CN102898396B - Method for preparing 3-(4-fluorophenyl)-4-benzyl-2-molindone - Google Patents
Method for preparing 3-(4-fluorophenyl)-4-benzyl-2-molindone Download PDFInfo
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- CN102898396B CN102898396B CN201210460630.8A CN201210460630A CN102898396B CN 102898396 B CN102898396 B CN 102898396B CN 201210460630 A CN201210460630 A CN 201210460630A CN 102898396 B CN102898396 B CN 102898396B
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- benzyl
- reaction
- morpholine
- morpholone mai
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Abstract
The invention discloses a method for preparing 3-(4-fluorophenyl)-4-benzyl-2-molindone. The method is characterized by comprising the following steps of: condensing morpholine which serves as a raw material to obtain 4-benzylmorpholine; oxidizing to obtain N-benzyl-2-molindone; and finally, carrying out a substitution reaction on N-benzyl-2-molindone and substituted fluorobenzene to obtain 3-(4-fluorophenyl)-4-benzyl-2-molindone. The method is low in raw material cost, available in raw materials, mild in reaction conditions, low in cost, high in yield and suitable for industrial production.
Description
Technical field
The preparation method who the present invention relates to a kind of 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, can be used for preparing neurokinin receptor retarding agent Aprepitant, belongs to field of medicine and chemical technology.
Background technology
Aprepitant is U.S. FDA in first neurokinin receptor (NK-1) retarding agent of approval listing in 2003, is mainly used in clinically the acute and retardance that Prophylactic chemotherapy causes and feels sick, vomits.This medicine determined curative effect, side effect is little, in the listing of multiple countries.The structure of Aprepitant is as follows:
Its molecular structure is comparatively complicated, is broadly divided into three fragments, i.e. triazolone fragment, morpholine ring plate section and 2-trifluoromethyl styroyl fragment.
3-(4-fluorophenyl)-4-benzyl-2-morpholone mai is the important intermediate of preparing Aprepitant, its structural formula as shown in the formula:
In recent years, this intermediate receives increasing concern, also there is the report of synthetic this compound of multiple route both at home and abroad: as Indian Pat.Appl., 2008MU01358 disclose taking to fluorophenyl glycine as raw material, through becoming imines with phenyl aldehyde, restore into secondary amine, last and ethylene dibromide cyclization obtains, and its main route is as follows:
Route 2
Tetrahedron Letters, 48 (45), 8001-8004; 2007 have reported taking p-Fluorobenzenecarboxaldehyde as raw material, first with sodium cyanide addition, then replace with N-benzyl ethyl alcohol amine, are hydrolyzed into acid amides, and last cyclization obtains, and main route is as follows:
Route 3
In aforesaid method, the raw material of route 2 is comparatively expensive, and reaction conditions is comparatively harsh, and the ring-closure reaction time is long, needs more than 17 hours.In route 3, need to use hypertoxic prussiate, working condition is had relatively high expectations.Above route is all not suitable for large-scale industrial production.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of new method of preparing 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai is provided.
Object of the present invention can reach by following measures:
A kind of preparation method of 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, it is taking morpholine as raw material, first obtain 4-benzyl morpholine through condensation reaction, reoxidize and obtain N-benzyl-2-morpholone mai, last and replacement fluorobenzene generation substitution reaction obtains 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, and its reaction scheme is:
Route 1
In the present invention, target compound 1-2 will be obtained after morpholine benzyl.It is specially: in condensation reaction, 4-benzyl morpholine is prepared in the condensation reaction under acid binding agent exists of morpholine and benzyl reagent.Wherein benzyl reagent is cylite or Benzyl Chloride, preferably adopts cylite.Acid binding agent is selected pyridine or triethylamine.Condensation reaction solvent is selected from one or more in acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), and preferably acetonitrile is as solvent.The mol ratio of morpholine and benzyl reagent is 2:1～1:1, preferably 1.2:1, and setting-up point is 60 DEG C～100 DEG C.
The preferred reaction conditions of one of condensation reaction is: under room temperature, morpholine is blended in solvent system, under the condition existing at triethylamine, drips cylite, the mol ratio of morpholine and cylite between 2:1-1:1, preferred 1.2:1.Drip cylite temperature be controlled at below 20 DEG C, after adding, be warming up to backflow.
The present invention, by compound 1-2 and oxidant reaction, can obtain morpholinones 1-3.Be specially: in oxidizing reaction, 4-benzyl morpholine and oxygenant carry out oxidizing reaction and prepare N-benzyl-2-morpholone mai under catalyst action.Wherein oxygenant is oxygen, and the pressure of general oxygen is less than 3MPa; Catalyzer is HP; Oxidation solvent is acetonitrile or Benzyl cyanide.Oxidizing reaction temperature is 30 DEG C～60 DEG C, preferably 60 DEG C.
In the present invention, compound 1-3 is reacted to the target compound that can make formula 1-4 with the fluorobenzene replacing under highly basic condition.Be specially: in substitution reaction, N-benzyl-2-morpholone mai under catalyst action, substitution reaction occurs with replacement fluorobenzene, obtains 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai.Wherein replace fluorobenzene and be selected from fluorine iodobenzene or p-Fluoro bromo benzene, preferably p-Fluoro bromo benzene; The catalyzer of substitution reaction is sodium methylate, sodium ethylate or tert.-butoxy sodium, preferred alcohol sodium; The solvent of substitution reaction is selected methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF) or DMF, preferred alcohol.The consumption mol ratio that replaces fluorobenzene and N-benzyl-2-morpholone mai is 2:1～3:1, and substitution reaction temperature is 0 DEG C～80 DEG C, preferably 50 DEG C～80 DEG C.
The preferred reaction conditions of one of substitution reaction is: under the condition existing at sodium ethylate, compound 1-3 and ethanol are mixed, slowly add p-Fluoro bromo benzene, control temperature of reaction lower than 10 DEG C.Finish, rise to room temperature or back flow reaction.
Compared with prior art, it is cheap and easy to get that this technique invention has raw material, reaction temperature and, yield is high, environmental friendliness, the feature such as cost is low, suitability for mass industrializedization is produced.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
The preparation of embodiment 1:4-benzyl morpholine
500 milliliters of three-necked flasks, mechanical stirring, drops into (17.4 grams of morpholines, 200mmol), 150 milliliters of acetonitriles, 5 milliliters of triethylamines, be cooled to below 10 DEG C, under stirring, be slowly added dropwise to cylite (28.5 grams, 166mmol), drip and finish, rise to 80 DEG C, react 4 hours, TLC monitoring reaction is complete.Solution is poured in 500 milliliters of frozen water, and with dichloromethane extraction (2*250 milliliter), organic layer washs with saturated sodium bicarbonate solution, and anhydrous magnesium sulfate drying filters, and decompression steams solvent.Obtain 25 grams of faint yellow oily matter, yield 85%, (
1hNMR, 300MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm 7.33-7.45 (m, 5H, Ar-H), 3.95 (t, 4H, CH
2-O-CH
2), 3.37 (s, 2H, CH
2), 2.84 (t, 4H, CH
2-N-CH
2).
The preparation of embodiment 2:N-benzyl-2-morpholone mai
250 milliliters of round-bottomed flasks, mechanical stirring, (9 grams of the 4-benzyl morpholines that upper step is obtained, 50mmol), 100 milliliters of acetonitriles, stir, add 1.6 grams of HPs, logical oxygen reaction 8 hours, controls temperature and is no more than 60 DEG C, TLC monitoring reaction is complete, and solution is poured in 100 milliliters of frozen water, is extracted with ethyl acetate (3*100 milliliter), anhydrous sodium sulfate drying, filters, and decompression steams solvent, obtain 8 grams of faint yellow oily matter, yield 83%.(
1hNMR, 300MHz, interior mark TMS, solvent C DCl
3) as follows: δ ppm 7.35-7.45 (m, 5H, Ar-H), 3.98 (t, 4H, CH
2-O), 3.69 (s, 2H, CH
2), 3.35 (s, 2H, CH
2), 2.94 (t, 2H, CH
2).
The preparation of embodiment 3:3-(4-fluorophenyl)-4-benzyl-2-morpholone mai
250 milliliters of round-bottomed flasks, mechanical stirring, by (10.5 grams of p-Fluoro bromo benzenes, 60mmol), mix with 100 milliliters of ethanol, add 0.68 gram of sodium ethylate, after stirring and dissolving, be cooled to below 10 DEG C, slowly drip N-benzyl-2-morpholone mai (5.7 grams, 30mmol), drip and finish, be warming up to backflow, react 6 hours, TLC monitoring reaction is complete.Evaporated under reduced pressure solvent, adds 50 milliliters of saturated sodium bicarbonate solutions to residue, mixes, and with dichloromethane extraction, organic layer washes with water, and anhydrous magnesium sulfate drying filters evaporate to dryness, obtains 6.6 grams of faint yellow oily matter, yield 77%.(
1hNMR, 300MHz, interior mark TMS, solvent DMSO-d6) as follows: δ ppm 7.55-7.58 (m, 2H, Ar-H), 7.35-7.45 (m, 5H, Ar-H), 6.94-6.98 (m, 2H, Ar-H), 5.15 (s, 1H, CH), 4.24 (s, 2H, CH
2), 3.35 (t, 2H, CH
2), 2.86 (t, 2H, CH
2).
Claims (9)
1. the preparation method of a 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, it is characterized in that taking morpholine as raw material, first obtain 4-benzyl morpholine through condensation reaction, reoxidize and obtain N-benzyl-2-morpholone mai, last and replacement fluorobenzene generation substitution reaction obtains 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, and described replacement fluorobenzene is selected from fluorine iodobenzene or p-Fluoro bromo benzene; Its reaction scheme is:
Wherein, in condensation reaction, 4-benzyl morpholine is prepared in the condensation reaction under acid binding agent exists of morpholine and benzyl reagent; Described benzyl reagent is cylite or Benzyl Chloride;
In oxidizing reaction, 4-benzyl morpholine and oxygenant carry out oxidizing reaction and prepare N-benzyl-2-morpholone mai under catalyst action; Described oxygenant is oxygen; The catalyzer of described oxidizing reaction is HP.
2. method according to claim 1, is characterized in that described acid binding agent selects pyridine or triethylamine; Condensation reaction solvent is selected from one or more in acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF).
3. method according to claim 1, the mol ratio that it is characterized in that morpholine and benzyl reagent is 2:1～1:1, setting-up point is 60 DEG C～100 DEG C.
4. method according to claim 3, the mol ratio that it is characterized in that morpholine and benzyl reagent is 1.2:1.
5. method according to claim 1, is characterized in that oxidation solvent is acetonitrile or Benzyl cyanide.
6. method according to claim 1, is characterized in that oxidizing reaction temperature is 30 DEG C～60 DEG C.
7. method according to claim 1, is characterized in that in substitution reaction, and N-benzyl-2-morpholone mai under catalyst action, substitution reaction occurs with replacement fluorobenzene, obtains 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai.
8. method according to claim 7, the catalyzer that it is characterized in that substitution reaction is sodium methylate, sodium ethylate or tert.-butoxy sodium; The solvent of substitution reaction is selected methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF) or DMF.
9. method according to claim 7, the consumption mol ratio that it is characterized in that replacing fluorobenzene and N-benzyl-2-morpholone mai is 2:1～3:1, substitution reaction temperature is 0 DEG C～80 DEG C.
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| CN103755657B (en) * | 2013-12-25 | 2015-10-14 | 湖南方盛制药股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
| CN105837526B (en) * | 2016-01-22 | 2018-02-27 | 浙江工业大学 | A kind of preparation method of the alcohol of 4 benzyl 3 (4 fluorophenyl) morpholine of the important synthetic intermediate of aprepitant (2S, 3R) 2 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6046325A (en) * | 1998-09-11 | 2000-04-04 | Merck Sharp & Dohme Limited | Chemical synthesis of 1,4-oxazin-2-ones |
| US6177564B1 (en) * | 1998-09-11 | 2001-01-23 | Merck & Co., Inc. | Process for the synthesis of N-benzyl-3-(4-fluorophenyl)-1-4-oxazin-2-one |
| US20110094321A1 (en) * | 2005-10-06 | 2011-04-28 | Dr. Reddy's Laboratories Limited | Preparation of aprepitant |
| CN102659717A (en) * | 2012-04-20 | 2012-09-12 | 浙江启明药业有限公司 | Synthetic method of 2-methyl-1-(4'-methylthiophenyl)-2-morpholinyl-1-acetone |
| CN102746288A (en) * | 2012-07-24 | 2012-10-24 | 常州制药厂有限公司 | Preparation methods of anticoagulant and key intermediate of anticoagulant |
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2012
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Patent Citations (5)
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|---|---|---|---|---|
| US6046325A (en) * | 1998-09-11 | 2000-04-04 | Merck Sharp & Dohme Limited | Chemical synthesis of 1,4-oxazin-2-ones |
| US6177564B1 (en) * | 1998-09-11 | 2001-01-23 | Merck & Co., Inc. | Process for the synthesis of N-benzyl-3-(4-fluorophenyl)-1-4-oxazin-2-one |
| US20110094321A1 (en) * | 2005-10-06 | 2011-04-28 | Dr. Reddy's Laboratories Limited | Preparation of aprepitant |
| CN102659717A (en) * | 2012-04-20 | 2012-09-12 | 浙江启明药业有限公司 | Synthetic method of 2-methyl-1-(4'-methylthiophenyl)-2-morpholinyl-1-acetone |
| CN102746288A (en) * | 2012-07-24 | 2012-10-24 | 常州制药厂有限公司 | Preparation methods of anticoagulant and key intermediate of anticoagulant |
Non-Patent Citations (5)
| Title |
|---|
| Chandrashekar R. Elati，等.A convergent approach to the synthesis of aprepitant:a potent human NK-1 receptor antagonist.《Tetrahedron Letters》.2009,第48卷(第45期), * |
| Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation;Karel M. J. Brands,等;《J. AM. CHEM. SOC.》;20030130;第125卷(第8期);第2129-2135页 * |
| Karel M. J. Brands,等.Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation.《J. AM. CHEM. SOC.》.2003,第125卷(第8期), * |
| Matthew M. Zhao，等.Practical Asymmetric Synthesis of Aprepitant, a Potent Human NK-1 Receptor Antagonist, via a Stereoselective Lewis Acid-Catalyzed Trans Acetalization Reaction.《J. Org. Chem.》.2002,第67卷(第19期), * |
| 马礼宽，等.阿瑞吡坦合成路线图解.《中国医药工业杂志》.2009,第40卷(第12期), * |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.9 Yanshan Road, ecological Chemical Technology Industrial Park, Suqian City, Yancheng City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |