CN101851200A - Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline - Google Patents
Synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline Download PDFInfo
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- CN101851200A CN101851200A CN201010194706A CN201010194706A CN101851200A CN 101851200 A CN101851200 A CN 101851200A CN 201010194706 A CN201010194706 A CN 201010194706A CN 201010194706 A CN201010194706 A CN 201010194706A CN 101851200 A CN101851200 A CN 101851200A
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Abstract
The invention relates to a synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The synthetic method of the 1-phenyl-1,2,3,4-tetrahydroisoquinoline (IQL) comprises the following steps of: acylating beta-phenylethylamine and benzoyl chloride as raw materials to generate N-phenethyl-benzamide, generating 1-phenyl-3,4-dihydroisoquinoline through the reaction of the N-phenethyl-benzamide and polyphosphoric acid, and generating the 1-phenyl-1,2,3,4-tetrahydroisoquinoline by reducing the 1-phenyl-3,4-dihydroisoquinoline. The invention simplifies the operation, does not need reactants with strong corrosion and easy moisture absorption, avoids the serious corrosion to equipment, has low cost, and is easy for industrialized production.
Description
Technical field
The present invention relates to 1-phenyl-1,2,3, the synthetic method of 4-tetrahydroisoquinoline, it belongs to technical field of organic chemistry, also belongs to the pharmaceutical chemistry technical field.
Background technology
1-phenyl-1,2,3,4-tetrahydroisoquinoline are the important intermediate of the novel urinary tract spasmolytic succsinic acid Suo Lifenxin of preparation.
Suo Lifenxin is the wing skin Attention Deficit Hyperactivity Disorder medicine of Japanese Yamanouchi company research and development, as M
3The receptor-selective antagonist works, and it is used to treat the symptom of bladder moving excessively (" OAB ").Commercial tablets obtains U.S. FDA (Food and Drug Administration) approval in November, 2004 and is used for treating once a day OAB with the title listing of Vesicare.
WO2005/087231, WO2005/75474 and WO2005/105795 have more specifically reported and have been used for the prepared in high purity Suo Lifenxin of suitable drug use and the method for salt thereof.The method of two kinds of synthetic Suo Lifenxin that described has been used the initiator of following material as key: (R)-(-)-3-hydroxyl quinuclidinol and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (" IQL ").
R-3-hydroxyl quinuclidinol 1-phenyl-1,2,3, the 4-tetrahydroisoquinoline
Mealy, N etc. are at Drugs of the Future 24 (8): the total synthetic route of report is shown in the scheme 1 among the 871-874 (1999):
Therefore, in the method for many synthetic Suo Lifenxin, IQL is the intermediate of a key.At Mealy, use POCl in the method for N etc.
3Or P
2O
5Cheng Huan, POCl
3Serious to equipment corrosion, meet the water reaction acutely, safety problem is big; P
2O
5Be solid, will at high temperature react with reactant, and reaction system viscosity be big under the high temperature, stir difficulty.Therefore, chemist is sought the practical approach that easy and simple to handle, safety, cost are low, be applicable to suitability for industrialized production always.
Summary of the invention
A kind of method is simple, productive rate is high, the 1-phenyl-1,2,3 of the low industrialization of cost but the purpose of this invention is to provide, 4-tetrahydroisoquinoline synthetic method.
To achieve these goals; technical scheme of the present invention is: 1-phenyl-1; 2; 3; the synthetic method of 4-tetrahydroisoquinoline; be to be that raw material generates compound N-styroyl-benzamide (III) through acidylate with β-phenylethylamine (I) and Benzoyl chloride (II); compound N-styroyl-benzamide (III) and polyphosphoric acid reacting generating compound 1-phenyl-3; 4-dihydro-isoquinoline (IV); compound 1-phenyl-3,4-dihydro-isoquinoline compound (IV) generates 1-phenyl-1 through reduction, 2.; 3,4-tetrahydroisoquinoline (V).
Method of the present invention can be represented with following reaction formula:
1) in non-polar solvent, β-phenylethylamine and Benzoyl chloride are no more than 5 hours in 0-80 ℃ of reaction in the presence of catalyzer, generate N-styroyl-benzamide.The mol ratio of non-polar solvent and β-phenylethylamine is 5-15: 1; The mol ratio of organic bases and β-phenylethylamine is 1-5: 1; The mol ratio of Benzoyl chloride and β-phenylethylamine is 1-3: 1.
Reaction formula is:
2) N-styroyl-benzamide is dissolved with polyphosphoric acid, be no more than 10 hours, generate 1-phenyl-3, the 4-dihydro-isoquinoline in 25-250 ℃ of reaction; The mol ratio of polyphosphoric acid and N-styroyl-benzamide is 1-10: 1;
Reaction formula is:
3) in certain solvent, 1-phenyl-3,4-dihydro-isoquinoline and reductive agent are no more than 24 hours 0-100 ℃ of reaction, generate 1-phenyl-1,2,3, the 4-tetrahydroisoquinoline; Solvent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 5-15: 1; Reductive agent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 1-5: 1
Reaction formula is:
The used non-polar solvent of step 1) is sherwood oil, benzene, toluene, ethyl acetate, chloroform, methylene dichloride, ethylene dichloride, tetracol phenixin etc.
The step 1) catalyst system therefor is yellow soda ash or salt of wormwood, saleratus or sodium bicarbonate, volatile salt, diethylamine, triethylamine, pyridine, sodium alkoxide or potassium alcoholate, sodium hydride, potassium hydride KH or hydrolith;
The step 3) solvent for use is that carbonatomss such as methyl alcohol, dehydrated alcohol, propyl alcohol are the Fatty Alcohol(C12-C14 and C12-C18) of 1-8; Reductive agent is borine, sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, sodium cyanoborohydride, sodium Metal 99.5 etc.
Major technique advantage of the present invention is: by compound (III) to compound (IV) without solvent and without reflux, reaction process is without the reactant of the easy moisture absorption of deep-etching, and is simple to operate, cost is low, has industrial use value.
In order to understand the present invention better, further illustrate content of the present invention below in conjunction with embodiment.
It needs to be noted, specific examples only is in order to illustrate, any have the technician of certain organic chemistry knowledge to make various corrections and change to the present invention within the scope of the invention according to the present invention, and these modifications and change have also been included in the scope of the present invention.In addition, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention.Their content is all included this paper invention in and is carried out reference, and the technology that just looks like them repeats the same in the present invention.
Embodiment
1-phenyl-1,2,3 of the present invention, the synthetic method of 4-tetrahydroisoquinoline (" IQL "), realized by following step:
1) in non-polar solvent, β-phenylethylamine and Benzoyl chloride are no more than 5 hours in 0-80 ℃ of reaction in the presence of catalyzer, generate N-styroyl-benzamide.The mol ratio of non-polar solvent and β-phenylethylamine is 5-15: 1; The mol ratio of organic bases and β-phenylethylamine is 1-5: 1; The mol ratio of Benzoyl chloride and β-phenylethylamine is 1-3: 1;
2) N-styroyl-benzamide is dissolved with polyphosphoric acid, be no more than 10 hours, generate 1-phenyl-3, the 4-dihydro-isoquinoline in 25-250 ℃ of reaction; The mol ratio of polyphosphoric acid and N-styroyl-benzamide is 1-10: 1;
3) in certain solvent, 1-phenyl-3,4-dihydro-isoquinoline and reductive agent are no more than 24 hours 0-100 ℃ of reaction, generate 1-phenyl-1,2,3, the 4-tetrahydroisoquinoline; Solvent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 5-15: 1; Reductive agent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 1-5: 1.
Following embodiment processing condition and raw material are to appoint value and the raw material of getting in aforesaid processing condition and raw material range, thereby content of the present invention not only is confined to the following examples.
Embodiment 1:
1-phenyl-1,2,3, the synthetic method of 4-tetrahydroisoquinoline, realize by following step:
1), N-styroyl-benzamide (III) is synthetic
Add 40ml β-phenylethylamine (I), 20g yellow soda ash, 300ml sherwood oil in being connected in the there-necked flask that mechanical stirring, dropping funnel, tail gas absorb of 1000ml, begin slowly Dropwise 5 0ml Benzoyl chloride (II) under-78 ℃, in 1 hour, drip off.Reaction was poured reaction solution in the water into after 6 hours under 25 ℃, stirred static layering 0.5 hour.Organic layer washes with water, drying, concentrate solid 70.97g N-styroyl-benzamide (III), yield 99%, fusing point 119-125 ℃.
2), 1-phenyl-3,4-dihydro-isoquinoline (IV) synthetic
In the there-necked flask that is connected to mechanical stirring, drying tube of 150ml, add the 47g polyphosphoric acid, be stirred and heated to 130 ℃, add 4.5g N-styroyl-benzamide (III) in batches, reaction system in 150 ℃ the reaction 3 hours after, transfer PH to 8 with saturated sodium bicarbonate aqueous solution, have oily matter to separate out, tell oily matter, oily matter activated carbon decolorizing 1h, filter weak yellow liquid, concentrate 2.84g1-phenyl-3,4-dihydro-isoquinoline (IV), yield 70%, 100 ℃ of fusing points.
3), 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) synthetic
Add 12.5g1-phenyl-3 in the single port bottle of 250ml, 4-dihydro-isoquinoline (IV) adds the 5.0g sodium borohydride in batches, 0 ℃ was reacted 16 hours, added the 10ml concentrated hydrochloric acid and stirred 1 hour for 78 ℃, concentrated, use the 150ml water dissolution, ethyl acetate extraction three times, drying, concentrate 10.7g1-phenyl-1,2,3,4-tetrahydroisoquinoline (V), yield 85%, fusing point 101-110 ℃.
Embodiment 2:
1-phenyl-1,2,3, the synthetic method of 4-tetrahydroisoquinoline, realize by following step:
1), N-styroyl-benzamide (III) is synthetic
Solvent for use is a benzene, and other is operated with embodiment 1, gets 68.81g N-styroyl-benzamide (III), yield 96%, fusing point 119-125 ℃.
2), 1-phenyl-3,4-dihydro-isoquinoline (IV) synthetic
Temperature of reaction is 140 ℃, and other are operated with embodiment 1, gets 2.92g1-phenyl-3,4-dihydro-isoquinoline (IV), yield 72%, 100 ℃ of fusing points.
3), 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) synthetic
Add 12.5g1-phenyl-3 in the single port bottle of 250ml, 4-dihydro-isoquinoline (IV) adds the 2.6g sodium Metal 99.5 in batches, 0 ℃ was reacted 16 hours, added the 10ml concentrated hydrochloric acid and stirred 1 hour for 78 ℃, concentrated, use the 150ml water dissolution, ethyl acetate extraction, drying, concentrate 10.48g1-phenyl-1,2,3,4-tetrahydroisoquinoline (V), yield 83%, fusing point 101-110 ℃.
Embodiment 3:
1-phenyl-1,2,3, the synthetic method of 4-tetrahydroisoquinoline, realize by following step:
1), N-styroyl-benzamide (III) is synthetic
Used alkali is the 9.6g sodium hydride, and solvent is the 300ml ethyl acetate, and other gets 68.10g N-styroyl-benzamide (III), yield 95%, fusing point 119-125 ℃ with embodiment 1.
2), 1-phenyl-3,4-dihydro-isoquinoline (IV) synthetic
Temperature of reaction is 140 ℃, and other gets 2.92g1-phenyl-3,4-dihydro-isoquinoline (IV), yield 72%, 100 ℃ of fusing points with embodiment 1.
3), 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) synthetic
Add 12.5g1-phenyl-3 in the single port bottle of 250ml, 4-dihydro-isoquinoline (IV) adds the 3.4g Lithium Aluminium Hydride in batches, 0 ℃ was reacted 16 hours, added the 10ml concentrated hydrochloric acid and stirred 1 hour for 78 ℃, concentrated, use the 150ml water dissolution, ethyl acetate extraction, drying, concentrate 10.60g1-phenyl-1,2,3,4-tetrahydroisoquinoline (V), yield 84%, fusing point 101-110 ℃.
The bound value and the interval value of each raw material of the present invention can both be realized the present invention, and each cited raw material can both be realized the present invention.
Claims (7)
1. 1-phenyl-1,2,3, the synthetic method of 4-tetrahydroisoquinoline is characterized in that, by following reaction formula preparation:
2. 1-phenyl-1,2 according to claim 1,3, the synthetic method of 4-tetrahydroisoquinoline is characterized in that, its acidylate is that β-phenylethylamine and Benzoyl chloride are in non-polar solvent, in the presence of basic catalyst, be no more than 5 hours in 0-80 ℃ of reaction, generate N-styroyl-benzamide; The mol ratio of non-polar solvent and β-phenylethylamine is 5-15: 1; The mol ratio of basic catalyst and β-phenylethylamine is 1-5: 1; The mol ratio of Benzoyl chloride and β-phenylethylamine is 1-3: 1.
3. 1-phenyl-1,2,3 according to claim 2, the synthetic method of 4-tetrahydroisoquinoline is characterized in that, described non-polar solvent is sherwood oil, benzene, toluene, ethyl acetate, chloroform, methylene dichloride, ethylene dichloride or tetracol phenixin.
4. 1-phenyl-1 according to claim 2,2,3, the synthetic method of 4-tetrahydroisoquinoline, it is characterized in that described basic catalyst is yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, volatile salt, diethylamine, triethylamine, pyridine, sodium alkoxide or potassium alcoholate, sodium hydride, potassium hydride KH or hydrolith.
5. 1-phenyl-1,2 according to claim 1,3, the synthetic method of 4-tetrahydroisoquinoline is characterized in that, its Cheng Huan dissolves N-styroyl-benzamide with polyphosphoric acid, be no more than 10 hours in 50-250 ℃ of reaction, generate 1-phenyl-3, the 4-dihydro-isoquinoline; The mol ratio of polyphosphoric acid and N-styroyl-benzamide is 1-10: 1.
6. 1-phenyl-1,2,3 according to claim 1, the synthetic method of 4-tetrahydroisoquinoline, it is characterized in that its reduction is in solvent, 1-phenyl-3,4-dihydro-isoquinoline and reductive agent are no more than 24 hours 0-100 ℃ of reaction, generate 1-phenyl-1,2,3, the 4-tetrahydroisoquinoline; Solvent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 5-15: 1; Reductive agent and 1-phenyl-3, the mol ratio of 4-dihydro-isoquinoline are 1-5: 1, and described solvent is that carbonatoms is the Fatty Alcohol(C12-C14 and C12-C18) of 1-8, described reductive agent is borine, sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, sodium cyanoborohydride or sodium Metal 99.5.
7. 1-phenyl-1,2,3 according to claim 6, the synthetic method of 4-tetrahydroisoquinoline is characterized in that: described solvent is methyl alcohol, dehydrated alcohol, n-propyl alcohol, Virahol, butanols, amylalcohol or primary isoamyl alcohol.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491945A (en) * | 2011-12-09 | 2012-06-13 | 南京威尔化工有限公司 | Method for recovering S-shaped tetrahydroisoquinoline |
| CN103159677A (en) * | 2013-03-19 | 2013-06-19 | 济南圣泉唐和唐生物科技有限公司 | 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method |
| CN105541712A (en) * | 2016-01-08 | 2016-05-04 | 山东金城医药化工股份有限公司 | Method for preparing solifenacin intermediate |
| CN105693607A (en) * | 2016-01-22 | 2016-06-22 | 苏州康润医药有限公司 | Synthesis method of 4-hydroxy-8-bromoisoquinoline |
| CN108997215A (en) * | 2018-06-25 | 2018-12-14 | 武汉大学 | A kind of preparation method of 1,2,3,4- tetrahydro isoquinoline derivative |
| CN111574448A (en) * | 2019-02-18 | 2020-08-25 | 广东东阳光药业有限公司 | Preparation method of phenyltetrahydroisoquinoline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008128028A2 (en) * | 2007-04-11 | 2008-10-23 | Dr. Reddy's Laboratories Ltd. | Solifenacin compositions |
-
2010
- 2010-06-01 CN CN201010194706A patent/CN101851200A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008128028A2 (en) * | 2007-04-11 | 2008-10-23 | Dr. Reddy's Laboratories Ltd. | Solifenacin compositions |
Non-Patent Citations (1)
| Title |
|---|
| 《Drugs of the future》 19991231 N. Mealy等 YM-905 第871-874页，尤其第871页第2段 2、3、4 第24卷, 第8期 2 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491945A (en) * | 2011-12-09 | 2012-06-13 | 南京威尔化工有限公司 | Method for recovering S-shaped tetrahydroisoquinoline |
| CN103159677A (en) * | 2013-03-19 | 2013-06-19 | 济南圣泉唐和唐生物科技有限公司 | 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method |
| CN103159677B (en) * | 2013-03-19 | 2016-03-16 | 济南圣泉唐和唐生物科技有限公司 | The preparation method of IQL |
| CN105541712A (en) * | 2016-01-08 | 2016-05-04 | 山东金城医药化工股份有限公司 | Method for preparing solifenacin intermediate |
| CN105541712B (en) * | 2016-01-08 | 2018-10-09 | 山东金城医药集团股份有限公司 | The preparation method of Solifenacin intermediate |
| CN105693607A (en) * | 2016-01-22 | 2016-06-22 | 苏州康润医药有限公司 | Synthesis method of 4-hydroxy-8-bromoisoquinoline |
| CN108997215A (en) * | 2018-06-25 | 2018-12-14 | 武汉大学 | A kind of preparation method of 1,2,3,4- tetrahydro isoquinoline derivative |
| CN111574448A (en) * | 2019-02-18 | 2020-08-25 | 广东东阳光药业有限公司 | Preparation method of phenyltetrahydroisoquinoline |
| CN111574448B (en) * | 2019-02-18 | 2023-10-20 | 广东东阳光药业股份有限公司 | Preparation method of phenyl tetrahydroisoquinoline |
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