CN1077108C - Precursor compound for preparing medicine 'Xiduofeng' - Google Patents
Precursor compound for preparing medicine 'Xiduofeng' Download PDFInfo
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- CN1077108C CN1077108C CN99115009A CN99115009A CN1077108C CN 1077108 C CN1077108 C CN 1077108C CN 99115009 A CN99115009 A CN 99115009A CN 99115009 A CN99115009 A CN 99115009A CN 1077108 C CN1077108 C CN 1077108C
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- xiduofeng
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Abstract
The present invention relates to a precursor compound used to prepare the medicine of xiduofeng, which has a structure disclosed in a general formula (I). In the general formula (I), X can be selected from F, Cl, Br, I, NO2 and NHX1, X1 can be selected from COX2, and X2 can be selected from H, substituted chain hydrocarbon or cyclic hydrocarbon or non-substituted chain hydrocarbon or cyclic hydrocarbon.
Description
What the present invention relates to is the precursor compound that is used to prepare medicine ' Xiduofeng ' (SILDENAFIL).
In the document of Chinese patent publication number CN1124926A, Pfizer Research and Development Company discloses a kind of Pyrazolopyrimidinonefor medicinal compound that can be used for treating impotence.In the document of Chinese patent publication number CN1168376A, this Pfizer Research and Development Company discloses a kind of concrete medicinal compound in such pyrazolopyrimidine ketone compound " the like vigorous ketone " preparation method of (SILDENAFIL, i.e. 'Xiduofeng ') again.This method is to be starting raw material by the 2-ethoxybenzoic acid, through reactions steps such as chlorosulphonation, acidylate and cyclizations and finish.Though it shows that this method is more effective and more favourable than previously disclosed methods such as EP-A-0463756 in the literature, but it provided with the 2-ethoxybenzoic acid is that this preparation method's the cost of starting raw material is very high, therefore consider from economic angle at least still can not be satisfactory for this preparation method's reasonableness, and have and can treat improvements.
Given this, the purpose of this invention is to provide a kind of precursor compound that is used to prepare the said medicine 'Xiduofeng ', and make it when being used to prepare 'Xiduofeng ', lower cost can be arranged, thus say from economic angle at least more reasonable.
The present invention is used to prepare the structure of precursor compound of medicine ' Xiduofeng ' suc as formula shown in (I)
Wherein: X can be at F, Cl, Br, I, NO
2, NHX
1The middle selection,
X
1Can be COX
2,
X
2Can select in the chain hydrocarbon of replacement or non-replacement or the cyclic hydrocarbon at H.
At the above-mentioned precursor compound that is used for preparing medicine ' Xiduofeng ' shown in structural formula (I), said X especially can be at the F of fontanel family element in the formula, Cl, and Br, I like and select.Further, said X can select F in the fontanel family element for use in this formula.
X in the above-claimed cpd structure
2Can be H, i.e. X in the formula especially
1Be formyl radical, but most convenient is to make X
2Be methyl, i.e. X in the formula
1Be ethanoyl.
The said said structure formula of the present invention (I) compound can be the starting raw material preparation by the simple industrial chemicals 2-X phenylformic acid with corresponding substituent X or its acyl derivative.For example; can use the 2-fluorobenzoic acid; the 2-chloro-benzoic acid; the 2-nitrobenzoic acid; 2-amino (or amido of replacement, non-replacement) phenylformic acid and derivative (this 2-amino wherein generally can adopt usual ways such as ethanoyl or formyl radical to protect) thereof; or basic chemical raw materials such as its corresponding benzoyl derivative can prepare through several step reactions steps as starting raw material.
Experimental result shows, in the compound of the said said structure formula of the present invention (I), adopt starting raw material, under the situation that does not change concrete reaction conditions and operation with different substituents X, to the yield of reaction product, particularly the yield to the first step reaction product can have more significantly influence.For example, when being raw material with the 2-fluorobenzoic acid, the yield of its first step reaction can be more than 50%; When being raw material with the 2-acetylamino benzoic acid, the yield of this step reaction more can be up to more than 70%; And when being starting raw material with the 2-nitrobenzoic acid, the yield of its first step reaction then is about 35%.
The compound of said structure formula of the present invention (I) can adopt the specific embodiment that is undertaken by following route to prepare.But the route shown in following is not to be the unique route that may be utilized when preparation above-claimed cpd of the present invention (I).
Embodiment 1:
1 °: in reaction flask, add 4-amino-1-methyl-3-propyl-pyrazole-5-methane amide (V) 30 grams (0.164 mole), at 4-(N, the N-dimethylamino) pyridine 0.2 gram and triethylamine 34 grams (0.33 mole), add 500 milliliters of methylene dichloride again, the temperature of reaction system is reduced to 0 ℃, splash into 2-fluorobenzoyl chloride 52.3 grams (0.33 mole) and be dissolved in 300 milliliters of solution that methylene dichloride became, dripped off in about 1 hour.Dripping off the back stirred 2 hours under room temperature, removal of solvent under reduced pressure, the adding volume ratio is 2000 milliliters of dissolvings of methylene chloride-methanol solution of 19: 1 in the resistates, use 1000 milliliters of washings of 5% hydrochloric acid soln again, organic layer with anhydrous sodium sulfate drying after, evaporated under reduced pressure is again through ethyl acetate-normal hexane recrystallization, get pinkish solid product (II) 25.9 grams, fusing point 130-133 ℃.Yield 52%.
2 °: will go up step product (II) 20.6 gram (0.0676 mole) and under agitation add by sodium hydroxide 5.4 grams (0.135 mole) and 22.4 milliliters of 30% hydrogen peroxide in batches and be dissolved in the solution that 200 ml waters are become.And then add 70 milliliters of ethanol, refluxed 2.5 hours.Be chilled to removal of solvent under reduced pressure after the room temperature, residue is handled with 10% aqueous sodium hydroxide solution under ice bath, after extracting with the methylene dichloride gradation again, organic layer washs with saturated sodium carbonate solution, anhydrous sodium sulfate drying after the evaporated under reduced pressure, adds ether and grinds, can obtain white solid product (III) 16.3 grams, fusing point 120-123.5 ℃.Yield 84%.
3 °: will go up step product (III) 15 gram (0.524 mole) under～0 ℃ and nitrogen protection; gradation adds 35 milliliters of chlorsulfonic acids on a small quantity; insulated and stirred about 24 little anti-after; slowly reactant is joined in 250 milliliters of frozen water; extract with the methylene dichloride gradation, merge organic layer and, removal of solvent under reduced pressure through anhydrous sodium sulfate drying; obtain white solid product (IV) 19 grams, fusing point 164-166 ℃.Yield 95%.
4 °: go on foot product (IV) 18 grams (0.0468 mole) in 600 milliliters of ethanol, adding, stir and add N methyl piperazine 14.3 grams (0.143 down, mole), room temperature condition stirred 6 hours down, removal of solvent under reduced pressure, the residue volume ratio is 500 milliliters of dissolvings of methylene chloride-methanol mixed solution of 9: 1, and washs with saturated sodium carbonate solution.Organic layer behind anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Solid is with the methyl alcohol-N of equal-volume ratio, 200 milliliters of recrystallizations of dinethylformamide, faint yellow solid product 11.3 grams, be the compound of the said structural formula of the present invention (I) (substituent X is a fluorine in the formula), fusing point 257-262 ℃.Yield 54%.
The related detection data of gained said structure formula (I) product are as follows:
1HNMR (DMSO-d
6) δ: 0.96 (3H, t, J=7.2Hz), 1.75 (2H, sextet, J=5.7Hz), 2.09 (3H, s), 2.38 (4H, brs), 2.76 (2H, 1, J=7.4Hz), 2.88 (4H, brs), 4.19 (3H, s), 7.43 (1H, m), 7.87 (2H, m), 12.27 (1H, brs, NH).Mass spectrum (FAB-MS): relative kurtosis (%) m/z
(1) 4.4 450.3
(2) 18.8 449.3
(3) 100.0 99.1
(4) 16.3 70.1
(5) 24.9 56.1
Embodiment 2:
With 2-nitrobenzoyl chloride 42.9 grams (0.33 mole) is starting raw material, the 1st ° of used 2-fluorobenzoyl chloride of step 52.3 grams (0.33 mole) in the alternative embodiment 1, all the other conditions, reagent and treatment process and equal identical with embodiment 1 with the operation in reserve step.Wherein the yield of the 1st ° of step product (II) is 35%; All the other respectively go on foot the similar of yield and embodiment 1.Substituent X in final product (I) structure is a nitro.
Embodiment 3:
With 2-kharophen Benzoyl chloride 33.0 grams (0.33 mole) is starting raw material, replacement is the 1st ° of used 2-fluorobenzoyl chloride of step 52.3 grams (0.33 mole) in embodiment 1, all the other conditions, reagent and treatment process and equal identical with embodiment 1 of operation in each step later on.Yield＞70% of the 1st ° of step product (II); All the other respectively go on foot the similar of yield and embodiment 1.Substituent X in final product (I) structure is a kharophen.
With the precursor compound of said structure formula of the present invention (I), under alkaline condition, the substituent X in this compound (I) structure is replaced with oxyethyl group with ethanol, but promptly obtain the final pyrazolopyrimidinones 'Xiduofeng ' of hyoscine.For example can adopt following concrete grammar preparation:
With precursor compound 9 gram (0.0201 mole) and the N of said structure formula (I), 100 milliliters of mixing of dinethylformamide add in 20 milliliters of the ethanol again, add 60% sodium hydride, 2.8 grams, stir 1 hour, in the reactant impouring water, with methylene dichloride gradation extraction.Extracting solution with anhydrous sodium sulfate drying after, evaporated under reduced pressure.With first ferment-normal hexane recrystallization, get solid product 'Xiduofeng ' 6.7 grams, fusing point 186.5-188 ℃.Yield 70%.
Experiment shows, adopts the above-mentioned precursor compound of the present invention (I), but by the final compound 'Xiduofeng ' of starting raw material to hyoscine, with known today be that the method preparation of starting raw material is compared with the 2-ethoxybenzoic acid, total cost can reduce more than 50%.Only this remarkable economic efficiency promptly can fully show compound of the present invention (I) and preparation method correspondingly, is can be more gratifying in the reasonableness that is had aspect the final medicinal compound 'Xiduofeng ' of preparation.
Claims (4)
1. be used to prepare the precursor compound of medicine ' Xiduofeng ', its structure is suc as formula shown in (I)
Wherein: X can be at F, Cl, Br, I, NO
2, NHX
1The middle selection,
X
1Can be COX
2,
X
2Can in the chain hydrocarbon of H or non-replacement or cyclic hydrocarbon, select.
2. the precursor compound that is used to prepare medicine ' Xiduofeng ' as claimed in claim 1 is characterized in that said X can be at F in the compound of structural formula (I), Cl, and Br selects arbitrarily among the I.
3. the precursor compound that is used to prepare medicine ' Xiduofeng ' as claimed in claim 2 is characterized in that said X is F in the compound of structural formula (I).
4. the precursor compound that is used to prepare medicine ' Xiduofeng ' as claimed in claim 1 is characterized in that said X in the compound of structural formula (I)
2Be methyl.
5. the precursor compound that is used to prepare medicine ' Xiduofeng ' as claimed in claim 1 is characterized in that said X in the compound of structural formula (I)
2Be H.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99115009A CN1077108C (en) | 1999-07-13 | 1999-07-13 | Precursor compound for preparing medicine 'Xiduofeng' |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99115009A CN1077108C (en) | 1999-07-13 | 1999-07-13 | Precursor compound for preparing medicine 'Xiduofeng' |
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| Publication Number | Publication Date |
|---|---|
| CN1243832A CN1243832A (en) | 2000-02-09 |
| CN1077108C true CN1077108C (en) | 2002-01-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99115009A Expired - Lifetime CN1077108C (en) | 1999-07-13 | 1999-07-13 | Precursor compound for preparing medicine 'Xiduofeng' |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112961160A (en) * | 2021-03-05 | 2021-06-15 | 遂成药业股份有限公司 | Improved synthesis process of sildenafil |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057464A (en) * | 1990-06-20 | 1992-01-01 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1068329A (en) * | 1991-07-09 | 1993-01-27 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1124926A (en) * | 1993-06-09 | 1996-06-19 | 辉瑞研究及发展公司 | Pyrazolopyrimidinones for the treatment of impotence |
| CN1168376A (en) * | 1996-06-14 | 1997-12-24 | 辉瑞研究开发公司 | Process for preparing sildenafil |
-
1999
- 1999-07-13 CN CN99115009A patent/CN1077108C/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057464A (en) * | 1990-06-20 | 1992-01-01 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1068329A (en) * | 1991-07-09 | 1993-01-27 | 美国辉瑞有限公司 | Pyrazolopyrimidinoneantianginal antianginal agents |
| CN1124926A (en) * | 1993-06-09 | 1996-06-19 | 辉瑞研究及发展公司 | Pyrazolopyrimidinones for the treatment of impotence |
| CN1168376A (en) * | 1996-06-14 | 1997-12-24 | 辉瑞研究开发公司 | Process for preparing sildenafil |
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|---|---|
| CN1243832A (en) | 2000-02-09 |
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