CN102311400A - Method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones - Google Patents

Abstract

The invention discloses a preparation method of 5-levo-aminomethyl-3-aryl-2-oxazolidinone, which comprises the steps of utilizing levo-epoxypropylphthalimide to react with aryl aniline to prepare an addition product, and then carrying out cyclization reaction and aminolysis reaction to prepare the 5-levo-aminomethyl-3-aryl-2-oxazolidinone. The invention has the advantages of high total yield and low cost, and all the intermediates and the product synthesis methods have the characteristics of convenient recovery and purification, and the purity of the final product is at least more than 99.9%.

Description

Method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones

technical field

The invention relates to a method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones (5(S)-Aminomethyl-3-Aryl-2-Oxazolidinone).

Background technique

5-L-aminomethyl-3-aryl-2-oxazolidinones (5(S)-Aminomethyl-3-Aryl-2-Oxazolidinones) (A) derivatives have been successfully used in anti-infective drugs and cardiology Vascular drugs and anticoagulants, especially the marketed anti-infective drug Linezolid and the oral coagulant rivaroxaban.

About the synthetic method of this type of 5-left-handed-aminomethyl-3-aryl-2-oxazolidinones (A)

Mainly convert 5-hydroxymethyl substituted oxazolidinones (5-hydroxymethyl substituted oxazolidinones) into 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) such as WO2007/064818; WO95/07271; US5688792 (1997); J.Med.chem.39,673 (1996), etc., all utilize n-BuLi to react at -78°C, which is not suitable for industrial production, while WO01/47919A1 reacts There are also some shortcomings in operation and cost considerations that need to be improved.

In addition, the 5-left-handed-aminomethyl-3-aryl-2-oxazolidinones (A) of high optical purity will depend on the left-handed epoxypropyl phthalimide ((S)- The preparation method of glycidylphthalimide) (I),

Therefore high optical purity L-epoxypropyl phthalimide (I) becomes an important key to prepare high optical purity 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) step. The preparation method of the compound L-glycidyl phthalimide (I) has been disclosed in EP1403267A1 in 2004. This method is to use potassium phthalimide (potassium phthalimide)/(PhCH ₂ )Me ₃ NCl/racemic epichlorohydrin (racemic epichlorohydrin) or right-handed epichlorohydrin ((R)-epichlorohydrin) or left-handed epichlorohydrin ((S)-epichlorohydrin) can be prepared by reacting in a solvent Racemic L-glycidyl phthalimide (I) or L-glycidyl phthalimide (I) with (R) or (S) optical activity, the disadvantage of this method The reason is that the reaction time is too long (at least more than one day) and the temperature should not be too high, otherwise the optical purity will be affected. Based on the analysis of the above documents, we have developed a more competitive method for preparing L-glycidyl phthalimide (I).

High optical purity L-glycidyl phthalimide (I) can be condensed with aromatic amine groups to obtain the intermediate (II) of the D-form ((R)-form),

Finally, 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) can be prepared by aminolysis reaction of hydrazine acetate (H ₂ NNH ₂ ) or methylamine (CH ₃ NH ₂ ), The relevant literature on the synthesis method of this dextrorotatory intermediate (II) has been disclosed in Figure (I) and Figure (J) of US6107519 (2000); WO2006/008754A1; US2006/0247435A1; WO2005/099353A2 and WO01/47919A1. Based on the above analysis, the present invention can develop a process for producing 5-L-aminomethyl-3-aryl-2-oxazolidinone (A) derivatives in line with the industry.

Contents of the invention

The present invention proposes a method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones (5(S)-Aminomethyl-3-Aryl-2-Oxazolidinones) (A) with high optical purity , the recipe is as follows:

Using L-epichlorohydrin ((S)-Epichlorohydrin) as the starting material, the high optical purity compound L-epoxypropyl o- Phthalimide ((S)-Glycidylphthalimide) (I), and then perform condensation reaction with aromatic amino group to obtain dextrorotary intermediate (II), and use alkyl carbonate substance (R ₂ CO ₃ ) for ring closure The reaction can obtain the L-type intermediate (III), and finally add 40% methylamine (CH ₃ NH ₂ ) for amination reaction to obtain the expected product 5-L-aminomethyl-3-aryl-2-oxazolidine Ketones (A), the obtained 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) with high optical purity can be used to obtain the pharmaceutical product Linezolid (Linezoid ) or Rivaroxaban (Rivaroxaban), etc.

Regarding the preparation method of L-epoxypropyl phthalimide, its optical purity will affect the optical purity of 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) , and then affect the quality of pharmaceutical products, so the preparation of L-epoxypropyl phthalimide (I) is particularly important, the present invention consists of L-epoxychlorohydrin ((S) Epichlorohydrin) and phthalimide Potassium phthalimide reacts in different phase transfer catalysts (see table), especially in benzyltrimethylammonium chloride (BTAC), benzyltriphenylphosphine chloride (BTPC) and benzyl Triphenylphosphine bromide (BTPB) has good optical purity, the solvent used is C1~C4 alcohols or reacts without solvent, the temperature range is 0~100°C, especially at 0~50°C, the lower the temperature , the longer the reaction time.

Preparation of (S)-Glycidylphthalimide

Phase transfer catalyst Reaction solvent Response time (hours) Optical purity (%ee) BTACBTACBTABTBABBTPCBTPB Isopropanol------------Isopropanol Isopropanol 4～710～545～306～151～41～4 97～98.588～9591～9785～9197～98.397～98.3

Reaction temperature: 25～30℃ Catalyst dosage: 0.05～0.025eq Reagent: L-epoxychlorohydrin & potassium phthalimide Phase transfer catalyst Benzyltrimethylammonium chloride: Benzyltrimethylammonium chloride, BTAC Benzyltriphenylphosphonium bromide: Benzyltriphenylphosphoniumbromide, BTPB High performance liquid chromatography (HPLC) analysis conditions Column: CHIRALPAK AD; 4.6ID*250mm Mobile phase: N-hexane: Isopropanol: Trifluoroacetic acid (TFA) = 80: 20: 0.1UV: 258nm flow rate (Flow rate): 1mL/min

Compound L-glycidyl phthalimide (I) and aromatic amine (ArNH ₂ ) carry out condensation reaction, the solvent used is C1～C6 alcohols or C1～C6 alcohols: water (H ₂ O)= 1～10:10～1 The reaction temperature is 0～100℃, the most suitable temperature is 25～80℃, the aromatic amine is a benzene ring with a halogen and a substituted amino group, and the substituted amino group is 4-morpholine 4-morpholinyl, 4-hydroxyacetyl piperazinyl (4-Hydroxyacetyl piperazinyl), 3-oxo-4-morpholinyl (3-oxo-4-morpholinyl), 5 or 6 ring heterocyclyl, etc. .

The dextrorotatory intermediate (II) obtained after ring opening can be reacted in the reaction of alkyl carbonate substance (R ₂ CO ₃ )/base or alkyl carbonate substance/base/phase transfer catalyst without solvent to obtain the ring-closing product L-type oxazolidinone (Oxazolidinone) compound (III), wherein the cyclizing agent is an alkyl carbonate substance (R ₂ CO ₃ ), R is a methyl group, an ethyl group; the base is an organic base or an inorganic weak base, and the organic base Triethylamine (Et ₃ N), pyridine (Py) or dimethylaminopropyl (DMAP), etc., inorganic bases are potassium carbonate (K ₂ CO ₃ ), potassium bicarbonate (KHCO ₃ ), sodium carbonate ( Na ₂ CO ₃ ) or sodium bicarbonate (NaHCO ₃ ), etc. In addition, the added phase transfer catalyst will increase the cyclization rate and shorten the reaction time. The added phase transfer catalyst is benzyltrimethylammonium chloride ( BTAC), benzyltrimethylammonium bromide (BTAB), tetrabutylammonium tribromide (TBAB), benzyltriphenylphosphine chloride (BTPC), benzyltriphenylphosphine bromide (BTPB) or Polyethylene glycol monomethyl ether (PEGM), the molecular weight (M) is 200-600 etc., the temperature range for the ring closure reaction is 80-200° C., and the reaction time is 1-50 hours.

The compound L-type intermediate (III) can obtain 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) of the primary amine after the aminolysis reaction, and the aminolysis reaction condition is The reaction temperature of hydrazine acetate (H ₂ NNH ₂ ) or 40% methylamine (CH ₃ NH ₂ ) in alcohols (C1-C4) is 25-100° C., and the reaction time is 1-24 hours. 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) can be further treated with hydrochloric acid or sulfuric acid to obtain 5-L-aminomethyl-3-aryl-2-oxazole Alkanones (A) hydrochloride or 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) sulfate, the yield of aminolysis is about 70-90%.

5-L-aminomethyl-3-aryl-2-oxazolidinones (A), 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) hydrochloride Or 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) sulfates are acylated by adding alkali and acid chlorides in an organic solvent, which can be refined to obtain raw materials for pharmaceutical products. Used acid chlorides include acetic anhydride ((CH ₃ CO) ₂ O), heterocyclic acid chlorides, etc.; used organic solvents are tetrahydrofuran (THF), ethyl acetate, acetonitrile, dichloromethane, used alkali It is triethylamine (Et ₃ N), pyridine or dimethylaminopropyl (DMAP), etc., the reaction temperature is 0-100°C, and the reaction time is 1-10 hours.

In summary, the improved synthetic method of 5-L-aminomethyl-3-aryl-2-oxazolidinones of the present invention has the advantages of high total yield and low cost, and all intermediates and products The synthesis method has the characteristics of easy recovery and purification, and the purity of the final product is at least 99.9%. From the above characteristics, the commercialization has the advantage of commercial mass production.

Detailed ways

Example 1:

The preparation method of L-glycidylphthalimide ((S)-glycidylphthalimide) (I):

Weigh potassium phthalimide (Potassium phthalimide) (8.01g, 43.25mmol) and place it in a double-neck flask, add (S)-Epichlorohydrin (10ml, 127.5mmol) and tetrabutyl Ammonium bromide (1.2g, 3.727mmol) (suspended as pale yellow solid) was reacted at 30°C for 5.5 hours. After the reaction, add 80ml of water and 80ml of ethyl acetate, extract, separate layers, extract the organic layer with 320ml of saturated brine, dry with anhydrous magnesium sulfate (MgSO ₄ ), filter, and concentrate the filtrate to dryness. After 16 hours of oil pumping and drying, 7.3 g of solid L-glycidyl phthalimide (I) was obtained. The optical purity was 87% ee.

¹ H-NMR (deuterated chloroform, 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 conditions of L-epoxypropyl phthalimide:

Column (Column): CHIRALPAK AD; 4.6ID*250mm

Mobile phase: n-Hexane (n-Hexane): Isopropanol (IPA): Trifluoroacetic acid (TFA) = 80:20:0.1

Flow rate: 1ml/min

U.V.: 258nm

Pressure: 193psi

Residence time (min) Area (%)

12.26 93.5-left type

15.10 6.50-right type

Example 2:

The preparation method of L-glycidyl phthalimide (I): embodiment is the same as Example 1, only benzyltrimethylammonium chloride is replaced with tetrabutylammonium bromide to obtain 7.5g solid L-phthalimide Oxypropylphthalimide (I). The optical purity is 98% ee.

Example 3:

The preparation method of L-glycidyl phthalimide (I): the embodiment is the same as in Example 1, only benzyltrimethylammonium chloride is replaced with tetrabutylammonium bromide, and the reaction solvent is Virahol simultaneously 7.7 g of solid L-glycidylphthalimide (I) were obtained. The optical purity is 98.3%ee.

Example 4:

The preparation method of L-glycidyl phthalimide (I): the embodiment is the same as in Example 1, only benzyltrimethylammonium bromide is replaced with tetrabutylammonium bromide to obtain 7.3g solid L-phthalimide Oxypropylphthalimide (I). The optical purity is 93% ee.

Example 5:

The preparation method of L-glycidyl phthalimide (I): the embodiment is the same as in Example 3, only benzyltriphenylphosphine chloride or benzyltriphenylphosphine bromide is substituted for tetrabutyl bromide Ammonium can obtain 7.2-7.5g of solid L-epoxypropyl phthalimide (I). The optical purity is 98-98.3%ee.

Embodiment 6:

N-[3-phthalimide-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholine) aniline (N-[3-phthalimido-2-(R)-hydroxypropyl The preparation method of ]-3-fluoro-4-(morpholinyl)aniline)[dextrorotary type intermediate (II)]

Take L-epoxypropyl phthalimide (I) (8.55g, 42.12mmol) and 3-fluoro-4-(morpholine) aniline (3-fluoro-morpholinyl aniline) (7.1g, 36.22mmol) Place in a double-necked bottle, add 71ml of isopropanol and 71ml of water, and react at 70°C for 6 hours. Remove from temperature, stir at room temperature for 1 hour, filter, wash the solid with 20 ml of water, filter, and dry the solid in an oven at 70°C for 18 hours to obtain 10.9 g of the dextrorotatory intermediate as a solid.

¹ H-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-Hydroxy-3-((4-(3-oxomorpholin-4-yl)-phenyl)amino]-1H-isoindole-1,3(2hydrogen)- Diketone (2-[[2R]-2-hydroxy-3-((4-(3-oxomorpholin-4-y1)-phenyl)amino)propyl]-1H-isoindole-1,3(2H)-dione) [D-type intermediate (II)] preparation method

Get 4-(4-aminophenyl) morpholin-3-one (4-(4-aminophenyl)morpholin-3-one) (1.43g, 7.45mmol) and L-epoxypropyl phthalimide ( I) (1.7g, 8.37mmol) in 17mL isopropanol and 17mL water, reflux at 60°C for 22 hours, remove from temperature, stir at room temperature for 6 hours, filter, dry the solid in an oven at 70°C for 24 hours, then dissolve the solid in 10mL water Wash, filter, and dry the solid in an oven at 70°C for 24 hours to obtain 2.1 g of the dextrorotatory intermediate as a solid.

¹ H-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:

L-N-[[3-[3-fluoro-4-4-(morpholinyl)phenyl]-2 oxo-5-oxazolidinyl]methyl]phthalimide ((S)-N- Preparation method of [[3-[3-fluoro-4-(4-morpholiny)lphenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide)[L-type intermediate (III)]

Get the dextrorotatory intermediate (II) (Example 6) (10.4g, 26.07mmol) and place it in a reaction flask and add potassium carbonate (K2CO3) (1.04g, 7.52mmol), suspend in 25ml of diethylcarbonate (Diethylcarbonate), Reflux at 143°C for 9-12 hours. Remove from temperature, add 200ml of dichloromethane (CH ₂ Cl ₂ ), 70ml of water and 70ml of saturated saline for extraction. After separation, the organic layer was concentrated to dryness and pumped for 16 hours with an oil-free pump to obtain 7.57g of white solid L-type intermediates.

¹ H-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:

Levo-nitro-[[3-[3-fluoro-4-(4-morpholine)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide ((S) -N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide)[Levorotatory intermediate (III)]

The implementation mode is the same as that in Example 8, an additional catalyst amount of benzyltrimethylammonium chloride or tetrabutylammonium bromide or benzyltrimethylammonium bromide or benzyltriphenylphosphine chloride or benzyltriphenyl Phosphorus bromide or polyethylene glycol 200-600 (PEG 200-600) can obtain 6.8-7.8g solid levorotatory intermediate (III).

Example 10:

2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)-phenyl-1,3-oxazolidin-5-yl]methyl]-1 hydrogen -Isoindole-1,3(2H)-dione (2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin -5-y1]methyl]-1H-isoindole-1,3(2H)-dione)[L-type intermediate (III)] preparation method

The dextrorotatory intermediate (II) (Example 7) (4.3g, 10.9mmol) and K2CO3 (0.3g, 2.2mmol) were suspended in 65mL of diethyl carbonate (Diethyl carbonate), and refluxed at 145°C for 36 hours. Remove from temperature, add 100ml of dichloromethane (CH2Cl2), 100ml of water and 100ml of saturated saline for extraction, after layering, the organic layer is concentrated to dryness, and pumped for 16 hours with an oil-free pump to obtain 3.9g of a white solid of the left-handed type intermediate body (III).

¹ H-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)

Example 11.:

2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]-1- Isoindole-1,3(2hydrogen)-dione (2-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-y1)phenyl]-1,3-oxazolidin- Preparation method of 5-y1]methyl]-1H-isoindole-1,3(2H)-dione)[Left-rotary type intermediate (III)]

The implementation mode is the same as that in Example 10. Catalyst benzyl trimethyl ammonium chloride or tetrabutyl ammonium bromide or benzyl trimethyl ammonium bromide or benzyl triphenylphosphine chloride or benzyl triphenyl bromide can be added additionally Phosphate or polyethylene glycol 200-600, the reaction time is 8-24 hours, 3.0-4.0g solid levorotatory intermediate (III) can be obtained.

Example 12:

(S)-N-[[3-[3-fluoro-4-4-(morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amines

((S)-N-[[3-[3-fluoro-4-4-(morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine)[5-L-aminomethyl-3-aryl The preparation method of base-2-oxazolidinones (A)]

Take the left-handed intermediate (III) (Example 8) (7.3g, 17.12mmol) and suspend it in 73ml of ethanol (EtOH), then add 38ml of 40% methylamine (CH ₃ NH ₂ ) and reflux at 85°C for 4.5 hours. Remove from temperature, add 73ml of water and 73ml of CH ₂ Cl ₂ for extraction, after the layers were separated, the aqueous layer was extracted with 730ml of dichloromethane (CH ₂ Cl ₂ ), after the layers were separated, the combined organic layers were concentrated to dryness, and the mixture was extracted with an oil-free pump After pumping for 16 hours, 3.9 g of solid 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) were obtained.

¹ H-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)

Example 13:

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-dione (4-[4- [(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-y1]phenyl]morpholin-3-one sulfate)[5-Levo-aminomethyl-3-aryl-2 - the preparation method of oxazolidinones (A) sulfate]

Take the left-handed intermediate (III) (Example 10) (3.85g, 7.5mmol) and suspend it in 55mL EtOH, then add 5ml 40% Methylamine and react at 60°C for 6 hours. Adjust the pH to 2.7 with concentrated sulfuric acid, stir at room temperature for 1 hour, filter, and dry the solid in an oven at 70°C for 16 hours to obtain 3.07 g of 5-L-aminomethyl-3-aryl-2-oxadiene as a sulfate solid Oxazolidinones (A).

¹ H-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)

Example 14:

4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-dione (4-[4- [(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-y1]phenyl]morpholin-3-one hydrochloride)[5-Levo-aminomethyl-3-aryl- The preparation method of 2-oxazolidinones (A) hydrochloride]

Take the left-handed intermediate (III) (Example 10) (3.85g, 7.5mmol) and suspend it in 55mL EtOH, then add 5ml 40% methylamine and react at 60°C for 6 hours. Adjust the pH to 2.7 with concentrated hydrochloric acid, stir at room temperature for 1 hour, filter, and dry the solid in an oven at 70°C for 16 hours to obtain 2.8 g of 5-L-aminomethyl-3-aryl-2-hydrochloride as a solid Oxazolidinones (A).

¹ H-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)

Example 15:

The preparation method of Linezolid (Linezoid)

Take 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) (about 4.31g, 14.6mmol) and _slowly add acetic anhydride ( _Ac2O ) (3.65g , 32.89mmol) at room temperature for 1 hour. After the reaction, add 73ml of saturated NaHCO ₃ for extraction, after separation, the organic layer is concentrated to dryness, add 47ml of Isopropnal and reflux at 85°C for 30 minutes to completely dissolve, leave the temperature, stir at room temperature for one hour, filter, and dry at 70°C After 16 hours, 40.2 g (69.45%) of the white solid compound linezolid was obtained.

¹ H-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)

Example 16:

The preparation method of Rivaroxaban (Rivaroxaban)

Take the compound 5-chlorothiophene-2-carboxylic acid (5-chlorothiophene-2-carboxylic acid) (1g, 6.2mmol), suspend in 10mL of toluene (Toluene), slowly add 0.62mL of thionyl dichloride (Thionyl chloride) (1.02g, 8.5mmol), and reacted at 125°C for 1 hour, then lowered to normal temperature and stood still (Solution A). Suspend the sulfate solid 5-L-aminomethyl-3-aryl-2-oxazolidinone (A) (1.0g, 2.5mmol) in 20mL CH ₂ Cl ₂ , add Triethylamine (1.1mL, 7.9mmol), slowly add the above solution A at room temperature, stir for 1.5 hours, filter, wash the solid with 20mL of water, then wash with 10mL of acetone (acetone), filter, and dry the solid in an oven at 70°C for 16 hours , 0.99 g of rivaroxaban was obtained as a white solid.

¹ H-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=4.1 Hz, 2H), 8.96(t, J=5.8Hz, 1H)

Example 17.:

The preparation method of rivaroxaban

The embodiment is the same as in Example 14. The preparation method of rivaroxaban only replaces 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) of the hydrochloride solid with 5 -L-aminomethyl-3-aryl-2-oxazolidinones (A) can give 0.92 g of rivaroxaban as a white solid.

However, the above-mentioned specific implementations are only exemplary, and are for better understanding of this patent by those skilled in the art, and cannot be interpreted as limiting the scope of this patent; as long as any Equivalent changes or modifications all fall within the scope of this patent.

Claims (10)

1. A method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones (A),

It is characterized in that: high optical purity L-epoxypropyl phthalimide (I) can be prepared by reacting with L-epoxychlorohydrin and potassium phthalimide in a phase transfer catalyst

L-epoxypropyl phthalimide (I) and aromatic amino group carry out condensation reaction and can make D-type intermediate (II), The dextrorotatory type intermediate (II) and the alkyl carbonate material carry out the ring closure reaction and can make the left-handed type intermediate (III),

Aminolysis of the L-type intermediate (III) can give 5-L-aminomethyl-3-aryl-2-oxazolidinones (A). 2. The method according to claim 1, characterized in that: the 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) can be further acylated to produce linenaide oxazolidine, rivaroxaban, and iprazolid.

3. method according to claim 1, is characterized in that: the synthetic method of described left-handed epoxy propyl phthalimide (I), wherein said reaction is left-handed epoxy chlorohydrin and phthalic dichlorohydrin Potassium formimide is reacted in a phase transfer catalyst, and the catalyst used is benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, tetrabutylammoniumtribromide, benzyltriphenylphosphine chloride compound or benzyl triphenylphosphine bromide; the solvent used is an alcohol with 1 to 4 carbons or no solvent is used for the reaction, and the temperature range used is 0-100°C. 4. The method according to claim 1, characterized in that: in the synthetic method of the dextrorotary type intermediate (II), wherein the levrotary epoxypropyl phthalimide (I) and aromatic The condensation reaction of amine groups uses alcohols with 1 to 6 carbons or alcohols with 1 to 6 carbons: water = 1-10: 10-1 as solvent; the reaction temperature used is 0-100°C. 5. method according to claim 4, it is characterized in that: in the aromatic amine group of described condensation reaction, described aromatic amine has-halogen and has-substituted amine group on the benzene ring, and this substituted amine group is 4-morpholinyl, 4-glycolylpiperazinyl, 3-oxo-4-morpholinyl or 5- or 6-ring heterocyclyl. 6. method according to claim 1, is characterized in that: in the synthetic method of described left-handed type intermediate (III), wherein said ring closure reaction is right-handed type intermediate (II) in alkyl carbonate material/ Alkali or alkyl carbonate substance/alkali/phase transfer catalyst reacts without solvent, wherein the alkyl carbonate substance used, the alkyl is methyl or ethyl; the alkali used is an organic base or an inorganic base, and the organic base is Triethylamine, pyridine or dimethylaminopropyl, the inorganic base is potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate; the phase transfer catalyst used is benzyltrimethylammonium chloride, benzyltrimethylammonium Methylammonium bromide, tetrabutylammoniumtribromide, benzyltriphenylphosphine chloride, benzyltriphenylphosphine bromide or polyethylene glycol monomethyl ether, molecular weight = 200-600, the temperature used The range is 80-200°C, and the reaction time used is 1-50 hours. 7. The method according to claim 1, characterized in that: in the synthetic method of the 5-L-aminomethyl-3-aryl-2-oxazolidinones (A), wherein the aminolysis The reaction is that the left-handed type intermediate (III) is reacted in hydrazine acetate or 40% methylamine in an alcoholic solvent with 1 to 6 carbons, the temperature used is 25-100 ° C, and the reaction time used is 1-24 Hour. 8. The method according to claim 7, characterized in that: in the aminolysis reaction, wherein the treatment method can utilize extraction or salt precipitation; the solvent used for extraction is ethyl acetate or dichloromethane; the used The salt precipitation method is to add hydrochloric acid or sulfuric acid to make 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) primary amine form its hydrochloride or sulfate and separate. 9. The method according to claim 1, characterized in that: said acylation reaction is said 5-L-aminomethyl-3-aryl-2-oxazolidinones (A) and 5-L- -Aminomethyl-3-aryl-2-oxazolidinones (A) hydrochloride or sulfate carry out acylation reaction in the presence of organic base and organic solvent, the organic base used is triethylamine, arsenic Pyridine or dimethylaminopropyl, the organic solvent used is tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile or acetone, the temperature used is 0-50°C, and the reaction time used is 1-10 hours . 10. The method according to claim 9, characterized in that: wherein the pharmaceutical raw material products obtained through the acylation reaction are linezolid, rivaroxaban and eprazolid, which can be produced through the recrystallization method To obtain high-purity products, the solvents used for recrystallization include alcohols with 1 to 6 carbons, acetone, acetonitrile, ethyl acetate or dimethylformamide.