CN104496930B - A kind of optical purity Aprepitant bulk drug intermediate preparation method - Google Patents
A kind of optical purity Aprepitant bulk drug intermediate preparation method Download PDFInfo
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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Abstract
The invention discloses a kind of preparation method of optical purity Aprepitant bulk drug intermediate: by Compound I I reacting generating compound III, and then make compound IV with chlorination reaction, compound IV reduction is made to compound V, under acid condition, make compound VI by heating again, obtain hemiacetal compound VI I through cyclization, again with the bromo-1-[3 of 1R-1-, 5-bis-(trifluoromethyl) phenyl] ethane synthetic compound VIII, react to obtain Compound I X with biconjugate fluorophenyl copper lithium, finally by the synthetic I of reduction. The present invention use raw material and reagent simple and easy to get, avoided expensive reagent to select, reaction condition gentleness, every step reaction yield is all higher, route is stable, environmental friendliness, is conducive to suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of optical purity Aprepitant bulk drug intermediate preparation method, belong to pharmaceutical chemistry field.
Background technology
Aprepitant is the whole world first " NK1 receptor antagonist of high selectivity ", process and central nervous system NK1Acceptor is combined closely, and because of feeling sick and vomiting that chemotherapy causes, contributes to improve cancer patient by the potent prevention of central mechanismLife quality.
Aprepitant is the selective high affinity antagonist of people's Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 neurokinin 1 (NK1) acceptor. Existing to otherThe cause nausea action target spot serotonin of medicine of vomiting (CINV) and postoperative nausea and vomiting (PONV) for the treatment of chemotherapyThe affinity of acceptor 3 (5-HT3), dopamine receptor and GCR is low or without affinity.
Preclinical study shows, NK1 receptor antagonist malicious chemotherapeutics capable of inhibiting cell is as cis-platinum, the vomiting causing. AhAuspicious smooth clinical before and human body positron emission cross-sectional imaging (PET) studies show that, Aprepitant can see through blood-brain barrier,Capture NK1 acceptor in brain. Aprepitant can suppress acute stage and vomiting period of delay that cis-platinum causes, and strengthens 5-HT3 and be subject toThe antiemetic activity of the vomiting that body antagonist Ondansetron and glucocorticoid Dexamethasone on Cisplatin cause. Structural formula is shown in following formula(A)：
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of system of optical purity Aprepitant bulk drug key intermediatePreparation Method, solves that the yield that synthetic Aprepitant bulk drug synthesis step too much causes is lower, cost is high and environmental pollutionThe technical problem such as large.
Object of the present invention can reach by following measures:
A preparation method for optical purity Aprepitant bulk drug intermediate, it comprises the steps: Compound I I logicalCross Hell-Volhard-Zelinski reacting generating compound III, and then make compound IV with chlorination reaction, by chemical combinationThing IV is reduced and is made compound V by Rosenmund, and compound V is made to chemical combination by heating under acid conditionThing VI, compound VI obtains hemiacetal compound VI I through cyclization, the bromo-1-[3 of compound VI I and 1R-1-, 5-bis-(trifluorosMethyl) phenyl] ethane synthetic compound VIII, compound VI II adopts Corey – House synthetic method and biconjugate fluorophenyl copperLithium reacts to obtain Compound I X, has optical activity intermediate compound I finally by the final synthesis material medicine of hydrogen reducing Aprepitant, itsReaction scheme is:
Wherein R is selected from hydrogen, methyl, methoxyl group or halogen.
The concrete technical scheme of one of the present invention is:
First step reaction (a): Compound I I is reacted and is generated chemical combination by Hell-Volhard-Zelinski under reaction reagent existsThing III, reaction reagent comprises Br2Phosphorus or phosphorus tribromide with catalytic amount.
N-methoxy ethyl-N-carboxymethyl benzylamine (II) be dissolved in certain solvent and uniform temperature in, drip bromine, logicalCross Hell-Volhard-Zelinski reaction and obtain N-methoxy ethyl-N-bromo carboxymethyl benzylamine (III). Solvent used isThe ether solvents such as acetonitrile, dioxane, isopropyl ether, oxolane, the common reagent of ester class such as ethyl acetate, butyl acetate.The preferably one in acetonitrile, oxolane, n-hexane.
Phosphorus or phosphorus tribromide are used in this reaction, play catalytic action.
In this step reaction, the consumption of bromine is 1.2～3 times of compound (II), preferably 1.5～2 times. Reaction temperature is20～60 DEG C, preferably 40～60 DEG C.
Second step reaction (b): N-methoxy ethyl-N-bromo carboxymethyl benzylamine (III) is prepared N-methoxyl group with chlorination reactionEthyl-N-acyl chlorides bromomethyl benzylamine (IV), chlorinating agent can be selected the reagent such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride.Preferably thionyl chloride. 80～100 DEG C of reaction temperatures. Solvent for use can be thionyl chloride or toluene, dimethylbenzene, n-hexaneEtc. common hydro carbons reagent. Preferably thionyl chloride. Thionyl chloride consumption is 3.0～5.0 times of compound (III).
The 3rd step (c): N-methoxy ethyl-N-acyl chlorides bromomethyl benzylamine (IV) makes N-first through Rosenmund reductionOxygen base ethyl-N-aldehyde radical bromomethyl benzylamine (V), used catalyst is Pd/BaSO4, solvent for use is toluene or diformazanBenzene. 140～160 DEG C of reaction temperatures. Hydrogen usage is 2.0～6.0 times of compound (IV), preferably 3.0～4.0 times.
The 4th step (d): N-methoxy ethyl-N-aldehyde radical bromomethyl benzylamine (V) is taken off methyl and generated N-(1-hydroxyethyl)-N-aldehyde radical bromomethyl benzylamine (VI), reaction condition is and excessive halogen acids heat altogether. Halogen acids used can be hydrobromic acid,Hydrochloric acid. Preferably hydrochloric acid. Hydrochloric acid consumption is 1.2～4.0 times of compound (V), preferably 1.5～2.0 times. ReactionTemperature is 70～100 DEG C.
The 5th step (e): N-(1-hydroxyethyl)-N-aldehyde radical bromomethyl benzylamine (VI) generates molecule inner hemiacetal, i.e. 2-The bromo-N-benzyl of hydroxyl-3-morpholine, is a pair of diastereoisomer, and solvent for use is the hydro carbons such as toluene, dimethylbenzene, cyclohexane,Preferably toluene. Acid used is hydrochloric acid, p-methyl benzenesulfonic acid etc. Preferably p-methyl benzenesulfonic acid reaction temperature is 40～100 DEG C. ?To compound (VII).
In this step reaction, p-methyl benzenesulfonic acid is catalyst and dehydrating agent.
The 6th step (f): by compound (VII) and R-3, the reaction of 5-bis-(trifluoromethyl) chlorobenzoyl chloride, takes off little molecule chlorinationHydrogen generates diastereoisomer, and this diastereoisomer, by crystallization in alcohol liquid, is obtained to optical purity compound2R, 3S-2-[(1R)-1-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl] the bromo-N-benzyl of-3-morpholine (VIII). Alkali used: hydrogenThe highly basic such as sodium oxide molybdena, potassium hydroxide, sodium methoxide, caustic alcohol. Reaction temperature is 40～100 DEG C. Solvent be DMF, DMSO,Oxolane, dioxane etc.
The 7th step (g): 2R, 3S-2-[(1R)-1-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl] the bromo-N-benzyl of-3-morpholine (VIII)By Corey – House synthetic method, react with biconjugate fluorophenyl copper lithium, generate 2R, 3S-2-[(1R) and-1-[3,5-bis-(threeMethyl fluoride) phenyl] ethyoxyl]-3-(4-fluorophenyl)-N-benzyl morpholine (IX). Solvent for use is ether, propyl ether, isopropylThe conventional ethers reagent such as ether, dioxane. Reaction temperature is-10～10 DEG C.
The 8th step (h): 2R, 3S-2-[(1R)-1-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl]-3-(4-fluorophenyl)-N-Benzyl morpholine (IX), by hydrogen reducing, removes the benzyl on nitrogen, generates 2R, 3S-2-[(1R)-1-[3,5-bis-(trifluorosMethyl) phenyl] ethyoxyl]-3-(4-fluorophenyl) morpholine (I). Solvent for use is methyl alcohol, ethanol. Catalyst is Pd/C.
Compared with prior art, the present invention has conditioned response gentleness, and reagent is easy to get and is cheap, and yield is high, specially three-dimensionalOne property is strong, environmental friendliness, and the feature such as cost is low, suitable with large-scale industrial production.
Detailed description of the invention
Embodiment 1: optical purity Aprepitant bulk drug intermediate preparation method
Chemical reaction skeleton symbol is as follows:
1:1000 milliliter there-necked flask, magnetic stirs, and drops into N-methoxy ethyl-N-carboxymethyl benzylamine (223g, 1mol), fourHydrogen furans 400ml, adds phosphorus 5g, and system is heated to 40 DEG C, starts slowly to drip bromine (120g. 1.5eq), drip ratio,Continue reaction 1.5h, be cooled to room temperature. Add water at twice approximately 200 milliliters, water layer is removed in layering. Finally remove reaction dissolventObtaining compound III is 289.9 grams, and yield is 96%.
2:1000ml round-bottomed flask, magnetic stirs, and upper step is made to compound III, adds 360g thionyl chloride, does anti-Answer thing to make again solvent, be heated to back flow reaction 1h. Removing unnecessary thionyl chloride, to obtain compounds Ⅳ be 303.7 grams, and yield is99％。
3:1000 milliliter there-necked flask, magnetic stirs, and upper step is made to compounds Ⅳ and be dissolved in 600ml toluene, adds and falls simultaneouslyThe Pd/BaSO of low catalytic activity4As catalyst, pass into the hydrogen of triplication, under room temperature, react 4h. Remove by filter catalysisAgent, then removing unnecessary solvent, to obtain compound V be 246.5 grams, yield is 97%.
4:1000 milliliter there-necked flask, magnetic stirs, and upper step is made to the concentrated hydrochloric acid that compound V directly adds 1.5 times, heatingTo 70 DEG C of reaction 40min, vacuum is revolved to steam and is removed first alcohol and water, makes compound VI, directly carries out next step reaction,Remove the first alcohol and water in system, directly add 500 milliliters of solvent toluenes, p-methyl benzenesulfonic acid 40g, is heated to back flow reaction5h, during this time azeotropic band water. After reaction finishes, remove reaction dissolvent, obtain 234.4 grams of compound VII, overall yield of reaction is 94%.
5:500ml there-necked flask, magnetic stirs, the bromo-1-[3 of compound VII and 1R-1-, 5-bis-(trifluoromethyl) phenyl] ethane (1.5eq)Reaction, adds 200 milliliters of oxolanes as solvent, and caustic alcohol (1.1eq), is heated to 60 DEG C, and reaction 8h is coolingFilter. Except desolventizing. By the material obtaining crystallization in ethanol, obtain 199.5 grams of compound VIII, yield 45%.
6:500ml round-bottomed flask, magnetic stirs, and upper step is made to compound VIII and be dissolved in 300 milliliters of ether solvents, adds2 times of amounts to two fluorophenyl copper lithium reagents, at about 0 DEG C reaction 4h, reaction finishes rear filtration, then except desolventizing, obtains164.3 grams of compound IX, yield is 80%.
7:500ml there-necked flask, magnetic stirs, and upper step synthetic compound IX is dissolved in ethanolic solution, adds 10%Pd/C,Then system is carried out nitrogen replacement, passes into 60 DEG C of reaction 8h of hydrogen, after reaction finishes. Filter, except desolventizing. Obtain chemical combinationThing crude product, through ethyl alcohol recrystallization, obtains 129.3 grams of compound X, yield 95%. Measure purity through HPLC (internal standard method)＞99％。
Mp＝250-251℃；[α]D 20＝+76(c＝1.10,methanol)
1HNMR(CDCl3)10.80(m,J＝10.2,1H)，10.44(m,J＝10.4,1H)，7.62(s,1H)，7.51(m,J＝5.0,2H)，7.19(s,2H)，7.03(m,J＝8.5,2H)，4.88(q,J＝6.5,1H)，4.45(m,2H)，4.20(d,J＝11.7,1H)，3.80(dd,J＝12.4,3.6,1H)，3.42(m,J＝12.1,1H)，3.21(m,J＝11.9,1H)，1.56(d,J＝6.5,1H)。
Embodiment 2
1:1000 milliliter there-necked flask, magnetic stirs, and drops into N-methoxy ethyl-N-carboxymethyl benzylamine (223g, 1mol), secondAcetoacetic ester 400ml, adds phosphorus 6g, and system is heated to 45 DEG C, starts slowly to drip bromine (120g. 1.5eq), drip ratio,Continue reaction 1.5h, be cooled to room temperature. Add water at twice approximately 200 milliliters, water layer is removed in layering. Finally remove reaction dissolventObtaining compound III is 290.1 grams.
2:1000ml round-bottomed flask, magnetic stirs, and upper step is made to compound III, adds 360g thionyl chloride, does anti-Answer thing to make again solvent, be heated to back flow reaction 1h. Removing unnecessary thionyl chloride, to obtain compounds Ⅳ be 303.8 grams.
3:1000 milliliter there-necked flask, magnetic stirs, and upper step is made to compounds Ⅳ and be dissolved in 600ml dimethylbenzene, adds simultaneouslyReduce the Pd/BaSO of catalytic activity4As catalyst, pass into the hydrogen of triplication, under room temperature, react 4h. Remove by filter and urgeAgent, then removing unnecessary solvent, to obtain compound V be 246.7 grams.
4:1000 milliliter there-necked flask, magnetic stirs, and upper step is made to the concentrated hydrochloric acid that compound V directly adds 1.5 times, heatingTo 70 DEG C of reaction 40min, vacuum is revolved to steam and is removed first alcohol and water, makes compound VI, directly carries out next step reaction,Remove the first alcohol and water in system, directly add 500 milliliters of solvent toluenes, p-methyl benzenesulfonic acid 40g, is heated to back flow reaction5h, during this time azeotropic band water. After reaction finishes, remove reaction dissolvent, obtain 234.6 grams of compound VII.
5:500ml there-necked flask, magnetic stirs, the bromo-1-[3 of compound VII and 1R-1-, 5-bis-(trifluoromethyl) phenyl] ethane (1.5eq)Reaction, adds 200 milliliters of DMSO as solvent, and caustic alcohol (1.1eq), is heated to 65 DEG C, reaction 8h, cooling mistakeFilter. Except desolventizing. By the material obtaining crystallization in ethanol, obtain 199.9 grams of compound VIII.
6:500ml round-bottomed flask, magnetic stirs, and upper step is made to compound VIII and be dissolved in 300 milliliters of propyl ether solvents, adds2 times of amounts to two fluorophenyl copper lithium reagents, at about 0 DEG C reaction 4h, reaction finishes rear filtration, then except desolventizing, obtains164.5 grams of compound IX.
7:500ml there-necked flask, magnetic stirs, and upper step synthetic compound IX is dissolved in ethanolic solution, adds 10%Pd/C,Then system is carried out nitrogen replacement, passes into 65 DEG C of reaction 8h of hydrogen, after reaction finishes. Filter, except desolventizing. Obtain chemical combinationThing crude product, through ethyl alcohol recrystallization, obtains 129.6 grams of compound X. Measure purity > 99% through HPLC (internal standard method).
Claims (10)
1. a preparation method for optical purity Aprepitant bulk drug intermediate, is characterized in that it comprises the steps: changeCompound II passes through Hell-Volhard-Zelinski reacting generating compound III, and then makes compound IV with chlorination reaction,Compound IV is reduced and is made compound V by Rosenmund, by compound V under acid condition by heating systemObtain compound VI, compound VI obtains hemiacetal compound VI I through cyclization, the bromo-1-[3 of compound VI I and 1R-1-, 5-bis-(trifluoromethyl) phenyl] ethane synthetic compound VIII, compound VI II adopts Corey – House synthetic method and biconjugate fluorinePhenyl copper lithium reacts to obtain Compound I X, has optical activity intermediate compound I finally by hydrogen reducing synthesis material medicine Aprepitant,Its reaction scheme is:
Wherein R is selected from hydrogen, methyl, methoxyl group or halogen.
2. method according to claim 1, is characterized in that reaction reagent used comprises Br in reaction a2With urgeThe phosphorus of change amount or phosphorus tribromide, its reaction temperature is 20～60 DEG C; Reaction dissolvent be selected from acetonitrile, dioxane, isopropyl ether,Oxolane, ethyl acetate or butyl acetate.
3. method according to claim 1, is characterized in that described chlorinating agent is selected from thionyl chloride, three in reaction bPhosphorus chloride or phosphorus pentachloride; Reaction temperature is 80～100 DEG C, and reaction dissolvent is selected from thionyl chloride, toluene, dimethylbenzene or justHexane.
4. method according to claim 1, is characterized in that described chlorinating agent is selected from thionyl chloride in reaction b.
5. method according to claim 1, is characterized in that catalysts is Pd/BaSO in reaction c4, reactionSolvent is toluene or dimethylbenzene, and reaction temperature is 140～160 DEG C.
6. method according to claim 1, is characterized in that in reaction d, compound V is warm altogether with excessive halogen acidsGenerate alcohol, described halogen acids is hydrobromic acid or hydrochloric acid, and its reaction temperature is 70～100 DEG C.
7. method according to claim 1, it is characterized in that reaction e in, compound VI under sour effect through cyclizationObtain hemiacetal compound VI I, described acid is hydrochloric acid or p-methyl benzenesulfonic acid, and reaction temperature is 40～100 DEG C, reaction dissolventFor toluene, dimethylbenzene or cyclohexane.
8. method according to claim 1, is characterized in that in reaction f the bromo-1-[3 of compound VI I and 1R-1-, 5-Two (trifluoromethyl) phenyl] ethane etherificate synthetic compound VIII under alkali condition, the alkali adopting be selected from NaOH,Potassium hydroxide, sodium methoxide or caustic alcohol, reaction temperature is 40～100 DEG C, reaction dissolvent is DMF, DMSO, tetrahydrochysene furanMutter or dioxane.
9. method according to claim 1, is characterized in that reaction temperature is-10～10 DEG C, reacts molten in reaction gAgent is ether, propyl ether, isopropyl ether or dioxane.
10. method according to claim 1, is characterized in that catalysts is Pd/C, reacts molten in reaction hAgent is methyl alcohol or ethanol.
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| CN111004190A (en) * | 2019-11-08 | 2020-04-14 | 广州曼翔医药有限公司 | Preparation method of aprepitant intermediate |
| CN110746371B (en) * | 2019-11-20 | 2022-07-15 | 山东鲁抗医药股份有限公司 | Intermediate for preparing aprepitant and preparation method and application thereof |
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| WO2007044829A2 (en) * | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
| CN103214426A (en) * | 2013-04-12 | 2013-07-24 | 上海开义医药化工有限公司 | Production method of aprepitant morpholine key intermediate body or aprepitant morpholine salt |
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| WO2007044829A2 (en) * | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
| CN103214426A (en) * | 2013-04-12 | 2013-07-24 | 上海开义医药化工有限公司 | Production method of aprepitant morpholine key intermediate body or aprepitant morpholine salt |
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