CN107021932A - The method for preparing the 5 left-handed oxazolidinones of 3 aryl of aminomethyl 2 - Google Patents

The method for preparing the 5 left-handed oxazolidinones of 3 aryl of aminomethyl 2 Download PDF

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CN107021932A
CN107021932A CN201610659371.XA CN201610659371A CN107021932A CN 107021932 A CN107021932 A CN 107021932A CN 201610659371 A CN201610659371 A CN 201610659371A CN 107021932 A CN107021932 A CN 107021932A
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handed
reaction
aminomethyl
aryl
oxazolidinones
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施凯翔
林惠英
谢幼容
刘清维
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OMEGA CO Ltd
Zhejiang Haisen Pharmaceutical Co Ltd
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OMEGA CO Ltd
Zhejiang Haisen Pharmaceutical 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

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention discloses a kind of method for preparing the 5 left-handed oxazolidinones of 3 aryl of aminomethyl 2, an addition product can be made using left-handed glycidyl phthalimide and aryl aniline reaction, then by cyclization reaction and aminolysis reaction, the 5 left-handed oxazolidinones of 3 aryl of aminomethyl 2 can be finally made.There is the present invention high gross production rate, inexpensive advantage, and all intermediates and product synthetic method to have the characteristic for being easy to recovery and purifying, its final product purity at least more than 99.9%.

Description

Prepare 5- it is left-handed-methods of aminomethyl -3- aryl -2- oxazolidinones
The present invention be submit on June 29th, 2010 it is entitled " prepare 5- it is left-handed-aminomethyl -3- aryl -2- oxazoles The divisional application of the Chinese patent application 201010212502.2 of the method for alkanone class ".
Technical field
The present invention relates to one kind prepare 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (5 (S)-Aminomethyl- Method 3-Aryl-2-Oxazolidinone).
Background technology
5- is left-handed-aminomethyl -3- aryl -2- oxazolidinones (5 (S)-Aminomethyl-3-Aryl-2- Oxazolidinones in terms of) (A) derivative has been successfully applied to anti-infectives and cardiovascular drugs anticoagulant, particularly Anti-infectious agent linwzolid (Linezoid) and coagulant razaxaban for oral use (Rivaroxaban) etc. are listed.
About such 5- it is left-handed-synthetic methods of aminomethyl -3- aryl -2- oxazolidinones (A)
Mainly with 5- methylol substituted oxazolidine ketones (5-hydroxymethyl substituted Oxazolidinones) be converted into 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) such as WO2007/064818； WO95/07271；US5688792(1997)；J.Med.chem.39,673 (1996) etc., entered using n-BuLi at -78 DEG C Row reaction, is not suitable for being applied to industrial quarters production, and also some lack WO01/47919A1 on operation and on cost viewpoint Point must be improved.
In addition the 5- for preparing high-optical-purity it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) will depend on a left side The preparation method of glycidyl phthalimide ((S)-glycidylphthalimide) (I) is revolved,
Therefore the left-handed glycidyl phthalimide (I) of high-optical-purity turn into prepare high-optical-purity 5- it is left-handed- The important committed step of aminomethyl -3- aryl -2- oxazolidinones (A).There is the left-handed glycidyl phthalyl of related compounds The preparation method of imines (I) has revealed that, in EP1403267A1 in 2004, the method is then to utilize potassium phthalimide (potassium phthalimide)/(PhCH2)Me3Racemic epoxychloropropane (the racemic of NCl/ Epichlorohydrin) or dextrorotation epoxychloropropane ((R)-epichlorohydrin) or left-handed epoxychloropropane ((S)- Epichlorohydrin) the left-handed glycidyl phthalimide (I) of paratartarics or tool can be made in reaction in a solvent (R) or (S) light rotation activity left-handed glycidyl phthalimide (I), this method shortcoming is that the reaction time is oversize (at least Need more than one day) and temperature is not suitable for too high, otherwise will have influence on optical purity.Analysis based on document above, Wo Menyi Develop the more competitive method for preparing left-handed glycidyl phthalimide (I).
The left-handed glycidyl phthalimide (I) of high-optical-purity can obtain dextrorotation with the condensation reaction of aromatic amine base row The intermediate (II) of pattern ((R)-form),
Finally via hydrazine acetate (H2NNH2) or methylamine (CH3NH2) carry out aminolysis reaction can be made 5- it is left-handed-aminomethyl -3- Aryl -2- oxazolidinones (A), about the intermediate (II) of such dextrorotation pattern synthetic method pertinent literature have revealed that in US6107519 (2000) figure (I) and figure (J)；WO2006/008754A1；US2006/0247435A1；WO2005/099353A2 And WO01/47919A1. be based on more than analyze, the present invention can develop one meet industrial quarters production 5- it is left-handed-aminomethyl -3- virtue The processing procedure of base -2- oxazolidinones (A) derivative.
The content of the invention
The present invention propose one kind prepare high-optical-purity 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (5 (S) - Aminomethyl-3-Aryl-2-Oxazolidinones) the method for (A), preparation method is as follows：
With left-handed epoxychloropropane ((S)-Epichlorohydrin) for initiation material, by potassium phthalimide High optical purity compound can be made in (potassium phthalimide) in the presence of a phase transfer catalyst, and (optical purity is 88~98.3%ee) left-handed glycidyl phthalimide ((S)-Glycidylphthalimide) (I), then with virtue Fragrant amido row condensation reaction can obtain dextrorotation pattern intermediate (II), utilize carbonic acid alkyl ester material (R2CO3) row cyclization reaction can obtain left Pattern intermediate (III) is revolved, finally adds 40% methylamine (CH3NH2) carry out aminolysis reaction can obtain desired product 5- it is left-handed-ammonia Methyl -3- aryl -2- oxazolidinones (A), the 5- of resulting high-optical-purity is left-handed-aminomethyl -3- aryl -2- oxazolidones Class (A), medical product linwzolid (Linezoid) or razaxaban (Rivaroxaban) etc. can be made via acylation reaction.
About the preparation method of left-handed glycidyl phthalimide, its optical purity will influence whether 5- it is left-handed- The optical purity of aminomethyl -3- aryl -2- oxazolidinones (A), and then influence the quality of medical product, therefore left-handed epoxy third The preparation of base phthalimide (I) is even more important, and the present invention is by left-handed epoxychloropropane ((S) Epichlorohydrin) From potassium phthalimide (potassium phthalimide) in different phase transfer catalyst (phase transfer Catalyst) in reaction (being shown in Table), especially benzyltrimethylammonium chloride (BTAC), benzyltriphenyl phosphonium phosphine chloride (BTPC) and Benzyltriphenylphosphonium bromide phosphorus (BTPB) has good optical purity, and used solvent is C1~C4 alcohols or anti-without using solvent Should, temperature range is at 0~100 DEG C, and especially at 0~50 DEG C, temperature is lower, and the reaction time is longer.In a preferred embodiment, it is left It is that reagent is also solvent to revolve epoxychloropropane, without using other solvent reactions.In a further preferred embodiment, the catalyst is During the phosphorus-containing compound of benzyltriphenyl phosphonium phosphine chloride or benzyltriphenylphosphonium bromide phosphorus, product optical purity height and reaction time It is short.(S)-Glycidylphthalimide preparation
The left-handed glycidyl phthalimide (I) of compound and aromatic amine (ArNH2) condensation reaction is carried out, used Solvent is C1~C6 alcohols or C1~C6 alcohols：Water (H2O)=1~10：10~1 reaction temperatures are 0~100 DEG C, are best suitable for temperature Spend for 25~80 DEG C, aromatic amine is that substituted amido is 4- morpholinyls (4- with-halogen and with-substituted amido on phenyl ring Morpholinyl), 4- ethoxyl acyl piperazines base (4-Hydroxyacetyl piperazinyl), 3- oxygen -4- morpholinyls (3- Oxo-4-morpholinyl), 5 or 6 Yuans ring heterocyclic radicals etc..
Gained dextrorotation pattern intermediate (II) after open loop, in carbonic acid alkyl ester material (R2CO3)/alkali or carbonic acid alkyl ester material/ Alkali/phase transfer catalyst reaction can obtain the left-handed pattern oxazolidinones of cyclization product without being reacted under solvent (Oxazolidinone) compound (III), wherein cyclizing agent are carbonic acid alkyl ester material (R2CO3), R is methyl, ethyl；Alkali is to have Machine alkali or inorganic weak bases, organic base are triethylamine (Et3N), pyridine (Py) or dimethylamino-propyl (DMAP) etc., inorganic base is carbon Sour potassium (K2CO3), saleratus (KHCO3), sodium carbonate (Na2CO3) or sodium acid carbonate (NaHCO3) etc., added phase transfer in addition Catalyst can make the increase of cyclisation speed, shorten the reaction time, and the phase transfer catalyst added is benzyltrimethylammonium chloride (BTAC), benzyltrimethylammonium bromide (BTAB), tetrabutyl tribromide ammonium (TBAB), benzyltriphenyl phosphonium phosphine chloride (BTPC), Benzyltriphenylphosphonium bromide phosphorus (BTPB) or poly glycol monomethyl ether (PEGM), molecular weight (M) are 200~600etc., carry out cyclization The temperature range of reaction is 80~200 DEG C, and the reaction time is 1~50 hour.In a preferred embodiment, carbonic acid alkyl ester material is Diethyl carbonate.
The left-handed pattern intermediate (III) of compound via the 5- that one-level amine can be made after aminolysis reaction it is left-handed-aminomethyl -3- Aryl -2- oxazolidinones (A), aminolysis reaction condition is with hydrazine acetate (H2NNH2) or 40% methylamine (CH3NH2) in alcohols (C1 ~C4) in carry out reaction temperature be 25~100 DEG C, the reaction time be 1~24 hour.5- is left-handed-and aminomethyl -3- aryl -2- dislikes (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides (A) can further using hydrochloric acid or sulfuric acid treatment can be made 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) hydrochloride or 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) sulfate, aminolysis yield about 70~90%.
5- is left-handed-and aminomethyl -3- aryl -2- oxazolidinones (A), 5- be left-handed-aminomethyl -3- aryl -2- oxazolidones Class (A) hydrochloride or 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) sulfate adds alkali and acyl in organic solvent Chloride row acylation reaction, can be refining to obtain medical product raw material, acyl chlorides compound has acetic anhydride used in acylation reaction ((CH3CO)2O), heterocycle acyl chlorides compound etc.；Used organic solvent is tetrahydrofuran (THF), ethyl acetate, acetonitrile, dichloro The combination of methane or toluene and methane dioxide, used alkali is triethylamine (Et3N), pyridine or dimethylamino-propyl (DMAP) It it is 0~100 DEG C Deng, reaction temperature, the reaction time is 1~10 hour.
In summary 5- of the invention it is left-handed-synthetic methods of aminomethyl -3- aryl -2- oxazolidinones Improvement types, tool There are high gross production rate, inexpensive advantage, and all intermediates and product synthetic method to have to be easy to reclaim the characteristic with purifying, its Final product purity at least more than 99.9%, it is seen by above-mentioned characteristic, and this commercialization has the advantage of commercial production.
Embodiment
Embodiment 1：
The preparation method of left-handed glycidyl phthalimide ((S)-glycidylphthalimide) (I)：
Weigh potassium phthalimide (Potassium phthalimide) (8.01g, 43.25mmol) and be placed in double necks In bottle, left-handed epoxychloropropane ((S)-Epichlorohydrin) (10ml, 127.5mmol) and TBAB are added (1.2g, 3.727mmol) (suspends) in faint yellow solid, is reacted 5.5 hours at 30 DEG C.Reaction terminate after, plus 80ml water and 80ml ethyl acetate, is extracted, and layering, organic layer adds 320ml saturated aqueous common salts to extract again, with anhydrous magnesium sulfate (MgSO4) dry, Filtering, filtrate is concentrated to dryness, gained solid with oil free type pumping 16 hours it is dry it, the left-handed glycidyl of 7.3g solids can be obtained Phthalimide (I).Optical purity is 87%ee.
1H-NMR (deuterochloroform, CDCl3)：
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 conditions of left-handed glycidyl phthalimide：
Tubing string (Column)：CHIRALPAK AD；4.6ID*250mm
Mobile phase (Mobile phase)：N-hexane (n-Hexane)：Isopropanol (IPA)：Trifluoroacetic acid (TFA)=80： 20:0.1
Flow velocity (Flow rate)：1ml/min
U.V.：258nm
Pressure (Pressure)：193psi
Holdup time (min) area (%)
12.26 93.5-levorotation formula
15.10 6.50-right pattern
Embodiment 2：
The preparation method of left-handed glycidyl phthalimide (I)：Embodiment be the same as Example 1 is only by benzyl front three Ammonium chloride substitution TBAB can obtain the left-handed glycidyl phthalimide (I) of 7.5g solids.Optical purity For 98%ee.
Embodiment 3：
The preparation method of left-handed glycidyl phthalimide (I)：Embodiment be the same as Example 1 is only by benzyl front three Ammonium chloride replaces TBAB, and simultaneous reactions solvent is that isopropanol can obtain the adjacent benzene two of left-handed glycidyl of 7.7g solids Carboximide (I).Optical purity is 98.3%ee.
Embodiment 4：
The preparation method of left-handed glycidyl phthalimide (I)：Embodiment be the same as Example 1 is only by benzyl front three Base ammonium bromide substitution TBAB can obtain the left-handed glycidyl phthalimide (I) of 7.3g solids.Optical purity For 93%ee.
Embodiment 5：
The preparation method of left-handed glycidyl phthalimide (I)：Embodiment be the same as Example 3 is only by benzyl triphen The left-handed glycidyl that base phosphine chloride or benzyltriphenylphosphonium bromide phosphorus substitution TBAB can obtain 7.2-7.5g solids is adjacent BIDA (I).Optical purity is 98-98.3%ee.Embodiment 6：
N- [3- phthalimides -2- (R)-hydroxypropyl] -3- fluoro- 4- (morpholine) aniline (N- [3-phthalimido- 2- (R)-hydroxypropyl] -3-fluoro-4- (morpholinyl) aniline) [dextrorotation pattern intermediate (II)] system Preparation Method
Take left-handed glycidyl phthalimide (I) (8.55g, 42.12mmol) and 3- fluoro- 4- (morpholine) aniline (3-fluoro-morpholinyl aniline) (7.1g, 36.22mmol) is placed in two-neck bottle, add 71ml isopropanols and 71ml water, reacts 6 hours in 70 DEG C.From temperature, stir 1 hour at normal temperatures, filtering, solid is cleaned with 20ml water again, filtering, Gu Body dries 18 hours in 70 DEG C of baking ovens, can obtain the dextrorotation pattern intermediate of 10.9g solids.
1H-NMR(CDCl3)：
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- hydroxyls -3- ((4- (3- oxygen morpholine -4- bases)-phenyl) amido] -1H- iso-indoles -1,3 (2 hydrogen)-two Ketone (2- [[2R] -2-hydroxy-3- ((4- (3-oxomorpholin-4-yl)-phenyl) amino) propyl] -1H- Isoindole-1,3 (2H)-dione) [dextrorotation pattern intermediate (II)] preparation method
Take 4- (4- aminobenzenes) morpholine -3- ketone (4- (4-aminophenyl) morpholin-3-one) (1.43g, 7.45mmol) and left-handed glycidyl phthalimide (I) (1.7g, 8.37mmol) is in 17mL isopropanols and 17mL water, Flow back 22 hours, from temperature, stir 6 hours at normal temperatures, filtering, solid dries 24 hours in 70 DEG C of baking ovens at 60 DEG C, then with 10mL Water is cleaned, and filtering, solid dries 24 hours in 70 DEG C of baking ovens, can obtain the dextrorotation pattern intermediate of 2.1g solids.
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：
Left-handed-N- [[3- [3- fluoro- 4-4- (morpholinyl) phenyl]-2-oxygen-5- oxazolidinyls] methyl] phthalimide ((S)- N-[[3-[3-fluoro-4-(4-morpholiny)lphenyl]-2-oxo-5-oxazolidinyl]methyl] Phthalimide) the preparation method of [left-handed pattern intermediate (III)]
Dextrorotation pattern intermediate (II) (embodiment 6) (10.4g, 26.07mmol) is taken to be placed in reaction bulb plus potassium carbonate (K2CO3) (1.04g, 7.52mmol), is suspended in 25ml diethyl carbonates (Diethyl carbonate), and flow back 9- at 143 DEG C 12 hours.From temperature, 200ml dichloromethane (CH is added2Cl2) and 70ml water and the extraction of 70ml saturated aqueous common salts, it is organic after layering Layer is concentrated to dryness, and with oil free type pumping 16 hours, can obtain the left-handed pattern intermediate of 7.57g white solids.
1H-NMR(CDCl3)：
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：
Left-handed-nitrogen-[[3- [the fluoro- 4- of 3- (4- morpholines) phenyl] -2- oxygen -5- oxazolidinyls] methyl] phthalimide ((S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] Phthalimide) the preparation method of [left-handed pattern intermediate (III)]
Embodiment be the same as Example 8 can additionally add catalytic amount benzyltrimethylammonium chloride or TBAB or benzyl Base trimethylammonium bromide or benzyltriphenyl phosphonium phosphine chloride or benzyltriphenylphosphonium bromide phosphorus or the (PEG of polyethylene glycol 200-600 It can 200-600) obtain the left-handed pattern intermediate (III) of 6.8-7.8g solids.
Embodiment 10：
2- [[(5S) -2- oxygen -3- [4- (3- oxygen morpholine -4- bases)-phenyl -1,3- oxazolidine -5- bases] methyl] -1 hydrogen-different Indoles -1,3 (2 hydrogen)-diketone (2- [[(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3- Oxazolidin-5-yl] methyl] -1H-isoindole-1,3 (2H)-dione) and [left-handed pattern intermediate (III)] system Preparation Method
Dextrorotation pattern intermediate (II) (embodiment 7) (4.3g, 10.9mmol) and K2CO3 (0.3g, 2.2mmol) is taken to suspend In 65mL diethyl carbonates (Diethyl carbonate), flowed back 36 hours at 145 DEG C.From temperature, 100ml dichloromethane is added (CH2Cl2) and 100ml water and 100ml saturated aqueous common salts extraction, after layering, organic layer is concentrated to dryness, small with oil free type pumping 16 When, the left-handed pattern intermediate (III) of 3.9g white solids can be obtained.
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- bases) phenyl] -1,3- oxazolidine -5- bases] methyl] different Yin of -1- Diindyl -1,3 (2 hydrogen)-diketone (2- [[(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3- Oxazolidin-5-yl] methyl] -1H-isoindole-1,3 (2H)-dione) and [left-handed pattern intermediate (III)] system Preparation Method
Embodiment be the same as Example 10 can additionally add catalyst benzyltrimethylammonium chloride or TBAB or benzyl Base trimethylammonium bromide or benzyltriphenyl phosphonium phosphine chloride or benzyltriphenylphosphonium bromide phosphorus or polyethylene glycol 200-600, during reaction Between be 8-24 hours, the left-handed pattern intermediate (III) of 3.0-4.0g solids can be obtained.
Embodiment 12：
(S)-N- [[3- [3- fluoro- 4-4- (morpholinyl) phenyl] -2- oxygen -5- oxazolidinyls] methyl] amine ((S)-N- [[3-[3-fluoro-4-4-(morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine)[5- Left-handed-aminomethyl -3- aryl -2- oxazolidinones (A)] preparation method
Left-handed pattern intermediate (III) (embodiment 8) (7.3g, 17.12mmol) is taken to be suspended in 73ml alcohol (EtOH), then Add the methylamine (CH of 38ml 40%3NH2) flowed back 4.5 hours at 85 DEG C.From temperature, plus 73ml water and 73ml CH2Cl2Extraction, layering Afterwards, water layer is again with 730ml dichloromethane (CH2Cl2) extraction, after layering, merge organic layer and be concentrated to dryness, with oil free type pumping 16 Hour, the 5- that can obtain 3.9g solids is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A).
1H-NMR(CDCl3)：
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- bases] phenyl] morpholine -3- diketone (4- [4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl] morpholin-3-one sulfate) The preparation method of [5- left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) sulfate]
Take left-handed pattern intermediate (III) (embodiment 10) (3.85g, 7.5mmol) to be suspended in 55mL EtOH, add The methylamines of 5ml 40% (Methylamine) react 6 hours in 60 DEG C.PH to 2.7 is adjusted with the concentrated sulfuric acid, is stirred 1 hour at normal temperatures, Filtering, solid was in 70 DEG C of oven dryings 16 hours, and the 5- that can obtain 3.07g sulfate solids is left-handed-aminomethyl -3- aryl -2- dislikes (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides (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- bases] phenyl] morpholine -3- diketone (4- [4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl] morpholin-3-one hydrochlorides) The preparation method of [5- left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) hydrochloride] takes left-handed pattern intermediate (III) (embodiment 10) (3.85g, 7.5mmol) is suspended in 55mL EtOH, adds the methylamines of 5ml 40% and is reacted 6 hours in 60 DEG C.With Concentrated hydrochloric acid adjusts pH to 2.7, stirs 1 hour at normal temperatures, filtering, and solid can obtain 2.8g hydrochloric acid in 70 DEG C of oven dryings 16 hours The 5- of salt solid is left-handed-aminomethyl -3- aryl -2- oxazolidinones (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)
Take 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) (about 4.31g, 14.6mmol) are in 40ml CH2Cl2 In be slowly added into acetic anhydride (Ac2O) (3.65g, 32.89mmol) at room temperature, react 1 hour.After having reacted, add 73ml and satisfy And NaHCO3Extraction, after layering, organic layer is concentrated to dryness, and add 47ml Isopropnal makes completely for 30 minutes in 85 DEG C of backflows Dissolving, from temperature, in being stirred one hour under normal temperature, filtering is dried 16 hours at 70 DEG C, can obtain 40.2g (69.45%) white solid Compound linwzolid.
1H-NMR(CDCl3)：
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：
The preparation method of razaxaban (Rivaroxaban)
Take compound 5- diuril -2- carboxylic acids (5-chlorothiophene-2-carboxylic acid) (1g, 6.2mmol), it is suspended in 10mL toluene (Toluene) and 0.62mL thionyl chlorides (Thionyl is slowly added at 75 DEG C Chloride) (1.02g, 8.5mmol), then at 125 DEG C reaction 1 hour after be down to normal temperature stand (solution A).Take sulfate solid 5- is left-handed-and aminomethyl -3- aryl -2- oxazolidinones (A) (1.0g, 2.5mmol) are suspended in 20mL CH2Cl2, add triethyl group Amine (Triethylamine) (1.1mL, 7.9mmol), at room temperature, is slowly added into above-mentioned solution A, stirs 1.5 hours, filtering, Solid is washed with 20mL, then adds 10mL acetone (acetone) to wash, and is filtered, and solid is dried 16 hours, can obtained in 70 DEG C of baking ovens The razaxaban of 0.99g white solids.
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.：
The preparation method of razaxaban
The preparation method of the razaxaban of embodiment be the same as Example 14. only by the 5- of HCl, solid it is left-handed-aminomethyl -3- The 5- of aryl -2- oxazolidinones (A) substituted vitriol salt solid is left-handed-and aminomethyl -3- aryl -2- oxazolidinones (A) can obtain The razaxaban of 0.92g white solids.
But, above-mentioned embodiment is exemplary, is to preferably enable those skilled in the art Understand this patent, it is impossible to be not understood as including this patent the limitation of scope；As long as the institute of spirit according to disclosed in this patent Any equivalent change or modification made, each fall within the scope that this patent includes.

Claims (11)

1. one kind prepare 5- it is left-handed-methods of aminomethyl -3- aryl -2- oxazolidinones (A),
It is characterized in that：Reacted with left-handed epoxychloropropane and potassium phthalimide in phase transfer catalyst, bloom is made The left-handed glycidyl phthalimide (I) of purity is learned, wherein the optical purity is 88~98.3%ee,
By left-handed glycidyl phthalimide (I)
Condensation reaction is carried out with aromatic amino, dextrorotation pattern intermediate (II) is made,
Dextrorotation pattern intermediate (II) and carbonic acid alkyl ester material are subjected to cyclization reaction, left-handed pattern intermediate (III) is made,
By left-handed pattern intermediate (III) carry out aminolysis reaction, obtain 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A)。
2. according to the method described in claim 1, it is characterised in that：The 5- is left-handed-aminomethyl -3- aryl -2- oxazolidones Linwzolid, razaxaban is made in class (A) further row acylation reaction.
3. according to the method described in claim 1, it is characterised in that：The left-handed glycidyl phthalimide (I) Synthetic method, reacts wherein the reaction is left-handed epoxychloropropane with potassium phthalimide in phase transfer catalyst, Used catalyst is benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, tetrabutyl tribromide ammonium, benzyltriphenyl phosphonium phosphine Chloride or benzyltriphenylphosphonium bromide phosphorus；Wherein left-handed epoxychloropropane is that reagent is also solvent, without using other solvent reactions, Used temperature range is 0~100 DEG C.
4. according to the method described in claim 1, it is characterised in that：The catalyst is benzyltriphenyl phosphonium phosphine chloride or benzyl Tri-phenyl-phosphorus bromide, product optical purity is high and the reaction time is short.
5. according to the method described in claim 1, it is characterised in that：In the synthetic method of the dextrorotation pattern intermediate (II), The condensation reaction of wherein described left-handed glycidyl phthalimide (I) and aromatic amino is the alcohol using 1 to 6 carbon： Water=1~10：10~1 be solvent；Used reaction temperature is 0~100 DEG C.
6. method according to claim 5, it is characterised in that：In the aromatic amino of the condensation reaction, the aromatic amine For, with-substituted amido, this substituted amido is 4- morpholinyls or 3- oxygen -4- morpholinyls on phenyl ring.
7. according to the method described in claim 1, it is characterised in that：In the synthetic method of the left-handed pattern intermediate (III), Wherein described cyclization reaction is dextrorotation pattern intermediate (II) in diethyl carbonate/alkali or diethyl carbonate/alkali/phase transfer catalysis (PTC) Agent under solvent without reacting, wherein used alkali is inorganic base, inorganic base is potassium carbonate；Used phase transfer catalyst For benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, tetrabutyl tribromide ammonium, benzyltriphenyl phosphonium phosphine chloride, benzyl three Phenyl phosphonium bromide or poly glycol monomethyl ether, molecular weight=200~600, used temperature range is 80~200 DEG C, is made Reaction time is 1~50 hour.
8. according to the method described in claim 1, it is characterised in that：The 5- is left-handed-aminomethyl -3- aryl -2- oxazolidones In the synthetic method of class (A), wherein the aminolysis reaction be left-handed pattern intermediate (III) in hydrazine acetate or 40% methylamine 1 Reacted into the alcohols solvent of 6 carbon, used temperature is 25~100 DEG C, the used reaction time is 1~24 small When.
9. method according to claim 8, it is characterised in that：In the aminolysis reaction, wherein processing method can utilize extraction Take or salt precipitation method；Solvent used in extraction is ethyl acetate or dichloromethane；Used salt precipitation method is to add hydrochloric acid Or sulfuric acid make 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) one-level amine forms its hydrochloride or sulfate and separates.
10. according to the method described in claim 1, it is characterised in that：The acylation reaction be the 5- it is left-handed-aminomethyl -3- Aryl -2- oxazolidinones (A) and 5- it is left-handed-aminomethyl -3- aryl -2- oxazolidinones (A) hydrochlorides or sulfate having Acylation reaction is carried out in the presence of machine alkali and organic solvent, used organic base is triethylamine, and used organic solvent is two The combination of chloromethanes or toluene and methane dioxide, used temperature is 0~50 DEG C, and the used reaction time is 1~10 small When.
11. method according to claim 10, it is characterised in that：It is wherein former via the medicine obtained by the acylation reaction Material product is linwzolid, razaxaban, and the product that purity is more than 99% is made via recrystallization method, recrystallization is used Solvent has the alcohols of 1 to 6 carbon.
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Cited By (1)

* Cited by examiner, † Cited by third party
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CN110054623A (en) * 2019-05-29 2019-07-26 浙江燎原药业股份有限公司 A kind of preparation method of Rivaroxaban intermediate

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012153155A1 (en) * 2011-05-06 2012-11-15 Egis Gyógyszergyár Nyilvãnosan Müködö Részvény-Társaság Process for the preparation of a rivaroxaban and intermediates formed in said process
CN103382200B (en) * 2012-05-02 2016-04-20 成都国弘医药有限公司 A kind of preparation method of S-Racemic glycidol phthalic imidine
CN103420933B (en) * 2012-05-26 2016-03-02 鲁南制药集团股份有限公司 A kind of preparation method of Linezolid
CN102702186B (en) * 2012-06-20 2014-11-19 安润医药科技（苏州）有限公司 Synthesis method of rivaroxaban
CN102702124B (en) * 2012-07-08 2014-03-12 罗梅 Preparation and synthesis method of chiral oxazoline
CN102786516B (en) * 2012-08-21 2014-10-01 湖南师范大学 Method for synthesizing rivaroxaban
CN104672217A (en) * 2013-11-27 2015-06-03 北京众和民健医药科技有限公司 New linezolid intermediate, preparation method thereof, and linezolid synthesis method
CN103951661B (en) * 2014-04-28 2017-06-23 南京斯贝源医药科技有限公司 A kind of preparation method of razaxaban
CN105130976A (en) * 2015-08-26 2015-12-09 浙江车头制药股份有限公司 Method for synthesizing rivaroxaban intermediate
CN106008490B (en) * 2016-01-11 2019-01-04 南京生命能科技开发有限公司 A kind of new crystal of razaxaban and preparation method thereof
CN107778303B (en) * 2016-08-27 2020-03-24 鲁南制药集团股份有限公司 Refining method of rivaroxaban
CN109232457A (en) * 2018-03-26 2019-01-18 华夏生生药业(北京)有限公司 A kind of preparation method of Linezolid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1434822A (en) * 1999-12-24 2003-08-06 拜尔公司 Substituted oxazolidinones and their use in the field of blood coagulation
EP1403267A1 (en) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Process for preparing glycidylphthalimide

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4461773A (en) * 1982-09-15 1984-07-24 E. I. Dupont De Nemours And Company P-Oxooxazolidinylbenzene compounds as antibacterial agents
DE10129725A1 (en) * 2001-06-20 2003-01-02 Bayer Ag Combination therapy of substituted oxazolidinones
DE102004002044A1 (en) * 2004-01-15 2005-08-04 Bayer Healthcare Ag manufacturing
ATE429423T1 (en) * 2004-07-20 2009-05-15 Symed Labs Ltd NEW INTERMEDIATE PRODUCTS FOR LINEZOLID AND RELATED COMPOUNDS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1434822A (en) * 1999-12-24 2003-08-06 拜尔公司 Substituted oxazolidinones and their use in the field of blood coagulation
EP1403267A1 (en) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Process for preparing glycidylphthalimide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110054623A (en) * 2019-05-29 2019-07-26 浙江燎原药业股份有限公司 A kind of preparation method of Rivaroxaban intermediate

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