CN1358722A - Process for preparing citrat - Google Patents
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- CN1358722A CN1358722A CN 01124175 CN01124175A CN1358722A CN 1358722 A CN1358722 A CN 1358722A CN 01124175 CN01124175 CN 01124175 CN 01124175 A CN01124175 A CN 01124175A CN 1358722 A CN1358722 A CN 1358722A
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Abstract
The present invention discloses a method for preparing compound with structural formula (I) (see patent specification), i.e. preparing sildenafil. Said compound sildenafil is made up another compound with structural formula (II) (see patent specification) through cyclization reaction in the presence of specific alkali. Said method also includes the intermediate product before the compound with structural formula (II) and its preparation process including chlorosulfonation reaction and sulfamidatino reaction with N-methylpiperazine.
Description
The present invention relates to the preparation method of medicinal heterocyclic compound.Specifically, be exactly that application structure formula (II) compound prepares the method for structural formula (I) compound at specified conditions again by structural formula (III) compound generating structure formula (II) compound.
The molecular structural formula of related compound is,
The name of structural formula (I) compound is called 1-[4-oxyethyl group-3-(6,7-dihydro-1-methyl-7-oxidation-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl) phenyl sulfonyl]-the 4-methylpiperazine, or claim Virga (Sildenafil).Virga as medicinal compound see Chinese patent " preparation method of Pyrazolopyrimidinoneantianginal antianginal agents " (patent No. ZL 91104162.1), Chinese patent application " prepares the method for liking vigorous ketone " (patent publication No. CN1168376A), and Chinese patent application " method for preparing Virga " (patent publication No. CN 1246478A).Virga citrate treatment male erectile dysfunction has good effect.
Than the above-mentioned background technology, the present invention use easier adopt, the more honest and cleaner raw material of price, use and the substantially different processing method of known technology the preparation Virga.The present invention prepares the method good reaction selectivity of Virga, and yield is very high, and has good practicability.
The processing step of its most critical has three:
(1) structural formula (IV) compound gets reaction product structural formula (III) compound through chlorosulfonation;
(2) structural formula (III) compound and N methyl piperazine sulfuryl amine get reaction product structural formula (II) compound;
(3) structural formula (II) compound obtains structural formula (I) compound, i.e. Virga through cyclization under the condition that specific alkali exists.With usual method Virga and Citric Acid are reacted afterwards, generate the citrate of Virga, can be clinical medicinal.
Used reactant and the reaction conditions of above-mentioned three steps be,
Step (1) is under the condition that chlorsulfonic acid exists, structural formula (IV) compound generation chlorosulfonation, generating structure formula (III) compound.The temperature of chlorosulfonation is controlled at-5～30 ℃, finishes through 8～20 hours.
Step (2) structural formula (III) compound and N methyl piperazine generation amidate action, 0～50 ℃ of controlled temperature was finished through 2～12 hours, made structural formula (II) compound.
The required specific alkali of step (3) cyclization is selected from the basic cpd of alkali family, alkaline-earth metal and phenols, thiophenol class, thio-alcohol formation, for example ArONa (phenol sodium), ArSNa (thiophenol sodium), RSNa (sodium mercaptides), ArOK (phenol potassium), ArSK (thiophenol potassium), RSK (mercaptan potassium) are (in the molecular formula, Ar is an aromatic hydrocarbyl, R is an aliphatic alkyl) etc. one or more and usefulness, wherein the consumption of alkali is 1.0～10.0 moles.
The solvent that cyclization is suitable for is selected from acetonitrile, methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol, 2-butanone, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide, pyridine and water and their mixture.
At cyclization post neutralization reaction mixture.Reaction process was carried out 2～72 hours under 50～170 ℃ of temperature condition.
The reaction product of above-described chlorosulfonation, N methyl piperazine amidate action and the cyclization under the alkali existence condition can use that routine techniques separates, purifying.The selectivity that a whole set of technical process shows reaction is good, and yield can reach more than 95%.
Structural formula (I), (II), (III) compound are proved conclusively its structure by ultimate analysis, mass spectroscopy.Structural formula (III) compound passes through again
1H nucleus magnetic resonance (NMR) is further proved conclusively its structure.
In the ultimate analysis, C, H, N content are used Foss CHN-O-Rapid elemental analyser and are measured; The S assay carries out according to People's Republic of China's GB GB4497-84 method.
Mass spectrum FTMS-2000 mass spectrograph record, m/z represents mass-to-charge ratio, M
+The expression molecular ion peak, the numeral relative abundance (%) in the bracket.
1H nucleus magnetic resonance (NMR) wave spectrum is with Bruker RM-500 spectrometer record, characterization displacement study (d) be from trimethyl silane to low move 1,000,000/, and with routine representation feature peak: the s that abridges, unimodal; D, doublet; T, triplet; Q, quartet; H, sextet; M, multiplet; Br, broad peak.
Prepare structural formula (I) compound as mentioned above then by the cyclisation and getting under specific alkali existence condition of structural formula (II) compound, structural formula (II) compound is then by structural formula (III) compound and N methyl piperazine generation sulfuryl amine.And required intermediate precursor substance one structural formula (IV) compound of preparation structural formula (III) compound can make by the described route of following reaction scheme.
The reaction scheme of preparation structural formula (IV) compound
The reaction scheme of preparation structural formula (IV) compound that last figure is indicated, its technical process is as follows:
Structure formula V compound name is called " 3-propyl group pyrazoles-5-ethyl formate ", can make by the method that " Chem.Pharm.Bull., 32:1568,1984 " are put down in writing.
Structure formula V compound through methylate structural formula (VI) compound;
Structural formula (VI) compound gets structural formula (VII) compound through hydrolysis;
Structural formula (VII) compound gets structural formula (VIII) compound through nitration;
Structural formula (VIII) compound gets structural formula (IX) compound through amidation (I);
Structural formula (IX) compound through reduce structural formula (X) compound;
Structural formula (X) compound makes structural formula (IV) compound through amidation once more (II).Structural formula (IV) compound name is called, [4-(2-2 oxygen base phenyl formamide base)-1-methyl-3-propyl group pyrazoles-5-methane amide].
In these reactions, technology of the present invention has been done the following adjustment and improvement than traditional processing method.
1. increased the use of acetone in amidation (I), made more convenient operation, gained intermediate quality is higher, and yield also increases.
2. on the reductive link, abandon tin protochloride (SnCl
2) reduction method, and the shortening method of employing alumino nickel.The benefit of this method has been to reduce the pollution of tin mud to environment, and it is convenient to operate.
3. in amidation (II), do not re-use special additive 4-Dimethylamino pyridine.
4. from the process of structural formula (X) compound structural formula (IV) compound, do not re-use the column chromatography for separation technology.
Make whole technological process be convenient to operation more through above adjustment and improvement, total recovery also increases.
The invention will be further described by the following examples.
Embodiment 1-7 be about structural formula (II) compound in the presence of specific alkali, the example of generating structure formula (I) compound (being Virga).Embodiment 8 is by chlorosulfonation generating structure formula (III) examples for compounds about structural formula (IV) compound.Embodiment 9 is through N methyl piperazine sulfuryl amine generating structure formula (II) examples for compounds about structural formula (III) compound.Embodiment 10 is about preparation structural formula (IV) examples for compounds.
Embodiment 1 preparation structural formula (I) compound
In the four-hole bottle that agitator, reflux condensing tube, thermometer are housed, add structural formula (II) compound 49.20g (0.1mol), add the sodium phenylate 70g (0.6mol) that has prepared again, acetonitrile 250ml stirs.Reflux 5-6 hour.Reaction finishes.Boil off acetonitrile, it is an amount of to add water, uses CH again
2Cl
2Extract, merge CH
2Cl
2Layer with the washing of 5% sodium hydroxide, steams CH
2Cl
2Oven dry gets class in vain so because of body 45.3g, fusing point: 186-188 ℃ yield 95.5%.95% ethyl alcohol recrystallization gets 41.5g, fusing point 188-190 ℃.
Ultimate analysis: measured value C, 55.62%; H, 6.31%; N, 17.7%; S, 6.71%
Theoretical value: C, 55.68%; H, 6.37%; N, 17.71%; S, 6.76%
1HNMR spectrum: δ (CD
3SOCD
3): 0.96 (3H.t), 1.30 (3H, t), 1.77 (2H, h), 2.68 (2H.t), 2.83 (4H, br, S), 2.92 (4H, br, S), 4.18 (3H, S), 4.29 (2H, q), 7.31 (1H, d), 7.80 (2H, m), 12.16 (1H, br, S)
Mass spectrum: m/z:474 (M
+, 3.09), 404 (38.44), 312 (100.00), 99 (89.3)
Embodiment 2～7 preparation structural formula (I) compounds
Use and embodiment 1 similar methods, select for use the listed condition of following table to prepare structural formula (I) compound.
| Embodiment | Alkali | Solvent | Reaction conditions | Reaction times (hour) | Yield (%) |
| ????2 | Sodium phenylate | 1, the 4-dioxane | Reflux | ????6 | ????83.2 |
| ????3 | Sodium phenylate | Ethanol | Reflux | ????6 | ????96.1 |
| ????4 | Sodium phenylate | Acetonitrile | Reflux | ????8 | ????90.6 |
| ????5 | Methylthio phenol sodium | Tetrahydrofuran (THF) | Reflux | ????12 | ????72.1 |
| ????6 | Butyl sulfhydryl sodium | Acetonitrile | Reflux | ????8 | ????65.3 |
| ????7 | Butyl sulfhydryl sodium | 2-butanone | Reflux | ????8 | ????68.7 |
Embodiment 8 preparation structural formula (III) compounds
Agitator, drying tube are being housed, in the four-hole boiling flask of thermometer, are adding chlorsulfonic acid 120ml and stir, temperature control adds structural formula (IV) compound 33g (0.1mol) below 5 ℃ in batches, after adding, stirs about 5 ℃ of temperature controls, coreaction 12 hours.Reaction is poured reactant in the ice cube into after finishing, and stirs, and uses CH then
2Cl
2500ml scoops up, CH
2Cl
2Layer is used anhydrous sodium sulfate drying, steams CH at last
2Cl
2, oven dry.Get structural formula (III) compound 4.08g, 160 ℃-162 ℃ of fusing points, yield 95.2%.
Ultimate analysis: measured value C, 47.72%; H, 4.89%; N, 13.15%; S, 7.56%
Theoretical value: C, 47.61%; H, 4.94%; N, 13.07%; S, 7.48%
Mass spectrum: m/z:428.9 (M
+, 4.01), 358.9 (35.32), 330.0 (100.00), 166 (25.41)
Embodiment 9 preparation structural formula (II) compounds
Add structural formula (III) compound 40.8g in the four-hole boiling flask that agitator, drying tube, thermometer are housed, dehydrated alcohol 300ml stirs.Add N methyl piperazine 24g then in batches, stirred under the room temperature 6 hours, after reaction finishes, filter, washing, dry 44.8g, yield 95.6%, 206 ℃-208 ℃ of fusing points.Get 41.2% behind 95% ethyl alcohol recrystallization, 208 ℃-210 ℃ of fusing points.
Ultimate analysis: measured value C, 53.72%; H, 6.52%; N, 17.13%; S, 6.47%
Theoretical value: C, 53.65%; H, 6.55%; N, 17.06%; S, 6.51%
Mass spectrum: m/z:492 (M
+, 3.86), 422 (30.52), 329 (80.41), 99 (100.00)
Embodiment 10 preparation structural formula (IV) compounds
Preparation structural formula (IV) compound carries out according to the following steps:
1, preparation structural formula (VI) compound---1-methyl-3-propyl group pyrazoles-5-ethyl formate
In the round-bottomed flask of reflux condensing tube is housed, adding structure formula V compound---3-propyl group pyrazoles-5-ethyl formate 31.9g (0.18mol) (presses Chem.Pharm.Bull., 32:1568,1984 method makes) and methyl-sulfate 22.1g (0.18mol), controlled temperature reacted 2.5 hours in 90 ℃, be cooled to room temperature, add methylene dichloride 50ml, get light brown liquid 29.1g, yield 82.4%.
2. prepare structural formula (VII) compound---1-methyl-3-propyl group pyrazoles-5-formic acid
In agitator, reflux condensing tube there-necked flask are housed, add structural formula (VI) compound---1-methyl-3-propyl group pyrazoles-5-ethyl formate 19.6g (0.1mol), 6mol.L
-1Sodium hydroxide 50ml, reflux 3 hours is after the ice-water bath cooling, with the 6mol.L of precooling
-1Hydrochloric acid is transferred pH to 2, obtains white solid 14.3g after the filtration, 150～154 ℃ of fusing points, yield 85.2%.
3. prepare structural formula (VIII) compound---1-methyl-4-nitro-3-propyl group pyrazoles-5-formic acid
In agitator, reflux condensing tube there-necked flask are housed, add oleum 18ml, nitrosonitric acid 15ml adds structural formula (VII) compound more in batches---and 1-methyl-3-propyl group pyrazoles-5-formic acid 16.8g (0.1mol) keeps temperature to be lower than 60 ℃.After adding, 60 ℃ of heated overnight after the cooling, are poured on ice, obtain white solid 19.4g after the filtration, 124～127 ℃ of fusing points, yield 91.2%.
4. prepare structural formula (IX) compound---1-methyl-4-nitro-3-propyl group pyrazoles-5-methane amide
Agitator is being housed, in the there-necked flask of reflux condensing tube, is adding structural formula (VIII) compound---1-methyl-3-propyl group pyrazoles-5-formic acid 21.3g (0.1mol), thionyl chloride 50ml, reflux 3 hours, after the cooling, the remaining thionyl chloride of pressure reducing and steaming, cooling, add 50ml acetone, then the acetone solution thing is poured into carefully in the mixture of ice 50g and strong aqua 50ml, obtain faint yellow solid 17.8g after the filtration, 141～143 ℃ of fusing points, yield 84.1%.
5. prepare structural formula (X) compound---4-amino-1-methyl-3-propyl group pyrazoles-5-methane amide
In the autoclave of 1 liter, add structural formula (IX) compound---1-methyl-4-nitro-3-propyl group pyrazoles-5-methane amide 21.3g (0.1mol), alumino nickel 20g, 95% ethanol 300ml, hydrogenation is caught up with oxygen post-heating to 70 ℃, slowly feed hydrogen, press in treating to reach 50kg/cm
2Shi Jixu leads to hydrogen, then reduces to normal pressure and filters, and solution goes in the 500ml there-necked flask, steams ethanol, gets gray solid, gets white crystal 14.9g, 98～101 ℃ of fusing points, yield 81.9% behind recrystallization.
6. prepare structural formula (IV) compound---4-(2-ethoxyl phenenyl formamido group)-1-methyl-3-propyl group pyrazoles-5-methane amide
In the there-necked flask that agitator, reflux condensing tube and dropping funnel are housed, add structural formula (X) compound---4-amino-1-methyl-3-propyl group pyrazoles-5-ammonium formate 18.2g (0.1mol), triethylamine 20g (0.2mol), methylene dichloride 300ml, cryosel is bathed and is cooled to below 0 ℃, stir, drip the mixture of 2-ethylphenyl formyl chloride 36.1g (0.2mol) and methylene dichloride 300ml.Finish, stirred 2 hours under the room temperature, add methyl alcohol 15ml, use 2mol.L
-1Organic layer is told in hydrochloric acid 200ml washing, and anhydrous sodium sulfate drying boils off solvent, and solid gets white solid 31.2g with amount of ethyl acetate-hexane (1: 2) washing, is structural formula (IV) compound, 153～155 ℃ of fusing points, yield 94.6%.
Claims (8)
1. the method for preparing structural formula (I) compound, it is characterized in that, comprise reaction conditions by the cyclization of structural formula (II) compound generating structure formula (I) compound, structural formula (IV) compound prepares structural formula (III) compound through chlorosulfonation, carries out the reaction conditions that sulfonamide reaction prepares structural formula (II) compound by structural formula (III) compound and N methyl piperazine again.
2. according to the method for claim 1, it is characterized in that, is to carry out under the condition that has specific alkali to exist by the cyclization of structural formula (II) compound generating structure formula (I) compound.
3. according to the method for claim 1, it is characterized in that, under 50～170 ℃ of temperature condition, carry out by the cyclization of structural formula (II) compound generating structure formula (I) compound.
4. according to the method for claim 1, it is characterized in that, by cyclization flow process time of structural formula (II) compound generating structure formula (I) compound be 2～72 hours.
5. according to the method for claim 2, it is characterized in that, used alkali is selected from the basic cpd of alkali family, alkaline-earth metal and phenols, thiophenol class, thio-alcohol formation, comprise that ArONa (phenol sodium), ArSNa (thiophenol sodium), RSNa (sodium mercaptides), ArOK (phenol potassium), ArSK (thiophenol potassium), RSK (mercaptan potassium) are (in the molecular formula, Ar is an aromatic hydrocarbyl, and R is an aliphatic alkyl) one or more and use.
6. according to the method for claim 1, it is characterized in that, cyclization solvent for use by structural formula (II) compound generating structure formula (I) compound is selected from acetonitrile, methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol, 2-butanone, tetrahydrofuran (THF), 1,4-dioxane, dimethyl formamide, pyridine and water and their mixture.
7. according to the method for claim 1, it is characterized in that structural formula (IV) compound carries out chlorosulfonation and prepares structural formula (III) compound under the condition that chlorsulfonic acid exists, its temperature of reaction is at-5～30 ℃, and the reaction times is 8～20 hours.
8. according to the method for claim 1, it is characterized in that structural formula (III) compound and N methyl piperazine carry out sulfonamide reaction, preparation structural formula (II) compound, its temperature of reaction is 0～50 ℃, the reaction times is 2～12 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011241756A CN1139590C (en) | 2001-08-21 | 2001-08-21 | Process for preparing citrat |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011241756A CN1139590C (en) | 2001-08-21 | 2001-08-21 | Process for preparing citrat |
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| Publication Number | Publication Date |
|---|---|
| CN1358722A true CN1358722A (en) | 2002-07-17 |
| CN1139590C CN1139590C (en) | 2004-02-25 |
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|---|---|---|---|
| CNB011241756A Expired - Lifetime CN1139590C (en) | 2001-08-21 | 2001-08-21 | Process for preparing citrat |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012097750A1 (en) | 2011-01-21 | 2012-07-26 | 浙江大德药业集团有限公司 | Pyrazolopyrimidinone compound and imidazo-triazone compound for treating erectile dysfunction |
| CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
| CN103044331A (en) * | 2013-01-14 | 2013-04-17 | 常州市亚邦医药研究所有限公司 | Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide |
| CN106117212A (en) * | 2016-06-25 | 2016-11-16 | 吉林医药学院 | A kind of sldenafil synthesis technique of improvement |
| CN109970744A (en) * | 2019-04-10 | 2019-07-05 | 重庆康刻尔制药有限公司 | A kind of synthetic method of sildenafil citrate intermediate |
-
2001
- 2001-08-21 CN CNB011241756A patent/CN1139590C/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012097750A1 (en) | 2011-01-21 | 2012-07-26 | 浙江大德药业集团有限公司 | Pyrazolopyrimidinone compound and imidazo-triazone compound for treating erectile dysfunction |
| CN102690273A (en) * | 2012-06-07 | 2012-09-26 | 杭州奥默医药技术有限公司 | Preparation method of sildenafil |
| CN103044331A (en) * | 2013-01-14 | 2013-04-17 | 常州市亚邦医药研究所有限公司 | Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide |
| CN103044331B (en) * | 2013-01-14 | 2017-09-15 | 常州市亚邦医药研究所有限公司 | Prepare the new method of the formamide of 3 n-propyl pyrazoles of silaenafil intermediate 4 amino, 1 methyl 5 |
| CN106117212A (en) * | 2016-06-25 | 2016-11-16 | 吉林医药学院 | A kind of sldenafil synthesis technique of improvement |
| CN106117212B (en) * | 2016-06-25 | 2019-10-11 | 吉林医药学院 | A kind of improved silaenafil synthesis technology |
| CN109970744A (en) * | 2019-04-10 | 2019-07-05 | 重庆康刻尔制药有限公司 | A kind of synthetic method of sildenafil citrate intermediate |
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| Publication number | Publication date |
|---|---|
| CN1139590C (en) | 2004-02-25 |
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Granted publication date: 20040225 |