CN103288813A - Preparation method of aprepitant - Google Patents
Preparation method of aprepitant Download PDFInfo
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- CN103288813A CN103288813A CN2013102185760A CN201310218576A CN103288813A CN 103288813 A CN103288813 A CN 103288813A CN 2013102185760 A CN2013102185760 A CN 2013102185760A CN 201310218576 A CN201310218576 A CN 201310218576A CN 103288813 A CN103288813 A CN 103288813A
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Abstract
The invention discloses a preparation method of aprepitant. The preparation method comprises the following steps of: in the presence of acid carrying out intermolecular cyclization on an intermediate II and an intermediate III to generate an intermediate IV, salifying the intermediate IV using hydrochloric acid, and simultaneously carrying out transformational configuration on the obtained salt to obtain a single isomer V; B, reducing the intermediate IV into alcohol and then carrying out esterification on alcohol and 3,5-bis(trifluoromethyl)benzoyl chloride to obtain an intermediate VI, and recrystallizing the obtained intermediate VI by using an alcohol solvent; C, reacting the intermediate VI with dimethyl titanocene in tetrahydrofuran to obtain crude intermediate VII; D, carrying out reduction hydrogenation on the crude intermediate VII in the presence of a metal catalyst to obtain an intermediate VIII, and salifying the intermediate VIII through acid and purifying; E, alkylating the purified intermediate VIII to obtain the aprepitant. The preparation method disclosed by the invention is skillful in design and simple in flow; the application of expensive raw materials is prevented; the used reagents are environment-friendly, and therefore the preparation method is very conductive to industrialized production.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of A Rui smooth preparation method.
Background technology
A Rui smooth (Aprepitant, trade(brand)name: Emend), chemical name: 5-[[2-(R)-[1 (R)-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3(S)-and (4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone, structural formula is as follows:
A Rui smooth is first NK1 receptor antagonist of drugs approved by FDA, and its brand-new mechanism of action makes its 5-hydroxytryptamine receptor retarding agent different from the past, has more excellent antiemetic drug effect, brings glad tidings to patients undergoing chemotherapy.
A Rui smooth synthetic method head sees the patent application that publication number is WO9516679A1, it is raw material that this method adopts rare this glycine of the fluorine of alpha-non-natural amino acid L-, with the cyclization of violent in toxicity glycol dibromide high temperature, reaction finishes the back underpressure distillation and removes unnecessary ethylene dibromide.The extremely difficult purifying of this route gained oily matter finished product, reaction scheme is long, and yield is low, is unfavorable for very much environment protection.
J Org Chem, 2002,67 (19): a kind of chiral induction method of utilizing of report is synthesized A Rui smooth method among the 6743-6747, but it is raw material that this method need be used the chiral alcohol that is difficult to obtain, chiral alcohol ee value is required more than 99%, cause with high costsly thus, be unfavorable for that industry changes into product.
Owing to have three chiral centres in A Rui smooth molecule, be respectively 1R, 2R, 3S thus, brings sizable difficulty for synthetic high optical purity bulk drug.At present, A Rui smooth synthetic method become the focus of research.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of A Rui smooth preparation method is provided.This preparation method is skillfully constructed, flow process is simple, has avoided the use of expensive raw material, and the agents useful for same environmental friendliness is beneficial to suitability for industrialized production very much.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A kind of A Rui smooth preparation method may further comprise the steps:
Wherein, R is selected from: hydrogen, methoxyl group, nitro or halogen atom.
A, in the presence of acid, intermolecular ring-closure reaction takes place by 1:1 ~ 3 equivalents in intermediate II and intermediate III, generates the intermediate IV, the intermediate IV is changed configuration simultaneously through the hydrochloric acid salify and is got the individual isomer V;
After B, intermediate V are reduced to alcohol, become ester to obtain the intermediate VI with 3,5-, two trifluoromethyl benzoyl chlorides by 1:1 ~ 2 equivalents, gained intermediate VI is with the alcoholic solvent recrystallization;
C, intermediate VI make intermediate VII crude product with dimethyl two luxuriant titanium reactions in tetrahydrofuran (THF);
D, intermediate VII crude product make the intermediate VIII through the reduction hydrogenation in the presence of metal catalyst, the intermediate VIII is by carrying out purifying with sour salify;
Intermediate VIII behind E, the purifying through alkylation make A Rui smooth.
As optimal way, in the described steps A, acid is selected from: hydrochloric acid, sulfuric acid, tosic acid or acetic acid.
As optimal way, in the described steps A, the temperature of cyclization is 35-150 ℃, and the reaction times is 1-24 hour.
As optimal way, in the described steps A, cyclization carries out in Iso Butyl Acetate.
As optimal way, in the described steps A, the range of reaction temperature that intermediate IV and hydrochloric acid salify are changed configuration simultaneously is 50-100 ℃, and the reaction times is 1-24 hour, and reaction solvent is selected from: ethyl acetate, Iso Butyl Acetate or propyl acetate.
Further preferred, in the described steps A, the intermediate IV is reacted 12h, cold filtration under 70 ℃ of temperature in the saturated hydrogen chloride solution of Iso Butyl Acetate.
As optimal way, among the described step B, reductive agent is selected from: sodium borohydride, Lithium Aluminium Hydride, 3-sec-butyl lithium borohydride, diisobutyl aluminium hydride or red aluminium.
As optimal way, among the described step B, reduction reaction temperature is-78-25 ℃.
As optimal way, among the described step B, reduction reaction is in anhydrous tetrahydro furan, and the intermediate V is reduced the agent 3-sec-butyl lithium borohydride and is reduced to alcohol under-78 ℃ of temperature.
As optimal way, among the described step B, alcohol becomes the temperature of ester reaction with acyl chlorides be 0-50 ℃, and the soda acid of tiing up that this reaction is used is selected from: triethylamine, diisopropyl ethyl amine, yellow soda ash, salt of wormwood or DBU.
As optimal way, among the described step B, alcoholic solvent is selected from: methyl alcohol, ethanol, Virahol or n-propyl alcohol.
Further preferred, described alcoholic solvent is Virahol.
As optimal way, among the described step C, temperature of reaction is 50-150 ℃, and the reaction times is 1-12 hour.
As optimal way, among the described step C, be reflected in the toluene and carry out, back flow reaction 10 hours.
As optimal way, among the described step D, metal catalyst is selected from: Pd, Pt, Pt
2O
3Or Rh, reaction pressure is the 1-5 normal atmosphere.
As optimal way, among the described step D, the reduction hydrogenation is that 10%Pd/C is catalyzer in the ethyl acetate, isopropyl alcohol mixture of 3:1 in volume ratio, and hydro-reduction is 5 hours under 3 normal atmosphere.
As optimal way, in the described step e, the used soda acid of tiing up of alkylated reaction is selected from: yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, diisopropyl ethyl amine or DBU.
As optimal way, in the described step e, alkylated reaction is in DMF solution, with salt of wormwood for tiing up soda acid, room temperature reaction 5 hours.
The present invention adopts raw material cheap and easy to get, it is smooth to have synthesized with three chiral centres A Rui efficiently with simple experimental operation, the creationary use of having avoided expensive raw material and poisonous reagent, gained A Rui smooth chemical purity reaches more than 99.9%, optical purity is more than 99.9%, and every index all reaches the pharmacopeia requirement.
The contriver has carried out a large amount of research to A Rui smooth preparation method, by experiment many times, and the discovery that we are surprised, when A Rui smooth preparation method adopting the present invention to put down in writing, this preparation method has reached the technique effect out of expection on the whole.
Beneficial effect of the present invention is: the inventive method combines preparation optical purity intermediate method in the existing method cleverly, and the creationary use of avoiding expensive raw material, preparation technology is with the obvious advantage, the agents useful for same environmental friendliness, simple to operate, be beneficial to very much suitability for industrialized production.
Embodiment
Disclosed all features in this specification sheets, or the step in disclosed all methods or the process except mutually exclusive feature and/or step, all can make up by any way.
Embodiment 1: intermediate IV synthetic
With 40g raw material II, the mixing of 50g raw material III is dissolved in the 500ml Iso Butyl Acetate, add the 30ml Glacial acetic acid, reflux 8 hours, reaction solution is chilled to room temperature, add saturated sodium bicarbonate conditioned reaction PH to 8, tell organic layer, and successively to wash twice, twice of saturated common salt washing, be concentrated into original volume 1/2 behind the anhydrous sodium sulfate drying, add the saturated hydrogen chloride solution of 40ml Iso Butyl Acetate, be heated to 70 ℃ and stir 12h, reaction solution is chilled to room temperature, filtering reacting liquid, gained solid are intermediate IV hydrochloride.This hydrochloride is dissolved in the aqueous sodium carbonate, and to wash twice, saturated common salt is washed 2 times successively for ethyl acetate extraction 2 times, ethyl acetate layer, and it is intermediate IV free alkali that anhydrous sodium sulfate drying, concentrating under reduced pressure get colorless oil.
1H?NMR(400MHz?CDCl
3)?δ（ppm）=7.546(m、2H)，7.312（m，4H），7.243（m，1H），7.085（m，2H），4.617（s，1H），4.438（dt，
J=3.2，10.4，1H），4.345（td，
J=2.8,10.4，1H），3.804（q，
J=6.4，1H），2.865（dt，
J=3.2,10.4，1H），2.792（td，
J=2.8,12.8，1H），1.361（d，
J=6.4,3H）。
Embodiment 2: intermediate VI synthetic
24g is dissolved in the 100ml anhydrous tetrahydro furan with intermediate V free alkali, be cooled to-78 ℃, slowly drip tetrahydrofuran (THF) (1N) solution of 100ml 3-sec-butyl lithium borohydride, keep this temperature stirring after 2 hours after dripping end, in reaction solution, slowly drip 21.8ml3, the 5-dual-trifluoromethyl benzoyl chloride was kept this thermotonus 2 hours after adding.Reaction finishes the back and adds saturated aqueous common salt in reaction solution, in stirring at room 10 minutes, adds normal hexane, tell organic layer, and wash twice with saturated sodium bicarbonate aqueous solution successively, wash twice, saturated common salt washing twice, anhydrous sodium sulfate drying, it is faint yellow solid that filtering and concentrating gets crude product.This crude product is got white solid 37g with the Virahol recrystallization, yield 88.9%, purity: the 98.2%(HPLC normalization method).
m.p=110-112℃，[α]
D 25=+63
。(c=1.00,?methanol)；
1H?NMR(400MHz，CDCl
3)?δ（ppm）=8.528（s，2H），8.109（s，1H），7.530（d，
J=7.6,4H），7.392（t，
J=7.6,2H），7.287（t，
J=7.2,1H），6.973（t，
J=8.4,2H），6.199（d，
J=1.6,1H），4.177（s，1H），4.128（m，1H），4.079（q，
J=6.8,1H），3.719（d，
J=10.8，1H），2.770（dt，
J=2.8,12.0，1H），2.55（d，
J=12.0，1H），1.223（d，
J=6.4,3H）。
Embodiment 3: synthetic the synthesizing of intermediate VI
20g is dissolved in the 100ml anhydrous tetrahydro furan with intermediate V free alkali, be cooled to-20 ℃, toluene (1N) solution of slow Dropwise 5 0ml diisobutyl aluminium hydride, keep this temperature stirring after 2 hours after dripping end, in reaction solution, slowly drip 18.3ml3, the 5-dual-trifluoromethyl benzoyl chloride was kept this thermotonus 2 hours after adding.Reaction finishes the back and adds saturated aqueous common salt in reaction solution, in stirring at room 20 minutes, adds normal hexane, tell organic layer, and wash twice with saturated sodium bicarbonate aqueous solution successively, wash twice, saturated common salt washing twice, anhydrous sodium sulfate drying, it is yellow solid that filtering and concentrating gets crude product.This solid gets white solid 30g with recrystallizing methanol, yield 80.2%. purity: the 97.2%(HPLC normalization method).
m.p=110-112℃，[α]
D 25=+63
。(c=1.00,?methanol)；
1H?NMR(400MHz，CDCl
3)?δ（ppm）=8.528（s，2H），8.109（s，1H），7.530（d，
J=7.6,4H），7.392（t，
J=7.6,2H），7.287（t，
J=7.2,1H），6.973（t，
J=8.4,2H），6.199（d，
J=1.6,1H），4.177（s，1H），4.128（m，1H），4.079（q，
J=6.8,1H），3.719（d，
J=10.8，1H），2.770（dt，
J=2.8,12.0，1H），2.55（d，
J=12.0，1H），1.223（d，
J=6.4,3H）。
Embodiment 4: intermediate VII synthetic
50g intermediate VI is added in the toluene solution of 147g dimethyl two luxuriant titaniums, add the 14.7g cyclopentadienyl titanium dichloride, the 10ml tert-butyl acetate, lucifuge is back to reaction and finishes, reaction solution is chilled to room temperature, to wherein adding the 50g sodium bicarbonate, 100ml water and 500ml ethanol stirred filtering reacting liquid 8 hours in 50 ℃, filter cake is washed twice with ethanol, concentration of reaction solution gets intermediate VII crude product to doing, and this crude product is got white solid 45g with the Virahol recrystallization, yield 91.3%, purity: the 97.8%(HPLC normalization method).
m.p=89-91℃,[α]
D 25=+49
。(c=1.00,methanol);
?1H?NMR(400MHz，CDCl
3)δ（ppm）=7.999（s，2H），7.826（s，1H），7.619（t，
J=6.0，2H），7.508（d，
J=8.0，2H），7.354（t，
J=7.6，2H），7.259（m，1H），7.052（t，
J=8.8,2H），5.331（d，
J=2.4，1H），4.858（d，
J=2.8,1H），4.708（d，
J=3.2，1H），4.101（d，
J=2.8,1H），4.062（q，
J=6.8，1H），4.023（dt，
J=2.4,11.6,1H），3.600（m，1H），2.709（dt，
J=3.2,12.0,1H），2.478（d，
J=11.6,1H），1.206（d，
J=6.8,3H）。
Embodiment 5: intermediate VIII synthetic
20g intermediate VII is dissolved among 200ml ethyl acetate/Virahol=3:1, add 2g 10% Pd/C, room temperature reaction to reaction finishes under 3 normal atmosphere, filtering reacting liquid, filter cake is washed twice with ethyl acetate, concentrating under reduced pressure filtrate is to doing, hexone 100ml will be dissolved in the resistates, to wherein adding the 16ml concentrated hydrochloric acid, do not increasing in stirring at room to solid, filtering, filter cake is washed twice with hexone, it is white solid that 50 ℃ of vacuum-dryings get intermediate VIII hydrochloride 13g, yield 70%.Mp=249-250℃;[α]
D 25=+78
。(c=1.12,methanol);
1HNMR(400MHz,CDCl
3)10.82(m,
J=10.3,1H),10.47(m,
J=10.6,1H),7.65(s,1H),7.59(m,
J=5.0,2H),7.21(s,2H),7.05(m,
J=8.6,2H),4.91(q,
J=6.6,1H),4.49(m,2H),4.23(d,
J=11.8,1H),3.81(dd,
J=12.5,3.7,1H),3.45(m,
J=12.2,1H),3.23(m,
J=12.0,1H),1.58(d,
J=6.6,1H)。
Embodiment 6: intermediate VIII synthetic
10g intermediate VII is dissolved among 100ml ethyl acetate/Virahol=3:1, adds 1g 10% Pt/C, room temperature reaction to reaction finishes under 5 normal atmosphere, filtering reacting liquid, filter cake washes twice with ethyl acetate, and concentrating under reduced pressure filtrate will be dissolved in acetone 50ml to doing in the resistates, to wherein adding the 16ml concentrated hydrochloric acid, do not increasing in stirring at room to solid, filtering, filter cake is washed twice with hexone, it is white solid that 50 ℃ of vacuum-dryings get intermediate VIII hydrochloride 5g, yield 60%.Mp=250-251℃;[α]
D 25=+78
。(c=1.12,methanol);
1HNMR(400MHz,CDCl
3)10.82(m,
J=10.3,1H),10.47(m,
J=10.6,1H),7.65(s,1H),7.59(m,
J=5.0,2H),7.21(s,2H),7.05(m,
J=8.6,2H),4.91(q,
J=6.6,1H),4.49(m,2H),4.23(d,
J=11.8,1H),3.81(dd,
J=12.5,3.7,1H),3.45(m,
J=12.2,1H),3.23(m,
J=12.0,1H),1.58(d,
J=6.6,1H)。
Embodiment 7: A Rui smooth synthesizing
10g intermediate VIII hydrochloride is dissolved in 40mlN, in the dinethylformamide, adds 3.8g salt of wormwood, 4.0g5-chloromethyl-2,4-dihydro-[1,2,4] triazole-3-ketone, reaction 5h is to the reaction end under the room temperature, in reaction solution impouring frozen water, filter the gained solid, filter cake washing three times, be 6.9g off-white color solid in 50 ℃ of vacuum-drying De Arui smooth crude product, yield 68%.
Embodiment 8: A Rui smooth synthesizing
10g intermediate VIII hydrochloride is dissolved in 40mlN, in the dinethylformamide, adds the 2g sodium bicarbonate, 4.0g5-chloromethyl-2,4-dihydro-[1,2,4] triazole-3-ketone, reaction 8h is to the reaction end under the room temperature, in reaction solution impouring frozen water, filter the gained solid, filter cake washing three times, be 5.2g off-white color solid in 50 ℃ of vacuum-drying De Arui smooth crude product, yield 53%.
Embodiment 9: A Rui smooth making with extra care
Gained A Rui among the embodiment 5 smooth crude product 5g is dissolved in the 50ml methyl alcohol, add the 1g gac in 50 ℃, 30 minutes after-filtration reflux, filter cake is washed 2 times with 10ml methyl alcohol, filtrate decompression is concentrated into dried, resistates is with 50ml acetonitrile recrystallization 1 time, again with the 50ml re-crystallizing in ethyl acetate once, gained A Rui smooth highly finished product purity〉the 99.9%.(HPLC normalization method) every index reaches the pharmacopeia requirement.
Mp:?255℃，[α]
D 25=+69
。(c=1.00,methanol);
1H?NMR(400MHz,CD
3OD)7.70(s,1H),7.51(m,2H),7.32(s,2H),7.04(t,J?=8.7,2H),4.94(q,J=6.3,1H),4.35(d,J=2.8,1H),4.28(td,J=11.5,2.8,1H),3.66(ddd,J=11.5,3.3,1.6,1H),3.54(d,J=14.3,1H),3.48(d,J=2.8,1H),2.88(brd,J=11.9,1H),2.86(d,J=14.3,1H),2.49(td,J=11.9,3.6,1H),1.44(d,J=6.3,3H)。
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature or any new combination that discloses in this manual, and the arbitrary new method that discloses or step or any new combination of process.
Claims (19)
1. A Rui smooth preparation method is characterized in that may further comprise the steps:
Wherein, R is selected from: hydrogen, methoxyl group, nitro or halogen atom.
2. a kind of A Rui smooth preparation method according to claim 1 is characterized in that may further comprise the steps:
A, in the presence of acid, intermolecular ring-closure reaction takes place by 1:1 ~ 3 equivalents in intermediate II and intermediate III, generates the intermediate IV, the intermediate IV is changed configuration simultaneously through the hydrochloric acid salify and is got the individual isomer V;
After B, intermediate V are reduced to alcohol, become ester to obtain the intermediate VI with 3,5-, two trifluoromethyl benzoyl chlorides by 1:1 ~ 2 equivalents, gained intermediate VI is with the alcoholic solvent recrystallization;
C, intermediate VI make intermediate VII crude product with dimethyl two luxuriant titaniums by 1:1 ~ 10 equivalent reactions in tetrahydrofuran (THF);
D, intermediate VII crude product make the intermediate VIII through the reduction hydrogenation in the presence of metal catalyst, the intermediate VIII is by carrying out purifying with sour salify;
Intermediate VIII behind E, the purifying through alkylation make A Rui smooth.
3. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: in the described steps A, acid is selected from: hydrochloric acid, sulfuric acid, tosic acid or acetic acid.
4. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: in the described steps A, the temperature of cyclization is 35-150 ℃, and the reaction times is 1-24 hour.
5. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: in the described steps A, cyclization carries out in Iso Butyl Acetate.
6. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: in the described steps A, the range of reaction temperature that intermediate IV and hydrochloric acid salify are changed configuration simultaneously is 50-100 ℃, reaction times is 1-24 hour, and reaction solvent is selected from: ethyl acetate, Iso Butyl Acetate or propyl acetate.
7. a kind of A Rui smooth preparation method according to claim 6, it is characterized in that: in the described steps A, the intermediate IV is reacted 12h, cold filtration under 70 ℃ of temperature in the saturated hydrogen chloride solution of Iso Butyl Acetate.
8. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step B, reductive agent is selected from: sodium borohydride, Lithium Aluminium Hydride, 3-sec-butyl lithium borohydride, diisobutyl aluminium hydride or red aluminium.
9. a kind of A Rui smooth preparation method according to claim 2 is characterized in that: among the described step B, reduction reaction temperature is-and 78-25 ℃.
10. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step B, reduction reaction is in anhydrous tetrahydro furan, and the intermediate V is reduced the agent 3-sec-butyl lithium borohydride and is reduced to alcohol under-78 ℃ of temperature.
11. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step B, alcohol becomes the temperature of ester reaction with acyl chlorides be 0-50 ℃, and the soda acid of tiing up that this reaction is used is selected from: triethylamine, diisopropyl ethyl amine, yellow soda ash, salt of wormwood or DBU.
12. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step B, alcoholic solvent is selected from: methyl alcohol, ethanol, Virahol or n-propyl alcohol.
13. a kind of A Rui smooth preparation method according to claim 12 is characterized in that: described alcoholic solvent is Virahol.
14. a kind of A Rui smooth preparation method according to claim 2 is characterized in that: among the described step C, temperature of reaction is 50-150 ℃, and the reaction times is 1-12 hour.
15. a kind of A Rui smooth preparation method according to claim 2 is characterized in that: among the described step C, be reflected in the toluene and carry out, back flow reaction 10 hours.
16. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step D, metal catalyst is selected from: Pd, Pt, Pt
2O
3Or Rh, reaction pressure is the 1-5 normal atmosphere.
17. a kind of A Rui smooth preparation method according to claim 2, it is characterized in that: among the described step D, the reduction hydrogenation is that 10%Pd/C is catalyzer in the ethyl acetate, isopropyl alcohol mixture of 3:1 in volume ratio, and hydro-reduction is 5 hours under 3 normal atmosphere.
18. a kind of A Rui smooth preparation method according to claim 2 is characterized in that: in the described step e, the used soda acid of tiing up of alkylated reaction is selected from: yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, diisopropyl ethyl amine or DBU.
19. a kind of A Rui smooth preparation method according to claim 2 is characterized in that: in the described step e, alkylated reaction is in DMF solution, with salt of wormwood for tiing up soda acid, room temperature reaction 5 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713497A (en) * | 2019-10-30 | 2020-01-21 | 成都海杰亚医药科技有限公司 | Preparation method of Brigatinib intermediate 2-aminophenyldimethylphosphine oxide |
| CN107698574B (en) * | 2017-11-23 | 2020-12-01 | 中山奕安泰医药科技有限公司 | Refining preparation process of high-purity aprepitant |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999001444A1 (en) * | 1997-07-02 | 1999-01-14 | Merck & Co., Inc. | Polymorphic form of the tachykinin receptor antagonist 2-(r)-(1-(r) -(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(s)-(4-fluoro) phenyl-4-(3-5 (-oxo-1h,4h-1,2,4,-triazolo) methylmorpholine |
| US6046325A (en) * | 1998-09-11 | 2000-04-04 | Merck Sharp & Dohme Limited | Chemical synthesis of 1,4-oxazin-2-ones |
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| CN1646525A (en) * | 2002-04-18 | 2005-07-27 | 麦克公司 | Process for 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one |
| CN101959870A (en) * | 2008-02-26 | 2011-01-26 | 桑多斯股份公司 | Preparation of morpholine derivatives |
| CN102153522A (en) * | 2010-03-29 | 2011-08-17 | 武汉启瑞药业有限公司 | Novel method for preparing N-substituted 2-hydroxy-morpholin-3-one compound |
| CN102675240A (en) * | 2012-04-13 | 2012-09-19 | 浙江海正药业股份有限公司 | 4-substitute-2-hydroxy morpholine-3-one and preparation method thereof |
-
2013
- 2013-06-04 CN CN2013102185760A patent/CN103288813A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999001444A1 (en) * | 1997-07-02 | 1999-01-14 | Merck & Co., Inc. | Polymorphic form of the tachykinin receptor antagonist 2-(r)-(1-(r) -(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(s)-(4-fluoro) phenyl-4-(3-5 (-oxo-1h,4h-1,2,4,-triazolo) methylmorpholine |
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| US6046325A (en) * | 1998-09-11 | 2000-04-04 | Merck Sharp & Dohme Limited | Chemical synthesis of 1,4-oxazin-2-ones |
| CN1646525A (en) * | 2002-04-18 | 2005-07-27 | 麦克公司 | Process for 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one |
| CN101959870A (en) * | 2008-02-26 | 2011-01-26 | 桑多斯股份公司 | Preparation of morpholine derivatives |
| CN102153522A (en) * | 2010-03-29 | 2011-08-17 | 武汉启瑞药业有限公司 | Novel method for preparing N-substituted 2-hydroxy-morpholin-3-one compound |
| CN102675240A (en) * | 2012-04-13 | 2012-09-19 | 浙江海正药业股份有限公司 | 4-substitute-2-hydroxy morpholine-3-one and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| JEFFREY J. HALE等: "Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor Antagonist", 《J. MED. CHEM.》 * |
| 马礼宽等: "阿瑞吡坦合成路线图解", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698574B (en) * | 2017-11-23 | 2020-12-01 | 中山奕安泰医药科技有限公司 | Refining preparation process of high-purity aprepitant |
| CN110713497A (en) * | 2019-10-30 | 2020-01-21 | 成都海杰亚医药科技有限公司 | Preparation method of Brigatinib intermediate 2-aminophenyldimethylphosphine oxide |
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