CN102898396A - 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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- CN102898396A CN102898396A CN2012104606308A CN201210460630A CN102898396A CN 102898396 A CN102898396 A CN 102898396A CN 2012104606308 A CN2012104606308 A CN 2012104606308A CN 201210460630 A CN201210460630 A CN 201210460630A CN 102898396 A CN102898396 A CN 102898396A
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- benzyl
- reaction
- morpholine
- morpholone mai
- fluorophenyl
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- 0 C(c1ccccc1)N1CC*CC1 Chemical compound C(c1ccccc1)N1CC*CC1 0.000 description 1
- DNJYQSXUZRHPPO-UHFFFAOYSA-N O=C1OCCN(CC2=CCCC=C2)C1 Chemical compound O=C1OCCN(CC2=CCCC=C2)C1 DNJYQSXUZRHPPO-UHFFFAOYSA-N 0.000 description 1
- GSZAAEJBPFTBKG-UHFFFAOYSA-N O=C1OCCN(Cc2ccccc2)C1c(cc1)ccc1F Chemical compound O=C1OCCN(Cc2ccccc2)C1c(cc1)ccc1F GSZAAEJBPFTBKG-UHFFFAOYSA-N 0.000 description 1
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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 present invention relates to the preparation method of a kind of 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, can be used for preparing neurokinin receptor retarding agent Aprepitant, belong to field of medicine and chemical technology.
Background technology
Aprepitant is first neurokinin receptor (NK-1) retarding agent that U.S. FDA goes on the market in approval in 2003, is mainly used in clinically nauseating, the vomiting of acute and retardance that Prophylactic chemotherapy causes.This medication effect is definite, and side effect is little, in the listing of a plurality of 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 be the preparation Aprepitant important intermediate, its structural formula as shown in the formula:
In recent years, this intermediate receives increasing concern, the report that synthetic this compound of multiple route is also arranged both at home and abroad: such as Indian Pat.Appl., 2008MU01358 disclose take 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 take p-Fluorobenzenecarboxaldehyde as raw material, first with the sodium cyanide addition, replace with N-benzyl ethyl alcohol amine again, are hydrolyzed into acid amides, and last cyclization obtains, and main route is as follows:
Route 3
In the 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 the route 3, need to use hypertoxic prussiate, working condition is had relatively high expectations.Above route all is not suitable for large-scale industrial production.
Summary of the invention
The objective of the invention is on the basis of existing technology, a kind of new method for preparing 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai is provided.
Purpose of the present invention can reach by following measures:
The preparation method of a kind of 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, it is take 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
Among the present invention, target compound 1-2 will be obtained behind the morpholine benzyl.It is specially: in condensation reaction, morpholine and the condensation reaction in the presence of acid binding agent of benzyl reagent prepare 4-benzyl morpholine.Wherein benzyl reagent is cylite or Benzyl Chloride, preferably adopts cylite.Acid binding agent is selected pyridine or triethylamine.The condensation reaction solvent is selected from one or more in acetonitrile, Isosorbide-5-Nitrae-dioxane, the tetrahydrofuran (THF), and preferred acetonitrile is as solvent.The mol ratio of morpholine and benzyl reagent is 2:1～1:1, preferred 1.2:1, and setting-up point is 60 ℃～100 ℃.
A kind of preferred reaction conditions of condensation reaction is: under the room temperature morpholine is blended in the solvent system, under the condition that triethylamine exists, 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 ℃, be warming up to backflow after adding.
The present invention can obtain morpholinones 1-3 with compound 1-2 and oxidant reaction.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 ℃～60 ℃, preferred 60 ℃.
Among the present invention compound 1-3 can be made the target compound of formula 1-4 with the fluorobenzene reaction that replaces under the highly basic condition.Be specially: in substitution reaction, substitution reaction occurs with the replacement fluorobenzene in N-benzyl-2-morpholone mai under catalyst action, obtain 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai.Wherein replace fluorobenzene and be selected from fluorine iodobenzene or p-Fluoro bromo benzene, preferred 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 the substitution reaction temperature is 0 ℃～80 ℃, preferred 50 ℃～80 ℃.
A kind of preferred reaction conditions of substitution reaction is: under the condition that sodium ethylate exists, with compound 1-3 and ethanol mixing, slowly add p-Fluoro bromo benzene, the control temperature of reaction is lower than 10 ℃.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 characteristics such as cost is low, suitability for mass industrialized production.
Embodiment
Below with specific embodiment technical scheme of the present invention is described, 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 morpholine (17.4 grams, 200mmol), 150 milliliters of acetonitriles, 5 milliliters of triethylamines, be cooled to below 10 ℃, under stirring, (28.5 restrain, 166mmol) slowly to be added dropwise to cylite, drip and finish, rise to 80 ℃, reacted 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 faint yellow oily thing 25 grams, 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 restrain the 4-benzyl morpholine that the upper step was obtained, 50mmol), 100 milliliters of acetonitriles stir, add HP 1.6 grams, logical oxygen reaction 8 hours, the control temperature is no more than 60 ℃, TLC monitoring reaction is complete, solution is poured in 100 milliliters of frozen water, with ethyl acetate extraction (3*100 milliliter), anhydrous sodium sulfate drying filters, and decompression steams solvent, obtain faint yellow oily thing 8 grams, 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 is with p-Fluoro bromo benzene (10.5 grams, 60mmol), mix with 100 milliliters of ethanol, add sodium ethylate 0.68 gram, after the stirring and dissolving, be cooled to below 10 ℃, (5.7 restrain, 30mmol) slowly to drip N-benzyl-2-morpholone mai, drip and finish, be warming up to backflow, reacted 6 hours, TLC monitoring reaction is complete.The evaporated under reduced pressure solvent adds 50 milliliters of saturated sodium bicarbonate solutions to residue, and mixing is used dichloromethane extraction, and organic layer washes with water, and anhydrous magnesium sulfate drying filters evaporate to dryness, obtains faint yellow oily thing 6.6 grams, 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 (10)
1. the preparation method of a 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai, it is characterized in that take 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:
2. method according to claim 1 is characterized in that in condensation reaction, and the condensation reaction in the presence of acid binding agent of morpholine and benzyl reagent prepares 4-benzyl morpholine.
3. method according to claim 2 is characterized in that described benzyl reagent is cylite or Benzyl Chloride, and described acid binding agent is selected pyridine or triethylamine; The condensation reaction solvent is selected from one or more in acetonitrile, Isosorbide-5-Nitrae-dioxane, the tetrahydrofuran (THF).
4. method according to claim 2, the mol ratio that it is characterized in that morpholine and benzyl reagent is 2:1～1:1, preferred 1.2:1, setting-up point is 60 ℃～100 ℃.
5. method according to claim 1 is characterized in that in oxidizing reaction, and 4-benzyl morpholine and oxygenant carry out oxidizing reaction and prepare N-benzyl-2-morpholone mai under catalyst action.
6. method according to claim 5 is characterized in that described oxygenant is oxygen; The catalyzer of described oxidizing reaction is HP; Oxidation solvent is acetonitrile or Benzyl cyanide.
7. method according to claim 1 is characterized in that oxidizing reaction temperature is 30 ℃～60 ℃.
8. 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 the replacement fluorobenzene, obtains 3-(4-fluorophenyl)-4-benzyl-2-morpholone mai.
9. method according to claim 8 is characterized in that, described replacement fluorobenzene is selected from fluorine iodobenzene or p-Fluoro bromo benzene; The catalyzer of 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.
10. method according to claim 8, the consumption mol ratio that it is characterized in that replacing fluorobenzene and N-benzyl-2-morpholone mai is 2:1～3:1, the substitution reaction temperature is 0 ℃～80 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755657A (en) * | 2013-12-25 | 2014-04-30 | 湖南方盛制药股份有限公司 | Preparation method of rivaroxaban intermediate |
| CN105837526A (en) * | 2016-01-22 | 2016-08-10 | 浙江工业大学 | Preparation method of important intermediate (2S, 3R)-4-benzyl-3-(4-fluorophenyl)morpholine-2-ol for aprepitant synthesis |
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 |
-
2012
- 2012-11-15 CN CN201210460630.8A patent/CN102898396B/en active Active
Patent 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 |
Non-Patent Citations (4)
| Title |
|---|
| CHANDRASHEKAR R. ELATI，等: "A convergent approach to the synthesis of aprepitant:a potent human NK-1 receptor antagonist", 《TETRAHEDRON LETTERS》, vol. 48, no. 45, 12 September 2009 (2009-09-12) * |
| KAREL M. J. BRANDS,等: "Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation", 《J. AM. CHEM. SOC.》, vol. 125, no. 8, 30 January 2003 (2003-01-30) * |
| 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.》, vol. 67, no. 19, 28 August 2002 (2002-08-28) * |
| 马礼宽，等: "阿瑞吡坦合成路线图解", 《中国医药工业杂志》, vol. 40, no. 12, 31 December 2009 (2009-12-31) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755657A (en) * | 2013-12-25 | 2014-04-30 | 湖南方盛制药股份有限公司 | Preparation method of rivaroxaban intermediate |
| 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 |
| CN105837526A (en) * | 2016-01-22 | 2016-08-10 | 浙江工业大学 | Preparation method of important intermediate (2S, 3R)-4-benzyl-3-(4-fluorophenyl)morpholine-2-ol for aprepitant synthesis |
| 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 |
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