CN108558890A - A kind of silaenafil intermediate synthetic method - Google Patents
A kind of silaenafil intermediate synthetic method Download PDFInfo
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- CN108558890A CN108558890A CN201810683506.5A CN201810683506A CN108558890A CN 108558890 A CN108558890 A CN 108558890A CN 201810683506 A CN201810683506 A CN 201810683506A CN 108558890 A CN108558890 A CN 108558890A
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- 0 CC(C)[C@](C)C(C)C(C(C(*)=O)N(*)N)N Chemical compound CC(C)[C@](C)C(C)C(C(C(*)=O)N(*)N)N 0.000 description 8
- MDKAAWDKKBFSTK-UHFFFAOYSA-N CCOc(cccc1)c1C(Cl)=O Chemical compound CCOc(cccc1)c1C(Cl)=O MDKAAWDKKBFSTK-UHFFFAOYSA-N 0.000 description 1
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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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Abstract
Silaenafil clinically has treatment male erectile dysfunction (ED) effect well, the preparation method of silaenafil to have many reports, and mostly two-step method synthesizes, and two step post-processing operations are relatively cumbersome, and yield is relatively low.The present invention provides a kind of synthetic method of silaenafil intermediate, and compound II is dissolved in organic aprotic solvents, and compound I is added and carries out condensation reaction；It alkali is added after monitoring compound II the reaction was complete carries out ring-closure reaction and obtain compound IV.The present invention is synthesized using " one kettle way ", is reduced the generation of " three wastes ", is substantially reduced the reaction time, improve reaction yield, stability is good.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to a kind of synthetic method of silaenafil intermediate.
Background technology
Silaenafil, trade name：Viagra, chemical name：1- [4- ethyoxyls -3- [5- (6,7- dihydro -1- methyl -7-
Oxo -3- propyl -1H- pyrazolos [4,3d] pyrimidine)] benzene sulfonyl] -4- methyl piperazines.The initial compound is as anti-pulmonary artery
High pressure drug is researched and developed, but is found in subsequent research, and silaenafil clinically has treatment male erectile dysfunction well
(ED) it acts on, the mechanism of action is that silaenafil high selectivity inhibits phosphodiesterase 5 type (PDE5), improves the high thuja acid of ring
(cGMP) horizontal, the NO effects of penis release are improved, so that corpus cavernosal smooth muscle is relaxed, increases penile blood flow amount and erect.
The preparation method of silaenafil has many reports.Patent CN97113261.5 discloses o-ethoxybenzoic acid elder generation
Chlorosulfonation is carried out, then connects N methyl piperazine group and then carries out condensation reaction with compound II, cyclization is carried out and obtains Xi Dina
Non-free alkali finally obtains finished product sildenafil citrate at salt.The synthetic method of silaenafil is as follows：
The process program can be the larger problem of linear step risk to avoid process route, but still remain condensation and ring
It is relatively low to close two-step reaction substep synthesis yield, operates relatively cumbersome problem.
Patent CN91104162.1 discloses one kind using 3- n-propyls pyrazole-5-ethyl formate as raw material, methylates to obtain
1- methyl -3- propylpyrazol -5- Ethyl formates, then hydrolyze to obtain 1- methyl -3- n-propyl pyrazoles -5- formic acid；Then with by sending out
The mixed acid nitrification of cigarette nitric acid and oleum composition, obtains 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formic acid；Via sulfonyl
After chlorine chloro, 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides are condensed to yield with concentrated ammonia liquor；Then use tin chloride reduction
4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides are obtained, then 4- (2- ethyoxyls are condensed to obtain with 2- ethoxy benzoyl chlorides
Benzamido) -1- methyl -3- n-propyl pyrazoles -5- formamides；5- (2- ethoxyl phenenyls) -1- methyl -3- is obtained after cyclization
N-propyl -1,6- dihydro -7H- pyrazolos [4,3-d] pyrimidin-7-ones；Then chlorosulfonation is carried out in chlorosulfonic acid obtain 5-
(5- chlorosulfonyl -2- ethoxyl phenenyls) -1- methyl -3- n-propyls -1,6- dihydro -7H- pyrazolos [4,3-d] pyrimidin-7-ones,
Again silaenafil is condensed to obtain with 1- methyl piperazines.Synthetic method is as follows：
The technique uses substep synthetic schemes, and two step post-processing operations are relatively cumbersome, and yield is relatively low, and two step yields are about
30%.Post-processing improvement is carried out in this scheme, is still washed, solvent is evaporated, recrystallization operation replaces
Column chromatography purifies, and two-step reaction total recovery is also below 70%.
Therefore, it is studied by the synthetic method to silaenafil intermediate, simplifies step, improve yield, form production
The intermediate that quality is good, stability is high is of great significance.
Invention content
The technical problem to be solved in the present invention is to provide a kind of synthetic method of silaenafil intermediate, present invention offer
Synthetic method using " one kettle way " synthesize, reduce the generation of " three wastes ", substantially reduce the reaction time, improve reaction receive
Rate, stability are good.
A kind of synthetic method of silaenafil intermediate of the present invention, which is characterized in that include the following steps：
1) compound II is dissolved in organic aprotic solvents, compound I is added and carries out condensation reaction；
2) it alkali is added after monitoring compound II the reaction was complete carries out ring-closure reaction and obtain compound IV.
Further, a kind of synthetic method of silaenafil intermediate, includes the following steps：
1) compound II is dissolved in organic aprotic solvents, the lower progress condensation reaction of compound I stirrings, decompression is added
The organic aprotic solvents are distilled off, obtain compound III；
2) it is purifying, dry after reaction dissolvent, the reaction of sodium hydroxide temperature rising reflux is added after monitoring compound II the reaction was complete
It is dry to obtain compound IV.
Further, a kind of synthetic method of silaenafil intermediate, includes the following steps：
1) compound II is dissolved in organic aprotic solvents, the lower progress condensation reaction of compound I stirrings, decompression is added
The organic aprotic solvents are distilled off, obtain compound III；
2) 200~300ml of reaction dissolvent, the reaction of sodium hydroxide temperature rising reflux is added after monitoring compound II the reaction was complete
2~8h is purified, is dried to obtain compound IV.
Further, the organic aprotic solvents are selected from dichloromethane, chloroform, tetrahydrofuran, acetonitrile, acetic acid second
Ester, isopropyl acetate, acetone, the one or several kinds in butanone.
Further, the ring-closure reaction solvent is selected from ethyl acetate, tetrahydrofuran, acetonitrile, acetone, butanone, methanol, second
Alcohol, isopropanol, n-butanol, the one or several kinds in isobutanol.
Further, 0-50 DEG C of step 1 setting-up point, step 2 ring-closure reaction temperature are 40-100 DEG C.
Further, acid binding agent is added in step 1 condensation reaction.
Further, the acid binding agent is selected from triethylamine, diethylamine, N ' N- diisopropylethylamine, piperidines, pyridine, piperazine
One or more of.
Further, the purification process is rear for the reaction was complete is added purified water, and dilute hydrochloric acid is added and adjusts solution pH value to 7
~9, filter to obtain product.
A kind of synthetic method of silaenafil intermediate of the present invention has following advantageous effects compared with prior art：
It is condensed, cyclization two-step reaction, condensation reaction prod is not detached using " one kettle way ", directly synthesize compound IV,
Reduce the post-processing required time that separation of intermediates III is carried out, while also avoiding the yield in last handling process
Loss, product yield is up to 90% or more, good product quality, and stability is high；In addition, reducing the discharge of " three wastes ", pollution is reduced；
Technological operation is simple, is suitble to industrialized production.
Specific implementation mode
A kind of synthetic method of silaenafil intermediate, includes the following steps：
1) compound II is dissolved in organic aprotic solvents, the lower progress condensation reaction of compound I stirrings, decompression is added
The organic aprotic solvents are distilled off, obtain compound III；
2) 200~300ml of reaction dissolvent, the reaction of sodium hydroxide temperature rising reflux is added after monitoring compound II the reaction was complete
2~8h is purified, is dried to obtain compound IV.Process route is as follows：
Embodiment one：
30g compounds II is added to reaction bulb, and dichloromethane 240ml is added, is stirred at room temperature, and compound I is added, and drips and finishes room
Temperature stirring 1h, is added 4 equivalent of sodium hydroxide, is warming up to back flow reaction 8h, and reaction, which finishes, to be cooled to room temperature, and reaction solution water extraction washes 3
Secondary, anhydrous sodium sulfate drying, vacuum distillation removes solvent, and isopropyl ether mashing purifying obtains compound IV 47g, yield 91%.
HPLC purity 99.70%.
Embodiment two：
50g compounds II is added to reaction bulb, and dichloromethane 400ml is added, is stirred at room temperature, and acid binding agent triethylamine 2 is added
Compound I is added in equivalent, and drop, which finishes, is stirred at room temperature 1h, and vacuum distillation removes dichloromethane, and ethyl alcohol 250ml is added, and hydroxide is added
3 equivalent of sodium is warming up to back flow reaction 3h, and reaction, which finishes, to be cooled to room temperature, and vacuum distillation removes about half solvent, and purified water is added
400ml is added dilute hydrochloric acid and adjusts PH=8-9, continues to stir 1h, filters, be dried to obtain product 80g, yield 93.3%, HPLC is pure
Degree 99.72%.
Embodiment three：
50g compounds II is added to reaction bulb, and tetrahydrofuran 400ml is added, is stirred at room temperature, and acid binding agent triethylamine 2 is added
Compound I is added in equivalent, and drop, which finishes, is stirred at room temperature 1h, and vacuum distillation removes tetrahydrofuran, and isopropanol 200ml is added, and hydrogen-oxygen is added
Change 3 equivalent of sodium, be warming up to back flow reaction 2h, reaction, which finishes, to be cooled to room temperature, and purified water 500ml is added, and dilute hydrochloric acid is added and adjusts
PH=7-8, ice-water bath are cooled to 0-5 DEG C, continue to stir 1h, filter, be dried to obtain product 79g, yield 92.2%, HPLC purity
99.68%.
Example IV：
50g compounds II is added to reaction bulb, and acetonitrile 400ml is added, is stirred at room temperature, and acid binding agent N ' N- diisopropyls are added
Compound I is added in 2 equivalent of ethamine, and drop, which finishes, is stirred at room temperature 1h, and 4 equivalent of sodium hydroxide is added, is warming up to back flow reaction 4h, reacts
It finishes and is cooled to room temperature, concentration removes about half solvent, and purified water 500ml is added, and dilute hydrochloric acid is added and adjusts PH=8-9, ice water
Bath is cooled to 0-5 DEG C, continues to stir 1h, filters, be dried to obtain product 70g, yield 81.7%, HPLC purity 99.78%
Embodiment five：
50g compounds II is added to reaction kettle, and dichloromethane 200ml is added, is stirred at room temperature, and acid binding agent triethylamine 2 is added
Compound I is added in equivalent, and drop, which finishes, is stirred at room temperature 1h, and vacuum distillation removes dichloromethane, and isopropanol 200ml is added, and hydrogen-oxygen is added
Change 3 equivalent of sodium, be warming up to back flow reaction 2h, reaction, which finishes, to be cooled to room temperature, and purified water 500ml is added, and dilute hydrochloric acid is added and adjusts
PH=8-9, ice-water bath are cooled to 0-5 DEG C, continue to stir 1h, filter, purify water wash, be dried to obtain product 78.5g, yield
91.6%, HPLC purity 99.75%.
Embodiment six：
50g compounds II is added to reaction kettle, and ethyl acetate 250ml is added, is stirred at room temperature, and acid binding agent triethylamine 2 is added
Compound I is added in equivalent, and drop, which finishes, is stirred at room temperature 1h, and 3 equivalent of sodium hydroxide is added, and is warming up to back flow reaction 3h, and reaction finishes cold
But it to room temperature, filters, filtrate purified water extracting and washing, anhydrous sodium sulfate drying, is concentrated to give product 78.0g, yield 91.0%,
HPLC purity 99.23%.
Embodiment seven：
50g compounds II is added to reaction kettle, and acetone 250ml is added, is stirred at room temperature, and 2 equivalent of acid binding agent triethylamine is added,
Compound I is added, drop, which finishes, is stirred at room temperature 1h, and 3 equivalent of sodium hydroxide is added, and is warming up to back flow reaction 6h, and reaction, which finishes, to be cooled to
Purified water 500ml is added in room temperature, and dilute hydrochloric acid is added and adjusts PH=7-8, and ice-water bath is cooled to 0-5 DEG C, continues to stir 1h, filter,
Water wash is purified, product 75.0g, yield 87.5%, HPLC purity 99.76% are dried to obtain.
| Embodiment | Aprotic solvent | Reaction dissolvent | The ring-closure reaction time (h) | Yield (%) |
| Two | Dichloromethane | Ethyl alcohol | 3 | 93.3 |
| Three | Tetrahydrofuran | Isopropanol | 2 | 92.2 |
| Four | Acetonitrile | Acetonitrile | 4 | 81.7 |
| Five | Dichloromethane | Isopropanol | 2 | 91.6 |
| Six | Ethyl acetate | Ethyl acetate | 3 | 91.0 |
| Seven | Acetone | Acetone | 6 | 87.5 |
The explanation of above example is only intended to facilitating the understanding of the method and its core concept of the invention, not limiting
The present invention, it is noted that for those skilled in the art, without departing from the principle of the present invention, can also be right
Some improvement and modification can also be carried out by the present invention, these improvement and modification are also fallen within the protection scope of the claims of the present invention.
Claims (8)
1. a kind of synthetic method of silaenafil intermediate, which is characterized in that include the following steps：
1) compound II is dissolved in organic aprotic solvents, compound I is added and carries out condensation reaction；
2) it alkali is added after monitoring compound II the reaction was complete carries out ring-closure reaction and obtain compound IV.
2. a kind of synthetic method of silaenafil intermediate as described in claim 1, which is characterized in that include the following steps：
1) compound II is dissolved in organic aprotic solvents, the lower progress condensation reaction of compound I stirrings, vacuum distillation is added
The organic aprotic solvents are removed, compound III is obtained；
2) it is purifying, dry after reaction dissolvent, the reaction of sodium hydroxide temperature rising reflux is added after monitoring compound II the reaction was complete
To compound IV.
3. a kind of synthetic method of silaenafil intermediate as claimed in claim 1 or 2, it is characterised in that：Organic non-matter
Sub- solvent is selected from dichloromethane, chloroform, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, acetone, and one in butanone
Kind is several.
4. a kind of synthetic method of silaenafil intermediate as claimed in claim 1 or 2, it is characterised in that：The ring-closure reaction
Solvent is selected from ethyl acetate, tetrahydrofuran, acetonitrile, acetone, butanone, methanol, ethyl alcohol, isopropanol, n-butanol, and one in isobutanol
Kind is several.
5. a kind of synthetic method of silaenafil intermediate as claimed in claim 1 or 2, it is characterised in that：Step 1 condensation reaction
0-50 DEG C of temperature, step 2 ring-closure reaction temperature are 40-100 DEG C.
6. a kind of synthetic method of silaenafil intermediate as claimed in claim 1 or 2, it is characterised in that：Step 1 condensation reaction
Middle addition acid binding agent.
7. a kind of synthetic method of silaenafil intermediate as claimed in claim 6, it is characterised in that：The acid binding agent is selected from three
Ethamine, diethylamine, N ' N- diisopropylethylamine, piperidines, pyridine, one or more of piperazine.
8. a kind of synthetic method of silaenafil intermediate as claimed in claim 2, it is characterised in that：It is purified described in step 2)
Method is rear for the reaction was complete to be added purified water, and dilute hydrochloric acid is added dropwise and adjusts solution pH value to 7~9, filters to obtain product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116591A (en) * | 2018-10-30 | 2020-05-08 | 天津科伦药物研究有限公司 | Method for preparing sildenafil citrate |
| 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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| CN102993205A (en) * | 2012-12-27 | 2013-03-27 | 华润赛科药业有限责任公司 | High-yield purification method for preparation of high-purity sildenafil freebases |
| WO2014131855A1 (en) * | 2013-03-01 | 2014-09-04 | Fundación Para La Investigación Médica Aplicada | Novel compounds as dual inhibitors of phosphodiesterases and histone deacetylases |
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2018
- 2018-06-28 CN CN201810683506.5A patent/CN108558890A/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116591A (en) * | 2018-10-30 | 2020-05-08 | 天津科伦药物研究有限公司 | Method for preparing sildenafil citrate |
| 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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Address after: 401121 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant after: Chongqing kangkere Pharmaceutical Co.,Ltd. Address before: 401121 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant before: CHONGQING CONQUER PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20180921 |