CN105646240A - Preparation method of avanafil important intermediate - Google Patents
Preparation method of avanafil important intermediate Download PDFInfo
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- CN105646240A CN105646240A CN201410720718.8A CN201410720718A CN105646240A CN 105646240 A CN105646240 A CN 105646240A CN 201410720718 A CN201410720718 A CN 201410720718A CN 105646240 A CN105646240 A CN 105646240A
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Abstract
The invention provides a preparation method of an avanafil important intermediate. The target compound (3-chloro-4-methoxybenzylamine) is prepared according to a route shown as the specification. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, short technical route, mild reaction conditions, low equipment requirement, and small health hazard to operators, and is in line with the idea of green chemistry. The method has high yield, and can obtain product with high purity, thus being suitable for industrial production.
Description
Technical field:
The present invention relates to avanaphil, it is specifically related to the preparation method of a kind of avanaphil important intermediate.
Background technology:
The chloro-4-methoxybenzylamine of 3-is the important intermediate for the treatment of ED medicine avanafil, lists in the U.S. in April, 2012 with treatment ED new drug avanafil, and its application prospect receives very big concern.
At present, synthetic method relevant report about the chloro-4-methoxybenzylamine of 3-mainly contains:
1) document JournalofMedicinalChemistry; Vol.31; Nb.10; (1988); P.1941-1946 disclosed is raw material taking 4-Methoxybenzylamine, and reaction solvent made by acetic acid, obtains its synthetic route through chlorinated with chlorine as follows:
It may be seen that chlorination reaction adopts chlorine from said synthesis route, in scale operation, operation and security requirement to factory personnel are higher, and it is low to obtain 3-chloro-4-methoxybenzylamine receipts rate. In patent WO2005066139, substituting chlorine with SULPHURYL CHLORIDE, security has bigger improvement.
2) document JournalofMedicinalChemistry; Vol.41; Nb.18; (1998); P.3367-3372 disclosed is raw material taking aubepine, through the Leuchart reaction of SULPHURYL CHLORIDE chlorination and formic acid and methane amide, finally adopts hydrochloric acid hydrolysis to obtain. Its synthetic route is as follows:
It may be seen that the temperature of reaction 130 DEG C of Leuchart reaction from said synthesis route, conversion unit is required very high, and receipts rate is not high.
In sum, in the technique of the chloro-4-methoxybenzylamine of synthesis 3-reported in disclosed document at present, severe reaction conditions, equipment requirements is higher, and the Health hazard of operator is big.
Summary of the invention:
In order to solve the problems of the prior art, it is an object of the invention to provide the preparation method of a kind of avanaphil important intermediate, the method prepares the chloro-4-methoxybenzylamine of 3-, and reaction conditions is gentle, receipts rate height, and operator ' s health harm is little.
For achieving the above object, present invention employs following technical scheme:
A preparation method for avanaphil important intermediate, described important intermediate is the chloro-4-methoxybenzylamine of 3-, it is characterised in that, adopt following route:
In the present invention, preparation method is taking the chloro-4-methoxyl group benzylalcohol of 3-as starting raw material, chlorine generation obtained 3-chloro-4-methoxybenzyl chlorine (Compound I) under the effect of organic solvent and chlorinating agent.
The one or more combination that above-mentioned organic solvent is selected from methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), acetonitrile, tetramethylene sulfone, N-Methyl pyrrolidone, preferentially selects the one in methylene dichloride, trichloromethane.The one that chlorinating agent is selected from phosphorus oxychloride, sulfur oxychloride, oxalyl chloride, N-chlorosuccinimide, phosphorus pentachloride, phosphorus trichloride, preferentially selects phosphorus oxychloride or sulfur oxychloride. Chlorination temperature 20��80 DEG C, it is preferable that temperature of reaction 35��45 DEG C;
Obtained 3-chloro-4-methoxybenzyl chlorine (Compound I) obtains Compound I I with urotropine again in organic alcohol solvent. The one or more combination that above-mentioned organic alcohol solvent is selected from propyl carbinol, sec-butyl alcohol, ethanol, methyl alcohol, Virahol, preferentially selects the one in propyl carbinol, sec-butyl alcohol, ethanol. Become quaternary ammonium salt temperature of reaction 0��80 DEG C, it is preferable that temperature of reaction 60��80 DEG C.
Compound I I is hydrolyzed under the action of an acid, alkali tune, distills to obtain the chloro-4-methoxybenzylamine of target compound 3-.
The one or more combination that above-mentioned acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, Glacial acetic acid, preferentially selects the one in hydrochloric acid, sulfuric acid, phosphoric acid. The one or more combination that above-mentioned alkali is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, salt of wormwood, lithium hydroxide, preferentially selects the one in sodium hydroxide, potassium hydroxide, sodium bicarbonate.
Said hydrolyzed temperature of reaction 0��80 DEG C, it is preferable that temperature of reaction 40��50 DEG C.
Technique effect:
The present invention is taking the chloro-4-methoxyl group benzylalcohol of 3-as starting raw material, the chlorine generation obtained chloro-4-methoxybenzyl chlorine of 3-under the effect of organic solvent and chlorinating agent, quaternary ammonium salt is become with urotropine, then the obtained chloro-4-methoxybenzylamine of 3-of hydrolysis, raw material is cheap and easy to get, and operational path is short, reaction conditions is gentle, equipment requirements is low, and the Health hazard of operator is little, meets green chemical concept. Receipts rate of the present invention is up to 74%��82%, and purity is more than 99%, and in end product, the content of Compound I is lower than 0.1%, product purity height, is applicable to suitability for industrialized production.
Embodiment:
Following examples are only for being described in further detail the technical scheme of the present invention; limiting the scope of the invention can not be interpreted as; the technician of this area is without departing from the spirit and scope of the present invention, it should various modifications may be made and change. Therefore protection scope of the present invention should be considered as appending claims limited range. The present invention is raw materials used is commercially available prod, as without dated especially, being commercially available purchase chemical pure or analytical pure.
The preparation (Compound I) of the chloro-4-methoxybenzyl chlorine of embodiment 13-
Adding 800ml methylene dichloride and the chloro-4-methoxyl group benzylalcohol of 138g3-in 2L there-necked flask, 5mlDMF, stirs lower and adds 96g sulfur oxychloride. Drip to finish and slowly it is warming up to back flow reaction, until HPLC shows the chloro-4-methoxyl group benzylalcohol of 3-is less than less than 0.5%. It is down to below room temperature, slowly adds saturated sodium bicarbonate solution 800ml, stir 10min layering. Water layer dichloromethane extraction, merges organic layer, and washing, anhydrous magnesium sulfate drying, steaming is revolved in 35 DEG C of water-baths, obtains the chloro-4-methoxybenzyl chlorine of 144g3-, receipts rate 94.3%, [M+H]+=191.
The preparation of embodiment 2 Compound I I
1L there-necked flask adds 500ml dehydrated alcohol, 93g urotropine, control 20��30 DEG C and add the chloro-4-methoxybenzyl chlorine of 114g3-. Drip to finish and slowly it is warming up to back flow reaction 2h, be cooled to 20 DEG C, obtain Compound I I, directly drop into next step reaction without separation.
The preparation of the chloro-4-methoxybenzylamine of embodiment 33-
In embodiment 2 drip add 350g concentrated hydrochloric acid, drip finish slowly be warming up to 50 DEG C reaction 1h.Being cooled to 20 DEG C, filter, filtrate is by sodium hydroxide alkali tune to pH value 13, and rectification under vacuum is collected and evaporated point 110��115 DEG C (1mmHg), obtains the chloro-4-methoxybenzylamine 81g of colorless oil 3-, receipts rate 80%. [M+H]+=172,1HNMR(DMSO-D6): 3.86 (3H, s), 3.94 (2H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.61 (1H, d), �� 8.40 (2H, brs).
Embodiment 4-7 tests according to following parameter, and all the other are with reference to embodiment 1-3 corresponding steps.
The compound that embodiment 4-8 is obtained is through structural confirmation, identical with the obtained 3-chloro-4-methoxybenzylamine of embodiment 3. The chloro-4-methoxybenzylamine total recovery of 3-that embodiment of the present invention 4-8 obtains is 74%��82%, and purity is more than 99%, and in end product, the content of Compound I is lower than thousandth. The inventive method is simple to operate, receipts rate height, purity height, is applicable to suitability for industrialized production.
Claims (9)
1. a preparation method for avanaphil important intermediate, its synthetic route is:
;
It is specially taking the chloro-4-methoxyl group benzylalcohol of 3-as starting raw material, Compound I obtained with chlorinating agent reaction in organic solvent, Compound I becomes quaternary ammonium salt to obtain Compound I I again with urotropine in organic alcohol solvent, and then Compound I I is hydrolyzed the chloro-4-methoxybenzylamine of obtained target compound 3-in acid condition.
2. preparation method according to claim 1, it is characterised in that: described chlorinating agent is the one or more combination in phosphorus oxychloride, sulfur oxychloride, oxalyl chloride, N-chlorosuccinimide, phosphorus pentachloride, phosphorus trichloride.
3. preparation method as claimed in claim 1 or 2, it is characterized in that: described obtained Compound I organic solvent used is the one or more combination in methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), acetonitrile, tetramethylene sulfone, N-Methyl pyrrolidone.
4. preparation method as claimed in claim 1 or 2, it is characterised in that: the temperature of reaction of described preparation Compound I is 20 ~ 80 DEG C.
5. preparation method as claimed in claim 4, it is characterised in that: the temperature of reaction of described preparation Compound I is 35 ~ 45 DEG C.
6. preparation method as claimed in claim 1, it is characterised in that: the organic alcohol solvent used during described preparation Compound I I is propyl carbinol, one or more combination in sec-butyl alcohol, ethanol, methyl alcohol, Virahol.
7. preparation method as described in claim 2 or 5, it is characterised in that: the organic alcohol solvent used during described preparation Compound I I is propyl carbinol, sec-butyl alcohol or ethanol.
8. preparation method as claimed in claim 1, it is characterised in that: the temperature of reaction of described preparation Compound I I is 0 ~ 80 DEG C.
9. preparation method as claimed in claim 1, it is characterised in that: the temperature of described acid hydrolysis is 0 ~ 80 DEG C.
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| CN201410720718.8A CN105646240A (en) | 2014-12-02 | 2014-12-02 | Preparation method of avanafil important intermediate |
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| CN201410720718.8A CN105646240A (en) | 2014-12-02 | 2014-12-02 | Preparation method of avanafil important intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108395377A (en) * | 2018-01-16 | 2018-08-14 | 吴江信凯医药科技有限公司 | A kind of preparation method of 3- chloro-4-methoxies benzylamine hydrochloride |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
| CN115677511A (en) * | 2022-10-26 | 2023-02-03 | 南通华祥医药科技有限公司 | Synthetic method of2, 2-difluoropropylamine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US7087597B1 (en) * | 1999-10-12 | 2006-08-08 | Takeda Pharmaceutical Company Limited | Pyrimidine 5-carboxamide compounds, process for producing the same and use thereof |
| CN102372697A (en) * | 2010-08-19 | 2012-03-14 | 山东轩竹医药科技有限公司 | Substituted miazines compound |
-
2014
- 2014-12-02 CN CN201410720718.8A patent/CN105646240A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7087597B1 (en) * | 1999-10-12 | 2006-08-08 | Takeda Pharmaceutical Company Limited | Pyrimidine 5-carboxamide compounds, process for producing the same and use thereof |
| CN102372697A (en) * | 2010-08-19 | 2012-03-14 | 山东轩竹医药科技有限公司 | Substituted miazines compound |
Non-Patent Citations (1)
| Title |
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| 丁雁等: ""盐酸奥兰西丁的合成工艺改进"", 《中国药物化学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108395377A (en) * | 2018-01-16 | 2018-08-14 | 吴江信凯医药科技有限公司 | A kind of preparation method of 3- chloro-4-methoxies benzylamine hydrochloride |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
| CN115677511A (en) * | 2022-10-26 | 2023-02-03 | 南通华祥医药科技有限公司 | Synthetic method of2, 2-difluoropropylamine hydrochloride |
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