WO2013027225A1 - Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one - Google Patents

Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one Download PDF

Info

Publication number
WO2013027225A1
WO2013027225A1 PCT/IN2011/000553 IN2011000553W WO2013027225A1 WO 2013027225 A1 WO2013027225 A1 WO 2013027225A1 IN 2011000553 W IN2011000553 W IN 2011000553W WO 2013027225 A1 WO2013027225 A1 WO 2013027225A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solvents
hours
phenyl
Prior art date
Application number
PCT/IN2011/000553
Other languages
French (fr)
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
Buthukuri Venkat Reddy
Original Assignee
Symed Labs Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Symed Labs Limited filed Critical Symed Labs Limited
Priority to PCT/IN2011/000553 priority Critical patent/WO2013027225A1/en
Publication of WO2013027225A1 publication Critical patent/WO2013027225A1/en

Links

Classifications

    • 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

Definitions

  • the present invention relates to processes for the preparation of 4- ⁇ 4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl] henyl ⁇ nlO holin-3-one of formula (II).
  • the intermediate compound is represented by structural formula II
  • the intermediate compound of formula II is a key intermediate in the synthesis of morpolinone oxazolidine derivatives like rivaroxaban.
  • Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is approved in US and Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe and US.
  • Rivaroxaban is chemically described as 5 -chloro-N-( ⁇ (5 S)-2-oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5-yl ⁇ methyl)- 2-thiophene-carboxamide (herein after referred as rivaroxaban) and is represented by the structural formula I shown below:
  • the present invention relates to processes for the preparation of 4- ⁇ 4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one of formula (II) a key intermediate in the synthesis of rivaroxaban (I).
  • the present invention relates to a process for the preparation of compound 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one of formula (II) or a salt thereof ,
  • L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate
  • R is substituted or unsubstituted benzyl group
  • the present invention provides intermediate compound of formula (III) or a salt thereof.
  • R is substituted or unsubstituted benzyl group
  • R group in compound of formula III is represented by
  • Rl, R2 are independently or same alkyl (C 1-C6) straight chain or branched, Ci-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro-, sulfonyl-, -OH and R3 is alkyl (C1-C6) straight chain or branched- and its use as intermediate in the synthesis of morpholinone oxazolidine derivatives like rivaroxaban.
  • the present invention relates to an alternate process for the preparation of compound 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l ,3-oxazolidin-3- yl]phenyl ⁇ morpholin-3-one of formula (II) or a salt thereof ,
  • Fig. 1 is a schematic representation of the generic process of present invention.
  • Fig. 2 is a schematic representation of the specific processes of present invention.
  • Fig. 3 is a schematic representation of the specific process of one embodiment.
  • the present invention relates to processes for the preparation of 4- ⁇ 4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one of formula (II) a key intermediate in the synthesis of rivaroxaban (I).
  • the present invention provides a process for the preparation of compound 4- ⁇ 4- [5(S)-(aminomethyl)-2-oxo- 1 ,3 -oxazolidin-3 -yljphenyl ⁇ morpholin-3 -one of formula (II) or a salt thereof ,
  • L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate
  • R is substituted or unsubstituted benzyl group.
  • R group in compound of formula III is represented by
  • Rl, R2 are independently or same alkyl (C1-C6) straight chain or branched, Ci- 6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro-, sulfon l-, -OH and R3 is alkyl
  • the suitable benzylamine derivative used in the step (a) is selected from benzylamine,
  • the organic solvents that can be used in step (a) is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), acetonitrile and the like; or mixture thereof.
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • NMP N-methyl pyrrolidone
  • acetonitrile or mixture thereof.
  • dichloromethane or toluene Preferably dichlor
  • reaction step a) is being performed in the absence of solvents and optionally in the presence of solvents.
  • the bases that can be used optionally in step a) is selected from inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, and the like ; organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine and the like; or mixture thereof, preferably sodium carbonate.
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, and the like
  • organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine and the like; or mixture thereof, preferably sodium carbonate.
  • the molar equivalents of compound of benzylamine derivative being used can be from about 0.5 to 7.5 moles to the compound of formula IV taken; preferably 1 to 2 moles is being used.
  • the reaction can be carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably at boiling point of the solvent (s) used.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
  • the leaving group for L in the compound of formula IV can be halogen (CI, Br, I), methanesulfonyl,p-toluenesulfonyl,o-toluenesulfonyl,4-nitrobenzenesulfonyl,4- bromobenzene sulfonyl, trifluromethanesulfonyl and the like; preferably halogen atom; more preferably chlorine atom.
  • the intermediate compound (III) obtained above may be used in next step with or without purification based on the purity of the compound.
  • the compound of formula III obtained is optionally purified by simple recrystallization in a solvent or mixture of solvents or aqueous mixture thereof, usually by using polar protic and polar aprotic solvents like alcohols, or by conversion into acid addition salts.
  • the deprotection reaction step (b) is performed using hydrogenation catalysts such as palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel and the like in the presence of hydrogen gas obtained by any source; preferably palladium on carbon of any percentage or any grade available can be used.
  • the catalyst is used in combination with supports (e.g., solid and liquid supports), which include silica, alumina, silica-alumina, titania, diatomaceous earth, kaolin, activated carbon, carbon, graphite, zeolite, montmorillonite and the like, clays, and alkaline earth metal silicates.
  • supports e.g., solid and liquid supports
  • the catalyst is Raney nickel.
  • the catalyst is Pd/C.
  • the step of hydrogenation is carried out with hydrogen pressure of up to about 200 bar, preferably with hydrogen pressure of about 1 to about 200 bar.
  • the hydrogenation is carried out with hydrogen pressure of about 5 to about 40 bar. In another alternative the hydrogenation is carried out with hydrogen pressure of about 50 to about 100 bar.
  • the solvents that can be used include but are not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), N- methyl pyrrolidone (NMP) and the like; or mixture thereof.
  • acetic acid or methanol or mixture thereof Preferably acetic acid or methanol or mixture thereof.
  • the reaction is performed at a temperature range from about 25 °C to about 100°C or the boiling point of the solvent(s) used, preferably from about 25°C to about 50 °C.
  • the time required for the reaction to complete may also vary widely, depending on several factors, notably the reaction temperature, the nature of the reagent and solvents employed.
  • the reaction is effected under the preferred conditions at time period from about 1 hour to about 24 hours, preferably from about 10 hours to 20 hours.
  • the product formed is recovered by filtration of the reaction suspension on celite to separate the hydrogenation catalyst like Pd/C and the filtrate is distilled to obtain the product.
  • the hydrogenation catalyst recovered is being recycled and reused thus making the process more cost-effective.
  • the intermediate compound (III) and (II) obtained herein above may be used in next step with or without purification based on the purity of the compound. They are optionally purified by simple recrystallization in a solvent or ' mixture of solvents or aqueous mixture thereof, usually by using polar protic and polar aprotic solvents like alcohols, ketones nitriles, esters, hydrocarbons, ethers and the like or by conversion into respective acid addition salts by the conventional methods known.
  • the compound of formula II herein described is a key intermediate in the synthesis of oxazolidine phenyl morpholinone derivatives like rivaroxaban is obtained usually in high yields and purity by the process of present invention and can be used in next step without any additional process steps like purification.
  • These compounds may optionally further purified by recrystallization or making slurry in suitable aprotic polar solvent for example acetone, acetonitrile, ethers and or mixtures thereof or by formation of salts.
  • suitable aprotic polar solvent for example acetone, acetonitrile, ethers and or mixtures thereof or by formation of salts.
  • the present invention provides intermediate compound of formula (III) or a salt thereof.
  • R is substituted or unsubstituted benzyl group
  • R group in compound of formula III is represented by
  • Rl, R2 are independently or same alkyl (C1-C6) straight chain or branched, d-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro ⁇ , sulfonyl-, -OH and R3 is alkyl (C1-C6) straight chain or branched- and its use as intermediate in the synthesis of morpholinone oxazolidine derivatives like rivaroxaban.
  • the present invention relates to an alternate process for the preparation of compound 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl ⁇ morpholi -3-one of formula (II) or a salt thereof ,
  • step a) subjecting the compound of formula Ila to reduction using suitable reducing agents in the presence of a suitable organic solvent to afford the compound of formula II.
  • suitable azide derivative that can be used in step a) is selected from the group consisting of sodium azide, potassium azide and the like; preferably sodium azide.
  • the suitable inorganic salt that can be used is selected from the group consisting of ammonium chloride , sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof.
  • ammonium chloride sodium
  • the suitable solvents that can be used in step (a) is selected from the group consisting of water, acetic acid, alcohols such as methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof.
  • aqueous ethanol or aqueous acetic acid Preferably aqueous ethanol or aqueous acetic acid.
  • reaction step a) can be carried out in the absence of solvents.
  • the molar equivalents of azide derivative being used can be from about 0.5 to 7.5 moles to the compound of formula VIII taken; preferably one mole is being used.
  • the reaction can be carried out at a temperature range from about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably at about 30°C.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 5 hour to about 24 hours, preferably about 12 hours.
  • the suitable bases that can be used in step b) is selected from the inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • pyridine Preferably pyridine.
  • the organic solvents that can be used in step (b) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like
  • esters such as ethyl acetate, isopropyl acetate and the like
  • hydrocarbon solvents such as toluene, xylene and the like
  • aprotic polar solvents such as ⁇ , ⁇ -d
  • the reaction can be carried out at a temperature range from about -10°C to about 40°C, preferably at about 0°C.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour.
  • the suitable bases that can be used in step c) is selected from the inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof.
  • potassium carbonate Preferably potassium carbonate.
  • the organic solvents that can be used in step (c) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like
  • esters such as ethyl acetate, isopropyl acetate and the like
  • hydrocarbon solvents such as toluene, xylene and the like
  • aprotic polar solvents such as N,N-dimethylform
  • the molar equivalents of compound of V being used can be from about 0.5 to 7.5 moles to the compound of formula VI taken; preferably one mole is being used.
  • the reaction can be carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably from about 75 to about 85°C.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 5 hour to about 25 hours, preferably about 15 hours.
  • the reaction step (d) is performed using reducing agents but not limited to hydrogenation catalysts such as palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel and the like in the presence of hydrogen gas obtained by any source; sodium borohydride, triphenyl phosphine, trimethyl silyl iodide and the like; preferably palladium on carbon of any percentage or any grade available can be used.
  • hydrogenation catalysts such as palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel and the like in the presence of hydrogen gas obtained by any source; sodium borohydride, triphenyl phosphine, trimethyl silyl iodide and the like; preferably palladium on carbon of any percentage or any grade available can be used.
  • the solvents that can be used in step d) include but are not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; or mixture thereof.
  • ethyl acetate or acetic acid Preferably ' ethyl acetate or acetic acid.
  • the reaction is performed at a temperature range from about 25°C to about 100°C or the boiling point of the solvent(s) used, preferably from about 45°C to about 50 °C.
  • the time required for the reaction to complete may also vary widely, depending on several factors, notably the reaction temperature, the nature of the reagent and solvents employed.
  • the reaction is effected under the preferred conditions at time period from about 1 hour to about 24 hours, preferably from about 8 hours to 12 hours.
  • the product formed is recovered by filtration of the reaction suspension on celite to separate the hydrogenation catalyst like Pd/C and the filtrate is distilled to obtain the product.
  • the hydrogenation catalyst recovered is being recycled and reused thus making the process more cost-effective.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • reaction mixtures especially in order to isolate desired compounds, follows customary procedures, known to the person, skilled in the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • process steps of present invention can be carried out by one pot synthesis independently.
  • the intermediate compounds of formula II and Ila or a salt thereof obtained by the process of present invention can be further converted to the morpholinone oxazolidine derivatives like rivaroxaban (I) by any process reported in the literature for example US 7,585,860.
  • Example 2 Preparation of 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide azido alcohol (56.5 gms,0.41 mol) obtained in above example, pyridine (56 ml) and methylene chloride (250 ml), were charged into a clean and dry 4 neck R.B.flask. (71.75 gms,0.46 mol) of phenyl chloroformate was added dropwise at about 0°C. The resultant reaction mixture was stirred at about 0°C for about 1 hr. After completion of the reaction, the reaction mixture was quenched by poured into water and dichloromethane mixture.
  • reaction mixture was quenched by pouring into water (500 ml) and extracted with ethyl acetate (3x100ml) .
  • ethyl acetate 3x100ml
  • the combined org. layer was washed with water (2x100 ml).
  • the organic layer was separated and distilled completely to afford the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention provides simple, eco-friendly, cost-effective, reproducible, robust and industrial processes for the preparation of intermediate compound 4-{4-[5(S)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (II). The present invention also provides novel intermediates and their use in the synthesis of morpholinone oxazolidine derivatives.

Description

PROCESSES FOR THE PREPARATION OF 4-{4-[5(S)-(AMINOMETHYL)-2-OXO- l,3-OXAZOLIDIN-3-YL]PHENYL}MORPHOLIN-3-ONE
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to processes for the preparation of 4-{4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl] henyl}nlO holin-3-one of formula (II).
The intermediate compound is represented by structural formula II
Figure imgf000002_0001
II
The intermediate compound of formula II is a key intermediate in the synthesis of morpolinone oxazolidine derivatives like rivaroxaban.
2. Description of the Related Art
Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is approved in US and Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe and US. Rivaroxaban is chemically described as 5 -chloro-N-( { (5 S)-2-oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5-yl }methyl)- 2-thiophene-carboxamide (herein after referred as rivaroxaban) and is represented by the structural formula I shown below:
Figure imgf000002_0002
U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
The US' 860 patent also discloses a process for the preparation of rivaroxaban which is illustrated by sc
Figure imgf000003_0001
U.S. Patent No. 7,351,823 describes a synthesis of intermediate (II) going upto rivaroxaban which is illustrated by scheme below:
Figure imgf000003_0002
U.S. Patent No. 7,816,355 describes a synthesis of intermediate (II) going upto rivaroxaban which is illustrated by scheme below:
Figure imgf000004_0001
The process disclosed in the patent US '860 patent has various disadvantages which has particularly unfavourable effects for preparation of the compounds of the formula (II) and formula (I) on the industrial scale.
The reported processes aforementioned involves hazardous and expensive reagents like haloformates, LDA, and bromine derivatives which have more scope for the formation of impurities and difficult to handle on commercial scale thus requires additional purification steps thus ending up with low yields and purities of the final product thus rendering the process not amenable on commercial scale.
Therefore, there is an unmet need for the development of a process for obtaining intermediates of rivaroxaban in an optically pure form which is cost effective, uses easily available reagents, which is scalable with ease and is industrially feasible.
Moreover the synthesis of intermediate compound of formula II going via intermediate compounds of formula III and Ila are not reported in the literature on rivaroxaban.
Hence, there is a need to provide improved processes for the preparation of intermediates of rivaroxaban, which avoids the use of potentially hazardous, expensive chemicals, the formation of isomeric and other process related impurities, while affording the desired intermediate products in high yield and purity. The processes of the present invention are simple, eco-friendly, cost-effective, reproducible, robust and are well amenable on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of 4-{4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula (II) a key intermediate in the synthesis of rivaroxaban (I).
In one aspect, the present invention relates to a process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula (II) or a salt thereof ,
Figure imgf000005_0001
(II)
comprising:
a) reacting the substituted oxazolidin-3-yl)-phenyl]-morpholin-3- one compound of formula (IV)
Figure imgf000005_0002
(IV)
Where L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate
with a suitable substituted or unsubstituted benzyl amine to give the compound of formula (III) or a salt thereof
Figure imgf000006_0001
(III)
Where R is substituted or unsubstituted benzyl group,
b) Subjecting the compound of formula (III) or a salt thereof to reduction using suitable hydrogenation catalysts to give the compound of formula (II).
In another aspect, the present invention provides intermediate compound of formula (III) or a salt thereof.
Figure imgf000006_0002
(III)
Where R is substituted or unsubstituted benzyl group
The R group in compound of formula III is represented by
Figure imgf000006_0003
Where Rl, R2 are independently or same alkyl (C 1-C6) straight chain or branched, Ci-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro-, sulfonyl-, -OH and R3 is alkyl (C1-C6) straight chain or branched- and its use as intermediate in the synthesis of morpholinone oxazolidine derivatives like rivaroxaban.
In yet another aspect, the present invention relates to an alternate process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo-l ,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula (II) or a salt thereof ,
Figure imgf000007_0001
(Π)
comprising
a) reacting the compound (R) - epichlorohydrin of formula VIII
O
CI
VIII with a suitable azide derivative to afford the compound (2R)-l-azido-3-chlorpropane-2-ol of formula VII
Figure imgf000007_0002
VII
b) reacting the compound of formula VII with a compound phenyl chloroformate to give the compound 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide of formula VI
Figure imgf000007_0003
VI
c) reacting the compound of formula VI with a compound 4-(4Tinorpholin-3-onyl)aniline of formula V
Figure imgf000007_0004
V to give the compound 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one o
Figure imgf000008_0001
Ila
d) Subjecting the compound of formula Ila to reduction using suitable reducing agents to afford the compound of formula II
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 : is a schematic representation of the generic process of present invention.
Fig. 2: is a schematic representation of the specific processes of present invention. Fig. 3: is a schematic representation of the specific process of one embodiment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to processes for the preparation of 4-{4-[5(S)- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula (II) a key intermediate in the synthesis of rivaroxaban (I).
In one embodiment, the present invention provides a process for the preparation of compound 4- { 4- [5(S)-(aminomethyl)-2-oxo- 1 ,3 -oxazolidin-3 -yljphenyl } morpholin-3 -one of formula (II) or a salt thereof ,
Figure imgf000008_0002
(Π)
comprising:
a) reacting the substituted oxazolidin-phenylmorpholinone compound of formula
(IV)
Figure imgf000009_0001
(IV)
Where L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate
with a suitable substituted or unsubstituted benzyl amine in the presence of an organic solvent to give the compound of formula (III) or a salt thereof
Figure imgf000009_0002
(III)
Where R is substituted or unsubstituted benzyl group.
b) Subjecting the compound of formula (III) or a salt thereof to reduction using suitable
hydrogenation catalysts to give the compound of formula (II).
The R group in compound of formula III is represented by
Figure imgf000009_0003
Where Rl, R2 are independently or same alkyl (C1-C6) straight chain or branched, Ci-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro-, sulfon l-, -OH and R3 is alkyl
(C1-C6) straight chain or branched-
The suitable benzylamine derivative used in the step (a) is selected from benzylamine,
4-(triflouromethyl)-benzylamine, 4- (trifluoromethyl)benzylamine, 4-(trifluoromethoxy)- benzylamine, 3-methoxy- benzylamine and 4- methoxybenzylamine and the like; preferably benzylamine. The organic solvents that can be used in step (a) is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), acetonitrile and the like; or mixture thereof. Preferably dichloromethane or toluene.
The reaction step a) is being performed in the absence of solvents and optionally in the presence of solvents.
The bases that can be used optionally in step a) is selected from inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, and the like ; organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine and the like; or mixture thereof, preferably sodium carbonate.
The molar equivalents of compound of benzylamine derivative being used can be from about 0.5 to 7.5 moles to the compound of formula IV taken; preferably 1 to 2 moles is being used.
The reaction can be carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably at boiling point of the solvent (s) used.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
The leaving group for L in the compound of formula IV can be halogen (CI, Br, I), methanesulfonyl,p-toluenesulfonyl,o-toluenesulfonyl,4-nitrobenzenesulfonyl,4- bromobenzene sulfonyl, trifluromethanesulfonyl and the like; preferably halogen atom; more preferably chlorine atom.
The intermediate compound (III) obtained above may be used in next step with or without purification based on the purity of the compound. The compound of formula III obtained is optionally purified by simple recrystallization in a solvent or mixture of solvents or aqueous mixture thereof, usually by using polar protic and polar aprotic solvents like alcohols, or by conversion into acid addition salts. The deprotection reaction step (b) is performed using hydrogenation catalysts such as palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel and the like in the presence of hydrogen gas obtained by any source; preferably palladium on carbon of any percentage or any grade available can be used.
In additional embodiments, the catalyst is used in combination with supports (e.g., solid and liquid supports), which include silica, alumina, silica-alumina, titania, diatomaceous earth, kaolin, activated carbon, carbon, graphite, zeolite, montmorillonite and the like, clays, and alkaline earth metal silicates. Each possibility represents a separate embodiment of the invention. In some embodiments, the catalyst is Raney nickel. In alternative embodiments the catalyst is Pd/C. In some embodiments, the step of hydrogenation is carried out with hydrogen pressure of up to about 200 bar, preferably with hydrogen pressure of about 1 to about 200 bar.
Alternatively, the hydrogenation is carried out with hydrogen pressure of about 5 to about 40 bar. In another alternative the hydrogenation is carried out with hydrogen pressure of about 50 to about 100 bar. The solvents that can be used include but are not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), Ν,Ν-dimethylacetamide (DMA), N- methyl pyrrolidone (NMP) and the like; or mixture thereof. Preferably acetic acid or methanol or mixture thereof.
The reaction is performed at a temperature range from about 25 °C to about 100°C or the boiling point of the solvent(s) used, preferably from about 25°C to about 50 °C.
The time required for the reaction to complete may also vary widely, depending on several factors, notably the reaction temperature, the nature of the reagent and solvents employed. The reaction is effected under the preferred conditions at time period from about 1 hour to about 24 hours, preferably from about 10 hours to 20 hours.
The product formed is recovered by filtration of the reaction suspension on celite to separate the hydrogenation catalyst like Pd/C and the filtrate is distilled to obtain the product. The hydrogenation catalyst recovered is being recycled and reused thus making the process more cost-effective.
The intermediate compound (III) and (II) obtained herein above may be used in next step with or without purification based on the purity of the compound. They are optionally purified by simple recrystallization in a solvent or' mixture of solvents or aqueous mixture thereof, usually by using polar protic and polar aprotic solvents like alcohols, ketones nitriles, esters, hydrocarbons, ethers and the like or by conversion into respective acid addition salts by the conventional methods known.
Advantageously, the compound of formula II herein described is a key intermediate in the synthesis of oxazolidine phenyl morpholinone derivatives like rivaroxaban is obtained usually in high yields and purity by the process of present invention and can be used in next step without any additional process steps like purification. These compounds may optionally further purified by recrystallization or making slurry in suitable aprotic polar solvent for example acetone, acetonitrile, ethers and or mixtures thereof or by formation of salts. The Examples included in this document illustrate the results obtained regarding purity and yield of these intermediates.
The processes reported for the preparation of intermediates especially the key intermediate compound of formula II results in various process related impurities and bye products thus leading to include additional several purification steps thus resulting in very poor yields and purities of the final product.
The reported processes aforementioned involves hazardous and expensive reagents like bromine derivatives has more scope for the formation of impurities, difficult to handle on commercial scale and also requires additional purification steps thus ending up with low yields and purities of the final product thus rendering the process not feasible on commercial scale.
The process of present invention has following advantages:
it makes it possible to obtain the intermediate compounds on an industrial scale in excellent yields, starting from a simple, low-cost starting materials, involve simple process steps and reagents thus making processes more cost effective than reported processes.
In another embodiment, the present invention provides intermediate compound of formula (III) or a salt thereof.
Figure imgf000013_0001
(III)
Where R is substituted or unsubstituted benzyl group
The R group in compound of formula III is represented by
Figure imgf000013_0002
Where Rl, R2 are independently or same alkyl (C1-C6) straight chain or branched, d-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro^, sulfonyl-, -OH and R3 is alkyl (C1-C6) straight chain or branched- and its use as intermediate in the synthesis of morpholinone oxazolidine derivatives like rivaroxaban.
The compound of formula III is identified, characterized and confirmed by NMR,
MASS and HPLC.
In another aspect, the present invention relates to an alternate process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholi -3-one of formula (II) or a salt thereof ,
Figure imgf000013_0003
(Π)
comprising
a) reacting the compound (R) - epichlorohydrin of formula VIII
Figure imgf000013_0004
VIII with a suitable azide derivative in the presence of a suitable solvent to give the compound (2R)-l-azido-3-chlorpropane-2-ol of formula VII
Figure imgf000014_0001
VII
b) reacting the compound of formula VII with a compound phenyl chloro formate in the presence of a suitable organic solvent to give the compound 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide of formula VI
Figure imgf000014_0002
VI
c) reacting the compound of formula VI with a compound 4-(4-morpholin-3-onyl)aniline of formula V
Figure imgf000014_0003
V
in the presence of suitable base and an organic solvent to give the compound 4-{4-[(5R)-5- (azidomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula Ila
Figure imgf000014_0004
Ila
d) subjecting the compound of formula Ila to reduction using suitable reducing agents in the presence of a suitable organic solvent to afford the compound of formula II. The suitable azide derivative that can be used in step a) is selected from the group consisting of sodium azide, potassium azide and the like; preferably sodium azide.
The suitable inorganic salt that can be used is selected from the group consisting of ammonium chloride , sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof. Preferably ammonium chloride.
The suitable solvents that can be used in step (a) is selected from the group consisting of water, acetic acid, alcohols such as methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof. Preferably aqueous ethanol or aqueous acetic acid.
Optionally the reaction step a) can be carried out in the absence of solvents.
The molar equivalents of azide derivative being used can be from about 0.5 to 7.5 moles to the compound of formula VIII taken; preferably one mole is being used.
The reaction can be carried out at a temperature range from about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably at about 30°C.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 5 hour to about 24 hours, preferably about 12 hours.
The suitable bases that can be used in step b) is selected from the inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof. Preferably pyridine.
The organic solvents that can be used in step (b) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof. Preferably dichloromethane. The molar equivalents of phenyl chloroformate being used can be from about 0.5 to 7.5 moles to the compound of formula VII taken; preferably one mole is being used.
The reaction can be carried out at a temperature range from about -10°C to about 40°C, preferably at about 0°C.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour.
The suitable bases that can be used in step c) is selected from the inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof. Preferably potassium carbonate.
The organic solvents that can be used in step (c) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof. Preferably Ν,Ν-dimethylformamide (DMF).
The molar equivalents of compound of V being used can be from about 0.5 to 7.5 moles to the compound of formula VI taken; preferably one mole is being used.
The reaction can be carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably from about 75 to about 85°C.
The time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 5 hour to about 25 hours, preferably about 15 hours.
The reaction step (d) is performed using reducing agents but not limited to hydrogenation catalysts such as palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel and the like in the presence of hydrogen gas obtained by any source; sodium borohydride, triphenyl phosphine, trimethyl silyl iodide and the like; preferably palladium on carbon of any percentage or any grade available can be used. The solvents that can be used in step d) include but are not limited to water, acetic acid, alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; or mixture thereof. Preferably ' ethyl acetate or acetic acid.
The reaction is performed at a temperature range from about 25°C to about 100°C or the boiling point of the solvent(s) used, preferably from about 45°C to about 50 °C.
The time required for the reaction to complete may also vary widely, depending on several factors, notably the reaction temperature, the nature of the reagent and solvents employed. The reaction is effected under the preferred conditions at time period from about 1 hour to about 24 hours, preferably from about 8 hours to 12 hours.
The product formed is recovered by filtration of the reaction suspension on celite to separate the hydrogenation catalyst like Pd/C and the filtrate is distilled to obtain the product.
The hydrogenation catalyst recovered is being recycled and reused thus making the process more cost-effective.
The starting compounds of formula (IV), VIII, and V are commercially available or known per se to the person skilled in the art or can be prepared by processes reported in the literature. For ex. US 7,585,860 which is incorporated herein for reference.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the person, skilled in the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Optionally the process steps of present invention can be carried out by one pot synthesis independently.
The intermediate compounds of formula II and Ila or a salt thereof obtained by the process of present invention can be further converted to the morpholinone oxazolidine derivatives like rivaroxaban (I) by any process reported in the literature for example US 7,585,860.
Having described the invention with reference to certain preferred embodiments, other„ embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Examples for scheme 1 (Fig. 1)
Example 1 : Preparation of 4-{4-[(5S)-5-(N-benzylaminomethyl)-2-oxo-l,3-Oxazolidin-3- yl]phenyl}morphoIin-3-one
31gms (0.1m) of 4-{4-[(5R)-5-(chloromethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one and benzylamine (21.5 gms) were charged into a clean and dry 4 neck R.B. Flask followed by heating to about 150°C for about 2 hrs. After completion of the reaction, the resultant mixture was cooled to about 30°C. 50 ml of methylene chloride was charged and stirred for 20 min. The solid separated was filtered and washed with 10 ml of methylene chloride. The filtrate obtained was distilled completely to afford off-white crystalline solid of the title compound.
Yield: 25 gms.
Example 2: Preparation of 4-{4-[(5S)-5-(ammomethyl)-2-oxo-l,3-Oxazolidin-3- yl]phenyl}morpholin-3-one
25 gms of 4-{4-[(5S)-5-(N-benzylaminomethyl)-2-oxo-l,3-Oxazolidin-3- yl]phenyl}morpholin-3-one obtained in above example, 4gms of palladium - carbon (Pd/C) (5%)w/w), acetic acid(25ml) and methanol (300ml) were charged into a clean and dry autoclave followed by heating to about 45°C and agitated under H2 pressure of 5-8 kgs/cm2 for about 8 hrs. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled off completely. To the residue 50ml of ethyl acetate was added and stirred for about 30 min at about 30°C. The solid separated was filtered and the solid was washed with ethyl acetate to yield white-off white crystalline solid of the title compound.
Yield: 15.5 gms
Examples for scheme 2 (Fig. 3) Example 1: Preparation of (2R)-l-azido-3-chlorpropane-2-ol sodium azide (50 gms,0.77 mole) and ammonium chloride (41 gms) in water(236 ml) were charged into a clean and dry 4 neck R.B.flask followed by cooling to about 0°C. A solution of (R) - epichlorohydrin (59.3 gms,0.64 mol) in ethanol (60ml) was added .The resultant reaction mixture was stirred at 0°C for 1 hr, then allowed to reach about 30 °C. and stirred for overnight. After completion of the reaction, the reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with water (3x100 ml) and concentrated to get compound as colorless liquid. Yield: 56.5 gms (65%).
Example 2: Preparation of 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide azido alcohol (56.5 gms,0.41 mol) obtained in above example, pyridine (56 ml) and methylene chloride (250 ml), were charged into a clean and dry 4 neck R.B.flask. (71.75 gms,0.46 mol) of phenyl chloroformate was added dropwise at about 0°C. The resultant reaction mixture was stirred at about 0°C for about 1 hr. After completion of the reaction, the reaction mixture was quenched by poured into water and dichloromethane mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x100 ml) and the combined organic extract was washed with dil.HCl (100ml) followed by water (2x100ml) and the organic layer was distilled completely to afford the title compound in thick syrup form. Yield: 97 gms (91%).
Example 3: Preparation of 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one
(30gms,0.117 mol) of 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide, 4-(4- morpholin-3-onyl)aniline 27 gms (0.14 mol) and 150 ml of Ν,Ν-dimethyl formamide, were charged into a clean and dry 4 neck R.B.flask. (40.5 gms,0.3 mol) potassium carbonate and catalytic amount of triethylbenzyl ammonium chloride were added. The resultant reaction mixture was stirred at about 80 °C for about .15 hrs. After completion of the reaction, the reaction mixture was quenched by pouring into water (500 ml) and extracted with ethyl acetate (3x100ml) .The combined org. layer was washed with water (2x100 ml). The organic layer was separated and distilled completely to afford the title compound.
Yield: 24.5 gms (65.8%).
Example 4: Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l,3-oxazoIidin-3- yl]phenyl}morpholin-3-one
24.5 gms of azido compound obtained in above example was dissolved in ethyl acetate (500 ml), 5 gms of 5% w/w of palladium - carbon ( Pd/C) were charged in a clean and dry autoclave followed by heating to about 45°C and agitated under ¾ pressure of 5-8 kgs/cm2 for about 8 hrs. After completion of the reaction, the catalyst was separated by filtration of the reaction suspension on a celite. The filtrate obtained was distilled off completely under reduced pressure to yield crude form of title compound. The crude was recrystallize from methanol to yield pure form of the title compound as off-white crystalline solid.
Yield: 18 gms (80%).

Claims

We Claim:
1) A process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl}morpholin-3-one of formula (II) or a salt thereof,
Figure imgf000021_0001
(Π)
comprising:
a) reacting the substituted oxazolidin-3-yl)-phenyl]-morpholin-3- one compound of formula (IV)
Figure imgf000021_0002
(IV)
Where L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifiuoromethyl sulphonate
with a suitable substituted or unsubstituted benzyl amine to give the compound of formula (III) or a salt thereof
Figure imgf000021_0003
(HI)
Where R is substituted or unsubstituted benzyl group,
b) subjecting the compound of formula (III) or a salt thereof to reduction using suitable
hydrogenation catalysts to give the compound of formula (II).
2) The process of claim 1 , wherein the suitable benzylamine derivative used in the step a) is selected from benzylamine, 4- methyl benzyl amine, 2- methyl benzyl .amine, a-methyl benzyl amine, 3-(triflouromethyl)-benzylamine, 4-trifluoromethyl)- benzylamine, 4-(trifluoromethoxy)benzylamine,3-methoxy- benzylamine and 4- methoxybenzylamine or mixtures thereof, preferably benzylamine.
3) The process of claim 1, wherein the organic solvents used in step (a) is selected from the group consisting of alcohols like methanol, ethanol, isopropanol, halogenated solvents like dichloromethane, ethylene dichloride, chloroform, esters like ethyl acetate, isopropyl acetate, hydrocarbon solvents like toluene, xylene, aprotic polar solvents like N,N- dimethylformamide(DMF), Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), acetonitrile or mixture thereof, preferably dichloromethane or toluene. 4) The process of claim 1 , wherein the reaction step (a) is carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably at boiling point of the solvent (s) used.
5) The process of claim 1 , wherein the time period required for the reaction to complete is from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
6) The process of claim 1 , wherein the reaction step (a) is optionally performed in the absence of solvents and optionally in the presence of bases including inorganic and organic bases, preferably sodium carbonate.
7) The process of claim 1 , wherein the leaving group for L in compound of formula IV can be halogen atom like CI, Br, I, or me hanesulfonyl, p- toluenesulfonyl, o-toluenesulfonyl, 4- nitrobenzene sulfonyl, 4- bromobenzene sulfonyl, trifluromethanesulfonyl, preferably halogen atom; more preferably chlorine atom.
8) The process of claim 1 , wherein the deprotection step (b) is performed using hydrogenation catalysts like palladium on carbon or platinum on carbon, platinum oxide, rhodium, cobalt, nickel in the presence of hydrogen gas preferably palladium on carbon of any percentage and of any grade.
9) The process of claim 1 , wherein the solvents used in step b) is selected from water,
acetic acid, alcohols like methanol, ethanol, isopropanol, esters like ethyl acetate, isopropyl acetate, hydrocarbons like toluene, xylene ethers such as tetrahydrofuran (THF), 1,4- dioxane, aprotic polar solvents like Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), Ν,Ν-dimethylacetamide (DMA), N-methyl pyrrolidone (NMP) or mixture thereof, preferably acetic acid or methanol or mixture thereof. 10) The process of claim 1, wherein the reaction step (b) is performed at a temperature range from about 25°C to about 100°C or the boiling point of the solvent(s) used, preferably from about 25°C to about 50 °C.
11) The process of claim 1, wherein the time period required for the reaction step (b) to complete is from about 1 hour to about 24 hours, preferably from about 10 hours to 20 hours.
12) A process for the preparation of compound of formula (III) or a salt thereof
Figure imgf000023_0001
(HI)
Where R is substituted or unsubstituted benzyl group.
by reacting the substituted oxazolidin-phenylmorpholinone compound of formula (IV)
Figure imgf000023_0002
(IV)
Where L is a leaving group like halogen (F, CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate
with a suitable substituted or unsubstituted benzyl amine.
13) A process for the preparation of compound of formula (Ilia) or a salt thereof
Figure imgf000024_0001
by reacting the substituted oxazolidin-phenylmorpholinone compound of formula (IVa)
Figure imgf000024_0002
(IVa)
with a benzyl derivative like benzyl amine in the presence or absence of an organic solvent.
14) A process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl}morpholin-3-one of formula (II) or a salt thereof,
Figure imgf000024_0003
(Π)
by deprotection of the compound of formula (III) or a salt thereof
Figure imgf000024_0004
(III)
Where R is substituted or unsubstituted benzyl group,
using hydrogenation catalysts like palladium on carbon. 15) A compound of formula (III) or a salt thereof
Figure imgf000025_0001
(III)
Where R is substituted or unsubstituted benzyl group.
Where the R group is represented by
Figure imgf000025_0002
Wherein Rl , R2 are independently or same alkyl (C1-C6) straight chain or branched, Ci-6 alkoxy straight chain or branched, halogen (CI, Br, I), nitro-, sulfonyl-, -OH and R3 is alkyl (C1-C6) straight chain or branched- and its use as intermediate in the synthesis of morpholinone oxazolidine derivatives like rivaroxaban.
16) An altemate.process for the preparation of compound 4-{4-[5(S)-(amino methyl)-2-oxo- l,3-oxazolidin-3-yl]phenyl}mo holin-3-one of formula (II) or a salt thereof ,
Figure imgf000025_0003
(Π)
comprising
a) reacting the compound (R) - epichlorohydrin of formula VIII
O.
CI
VIII with a suitable azide derivative to afford the compound (2R)-l -azido-3-chlorpropane-2-ol of formula VII
Figure imgf000026_0001
VII
b) reacting the compound of formula VII with a compound phenyl chloroformate to give the compound 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide of formula VI
Figure imgf000026_0002
VI
c) reacting the compound of formula VI with a compound 4-(4-morpholin-3-onyl)aniline of formula V
Figure imgf000026_0003
V
to give the compound 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula Ila
Figure imgf000026_0004
Ila
d) subjecting the compound of formula Ila to reduction using suitable reducing agents to afford the compound of formula II
17) The process of claim 16, wherein suitable azide derivative that can be used in step a) is selected from the group consisting of sodium azide, potassium azide or mixture thereof, preferably sodium azide.
18) The process of claim 16, wherein the suitable inorganic salt that can be used in step a) is selected from the group consisting of ammonium chloride , sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, or mixture thereof, preferably ammonium chloride.
19) The process of claim 16, wherein the suitable solvents that can be used in step (a)
is selected from the group consisting of water, acetic acid, alcohols like methanol, ethanol, isopropanol or their mixtures thereof; halogenated solvents like dichloromethane, ethylene dichloride, chloroform and the like; esters like ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents like toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF),- Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; or mixture thereof, preferably aqueous
Ethanol or aqueous acetic acid.
20) The process of claim 16, wherein the reaction step a) is carried out at a temperature
range from about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably about 30°C.
21) The process of claim 16, wherein the time required for the reaction step a) is from about 5 hours to about 24 hours, preferably about 12 hours.
22) The process of claim 16, wherein the suitable bases that can be used in step b) is selected from the inorganic bases like sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride; organic bases like such as methyl amine, ethyl amine, pyridine, triethyl amine or mixture thereof, preferably pyridine.
23) The process of claim 16, wherein the suitable organic solvents that can be used in step (b) is selected from the group consisting of alcohols like methanol, ethanol, isopropanol, halogenated solvents like dichloromethane, ethylene dichloride, chloroform ,
esters like ethyl acetate, isopropyl acetate, hydrocarbon solvents like
toluene, xylene, aprotic polar solvents like N,N-dimethylformamide
(DMF), Ν,Ν-dimethylacetamide, dimethylsulfoxide (DMSO), N-methyl pyrrolidone
(NMP) or mixture thereof, preferably dichloromethane.
24) The process of claim 16, where in the reaction step b) is carried out at a temperature range from about - 10°C to about 40°C, preferably about 0°C. 25) The process of claim 16, wherein'the time required for the reaction step b) to complete is from about 1 hour to about 10 hours, preferably from about 1 hour.
26) The process of claim 16, wherein the suitable bases that can be used in step c) is selected from the inorganic bases like sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, ammonium chloride, organic bases like methyl amine, ethyl amine, pyridine, tri ethyl amine or mixture thereof, preferably potassium carbonate.
27) The process of claim 16, wherein the suitable organic solvents that can be used in step (c) is selected from the group consisting of halogenated solvents like dichloromethane, ethylene dichloride, chloroform, esters like ethyl acetate, isopropyl acetate
hydrocarbon solvents like toluene, xylene, aprotic polar solvents like N,N- dimethylformamide (DMF), Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N- methyl pyrrolidone (NMP) or mixture thereof, preferably N,N- dimethylformamide (DMF).
28) The process of claim 16, wherein the reaction step c) is carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably from about 75 to about 85°C.
29) The process of claim 16, wherein the time required for the reaction step c) to complete is from about 5 hour to about 25 hours, preferably about 15 hours.
30) The process of claim 16, wherein the reaction step (d) is performed using reducing agents including hydrogenation catalysts like palladium on carbon, platinum on carbon, platinum oxide, rhodium, cobalt, nickel in the presence of hydrogen gas obtained by any source, sodium borohydride, triphenyl phosphine, trimethyl silyl iodide, preferably palladium on carbon of any percentage and any grade available can be
used.
31) The process of claim 16, wherein the suitable solvents that can be used in step d) is
selected from water, acetic acid, alcohols like methanol, ethanol, isopropanol, esters such as ethyl acetate, isopropyl acetate, hydrocarbon solvents like toluene, xylene, ethers like tetrahydrofuran (THF), 1 ,4-dioxane or mixture thereof, preferably ethyl acetate or acetic acid.
32) The process of claim 16, wherein the reaction step d) is performed at a temperature range from about 25°C to about 100°C or the boiling point of the solvent(s) used, preferably from about 45°C to about 50 °C.
33) The process of claim 16, wherein the time required for the reaction step d) to complete is from about 1 hour to about 24 hours, preferably from about 8 hours to 12 hours.
34) A process of claim 16, wherein the compound 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl}morpholin-3 -one of formula Ila
Figure imgf000029_0001
Ila
is prepared by reacting the compound 3-Chloro-(2R)-2-[(phenyloxy carbonyl)-oxy] propyl azide of formula VI
Figure imgf000029_0002
VI
with a compound 4-(4-morpholin-3-onyl)aniline of formula V
Figure imgf000029_0003
V
in the presence of suitable base and an organic solvent.
35) A process for the preparation of compound 4-{4-[5(S)-(aminomethyl)-2-oxo- l,3-o azolidin-3-yl]phenyl}mo holin-3-one of formula (II) or a salt thereof ,
Figure imgf000030_0001
(II)
by subjecting the compound 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula Ila
Figure imgf000030_0002
Ila
reduction using suitable reducing agents in the presence of suitable organic solvent.
PCT/IN2011/000553 2011-08-19 2011-08-19 Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one WO2013027225A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000553 WO2013027225A1 (en) 2011-08-19 2011-08-19 Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000553 WO2013027225A1 (en) 2011-08-19 2011-08-19 Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one

Publications (1)

Publication Number Publication Date
WO2013027225A1 true WO2013027225A1 (en) 2013-02-28

Family

ID=47746012

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000553 WO2013027225A1 (en) 2011-08-19 2011-08-19 Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one

Country Status (1)

Country Link
WO (1) WO2013027225A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626630A (en) * 2013-11-15 2014-03-12 深圳致君制药有限公司 Rivaroxaban intermediate and preparation method thereof
EP2753619A2 (en) 2011-09-08 2014-07-16 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN115477720A (en) * 2022-09-28 2022-12-16 国家电投集团氢能科技发展有限公司 Heterocyclic quaternary ammonium salt functionalized perfluorinated anion exchange resin, preparation method thereof and ion exchange membrane with same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAJWA.: "Chemoselective Deprotection of Benzyl Esters in the Presence of Benzyl Ethers, Benzyloxymethyl Ethers and N-Benzyl Groups by Catalytic Transfer Hydrogenation", TETRAHEDRON LETTERS, vol. 33, 1992, pages 2299 - 2302 *
ELLA-MENYE ET AL.: "New Synthesis of Chiral 1,3-Oxazinan-2-ones from Carbohydrate Derivatives", JOURNAL OF ORGANIC CHEMISTRY, vol. 70, 2005, pages 463 - 469 *
LIN ET AL.: "Reduction of Azides to Amines or Amides with Zinc and Ammonium Chloride as Reducing Agent", SYNTHETIC COMMUNICATIONS, vol. 32, 2002, pages 3279 - 3284 *
MADHUSUDHAN ET AL.: "A Novel and Short Convergent Approach For N-aryl-5-aminomethyl-2-oxazolidinone derivatives of Linezolid and DUP-721", INDIAN JOURNAL OF CHEMISTRY, vol. 44B, 2005, pages 1236 - 1238 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753619A2 (en) 2011-09-08 2014-07-16 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
CN103626630A (en) * 2013-11-15 2014-03-12 深圳致君制药有限公司 Rivaroxaban intermediate and preparation method thereof
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN115477720A (en) * 2022-09-28 2022-12-16 国家电投集团氢能科技发展有限公司 Heterocyclic quaternary ammonium salt functionalized perfluorinated anion exchange resin, preparation method thereof and ion exchange membrane with same
CN115477720B (en) * 2022-09-28 2024-05-24 国家电投集团氢能科技发展有限公司 Heterocyclic quaternary ammonium salt functionalized perfluorinated anion exchange resin, preparation method thereof and ion exchange membrane with heterocyclic quaternary ammonium salt functionalized perfluorinated anion exchange resin

Similar Documents

Publication Publication Date Title
KR102593431B1 (en) PROCESSES AND INTERMEDIATES IN THE PREPARATION OF C5aR ANTAGONISTS
CA2810478A1 (en) Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one
TWI646071B (en) Producing method of (r)-1,1,3-trimethyl-4-aminoindane
DK1664004T3 (en) METHOD FOR PREPARING 4- (4-AMINOPHENYL) -3-MORPHOLINON
WO2013046211A1 (en) Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof
WO2013105100A1 (en) Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof
CA2815063C (en) Processes for the preparation of rivaroxaban and intermediates thereof
WO2011124704A1 (en) Process for preparing an intermediate for silodosin
WO2013027225A1 (en) Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one
EP2722330B1 (en) Novel method for synthesizing rivaroxaban intermediate, 4-{4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one
KR20150041650A (en) Processes for the preparation of (s)-3-4-((4-(morpholinomethyl) benzyl)oxy)-1-oxoisoindolin-2-yl) piperidine-2,6-dione and pharmaceutically acceptable forms thereof
WO2012156983A1 (en) Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
SI20071A (en) Asymmetric synthesis of benzoxazinones
WO2010031769A1 (en) Process for the preparation of an oxazolidinone antibacterial agent and intermediates thereof
CN103339116A (en) Substituted n-pentanamide compounds, preparation methods and uses thereof
EP2697209B1 (en) Method for the preparation of substituted oxazolidinones
CN110746370A (en) Preparation method of 4- (4-aminophenyl) morpholine-3-one
CN111170992B (en) Preparation method of 5, 6-dihydropyridine-2 (1H) -ketone derivative
WO2012041263A2 (en) A method of manufacturing 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l,3-oxazolidin-5-yl}methyl)-lh-isoindol-l,3(2h)-dione with a high optical purity
JP2017502009A (en) Method for producing silodosin and its intermediate
Ashcroft et al. An efficient and scalable synthesis of the endothelin antagonists UK-350,926 and UK-349,862 using a dynamic resolution process
CN111471041B (en) Synthetic method of oxazolidinone antibacterial drug intermediate
JP2023532362A (en) Method for producing phenylisoxazoline compound
EP2603505A1 (en) Process for making linezolid
KR101128029B1 (en) Method for preparing of R-3-3-fluoro-4-1-methyl-5,6-dihydro-1,2,4-triazin-41H-ylphenyl-5-substituted methyloxazolidin-2-one derivatives

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 15/CHENP/2012

Country of ref document: IN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11871278

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11871278

Country of ref document: EP

Kind code of ref document: A1