CN105712891A - Method used for preparing high purity 3-chloro-4-methoxybenzylamine - Google Patents
Method used for preparing high purity 3-chloro-4-methoxybenzylamine Download PDFInfo
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- CN105712891A CN105712891A CN201410718493.2A CN201410718493A CN105712891A CN 105712891 A CN105712891 A CN 105712891A CN 201410718493 A CN201410718493 A CN 201410718493A CN 105712891 A CN105712891 A CN 105712891A
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Abstract
The invention provides a method used for preparing 3-chloro-4-methoxybenzylamine. According to the method, 3-chloro-4-methoxybenzyl alcohol is taken as a staring material; 3-chloro-4-methoxy benzyl chloride is obtained via chlorine substitution in tetrahydrofuran under the action of phosphorus oxychloride; 3-chloro-4-methoxy benzyl chloride and urotropin are prepared into a quaternary ammonium salt in ethyl alcohol; the quaternary ammonium salt is subjected to hydrolysis under the action of hydrochloric acid; pH value of an obtained product is adjusted to be higher than 7 with potassium hydroxide; and target compound 3-chloro-4-methoxybenzylamine is obtained via distillation. Operation of the method is simple; yield is as high as 72 to 85%; purity is 99.3% or higher; problems of the prior art are solved; and the method is suitable for large-scale production.
Description
Technical field:
The invention belongs to organic synthesis field, the method being specifically related to prepare 3-chloro-4-methoxy benzylamine.
Background technology:
3-chloro-4-methoxy benzylamine, No. CAS is 247569-42-2, and structure is as follows:
3-chloro-4-methoxy benzylamine is the important intermediate preparing avanaphil (avanafil), and avanaphil is the treatment ED medicine of function well, Chinese patent CN103845333A also shows that it has and improves climacteric such as the effect of the symptom such as anxiety, depression, thus the technique of research 3-chloro-4-methoxy benzylamine has great importance.
Preparation method relevant report currently, with respect to 3-chloro-4-methoxy benzylamine mainly has:
1) document JournalofMedicinalChemistry；Vol.31；Nb.10；(1988)；P.1941-1946 disclosed with 4-Methoxybenzylamine for raw material, reaction dissolvent made by acetic acid, prepares its syntheti c route through chlorinated with chlorine as follows:
It can be seen that chlorination reaction adopts chlorine from above-mentioned syntheti c route, in large-scale production, operation and security requirement to factory personnel are higher, and it is low to obtain 3-chloro-4-methoxy benzylamine yield.In patent WO2005066139, substituting chlorine with sulfonic acid chloride, safety has bigger improvement.
2) document JournalofMedicinalChemistry；Vol.41；Nb.18；(1998)；P.3367-3372 with P-methoxybenzal-dehyde for raw material disclosed in, react through the Leuchart of sulfonic acid chloride chlorination with formic acid and Methanamide, finally adopt hydrochloric acid hydrolysis to prepare.Its syntheti c route is as follows:
It can be seen that the reaction temperature 130 DEG C of Leuchart reaction from above-mentioned syntheti c route, consersion unit is required significantly high, and yield is not high.
At present, the 3-chloro-4-methoxy benzylamine purity of the method synthesis disclosed in prior art is general not high, as medicine intermediate, is unfavorable for that next step reacts.
In sum, the yield of synthesis is relatively low at present, and purity is not high, is unfavorable for industrialized production.
Summary of the invention:
In order to solve the above-mentioned problems in the prior art, the present invention provides a kind of method preparing 3-chloro-4-methoxy benzylamine.
In order to realize goal of the invention, the present invention by the following technical solutions:
A kind of method preparing 3-chloro-4-methoxy benzylamine, adopts following steps:
1) with 3-chloro-4-methoxy benzylalcohol for initiation material, in oxolane and under the effect of phosphorus oxychloride, chloro prepares 3-chloro-4-methoxy benzyl chlorine；
2) by step 1) prepare 3-chloro-4-methoxy benzyl chlorine prepare corresponding quaternary ammonium salt in ethanol to hexamethylenamine；
3) by step 2) quaternary ammonium salt for preparing be hydrolyzed under the effect of hydrochloric acid, alkaline with potassium hydroxide furnishing, distills to obtain target compound 3-chloro-4-methoxy benzylamine.
The technology of the present invention route is as follows:
Step 1) chlorination temperature be 30～80 DEG C, it is preferable that reaction temperature 35～45 DEG C；
The ratio of above-mentioned 3-chloro-4-methoxy benzylalcohol and the amount of substance of phosphorus oxychloride is preferred with 1: 1～1.5.
Step 2) become quaternary ammonium salt reaction temperature be 20～75 DEG C, it is preferable that reaction temperature 60～75 DEG C.
The ratio of above-mentioned 3-chloro-4-methoxy benzyl chlorine and the amount of substance of hexamethylenamine is preferred with 1: 1～1.2.
Step 3) hydrolysising reacting temperature is 20～80 DEG C, it is preferable that reaction temperature 40～50 DEG C.
Technique effect:
1, the present invention is with 3-chloro-4-methoxy benzylalcohol for initiation material, under the effect of oxolane and phosphorus oxychloride, chloro prepares 3-chloro-4-methoxy benzyl chlorine, quaternary ammonium salt is become with hexamethylenamine, then hydrolysis prepares 3-chloro-4-methoxy benzylamine, raw material is cheap and easy to get, process route is short, and reaction condition is gentle, and equipment requirements is low.
2, present invention operation is little to the health hazard of experimenter, meets green chemical concept, and solvent for use can realize synchronizing to reclaim, and reduce further cost.
3, yield of the present invention is up to 72%～85%, and purity is more than 99%, and in end-product, the content of 3-chloro-4-methoxy benzyl chlorine is lower than one thousandth, is suitable for industrialized production.
Detailed description of the invention:
The preparation of embodiment 1 compound I3-chloro-4-methoxy benzyl chlorine
2L there-necked flask adds 800ml oxolane and 138g3-chloro-4-methoxy benzylalcohol, 5mlDMF, the lower dropping 96g phosphorus oxychloride of stirring.Drip to finish and be to slowly warm up to back flow reaction, until HPLC shows that 3-chloro-4-methoxy benzylalcohol is less than less than 0.5%.It is down to below room temperature, is slowly added to saturated sodium bicarbonate solution 800ml, stirring 10min layering.Water layer oxolane extracts, and merges organic layer, washing, and anhydrous magnesium sulfate dries, and 35 DEG C of water-bath rotations are steamed, and obtain 144g3-chloro-4-methoxy benzyl chlorine, yield 94.3%, [M+H]+=191.
The preparation of embodiment 2 Compound II per
1L there-necked flask adds 500ml dehydrated alcohol, 93g hexamethylenamine, controls 20～30 DEG C of dropping 114g3-chloro-4-methoxy benzyl chlorine.Drip finish be to slowly warm up to back flow reaction 2h, be cooled to 20 DEG C, obtain Compound II per, not separated direct plunge into next step reaction.
The preparation of embodiment 33-chloro-4-methoxy benzylamine
In embodiment 2 drip 350g concentrated hydrochloric acid, drip finish be to slowly warm up to 50 DEG C reaction 1h.Being cooled to 20 DEG C, filter, filtrate, with potassium hydroxide alkali tune to pH value 13, rectification under vacuum collection fraction 110～115 DEG C (1mmHg), obtains colorless oil 3-chloro-4-methoxy benzylamine 81g, and yield 80%, purity is 99.3%.[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), δ 8.40 (2H, brs).
Embodiment 4-6, runs with following parameter, and all the other are identical with embodiment 1-3 corresponding steps.
The 3-chloro-4-methoxy benzylamine total recovery that embodiment of the present invention 4-6 prepares is 74%～82%, and purity is more than 99.3%, and in end-product, the content of compound I is lower than one thousandth.The inventive method is simple to operate, and yield is high, and purity is high, is suitable for industrialized production.
Above example is served only for technical scheme is described in further detail; it is not intended that limiting the scope of the invention; those skilled in the art 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.
Claims (7)
1. the method preparing 3-chloro-4-methoxy benzylamine, adopts following steps:
1) with 3-chloro-4-methoxy benzylalcohol for initiation material, in oxolane and under the effect of phosphorus oxychloride, chloro prepares 3-chloro-4-methoxy benzyl chlorine, and the ratio of described 3-chloro-4-methoxy benzylalcohol and the amount of substance of phosphorus oxychloride is 1:1～1.5；
2) 3-chloro-4-methoxy benzyl chlorine prepares corresponding quaternary ammonium salt in ethanol to hexamethylenamine, and the ratio of described 3-chloro-4-methoxy benzyl chlorine and the amount of substance of hexamethylenamine is 1:1～1.2；
3) by step 2) quaternary ammonium salt for preparing be hydrolyzed under the effect of hydrochloric acid, alkaline with potassium hydroxide furnishing, distills to obtain target compound 3-chloro-4-methoxy benzylamine；
Concrete technology path is as follows:
。
2. the method for claim 1, it is characterised in that: the chlorination temperature of described step 1) is 30 ~ 80 DEG C.
3. method as claimed in claim 2, it is characterised in that: the chlorination temperature of described step 1) is 35 ~ 45 DEG C.
4. method as claimed in claim 1 or 2, it is characterised in that: described step 2) to become quaternary ammonium salt reaction temperature be 20 ~ 75 DEG C.
5. method as claimed in claim 3, it is characterised in that: described step 2) to become quaternary ammonium salt reaction temperature be 60 ~ 75 DEG C.
6. the method as described in claim 1 or 2 or 3, it is characterised in that: described step 3) hydrolysising reacting temperature is 20 ~ 80 DEG C.
7. the method preparing 3-chloro-4-methoxy benzylamine, adopts following steps:
1) with 3-chloro-4-methoxy benzylalcohol for initiation material, in oxolane and under the effect of phosphorus oxychloride, chloro prepares 3-chloro-4-methoxy benzyl chlorine, the ratio of described 3-chloro-4-methoxy benzylalcohol and the amount of substance of phosphorus oxychloride is 1:1～1.2, and chlorination temperature is 35 ~ 45 DEG C；
2) 3-chloro-4-methoxy benzyl chlorine step 1) prepared prepares corresponding quaternary ammonium salt in ethanol to hexamethylenamine, the ratio of described 3-chloro-4-methoxy benzyl chlorine and the amount of substance of hexamethylenamine is 1:1～1.2, described step 2) to become quaternary ammonium salt reaction temperature be 60 ~ 70 DEG C；
3) by step 2) quaternary ammonium salt for preparing be hydrolyzed under the effect of hydrochloric acid, alkaline with sodium hydroxide furnishing, distills to obtain target compound 3-chloro-4-methoxy benzylamine, and described hydrolysising reacting temperature is 40 ~ 50 DEG C.
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Cited By (2)
| 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 |
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
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| US6531494B1 (en) * | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
| CN102239164A (en) * | 2008-12-05 | 2011-11-09 | 安斯泰来制药有限公司 | 2h-chromene compound and derivative thereof |
| CN101704755A (en) * | 2009-11-18 | 2010-05-12 | 华中农业大学 | Method for preparing p-tert-butylbenzylamine |
| JP2011178724A (en) * | 2010-03-02 | 2011-09-15 | Nissan Chem Ind Ltd | Substituted acetophenone compound and application thereof |
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Cited By (2)
| 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 |
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
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Application publication date: 20160629 |