CN104774183A - Preparation method of formoxyl rosuvastatin calcium intermediate - Google Patents
Preparation method of formoxyl rosuvastatin calcium intermediate Download PDFInfo
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- CN104774183A CN104774183A CN201510204506.9A CN201510204506A CN104774183A CN 104774183 A CN104774183 A CN 104774183A CN 201510204506 A CN201510204506 A CN 201510204506A CN 104774183 A CN104774183 A CN 104774183A
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- IAPKQCWZXNMPSL-UHFFFAOYSA-N CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1N Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1N IAPKQCWZXNMPSL-UHFFFAOYSA-N 0.000 description 1
- DXYCKZIBRXBGCE-UHFFFAOYSA-N CNC(N(C)S(C)(=O)=O)=N Chemical compound CNC(N(C)S(C)(=O)=O)=N DXYCKZIBRXBGCE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Abstract
The invention discloses a preparation method of a formoxyl rosuvastatin calcium intermediate. With 2-methyl-3-carbonyl valeronitrile, 4-fluorobenzaldehyde and urea as raw materials, the formoxyl rosuvastatin calcium intermediate 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-formoxyl-2-(N-methyl-N-methylsulfonyl) pyrimidine is synthesized by reactions such as cyclization, oxidation, N-substitution and reduction. Compared with an existing method, the method has the advantages that reaction conditions are mild, the used reagent is relatively cheap and the yield is high.
Description
Technical field
The invention belongs to the field of chemical synthesis of compound, more particularly, the present invention relates to a kind of new chemical synthesis process of formyl radical rosuvastain calcium intermediate.
Background technology
Rui Shu cuts down spit of fland calcium (rosuvastation calcium); CAS No:147098-20-2; chemical name: two-[(E)-7 [4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino] (3R; 5S)-3; 5-dihydroxyl-6-diluted acid in heptan] calcium salt (2:1), molecular formula: (C
22h
27fN
3o
6s)
2ca, molecular weight: 1001.15, is the Statins blood lipid regulation medicine of new generation of the complete synthesis single enantiomer researched and developed by Japanese Shionogol company, belongs to aminopyridine derivative, powerfully can suppress HMG-CoA reductase, and have liver cell selective action.Structural formula is as follows:
Method one: patent WO2003006439 and EP052147 discloses a kind of synthetic method of rosuvastain calcium, and wherein, just relate to the preparation method of intermediate I, key step is as follows:
Synthetic method disclosed in above-mentioned patent needs the reagent concentrated nitric acid used comparatively large to equipment corrosion, is unfavorable for suitability for industrialized production; DIBAL-H is expensive; DIBAL-H reduction need be reacted at low temperatures, is unfavorable for suitability for industrialized production; Clorox is easily oxidized to acid intermediate ethanol, and reaction yield is not high.
Method two: patent US20050124639 and patent WO03097614 individually discloses a kind of synthetic method of rosuvastain calcium, and wherein, just relate to the preparation method of intermediate I, key step is as follows:
Synthetic method disclosed in above-mentioned patent needs reagent D DQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) toxicity used very large; TPAP (four n-propyls cross ruthenium (VII) acid amide) and DIBAL-H (diisobutyl aluminium hydride) is expensive; DIBAL-H reduction need be reacted at low temperatures, is unfavorable for suitability for industrialized production; Reaction yield is not high.
Method three: patent WO0104100 and patent WO0049014 individually discloses a kind of synthetic method of rosuvastain calcium, and wherein, just relate to the preparation method of intermediate I, key step is as follows:
The most of raw material of synthetic method disclosed in above-mentioned patent oneself synthesizes, and nitriles substance is hypertoxic, the industrial application of this route is restricted, is unfavorable for suitability for industrialized production.
The object of the present invention is to provide that a kind of production cost is low, mild condition, preparation method that is easy and simple to handle, a kind of rosuvastain calcium intermediate safely and effectively.Can be reached by following measures:
The preparation method of a kind of rosuvastain calcium intermediate 4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-containing formyl radical [methyl (methylsulfonyl) is amino] pyrimidines (i.e. type I compound); its with 2-methyl-3-carbonyl valeronitrile for raw material and 4-fluorobenzaldehyde and urea reaction synthesis type IV compound; then formula III compound is obtained with oxidizing; formula III compound and N-methylmethanesulfonamide react preparation formula II compound, and last and raney ni catalysis is obtained by reacting type I compound.
Each step reaction in the present invention is in detail as follows:
A () 2-methyl-3-carbonyl valeronitrile is that raw material and 4-fluorobenzaldehyde and urea carry out reaction in 70-90 DEG C and prepares compounds Ⅳ compound under cuprous chloride, vitriol oil effect; 2-methyl-3-carbonyl valeronitrile and 4-fluorobenzaldehyde mol ratio 1:0.9 ~ 1:1.2, with urea mol ratio 1:1 ~ 1:3, with cuprous chloride mol ratio 1:0.01 ~ 1:0.1, with vitriol oil mol ratio 1:0.1-1:1; Solvent selected from methanol, ethanol, propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
A kind of preferred reaction process is: the 4-fluorobenzaldehyde (amount of substance is unit) of 1 times amount 2-methyl-3-carbonyl valeronitrile (amount of substance is unit) and 0.90 ~ 1.2 times amount is dissolved in organic solvent, stirs the lower vitriol oil (amount of substance is unit) of dropping 0.1-1 times amount and the cuprous chloride (amount of substance is unit) of 0.01 ~ 0.1 times amount.At 70-90 DEG C of stirring reaction 6-10 hour, obtain formula IV compound finally by separating-purifying.Reacting the organic solvent selected is methyl alcohol, ethanol, propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, preferred alcohol.
(b) compounds Ⅳ and be oxidizingly obtained by reacting formula III compound; Wherein the mol ratio of compound III and oxygenant is 1:1 ~ 1:2; Oxygenant is selected from: Manganse Dioxide, iron trichloride, ceric ammonium nitrate; The solvent selected from methanol of this reaction, ethanol, Virahol, acetonitrile.
A kind of preferred reaction process is, by the compounds Ⅳ (amount of substance is unit) of 1 times amount, the oxide compound (amount of substance is unit) of 1 ~ 2 times amount is dissolved in organic solvent, and stirring at room temperature 12-24 hour, last separating-purifying obtained formula compound III.This reaction oxygenant is selected from: Manganse Dioxide, iron trichloride, ceric ammonium nitrate, preferred iron trichloride; The solvent selected from methanol of this reaction, ethanol, Virahol, acetonitrile, preferred alcohol.
C () compound III and N-methylmethanesulfonamide and salt of wormwood are obtained by reacting formula II compound at 100-120 DEG C; Wherein the mol ratio of compound III, N-methylmethanesulfonamide and salt of wormwood is 1:1 ~ 1:2; 1:1 ~ 1:3; The solvent of this reaction is selected from n-butyl acetate, DMF, toluene.
A kind of preferred reaction process is: by the compound III (amount of substance is unit) of 1 times amount, the N-methylmethanesulfonamide (amount of substance is unit) of 1-1.2 times amount and salt of wormwood (amount of substance is unit) the molten organic solvent of 1-3 times amount, at 100-120 DEG C, individual hour of stirring reaction 4-6, obtains formula II compound finally by separating-purifying.React the positive butyl ester of solvent acetic acid, DMF, the toluene selected, preferred n-butyl acetate.
(d) II compound and Raney's nickel, formic acid back flow reaction obtain type I compound; The mass ratio of its Chinese style II compound and Raney's nickel is 1:1 ~ 1:5.
A kind of preferred reaction process is: by the compound ii (substance weight is unit) of 1 times amount, react 2-8 hour under the Raney's nickel (substance weight is unit) of 1-5 times amount and formic acid return stirring, obtain type I compound finally by separating-purifying.Beneficial effect of the present invention: the method is compared with existing method, and reaction conditions is gentle, reagents ratio used is comparatively cheap, and productive rate is higher.
Embodiment
Following specific embodiment is used for further illustrating the present invention
The preparation method of embodiment 1:4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand
Be equipped with at 500ml in the glass flask of agitator, thermometer and reflux condensing tube and add 22.2g (0.2mol) 2-methyl-5 carbonyl valeronitrile, 24.8g (0.2mol) 4-fluorobenzaldehyde, 21.0g (0.35mol) urea, 200mg (2mmol) cuprous chloride, the 2ml vitriol oil and 250ml ethanol.By the material in flask backflow and stir under be heated to 80-85 DEG C 10 hours to react, form the crystallized product of precipitation, crystallized product is collected on filter paper, by washing with alcohol to obtain 49g4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand, yield 94.6%, mp:220-223 DEG C.
The preparation method of embodiment 2:4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand
Be equipped with at 500ml in the glass flask of agitator, thermometer and reflux condensing tube and add 22.2g (0.2mol) 2-methyl-5 carbonyl valeronitrile, 27.2g (0.22mol) 4-fluorobenzaldehyde, 24.0g (0.4mol) urea, 200mg (2mmol) cuprous chloride, the 2ml vitriol oil and 250ml methyl alcohol.By the material in flask backflow and stir under be heated to 65-70 DEG C 12 hours to react, form the crystallized product of precipitation, crystallized product is collected on filter paper, by washing with alcohol to obtain 48g4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand, yield 92.6%.
The preparation method of embodiment 3:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine
500ml ethanol is added in the 1000ml glass flask of being furnished with agitator and thermometer, 25.3g (0.1mol) iron trichloride 51.8mol (0.2mol) 4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand, 80ml glacial acetic acid mixture stirring at room temperature 14 hours, after having reacted, concentrated ethanol, then water and ethyl acetate is added, layering, concentration of organic layers obtains 49g white solid 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine, yield 95%, fusing point: 180-182 DEG C.
The preparation method of embodiment 4:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine
500ml ethanol is added in the 1000ml glass flask of being furnished with agitator and thermometer, 13.1g (0.15mol) Manganse Dioxide, 51.8mol (0.2mol) 4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand, mixture stirring at room temperature 16 hours, after having reacted, concentrated ethanol, then water and ethyl acetate is added, layering, concentration of organic layers obtains 45g white solid 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine, yield 87.5%.
The preparation method of embodiment 5:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine
500ml ethanol is added in the 1000ml glass flask of being furnished with agitator and thermometer, 82.2g (0.15mol) ceric ammonium nitrate, 51.8g (0.2mol) 4-(4-fluorophenyl)-6-sec.-propyl-5-cyano group-3,4-2 (1H)-dihydropyrimidinonesand, 100ml glacial acetic acid mixture stirring at room temperature 12 hours, after having reacted, concentrated ethanol, then water and ethyl acetate is added, layering, concentration of organic layers obtains 46g white solid 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine, yield 89.5%.
The preparation method of embodiment 6:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyano group-2-(N-methyl-N-methylsulfonyl) pyrimidine
At outfit agitator, 25.7g (0.1mol) 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyanopyrimidine is added in the 500ml glass flask of thermometer and reflux exchanger, 13.8g (0.1mol) salt of wormwood, 300ml n-butyl acetate, under agitation add 19.6g (0.1mol) Tosyl chloride, reaction is carried out 4 hours at 40 DEG C, subsequently by reaction mixture cool to room temperature, 10.9g (0.1mol) N-methylmethanesulfonamide and (0.1mol) salt of wormwood is added in the reaction mixture of cooling, mixture is heated to 120-125 DEG C of reaction 5 hours under reflux, after having reacted, by mixture cool to room temperature, mixture to cooling adds water and acetone, be separated organic moiety, organic moiety saturated sodium-chloride water solution washs, with anhydrous sodium sulfate drying, concentrating under reduced pressure, the crystallization of resistates normal hexane obtains 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyano group-2-(N-methyl-N-methylsulfonyl) pyrimidine Light yellow crystals product 31.5g, yield: 90%, fusing point: 120-122 DEG C.
The preparation method of embodiment 7:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine
10g4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyano group-2-(N-methyl-N-methylsulfonyl) pyrimidine 10g Raney's nickel is added and 100ml formic acid return stirring reacts 2 hours in the 250ml glass flask being equipped with agitator, thermometer and reflux exchanger; reaction terminates rear suction filtration and obtains light yellow solid; 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine white solid 33.5g is obtained by re-crystallizing in ethyl acetate; yield 95%, fusing point: 178-179 DEG C.
The preparation method of embodiment 8:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine
10g4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyano group-2-(N-methyl-N-methylsulfonyl) pyrimidine 20g Raney's nickel is added and 80ml formic acid return stirring reacts 3 hours in the 250ml glass flask being equipped with agitator, thermometer and reflux exchanger; reaction terminates rear suction filtration and obtains light yellow solid; 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine white solid 33g is obtained by re-crystallizing in ethyl acetate; yield 94%, fusing point: 178-179 DEG C.
The preparation method of embodiment 9:4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine
10g4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-cyano group-2-(N-methyl-N-methylsulfonyl) pyrimidine 30g Raney's nickel is added and 100ml formic acid return stirring reacts 5 hours in the 250ml glass flask being equipped with agitator, thermometer and reflux exchanger; reaction terminates rear suction filtration and obtains light yellow solid; 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-formyl radical-2-(N-methyl-N-methylsulfonyl) pyrimidine white solid 33.2g is obtained, yield 94.5% by re-crystallizing in ethyl acetate.Fusing point: 178-179 DEG C,
1h-NMR (CDCl
3, 400MHz): δ ppm9.88 (s, 1H, CHO), 7.69-7.71 (m, 2H, Ar-H), 7.37-7.42 (m, 2H, Ar-H), 3.90 (m, 1H, CH of
ipr), 3.59 (s, 3H, CH
3sO
2), 3.49 (s, 3H, NCH
3), 1.24 (d, 6H, CH
3of
ipr).
Claims (5)
1. the preparation method of a type I compound, it is characterized in that with 2-methyl-3-carbonyl valeronitrile for raw material and 4-fluorobenzaldehyde and urea reaction synthesis type IV compound, then formula III compound is obtained by reacting through oxidizing, formula III compound and N-methylmethanesulfonamide react preparation formula II compound, last and raney ni catalysis is obtained by reacting type I compound, and its reaction scheme is:
2. method according to claim 1, is characterized in that preparing compounds Ⅳ compound with 2-methyl-3-carbonyl valeronitrile for raw material and 4-fluorobenzaldehyde and urea carry out reaction in 70-90 DEG C under cuprous chloride, vitriol oil effect; 2-methyl-3-carbonyl valeronitrile and 4-fluorobenzaldehyde mol ratio 1:0.9 ~ 1:1.2, with urea mol ratio 1:1 ~ 1:3, with cuprous chloride mol ratio 1:0.01 ~ 1:0.1, with vitriol oil mol ratio 1:0.1-1:1; Solvent selected from methanol, ethanol, propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
3. method according to claim 1, its characteristic compounds IV is obtained by reacting formula III compound with oxidizing; Wherein the mol ratio of compound III and oxygenant is 1:1 ~ 1:2; Oxygenant is selected from: Manganse Dioxide, iron trichloride, ceric ammonium nitrate, the solvent selected from methanol of reaction, ethanol, Virahol, acetonitrile.
4. method according to claim 1, its characteristic compounds III is obtained by reacting formula II compound with N-methylmethanesulfonamide and salt of wormwood at 100-120 DEG C; Wherein the mol ratio of compound III, N-methylmethanesulfonamide and salt of wormwood is 1:1 ~ 1:2; 1:1 ~ 1:3; The solvent of this reaction is selected from n-butyl acetate, DMF, toluene.
5. method according to claim 1, is characterized in that formula II compound and Raney's nickel, formic acid are obtained by reacting type I compound; The mass ratio of its Chinese style II compound and Raney's nickel is 1:1 ~ 1:5.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113135859A (en) * | 2021-04-26 | 2021-07-20 | 安徽省庆云医药股份有限公司 | Green synthesis method of rosuvastatin calcium intermediate |
| CN114805218A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Preparation method of rosuvastatin calcium intermediate |
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| US5945422A (en) * | 1997-02-05 | 1999-08-31 | Warner-Lambert Company | N-oxides of amino containing pyrido 2,3-D! pyrimidines |
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| CN1169726A (en) * | 1994-11-14 | 1998-01-07 | 沃尼尔·朗伯公司 | 6-aryl pyrido (2,3-d) pyrimidines and naphthyridines for inhibiting protein tyrosine kinase medicated cellular proliferation |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113135859A (en) * | 2021-04-26 | 2021-07-20 | 安徽省庆云医药股份有限公司 | Green synthesis method of rosuvastatin calcium intermediate |
| CN113135859B (en) * | 2021-04-26 | 2022-08-26 | 安徽省庆云医药股份有限公司 | Green synthesis method of rosuvastatin calcium intermediate |
| CN114805218A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Preparation method of rosuvastatin calcium intermediate |
| CN114805218B (en) * | 2022-03-30 | 2024-02-09 | 重庆普佑生物医药有限公司 | Preparation method of rosuvastatin calcium intermediate |
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