WO2013105100A1

WO2013105100A1 - 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

Info

Publication number: WO2013105100A1
Application number: PCT/IN2012/000025
Authority: WO
Inventors: Dodda Mohan Rao; Buthukuri Venkat Reddy
Original assignee: Symed Labs Limited
Priority date: 2012-01-09
Filing date: 2012-01-09
Publication date: 2013-07-18

Abstract

The present invention relates to processes for the preparation of oxazolidinone derivatives. More particularly the present invention provides processes for the preparation of 5-chloro-N-( {(5S)-2-oxo-3-[4-(3-oxo-4-moφholinyl)phenyl]-1,3-oxazolidin-5-yl methyl)-2-thiophene-carboxamide and intennediates thereof. Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS02R where R = C'-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable reagent to provide the compound of formula (II). The reaction step is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol. For example ammonium hydroxide.

Description

"PROCESSES FOR THE PREPARATION OF 5-CHLORO-N-({(5S)-2-OXO-3- [4-(3- OXO-4-MORPHOLINYL)PHENYL]-l,3-OXAZOLIDIN-5-YL}METHYL)-2- THIOPHENE-CARBOXAMIDE AND INTERMEDIATES THEREOF"

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl}methyl)-2-thiophene- carboxamide and intermediates thereof.

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-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is represented by the structural formula I shown below:

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 scheme below.

U.S. Patent No. 7,351,823 describes a synthesis of intermediate (II) going upto rivaroxaban which is illustrated by scheme below:

U.S. Patent No. 7,816,355 describes a synthesis of intermediate (II) going upto rivaroxaban which is illustrated by scheme below:

PCT application publication WO 2011/080341A1 describes processes for rivaroxaban

The process disclosed in the patent US'860 has several disadvantages like

a) The yield of the first step process cannot be reproducible and the starting materials cannot be converted completely, the bye product i.e., bisalkylated compound formed is difficult to remove completely.

b) Synthesis of (S)-glycidyl pthalimide on commercial scale is difficult. And the final compound is being purified by chromatography, it is not possible on commercial scale.

The process disclosed in the patent US'355 involves the use of highly corrosive and hazardous haloformates and highly reactive reagents like n-Butyl lithium , handling of these reagents on commercial scale is very difficult. Moreover the process has scope for the formation of various bye products leading to very less purity and requires purifications thus leading to low yields. The process disclosed in the European patent application publication EP' 128A1 involves the highly toxic phosgene and their equivalents which is very difficult to handle on commercial scale and also the products yields of the all the reaction steps are not reproducible.

The process disclosed in the PCT application publication W0'341A1 involves n-Butyl lithium and lithium tert.butoxide which are very difficult to handle on industrial scale and the yield of the first step is not reproducible.The reaction of mesyl compound with tertiary amines is performed in a sealed vessel and at elevated temperature which is not possible on

commercial scale.

The aforementioned processes entails the use of hazardous and expensive reagents like haloformates, LDA, and bromine derivatives which have large scope for the formation of impurities and difficult to handle hazardous chemicals on industrial scale, which requires additional purification steps to remove the impurities thus ending up with low yields and purities of the final product thus rendering the process not amenable on commercial scale.

All these alternative processes reported in the art_tO— yield— rivaroxaban— present^" drawbacks which should be solved.

The wide prevalence of illnesses related to blood coagulation makes rivaroxaban an important active ingredient. As exposed before, to date the field provides hazardous, multi- step, and complex methods for obtaining rivaroxaban. Thus, synthetic approaches solving the disadvantages of the known methods are of special interest while providing rivaroxaban in high yield and purity.

Moreover the synthesis of key intermediate compound of formula II going via novel intermediate compounds of formula IV, VI 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 hazardous, expensive chemicals, the formation of isomeric and other process related impurities, while affording the desired intermediate compounds with high yield and purity.

The novel processes for the preparation of rivaroxaban from novel intermediate compounds of present invention proceeds with good yields while achieving a good chemical and optical purity. The new process comprises preparation of an alcohol precursor of rivaroxaban by novel methods and activation of an alcohol precursor, amination with some specific amines, which may be removed. The herewith proposed processes of the present invention are particularly advantageous in its practical industrial application since it is much more cost effective. No chromatography is required and final rivaroxaban is obtained with high purity. Thus, by the processes of the present invention, rivaroxaban can be produced safely and simply with high yields and purities.

SUMMARY OF THE INVENTION

The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3 -oxo-4-morphol inyl)phenyl]- 1 ,3 -oxazol idin-5 -y 1 } methyl)-2-thiophene- carboxamide and intermediates thereof.

In one aspect, the present invention relates to a process for the preparation of 4-{4- [5(S)-(aminomethyl)-2-oxo-l,3-oxazolίdin-3-yl]phenyl}moφholin-3-one compound of formula (II) or a salt thereof ,

(II)

comprising:

reacting the substituted oxazolidinone-phenylj-morpholinone compound of formula

(IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = Ci_-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl;

with a suitable reagent to provide the compound of formula (II).

The reaction step is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol. For example ammonium hydroxide.

Where HL =inorganic acids such as HC1, HI and the like; organic acids such as methane sulfonic acid, p -toluene sulfonic acid and the like which can form salt with the amine compound of formula II.

In another aspect, the present invention relates to an alternate process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one compound of formula (II) or a salt thereof

comprising:

a) reacting the compound substituted oxazolidinone-phenylj-morpholinone of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = C_]-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl;

with a suitable azide derivative to provide the compound of formula (IVa)

(IVa)

b) subjecting the compound of formula (IVa) to reduction using suitable reducing agent to provide the compound of formula II.

In yet another aspect, the present invention relates to an alternate process for the

comprising:

a) reacting the compound substituted oxazolidinone -phenyl-morpholinone of

formula (IV) with a sub or unsubstituted dibenzyl amine or a salt thereof to provide the compound of formula

(IVb)

(IVb)

b) subjecting the compound of formula (IVb) to reduction using suitable reducing agent to provide the compound of formula II.

In another aspect, the present invention provides a process for the preparation of substituted oxazolidinone-phenyl-morpholinone compound of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; comprising:

a) reacting the substituted phenyl morphilinone compound of formula VIII

Where Rl is -OR2,-CX3 or NR₄

R₂^C _i.₂_alk l-Straight-cham^ with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;

R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring;

X= halogen atom;

with the compound of formula VII

OR. ^"

^ ^OR₆

VII

Where W=halogen atom or sulfonyloxy group;

Rs= -H or -CO-R⁷ where R⁷ =C M₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;

R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as

i)R⁸=C i_i2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl staright or branched chain;

where R9= C i.]₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1- 12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy (Fmoc);

Rl l

>'— RIO

iii) R⁸= ^R12

Where R10, Rl 1, 12= independently selected from the group consisting of C i_i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

to afford substituted oxazolidinone morpholinone phenyl compound of formula VI

VI

Where R6 is same as defined above,

b) deprotection of the compound of formula VI using a suitable reagent to afford the

compound of formula V (when the R6 is hydroxyl protecting group)

c) reacting the compound of formula V with a suitable reagent to afford the compound of formula IV

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = Ci alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl;

The above processes are schematically represented by Fig. 1.

In another aspect, the present invention provides substituted oxazolidinone phenyl morpholinone compound of formula VI.

VI

R6= -H or R , where R =hydroxyl protecting group such as

i) R⁸=C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl staright or branched chain;

o

_{II) R}8₌— c_R9

where R9= C ₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy

Where R10, Rl 1 , 12= independently selected from the group consisting of C i.i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In yet another aspect, the present invention provides a compound of formula VII.

Where W=halogen atom or sulfonyloxy group;

R₅= -CO-R⁷ where R⁷ =C 1.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as

i) R⁸=C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain; where 9= C _\. alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc)

iii) R^e= R12

Where RIO, Rl 1, 12= independently selected from the group consisting of C ].i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In another aspect, the present invention provides a process for the synthesis of compound of formula VII. — . -

Where W, R6 are same as defined above; R5= -CO-R7, R7 = same as defined above, comprising:

reacting the compound of formula VII (where R5=H)

Where W, R6 are same as defined above

with a compound of formula

o

I I

R7— ^c— ^x or (R7CO)₂0

Where R7 is same as defined above and X is a halogen atom;

to provide the compound of formula VII.

In yet another aspect, the present invention relates to an alternate process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above;

comprising:

reacting the morpholinone phenyl amine compound of formula Ila

Ila

with the compound of formula IX

IX

W-here-W≡halogen-atom-or-sulfonyioxy^"group; R]= -OR2, NR3R4, or -CX₃ where

R2,R3,R4,X =same as defined for compound of formula VIII;

R₆= -H or R , where R =hydroxyl protecting group such as

i) R⁸=C H2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain;

o

I I

ii) R⁸= C— R9

where R9= C 1-12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);

Where R10, Rl 1, 12= independently selected from the group consisting of C i-i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl; to provide the compound of formula VI.

The above process is schematically represented by Fig. 2.

In another aspect, the present invention provides compound of formula IX

OCOR,

^OR,

IX

Where W=halogen atom or sulfonyloxy group;

Where Rl is -OR2,-CX3 or NR4R3

R2 =C_1-i2 alkyl straight chain or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;

X= halogen atom;

Q Q

R₆= -H or R , where R =hy^rMy proLec.ting-group-such-as

i) R =C i-i₂ alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain;

o

I I

i_{i) R}8₌— C— R9

where R9= C i-i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C i-i₂ alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);

Rl l

—>'— RIO

iii) R⁸= ^R12

Where R10, Rl 1, 12= independently selected from the group consisting of C ].i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl.

In another aspect, the present invention relates to a process for the preparation of compound of formula IX OCOR,

IX

Where W, Rl, R6 are same as defined above,

comprising:

reacting the compound of formula of formula VII (where R5=H)

OH v^{^} VII

Where W, R6 are same as defined above.

o o

I I I I

With the compound of formula ^{R1 c x} or ^{R1 c R1}

Where Rl is same as defined above; X= halogen atom

to provide the compound of formula IX.

In yet anotheiiaspect,-the^ an alternate process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above

comprising:

reacting the morpholinone phenyl amine compound of formula Ha

Ila

with the compound of formula X

,OR_fi

X

Where X and Y are i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when i) X and Y are separate groups, X is halogen or sulfonyloxy group; Y is OR⁵ where R⁵= -H or -CO-R⁷, R⁷ = C _1-12 alkyl straight or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub. aryl, sub or unsub aryl alkyl ; or ii) X and Y together form a single ring group with the two carbons to

which they are bonded, they are an oxygen atom; R6 is same as defined above, to give substituted morpholinone phenyl amine compound of formula XI

XI

Where R₅, R are same as defined above

b) carbonylation of the compound of formula XI with a suitable carbonylating agent to give the compound of formula VI

(or)

c) reacting the compound of formula XI with a suitable reagent to give the compound of

formula XIa. ·

Where R₅, R₆ is same as defined above; R14=-OR¹⁵, NR₃R₄, CX₃ or X, where R₃, R₄ together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring; R15= C _\. 2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X= halogen atom;

d) reacting the compound of formula XIa with a suitable reagent to give the compound of formula VI.

The above process is schematically represented by Fig. 3.

In another aspect, the present invention provides a compound of formula XI

XI Where R₅ =-H or -CO-R⁷ where R⁷ =C 1 -12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub aryl alkyl; R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as

o

i) R =C 1 -12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-i o alkenyl straight or branched chain;

o

II

ii) R*=— C— R9

where R9= C 1.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1 -12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy (Fmoc);

Where R10, Rl 1 , 12= independently selected from the group consisting of C i- i ₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In yet another aspect, the present invention provides the compound of

formula XIa

Where R₅ =-H or -CO-R⁷ where R⁷ =C 1.12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub aryl alkyl; R14=- OR¹⁵, NR₃R4, CX₃ or X, where R₃, R₄ together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring, R¹⁵=C i _ i ₂ alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X=halogen atom; R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as i)R =C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl staright or branched chain;

o

II

ii) R⁸=— c— R9

where R9= C alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);

Rl l

— RIO

iii) R⁸= ^R12

Where R10, Rl 1, R12= independently selected from the group consisting of C i-i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen-atom-(-s-)rSub-orunsub aryl, sub or unsub arylalkyl;

In yet another aspect, the present invention relates to a process for the preparation of compound 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyI]-l ,3-oxazolidin-5- yl}methyl)-2-thiophene-carboxamide of formula I

comprising:

a) reacting substituted oxazolid ne compound of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), -OS0₂R where R = Ci alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable reagent to provide the compound of formula III

III

Where R13 is sub or unsub. benzyl, C ₃.₁₀ alkenyl straight or branched chain;

b) reacting the compound of formula III with 5-chloro-thiophene carboxylic acid of formula IXa or a derivative thereof

to provide the compound of formula la

c) deprotection of the compound of formula la using a suitable reagent to give the

compound of formula I.

The above process is schematically represented by Fig. 4.

In yet another aspect, the present invention provides a compound of formula III

III

Where Rn is C ₃.₁₀ alkenyl straight or branched chain;

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 -4: are schematic representations of the processes of present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides the processes for the preparation of 5-chloro-N-({(5S)-2-oxo- 3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof. In one embodiment, the present invention provides a process for the preparation of 4- {4-[5(S)-(aminomethyl)-2-oxo-l,3-o azolidin-3-yl]phenyl}mo holin-3-one compound of formula (II) or a salt thereof ,

(II)

comprising:

reacting the substituted oxazolidinone-phenyl-morpholinone compound of formula

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or) -OS0₂R where R = C]_-4 alkyl straight chain or branched chain, sub. or unsubstituted aryl, sub or unsub. aryl alkyl; with a suitable reagent to provide the compound of formula (II).

The reaction is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol. For example ammonium hydroxide.

The solvents as defined herein in this reaction step is selected from alcohols such as methanol, ethanol, isopropanol and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like;_Jialogenated— solvents— suclr^~as^~~ dichloromethane, ethylene dichloride and the like; esters such as ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF) and the like; or a mixture thereof. Preferably tetrahydrofuran or isopropyl alcohol or a mixture thereof.

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 period 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 8 hour to about 36 hours, preferably from about 12 to 24 hours.

In another embodiment of the present invention, there is provided acid addition salts of a compound of formula II

It would be beneficial to improve the thermodynamic properties of intermediate compound of formula II by providing other salt forms, which have consistent physical and chemical properties. The present invention seeks to provide these and other benefits, which will become apparent as the description progresses.

Beneficially, salt formation provides a means of altering the physicochemical characteristics without modifying its chemical structure. A salt form can have a dramatic influence on the properties of the compound. The selection of a suitable salt is partially dictated by yield, rate and quantity of the crystalline structure. In addition, hygroscopicity, stability, solubility and the process profile of the salt form are important considerations.

Advantageously the present invention provides various inorganic and organic salt forms of compound of formula II.

The acid addition salts are selected from organic salts such as mesylate, para toluene sulfonate, fumarate, succinate, citrate, maleate, acetate, formate, oxalate and like; Inorganic acid salts such as HC1, hydrobromide, hydroiodide, hydrogen sulfate, phosphoric acid salt and like.

The salt of compound of formula II are obtained by forming a solution of compound formula II by dissolving in a solvent or mixture of solvents or their aqueous mixtures.

In an embodiment the solvents that can be used include, but are not limited to ; Ci -C₆ aliphatic alcohols selected form the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; C3-Ci₀ aliphatic ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; C₂-C₅ aliphatic nitriles such as acetonitrile, propionitrile and the like; C3-C10 aliphatic esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions or their aqueous mixtures.

There is no specific order in which the compound of formula II and the acid must be combined in the solvent to form the solution. Generally the conditions are such that the entire compound of formula II (and all of the acid) is dissolved in the solvent, The contacting or combining of the compound of formula II -containing solvent with the acid is advantageously performed at an ambient or higher than ambient temperature, including the reflux temperature of the solvent. In other embodiments, the acid can be added, e.g., substantially at the same time as the base, before the base, etc.

The isolation of the salt in crystalline or amorphous form can be accomplished in various ways. For example, the precipitation can occur spontaneously upon contacting of the compound of formula II with the acid in the organic solvent. Precipitating of the acid addition salt of compound of formula II can also be induced by seeding the solution, cooling the solution, stirring at the same temperatures for longer time period evaporating at least part of the solvent, adding an antisolvent, and by combining one or more of these techniques. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.

The antisolvents include, but are not limited to, hydrocarbon solvents such as n-hexane, n- heptane, cyclohexane, petroleum ether, toluene and the like or mixtures thereof in various proportions without limitation. Preferably, n-hexane.

Advantageously the volume of solvent and antisolvent used to precipitate the solid can range from about 5 volumes to about 100 volumes with reference to starting compound taken. Preferably, from about 40 volumes to about 60 volumes with reference to starting compound are taken.

In another embodiment, the present invention provides an alternate process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one compound of formula (II) or a salt thereof

comprising:

a) reacting the compound substituted oxazolidinone-3-yl-phenyl-morpholinone of formula

(IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or) -OS0₂R where R = alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; 5 with a suitable metal azide to provide the compound of formula (IVa)

(IVa)

10 The suitable metal azides that can be used in the step (a) is selected from the group consisting of sodium azide, potassium" azide, lithium azide or a mixture thereof ; preferably sodium azide is being used.

The solvents that can be used in step (a) is selected from nitriles such as acetonitrile and the like; ketones such as acetone and the like; esters such as ethyl acetate, isopropyL

-1.5 acetate-and-the-like aprotic^{^}polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a mixture thereof. Preferably Ν,Ν-dimethylformamide (DMF).

The reaction step (a) is carried out at a temperature from about 30°C to about boiling point of the solvent(s) used, preferably at from about 70 °C to about 90°C.

The time required for the reaction to complete may also vary widely, depending on 20 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 suitable reducing agents that can be used in the step (b) is selected from metal catalysts such as zinc, nickel, platinum, palladium and the like combined with hydrogen 25 source.

The said hydrogen source is preferably one or more selected from hydrogen gas, hydrazine hydrate, ammonium formate, formic acid and formic acid azotrope. Preferably hydrogen gas.

The metal catalyst may be provided on an inert support such as carbon, activated 30 carbon or alumina. Other reducing agents such as triphenyl phosphine, metal borohydrides such as zinc borohydride, sodium borohydride and the like; trimethyl silyl iodide and the like; preferably triphenyl phosphine or catalytic reduction is being used. The other reducing agents which can convert azides into amines known in the literature are also contemplated within this invention.

The solvents that can be used in step (b) is selected from the group consisting of alcohols such as methanol, ethanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; hydrocarbons such as toluene and the like; nitriles such as acetonitrile and the like; halogenated solvents such as dichloromethane, chloroform and the like; or a mixture thereof. Preferably methanol or ethyl acetate is being used.

The reaction step (b) is usually carried out at a temperature range from about 30°C to about boiling point of the solvent(s) used, preferably at about 30°C.

The time required for the reaction step (b) 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 1 hour to 5 hours.

In yet another embodiment, the present invention provides an alternate process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one compound of formula (II) or a salt thereof

comprising:

a) reacting the compound substituted oxazolidinone-phenyl-morpholinone of

formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or)-OS0₂R where R = C i alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable sub. or substituted dibenzyl amine or a salt thereof to provide the compound of formula (IVb)

The suitable sub. or unsubstituted dibenzylamine used in the step (a) is selected from the group consisting of dibenzylamine , 4,4' -dimethyl dibenzylamine,

4-methyldibenzylamine, 4-methoxy dibenzylamine, 3-chlorodibenzylamine and the like;

preferably dibenzylamine.

The solvents that can be_used_in-step-faVis-selected-from^~the group consisting of alcohols such as methanol, ethanol, and the like; halogenated solvents such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; hydrocarbon solvents such as toluene, xylene and the like; ketones such as acetone and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or mixture thereof. Preferably acetonitrile or DMF.

Optionally the reaction step a) is carried out in the presence of a base, the base that can used is selected from organic bases such as triethyl amine, pyridine and the like; inorganic bases alkali and alkaline earth metal carbonates such as sodium carbonate and the like; bicarbonates such as sodium bicarbonate and the like ; or mixture thereof.

The reaction can be carried out at a temperature range from about 30°C to about the boiling point of the solvent(s) used, preferably from about 50°C to about 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 reaction step (b) can be carried out using suitable reducing agents reported for debenzylation in the literature. The preferable reducing agents are metal catalyst and a hydrogen source, wherein the said metal catalyst is preferably palladium on carbon and or platinum on carbon; more preferably, palladium - carbon.

The said hydrogen source is preferably one or more selected from the group consisting of hydrogen, hydrazine hydrate, ammonium formate, formic acid and formic acid azotrope, most preferably hydrogen.

The solvents that can be used in step (b) is selected from alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; ketones such as acetone and the like; hydrocarbons such as toluene and the like or a mixture thereof. Preferably methanol or ethyl acetate.

The reaction step (b) is usually carried out at a temperature range from about 0°C to about 50°C, more preferably at about 30°C.

The reaction step (b) is carried out in pjOs^nm-Of-hydrogen-pressure-range-from-about^" 1 to 50 atmospheres, preferably at 1-5 atmospheres.

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 atom (F, CI, Br, I) or sulfonyloxy group like methanesulfonyloxy, p-toluenesulfonyloxy,

4-nitrobenzenesulfonyoxy,4- bromobenzene sulfonyloxy, trifluromethanesulfonyloxy and the like; preferably sulfonyloxy group; more preferably p-toluenesulfonyloxy.

In another embodiment of the present invention, there is provided a process for the preparation of substituted oxazolidino -phenyl-morpholin-3-one compound of formula (IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or) -OS0₂R where R = C i_-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; comprising:

a) reacting the substituted phen nd of formula VIII

Where Rl is -OR2,-CX3 or NR₄R₃

2 ⁼C M2 alkyl straight chain or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;

X= halogen atom;

with the compound of formula VII

OR,

W_ ^ ^OR₆

VII

Where W=halogen atom or sulfonyloxy group;

R₅= -H or -CO-R⁷ where R⁷ =C i -i₂ alkyl straight or branched chain, optionally sub.with 1- 3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

Q Q

R = -H or R , where R =hydroxyl protecting group such as

i) R⁸=C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s),

sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain;

0

II

ii) R⁸=— c—

where R9= C 1-12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy;

9-fluoroenylmethyloxy (Fmoc); Rl l

RIO

iii) R R12

Where RIO, Rl 1, 12= independently selected from the group consisting of C i_-12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

to afford substituted oxazolidinone und of formula VI

VI

Where R6 is same as defined above,

b) deprotection of the compound of formula VI (when the R6 is hydroxyl protecting group) using a suitable reagent to afford the

compound of formula V

c) reacting the compound of formula V with a suitable reagent to afford the compound of formula IV.

VII Vllb VIII

VI

The use of base in not critical, the suitable bases that can be used in step a) is selected from base having an alkoxide group with C i_-7; C i_-4 alkyl carbanion such as methyl, sec-butyl, butyl or tert-butyl; a conjugate base of a carbamate; lithium diisopropyl amide, lithium amide, n-butyl lithium and the like or mixture thereof. Preferably a base with alkoxide group having C₄.₅ carbon atoms. More preferably tertiary amylate or tertiary butoxide is being used.

The most preferred bases containing a lithium cation and an alkoxide group such as tert-amylate or tert-butoxide.

When a base does not contain a lithium cation (bases for ex. Sodium, potassium or tetra alkyl ammonium salt) is used, mixing such a base with lithium salt, such as lithium chloride, lithium bromide, lithium iodide, lithium acetate, lithium tetraflouroborate and other lithium inorganic salts can be used to form the lithium cation and base in situ.

Optionally the reaction step a) is carried out using a nucleophile.

The use of nucleophile is not critical. An example of a nucleophile is an alkoxide group, linear or branched, having C i_-7 atoms. Preferred nucleophile is methoxide or ethoxide or isopropoxide or isobutoxide or 2-ethoxyethyl, 2-(N,N-dimethylamino) ethoxide or 2,2,2- trichloroethoxide or 2,2,2-trifluoroethoxide.

Commercial alkoxide salts such as lithium, sodium or potassium methoxide, ethoxide or isopropoxide can be used or the alkoxide formed insitu by reacting a_base-as-referred-above with a corresponding alcohol such as methanol, ethanol or isopropanol. Where a lithium alkoxide is used as a nucleophile and a base, the lithium cation, the base and the nucleophile required may be from the same chemical substance and atleast two equivalents of such chemical substance are needed for reaction.

The solvents that can be used in step a) should be neutral but are not limited to alcohols such as tert-amyl alcohol, tert-butyl alcohol and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF), 2-methyl THF and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonitrile and the like; halogenated solvents such as dichloromethane, chloroform and the like; Preferably, Ν,Ν-dimethylformamide (DMF) or THF or mixture thereof is being used.

The reaction step a) can be carried out at a temperature range from about -78°C to the boiling point of the solvent(s) used, preferably from about 0°C to 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, a period of from about 1 hour to about 24 hours, preferably from about 8 hour to about 20 hours. The deprotection reaction step (b) can be carried out by using any deprotecting agent reported in the art and capable of disassociating the desired protecting group. The use of suitable deprotecting reagents depends upon the protecting group present.

The suitable deprotection reagents used is selected from the group consisting of trimethyl silyl chloride; trimethyl silyl iodide; inorganic acids such as HC1, HBr, sulfuric acid, phosphoric acid and the like; alkali or alkaline earth metal alkoxides such as sodium

methoxide, magnesium methoxide and the like;metal carbonates such as potassium carbonate, and the like ; hydrazine hydrate, catalysts comprising of zinc, nickel, platinum, palladium and the like combined with hydrogen source. Alkali hydroxides such as potassium hydroxide and the like.

The solvents that can be used in step (b) is selected from the group consisting of water, acetic acid, alcohols such as methanol, ethanol, and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate,

ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), acetonitrile and the like; or mixture thereof.

The reaction step (b) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably at about 30°C.

The time required for the reaction step (b) 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 10 hours.

The reaction step (c) can be carried out by reacting the compound of formula V obtained in step (b) with a suitable reagent such as R-S0₂C1

Where R=C 1 -4 alkyl straight or branched chain, sub or unsub. aryl, sub or unsub arylalkyl.

The reaction step c) is carried out in the presence of a base. The base that can be used is selected from the group consisting of organic bases such as tri (C i_-6 alkyl) amines like triethyl amine and the like;pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like or mixture thereof; preferably triethyl amine.

The solvents that can be used in step (c) include but are not limited to nitriles such as acetonitrile and the like; ketones such as acetone and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; ester such as ethyl acetate and the like; halogenated solvents such as dichloromethane, chloroform and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF) and the like; or mixture thereof; Preferably dichloromethane.

The reaction step (c) can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 30°C.

The duration of time for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.

In one of the embodiment, the compound of formula IVd can be converted into the compound of formula IVe

IVd IVe

Where R is same as defined above and X is a halogen atom (F, CI, Br, I )

The reaction is carried out by reacting the compound of formula IVd with metal halides selected from lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, potassium bromide and potassium iodide in the presence of an organic solvent selected from ketones such as acetone and the like; ether such as tetrahydrofuran (THF) and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), acetonitrile and the like; or a mixture thereof; Preferably acetone is being used.

In yet another embodiment of the present invention, there is provided a compound of formula VII

VII

Where W=halogen atom or sulfonyloxy group; R₅= -CO-R⁷ where R⁷ =C i_{-] 2} alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

R₆= -H or R , where R =hydroxyl protecting group such as

i) R⁸=C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain;

o

I I

ii) R*=— C— R9

where R9= C alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy;

9-fluorenylmethyloxy (Fmoc);

Rl l

Where R10, Rl 1, 12 are independently selected from the group consisting of C M₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In another embodiment of the present invention, there is provided substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R = -H or R , where R =hydroxyl protecting group such as

i)R⁸=C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-i₀ alkenyl staright or branched chain;

o

I I

i_{j) R}8₌ _c __ R9

where R9= C .n alkyl straight or branched chain, optionally sub.with 1 -3 halogen atom(s), C i_i2 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);

Rl l

— i— R10

iii) R⁸= ^R12

Where R10, Rl 1, 12= independently selected from the group consisting of C _1-12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In another embodiment, the present invention provides a process for the synthesis of compound of formula VII.

Where W, R6 are same as defined above; R5= -CO-R7, R7

comprising:

reacting the compound of formula VII (where R5=H)

OH

^ ^OR₆

VII

Where W, R6 are same as defined above

With a compound of formula

o

I I

R7— ^c— ^x or (R7CO)₂0

Where R7 is same as defined above and X is a halogen atom;

to provide the compound of formula VII.

The above reaction step can be optionally carried out in the presence of a solvent selected from halogenated solvents such as dichloromethane, ethylene dichloride and the like; esters such as ethyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; hydrocarbon solvents such as toluene, xylene and the like; polar aprotic solvents such as acetonitrile, Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide, and the like or a mixture thereof, preferably dichloromethane is being used.

The reaction step is generally carried out without the use of a base and optionally performed using a base which can be selected from organic bases such as tri (C i_-6 alkyl) amines like triethyl amine and the like; pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.

The reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 0°C to about 30°C.

The time period required for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.

In yet another embodiment of the present invention, there is provided an alternate process for the preparation of substituted oxazolidinone morpholinoncpheny-l-compound of formula VI

VI

Where R6 is same as defined above.

reacting the morpholinone phenyl amine la Ila

Ila

with a compound of formula IX

OCOR,

IX

Where W = halogen atom or sulfonyloxy group; Rl =-OR2, NR3,R4 or CX3; Where R2, R3, R4, X are same as defined for compound VIII; Where R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as i) R =C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkeny! straight or branched chain;

o

i_{i) R}8₌ __C II _ . R9

where R9= C 1.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9- fluoroenylthethyloxy (Fmoc);

Where R10, Rl 1, 12= independently selected from the group consisting of C 1.12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

in the presence of suitable base and an organic solvent to provide the compound of formula VI.

The use of base in not critical, the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metai carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; preferably potassium carbonate.

The suitable organic solvents that can be used include but are not limited to alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; nitriles such as acetonitrile and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF) and the like; or mixture thereof. Preferably acetonitrile or DMF is being used. The reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably from about 50°C to the boiling point of the solvent(s) used.

The duration of time for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 12 hours.

In another embodiment of the present invention, there is provided a compound of formula IX

Where W=halogen atom or sulfonyloxy group;

Where Rl is -OR2,-CX3 or NR4R3

¾ ⁼Ci-i₂ alkyl straight chain or branched chain,^ptimally_substituted-with-l-3-halogen atom(s), sub or unsub aryl, sub or unsub arylalkyi;

R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring; X= halogen atom; R₆= -H or R , where R =hydroxyl protecting group such as

i) R⁸=C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain;

o

II

ii) R⁸= ^{c R9}

where R9= C j.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyi, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);

Where R10, Rl l, 12= independently selected from the group consisting of C i.i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula IX

OCOR,

IX

Where W, Rl, R6 are same as defined above,

comprising:

reacting the compound of formula of formula VII (where Κ5=Η)

Where W, R6 are same as defined above.

o

with the compound of formula ^{' R1} J ^cL ^x

Where Rl is same as defined above; X= halogen atom;

to provide the compound of formula IX.

The above reaction step is carried out in the presence of a solvent selected from ethers such as tetrahydrofuran (THF) and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; hydrocarbon solvents such as toluene, xylene and the like; polar aprotic solvents such as acetonitrile, Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide, and the like or a mixture thereof, preferably dichloromethane is being used.

The reaction step is generally carried out without the use of a base and optionally performed using a base which can be selected from organic bases such as tri (C i_-6 alkyl) amines like triethyl amine and the like;pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.

The reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 0°C to about 30°C. The time period required for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.

In yet another embodiment of the present invention, there is provided an alternate process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above

comprising:

reacting the morpholinone phenyl amine Ila

Ila

with the compound of formula X

Where X and Y are i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when i) X and Y are separate groups, X is halogen or sulfonyloxy group; Y is OR⁵ where R⁵= -H or -CO-R⁷, R⁷ = C alkyl straight or branched chain, optionally substituted with 1 -3 halogen atom(s), sub or unsub. aryl, sub or unsub aryl alkyl ; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; R6 is same as defined above;

to give substituted morpholinone phenyl amine compound of formula XI

XI

Where R₅, R₆ are same as defined above; b) carbonylation of the compound of formula XI with a suitable carbonylating agent to give the compound of formula VI

(or)

c) reacting the compound of formula XI with a suitable reagent to give the compound of formula XIa

.

Where R₅= -H or -CO-R⁷ where R⁷ =C alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

R6= -H or R⁸, where R⁸ =hydroxyl protecting group such as

i) R⁸=C i-i ₂ alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl staright or branched chain;

o

. I I

i_{i) R}8₌ __C _R9

where R9= C i .i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);

Where RI O, Rl l, 12= independently selected from the group consisting of C i.i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl; R14=-OR¹⁵, NR₃R , CX₃ or X, where R₃, R₄

together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring; R¹⁵= Ci-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X= halogen atom;

The suitable organic solvents that can be used in step (a) include but are not limited to alcohols such as methanol, ethanol and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or a mixture thereof. Preferably ethanol or aqueous ethanol is being used.

Optionally the reaction step (a) can be carried in the presence of catalyst selected from inorganic salts such as zinc chloride, ferric chloride, sodium iodide, lithium chloride, lithium bromide, stannic chloride and the like; β-cyclodextrin.

The amount of catalyst employed can be in the range from about 0.01 mole to about 1 mole on the 1 mole of compound of formula Ila taken.

Optionally the reaction step (a) is carried out in the presence of a base, the suitable bases that can be used is selected from the group consisting_piLinorganic-bases-sueh-as-aIkalr or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, collidine, diisopropylethyl amine, pyridine and the like or a mixture thereof; preferably collidine.

The reaction step a) can be carried out at a temperature range from about 30°C to the boiling point of the solvent(s) used, preferably at boiling point of the solvent used.

The time period 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, a period of from about 12 hour to about 64 hours, preferably from about 8 hours to about 24 hours.

The carbonylation step (b) is being carried out in the presence of suitable carbonylating agent selected from the group consisting of phosgene or phosgene equivalent such as diphosgene, triphosgene and like; carbon monoxide equivalents such as N,N- carbonyldiimidazole (CDI), diethyl carbonate and the like; mixture thereof. Preferably N,N- carbonyldiimidazole (CDI) is being used.

The suitable solvents that can be used in step (b) is selected from the group consisting of alcohols such as methanol, ethanol and the like; hydrocarbons such as toluene and the like; halogenated solvent such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; ethers such as tetrahydrofuran (THF), 2-methyl THF and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), N,N-dimethyIacetamide (DMA) and the like; or mixture thereof. Preferably dichloromethane is being used.

The reaction step (b) can be performed at any suitable temperature, specifically at a range from about 20°C to the boiling temperature of the solvent(s) used. Preferably from about 30 °C to about 35°C.

The time period for the reaction to complete may vary widely, depending upon various factors, typically a period of from about 30 minutes to about 48 hours, preferably from about 2 hours to about 24 hours is being used.

The reaction step (c) is carried out by reacting the compound of formula XI with reagent of formula

_as defined above; X=halogen atom. -

The suitable organic solvents that can be used in step (c) include but are not limited to alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; halogenated solvent such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF) and the like; or a mixture thereof. Preferably methanol or acetonitrile is being used.

Optionally the reaction step (c) is carried out in the presence of base, the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; preferably diisopropylethyl amine.

The reaction step (c) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably from about 0° C to about 30°C. The time period 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, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 10 hours.

The reaction step (d) is being carried out by reacting the compound of formula XIa with a suitable base, the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; n-butyl lithium, lithium diisopropyl amide and the like or mixture thereof; preferably sodium methoxide or lithium tert-butoxide or a mixture thereof.

Optionally the reaction step (d) is carried out using a nucleophile

The use of nucleophile is not critical. An example of a nucleophile is methoxide or

The suitable solvents that can be used in step (d) is selected from the group consisting of alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran (THF), 2- rriethyl THF and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), acetonitrile and the like; or a mixture thereof. Preferably methanol or DMF is being used.

The reaction step (d) can be performed at any suitable temperature, specifically at a range from about 25°C to the boiling temperature of the solvent(s) used. Preferably at boiling point of the solvent(s) used.

The duration of time for the reaction step (d) to complete may also vary widely, depending upon various factors, typically a period of'from about 30 minutes to about 48 hours, preferably from about 2 hours to about 24 hours is being used.

Optionally, the reaction steps (c) and (d) can be carried out in a single pot.

In another embodiment of the present invention, there is provided a compound of formula XI

XI -H or -CO-R⁷ where R⁷ =C i- i₂ alkyl straight or branched chain, optionally sub.with

1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

-H or R , where R =hydroxyl protecting group such as

i) R =C i.i₂ alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain;

o

i_{i) R}8₌ — c II _R9

where R9= C i.i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);

Where RIO, Rl 1, 12= independently selected from the group consisting of C i.i₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

In yet another embodiment of the present invention, there is provided an intermediate compound of formula XIa

Where R5, R6 are same as defined above and Ri₄=OR¹⁵, NR³R⁴, -CX₃ or X

R¹⁵=C i-i₂ alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; R3 and R4 together form a single ring with 'N' to which they are bonded or a heteroaryl ring; X=halogen atom;;

In yet another embodiment of the present invention, there is provided a process for the preparation of compound 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3- oxazolidin-5-yl}methyl)-2-thiophene-carboxamide of formula I

comprising: a) reacting substituted oxazolidinone-phenyl-morpholinone compound of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or) -OS0₂R where R = i_-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a reagent of formula R -NH₂ or a salt thereof to provide the compound of formula III

III

Where Ri₃ is sub or unsub. benzyl, C -i₀ alkenyl straight or branched chain;

b) reacting the compound of formula III with a compound 5-chloro-thiophene carboxylic acid of formula IXa or a derivative thereof

to provide the compound of

compound of formula I.

Optionally the reaction step (a) is carried out in the presence of base, the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; Optionally, the reaction step (a) is carried out in the presence of a solvent, the suitable organic solvents that can be used in step (c) include but are not limited to esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; nitriles such as acetonitrile and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or a mixture thereof, preferably N,N- dimethylformamide (DMF).

The reaction step (a) can be carried out at a temperature range from about 50°C to about 150 °C, preferably from about 70°C to 150 °C.

The time period 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, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 10 hours.

The reaction step (b) is carried out by reacting the compound of formula III with the compound of formula IXa or with a corresponding_c^rbonyLhalides-preferably--carbonyl^"

carboxylic acid of the compound of formula IXa in the presence of solvent and an activating or coupling agent and or a base to the compound of formula la.

The suitable bases that can be used in step (b) is selected from the group consisting of inorganic bases such as alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; amines such as triethyl amine, N,N-diethylamine, pyridine and the like or mixture thereof; Preferably triethylamine or sodium bicarbonate.

The suitable activating or coupling agents used in step (b) is selected from the group consisting of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide. HC1, Ν,Ν'- dicyclohexylcarbodiimide, 1-hydroxybenzotriazole monohydrate and the like.

The solvents that can be used in step (b) include but are not limited to water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as toluene and the like; ethers such as diethyl ether, tetrahydrofuran (THF) and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA), acetonitrile, pyridine, hexamethyl phosphoric triamide and the like; or mixture thereof. Preferably dichloromethane or toluene. The reaction step (b) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably from about 0°C to about 50°C.

The time period required for the reaction to complete may vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 4 hours.

The suitable deprotecting agent used in step (c) is selected depends upon protecting group present.

The suitable deprotecting reagents that can be used in step (c) is selected from the group consisting of p-toluene sulfonic acid, N-bromosuccinimide, triflouro acetic acid; hydrogenation catalysts like palladium on carbon, platinum oxide combined with hydrogen source and the like; inorganic acids such as HCl, HBr, sulfuric acid, phosphoric acid and the like or mixture thereof.

The suitable solvents that can be used in step (c) is selected from the group consisting of water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, chloroform and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), acetonitrile and the like; or mixture thereof. Preferably methanol or toluene is being used.

The reaction step (c) can be carried out at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably from about 30°C to about 50°C.

The time period required for the reaction step (c) to complete may vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 4 hours.

Optionally the process steps of present invention can be carried out by one pot synthesis independently.

In yet another embodiment of the present invention, there is provided a compound of formula III

Where R13 is C _3-io alkenyl straight or branched chain;

The novel processes of present invention for the preparation of rivaroxaban from novel intermediate compounds proceeds with high yields while achieving a good chemical and optical purity.

The novel process comprises preparation of alcohol precursor of rivaroxaban (I) by novel methods and the activation of an alcohol precursor, amination with some specific amines, which may be removed, and the submission of the compound obtained to an acetylation reaction and to a dealkylation reaction.

The herewith proposed novel processes of present invention are particularly advantageous in its practical industrial application since it is much more cost effective. No chromatography is required and final rivaroxaban (I) is obtained with high purity which is greater than 98%w/w. Additionally the last two steps of the process may be performed in one pot. The process represents a safer route to yield rivaroxaban (I), and has minimum environmental impact. All these advantages allow for advantageous_scale-up

For the transformation of the activated alcohol to the amine, the process of the present invention is advantageous since it avoids some of the drawbacks of the previously reported processes. Indeed, when phthalimide is used instead of the amines of the present invention, while being an expensive reactive, there are difficulties due to the obtention of side-products difficult to be isolated from the desired product. The deprotection reaction of phthalimide compounds can be carried out with hydrazine or using basic conditions. As known in the art, the use of hydrazine involves several process difficulties and the basic conditions require high temperatures which may not be compatible with rivaroxaban.

Advantageously, the compounds of formula (VI), (VII), (IX), (XI) and (XIa) obtained according to the processes of the present invention are novel and useful as intermediates in the synthesis of active oxazolidinone derivatives like rivaroxaban (I), which were identified, characterized and confirmed by the characterization data like C¹³ NMR, 1 H¹ NMR, MASS, IR.

The rivaroxaban (I) obtained following the processes of the present invention is of high purity with respect to the R-enantiomer and other impurities, without the need of tedious complicated purification steps such as chromatography. This is due to the abstention of pure intermediates, in particular the intermediate compounds of formula (II), (IV) and (VI) of the processes of the present invention. Intermediates of formula (II),(IV) and (VI) can be purified by crystallization or by formation of salts.

Thus, by the process of the present invention, rivaroxaban (I) can be produced safely and simply in high yield.

The intermediate compounds of formula (II), (IV) and (VI) are being key intermediates of the process, are obtained with good yields and good chemical and optical purity.

Rivaroxaban (I) is a compound with a low solubility in most solvents. This fact represents a drawback for the purification of the same. The inventors have further found that rivaroxaban may be obtained at high yields and purity levels if once synthesized it is recrystallized from a solvent of the group consisting of ketones, a mixture of (Ci-C₄)-alcohol/water, a mixture of (C2-Cg)-ethers and (Ci-C4)-alcohols. A preferred solvents are a mixture of (Ci-C₄)-alcohol with water or ketones alone or a mixture with water.

The starting amine compound of formula (Ila) is commercially available and can be prepared by any of the methods known in the art.

The intermediate compounds of formula II or a salt thereof obtained by the process of present invention can be further converted to the oxazolidinone derivatives like rivaroxaban (I) by the processes 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

Example 1: Preparation of [4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester

(Compound-VIII, R = -OCH₂Ph):

3.73g, (19.40 mmol ) of 4-(4-aminophenyl)morpholin-3-one and 80ml of acetone were charged in a clean and dry R.B. flask and stirred. A mixture of 40 ml of water and sodium bicarbonate (3.26g,38.80 mmol) was added. The resultant reaction mixture was cooled to about 0°C and benzyl chloroformate ( 50% w/w in toluene, 20.60 mmol) was added drop-wise. The reaction mixture was stirred at about 30°C for about 4 hours. After the completion of reaction, the reaction mixture was quenched by pouring into ice-water. The separated solid product was filtered and the solid was washed with water followed by n- hexane and dried to afford title compound as a white solid. Yield: 6.2 g, (% Yield: 98%).

Example 2: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound-V):

3.0g, (9.20 mmol) of [4-(3-oxo-morpho!in-4-yl) phenyl] carbamic acid benzyl ester and 25 ml of anhydrous tetrahydrofuran (THF) were charged in a clean and dry R.B. flask. Lithium-t-butoxide in tetrahydrofuran (THF) (1.0 MjJ jnl^LS^-mmoO-was-added-drop^^" wise followed by addition of S-(+)-3-chloro-l,2-propane diol (1.22g, 1 1 mmol) The resultant reaction mixture was stirred at about 30°C for about 24hours. The reaction mixture was diluted by adding 20ml of saturated ammonium chloride solution and tetrahydrofuran (THF) was evaporated under reduced pressure. The aqeous phase was extracted with dichloromethane (5 X 20 ml). The combined organic phases were dried over anhydrous magnesium sulphate. The solvent was distilled completely at about 30°C under vacuum. The crude obtained was suspended in 10 ml of ethyl acetate followed by heating to about reflux for about 30 min. The reaction suspension was cooled to about 30°C. The solid separated was filtered and the solid was washed with 2 ml of ethyl acetate to afford the title compound as light brownish solid. Yield : 2.0 gms, (% Yield: 74.8%).

Example 3: Alternative preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound-V):

Step-I: Preparation of 4-[4-{(R)-2,3-dihydroxy-prop lamino}phen l]mo holin-3-one

(Compound-XI, where R⁵=R⁶= -H):

19.2 g, (0.1 mol) of 4-(4-aminophenyl) morpholin-3-one and 200ml of methanol were charged in a clean and dry 500ml 4 neck R.B. flask. 7.4 g (0.1 mol) of (R)-glycidol was added under reflux in 6 lots over about 8 hours. The resultant reaction mixture was stirred at reflux for about 6 hours. The solvent was distilled completely under vacuum to afford the title compound as a thick residue. Yield: 26.6 g, (% Yiled: 100% ).

Step-II: Preparation of 4-(4-((R)-5-hydroxymethyl)-2-oxo-oxazolidin-3- yl) henyl)morpholin-3-one:

26.6 gms, (0.1 mol) of 4-[4-{N-(R)-2,3-dihydroxy propyl amino}phenyl]morpholin-3- one obtained from Step-I and 100ml of methanol were charged into a clean and dry R.B.flask. 22.8g, (0.1 1 mol) of di-tert-butyl dicarbonate (BOC anhydride) was added and the resultant reaction mixture was stirred at about 30°C for about 48 hrs. 5.4 g, (0.1 mol) of anhydrous sodium methoxide was added and stirred at reflux for about 2hrs. After completion of the reaction as indicated by TLC, the solvent was distilled off completely under vacuum to afford the title compound as a semi-solid. The solid obtained was re-crystallized in methanol -water mixture to yield the title compound as off-white crystalline solid.

Yield: 21g, (% Yield: 72%.).

Example 4: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound- V):

Step I: Preparation of (S)-Butyric acid-2-butyryloxy-l-(chIoromethyl)-ethyl ester

(Compound -VII, where R⁵ = R⁶ = -CO-C₃H₇ and W=-C1):

1 1.05g, (0.1 mol) of S-(+)-3-chloro-l ,2-propanediol and 100ml of dichloromethane were charged into a clean and dry R.B.flask. 30.3g, (0.3 mol) of triethylamine was added and cooled to about 0°C. 24.5g (0.23 mol) of butyryl chloride was added drop-wise. The resultant reaction mixture was brought to about 30°C and stirred for over-night. The organic layer was washed with dil.HCl (20 ml x 2), water (20 ml) and saturated sodium bicarbonate solution (20 ml x 2). The organic and aqeous layers were separated and the organic layer was dried over anhydrous sodium sulfate. The organic layer was distilled completely under vacuum to afford the title compound as colorless liquid. Yield: 16,89g, (% Yield: 72.1%).

Step II: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one:

3.0g, (9.2 mmol) of [4-(3-oxo-mo holin-4-yl)phenyl]carbamic acid benzyl ester and

10 ml of anhydrous DMF were charged into a clean and dry R.B. flask, methanol (368 mg, 11.5 mmol) was added and cooled the reaction mass to about 0°C. and 1.0 M,28.4 ml, (28.4 mmol) of Lithium-t-butoxide in THF was added and stirred for about 10 min. 3.45g, (13.9 mmol) of (S)-Butyric acid-2-butyryloxy-l -(chloromethyl)-ethyl ester obtained in Step-I was added drop-wise and the resultant reaction mixture was stirred at about 30 °C for about 18 hrs. The reaction mixture was quenched with 20ml of saturated NH₄C1 solution and water (20 ml). The reaction mass was extracted with dichloromethane (20ml x 4). The organic phases were combined and dried over anhydrous MgS0₄ and concentrated under vacuum. The crude obtained was purified by column chromatography (n-hexane-ethyl acetate (80:20) as a eluant) to yield title compound as an off-white solid.

Yield: 1.22g, (% Yield: 45.6%).

Example 5: Alternative preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound- V):

Step I: Preparation of Butyric acid-2(R)-2-hydroxy-3-[4-(3-oxo-morpholin-4-yl)phenyl

aminoj-propyl ester (Compound-XI, R⁶ = -CO-C3H7 and R⁵=-H):

19.2g, (0.1 mol) of 4-(4-aminophenyl)-morpholin-3-one and 200ml of isopropyl alcohol were charged into a clean and dry R.B. flask. 14.4g, (0.1 mol) of (R)-glycidyl butyrate was added and the resultant reaction mixture was refluxed for about 20 hrs. The solvent was distilled off completely and the crude was used for further reactions without further

purification. Yield: 33.6g, (% Yield: 100 %) Step II: Preparation of Butyric acid -2-oxo-5(R)-3-[4-(3-oxomorpholin-4-yl)- phenyl]oxazolidin-5-yl-methyl ester: (Compound-VI , where R⁶ = -CO-C₃H₇):

33.6g, (0.1 mol) of Butyric acid -2(R)-2-hydroxy-3-[4-(3-oxomorpholin-4- yl)phenylamino]propyl ester and 160ml of dichloromethane were charged into a clean and dry R.B. flask. 17.82g, (l . lmol) KN'-Carbonyldiimidazole was added and the resultant reaction mixture was stirred at about 30°C for about 48 hrs. The reaction mixture was quenched by adding 150ml of water. The organic and aqueous phases were separated and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum to yield title compound. Yield: 34g, (% Yield: 93.9%).

Step III: Preparation of 4-(4(R)-5-hydroxymethyl)-2-oxo-oxazolidin-3- I)phenyl)morpholin-3-one:

34.0g, (0.094 mol) of Butyric acid-5(R)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)- phenyl]oxazolidin-5-yl-methyl ester and 170 ml of methanol were charged into a clean and dry R.B.flask. 500mg, (0.0093mol) of sodium methoxide was added and stirred at about 30 °C for about 1 hr. The solvent was distilled-off under vacuum. The pH of reaction mixture was adjusted to about 2 with dil.HCl. The solid separated was filtered and the solid was washed with water. The solid obtained was dried at about 60°C to yield title compound as off-white to light brown color solid. Yield: 15. lg, (% Yield: 55 %).

Example 6: Alternative preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound-V):

33.6g, (0.1 mol) of 2(R)-Butyric acid -2-hydroxy-3-[4-(3-oxo-morpholin-4-yl)phenyl amino]propyl ester (prepared in Ex-5, Step-I) and 170 ml of methanol were charged into a clean and dry 500ml 4 neck R.B.flask. 24.9 g, (0.12 mol) of BOC-anhydride was added and the resultant reaction mixture was stirred at about 30 °C for about 48 hrs. After completion of the reaction as indicated by TLC, 5.4g, (0.1 mol) of sodium methoxide was added and refluxed till completion of the reaction as indicated by TLC (for about 2 hrs). The solvent was distilled- off completely and the solid obtained was crystallized from methanol-water to yield the title compound as light brown to off-white crystalline solid.

Yield: 18.2g, (% Yield: 62.3%)

Example 7: Preparation of 4-(4-((R)-5-Benzyloxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound-VI, where R⁶ = -CH₂Ph):

3.0g, (9.2 mmol) of [4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester and ml of anhydrous THF were charged into a clean and dry R.B.flask. 1.0M,

2776fnl 27.6mmol of Lithium-t-Butoxide in THF was added dropwise followed by 4.2g, (12.5 mmol) of (S)-l-0-benzyl-3-p-toluenesulfonyl-syn-glycerol (prepared as per TL,Vol-30 (21),P- 2751) in THF (10 ml) was added drop-wise at about 0°C. The resultant reaction mixture was stirred at about 30°C for about 22 hrs. The reaction mixture was quenched with 25 ml of sat. NH₄C1 solution and water (25 ml). The reaction solution was extracted with dichloromethane (25 ml X 4). The combined org. phases were dried over anhydrous MgS0₄ and the organic phase was concentrated in vacuum. The crude obtained was re-crystallized from isopropyl alcohol-hexane to yield the title compound. Yield: 1.84 g, (% Yield: 48%).

Example 8: Alternative preparation of 4-(4-(R)-5-(BenzyloxymethyI)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound-VI, where R⁶ = -CH2Ph):

Step-I: Preparation of (S)-Toluene-4-Sulfonic acid -3-benzyloxy-2-

(phenoxycarbonyloxy)-propyl ester (Compound-IX where w = -OTs,R' = OPh, R⁶ = -CH2Ph):

O-CO-OPh

TsO^ - ^OCH,Ph ^ ur .

¹ - TsO.^/ ^OCH_jPh

3.36 gms,(10 mmol) of (S)-l-0-benzyl-3-p-toluene sulfonyloxy-syn glycerol, pyridine (1.98g,25 mmol) and 35 ml of dichloromethane were charged into a clean and dry R.B.flask. 2.35 g, (15 mmol) of phenylchloro formate was added by drop-wise at 0°C. The resultant reaction mixture was stirred at about 30°C for over-night. The reaction mixture was washed with IN HCl solution until the aq. wash is acidic followed by sat. sodium bicarbonate solution( 10 ml x 2) and water ( 10 ml x 2). The separated organic layer was distilled-off completely to provide title compound (Yield: 3.79 g, (% Yield: 82% ) and used in next step as such.

Step-II: Preparation of 4-(4-((R)-5-(Benzyloxy methyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one:

3.79g, (8.3 mmol) of (S)-toluene-4-sulfonic acid-3-benzyloxy-2-(phenoxy carbonyloxy)-propyl ester (prepared in Step-I) and 4-(4-aminophenyl)morpholin-3-one (2.28g, 11.8 mmol) in DMF (25 ml) were charged into a clean and dry R.B. flask, potassium carbonate ( 2.86g, 20.7 mmol) and catalytic amount of triethyl benzyl ammonium chloride were added and then stirred at 90-95°C for over-night. The reaction mix. was poured into water (100 ml) and extracted with ethyl acetate (25 ml X 3). The combined organics were washed with dil.HCl (10 ml X 2) and water (10 ml X2). Distilled-off solvent completely and the crude product obtained was purified by column chromatography (n-hexane-ethyl acetate (90:10) as a eluent) to yield title compound as an off- white crystalline solid. Yield: 1.14g, (%YieId: 36%). Example 9: Alternative preparation of 4-(4-(R)-5-(Benzyloxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (Compound- VI, where R⁶ = -CH₂Ph):

Step.I: Preparation of 4-(4-((R)-3-benzyIoxy-2-hydroxy propylamino)phenyl-morpholin-3-one

To a suspension of 4-(4-aminophenyl)-morpholin-3-one (19.2 g, 0.1 mol) in ethanol (200 ml) was added (R)-Benzylglycidyl ether ( 16.4 g, 0.1 mol) prepared as per TL , V- 30(21),P-2751) and refluxed for 20 hrs. Distilled-off solvent completely and used for next reaction as such without further purification. Yield: 35.6g, (% Yield: 100 %). Step. II: Preparation of 4-(4-((R)-5-(benzyloxymethyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one:

To a solution of 4-(4-((R)-3-(benzyloxy-2-hydroxy-propylamino)phenyl)morpholin-3- one (35.6g,0.1 mol) in dichloromethane (300 ml) was added N,N^!-Carbonyldiimidazole(19.4g, 0.12 mol) and stirred for 44 hrs at about 30°C. Added water( 200 ml) and separated the org. layer and distilled-off solvent completely and re-crystallized from diisopropyl ether.

Yield: 29.2g, (% Yield: 76%).

Example 10: Preparation of 4-(4-((R)-5-(Benzyloxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)-morpholin-3-one(Comp-XI, Where R⁶ = -CH₂ Ph)

Step-I: Preparation of (S)-Acetic acid-l-benzyloxymethyl-2-(toluene-4-sulfonyloxy)-ethyl ester (Comp-X Where X = -OTs, Y = -OCOCH3, R⁶ = -CH₂Ph):

.. . - - OH ^"

TsO. CoCH.Ph

To a solution of (S)-l -0-benzyl-3-p-toluene sulfonyloxy-syn glycerol (3.36g,10mmol) in dichloromethane (35ml) was added acetic anhydride (1.275g,12.5mmol) and refluxed for 4hrs. Added water (20ml) and separated the layers. Concentrated the org. layer to yield title compound (Yield: 2.9g,76.7% of theory).

Step-II: Preparation of acetic acid-l-benzyloxymethyl-2-[(R)-4-(3-oxo-morpholin-4- yl)phenylamino]-ethylester (Comp-XI,where R⁵ = -COCH₃,R⁶ = -CH₂Ph):

To a suspension of (S)- Acetic acid-l-benzyloxy methyl-2-(toluene-4-sulphonyloxy)- ethyl ester (2.9g,7.7mmol) (prepared in step-I) in 25ml toluene were added 4-(4-amiriophenyl)- morpholin-3-one (1.62g,8.4 mmoI),collidine (1.39g,1 1.5 mmol)and ethanol (0.5 ml).The reaction mixture was heated to 105°C and stirred for 6hrs. RM cooled to RT and stirred for lhr at RT. Filtered the solid and washed with toluene and water to yield title compound.

Yield: 2.0g, (66.6% of theory). Step-III: Preparation of acetic acid-l-benzyloxymethyl-2-{[(R)-(3-oxo-morpholin-4-yl)- phenyl]-chloro carbonyl-amino} ethyl ester (Comp-XI a,where R¹⁴ = CI, R^s = - COCH3, R⁶ = -CH₂Ph):

To a solution of acetic acid-l-benzyloxymethyl-2-[(R)-4-(3-oxo-morpholin-4- yl)phenylamino]-ethyl ester (2.0g,5mmol) in chloroform (25 ml) was added triphosgene (0.5g, 1.68 mmol) and stirred for 2 hrs at 50°C.Cooled the RM to RT and added water (20ml) and separated the layers, washed the org. layer with dil.HCl (20ml) followed by saturated sodium chloride solution (20ml). Concentrated the org.layer to yield title compound.

Yield: 1.9g (82.6% of theory).

Step-IV: Preparation of 4-(4-((R)-5-(benzyloxyrnethyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one:

A solution of acetic acid-l -benzyloxymethyl-2-{[(R)-(3-oxo-morpholin-4-yl]-phenyl]- chlorocarbonyl-amino}ethyl ester (1.8g,4.2mmol) (prepared in Step-III) and methanol (0.15g,4.7mmol) in anhydrous DMF (10ml) was cooled to 0°C and 1.0 M solution (8.4 ml,8.4mmol) of lithium-tert-butoxide in . anhydrous THF was added by drop-wise and stirred for about 2hrs. Quenched the RM with sat. NH₄C1 solution (10ml) and water (10ml). The RM extracted with ethylacetate (10ml X 4) and combined org. layer washed with water and dried with MgS04 and concentrated under vacuum. The crude obtained was re-crystallized from ethyl acetate-hexane to yield title compound. Yield: 1.15g (71.8 % of theory).

Example 11: Preparation of 4-(4-((R)-5-(hydroxy methyl)-2-oxo-l,3-oxazolidin-3- yl)phenyl)-morpholin-3-one (Compound- V :

To suspension of 4-(4-((R)-5-(benzyloxymethyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one (17.5g, 0.046 mol) (prepared in the previous examples) and 2g of 10% w/w Palladium on carbon in 400 ml of absolute alcohol was hydrogenised in an autoclave, at R.T under a pressure of 4-5 kg of hydrogen. Then it was filtered, the solvent evaporated and re- crystallized in ethyl alcohol-water to yield title compound as off-white crystalline solid.

Yield: 1 1.86g, (% Yield: 88.7%).

Example 12: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- y l)phenyl)morphol in-3-one (Compound- V) :

Step-I: Preparation of (S)-toluene-4-Sulfonic acid-2,3-bis-(phenoxy carbonyl oxy)-propyl ester (Compound-IX, where R⁶ = -CO-OPh,R' = -OPh and W= - OTs):

To a cold solution of (S)-3-tosyloxy-l,2-propanediol (2.46g, lOmol) (prepared as per JOCV-43 (25),P-1978) and pyridine (3.95g, 50 mmol) in dichloromethane (25 ml) was added phenyloxy carbonyl chloride (4.68g, 30mol) and stirred for 18 hrs at about 30°C . Diluted the reaction mass with water (20 ml) and dichloromethane (20 ml). Separated the layers and org. layer washed with IN HC1 solution until aqeous wash is acidic followed by sat. NaHC0₃ solution (10 ml x 2) and water (20 ml x 2). Dried the org. layer with MgS0₄ and concentrated to give title compound. Yield: 3.16g, (% Yield: 65 %).

Step-II: Preparation of 4-(4-((R)-5-((phenyloxycarbonyloxy)methyl)-2-oxo-oxazolidin-3- yl)phenyl)-morpholin-3-one (Compound-VI, where VI = -CO-OPh):

To a solution of (S)-toluene-4-Sulfonic acid-2,3, bis-(phenoxy carbonyloxy)propyl ester (3.1 g,6.38 mmol) and 4-(4-aminophenyl)-morpholin-3-one (1.53 g,7.97 mmol) in DMF (25 ml), potassium carbonate (2.2g, 15.95 mol) and catalytic amount of triethylbenzyl ammonium chloride were added and then stirred at 90°C for overnight. The reaction mix. was poured into water (100 ml) and extracted with ethyl acetate (25 ml X 4). The combined organics were washed with dil.HCl (10 ml X 2) and water (10 ml X 2). Distilled-off solvent completely and the crude compound obtained was purified by column chromatography (Ethyl acetate-Hexane (10: 90) as a eluent) to yield the title compound.

Yield: 1.3 g, (% Yield: 49.9%). Step-III: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl)-phenyl)- orpholin-3-one:

To a solution of 4-(4-((R)-5-((phenyloxy carbonyloxy)methyl-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (4.12 g, 10mmol) in methanol (40 ml) was added sodium methoxide (0.54g, 10 mmol) and stirred for 4 hrs at about 30°C . Distilled-off solvent completely and re-crystallized from methanol-water to yield title compound as an off-white crystalline solid. Yield : 2.28g, (% Yield: 78 %).

Example 13: Preparation of 4-[4-((R)-5-(p-toluenesulfonyloxy methyl)-2-oxo-oxazolidin- 3-yl)phenyl]-morpholin-3-one (Compound-IV,where L = -OTs)

4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxaolidin-3-yI) phenyl) morpholin-3-one (29.2g, 0.1 mol) and triethylamine (17.67 g, 0.175 mol) were dissolved in dichloromethane (180 ml). The resulting solution was cooled to 0-5°C and to the cold solution p-toluene sulfonyl chloride (28.5g, 0.15 mol) was added. The obtained solution was warmed to RT and stirred for 18 hrs. After the completion of reaction, water (100 ml) was added and stirred for 10 min. DCM layer was collected and concentrated. Further, methanol (150 ml) was added and was stirred at RT for 30 min. The solid was filtered, washed with methanol and dried to obtain the title compound as an off-white solid. Yield: 37.9 g, (% Yield: 85% ).

Example 14: Preparation of 4-[4-((R)-5-(iodomethyl)-2-oxo-oxazolidin-3-yl)phenyl]- morpholin-3-one (Compound-IV where L = iodo):

To a solution of 4-[4-((R)-5-(p-toluene sulfonyloxy methyl-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one (4.46 g, 10 mmol) in acetone ( 45 ml) was added Sodium iodide (6.0 g, 40 mmol) and refluxed for 18 hrs . Filtered the inorg. Salts and washed with acetone (10 ml). Concentrated the filterate and re-crystallized from methanol to yield title compound as a off-white solid. Yield :3.2g, (Yield: 80 %).

Example 15: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}-morpholin-3-one . p-TSA salt (Comound-II):

4-[4-((R)-5-(p-toluene sulfonyloxy methyl)-2-oxo-oxazolidin-3-yl)phenyl]-morpholin-

3-one (60 g) was dissolved in a mix. of (1 :1 :1) THF/IPA /aq. ammonium hydroxide (900 ml) and heated in an auto clave to 85°C , further stirred at 80-85°C for 24 hrs. After completion of reaction,it was cooled to RT. The reaction mass was filtered. The filterate was concentrated to dryness. Residual moisture was removed by using IPA (120 ml). To the resulting residue Isopropyl alcohol (180 ml) was added , heated to 50-55°C for 2hrs and cooled to about 30°C.The solid mass was filtered and washed with dichloromethane (50 ml). Dried the solid obtained at 60-65°C to yield title compound as light brown color solid.

Yield: 42 g, (% Yield: 67.2 %).

Example 16: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}-morpholin-3-one (Compound-II):

Step-I: Preparation of 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}- morpholin-3-one (Compound-IV a):

To a solution of 4-[4-((R)-5-(p-toluene sulfonyloxy methyl)-2-oxo-oxazolidin-3- yl)phenyl]morpholin-3-one (44.6 g, 0.1 mol) in DMF (150 ml) added Sodium azide (13.0 g, 0.2 mol) to the solution and heated to 80-85°C and stirred at the same temperature for 4 hrs. After completion of reaction as indicated by TLC, it was cooled to RT and diluted with water (300 ml). Further , stirred for 1 hr. The solid mass was filtered, washed with water and dried the title compound as off-white solid. Yield: 30.1g (% Yield: 95%). Step-II: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-

To a solution of 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}- morpholin-3-one (30 g, 0.095 mol) in methanol (1.0 lit) was added 10 %w/w Pd/C (3.0 g).The reaction mix. was hydrogenated under 2-4 kg/cm² hydrogen pressure for 4hr. After completion of reaction (as indicated by TLC); catalyst was removed by filtration. The filtrate was concentrated and re-crystallized from methanol. Yield: 25g (% Yield: 90.9% ).

Example 17: Preparation of4-{4-[(5S)-5-aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (Compound-II):

Step-I: Preparation of 4-{4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (Compound-IVb):

To a suspension of 4-[4-(R)-5-(p-toluenesulfonyloxy methyl)-2-oxo-oxazolidin-3- yl)phenyl]morpholin-3-one (4.46g, 10 mmol) and Sodium carbonate (21.2g, 20 mmol) in DMF ( 50 ml) was added dibenzylamine (2.95 g, 15 mmol) and heated to 90°C and maintained at 90°C for 2hrs. After completion of reaction (as indicated by TLC),it was cooled to RT and added water (100 ml) and stirred for 30 min. Filtered the solid obtained and washed with water (20 ml) to yield title compound as an off- white solid. Yield: 3.62g (% Yield: 77 % ).

Step-II: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one:

To a solution of 4-{4-[(5S)-5-(dibenzylamino)methyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (3.5 g,7.4 mmol) in ethyl acetate (50 ml) was added 10 % Pd- C(0.5 g) and the air was replaced with Nitrogen. Hydrogen was passed into the mix. and the mix. was heated to 50°C and reacted for 18 hrs. Filtered and the solvent was evaporated to provide title compound as white crystalline solid. Yield: 2.0 g (% Yield: 92.6%).

Example 18: Preparation of Rivaroxaban Compound-!):

Step-I: Preparation of 4-{4-[(5S)-5-(benzylaminomethyl)-2-oxo-l,3-oxazolidin-3-yl]- mor holin-3-one (Compound-Ill, Where R¹³ = Benz l):

To 4-[4-((R)-5-(p-toluenesulfonyloxy methyl)-2-oxo-oxazolidin-3-yl)phenyl]- mo holin-3-one (4.46g,10 mmol) was added benzylamine (15.8 g, 0.145 mol) and heated to 70°C and further , stirred for 5 hr. After completion of reaction it was cooled to RT and diluted with toluene (50 ml). The solution was successively washed with 10 % NaHC03 solution , 10 % NH4C1 solution and water. Toluene layer was concentrated to obtain the title compound as an oil. Yield:4.8 g. - -

Step-II: Preparation of 5-chloro-N-[{(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3- oxazolin-5-yl]methyl]-N'-Benzyl-2-thiophene carboxamide (Compound-la, where R¹³= Benzyl): rtry

At 0°C , 5-cholorothiopene-2-carbonyl chloride (2.29g, 12.7 mmol) was added drop- wise to a solution of above prepared benzylaminocompound (4.8g) in pyridine (90 ml). Ice- cooling is removed and the reaction mix. was stirred at RT for 1 hr and admixed with water. Dichloromethane is added and the phases are separated, and the aq. phase is then extracted with dichloromethane. The combined organic phases are dried on anhydrous sodium sulphate, filtered and concentrated under reduced pressure and used for next step without further purification. Yield: 5.0 g. (% Yield: 75.7 %).

Step-Ill: Preparation of Rivaroxaban (I):

To a solution of 5-ο1ι1θΓθ-Ν-[{(58)-2-οχο-3-[4-(3-οχο-4-ηιοφΗοΗη>Ί)ρ1ιεη>Ί]-1,3- oxazolidin-5-yl}methyl]-N'-benzyl-2-thiophene carboxamide (Prepared in Step-II) (5.0 g) in ethanol ( 100 ml) was added 10 % Pd-C( l.Og) and the mixture was hydrogenated at 50-55°C under a hydrogen pressure of 4-5 kgs for about 18 hrs. Filtered the catalyst and concentrated the filtrate and the crude obtained was re-crystallized from acetone to yield the title compound as white crystalline solid. Yield: 2.25g (% Yield: 54.3%).

Claims

We Claim:

1) A process for the preparation of 4-{4-[5(S)-(amino methyl)-2-oxo- 1,3-oxazolidinone-phenyl-morpholinone compound of formula (II) or a salt thereof ,

(II)

comprising:

reacting the substituted oxazolidinone-phenyl-morpholinone compound of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), (or) -OS0₂R where R = C alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable reagent to provide the compound of formula (II). The reaction step is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol. For example ammonium hydroxide.

2) The process of claim 1 , wherein the solvents that can be used is selected from alcohols like, as methanol, ethanol, isopropanol; nitriles like acetonitrile; ketones like acetone;

halogenated solvents like dichloromethane, ethylene dichloride; esters like ethyl acetate, isopropyl acetate, ethers like tetrahydrofuran (THF); aprotic polar solvents like N,N- dimethylformamide (DMF) or a mixture thereof, preferably tetrahydrofuran or isopropyl alcohol.

3) An alternate process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin 3-yl]phenyI}morpholin-3-one compound of formula (II) or a salt thereof

(ID

comprising:

a) reacting the substituted oxazolidinone-phenyl-morpholinone compound of formula

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), or -OS0₂R where R = Ci_-4 alky] straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable metal azide to a)

b) subjecting the compound of formula (IVa) to reduction using suitable reducing agent to provide the compound of formula II. 4) The process of claim 3, wherein the suitable metal azides used in the step (a) is selected from the group consisting of sodium azide, potassium azide, lithium azide or a mixture thereof ; preferably sodium azide is being used.

5) The process of claim 3, wherein the solvents used in step (a) is selected from nitriles like acetonitrile; ketones like acetone; esters like ethyl acetate, isopropyl acetate; aprotic polar solvents like Ν,Ν-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a mixture thereof, preferably Ν,Ν-dimethylformamide (DMF).

6) The process of claim 3, wherein the suitable reducing agents used in the step (b) is selected from metal catalysts like zinc, nickel, platinum, palladium combined with

hydrogen source; triphenyl phosphine; metal borohydrides like sodium borohydride, zincborohydride; lithium aluminium hydride, trimethylsilyl iodide.

7) The process of claim 3, wherein the solvents used in step (b) is selected from the

. group consisting of alcohols like methanol, ethanol; esters like ethyl acetate; ethers like tetrahydrofuran (THF); nitriles like acetonitrile; halogenated solvents like

dichloromethane, chloroform; hydrocarbons like toluene; or a mixture thereof, preferably methanol or ethyl acetate.

8) An alternate process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l ,3- oxazolidin-3-yl]phenyl}morpholin-3-one compound of formula (II) or a salt thereof

(Π)

comprising:

a i) reacting the compound substituted oxazolidinone-phenyl-morpholinone of

formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = CM alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable sub. or un substituted dibenzyl amine or a salt thereof to provide the compound of formula (IVb)

(IVb)

9) The process of claim 8, wherein the suitable sub. or unsubstituted dibenzylamine used in the step (a) is selected from the group consisting of dibenzylamine, 4- methyldibenzylamine, 4,4^l -dimethyldibenzylamine, 3-chiorodibenzylamine, 4- methoxydibenzylamine and the like;

10) The process of claim 8, wherein the solvent used in step (a) is selected from

the group consisting of alcohols like methanol, ethanol; halogenated solvents like dichloromethane, chloroform; nitriles like acetonitrile; hydrocarbon solvents like toluene, xylene ; ketones like acetone; aprotic polar solvents like N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO); or a mixture thereof, preferably acetonitrile or DMF.

1 1) The process of claim 8, wherein the reaction step (a) is optionally carried out in the

presence of a base, the base used is selected from organic bases like triethyl amine, pyridine ; inorganic bases include alkali and alkaline earth metal carbonates like sodium carbonate ;bicarbonates like sodium bicarbonate or a mixture thereof. 12) The process of claim 8, wherein the reaction step (b) is carried out using suitable reducing agents are metal catalyst and a hydrogen source, wherein the said metal catalyst is preferably palladium on carbon and or platinum on carbon; more preferably, palladium - carbon, the said hydrogen source is preferably one or more selected from the group consisting of hydrogen, hydrazine hydrate, ammonium formate, formic acid and formic acid azotrope, most preferably hydrogen.

13) The process of claim 8, wherein the solvent used in step (b) is selected from alcohols like methanol, ethanol; esters like ethyl acetate; ethers like tetrahydrofuran (THF), ketones like acetone; hydrocarbons like toluene or a mixture thereof, preferably methanol or ethyl acetate.

14) A process for the preparation of substituted oxazolidinone-phenyl-morpholinone

compound of formula (I V)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), or -OS0₂R where R = CM alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; comprising:

a) reacting the substituted phenyl morphilinone compound of formula VIII

Where Rl is -OR2,-CX3 or NR₄R₃

R2 ⁼Ci-i2 alkyl straight chain or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring; X= halogen atom;

with the compound of formula VII OR₅

VII

Where W=haIogen atom or sulfonyloxy group;

R₅= -H or -CO-R⁷ where R⁷ =C _\._l2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyi;

Q Q

R₆= -H or R , where R ^hydroxy! protecting group such as

i)R⁸=C 1 -12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain; ii) R⁸=— c— R9

where R9= C i.i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1 -12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyi, sub/unsub arylalkoxy;9- fluorenylmethyloxy (Fmoc)

iii) R*= R12

Where RIO, Rl 1 , 12= independently selected from the group consisting of C 1.12 alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyi;

to afford substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above,

compound of formula V (when the R6 is hydroxyl protecting group)

15) The process of claim 14, wherein the use of base is not critical in step (a), the suitable base that can be used in step a) is selected from base having an alkoxide group with C i_-7; C i_4 alkyl carbanion such as methyl, sec-butyl, butyl or tert-butyl; a conjugate base of a carbamate; lithium diisopropyl amide, lithium amide, n-butyl lithium or mixture thereof, preferably a base with alkoxide group having C4-5 carbon atoms, more preferably tert-amylate or t-butoxide , most preferably bases containing a lithium cation and an alkoxide group such as tert-amylate or tert-butoxide.

16) The process of claim 14, wherein the reaction step a) is carried out optionally using a

nucleophile, which is selected having an alkoxide group, linear or branched, having C i_-7 atoms, preferably nucleophile is methoxide or ethoxide or isopropoxide or isobutoxide or 2-ethoxyethyl, 2-(N,N-dimethylamino) ethoxide or 2,2,2-trichloroethoxide or 2,2,2- Trifluoroethoxide or a mixture thereof.

17) The process of claim 14, wherein the solvent used in step a) is selected from alcohols like tert-amyl alcohol, tert-butyl alcohol, hydrocarbon solvents like toluene and ethers such as tetrahydrofuran (THF), 2-methyl THF, aprotic polar solvents like N,N- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonttrile or a mixture thereof. Preferably N,N-dimethylformamide (DMF) or THF or mixture thereof.

18) The process of claim 14, wherein the deprotection reaction step (b) the deprotecting agents depends upon the protecting group present, the suitable deprotecting agents used is selected from trimethyl silyl chloride; trimethyl silyl iodide;inorganic acids like HC1, HBr, sulfuric acid, phosphoric acid, alkali or alkaline earth metal alkoxides like sodium methoxide, magnesium methoxide, metal carbonates like potassium carbonate; hydrazine- hydrate, catalysts comprising of zinc, nickel, platinum, palladium

combined with hydrogen source, alkali hydroxide like potassium hydroxide.

19) The process of claim 14, wherein the solvent used in step (b) is selected from the

group consisting of water, acetic acid, alcohols like methanol, ethanol, halogenated solvents like dichloromethane, ethylene dichloride, chloroform esters like ethyl acetate, hydrocarbon solvents like toluene, ethers like tetrahydrofuran (THF), protic polar solvents like Ν,Ν-dimethylformamide (DM F), acetonitrile or a mixture thereof.

20) The process of claim 14, wherein the reaction step (c) is carried out by reacting the

compound of formula V with a suitable reagent like R-S0₂C1, where R=C _1-4 alkyl, straight or branched chain, sub or unsub. aryl, sub or unsub arylalkyl.

21) The process of claim 14, wherein the reaction step c) is carried out in the presence of a base selected from the group consisting of organic bases include tri (C i_-6 alkyl) amines like triethyl amine; pyridine and collidine; inorganic bases like alkali or alkaline earth metal carbonates include sodium carbonate, bicarbonates like sodium bicarbonate, hydroxides like sodium hydroxide or a mixture thereof, preferably triethyl amine.

22) The process of claim 14, wherein the solvent used in step (c) is selected from nitriles like acetonitrile; ketones like acetone; ethers like tetrahydrofuran (THF);esters like ethyl acetate; halogenated solvents 1 i ke_d i c h I o ro met hane ; aprot ic-polar-so 1 vents-1 ike- ^N- dimethylformamide (DMF) or a mixture thereof, preferably dichloromethane.

23) A process for the preparation of formula IVe

l^vd IVe

Where R is same as defined above and X is a halogen atom (F, CI, Br, I )

comprising

reacting the compound of formula IVd with metal halides selected from lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, potassium bromide and potassium iodide in the presence of an organic solvent selected from ketones like acetone; ether like tetrahydrofuran (THF); aprotic polar solvents like N,N-dimethylformamide

(DMF), acetonitrile or a mixture thereof; Preferably acetone.

24) A substituted oxazolidinone phenyl morphol inone compound of formula VI

VI

R₆= -H or R , where R =hydroxyl protecting group such as

i) R⁸=C 1 - 12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-i₀ alkenyl straight or branched chain;

o

II

ii) R⁸=— c— R9

where R9= C . alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy (Fmoc);

Rl l

— j>'— R10

iii) R⁸= ^R12 . .

Where R10, Rl 1, 12= independently selected from the group consisting of C M₂ alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl.

25) A compound of formula VII

O .

W_ ^ ^OR₆ VII

Where W=halogen atom or sulfonyloxy group;

R5=-CO-R where R =C 1.12 alkyl straight or branched chain, optionally sub.with 1- 3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

R₆= -H or R⁸, where R⁸ =hydroxyI protecting group such as

i) R⁸=C 1 -12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-io alkenyl straight or branched chain;

where R9= C i_i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc)

Rl l

— '— RI O

iii) R⁸= ^R12

Where RIO, Rl 1, 12= independently selected from the group consisting of C M₂ alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;

26) A process for the synthesis of compound of formula VII.

Vll

Where W, R6 are same as defined above; R5= -CO-R7, R7 = same as defined above; comprising:

reacting the compound of formula Vll (where R5=H)

Where W, R6 are same as defined above;

With a compound of formula

o

II

R7— ^c— ^x or (R7CO)₂0

Where R7 is same as defined above and X is a halogen atom ;

to provide the compound of formula Vl l.

27) The process of claim 26, wherein the reaction is generally carried out in the absence of solvent and optionally carried out in the presence of a solvent selected from halogenated solvents like dichloromethane, chloroform; esters like ethyl acetate; ethers like tetrahydrofuran (THF); hydrocarbon solvents like toluene, xylene; polar aprotic solvents like aceotnitrile, Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide or a mixture thereof, preferably dichloromethane is being used.

28) The process of claim 26, wherein the reaction is generally carried out in the absence of a base and optionally performed using a base which is selected from organic bases include tri (C i_-6 alkyl) amines like triethyl amine;pyridine, collidine; inorganic bases like alkali or alkaline earth metal carbonates including sodium carbonate, bicarbonates like sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.

29) A process for the preparation of substituted oxazolidinone phenyl morpholinone

compound of formula VI

Where R6 is same as defined above.

reacting the morpholinone phenyl amine compound of formula Ila

with a compound of formula IX

Where W =halogen atom or sulfonyloxy group; R 1 is -OR2,-CX3 or NR4R3

R-2 =C 1.1 alkyl straight chain or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyi; R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring; X= halogen atom;

R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as

i) R⁸=C i-i₂ alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-10 alkenyl straight or branched chain;

where R9= C _\. alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C i.)₂ alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9- fluoroenylmethyloxy (Fmoc);

Rl l

— RI O

iii) R⁸= ^{R 12}

Where RI O, Rl 1 , 12- independently selected from the group consisting of C M₂ alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl* sub or unsub arylalkyl;

in the presence of suitable base and a solvent.

30) The process of claim 29, wherein the suitable base used is selected from inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates like sodium bicarbonate, hydroxides like sodium hydroxide, metal alkoxides like sodium methoxide, lithium tert-butoxide, organic bases like triethyl amine, diisopropylethyl amine, pyridine or a mixture thereof; preferably potassium carbonate.

31) The process of claim 29, wherein the suitable solvent used is selected from

alcohols like methanol, ethanol; esters like ethyl acetate, hydrocarbons like toluene, ethers like tetrahydrofuran (THF); nitrites like acetonitrile ; aprotic polar solvents like Ν,Ν-dimethylformamide (D F) or a mixture thereof, preferably acetonitrile or

DMF is being used.

32) A compound of formula IX

Where W=halogen atom or sulfonyloxy group;

Where Rl is -OR2,-CX3 or NR₄R₃

R₂ =C -12 alkyl straight chain or branched chain, optionally substituted with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;

R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring; X= halogen atom; R₆= -H or R⁸, where R⁸ =hydroxyl protecting group such as

i) R⁸=C 2 alkyl straight or branched chain, optional ly sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain;

o

II

ii) R⁸=— ^c—

where R9= C i-i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C i-i₂ alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethylbxy (Fmoc);

Where R10, Rl 1 , 12= independently selected from the group consisting of C 1.12 alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl.

33) A process for the preparation of compound of formula IX

IX

Where W=halogen atom or sulfonyloxy group;

Rl, R6 are same as defined above,

comprising:

reacting the compound of formula of formula VII (R⁵=H)

Where W, R6 are same as defined above. with the compound of formula ^L or ^{l - K}

Where Rl is same as defined above; X= halogen atom ;

to provide the compound of formula IX.

34) The process of claim 33, wherein the reaction is carried out in the presence of a solvent selected from ethers like tetrahydrofuran (THF); halogenated solvents like

dichloromethane; hydrocarbon solvents like toluene; polar aprotic solvents like acetonitrile, Ν,Ν-dimethyl formamide (DMF) or a mixture thereof, preferably

dichloromethane.

35) The process of claim 33, wherein the reaction is generally carried out in the absence of a base and optionally performed using a base selected from organic bases include tri (C i_-6 alkyl) amines like triethyl amine;pyridine and coll idine ; inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates like sodium bicarbonate or a mixture thereof; preferably triethyl amine. ^{" '}

36) An alternate process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above

comprising:

reacting the morpholinone phenyl amine compound of formula Ila

I la

with the compound of formula X

Where X and Y are i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when i) X and Y are separate groups, X is halogen or sulfonyloxy group; Y is OR⁵ where R⁵= -H or -CO-R⁷, R⁷ = C i.i₂ alkyl straight or branched chain, optionally substituted with 1 -3 halogen atom(s), sub or unsub. aryl, sub or unsub aryl alkyl ; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; R6 is same as defined above;

to give substituted morpholinone phenyl amine compound of formula XI

Where R₅, R₆ are same as defined above;

b) carbonylation of the compound of formula XI with a suitable carbonylating agent to give the compound of formula VI c) reacting the compound of formula XI with a suitable reagent to give the compound of formula XIa

Where R₅, R₆ are same as defined above; R 14=-OR^{l 5}, NR₃R , CX₃ or X, where R₃, ¾ together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring; R^I5= Ci- 12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X= halogen atom;

37) The process of claim 36, wherein the suitable solvents used in step (a) is selected from alcohols like methanol, ethanol; hydrocarbons like toluene; ethers like

tetrahydrofuran(THF);nitriles like acetonitrile; ketones like acetone; aprotic polar solvents like Ν,Ν-dimethylformamide (DMF), or a mixture thereof, preferably ethanol or aqueous ethanol is being used.

38) The process of claim 36, wherein the reaction step (a) is optionally carried out in the

presence of catalysts selected from inorganic salts like zinc chloride, ferric chloride, sodium iodide, lithium chloride, lithium bromide, stannic chloride; β-cylodextrin or a mixture thereof.

39) The process of claim 36, wherein the reaction step (a) is optionally carried out in the

presence of a base, the suitable bases that can be used is selected from inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates like sodium bicarbonate, hydroxides like sodium hydroxide, metal alkoxides like sodium methoxide, lithium tert-butoxide, organic base include amines like triethyl amine, diisopropylethyl amine, pyridine, collidine or a mixture thereof, preferably collidine.

40) The process of claim 36, wherein the carbonylation step (b) is carried out in the

presence of suitable carbonylating agent selected from phosgene or phosgene equivalent like diphosgene, triphosgene; carbon monoxide equivalents like N,N-carbonyldiimidazole (CDI), diethyl carbonate or mixture thereof, preferably N,N-carbonyldiimidazole.

41) The process of claim 36, wherein the suitable solvents used in step (b) is selected alcohols like methanol, ethanol;hydrocarbons like toluene; halogenated solvents like

dichloromethane; nitriles like acetonitrile; ethers like tetrahydrofuran (THF); aprotic polar solvents like Ν,Ν-dimethylformami^'de (DMF) or a mixture thereof, preferably

dichloromethane.

42) The process of claim 36, wherein the reaction step (c) is carried out by reacting the

o

compound of formula XI with the reagent of formula R'4-c— x _; (R 4 C0)₂0 (or)

where R14 is same as defined above; X= halogen atom.

43) The process of claim 36, wherein the suitable solvents used in step (c) is selected from alcohols like methanol, ethanol; esters like ethyl acetate; hydrocarbon solvents like toluene; ethers like tetrahydrofuran (THF); halogenated solvents like

dichloromethane; nitriles like acetonitrile ; ketones like acetone; aprotic polar solvents like Ν,Ν-dimethylformamide (DM F) or a mixture thereof, preferably methanol or acetonitrile.

44) The process of claim 36, wherein the reaction step (c) is optionally carried out in the

presence of base, the suitable bases that can be used is selected from inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates like sodium bicarbonate; hydroxides like sodium hydroxide; metal alkoxides like sodium methoxide, lithium tert-butoxide, amines like triethyl amine, diisopropylethyl amine, pyridine or a mixture thereof, preferably diisopropylethyl amine.

45) The process of claim 36, wherein the reaction step (d) is being carried out by reacting the compound of formula XIa with a suitable base, the suitable bases used is selected from the group consisting of inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates such as sodium bicarbonate; hydroxides like sodium hydroxide, metal alkoxides like sodium methoxide, lithium tert-butoxide, n-butyl lithium, LDA; preferably sodium methoxide (or) lithium tert-butoxide.

46) The process of claim 36, wherein the suitable solvents used in step (d) is selected from alcohols like methanol, ethanol; ethers like tetrahydrofuran (THF);aprotic polar solvents like N,N-dimethylformamide (DMF), aceionitrile or a mixture thereof, preferably methanol or DMF.

47) The process of claim 36, wherein the reaction step a) js_camedj3ut_optionally-using-a— nucleophile, which is selected having an alkoxide group, linear or branched, having C i_-7 atoms, preferably nucleophile is methoxide or ethoxide or isopropoxide or isobutoxide or 2-ethoxyethyl, 2-( ,N-dimethylamino) ethoxide or 2,2,2-trichloroethoxide or 2,2,2- Trifluoroethoxide or a mixture thereof.

48) The process of claim 36, wherein the reaction steps (c) and (d) can be performed in a single pot.

49) A compound of formula XI

XI

Where R₅ =-H or -CO-R⁷ where R⁷ =C i.|₂ alkyl straight or branched chain optionally sub. with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub aryl alkyl; R₆= -H or R⁸, where

R⁸ =hydroxyl protecting group such as

i) R⁸=C ₁.12 alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C ₃.i₀ alkenyl straight or branched chain; o

II

ii) R⁸= C— R9

where R9= C i-i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9- Fluorenyl methyloxy (Fmoc);

Rl l

— ^'— Ri o

10 iii) R^e i_= R12

Where R10, Rl 1 , 12= independently selected from the group consisting of C i.i₂ alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl,^' sub or unsub arylalkyl.

-15 50) A compound of formula XIa

Where R₅ =-H or -CO-R⁷ where R⁷ =C 1 - 12 alkyl straight or branched chain optionally sub. with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub aryl alkyl; Re is same as defined above and R14=-OR¹⁵, NR3R4, CX3 or X, where R₃, R₄ together form a single ring group 20 with the 'N' to which they are bonded or a heteroaryl ring, R¹⁵=C \.\2 alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X=halogen atom.

51) A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l ,3-oxazolidin-5-yl} methyl)-2-thiophene-carboxamide compound of 25 formula I

comprising:

a) reacting substituted oxazol idinone-phenyl-morpholinone compound of formula

(IV)

(IV)

with a reagent of formula R^{I 3}-NH₂ or a salt thereof to provide the compound of formula III

III

Where Ru is sub or unsub. benzyl, C 3. 1 0 alkenyl straight or branched chain;

b) reacting the compound of formula 111 with a compound 5-chloro-thiophene carboxylic acid of formula IXa or a derivative thereof

to provide the compound of formula la

c) deprotection of the compound of formula la using a suitable reagent to give the compound of formula I.

52) The process of claim 5 1 , wherein the reaction step (a) is optionally carried out in the

presence of base, the suitable bases that can be used is selected from the group

consisting of inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates such as sodium bicarbonate; hydroxides like sodium hydroxide; amines like triethyl amine, diisopropylethyl amine, pyridine or

a mixture thereof.

53) The process of claim 5 1 , wherein the reaction step (a) is optionally carried out in the

presence of a solvent, the suitable solvents that can be used in step (a) is selected from esters like ethyl acetate; hydrocarbon solvents like toluene; nitriles like acetonitrile; aprotic polar solvents like Ν,Ν-dimethylformamide (DMF) or a mixture thereof.

54) The process of claim 5 1 , wherein the reaction step (b) is carried out by reacting the

compound of formula II I with the compound of formula IXa or with a corresponding carbonyl halides preferably carbonyl chlorides or with the corresponding symmetric or mixed carboxylic anhydrides of the carboxylic acid of the compound of formula IXa in the presence of solvent and an activating or coupling agent and or a base to give the compound of formula la.

55) The process of claim 5 1 , wherein the suitable_^base-that-can-be-used-in-step-f-bHs-selected— from inorganic bases include alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, amines like triethyl amine, Ν,Ν-diethylamine, pyridine or a mixture thereof, preferably triethylamine or sodium bicarbonate.

56) The process of claim 5 1 , wherein the suitable activating or coupling agents used in step (b) is selected from the group consisting of N'-(3-diinethylaminopropyl)-N-ethylcarbo- diimide. HC1, Ν,Ν'-dicyclohexylcarbodiimide, 1 -hydroxybenzotriazole monohydrate. 57) The process of claim 5 1 , wherein the solvents that can be used in step (b) is selected from water, alcohols like methanol, ethanol; halogenated solvents like dichloromethane, hydrocarbon solvents like toluene; ethers like tetrahydrofuran (THF); aprotic polar solvents like Ν,Ν-dimethylformamide (DMF), or a mixture thereof, preferably dichloromethane or toluene.

58) The process of claim 5 1 , wherein the suitable deprotecting agent used in step (c) is

selected from p-toluene sulfonic acid, N-bromosuccinimide, triflouro acetic acid;

hydrogenation catalysts like palladium on carbon, platinum oxide combined with hydrogen sourceor mixture thereof; inorganic acids like HC1, HBr, sulfuric acid, phosphoric acid or a mixture thereof. 59) The process of claim 51 , wherein the suitable solvents that can be used in step (c) is selected from water, alcohols like methanol; halogenated solvents like

dichloromethane; esters like ethyl acetate, hydrocarbon solvents like toluene; aprotic polar solvents like N,N-dimethylformamide (D F), acetonitrile or a mixture thereof, preferably hydrocarbon solvent tol uene (or) methanol.

60) A process for the preparat-ion-e-f-4-{-4-[-5(-S-)-(-am-inomethyl)-2-oxo- 1 ,3-oxazolidin- 3-yl]phenyl}morpholin-3-one compound of formula (II) or a salt thereof

comprising:

subjecting the compound of formula (IVa)

to reduction using suitable reducing agent to provide the compound of formula 1 61) A process for the preparation of compound of formula (IVa)

(IVa)

comprising:

Where L is a leaving group like halogen atom (F, CI, Br, I), or -OS0₂R where R = Ci_-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable metal azide to provide the compound of formula (IVa).

62) A process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-l ,3- oxazolidin-3-yl]phenyl }morpholin-3-one compound of formula (II) or a salt thereof

(")

comprising:

subjecting the compound of formula (IVb)

to reduction using suitable reducing agent to provide the compound of formula II.

63) A process for the preparation of compound of formula (IVb)

comprising:

reacting the compound substituted oxazolidinone-phenyl-morpholinone of formula (IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = Ci_-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable sub. or un substituted dibenzyl amine or a salt thereof to provide the compound of formula (IVb).

64) A process for the preparation of substituted oxazolidinone-phenyl-morpholinone

compound of formula (IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I), or -OS0₂R where R = C_1-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; comprising:

reacting the compound of formula V

with a suitable reagent to afford the compound of formula IV.

65) The process of claim 64, wherein the suitable reagent is R-S0₂C1, where R=C i_-4 alkyl, straight or branched chain, sub or unsub. aryl, sub or unsub arylalkyl.

66) A method for the synthesis of substituted oxazohdinone phenyl morpholinone compound of formula VI

Where R6 is same as defined above;

comprising:

a) reacting the substituted phenyl morphilinone compound of formula VIII

VIII

Where Rl is -OR2,-CX3 or NR4R3

R2 ⁼CM2 alkyl straight chain or branched chain, optionally substituted with 1-3 halogi atom(s), sub or unsub aryl, sub or unsub arylalkyl; R₃and R₄ together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring; X= halogen atom; ._.. - - with the compound of formula VI 1

Where W=halogen atom or sulfonyloxy group;

R₅= -H or -CO-R⁷ where R⁷ =C |.i₂ alkyl straight or branched chain, optionally sub.with

1-3 halogen atom(s) sub or unsub aryl, sub or unsub arylalkyl;

Rs= -H or R , where R =hydroxyl protecting group such as

i)R =C 1 - 12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C _3-i₀ alkenyl straight or branched chain;

o

II

8₌— c _R9

where R9= C i-i₂ alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1 -12 alkoxy straight or branched chain optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy;9- fluorenylmethyloxy (Fmoc) Rl l

iii) R⁸= R12

Where RIO, Rl 1 , 12= independently selected from the group consisting of C \.\2 alkyl straight or branched chain optionally sub. with 1 -3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyi;

to afford substituted oxazolidinone phenyl morpholinone compound of formula VI.

67) A method for the synthesis of compound of formula V

comprising :

deprotection of the compound of formula VI (when R6 is hydroxyl protecting group)

VI

Where R6 is same as defined above;

using a suitable reagent to afford the compound of formula V.

68) A process for the preparation of substituted oxazolidinone phenyl morpholinone

compound of formula VI

VI

Where R6 is same as defined above

comprising:

reacting the compound of formula Xla

Where R₅, R₆ are same as defined above; R.14=-OR ¹⁵, NR₃R₄, CX₃ or X, where R₃, R4 together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring; R^{1 5}= CM₂ alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X= halogen atom;

with a suitable reagent to give the compound of formula VI.

69) The process of claim 68, wherein the reaction is being performed by reacting the

compound of formula XIa with a suitable base selected from the group consisting of inorganic bases include alkali or alkaline earth metal carbonates like sodium carbonate, bicarbonates such as sodium bicarbonate; hydroxides .like sodium hydroxide, metal alkoxides like sodium methoxide, lithium tert-butoxide, n-butyl lithium, LDA; preferably sodium methoxide (or) lithium tert-butoxide.

70) A process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI

VI

Where R6 is same as defined above

comprising:

carbonylation of the compound of formula XI

XI

Where R₅, R₆ are same as defined above;

with a suitable carbonylating agent to give the compound of formula VI.

71) A method for the synthesis of substituted morpholinone phenyl amine compound of formula XI

XI

Where R₅, R₆ are same as defined above;

comprising: reacting the morpholinone phenyl a mula Ha

Ila

with the compound of formula X

Where X and Y are i) separate groups or i i) together form a single ring group with the two carbons to which they are bonded; and when i) X and Y are separate groups, X is halogen or sulfonyloxy group; Y is OR⁵ where R⁵= -H or -CO-R⁷, R⁷ = C alkyl straight or branched chain, optionally substituted with 1 -3 halogen atom(s), sub or unsub. aryl, sub or unsub aryl alkyl ; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; R6 is same as defined above;

to give the compound of formula XI.

72) A method for the synthesis of com ound of formula II I

III

Where Rn is sub or unsub. benzyl, C 3.10 alkenyl straight or branched chain;

comprising:

a) reacting substituted oxazolidinone-phenyl-morpholinone compound of formula

(IV)

(IV)

Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS0₂R where R = C alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl;

with a reagent of formula R¹³-NH₂ or a salt thereof (where R¹³ is same as defined above) to provide the compound of formula III.

73) A method for the synthesis of compound of formula la

Where R is same as defined above

comprising:

reacting the compound of formula 111

111

Where Rn is sub or unsub. benzyl, C 3.10 alkenyl straight or branched chain;

with a compound 5-chloro-thiophene carbox lic acid of formula IXa or a derivative thereof

to give the compound of formula la.

74) A method for the synthesis of compound of formula Xla

Where R5, R6 are same as defined above and

or -CX₃

R¹⁵=C 1-12 alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl; X=halogen atom;

comprising:

reacting the compound of formula XI

XI

Where R5,R6 are same as defined above

with a suitable reagent to give the compound of formula

75) Acid addition salts of a compound of formula I I

Where HL -inorganic acids such as HCI, HI and the like; organic acids such as methane sulfonic acid, p -toluene sulfonic acid and the like which can form salt with the amine compound of formula I I. ^■■ -

76) A compound of formula III

Where R13 is C 3.10 alkenyl straight or branched chain;

77) Rivaroxaban (I) obtained by the processes of preceding claims has a purity of at least about 99 area % by HPLC.

78) Rivaroxaban (I ) obtained by the processes of preceding claims has less than about 0.1 area % of individual impurity and 0.5 area % of total impurities by HPLC.