CN105085370B - (S)-1-halo-2-[2-(1,3-dioxo-isoindol)yl]ethyl chloroformate and preparation method thereof - Google Patents

Abstract

The invention discloses a compound of formula V (S)-1-halo-2-[2-(1,3-dioxoisoindol)yl]ethyl chloroformate and a preparation method thereof, wherein X represents halogen. The compound is used to prepare rivaroxaban key intermediate (S)-2-{[2-oxygen-3-(4-(3-oxymorpholine)phenyl)oxazolidin-5-yl]methyl } The intermediate of isoindole-1,3-dione and/or rivaroxaban is obtained for the first time in the present invention. Its preparation method is safe and convenient, and the yield can be as high as about 85%, and the obtained product has high purity, which can be as high as More than 97%.

Description

(S)-1-Halo-2-[2-(1,3-dioxoisoindol)yl]ethyl chloroformate and its Preparation

technical field

The invention belongs to the technical field of chemical synthesis, and specifically relates to a new key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)) for synthesizing rivaroxaban Phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione and/or intermediate (S)-1-halo-2-[2-(1 , 3-dioxoisoindol) base] ethyl chloroformate and a preparation method thereof.

Background technique

Thrombosis, which is the formation of localized blood clots. Among them, arterial thrombosis can lead to myocardial infarction, stroke, acute coronary syndrome and peripheral arterial disease. Arterial and venous thrombosis is the leading cause of cardiovascular disease morbidity and death, and it is also one of the leading causes of death in cancer patients. The traditional anticoagulant drugs heparin and warfarin are routine methods for the treatment and prevention of arterial and venous thrombosis. Large-scale clinical trials and clinical applications have established their status as traditional anticoagulant drugs. However, heparin is administered parenterally, and the patient's compliance is poor, so it is not suitable for long-term use.

Rivaroxaban chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide, its chemical structure is as follows:

(S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione is prepared The key intermediate of rivaroxaban, its structural formula is as follows:

Rivaroxaban is a highly effective FXa inhibitor jointly developed by Bayer and Johnson & Johnson. It was first launched in Canada in 2008. It is the world's first FXa factor inhibitor that can be directly taken orally. It is used to prevent and treat blood clots .

At this stage (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione And the synthetic route of rivaroxaban mainly contains the following kinds:

1. Patent WO2001047919 discloses that rivaroxaban key intermediate 4-{4-[(5S)- 5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one is further prepared into rivaroxaban, and the reaction scheme is as follows:

In this scheme, reagents such as poisonous DMAP are used, and column chromatography is required for separation, and the yield is low.

2. Patent WO2005068456 discloses that rivaroxaban key intermediate 4-{4-[(5S)- 5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride, and then the method for further preparing rivaroxaban, its reaction The route is as follows:

This route avoids the use of toxic reagents such as DMAP, and does not need to be separated by a chromatographic column, but the yield is still very low, only 65.9%.

3. WO2009023233 discloses the use of morpholine and p-fluoronitro as starting materials to obtain 4-morpholine nitrobenzene through condensation, and then oxidize with potassium permanganate to obtain 4-morpholinone-nitrobenzene, and then Catalytic hydrogenation and other steps finally prepare rivaroxaban with 2-chloro-thiophene-5-formyl chloride under the catalysis of pyridine, and the reaction route is as follows:

The synthesis route of the above-mentioned method is relatively long, and the overall yield is on the low side, resulting in high cost.

4. US2007157456 and WO2006055951 reported that ethyl chloroacetate and aminoethanol were used as raw materials to synthesize rivaroxaban through the following route:

The above-mentioned method requires chiral separation, has high cost and low yield, and is not suitable for large-scale production.

Five, CN1852902A has reported that with aniline as raw material, 2-phenylaminoethanol is obtained by reflux reaction with chloroethanol in aqueous solution, and 4-phenyl-3-morpholinone is obtained by reacting with chloroacetyl chloride under alkaline conditions. The steps of nitration, catalytic hydrogenation, and epoxide ring-opening are used to prepare the racemate of rivaroxaban, which is then resolved by a chiral column to obtain rivaroxaban. The reaction scheme is as follows:

The above-mentioned route also has the problem of requiring a chromatographic column for chiral separation, resulting in increased costs.

Contents of the invention

In order to solve the various problems in the above-mentioned prior art, the present invention provides a new method for preparing (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) phenyl) Intermediates of oxazolidin-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban and methods for their preparation.

Specifically, the preparation of (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}iso The intermediate of indole-1,3-dione and/or rivaroxaban has the structure shown in formula V, and its chemical name is (S)-1-halo-2-[2-(1,3- Dioxindol) ethyl] ethyl chloroformate:

Wherein, X is halogen, preferably chlorine or bromine, more preferably chlorine.

The present invention also provides a preparation method of the above-mentioned compound of formula V: the starting material (S)-2-(2-halo-2-hydroxyethyl)isoindole-1,3-dione (formula IV) and Triphosgene is carried out acylation reaction to obtain intermediate (S)-1-halo-2-[2-(1,3-dioxoisoindol) base] ethyl chloroformate (formula V):

In the above reaction formula, X is halogen, preferably chlorine or bromine, more preferably chlorine.

Preferably, the reaction time of the above reaction is 1-12 hours; more preferably 2-7 hours. If the reaction time is too long, impurities will increase; if the time is too short, the reaction will be incomplete.

Preferably, the reaction temperature of the above reaction is -10°C to 50°C; more preferably 0°C to 30°C. If the reaction temperature is too high, impurities will increase, and there is a possibility of partial racemization; if the temperature is too low, the reaction time will be prolonged.

Preferably, the above reaction is carried out under the catalysis of an organic base, and the organic base used is pyridine, triethylamine or N,N-dimethylaniline, more preferably pyridine. Wherein, the molar ratio of the compound of formula IV to the organic base is 1:(1.0-6.0), more preferably 1:(1.5-2.5). If the molar ratio is too high, the reaction will not be complete; if it is too low, the raw material cost will be increased.

Preferably, the molar ratio of the compound of formula IV to triphosgene in the above reaction is 1:(0.5-3.0), more preferably 1:(1.0-1.2). If the molar ratio is too high, the reaction will not be complete; if it is too low, the raw material cost will be increased.

Preferably, the reaction solvent for the above reaction is tetrahydrofuran, 1,4-dioxane, toluene and/or ethyl acetate, more preferably tetrahydrofuran.

The above compound IV can be prepared by referring to the method in the literature Yu, Jianping; Zhang, Changfu; Synthetic Communications, 2008, vol.38, #12P.1875-1887.

The compound of formula V of the present invention can be used for preparing (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) base] ethyl} halide salt (formula VI ):

Wherein, X represents halogen, preferably chlorine or bromine; M is magnesium or zinc.

(S)-1-halo-2-[2-(1,3-dioxoisoindol) base]ethyl chloroformate (formula V) is triggered by an initiator, in an aprotic solvent, with The free radical reaction of the metal produces (S)-{1-(chloroformate)-2-[2-(1,3-dioxoisoindol)yl]ethyl}halide salt (Formula VI).

And formula VI compound and 4-(4-carbaaminophenyl)-3-morpholinone (formula III) can prepare rivaroxaban key intermediate (S)-2-{[2- Oxygen-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione (formula VII):

Further, the compound of formula VII is deprotected to obtain 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]benzene Base} morpholin-3-one hydrochloride (formula VIII); formula VIII reacts with 2-chloroformyl-5-chlorothiophene to obtain rivaroxaban (formula I).

Above-mentioned formula III compound 4-(4-carbaaminophenyl)-3-morpholinone is prepared by reacting 4-(4-aminophenyl)-3-morpholinone (formula II compound) with formaldehyde:

In summary, (S)-1-dione (S)-1- Halo-2-[2-(1,3-dioxoisoindol) base]ethyl chloroformate (formula V), which can be used as a key intermediate for the synthesis of rivaroxaban (S)-2-{ Intermediate of [2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban body.

Compared with the prior art, the present invention has the following advantages and positive effects:

1. The present invention firstly provides a new rivaroxaban intermediate 4-(4-carbaaminophenyl)-3-morpholinone (formula III) and a preparation method thereof.

The intermediate 4-(4-aminophenyl)-3-morpholinone (formula III) is obtained for the first time in the present invention, and its preparation method refers to the use of 4-(4-aminophenyl)-3-morpholine Ketones are used as raw materials to react with formaldehyde under suitable experimental conditions to obtain the compound represented by formula III. The above preparation method is easy to operate, the obtained intermediate III has good purity, and the yield is as high as about 90%.

2. The present invention secondly provides another new rivaroxaban intermediate (S)-1-halo-2-[2-(1,3-dioxoisoindol) base] ethyl chloroformic acid Esters (Formula V) and methods for their preparation.

The intermediate (S)-1-halo-2-[2-(1,3-dioxoisoindol) base]ethyl chloroformate (Formula V) is obtained for the first time in the present invention, and its preparation method refers to Using (S)-2-(2-halo-2-hydroxyethyl)isoindole-1,3-dione (formula IV) as the starting material to carry out acylation reaction with triphosgene under organic base catalysis, The compound represented by formula V is prepared. The above-mentioned preparation method is safe and simple, and the obtained intermediate V has high purity, and the reaction yield of this step can be as high as about 85%, especially the purity of the preferred technical solution of the present invention can be as high as 97%.

3. The present invention also provides a new intermediate (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) group]ethyl} Halide salts (formula VI) and methods for their preparation.

The intermediate (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) group]ethyl} halide salt (formula VI) is obtained for the first time in the present invention , its preparation method is (S)-1-halo-2-[2-(1,3-dioxoisoindol) base] ethyl chloroformate (formula V) initiated by an initiator, in the aprotic (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) base] ethyl} halide salt ( Formula VI). The above-mentioned preparation method is mature and reliable, and can realize large-scale industrial production.

4. The present invention also provides a synthetic (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) phenyl) oxazolidin-5-yl] methyl} isoind A new approach to indole-1,3-diones.

The method consists of intermediate 4-(4-carbaaminophenyl)-3-morpholinone (formula III) and intermediate (S)-{1-(chloroformate group)-2-[2- (1,3-dioxoisoindol) base] ethyl } halide salt (formula VI) to prepare (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) by cyclization reaction )phenyl)oxazolidin-5-yl]methyl}isoindole-1,3-dione (formula VII). (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) phenyl) oxazolidin-5-yl] methyl}isoindole-1 prepared by the method , 3-diketone (formula VII) has good purity and high yield, especially the yield of the preferred technical solution of the present invention can be as high as about 90%, and the purity can be as high as 98% or more. Moreover, the method of the invention is easy to operate, and the raw materials are easy to obtain, so it is suitable for industrialized large-scale production.

5. The present invention finally provides a new method for synthesizing rivaroxaban

Based on the method of the present invention, the purity of the finally prepared rivaroxaban can be as high as 99.0%, especially the preferred technical solution of the present invention, its chemical purity and optical purity are all above 99.5%; and the method of the present invention is easy to operate , the raw material is easy to get, and is suitable for industrialized large-scale production.

6. The preparation process of the present invention uses the new intermediates III and VI to carry out a one-step ring closure reaction to prepare the key intermediate (S)-2-{[2-oxo-3-(4-(3-oxo) of rivaroxaban phenoline) phenyl) oxazolidin-5-yl] methyl} isoindole-1,3-dione (formula VII), and then through deprotection and acylation to obtain rivaroxaban, the process avoids the use of Seriously polluted DMAP effectively reduces the discharge pressure. In addition, the product obtained in the invention does not need to use a chromatographic column for chiral separation, which improves the yield and reduces the production cost.

7. The preparation of rivaroxaban in the present invention has mild conditions, simple process, low cost and high yield, and is suitable for industrial production.

detailed description

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

In the following examples, the instrument used for HPLC detection can be, for example, ShimadzuLC-20A produced by Shimadzu Corporation. The calculation method of chemical purity and optical purity adopts the area normalization method; the calculation formula of molar yield is: (moles of product/moles of main raw material)×100%. The instrument used for mass spectrometry detection can be the API5500 type liquid chromatography mass spectrometry instrument of American ABSCIES Company. The instrument used for NMR detection can be AM400MHZ nuclear magnetic resonance instrument of BRUKER company.

The reagents used in the present invention are all commercially available.

In a specific embodiment of the invention, (S)- 1-Halo-2-[2-(1,3-dioxoisoindol)yl]ethyl chloroformate (Formula V), then initiated by an initiator, in an aprotic solvent, reacts with a metal Free radical reaction produces (S)-{1-(chloroformate)-2-[2-(1,3-dioxoisoindol)yl]ethyl}halide salt (Formula VI). In addition, 4-(4-methaminophenyl)-3-morpholinone (formula III) is prepared from raw material 4-(4-aminophenyl)-3-morpholinone (formula II). A ring-closing reaction occurs between intermediate III and intermediate VI to prepare the key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazole) of rivaroxaban Alk-5-yl]methyl}isoindole-1,3-dione (Formula VII). Finally, the intermediate VII was deprotected and acylated to obtain rivaroxaban. Its reaction process is as follows:

Embodiment 1: Preparation of 4-(4-carbaaminophenyl)-3-morpholinone (formula III):

Add 192.2g (1.0mol) of 4-(4-aminophenyl)-3-morpholinone (formula II) into the reaction flask, stir and dissolve with 700ml dichloromethane, cool to 25°C, add dropwise 45.0g (1.5 mol) formaldehyde, the temperature of the dropping process is controlled at 20°C to 30°C, the dropwise addition is completed, and the reaction is stirred for 5 hours, controlled by TLC (dichloromethane:methanol:triethylamine=20:1:0.5, volume ratio), the reaction Completely, stop stirring, distill dichloromethane under reduced pressure (-0.1MPa～-0.09MPa), add 600ml ethyl acetate to raise temperature and reflux, cool down naturally under stirring, drop to 10°C to 15°C for 8 hours, filter, reduce After drying under pressure, 185.4 g of off-white intermediate III was obtained, with a molar yield of 90.8% and an HPLC purity of 98.8%.

The detection data of the title product obtained by NMR and MS analysis are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ=50.56 (s, 2H), 7.65 (d, 2H), 6.59 (d, 2H), 4.30 ( s, 2H), 3.51 (q, 4H); ¹³ C NMR (75MHz, CDCl ₃ ): δ=164.5, 162.7, 143.6, 136.3, 131.0, 131.0, 122.5, 122.4, 73.0, 65.9, 54.8ppm; HR-MS (ESI ^{): C11H12N2O2 Molecular weight: 204.2, [M+H]+} _{measured : 205.6 .}

Embodiment 2: Preparation of 4-(4-carbaaminophenyl)-3-morpholinone (formula III):

Add 192.2g (1.0mol) of 4-(4-aminophenyl)-3-morpholinone into the reaction flask, stir and dissolve with 700ml of dichloromethane, cool to 25°C, add 75.0g (2.5mol) of formaldehyde dropwise, The temperature of the dropping process was controlled at 20°C to 30°C. After the dropwise addition was completed, the reaction was stirred for 2 hours. TLC was controlled (dichloromethane:methanol:triethylamine=20:1:0.5, volume ratio), the reaction was complete, and the stirring was stopped. , dichloromethane was evaporated under reduced pressure (-0.1MPa～-0.09MPa), 600ml of ethyl acetate was added to raise the temperature and reflux, the temperature was naturally lowered under stirring, and the crystallization was carried out at 10°C to 15°C for 8 hours, filtered, and dried under reduced pressure. 188.1 g of off-white intermediate III was obtained, the molar yield was 92.1%, and the HPLC purity was 98.3%.

The detection data of the title product obtained by NMR and MS analysis are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ=50.56 (s, 2H), 7.65 (d, 2H), 6.59 (d, 2H), 4.30 ( s, 2H), 3.51 (q, 4H); ¹³ C NMR (75MHz, CDCl ₃ ): δ=164.5, 162.7, 143.6, 136.3, 131.0, 131.0, 122.5, 122.4, 73.0, 65.9, 54.8ppm; HR-MS (ESI ^{): C11H12N2O2 Molecular weight: 204.2, [M+H]+} _{measured : 205.1 .}

Example 3: Preparation of (S)-1-chloro-2-[2-(1,3-dioxoisoindol)yl]ethyl chloroformate (Formula V):

In this embodiment, X in the above is Cl.

Add 270.7g (1.2mol) of (S)-2-(2-chloro-2-hydroxyethyl)isoindole-1,3-dione (formula IV), 158.2g (2.0mol) Pyridine and 1000ml tetrahydrofuran, stir evenly, cool down to 10°C to 20°C, add 267.1g (0.9mol) triphosgene, keep stirring and react for 2 hours, then add 89.0g (0.3mol) triphosgene, continue stirring for 3 hours, Under the control of HPLC, the raw materials basically disappeared, and the reaction was stopped. The tetrahydrofuran was evaporated under reduced pressure (-0.1MPa～-0.09MPa), and 800ml of dichloromethane was added to the residual oil and stirred to dissolve. Wash with purified water in sequence until the pH value of the aqueous phase is about 6, and distill the organic layer obtained by liquid separation under reduced pressure (-0.1MPa～-0.09MPa) to remove dichloromethane to obtain 94.6g of a yellowish oily intermediate V, The molar yield is 85.2%, and the HPLC purity is 97.8%.

The detection data of the title product obtained by NMR and MS analysis are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.89 (q, 2H), 7.83 (q, 2H), 6.55 (t, 1H), 4.15 ( q, 2H); ¹³ C NMR (75MHz, CDCl ₃ ): δ=168.2, 168.2, 150.5, 132.3, 132.3, 131.8, 131.8, 123.5, 123.5, 89.7, 50.1ppm; HR-MS (ESI): C ₁₁ H ₇ Cl ₂ NO ₄ molecular weight: 288.1, [M+H] ⁺ measured: 289.0.

Example 4: Preparation of (S)-1-chloro-2-[2-(1,3-dioxoisoindol) base]ethyl chloroformate (Formula V):

Add 270.7g (1.2mol) of (S)-2-(2-halo-2-hydroxyethyl)isoindole-1,3-dione, 197.8g (2.5mol) of pyridine and 1000ml of tetrahydrofuran into the reaction flask , Stir evenly, cool down to 10°C to 20°C, add 267.1g (0.9mol) triphosgene, heat and stir for 2 hours, then add 89.0g (0.3mol) triphosgene, continue stirring for 3 hours, HPLC control, The raw material basically disappears, stop the reaction, distill THF under reduced pressure (-0.1MPa～-0.09MPa), add 800ml dichloromethane to the residual oil and stir to dissolve, then use 1% glacial acetic acid and purified water from 0°C to 5°C in sequence Wash until the pH of the aqueous phase is about 6, distill the organic layer obtained by liquid separation under reduced pressure (-0.1MPa～-0.09MPa) to remove dichloromethane, and obtain 298.4g of a yellowish oily intermediate V with a molar yield of 86.3 %, HPLC purity 97.2%.

The detection data of the title product obtained by NMR and MS analysis are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.89 (q, 2H), 7.83 (q, 2H), 6.55 (t, 1H), 4.15 ( q, 2H); ¹³ C NMR (75MHz, CDCl ₃ ): δ=168.2, 168.2, 150.5, 132.3, 132.3, 131.8, 131.8, 123.5, 123.5, 89.7, 50.1ppm; HR-MS (ESI): C ₁₁ H _{7 Cl2NO4} Molecular weight: _288.1 , [M+H] ⁺ measured: 289.3.

Example 5: Preparation of (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) base]ethyl}magnesium chloride (formula VI):

In this embodiment, X in the above formula is Cl, and M is Mg.

Add 300ml THF, 23.1g (0.95mol) of pretreated magnesium chips, and 3.55g (0.014mol) of iodine into the reaction flask, stir evenly under the protection of nitrogen, control the temperature at 10°C to 20°C, and slowly add the dissolved 224.7g (0.78mol) (S)-1-halo-2-[2-(1,3-dioxoisoindol) base] ethyl chloroformate (formula V), after dropping, keep warm for 5 hours to prepare (S)-{1-(chloroformate)-2-[2-(1,3-dioxoisoindol) base]ethyl}magnesium chloride (Formula VI), for use.

Magnesium shavings pretreatment method: washing with 10% hydrochloric acid for 30 minutes, rapid suction filtration, rinsing with acetone, vacuum drying, and directly putting it into the reaction for use.

Embodiment 6: Preparation of (S)-{1-(chloroformate group)-2-[2-(1,3-dioxoisoindol) base]ethyl}magnesium chloride (formula VI):

Add 300ml THF, 23.1g (0.95mol) of pretreated magnesium chips, and 3.55g (0.014mol) of iodine into the reaction flask, stir evenly under the protection of nitrogen, control the temperature at 30°C to 40°C, and slowly add the dissolved 224.7g (0.78mol) (S)-1-halo-2-[2-(1,3-dioxoisoindol) base] ethyl chloroformate (formula V), after dropping, keep warm for 5 hours to prepare (S)-{1-(chloroformate)-2-[2-(1,3-dioxoisoindol) base]ethyl}magnesium chloride (Formula VI), for use.

Magnesium shavings pretreatment method: washing with 10% hydrochloric acid for 30 minutes, rapid suction filtration, rinsing with acetone, vacuum drying, and directly putting it into the reaction for use.

Example 7: (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3- Preparation of diketones (formula VII):

In this embodiment, X in the above formula is Cl, and M is Mg.

Add 159.3g (0.78mol) of 4-(4-carbaaminophenyl)-3-morpholinone (formula III) and 300ml of tetrahydrofuran prepared in Example 1 into the reaction flask, stir well, and control the temperature at 0°C to Add the intermediate VI prepared in Example 5 dropwise at 5°C. After the dropwise addition, keep it warm for 7 hours, take the clear liquid in the reaction solution for HPLC control, intermediate III reacts completely, filter, and filter the cake with 200ml of tetrahydrofuran and 200ml of 95% ethanol was washed successively, and dried under reduced pressure to obtain 300.4 g of an off-white solid (compound of formula VII), with a molar yield of 91.4% and an HPLC purity of 98.9%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₂₂ H ₁₉ N ₃ O ₆ molecular weight: 421.4, [M+H] ⁺ measured value: 422.5.

Example 8: (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl]methyl}isoindole-1,3- Preparation of diketones (formula VII):

Add 159.3g (0.78mol) of 4-(4-carbaaminophenyl)-3-morpholinone (formula III) and 300ml tetrahydrofuran prepared in Example 2 into the reaction flask, stir well, and control the temperature at -10°C Add the intermediate VI prepared in Example 6 dropwise at 0°C. After the dropwise addition, keep it warm for 4 hours, take the clear liquid in the reaction solution for HPLC control, intermediate III reacts completely, filter, and filter the cake with 200ml tetrahydrofuran and 200ml 95% ethanol was washed sequentially, and dried under reduced pressure to obtain 293.5 g of an off-white solid (compound of formula VII), with a molar yield of 89.3% and an HPLC purity of 98.4%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₂₂ H ₁₉ N ₃ O ₆ molecular weight: 421.4, [M+H] ⁺ measured value: 422.1.

Example 9: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride Preparation of salt (formula VIII):

Add 210.7g (0.5mol) (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) phenyl) oxazolidin-5-yl] prepared in Example 7 to the reaction flask Methyl}isoindole-1,3-dione (formula VII), 1500ml of absolute ethanol, 500ml of 30% methylamine aqueous solution, stirred evenly, heated up to 40°C to 60°C for 8 hours, controlled in TLC (two Chloromethane:methanol=20:1, volume ratio) reacted completely, adjusted the pH value to between 1-2 with 10% hydrochloric acid, precipitated a large amount of white solid, cooled to about 15°C, stirred for 2 hours, filtered, and 300ml of filter cake was used After washing with absolute ethanol and drying under reduced pressure, 147.0 g of an off-white solid (compound of formula VIII) was obtained, with a molar yield of 89.7% and an HPLC purity of 98.7%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₁₄ H ₁₈ ClN ₃ O ₄ molecular weight: 327.8, [M+H] ⁺ measured value: 328.3.

Example 10: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride Preparation of salt (formula VIII):

Add 210.7g (0.5mol) (S)-2-{[2-oxo-3-(4-(3-oxomorpholine) phenyl) oxazolidin-5-yl] prepared in Example 8 to the reaction flask Methyl}isoindole-1,3-dione (formula VII), 1500ml of absolute ethanol, 500ml of 30% methylamine aqueous solution, stir evenly, heat up to 40°C to 60°C for 3 hours, control in TLC (two Chloromethane:methanol=20:1, volume ratio) reacted completely, adjusted the pH value to between 1-2 with 10% hydrochloric acid, precipitated a large amount of white solid, cooled to about 15°C, stirred for 2 hours, filtered, and 300ml of filter cake was used After washing with absolute ethanol and drying under reduced pressure, 144.4 g of an off-white solid (compound of formula VIII) was obtained, with a molar yield of 88.1% and an HPLC purity of 98.6%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₁₄ H ₁₈ ClN ₃ O ₄ molecular weight: 327.8, [M+H] ⁺ measured value: 328.8.

Example 11: Preparation of lidoxaban:

Add 131.1g (0.4mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] prepared in Example 9 to the reaction flask Phenyl}morpholin-3-one hydrochloride (formula VIII), 500ml of N,N-dimethylformamide, 50.6g (0.5mol) triethylamine, 86.9g (0.48mol) 2-chloroformyl -5-Chlorothiophene, stirred evenly, reacted at 30°C to 40°C for 5 hours, TLC control (dichloromethane:methanol=20:1, volume ratio) reacted completely, added 500ml of purified water, a large amount of solids precipitated, stirred After 2 hours, filter, wash the filter cake with 200ml of purified water, and dry under reduced pressure to obtain rivaroxaban product 149.1g, with a molar yield of 85.5%, HPLC chemical purity of 99.7%, and optical purity of 100.0%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₁₉ H ₁₈ ClN ₃ O ₅ S molecular weight: 435.9, [M+H] ⁺ measured value: 436.6.

Example 12: Preparation of lidoxaban:

Add 131.1g (0.4mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] prepared in Example 10 to the reaction flask Phenyl}morpholin-3-one hydrochloride (formula VIII), 500ml of N,N-dimethylformamide, 50.6g (0.5mol) triethylamine, 101.4g (0.56mol) 2-chloroformyl -5-Chlorothiophene, stirred evenly, reacted at 30°C to 40°C for 5 hours, TLC control (dichloromethane:methanol=20:1, volume ratio) reacted completely, added 500ml of purified water, a large amount of solids precipitated, stirred After 2 hours, filter, wash the filter cake with 200ml of purified water, and dry under reduced pressure to obtain rivaroxaban product 150.1g, molar yield 86.1%, HPLC chemical purity 99.8%, optical purity 100.0%.

The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI): C ₁₉ H ₁₈ ClN ₃ O ₅ S molecular weight: 435.9, [M+H] ⁺ measured value: 436.5.

Claims (15)

1. compound (S) -1- halo -2- [2- (1,3- dioxy iso-indoles) base] ethyl chloroformate, with the knot shown in Formula V Structure：

Wherein, X is halogen.

2. compound (S) -1- halo -2- [2- (1,3- dioxy iso-indoles) base] ethylchloroformate according to claim 1 Ester, it is characterised in that X is chlorine or bromine.

3. the preparation method of (S) -1- halo -2- [2- (1,3- dioxy iso-indoles) base] ethyl chloroformate, by shown in formula IV (S) -2- (2- halo -2- hydroxyethyls) iso-indoles -1,3- diketone and triphosgene carry out acylation reaction be obtained (S) shown in Formula V - 1- halo -2- [2- (1,3- dioxy iso-indoles) base] ethyl chloroformate：

Wherein, X is halogen.

4. preparation method according to claim 3, it is characterised in that X is chlorine or bromine.

5. preparation method according to claim 3, it is characterised in that the reaction time is 1～12 hour.

6. preparation method according to claim 5, it is characterised in that the reaction time is 2～7 hours.

7. preparation method according to claim 3, it is characterised in that reaction temperature is -10 DEG C～50 DEG C.

8. preparation method according to claim 7, it is characterised in that reaction temperature is 0 DEG C～30 DEG C.

9. preparation method according to claim 3, it is characterised in that the acylation reaction is carried out under organic base catalytic , organic base used is pyridine, triethylamine or DMA.

10. preparation method according to claim 9, it is characterised in that the mol ratio of the formula IV compound and organic base For 1:1.0～6.0.

11. preparation methods according to claim 10, it is characterised in that the mol ratio of the formula IV compound and organic base For 1:1.5～2.5.

12. preparation methods according to claim 3, it is characterised in that the mol ratio of the formula IV compound and triphosgene For 1:0.5～3.0.

13. preparation methods according to claim 12, it is characterised in that the mol ratio of the formula IV compound and triphosgene For 1:1.0～1.2.

14. preparation methods according to claim 3, it is characterised in that the reaction dissolvent of the acylation reaction is tetrahydrochysene furan Mutter, 1,4- dioxane, toluene and/or ethyl acetate.

Compound (S) -1- halo -2- [2- (1,3- dioxy iso-indoles) base] ethylchloroformate described in 15. claims 1 or 2 Ester is preparing razaxaban key intermediate (S) -2- { [2- oxygen -3- (4- (3- oxygen morpholines) phenyl) oxazolidine -5- bases] methyl } Application in iso-indoles -1,3- diketone and/or razaxaban.