CN104211705A - Preparation method of sildenafil - Google Patents
Preparation method of sildenafil Download PDFInfo
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- CN104211705A CN104211705A CN201410384199.2A CN201410384199A CN104211705A CN 104211705 A CN104211705 A CN 104211705A CN 201410384199 A CN201410384199 A CN 201410384199A CN 104211705 A CN104211705 A CN 104211705A
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- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
Abstract
The invention discloses a preparation method of sildenafil and relates to the technical filed of chemical medicine synthesis. The method includes following steps: (1) carrying out a reaction between 2-ethyoxyl-5-(4-methylpiperazine-1-ylsulfonyl)benzoic acid with thionyl chloride in the presence of a catalyst to prepare an intermediate I; (2) carrying out a reaction between the intermediate I with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-methanamide in the presence of an acid-binding agent to prepare an intermediate II; (3) carrying out a cyclization reaction to the intermediate II in the presence of a specific alkali to obtain a crude product of sildenafil; and (4) performing recrystallization to obtain a pure product of sildenafil. In the invention, reduced pressure distillation for removing exceeded thionyl chloride is unnecessary so that pollution is avoided. Meanwhile, the preparation method can reduce device investment, can simplify technology and can increase efficiency.
Description
Technical field:
The present invention relates in chemicals synthesis technical field, be specifically related to a kind of preparation method of Virga.
Background technology:
Sildenafil citrate, English name: sildenafil citrate, trade(brand)name: viagra, first oral 5 type phosphodiesterase (PDE-5) inhibitor, current sildenafil citrate, except except the clinical application in erective dysfunction field, also can be used for pulmonary hypertension, altitude sickness, woman's acyesis, the treatment of the diseases such as pulmonary hypertension.
Sildenafil citrate synthetic route is numerous, that wherein have essential industry using value is synthetic route (the Organic Process Research & Development2005 of Pfizer, 9,88-97, Organic Process Research & Development2000,4,17-22), but this route uses N, N-carbonyl dimidazoles (CDI) to be condensation reagent, and this reagent is expensive, perishable inactivation, and anhydrous require high, and reaction reach 70h, be unfavorable for suitability for industrialized production.Shen is waited quietly (Chinese pharmaceutical chemistry magazine; 1999; 9 (3): 220) this route is optimized and is improved; but also there is certain defect: adopt a large amount of thionyl chloride to be chlorination reagent; concentrating under reduced pressure is needed to remove excessive thionyl chloride after reaction; and thionyl chloride heating, chance water or moisture can decompose irritating poison gas such as releasing sulfurous gas, hydrogenchloride etc., all larger harm can be brought to staff and environment protection.
Summary of the invention:
Technical problem to be solved by this invention is to provide a kind of preparation method of simple to operate, security is high, production cost is low Virga.
Technical problem to be solved by this invention adopts following technical scheme to realize:
A preparation method for Virga, the method comprises the following steps:
(1) 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid, under catalyst action, reacts with thionyl chloride and prepares intermediate compound I, after reaction terminates, and solution for later use.
(2) intermediate compound I is under acid binding agent effect, prepares intermediate II with 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide generation acylation reaction, after reaction terminates; reaction solution is washed, and gets organic phase drying, filters; solvent evaporated obtains solid, and gained dissolution of solid is stand-by.
(3) intermediate II is under the existence of specific alkali, generates Virga crude product through cyclization, after reaction terminates, removes partial solvent under reduced pressure, is dissolved in water, and adds dilute hydrochloric acid and adjusts pH to 7, stirring and crystallizing, and filtration, drying, obtain Virga crude product.
(4) Virga crude product is through recrystallization, obtains Virga sterling.
The temperature of reaction of step (1) is 0-40 DEG C; reaction times is 8-20h; reaction solvent is selected from methylene dichloride, chloroform, ethyl acetate, acetone, N; one or more in dinethylformamide; catalyzer is selected from pyridine, N; one in dinethylformamide, the mol ratio of 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid, thionyl chloride and catalyzer is 1:1.2:0.04.
The preferred 25-30 DEG C of temperature of reaction of step (1), reaction times preferred 10-15h, the preferred methylene dichloride of reaction solvent, the preferred DMF of catalyzer.
The temperature of reaction of step (2) is 10-50 DEG C, reaction times is 2-24h, reaction solvent is selected from methylene dichloride, chloroform, ethyl acetate, acetone, N, one or more in dinethylformamide, acid binding agent is selected from triethylamine, diisopropylethylamine, N, N-Dimethylamino pyridine, N, one in accelerine, pyridine, triethylamine, 4-pyrollidinopyridine, the mol ratio of 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide, intermediate compound I and acid binding agent is 1:1.05:1-10.
The preferred 25-30 DEG C of temperature of reaction of step (2), reaction times preferred 10-15h, the preferred methylene dichloride of reaction solvent, the preferred triethylamine of acid binding agent.
The temperature of reaction of step (3) is 50-170 DEG C, reaction times 2-72h, one or more in the basic cpd that specific alkali is selected from basic metal, alkaline-earth metal and alcohols, phenols is formed, the mol ratio of intermediate II and specific alkali is 1:1-10, and reaction solvent is selected from one or more in methyl alcohol, ethanol, Virahol, propyl carbinol.
The preferred 75-85 DEG C of temperature of reaction of step (3), reaction times preferred 12-14h, specific alkali preferred alcohol sodium, reaction solvent preferred alcohol.
Step (4) Virga crude product recrystallization solvent is selected from one or more in ethanol, methyl alcohol, and the mol ratio of Virga crude product and recrystallization solvent is 1:7.
The invention has the beneficial effects as follows: solution of acid chloride prepared by step (1) is without the need to removing excessive thionyl chloride and solvent through underpressure distillation, but under excessive acid binding agent existent condition directly with 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide generation acylation reaction, prepare intermediate II; This operation decreases the consumption of thionyl chloride, avoids pollution, simultaneously without vacuum distillation process, reduces equipment investment, Simplified flowsheet, improves security and efficiency.
Embodiment:
The technique means realized to make the present invention, creation characteristic, reaching object and effect is easy to understand, setting forth the present invention further below in conjunction with embodiment.
Embodiment 1:
(1) drying three mouthfuls of round-bottomed flasks are got, by methylene dichloride (CH
2cl
2) 500ml and 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid (100g, 0.305mol) adds in reaction flask successively, stirring and evenly mixing, solid can not be entirely molten.Ice bath is cooled to 5-10 DEG C, slowly adds thionyl chloride (SOCl
2) (43.5g, 0.365mol) temperature control 5-15 DEG C.Treat that thionyl chloride adds, add 1mlN, dinethylformamide (DMF), at 25-30 DEG C, reaction is spent the night.Sampling spot plate reacts completely, and reaction solution is stand-by.
(2) get a drying three mouthfuls of round-bottomed flasks, add 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide (63.35g, 0.29mol), use 500ml CH
2cl
2stir, solid can not be entirely molten.Ice bath is cooled to 10-15 DEG C, adds triethylamine (TEA) (123g, 1.22mol), is added dropwise to above-mentioned chloride product methylene dichloride reaction solution, ice bath temperature control less than 10-15 DEG C after stirring 30min.Finish, be incubated 20-25 DEG C of stirring reaction and spend the night, TLC monitors reaction process.Reaction completes, and reaction solution 900ml washes 2 times, organic layer anhydrous sodium sulfate drying 5-6h.Filter, 45 DEG C are spin-dried for solvent, obtain Light brown foam shape solid, add 700ml anhydrous alcohol solution stand-by.
(3) get a drying three mouthfuls of round-bottomed flasks, 500ml dehydrated alcohol is added reaction flask, take sodium Metal 99.5 (28.6g, 1.25mol) in batches fast and add wherein, stirring and dissolving, obtained alcohol sodium solution.Treat alcohol sodium solution, when being cooled to 40-50 DEG C, under agitation condition, the ethanolic soln of upper step enriched product is joined in alcohol sodium solution.Finish, be heated with stirring to 75-85 DEG C of back flow reaction.The process reaction of TLC monitoring reaction is complete 12-14h hour interaction energy primitive reaction.Question response is complete, removes reaction solution under reduced pressure partial solvent, and the water adding about 140ml, by after enriched material dissolving, under condition of ice bath, with the salt acid for adjusting pH to 7 of 17%, generates a large amount of light yellow solid.Stir the abundant crystallization of 0.5-1h.Filtration under diminished pressure, obtains Virga crude product, puts into 50 DEG C of forced air drying 6h, and weigh to obtain off-white powder solid m=117g, yield 85.6%, m.p185.1-187.9 DEG C.
(4) by crude product 7 times amount alcohol heating reflux, to solid CL, water-bath cooling crystallization spends the night, decompress filter, and 1L ice washing with alcohol, obtains sildenafil base sterling, is off-white color crystalline solid.
1HNMR[DMSO-d]δ0.93(t,3H),1.31(t,3H),1.72(m,2H),2.14(s,3H),2.34(Brs,4H),2.77(t,2H),2.88(Brs,4H),4.15(s,3H),4.16(q,2H),7.34(d,1H),7.79(m,2H),12.16(Brs,1H)。MS(EI)m/e:474(M
+).
Embodiment 2:
(1) drying three mouthfuls of round-bottomed flasks are got, by 500ml CH
2cl
2add successively in reaction flask with 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid (100g, 0.305mol), stirring and evenly mixing, solid can not be entirely molten.Ice bath is cooled to 5-10 DEG C, slowly adds SOCl
2(43.5g, 0.365mol) temperature control 5-15 DEG C.Treat SOCl
2add, add 1ml pyridine (Py), at 25-30 DEG C, reaction is spent the night.Sampling spot plate reacts completely, and reaction solution is stand-by.
(2) get a drying three mouthfuls of round-bottomed flasks, add 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide (63.35g, 0.29mol), use 500ml CH
2cl
2stir, solid can not be entirely molten.Ice bath is cooled to 10-15 DEG C, adds diisopropylethylamine (DIPEA) (157g, 1.22mol), is added dropwise to above-mentioned chloride product methylene dichloride reaction solution, ice bath temperature control less than 10-15 DEG C after stirring 30min.Finish, be incubated 20-25 DEG C of stirring reaction and spend the night, TLC monitors reaction process.Reaction completes, and reaction solution 900ml washes 2 times, organic layer anhydrous sodium sulfate drying 5-6h.Filter, 45 DEG C are spin-dried for solvent, Light brown foam shape solid, add 700ml dry isopropyl and dissolve stand-by.
(3) get a drying three mouthfuls of round-bottomed flasks, 500ml dry isopropyl (IPA) is added reaction flask, take sodium Metal 99.5 (28.6g, 1.25mol) in batches fast and add wherein, stirring and dissolving, obtained alcohol sodium solution.Treat alcohol sodium solution, when being cooled to 40-50 DEG C, under agitation condition, the aqueous isopropanol of upper step enriched product is joined in alcohol sodium solution.Finish, be heated with stirring to 75-85 DEG C of back flow reaction.The process reaction of TLC monitoring reaction is complete 12-14h hour interaction energy primitive reaction.Question response is complete, removes reaction solution under reduced pressure partial solvent, and the water adding about 140ml, by after enriched material dissolving, under condition of ice bath, with the salt acid for adjusting pH to 7 of 17%, generates a large amount of light yellow solid.Stir the abundant crystallization of 0.5-1h.Filtration under diminished pressure, both obtained Virga crude product.Put into 50 DEG C of forced air drying 6h, weigh to obtain off-white powder solid m=110g, yield 80.3%, m.p185.1-187.9 DEG C.
(4) get a drying three mouthfuls of round-bottomed flasks, by crude product 7 times amount alcohol heating reflux, to solid CL, water-bath cooling crystallization spends the night, decompress filter, 1L ice washing with alcohol, and both obtaining sildenafil base sterling, is off-white color crystalline solid.
Embodiment 3:
(1) drying three mouthfuls of round-bottomed flasks are got, by 500ml chloroform (CHCl
3) and 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid (100g, 0.305mol) add successively in reaction flask, stirring and evenly mixing, solid can not be entirely molten.Ice bath is cooled to 5-10 DEG C, slowly adds SOCl
2(43.5g, 0.365mol) temperature control 5-15 DEG C.Treat SOCl
2add, add 1ml DMF, at 25-30 DEG C, reaction is spent the night.Sampling spot plate reacts completely, and reaction solution is stand-by.
(2) get a drying three mouthfuls of round-bottomed flasks, add 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide (63.35g, 0.29mol), use 500ml CHCl
3stir, solid can not be entirely molten.Ice bath is cooled to 10-15 DEG C, adds TEA (123g, 1.22mol), is added dropwise to above-mentioned chloride product haloform reaction liquid, ice bath temperature control less than 10-15 DEG C after stirring 30min.Finish, be incubated 20-25 DEG C of stirring reaction and spend the night, TLC monitors reaction process.Reaction completes, and reaction solution 900ml washes 2 times, organic layer anhydrous sodium sulfate drying 5-6h.Filter, 45 DEG C are spin-dried for solvent, and Light brown foam shape solid, adds 700ml anhydrous alcohol solution stand-by.
(3) get a drying three mouthfuls of round-bottomed flasks, 500ml dehydrated alcohol is added reaction flask, take sodium Metal 99.5 (28.6g, 1.25mol) in batches fast and add wherein, stirring and dissolving, obtained alcohol sodium solution.Treat alcohol sodium solution, when being cooled to 40-50 DEG C, under agitation condition, the ethanolic soln of upper step enriched product is joined in alcohol sodium solution.Finish, be heated with stirring to 75-85 DEG C of back flow reaction.The process reaction of TLC monitoring reaction is complete 12-14h hour interaction energy primitive reaction.Question response is complete, removes reaction solution under reduced pressure partial solvent, and the water adding about 140ml, by after enriched material dissolving, under condition of ice bath, with the salt acid for adjusting pH to 7 of 17%, generates a large amount of light yellow solid.Stir the abundant crystallization of 0.5-1h.Filtration under diminished pressure, obtains Virga crude product, puts into 50 DEG C of forced air drying 6h, and weigh to obtain off-white powder solid m=114g, yield 82.9%, m.p185.1-187.9 DEG C.
(4) by crude product 7 times amount alcohol heating reflux, to solid CL, water-bath cooling crystallization spends the night, decompress filter, and 1L ice washing with alcohol, obtains sildenafil base sterling, is off-white color crystalline solid.
The reaction conditions of embodiment 1-3 and reference and yield are contrasted, result is as shown in table 1.
The reaction conditions of table 1 embodiment 1-3 and reference and yield
1.: Shen Jing, You Chaocong, Wu Song. Chinese pharmaceutical chemistry magazine [J] .1999,9 (3): 220.
As can be seen from Table 1, the total recovery of embodiment 1-3 is all far above the total recovery of reference, reach more than 80%, and from synthesis technique, the solution of acid chloride that in embodiment prepared by step (1) is without the need to removing excessive thionyl chloride and solvent through underpressure distillation, but under excessive acid binding agent existent condition directly and 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide generation acylation reaction, preparation intermediate II, this not only reduces the consumption of thionyl chloride, avoid pollution, simultaneously without vacuum distillation process, reduce equipment investment, Simplified flowsheet, improve security and efficiency.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (8)
1. a preparation method for Virga, is characterized in that, the method comprises the following steps:
(1) 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid, under catalyst action, reacts with thionyl chloride and prepares intermediate compound I, after reaction terminates, and solution for later use;
(2) reaction mixture of step (1) is under acid binding agent effect, intermediate II is prepared with 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide generation acylation reaction, after reaction terminates, reaction solution is washed, get organic phase drying, filter, solvent evaporated obtains solid, and gained dissolution of solid is stand-by;
(3) there is cyclization in the reaction mixture of step (2) under the existence of specific alkali, after reaction terminates, removes partial solvent under reduced pressure, be dissolved in water, and adds dilute hydrochloric acid and adjust pH to 7, stirring and crystallizing, and filtration, drying, obtain Virga crude product;
(4) Virga crude product is through recrystallization, obtains Virga sterling.
2. the preparation method of Virga according to claim 1; it is characterized in that: the temperature of reaction of described step (1) is 0-40 DEG C; reaction times is 8-20h; reaction solvent is selected from methylene dichloride, chloroform, ethyl acetate, acetone, N; one or more in dinethylformamide; catalyzer is selected from pyridine, N; one in dinethylformamide, the mol ratio of 2-oxyethyl group-5-(4-methylpiperazine-1-yl alkylsulfonyl) phenylformic acid, thionyl chloride and catalyzer is 1:1.2:0.04.
3. the preparation method of Virga according to claim 2, it is characterized in that: the preferred 25-30 DEG C of temperature of reaction of described step (1), reaction times preferred 10-15h, the preferred methylene dichloride of reaction solvent, the preferred DMF of catalyzer.
4. the preparation method of Virga according to claim 1, it is characterized in that: the temperature of reaction of described step (2) is 10-50 DEG C, reaction times is 2-24h, reaction solvent is selected from methylene dichloride, chloroform, ethyl acetate, acetone, N, one or more in dinethylformamide, acid binding agent is selected from triethylamine, diisopropylethylamine, N, N-Dimethylamino pyridine, N, accelerine, pyridine, triethylamine, one in 4-pyrollidinopyridine, 4-amino-1-methyl-3-n-propyl-1H-pyrazoles-5-methane amide, the mol ratio of intermediate compound I and acid binding agent is 1:1.05:1-10.
5. the preparation method of Virga according to claim 4, is characterized in that: the preferred 25-30 DEG C of temperature of reaction of described step (2), reaction times preferred 10-15h, the preferred methylene dichloride of reaction solvent, the preferred triethylamine of acid binding agent.
6. the preparation method of Virga according to claim 1, it is characterized in that: the temperature of reaction of described step (3) is 50-170 DEG C, reaction times is 2-72h, one or more in the basic cpd that specific alkali is selected from basic metal, alkaline-earth metal and alcohols, phenols is formed, the mol ratio of intermediate II and specific alkali is 1:1-10, and reaction solvent is selected from one or more in methyl alcohol, ethanol, Virahol, propyl carbinol.
7. the preparation method of Virga according to claim 6, is characterized in that: the preferred 75-85 DEG C of temperature of reaction of described step (3), reaction times preferred 12-14h, specific alkali preferred alcohol sodium, reaction solvent preferred alcohol.
8. the preparation method of Virga according to claim 1, it is characterized in that: described step (4) Virga crude product recrystallization solvent is selected from one or more in ethanol, methyl alcohol, the mol ratio of Virga crude product and recrystallization solvent is 1:7.
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| CN112608317A (en) * | 2020-12-15 | 2021-04-06 | 植恩生物技术股份有限公司 | Sildenafil citrate preparation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
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| CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
Non-Patent Citations (2)
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| HONGLIANG DUAN ET AL.: "2-Phenylquinazolin-4(3H)-one, a class of potent PDE5 inhibitors with high selectivity versus PDE6", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| CN112608317A (en) * | 2020-12-15 | 2021-04-06 | 植恩生物技术股份有限公司 | Sildenafil citrate preparation method |
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