaction finishes; Add saturated brine, aftertreatment obtains 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines; 4; The mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and methylene dichloride is 1:5,4, and the mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and chlorinating agent is 1:2.7-2.8;
Figure 845981DEST_PATH_IMAGE010
compound IV;
adds iron powder in the organic solvent, adds 4 in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines; After insulation reaction finishes, filter the filtrate decompression evaporate to dryness; Add methylene dichloride and water dissolution residue, separatory, organic layer evaporated under reduced pressure; Obtain oily matter, add the crystallization solvent, obtain 4; 6-two chloro-5-amino-2-rosickyite yl pyrimidines; Reductive agent and 4, the mass ratio of 6-two chloro-5-nitros-2-rosickyite yl pyrimidines is 1:1.6-1.7, the mass ratio of reductive agent and organic solvent is 1:3;
Figure 750800DEST_PATH_IMAGE011
compound V.
Temperature of reaction is 0 ~ 5 ℃ in the step of the present invention
Figure 493628DEST_PATH_IMAGE004
, and the reaction times is 3 hours.
Chlorinating agent is a phosphorus pentachloride in the step of the present invention
Figure 750297DEST_PATH_IMAGE012
.
Temperature of reaction is-5 ~ 0 ℃ in the step of the present invention
Figure 527760DEST_PATH_IMAGE012
, and the reaction times is 2 hours.
Organic solvent of the present invention is the mixed solvent of glacial acetic acid and methyl alcohol, and the mass ratio of glacial acetic acid and methyl alcohol is 2:1, and the crystallization solvent is a sherwood oil.
Temperature of reaction is 60～65 ℃ in the step of the present invention
Figure 680524DEST_PATH_IMAGE013
, and the reaction times is 2 hours.
Below will combine embodiment to explain the present invention in more detail, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Example 1: a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines, step is following:
With 700g 4,6-dihydroxyl-2-mercaptopyrimidine adds in the 10kg water
Figure 433018DEST_PATH_IMAGE003
, stirs to drip 10% sodium hydroxide solution 5kg down; Temperature control < 25 ℃ dropwise the back and add 5kg methyl alcohol, 1.19kg 1-bromo propane; Spend the night in 40 ~ 45 ℃ of stirring reactions, be cooled to room temperature, dripping Hydrogen chloride accent pH is 2～3; Stir 1h, filter, washing; 45 ℃ of drying under reduced pressure obtain 700g 4,6-dihydroxyl-2-rosickyite yl pyrimidines;
adds the 910g nitrosonitric acid in the 700g glacial acetic acid; Be cooled to 0～5 ℃, add 700g 4 in batches, 6-dihydroxyl-2-rosickyite yl pyrimidines; Add back stirring reaction 3h; Add the elutriation crystalline substance, filter, washing; 45 ℃ of drying under reduced pressure obtain 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines;
Compound identification: MS m/z: theoretical value: 231.03 [M +], measured value: 254.1 [M+Na +];
Figure 328610DEST_PATH_IMAGE005
adds the 1.97kg phosphorus pentachloride in the 9.85kg methylene dichloride; Be cooled to-5 ~ 0 ℃; Add 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines adds afterreaction 2h in batches; Add the 5kg saturated brine; Separatory, the organic layer evaporated under reduced pressure obtains 798g 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines;
Figure 449012DEST_PATH_IMAGE006
The 500g reduced iron powder is added in 10kg glacial acetic acid and the 5kg methyl alcohol, add 798g 4 under stirring in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines add the back in 60～65 ℃ of reaction 2h; Filter, the filtrate decompression evaporate to dryness, resistates adds 5kg methylene dichloride and 2.5kg water stirring and dissolving resistates; Separatory adds 1.5kg sherwood oil crystallization and spends the night after the organic layer evaporated under reduced pressure, filter; Reduced pressure at room temperature obtains: 572g 4,6-two chloro-5-amino-2-rosickyite yl pyrimidines, purity; 99%, total recovery: 49.4%; Product is identified: MS m/z: theoretical value: 236.99 [M +], measured value: 237.1 [M +].
Example 2: a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines, step is following:
With 1.4kg 4,6-dihydroxyl-2-mercaptopyrimidine adds in the 20kg water
Figure 900853DEST_PATH_IMAGE003
, stirs to drip 10% sodium hydroxide solution 10kg down; Temperature control < 25 ℃ dropwise the back and add 10kg methyl alcohol, 2.52kg 1-bromo propane; Spend the night in 40 ~ 45 ℃ of stirring reactions, be cooled to room temperature, dripping Hydrogen chloride accent pH is 2～3; Stir 1h, filter, washing; 45 ℃ of drying under reduced pressure obtain 1.42kg 4,6-dihydroxyl-2-rosickyite yl pyrimidines;
Figure 499325DEST_PATH_IMAGE004
adds the 1.99kg nitrosonitric acid in the 1.42kg glacial acetic acid; Be cooled to 0～5 ℃, add 1.42kg 4 in batches, 6-dihydroxyl-2-rosickyite yl pyrimidines; Add back stirring reaction 3h; Add the elutriation crystalline substance, filter, washing; 45 ℃ of drying under reduced pressure obtain 1.47kg 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines;
Figure 251380DEST_PATH_IMAGE005
adds the 4.12kg phosphorus pentachloride in the 20.6kg methylene dichloride; Be cooled to-5 ~ 0 ℃; Add 1.47kg 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines adds afterreaction 2h in batches; Add the 10kg saturated brine; Separatory, the organic layer evaporated under reduced pressure obtains 1.7kg 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines;
adds the 1kg reduced iron powder in 20kg glacial acetic acid and the 10kg methyl alcohol, stirs to add 1.7kg 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines down in batches; Add the back in 60～65 ℃ of reaction 2h, filter the filtrate decompression evaporate to dryness; Resistates adds 10kg methylene dichloride and 5kg water stirring and dissolving resistates; Separatory adds 3kg sherwood oil crystallization and spends the night after the organic layer evaporated under reduced pressure, filter; Reduced pressure at room temperature obtains: 1.16kg 4; 6-two chloro-5-amino-2-rosickyite yl pyrimidines, purity>99%, total recovery: 50.1%.

Claims (7)

1. one kind 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines is characterized in that: comprise the steps:
With 4,6-dihydroxyl-2-mercaptopyrimidine adds in the entry
Figure 2012101619236100001DEST_PATH_IMAGE002
, drip 10% sodium hydroxide solution dissolving after; Add methyl alcohol and 1-bromo propane,, be cooled to room temperature at 40-45 ℃ of following insulation reaction 15-20 hour; The acidifying crystallization; Obtain 4,6-dihydroxyl-2-rosickyite yl pyrimidines, the mass ratio of sodium hydroxide solution and methyl alcohol is 1:1; 4; The mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and water is 0.14:2,4, and the mass ratio of 6-dihydroxyl-2-mercaptopyrimidine and 1-bromo propane is 1:1.7-1.8;
adds nitrosonitric acid in the glacial acetic acid, and low temperature adds 4 down, 6-dihydroxyl-2-rosickyite yl pyrimidines; After reaction finishes; Add the elutriation crystalline substance, obtain 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines; 4; The mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and glacial acetic acid is 1:1,4, and the mass ratio of 6-dihydroxyl-2-rosickyite yl pyrimidines and nitrosonitric acid is 1:1.3-1.4;
Under
Figure 2012101619236100001DEST_PATH_IMAGE006
low temperature chlorinating agent is added in the methylene dichloride; Add 4 in batches; 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines after reaction finishes, adds saturated brine; Aftertreatment obtains 4; 6-two chloro-5-nitros-2-rosickyite yl pyrimidines, 4, the mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and methylene dichloride is 1:5; 4, the mass ratio of 6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines and chlorinating agent is 1:2.7-2.8;
Figure 2012101619236100001DEST_PATH_IMAGE008
adds iron powder in the organic solvent, adds 4 in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines; After insulation reaction finishes, filter the filtrate decompression evaporate to dryness; Add methylene dichloride and water dissolution residue, separatory, organic layer evaporated under reduced pressure; Obtain oily matter, add the crystallization solvent, obtain 4; 6-two chloro-5-amino-2-rosickyite yl pyrimidines; Reductive agent and 4, the mass ratio of 6-two chloro-5-nitros-2-rosickyite yl pyrimidines is 1:1.6-1.7, the mass ratio of reductive agent and organic solvent is 1:3.
2. according to claim 1 a kind of 4; The preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines; It is characterized in that: temperature of reaction is 0～5 ℃ in the step
Figure 840878DEST_PATH_IMAGE004
, and the reaction times is 3 hours.
3. according to claim 1 a kind of 4; The preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines is characterized in that: chlorinating agent is a phosphorus pentachloride in the step
Figure 85914DEST_PATH_IMAGE006
.
4. according to claim 1 a kind of 4; The preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines; It is characterized in that: temperature of reaction is-5 ~ 0 ℃ in the step , and the reaction times is 2 hours.
5. according to claim 1 a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines, it is characterized in that: organic solvent is the mixed solvent of glacial acetic acid and methyl alcohol, and the mass ratio of glacial acetic acid and methyl alcohol is 2:1, and the crystallization solvent is a sherwood oil.
6. according to claim 1 a kind of 4; The preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines; It is characterized in that: temperature of reaction is 60～65 ℃ in the step
Figure 618450DEST_PATH_IMAGE008
, and the reaction times is 2 hours.
7. according to claim 1 a kind of 4, the preparation method of 6-two chloro-5-amino-2-rosickyite yl pyrimidines, it is characterized in that: step is following:
With 700g 4,6-dihydroxyl-2-mercaptopyrimidine adds in the 10kg water
Figure 760719DEST_PATH_IMAGE002
, stirs to drip 10% sodium hydroxide solution 5kg down; Temperature control < 25 ℃ dropwise the back and add 5kg methyl alcohol, 1.19kg 1-bromo propane; Spend the night in 40 ~ 45 ℃ of stirring reactions, be cooled to room temperature, dripping Hydrogen chloride accent pH is 2～3; Stir 1h, filter, washing; 45 ℃ of drying under reduced pressure obtain 700g 4,6-dihydroxyl-2-rosickyite yl pyrimidines;
Figure 379919DEST_PATH_IMAGE004
adds the 910g nitrosonitric acid in the 700g glacial acetic acid; Be cooled to 0～5 ℃, add 700g 4 in batches, 6-dihydroxyl-2-rosickyite yl pyrimidines; Add back stirring reaction 3h; Add the elutriation crystalline substance, filter, washing; 45 ℃ of drying under reduced pressure obtain 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines;
Compound identification: MS m/z: theoretical value: 231.03 [M +], measured value: 254.1 [M+Na +];
Figure 476313DEST_PATH_IMAGE006
adds the 1.97kg phosphorus pentachloride in the 9.85kg methylene dichloride; Be cooled to-5～0 ℃; Add 728g 4,6-dihydroxyl-5-nitro-2-rosickyite yl pyrimidines adds afterreaction 2h in batches; Add the 5kg saturated brine; Separatory, the organic layer evaporated under reduced pressure obtains 798g 4,6-two chloro-5-nitros-2-rosickyite yl pyrimidines;
Figure 675213DEST_PATH_IMAGE008
The 500g reduced iron powder is added in 10kg glacial acetic acid and the 5kg methyl alcohol, add 798g 4 under stirring in batches, 6-two chloro-5-nitros-2-rosickyite yl pyrimidines add the back in 60～65 ℃ of reaction 2h; Filter, the filtrate decompression evaporate to dryness, resistates adds 5kg methylene dichloride and 2.5kg water stirring and dissolving resistates; Separatory adds 1.5kg sherwood oil crystallization and spends the night after the organic layer evaporated under reduced pressure, filter; Reduced pressure at room temperature obtains: 572g 4,6-two chloro-5-amino-2-rosickyite yl pyrimidines, purity; 99%, total recovery: 49.4%; Product is identified: MS m/z: theoretical value: 236.99 [M +], measured value: 237.1 [M +].
CN201210161923.6A 2012-05-23 2012-05-23 Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine Active CN102659691B (en)

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Cited By (7)

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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
CN103923020A (en) * 2014-04-02 2014-07-16 黄河三角洲京博化工研究院有限公司 Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine
CN104003943A (en) * 2014-05-06 2014-08-27 南通常佑药业科技有限公司 Preparation method for ticagrelor intermediate
CN107814772A (en) * 2017-11-24 2018-03-20 常州沃腾化工科技有限公司 The process for purification of the rosickyite yl pyrimidines ester of 4,6 dichloro, 5 amino 2
CN110372605A (en) * 2019-06-24 2019-10-25 南京普锐达医药科技有限公司 Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine
CN115626897A (en) * 2022-11-01 2023-01-20 常州佳德医药科技有限公司 Preparation method of 5-amino-4, 6-diisopropyl pyrimidine

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WO2011101740A1 (en) * 2010-02-16 2011-08-25 Actavis Group Ptc Ehf Improved processes for preparing ticagrelor intermediate, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine

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CN1068574A (en) * 1991-04-06 1993-02-03 菲索斯有限公司 The preparation method of adenosine triphosphate acid-like substance
CN1271359A (en) * 1997-07-22 2000-10-25 英国阿斯特拉药品有限公司 Novel compounds
WO2011101740A1 (en) * 2010-02-16 2011-08-25 Actavis Group Ptc Ehf Improved processes for preparing ticagrelor intermediate, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103923020A (en) * 2014-04-02 2014-07-16 黄河三角洲京博化工研究院有限公司 Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine
CN104003943A (en) * 2014-05-06 2014-08-27 南通常佑药业科技有限公司 Preparation method for ticagrelor intermediate
CN107814772A (en) * 2017-11-24 2018-03-20 常州沃腾化工科技有限公司 The process for purification of the rosickyite yl pyrimidines ester of 4,6 dichloro, 5 amino 2
CN110372605A (en) * 2019-06-24 2019-10-25 南京普锐达医药科技有限公司 Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine
CN110372605B (en) * 2019-06-24 2022-05-13 南京普锐达医药科技有限公司 Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine
CN115626897A (en) * 2022-11-01 2023-01-20 常州佳德医药科技有限公司 Preparation method of 5-amino-4, 6-diisopropyl pyrimidine

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