CN102311400A - Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone - Google Patents

Method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone Download PDF

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CN102311400A
CN102311400A CN2010102125022A CN201010212502A CN102311400A CN 102311400 A CN102311400 A CN 102311400A CN 2010102125022 A CN2010102125022 A CN 2010102125022A CN 201010212502 A CN201010212502 A CN 201010212502A CN 102311400 A CN102311400 A CN 102311400A
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aminomethyl
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施凯翔
林惠英
谢幼容
刘清维
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OMEGA CO Ltd
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XIANGZHEN BIOTECHNOLOGY CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention discloses a method for preparing 5(S)-aminomethyl-3-aryl-2-oxazolidinone. The method comprises the following steps of: reacting (S)-glycidyl phthalimide and aryl aniline to prepare an addition compound; and finally preparing the 5(S)-aminomethyl-3-aryl-2-oxazolidinone through cyclization reaction and aminolysis reaction. The method has the advantages of high total yield and low cost; all intermediates and a product synthesis method have the characteristics of convenience in recovery and purification; and the purity of a final product of the method is at least over 99.9 percent.

Description

Prepare 5-left-handed-method of aminomethyl-3-aryl-2-oxazolidine ketone
Technical field
The present invention relates to a kind of 5-of preparation left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (method of 5 (S)-Aminomethyl-3-Aryl-2-Oxazolidinone).
Background technology
5-is left-handed-and (5 (S)-Aminomethyl-3-Aryl-2-Oxazolidinones) (A) verivate has been successfully applied to anti-infectives and cardiovascular agent anti-coagulant aspect to aminomethyl-3-aryl-2-oxazolidine ketone, and particularly gone on the market anti-infective linwzolid (Linezoid) and coagulant profit for oral use are cut down husky class (Rivaroxaban) etc.
Relevant this type of 5-is left-handed-compound method of aminomethyl-3-aryl-2-oxazolidine ketone (A)
Figure BDA0000022828650000011
Mainly with 5-methylol substituted oxazoline alkane ketone (5-hydroxymethyl substitutedoxazolidinone s) convert to 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) is like WO2007/064818; WO95/07271; US5688792 (1997); J.Med.chem.39,673 (1996) etc., all utilize n-BuLi under-78 ℃, to react, be not suitable for being applied to industry member production, and WO01/47919A1 on the operation and cost also consider some shortcoming and must improve.
In addition the preparation high-optical-purity 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) will depend on left-handed epoxypropyl phthalic imidine (preparation method of (S)-glycidylphthalimide) (I),
The important committed step of therefore the left-handed epoxypropyl phthalic imidine of high-optical-purity (I) becomes preparation high-optical-purity 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A).The preparation method of the left-handed epoxypropyl phthalic imidine of allied compound (I) has been disclosed in EP1403267A1 in 2004, and this method then is to utilize potassium phthalimide (potassium phthalimide)/(PhCH 2) Me 3Racemic epoxy chloropropane of NCl/ (racemic epichlorohydrin) or dextrorotation epoxy chloropropane ((R)-epichlorohydrin) or left-handed epoxy chloropropane ((S)-epichlorohydrin) in solvent, react can make the left-handed epoxypropyl phthalic imidine of paratartarics (I) or tool (R) or (S) light revolve active left-handed epoxypropyl phthalic imidine (I); It is not too high that this method shortcoming is that reaction times oversize (needing more than one day at least) and temperature do not suit, otherwise will have influence on optical purity.Based on the analysis of above document, we have developed the method that has more the competitive left-handed epoxypropyl phthalic imidine of preparation (I).
The left-handed epoxypropyl phthalic imidine (I) of high-optical-purity and the condensation reaction of aromatic amine base row can get the dextrorotation pattern (midbody of (R)-form) (II),
Figure BDA0000022828650000022
At last via hydrazine acetate (H 2NNH 2) or methylamine (CH 3NH 2) carry out aminolysis reaction can make 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A), the compound method pertinent literature of the midbody (II) of relevant this type of dextrorotation pattern has been disclosed in US6107519 (2000) figure (I) and figure (J); WO2006/008754A1; US2006/0247435A1; WO2005/099353A2 and WO01/47919A1. be based on above analysis, the present invention can develop one meet industry member produce 5-left-handed-processing procedure of aminomethyl-3-aryl-2-oxazolidine ketone (A) verivate.
Summary of the invention
The present invention propose a kind of prepare high-optical-purity 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (method of 5 (S)-Aminomethyl-3-Aryl-2-Oxazolidinones) (A), method for making is as follows:
Figure BDA0000022828650000041
((S)-Epichlorohydrin) is starting raw material with left-handed epoxy chloropropane; In the presence of phase-transfer catalyst, can make the left-handed epoxypropyl phthalic imidine of high optical purity compound ((S)-Glycidylphthalimide) (I) by potassium phthalimide (potassium phthalimide); Can get dextrorotation pattern midbody (II) with the condensation reaction of aromatic amine base row then, utilize carbonic acid alkane ester material (R 2CO 3) row cyclization reaction can get left-handed pattern midbody (III), adds 40% methylamine (CH at last 3NH 2) carry out aminolysis reaction can obtain expect product 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A); The 5-of resultant high-optical-purity is left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A), can make pharmaceutical prod linwzolid (Linezoid) or profit is cut down husky class (Rivaroxaban) etc. via acylation reaction.
The preparation method of relevant left-handed epoxypropyl phthalic imidine; The optical purity of its optical purity will have influence on 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A); And then influence the quality of pharmaceutical prod; Therefore the preparation of left-handed epoxypropyl phthalic imidine (I) is even more important; The present invention reacts (seeing table) by left-handed epoxy chloropropane ((S) Epichlorohydrin) with potassium phthalimide (potassium phthalimide) in different phase-transfer catalyst (phase transfercatalyst), especially at benzyl trimethyl ammonium chloride (BTAC), benzyl triphenylphosphine muriate (BTPC) and benzyl tri-phenyl-phosphorus bromide (BTPB) good optical purity is arranged, and employed solvent is C1～C4 alcohols or does not use solvent reaction; TR is at 0～100 ℃; At 0～50 ℃, temperature is lower especially, and the reaction times is longer.
(S)-preparation of Glycidylphthalimide
Phase-transfer catalyst Reaction solvent Reaction times (hour) Optical purity (%ee)
BTAC BTAC BTAB TBAB BTPC BTPB Virahol------------Virahol Virahol 4～7 10～54 5～30 6～15 1～4 1～4 97～98.5 88～95 91～97 85～91 97～98.3 97～98.3
Temperature of reaction: 25～30 ℃ of catalyst levelss: 0.05～0.025eq reaction reagent: left-handed epoxy chloropropane & potassium phthalimide
Phase-transfer catalyst Benzyl trimethyl ammonium chloride: Benzyltrimethylammonium chloride; BTAC benzyltrimethylammonium bromide: Benzyltrimethylammonium bromide; BTAB tetrabutyl tribromide ammonium: Tetrabutylammonium bromide; TBAB benzyl triphenylphosphine muriate: Benzyltriphenylphosphonium chloride, BTPC benzyl tri-phenyl-phosphorus bromide: Benzyltriphenylphosphonium bromide, BTPB
Efficient liquid chromatograph (HPLC) analysis condition Tubing string (Column): CHIRALPAK AD; 4.6ID*250mm mobile phase (Mobile phase): normal hexane (N-hexane): Virahol (Isopropanol): three difluoroacetic acids (TFA)=80: 20: 0.1 UV: 258nm flow velocity (Flow rate): 1mL/min
Left-handed epoxypropyl phthalic imidine of compound (I) and aromatic amine (ArNH 2) carry out condensation reaction, the solvent that uses be C1～C6 alcohols or C1～C6 alcohols: water (H 2O)=1～10: 10～1 temperature of reaction are 0～100 ℃; The most suitable temperature is 25～80 ℃; Aromatic amine is to have on the phenyl ring-halogen and having-substituted amido, and substituted amido is 4-morpholinyl (4-morpholinyl), 4-ethoxyl acyl piperazine base (4-Hydroxyacetyl piperazinyl), 3-oxygen-4-morpholinyl (3-oxo-4-morpholinyl), 5 or 6 annulus heterocyclic radicals etc.
Gained dextrorotation pattern midbody (II) after the open loop is at carbonic acid alkane ester material (R 2CO 3)/alkali or carbonic acid alkane ester material/alkali/phase-transfer catalyst are reflected at and do not contain reaction under the solvent, can get the left-handed pattern oxazolidine of cyclization product ketone (Oxazolidinone) compound (III), and wherein cyclizing agent is carbonic acid alkane ester material (R 2CO 3), R is a methyl, ethyl; Alkali is organic bases or inorganic weak bases, and organic bases is triethylamine (Et 3N), arsenic pyridine (Py) or dimethylamino-propyl (DMAP) etc., mineral alkali is salt of wormwood (K 2CO 3), saleratus (KHCO 3), yellow soda ash (Na 2CO 3) or sodium hydrogencarbonate (NaHCO 3) etc.; Added in addition phase-transfer catalyst can make cyclisation speed increase; Shorten the reaction times; The phase-transfer catalyst that is added is benzyl trimethyl ammonium chloride (BTAC), benzyltrimethylammonium bromide (BTAB), tetrabutyl tribromide ammonium (TBAB), benzyl triphenylphosphine muriate (BTPC), benzyl tri-phenyl-phosphorus bromide (BTPB) or poly glycol monomethyl ether (PEGM); Molecular weight (M) is 200～600etc., and the TR of carrying out the cyclization reaction is 80～200 ℃, and the reaction times is 1～50 hour.
The left-handed pattern midbody of compound (III) via the 5-that can make primary amine behind the aminolysis reaction left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A), the aminolysis reaction condition is with hydrazine acetate (H 2NNH 2) or 40% methylamine (CH 3NH 2) (carrying out temperature of reaction among the C1～C4) is 25～100 ℃, and the reaction times is 1～24 hour at alcohols.5-is left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) can further utilize hydrochloric acid or vitriolization can make 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) hydrochloride or 5-be left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) vitriol, aminolysis productive rate about 70～90%.
5-is left-handed-and aminomethyl-3-aryl-2-oxazolidine ketone (A), 5-be left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) hydrochloride or 5-be left-handed-and aminomethyl-3-aryl-2-oxazolidine ketone (A) vitriol adds alkali and the capable acylation reaction of chloride thing in organic solvent; Can make with extra care the pharmaceutical prod raw material, the employed chloride thing of acylation reaction has diacetyl oxide ((CH 3CO) 2O), heterocycle chloride thing etc.; Employed organic solvent is THF (THF), ETHYLE ACETATE, second eyeball, methylene dichloride, and employed alkali is triethylamine (Et 3N), arsenic pyridine or dimethylamino-propyl (DMAP) etc., temperature of reaction is 0～100 ℃, the reaction times is 1～10 hour.
5-of the present invention in sum is left-handed-compound method of aminomethyl-3-aryl-2-oxazolidine ketone Improvement type; Has high overall yield; Advantage, and all midbodys cheaply and product compound method have the characteristic of being convenient to reclaim with purifying, and its final product purity is more than at least 99.9%; By above-mentioned characteristic sight, this commercialization has the advantage of commercial production.
Embodiment
Embodiment 1:
Left-handed epoxypropyl phthalic imidine (preparation method of (S)-glycidylphthalimide) (I):
Take by weighing potassium phthalimide (Potassium phthalimide) (8.01g; 43.25mmol) place two-neck bottle; Add left-handed epoxy chloropropane ((S)-Epichlorohydrin) (10ml; 127.5mmol) and Tetrabutyl amonium bromide (1.2g, 3.727mmol) (be faint yellow solid suspend) was 30 ℃ of reactions 5.5 hours.Reaction adds 80ml water and 80ml ETHYLE ACETATE after finishing, extraction, and layering, organic layer adds the extraction of 320ml saturated aqueous common salt again, with anhydrous magnesium sulfate (MgSO 4) drying, to filter, filtrating is concentrated into dried, and the gained solid is taken out 16 hours dryings with the oil free type pump, can get the left-handed epoxypropyl phthalic imidine of 7.3g solid (I).Optical purity is 87%ee.
1H-NMR (deuterochloroform, CDCl 3):
2.65(dd，J＝4.8Hz，2.5Hz，1H)，2.78(dd，J＝4.8Hz，2.5Hz，1H)，3.21(m，1H)，3.78(dd，J＝14.4Hz，5.0Hz，1H)，3.93(dd，J＝14.4Hz，5.0Hz，1H)，7.70(m，2H)，7.84(m，2H)
The HPLC analysis condition of left-handed epoxypropyl phthalic imidine:
Tubing string (Column): CHIRALPAK AD; 4.6ID*250mm
Mobile phase (Mobile phase): normal hexane (n-Hexane): Virahol (IPA): trifluoroacetic acid (TFA)=80: 20: 0.1
Flow velocity (Flow rate): 1ml/min
U.V.：258nm
Pressure (Pressure): 193psi
Residence time (min) area (%)
12.26 93.5-levorotation formula
15.10 the right pattern of 6.50-
Embodiment 2:
The preparation method of left-handed epoxypropyl phthalic imidine (I): embodiment only replaces Tetrabutyl amonium bromide with benzyl trimethyl ammonium chloride with embodiment 1 can get the left-handed epoxypropyl phthalic imidine of 7.5g solid (I).Optical purity is 98%ee.
Embodiment 3:
The preparation method of left-handed epoxypropyl phthalic imidine (I): embodiment only replaces Tetrabutyl amonium bromide with benzyl trimethyl ammonium chloride with embodiment 1, and reaction solvent is that Virahol can get the left-handed epoxypropyl phthalic imidine of 7.7g solid (I) simultaneously.Optical purity is 98.3%ee.
Embodiment 4:
The preparation method of left-handed epoxypropyl phthalic imidine (I): embodiment only replaces Tetrabutyl amonium bromide with benzyltrimethylammonium bromide with embodiment 1 can get the left-handed epoxypropyl phthalic imidine of 7.3g solid (I).Optical purity is 93%ee.
Embodiment 5:
The preparation method of left-handed epoxypropyl phthalic imidine (I): embodiment only can get the left-handed epoxypropyl phthalic imidine of 7.2-7.5g solid (I) with benzyl triphenylphosphine muriate or benzyl tri-phenyl-phosphorus bromide replacement Tetrabutyl amonium bromide with embodiment 3.Optical purity is 98-98.3%ee.
Embodiment 6:
The preparation method of N-[3-phthalic imidine-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholine) aniline (N-[3-phthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl) aniline) [dextrorotation pattern midbody (II)]
Get left-handed epoxypropyl phthalic imidine (I) (8.55g; 42.12mmol) and 3-fluoro-4-(morpholine) aniline (3-fluoro-morpholinyl aniline) (7.1g; 36.22mmol) place two-neck bottle, add 71ml Virahol and 71ml water, in 70 ℃ of reactions 6 hours.From temperature, stirred at normal temperatures 1 hour, filter, solid cleans with 20ml water again, filters, and solid can get 10.9g solid dextrorotation pattern midbody in 70 ℃ of baking oven bakings 18 hours.
1H-NMR(CDCl 3)：
2.95(m，4H)，3.11-3.19(m，2H)，3.82(m，4H)，3.88(m，2H)，4.11(m，1H)，6.38(m，2H)，6.83(m，1H)，7.7(m，2H)，7.84(m，2H).
Embodiment 7:
2-[[2R]-2-hydroxyl-3-((4-(3-oxygen morpholine-4-yl)-phenyl) amido]-1H-iso-indoles-1; 3 (2 hydrogen)-diketone (2-[[2R]-2-hydroxy-3-((4-(3-oxomorpholin-4-y1)-phenyl) amino) propyl]-1H-isoindole-1, the preparation method of 3 (2H)-dione) [dextrorotation pattern intermediate (II)]
Get 4-(4-amino-benzene) morpholine-3-ketone (4-(4-aminophenyl) morpholin-3-one) (1.43g, 7.45mmol) and left-handed epoxypropyl phthalic imidine (I) (1.7g is 8.37mmol) in 17mL Virahol and 17mL water; Refluxed 22 hours at 60 ℃,, stirred at normal temperatures 6 hours from temperature; Filter, solid cleans with 10mL water in 70 ℃ of baking oven bakings 24 hours again; Filter, solid can get 2.1g solid dextrorotation pattern midbody in 70 ℃ of baking oven bakings 24 hours.
1H-NMR(DMSO)：
3.3-3.0(m，2H)，3.6(m，4H)，4.1-3.9(m，3H)，4.2(s，2H)，5.2(d，J＝5.3Hz，1H)，5.6(t，J＝5.3Hz，1H)，6.7(d，J＝8.6Hz，2H)，7.0(d，J＝8.6Hz，2H)
Embodiment 8:
The preparation method of left-handed-N-[[3-[3-fluoro-4-4-(morpholinyl) phenyl]-2 oxygen-5-oxazolidinyl] methyl] phthalimide ((S)-N-[[3-[3-fluoro-4-(4-morpholiny) lphenyl]-2-oxo-5-oxazolidinyl] methyl] phthalimide) [left-handed pattern midbody (III)]
(10.4g, (1.04g 7.52mmol), was suspended in 25ml diethyl carbonate (Diethylcarbonate), at 143 ℃ of backflow 9-12 hours 26.07mmol) to place reaction flask to add salt of wormwood (K2CO3) to get dextrorotation pattern midbody (II) (embodiment 6).From temperature, add 200ml methylene dichloride (CH 2Cl 2) and 70ml water and the extraction of 70ml saturated aqueous common salt, after the layering, organic layer is concentrated into dried, takes out 16 hours with the oil free type pump, can get the left-handed pattern midbody of 7.57g white solid.
1H-NMR(CDCl 3)：
3.04(m，4H)，3.84(m，4H)，3.92～4.13(m，4H)，4.95(m，1H)，6.96(m，1H)，7.08(m，1H)，7.41(m，1H)，7.73(m，2H)，7.85(m，2H)
Embodiment 9:
The preparation method of left-handed-nitrogen-[[3-[3-fluoro-4-(4-morpholine) phenyl]-2-oxygen-5-oxazolidinyl] methyl] phthalic imidine ((S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] phthalimide) [left-handed pattern midbody (III)]
Embodiment can extra adding catalytic amount benzyl trimethyl ammonium chloride with embodiment 8 or Tetrabutyl amonium bromide or benzyltrimethylammonium bromide or benzyl triphenylphosphine muriate or benzyl tri-phenyl-phosphorus bromide or Macrogol 200-600 (PEG 200-600) can get the left-handed pattern midbody of 6.8-7.8g solid (III).
Embodiment 10:
2-[[(5S)-2-oxygen-3-[4-(3-oxygen morpholine-4-yl)-phenyl-1; 3-oxazolidine-5-yl] methyl]-1 hydrogen-iso-indoles-1; 3 (2 hydrogen)-diketone (2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-1; 3-oxazolidin-5-y1] methyl]-1H-isoindole-1, the preparation method of 3 (2H)-dione) [left-handed pattern intermediate (III)]
Get dextrorotation pattern midbody (II) (embodiment 7) (4.3g, 10.9mmol) and K2CO3 (0.3g 2.2mmol) is suspended in 65mL diethyl carbonate (Diethyl carbonate), refluxes 36 hours at 145 ℃.From temperature, add the extraction of 100ml methylene dichloride (CH2Cl2) and 100ml water and 100ml saturated aqueous common salt, after the layering, organic layer is concentrated into dried, takes out 16 hours with the oil free type pump, can get the left-handed pattern midbody (III) of 3.9g white solid.
1H-NMR(DMSO)：
3.71(dd，J＝5.4Hz，4.6Hz，2H)，4.04-3.84(m，5H)，4.19(s，2H)，4.22(t，J＝9.1Hz，1H)，5.04-4.87(m，1H)，7.40(t，J＝9.1Hz，2H)，7.53(d，J＝9.1Hz，2H)，7.98-7.8(m，4H)
Embodiment 11.:
2-[[(5S)-2-oxygen-3-[4-(3-oxygen morpholine-4-yl) phenyl]-1; 3-oxazolidine-5-yl] methyl]-1-isoindole-1; 3 (2 hydrogen)-diketone (2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-y1) phenyl]-1; 3-oxazolidin-5-y1] methyl]-1H-isoindole-1, the preparation method of 3 (2H)-dione) [left-handed pattern midbody (III)]
Embodiment can extra adding catalyzer benzyl trimethyl ammonium chloride or Tetrabutyl amonium bromide or benzyltrimethylammonium bromide or benzyl triphenylphosphine muriate or benzyl tri-phenyl-phosphorus bromide or Macrogol 200-600 with embodiment 10; Reaction times is 8-24 hour, can get the left-handed pattern midbody of 3.0-4.0g solid (III).
Embodiment 12:
(S)-N-[[3-[3-fluoro-4-4-(morpholinyl) phenyl]-2-oxygen-5-oxazolidinyl] methyl] amine
The preparation method of ((S)-N-[[3-[3-fluoro-4-4-(morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] amine) [5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A)]
(7.3g 17.12mmol) is suspended in 73ml alcohol (EtOH), adds 38ml 40% methylamine (CH again to get left-handed pattern midbody (III) (embodiment 8) 3NH 2) refluxed 4.5 hours at 85 ℃.From temperature, add 73ml water and 73ml CH 2Cl 2Extraction, after the layering, water layer is again with 730ml methylene dichloride (CH 2Cl 2) extraction, after the layering, merge organic layer and be concentrated into driedly, took out 16 hours with the oil free type pump, can get 3.9g solid 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A).
1H-NMR(CDCl 3)：
2.91-3.09(m，6H)，3.78(m，4H)，3.99(m，2H)，4.63(m，1H)，
6.87(t，J＝9.2Hz，1H)，7.11(dd，J＝8.8Hz，2.0Hz，1H)7.44(dd，J＝14.4Hz，2.8Hz，1H)
Embodiment 13:
4-[4-[(5S)-5-(aminomethyl)-2-oxygen-1; 3-oxazolidine-3-yl] phenyl] preparation method of morpholine-3-diketone (4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-y1] phenyl] morpholin-3-one vitriol) [5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) vitriol]
(3.85g 7.5mmol) is suspended in 55mL EtOH, adds 5ml 40% methylamine (Methylamine) again in 60 ℃ of reactions 6 hours to get left-handed pattern midbody (III) (embodiment 10).Transfer pH to 2.7 with the vitriol oil, stirred at normal temperatures 1 hour, filter, solid is in 70 ℃ of oven dryings 16 hours, can get 3.07g vitriol solid 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A).
1H-NMR(D2O)：
3.46(m，2H)，3.81(t，J＝5.04Hz，2H)，3.97(m，1H)，4.12(t，J＝4.9Hz，2H)，4.39(t，J＝9.5Hz，3H)，5.13(m，1H)，7.40(t，J＝8.6Hz，2H)，7.61(d，J＝8.6Hz，2H)
Embodiment 14:
4-[4-[(5S)-5-(aminomethyl)-2-oxygen-1; 3-oxazolidine-3-yl] phenyl] preparation method of morpholine-3-diketone (4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-y1] phenyl] morpholin-3-one hydrochloride) [5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) hydrochloride]
(3.85g 7.5mmol) is suspended in 55mLEtOH, adds 5ml 40% methylamine again in 60 ℃ of reactions 6 hours to get left-handed pattern midbody (III) (embodiment 10).Transfer pH to 2.7 with concentrated hydrochloric acid, stirred at normal temperatures 1 hour, filter, solid is in 70 ℃ of oven dryings 16 hours, can get 2.8g hydrochloride solid 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A).
1H-NMR(DMSO)：
3.23(m，2H)，3.70(t，J＝6.3Hz，2H)，3.88-3.97(m，3H)，4.20(t，J＝9.1Hz，3H)，4.97(m，1H)，7.40(t，J＝8.7Hz，2H)，7.55(d，J＝8.7Hz，2H)，8.41(s，2H)
Embodiment 15:
The preparation method of linwzolid (Linezoid)
Get 5-left-handed-(about 4.31g is 14.6mmol) at 40ml CH for aminomethyl-3-aryl-2-oxazolidine ketone (A) 2Cl 2In slowly add diacetyl oxide (Ac2O) (3.65g 32.89mmol) under room temperature, reacted 1 hour.After having reacted, add the saturated NaHCO of 73ml 3Extraction, after the layering, organic layer is concentrated into dried; Adding 47ml Isopropnal refluxes in 85 ℃ and made dissolving fully in 30 minutes, from temperature, under normal temperature, stirs one hour; Filter,, can get 40.2g (69.45%) white solid compound linwzolid 70 ℃ of dryings 16 hours.
1H-NMR(CDCl 3)：
1.98(s，3H)，3.01(m，4H)，3.61(m，2H)，3.73(m，1H)，3.83(m，4H)，3.98(t，J＝8.8Hz，1H)，4.74(m，1H)，6.46(brs，1H)，6.89(t，J＝9.2Hz，1H)，7.02(dd，J＝8.8Hz，2.0Hz，1H)，7.38(dd，J＝14.4Hz，2.8Hz，1H)
Embodiment 16:
Profit is cut down the preparation method of husky class (Rivaroxaban)
Get compound 5-diuril-2-carboxylic acid (5-chlorothiophene-2-carboxylic acid) (1g; 6.2mmol); Be suspended in 10mL toluene (Toluene) and slowly add 0.62mL thionyl chloride (Thionyl chloride) (1.02g at 75 ℃; 8.5mmol), reduce to normal temperature in 125 ℃ of reactions after 1 hour again and leave standstill (solution A).Get vitriol solid 5-left-handed-(1.0g 2.5mmol) is suspended in 20mL CH to aminomethyl-3-aryl-2-oxazolidine ketone (A) 2Cl 2, adding triethylamine (Triethylamine) (1.1mL, 7.9mmol), at room temperature; Slowly add above-mentioned solution A, stirred 1.5 hours, filter; Solid is washed with 20mL, adds 10mL acetone (acetone) again and washes, and filters; Solid is in 70 ℃ of baking ovens, and dry 16 hours, the profit that can get the 0.99g white solid was cut down husky class.
1H-NMR(DMSO)：
3.58(m，2H)，3.69(m，2H)，3.84(dd，J＝9.2Hz，6.2Hz，1H)，3.95(m，2H)，4.18(s，2H)，4.19(m，1H)，4.83(m，1H)，7.18(d，J＝4.1Hz，1H)，7.40(d，J＝9.0Hz，2H)，7.55(d，J＝9.0Hz，2H)，7.68(d，J＝4.1Hz，2H)，8.96(t，J＝5.8Hz，1H)
Embodiment 17.:
Profit is cut down the preparation method of husky class
The preparation method that embodiment cuts down husky class with embodiment 14. profits only with hydrochloride solid 5-left-handed-profit of aminomethyl-3-aryl-2-oxazolidine ketone (A) replaces vitriol solid 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) can get 0.92g white solid cuts down husky class.
But above-mentioned embodiment is exemplary, is to be the restriction that this patent is comprised scope in order better to make those skilled in the art can understand this patent, can not to be interpreted as; So long as according to spirit that this patent discloses done anyly be equal to change or modify, all fall into the scope that this patent comprises.

Claims (10)

  1. One kind prepare 5-left-handed-method of aminomethyl-3-aryl-2-oxazolidine ketone (A),
    Figure FDA0000022828640000011
    It is characterized in that: react at phase-transfer catalyst with left-handed epoxy chloropropane and potassium phthalimide, can make the left-handed epoxypropyl phthalic imidine of high-optical-purity (I)
    Figure FDA0000022828640000012
    Left-handed epoxypropyl phthalic imidine (I) carries out condensation reaction with aromatic amino can make dextrorotation pattern midbody (II),
    Dextrorotation pattern midbody (II) carries out the cyclization reaction with carbonic acid alkane ester material can make left-handed pattern midbody (III),
    Figure FDA0000022828640000021
    Left-handed pattern midbody (III) carry out aminolysis reaction can obtain 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A).
  2. 2. method according to claim 1 is characterized in that: and said 5-is left-handed-and aminomethyl-3-aryl-2-oxazolidine ketone (A) goes further that acylation reaction can make linwzolid, profit is cut down Sha Ban and eperezolid.
    Figure FDA0000022828640000022
  3. 3. method according to claim 1; It is characterized in that: the compound method of said left-handed epoxypropyl phthalic imidine (I); Wherein said reaction is that left-handed epoxy chloropropane and potassium phthalimide react in phase-transfer catalyst, and employed catalyzer is benzyl trimethyl ammonium chloride, benzyltrimethylammonium bromide, tetrabutyl tribromide ammonium, benzyl triphenylphosphine muriate or benzyl tri-phenyl-phosphorus bromide; Employed solvent is the alcohol of 1 to 4 carbon or not use solvent reaction, employed TR be 0～100 ℃.
  4. 4. method according to claim 1; It is characterized in that: in the compound method of said dextrorotation pattern midbody (II), wherein said left-handed epoxypropyl phthalic imidine (I) is to use the alcohols of 1 to 6 carbon or the alcohol of 1 to 6 carbon with the condensation reaction of aromatic amino: water=1～10: 10～1 are solvent; The temperature of reaction of using is 0～100 ℃.
  5. 5. method according to claim 4; It is characterized in that: in the aromatic amino of said condensation reaction; Said aromatic amine is to have on the phenyl ring-halogen and having-substituted amido, and this substituted amido is 4-morpholinyl, 4-ethoxyl acyl piperazine base, 3-oxygen-4-morpholinyl or 5 or 6 annulus heterocyclic radicals.
  6. 6. method according to claim 1; It is characterized in that: in the compound method of said left-handed pattern midbody (III); Wherein said cyclization reaction is that dextrorotation pattern midbody (II) is not containing reaction under the solvent at carbonic acid alkane ester material/alkali or carbonic acid alkane ester material/alkali/phase-transfer catalyst; Wherein use carbonic acid alkane ester material, alkyl is methyl or ethyl; Employed alkali is organic bases or mineral alkali, and organic bases is triethylamine, arsenic pyridine or dimethylamino-propyl, and mineral alkali is salt of wormwood, saleratus, yellow soda ash or sodium hydrogencarbonate; Employed phase-transfer catalyst is benzyl trimethyl ammonium chloride, benzyltrimethylammonium bromide, tetrabutyl tribromide ammonium, benzyl triphenylphosphine muriate, benzyl tri-phenyl-phosphorus bromide or poly glycol monomethyl ether; Molecular weight=200～600; Employed TR is 80～200 ℃, and the employed reaction times is 1～50 hour.
  7. 7. method according to claim 1; It is characterized in that: said 5-is left-handed-compound method of aminomethyl-3-aryl-2-oxazolidine ketone (A) in; Wherein said aminolysis reaction is that left-handed pattern midbody (III) reacts in the alcoholic solvent of 1 to 6 carbon at hydrazine acetate or 40% methylamine; Employed temperature is 25～100 ℃, and the employed reaction times is 1～24 hour.
  8. 8. method according to claim 7 is characterized in that: in the said aminolysis reaction, and wherein treatment process extraction capable of using or salt precipitation method; Extracting employed solvent is ETHYLE ACETATE or methylene dichloride; Employed salt precipitation method be add hydrochloric acid or sulfuric acid make 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) primary amine forms its hydrochloride or vitriol and separates.
  9. 9. method according to claim 1; It is characterized in that: said acylation reaction be said 5-left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) and 5-be left-handed-aminomethyl-3-aryl-2-oxazolidine ketone (A) hydrochloride or vitriol carries out acylation reaction in the presence of organic bases and organic solvent; Employed organic bases is triethylamine, arsenic pyridine or dimethylamino-propyl; Employed organic solvent is THF, ETHYLE ACETATE, methylene dichloride, second eyeball or acetone; Employed temperature is 0～50 ℃, and the employed reaction times is 1～10 hour.
  10. 10. method according to claim 9; It is characterized in that: be that linwzolid, profit are cut down Sha Ban and eperezolid wherein via the prepared medical material product of said acylation reaction; Can make highly purified product via recrystallization method, the solvent of the recrystallize that uses has alcohols, acetone, acetonitrile, ETHYLE ACETATE or the N of 1 to 6 carbon.
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