WO2011121602A1 - Process for preparation of dibenzothiazepinone compounds - Google Patents

Process for preparation of dibenzothiazepinone compounds Download PDF

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Publication number
WO2011121602A1
WO2011121602A1 PCT/IN2011/000163 IN2011000163W WO2011121602A1 WO 2011121602 A1 WO2011121602 A1 WO 2011121602A1 IN 2011000163 W IN2011000163 W IN 2011000163W WO 2011121602 A1 WO2011121602 A1 WO 2011121602A1
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formula
compound
unsubstituted
substituted
preparation
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PCT/IN2011/000163
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French (fr)
Inventor
Kuppuswamy Nagarajan
Rajenderpershad Gupta
Krishnamoorthy Pasupathy
Sakthivel Vijaikumar
Pasupuleti Pradeep
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Hikal Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed

Definitions

  • the present invention relates to a process for the preparation of dibenzothiazepinone compounds of formula I, by reacting compound of formula II in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid.
  • the dibenzothiazepinone compounds of Formula I are key intermediate for the preparation of 2-(2-(4-dibenzo( ,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol known as quetiapine and its derivatives, which are effective antipsychotic substances.
  • the process of the present invention is relatively safe, cost effective and commercially viable for industrial preparation of dibenzothiazepinone compound of Formula I.
  • EP0282236 discloses a process for preparing dibenzo[b,fJ[l, 4]thiazepin-l 1-(10H)- one which comprises cyclization of phenyl-2- phenylthio)-phenylcarbamate in the presence of polyphosphoric acid.
  • PPA highly viscous polyphosphoric acid
  • Helv. Chim. Acta, 48, 336 (1965) also discloses a process for the preparation of dibenzo[b,fJ[l,4]thiazepine-l l-(10H)-one by reacting 2-chloronitrobenzene with thiosalicylic acid methyl ester.
  • this method suffers from the use of expensive thiosalicyclic acid methyl ester.
  • WO 2004/047722 A2 discloses a process for the preparation of dibenzo
  • This process involves multi steps to prepare dibenzo[b,fJ[l ,4]thiazepine- 11 -(10H)-one.
  • the present invention provides a process for the preparation dibenzothiazepinone
  • dibenzothiazepinone compound of Formula I in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid; to obtain dibenzothiazepinone compound of Formula I;
  • Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of H, OH, F, CI, Br, I, -OR 8 , -SR a , -N0 2 , -CN unsubstituted or substituted Cj- linear or branched alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted C3-7 cycloalkyl, unsubstituted or substituted Ci-e fluoroalkyl or perfluoroalky, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
  • R a is selected from H; Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, C3.7 cycloalkyl, Ci-6 fluoroalkyl, aryl, or heteroaryl; R9 is -OR b , wherein R b is selected from a group consisting of C 1- linear or branched alkyl, substituted or unsubstituted benzyl, C3.7 cycloalkyl, Ci-6 fluoroalkyl or perfluoroalkyl, aryl and heteroaryl.
  • the present invention relates to a process for preparation of dibenzothiazepinone compound of Formula I,
  • dibenzothiazepinone compound of Formula I in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid; to obtain dibenzothiazepinone compound of Formula I;
  • Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of H, OH, F, CI, Br, I, -OR a , -SR a , -N0 2 , -CN, unsubstituted or substituted linear or branched alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted Ci ⁇ fluoroalkyl or perfluoroalky, substituted or unsubstituted aryl, and unsubstituted or substituted heteroaryl;
  • R a is selected from H, Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, C3.7 cycloalkyl, Ci ⁇ fluoroalkyl, aryl, or heteroaryl;
  • R9 is -OR b , wherein R b is selected from the group consisting of Ci ⁇ linear or branched alkyl, substituted or unsubstituted benzyl, C3-7 cycloalkyl, C
  • Still another embodiment of the present invention provides a process of preparing compound of formula I, wherein Ci ⁇ linear or branched alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3- pentyl, neo-pentyl or n-hexane
  • Yet another embodiment of the present invention provides a process of preparing compound of Formula I, wherein aryl is selected from phenyl, tolyl, xylyl or benzyl.
  • Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein heteroaryl is selected from pyridyl, quinolyl, pyrimidinyl, imidazolyl, purinyl, pyrrolyl or indolyl.
  • An embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst comprises phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1 : 1 to 1 : 15.
  • Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst is obtained by mixing phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1:1 to 1:15 at temperature range of 20 °C to 80 °C to obtain a mixture, heating and stirring the mixture at a temperature of 80 °C to 150 °C, and cooling the heated mixture to about 80 °C.
  • the acid catalyst is obtained by mixing phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1:1 to 1:15 at temperature range of 20 °C to 80 °C to obtain a mixture, heating and stirring the mixture at a temperature of 80 °C to 150 °C, and cooling the heated mixture to about 80 °C.
  • Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein each of Rl, R2, R3, R4, R5, R6, R7 and R8 is H.
  • Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein R b is phenyl. Further embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide and methanesulfonic acid is 1:6 to 1:10.
  • Still another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is in the ratio range of 1 : 1 : 1 to 10: 1 : 15.
  • Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is preferably in the ratio range of 1 : 1 :6 to 3 : 1 : 10.
  • An embodiment of the present invention provides a process for preparing compound of Formula I, said process comprising mixing phosphorous pentoxide and methanesulfonic acid in a molar ratio in a range of 1 : 1 to 1 : 15 at a temperature range of 20 °C to 80 °C to obtain a mixture, heating and stirring the mixture at a temperature range of 80 °C to 150 °C, cooling the heated mixture to 80 °C to 20 °C to obtain an acid catalyst, mixing compound of Formula II and the acid catalyst to obtain a reaction mixture, raising temperature of the reaction mixture to 105 °C to 110 °C for a time period of 2 hour to 4 hour, adding ice- water mixture to the reaction mixture to obtain a product, filtering the product, and washing the product with water and acetone to obtain the compound of Formula I.
  • a process for preparing compound of Formula I comprising mixing phosphorous pentoxide (P 2 O 5 ) and methanesulfonic acid in a molar ratio of 1 : 1 to 1 : 15 at temperature of 20 °C to 80 °C to obtain a suspension, heating and stirring the suspension at a temperature range of 80 °C to 150°C to obtain a solution, cooling the solution to 80 °C to 20 °C to obtain an acid catalyst, mixing compound of Formula II and the acid catalyst to obtain a reaction mixture.
  • the temperature was raised to 100-105 °C and maintained for about 3 h, after which, byproducts and excess acid were distilled under reduced pressure. To the residue obtained, ice-water mixture was added slowly. After further stirring, the product was filtered off, washed with water and acetone. The wet solid was then dried to obtain compound of Formula I.
  • Still another embodiment of the present invention provides a process for preparing compound of Formula I, optionally comprises heating compound of Formula II before mixing with the acid catalyst.
  • Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is heated at a temperature range of 95°C to 105°C.
  • the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is heated at a temperature of 100°C.
  • Still another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst is obtained by mixing phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1:6 to 1:10 at a temperature range of 20°C to 80°C to obtain a mixture, heating and stirring the mixture at a temperature of 80°C to 150°C, and cooling the heated mixture to a temperature of about 80°C or below.
  • Yet another embodiment of the present invention provides a process of preparing compound of Formula I, wherein mixing of phosphorus pentoxide and methanesulfonic acid is preferably at 20°C to 50°C, heating is preferably at a temperature of 80°C to 120°C with stirring and cooling is preferably to a temperature of 50°C to 80°C.
  • Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein compound of "Formula II" is added with stirring to the acid catalyst comprising phosphorus pentoxide and methanesulfonic acid at a temperature of 20°C to 80°C.
  • the mixture of compound of Formula II and acid catalyst is heated at a temperature of 40°C to 150°C and the same temperature is maintained for 1 h to 10 h.
  • Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein compound of "Formula II" is added with stirring to the acid catalyst comprising phosphorus pentoxide and methanesulfonic acid at a temperature of 60°C to 80°C.
  • the mixture of compound of Formula II and acid catalyst is heated at a temperature of 80°C to 120°C and the same temperature is maintained for 2 h to 6 h.
  • Another embodiment of the present invention provides a process of preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is in the range of 1 : 1 : 1 to 10: 1 : 15.
  • Yet another embodiment of the present disclosure provides a process of preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is preferably in the range of 1 : 1 :6 to 3 : 1 : 10.
  • Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein the completion of the reaction is monitored by the 163
  • An embodiment of the present invention provides a process of preparing compound of Formula I, which comprises reaction of 2-aminodiphenylsulfide derivative with alkyl or aryl chloroformate or heteroaryl chloroformate to obtain alkyl or aryl or heteroaryl phenylthiopheriyl carbamate derivative of Formula II.
  • An embodiment of the present invention provides a process for preparing compound of Formula I which further comprising treating reaction mixture with mixture of ice-water at a temperature within the range from— 30°C to 80°C.
  • Another embodiment of the present invention provides a process for preparing compound of Formula I, further comprising treating reaction mixture with mixture of ice- water preferably at a temperature within the range from 0°C to 30°C.
  • an embodiment of the present invention provides a process of preparing compound of Formula I; wherein the compound of Formula II, is subjected to acid catalyzed cyclization to obtain dibenzothiazepinone compound of Formula I.
  • Further embodiment of the present invention provides a process with or without the distillation of excess acid and the by-product phenyl mesylate, wherein after quenching the reaction mixture in ice-water, material is filtered, washed with water followed by an organic solvent such as acetone.
  • Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is selected from Phenyl 2- (phenylthio)-phenylcarbamate, Phenyl 2-(4-methyl phenylthio)-phenylcarbamate, 5- Chloro phenyl 2-(4-methyl phenylthio)-phenylcarbamate and 5-Chloro phenyl 2- (phenylthio)-phenylcarbamate.
  • Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula I is selected from
  • dibenzothiazepinone compounds of Formula I which are key intermediates for the preparation of 2-(2-(4-dibenzo[b,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol known as quetiapine and its derivatives, which are effective antipsychotic substances.
  • Hemifumarate salt of quetiapine is indicated for the treatment of schizophrenia as well as for the treatment of acute manic episodes associated with bipolar I disorder, as either mono therapy or adjunct therapy to lithium or divalproex.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

The present invention discloses a process for the preparation of dibenzothiazepinone compounds of Formula I. The process for preparation of a dibenzothiazepinone compound of Formula I comprises reaction of compound of formula II in the presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid. The dibenzothiazepinone compounds of Formula I are key intermediate for the preparation of 2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol known as quetiapine and its derivatives, which are effective antipsychotic substances.

Description

PROCESS FOR PREPARATION OF DIBENZOTHIAZEPINONE
COMPOUNDS
Field of Invention
The present invention relates to a process for the preparation of dibenzothiazepinone compounds of formula I, by reacting compound of formula II in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid.
The dibenzothiazepinone compounds of Formula I are key intermediate for the preparation of 2-(2-(4-dibenzo( ,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol known as quetiapine and its derivatives, which are effective antipsychotic substances.
The process of the present invention is relatively safe, cost effective and commercially viable for industrial preparation of dibenzothiazepinone compound of Formula I.
Background and prior art
EP0282236 discloses a process for preparing dibenzo[b,fJ[l, 4]thiazepin-l 1-(10H)- one which comprises cyclization of phenyl-2- phenylthio)-phenylcarbamate in the presence of polyphosphoric acid. Use of highly viscous polyphosphoric acid (PPA) for cyclization affects the free stirring of the reaction mixture, eventually resulting in the product being isolated in poor yields.
Helv. Chim. Acta, 48, 336 (1965) described a method to prepare compound of type "Formula 1", which comprises reacting l-chloro-2-nitrobenzene with thiophenol to obtain 2-nitrodiphenylsulfide and the nitro group of the obtained compound is reduced to an amino group. The reduced amino group is activated to isocyano using phosgene which is then cyclized by using aluminium trichloride to give dibenzorb,fJ[l,4]thiazepin-l 1-(10H)- one. The drawback of this method is the use of hazardous phosgene and stoichiometric quantity of AICI3 for cyclization.
Helv. Chim. Acta, 48, 336 (1965) also discloses a process for the preparation of dibenzo[b,fJ[l,4]thiazepine-l l-(10H)-one by reacting 2-chloronitrobenzene with thiosalicylic acid methyl ester. However this method suffers from the use of expensive thiosalicyclic acid methyl ester.
The process for the preparation of dibenzo[b,fJ[l,4]thiazepine-l l-(10H)-one from 2-bromonitrobenzene and thiosalicylic acid has been described by J.Med.Chem, 44, 372- 389, 2001. This process is inconvenient to commercialize due to the use of toxic tin chloride for the reduction of nitro group.
WO 2004/047722 A2 discloses a process for the preparation of dibenzo|¾,fj[l,4]tWazepine-l l-(10H)-one by reacting dithiosalicylic acid with l-chloro-2- nitrobenzene to prepare 2-[(2-nitrophenyl)thioJbenzoic acid, reduction of nitro group in the presence of hydrogen, a solvent and a heterogeneous metal catalyst to prepare 2-[(2- aminophenyl)thio]benzoic acid and further cyclizing the 2-[(2-aminophenyl)thio]benzoic acid in the presence or absence of an acid catalyst. This process involves multi steps to prepare dibenzo[b,fJ[l ,4]thiazepine- 11 -(10H)-one.
Hence there is a need to provide a process for industrial preparation of dibenzothiazepinone compound of Formula 1, which is relatively safe, cost effective and commercially viable. It is an objective, of the present invention to provide such a process.
SUMMARY
The present invention provides a process for the preparation dibenzothiazepinone
Figure imgf000003_0001
Formula I
said process comprising reacting the compound of Formula II
Figure imgf000003_0002
Formula II
in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid; to obtain dibenzothiazepinone compound of Formula I;
wherein Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of H, OH, F, CI, Br, I, -OR8, -SRa, -N02, -CN unsubstituted or substituted Cj- linear or branched alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted C3-7 cycloalkyl, unsubstituted or substituted Ci-e fluoroalkyl or perfluoroalky, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
wherein Ra is selected from H; Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, C3.7 cycloalkyl, Ci-6 fluoroalkyl, aryl, or heteroaryl; R9 is -ORb, wherein Rb is selected from a group consisting of C 1- linear or branched alkyl, substituted or unsubstituted benzyl, C3.7 cycloalkyl, Ci-6 fluoroalkyl or perfluoroalkyl, aryl and heteroaryl.
Detailed Description of the invention:
The present invention relates to a process for preparation of dibenzothiazepinone compound of Formula I,
Figure imgf000004_0001
Formula I
said process comprising, reacting a compound of Formula II
Figure imgf000004_0002
in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid; to obtain dibenzothiazepinone compound of Formula I;
wherein Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of H, OH, F, CI, Br, I, -ORa, -SRa, -N02, -CN, unsubstituted or substituted linear or branched alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted Ci^ fluoroalkyl or perfluoroalky, substituted or unsubstituted aryl, and unsubstituted or substituted heteroaryl;
wherein Ra is selected from H, Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, C3.7 cycloalkyl, Ci^ fluoroalkyl, aryl, or heteroaryl; R9 is -ORb, wherein Rb is selected from the group consisting of Ci^ linear or branched alkyl, substituted or unsubstituted benzyl, C3-7 cycloalkyl, C|-e fluoroalkyl or perfluoroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
Still another embodiment of the present invention provides a process of preparing compound of formula I, wherein Ci^ linear or branched alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3- pentyl, neo-pentyl or n-hexane
Yet another embodiment of the present invention provides a process of preparing compound of Formula I, wherein aryl is selected from phenyl, tolyl, xylyl or benzyl.
Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein heteroaryl is selected from pyridyl, quinolyl, pyrimidinyl, imidazolyl, purinyl, pyrrolyl or indolyl.
An embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst comprises phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1 : 1 to 1 : 15.
Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst is obtained by mixing phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1:1 to 1:15 at temperature range of 20 °C to 80 °C to obtain a mixture, heating and stirring the mixture at a temperature of 80 °C to 150 °C, and cooling the heated mixture to about 80 °C.
Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein each of Rl, R2, R3, R4, R5, R6, R7 and R8 is H.
Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein Rb is phenyl. Further embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide and methanesulfonic acid is 1:6 to 1:10.
Still another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is in the ratio range of 1 : 1 : 1 to 10: 1 : 15.
Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is preferably in the ratio range of 1 : 1 :6 to 3 : 1 : 10.
An embodiment of the present invention provides a process for preparing compound of Formula I, said process comprising mixing phosphorous pentoxide and methanesulfonic acid in a molar ratio in a range of 1 : 1 to 1 : 15 at a temperature range of 20 °C to 80 °C to obtain a mixture, heating and stirring the mixture at a temperature range of 80 °C to 150 °C, cooling the heated mixture to 80 °C to 20 °C to obtain an acid catalyst, mixing compound of Formula II and the acid catalyst to obtain a reaction mixture, raising temperature of the reaction mixture to 105 °C to 110 °C for a time period of 2 hour to 4 hour, adding ice- water mixture to the reaction mixture to obtain a product, filtering the product, and washing the product with water and acetone to obtain the compound of Formula I.
In an embodiment of the present invention provides a process for preparing compound of Formula I, said process comprising mixing phosphorous pentoxide (P2O5) and methanesulfonic acid in a molar ratio of 1 : 1 to 1 : 15 at temperature of 20 °C to 80 °C to obtain a suspension, heating and stirring the suspension at a temperature range of 80 °C to 150°C to obtain a solution, cooling the solution to 80 °C to 20 °C to obtain an acid catalyst, mixing compound of Formula II and the acid catalyst to obtain a reaction mixture. The temperature was raised to 100-105 °C and maintained for about 3 h, after which, byproducts and excess acid were distilled under reduced pressure. To the residue obtained, ice-water mixture was added slowly. After further stirring, the product was filtered off, washed with water and acetone. The wet solid was then dried to obtain compound of Formula I.
Still another embodiment of the present invention provides a process for preparing compound of Formula I, optionally comprises heating compound of Formula II before mixing with the acid catalyst. IN2011/000163
Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is heated at a temperature range of 95°C to 105°C.
Further an embodiment of the present the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is heated at a temperature of 100°C.
Still another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the acid catalyst is obtained by mixing phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1:6 to 1:10 at a temperature range of 20°C to 80°C to obtain a mixture, heating and stirring the mixture at a temperature of 80°C to 150°C, and cooling the heated mixture to a temperature of about 80°C or below.
Yet another embodiment of the present invention provides a process of preparing compound of Formula I, wherein mixing of phosphorus pentoxide and methanesulfonic acid is preferably at 20°C to 50°C, heating is preferably at a temperature of 80°C to 120°C with stirring and cooling is preferably to a temperature of 50°C to 80°C.
Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein compound of "Formula II" is added with stirring to the acid catalyst comprising phosphorus pentoxide and methanesulfonic acid at a temperature of 20°C to 80°C. The mixture of compound of Formula II and acid catalyst is heated at a temperature of 40°C to 150°C and the same temperature is maintained for 1 h to 10 h.
Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein compound of "Formula II" is added with stirring to the acid catalyst comprising phosphorus pentoxide and methanesulfonic acid at a temperature of 60°C to 80°C. The mixture of compound of Formula II and acid catalyst is heated at a temperature of 80°C to 120°C and the same temperature is maintained for 2 h to 6 h.
Another embodiment of the present invention provides a process of preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is in the range of 1 : 1 : 1 to 10: 1 : 15.
Yet another embodiment of the present disclosure provides a process of preparing compound of Formula I, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is preferably in the range of 1 : 1 :6 to 3 : 1 : 10.
Still another embodiment of the present invention provides a process of preparing compound of Formula I, wherein the completion of the reaction is monitored by the 163
disappearance of compound of formula II using thin layer chromatography or high pressure liquid chromatography.
An embodiment of the present invention provides a process of preparing compound of Formula I, which comprises reaction of 2-aminodiphenylsulfide derivative with alkyl or aryl chloroformate or heteroaryl chloroformate to obtain alkyl or aryl or heteroaryl phenylthiopheriyl carbamate derivative of Formula II.
An embodiment of the present invention provides a process for preparing compound of Formula I which further comprising treating reaction mixture with mixture of ice-water at a temperature within the range from— 30°C to 80°C.
Another embodiment of the present invention provides a process for preparing compound of Formula I, further comprising treating reaction mixture with mixture of ice- water preferably at a temperature within the range from 0°C to 30°C.
Further an embodiment of the present invention provides a process of preparing compound of Formula I; wherein the compound of Formula II, is subjected to acid catalyzed cyclization to obtain dibenzothiazepinone compound of Formula I.
Further embodiment of the present invention provides a process with or without the distillation of excess acid and the by-product phenyl mesylate, wherein after quenching the reaction mixture in ice-water, material is filtered, washed with water followed by an organic solvent such as acetone.
Yet another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula II is selected from Phenyl 2- (phenylthio)-phenylcarbamate, Phenyl 2-(4-methyl phenylthio)-phenylcarbamate, 5- Chloro phenyl 2-(4-methyl phenylthio)-phenylcarbamate and 5-Chloro phenyl 2- (phenylthio)-phenylcarbamate.
Another embodiment of the present invention provides a process for preparing compound of Formula I, wherein the compound of Formula I is selected from
dibenzo|¾,fl[l,4]thiazepine-l l-(10H)-one, 2-me ldibeiizo| ,fJ[l,4]thiazepine-l 1-(10H)- one, 8-cMoro,2-memyldibenzo|¾,i][l,4]thiazepine-l l-(10H)-one and 8- chlorodibenzo[b,fj [ 1 ,4]thiazepine- 11 -( 10H)-one
In an embodiment of the present invention provides a process for preparing dibenzothiazepinone compounds of Formula I, which are key intermediates for the preparation of 2-(2-(4-dibenzo[b,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol known as quetiapine and its derivatives, which are effective antipsychotic substances. 163
Hemifumarate salt of quetiapine is indicated for the treatment of schizophrenia as well as for the treatment of acute manic episodes associated with bipolar I disorder, as either mono therapy or adjunct therapy to lithium or divalproex.
The process steps of the present invention are described in the following embodiments. Selected embodiments have been described by way of examples. They are only illustrative in nature and should not be construed as limiting the scope of the invention in any manner. It is obvious for a person skilled in the art that changes can be made without deviating from the scope of the invention as defined in the claims.
Figure imgf000009_0001
1 000163
Example: 1
Preparation of Phenyl 2-(phenylthio)-phenylcarbamate (1 A) - compound of formula
II
Figure imgf000010_0001
2-amino diphenylsulfide 1A
2- Amino diphenylsulfide 150 g (0.75 moles) was dissolved in toluene and was cooled to 5°C. To the stirred solution was added phenylchloroformate 56.5 mL (0.45 mole) in toluene over a period of 1 h. Additional phenylchloroformate 56.5 mL (0.45 mole) in toluene, an aqueous solution (375 mL) of sodium hydroxide 22.4 g (0.56 mole) and sodium carbonate 67.5 g (0.65 mole) were added simultaneously over a period of 1 h. After the addition was completed, the reaction mixture was further stirred at ambient temperature for 1 h. The organic layer was separated and washed with dil. HCl. Further the organic layer was washed with water. To the resulting residue after removal of toluene was added hexane and the mixture allowed to stand for 2 h. The solid obtained was filtered and further washed with of hexane. Drying afforded the desired phenyl 2-(phenylthio)- phenylcarbamate in 92% yield (220 g).
Example: 2
Preparation of dibenzo [b, fj [1,4] thiazepine-ll-(10H)-one (IB) - compound of formula I
Figure imgf000010_0002
Method A:
To phosphorous pentoxide (P2O5) 132 g (0.94 mole), methanesulfonic acid 364 mL (5.62 mole) was added at ambient temperature. The suspension was heated to 120°C with stirring. The clear solution was cooled to 80 °C and phenyl 2-(phenylthio)- phenylcarbamate 300 g (0.93 mole) was added in one lot with stirring. The temperature was raised to 105 - 110 °C and maintained for about 3 h. After allowing the reaction mixture to cool to ambient temperature, ice-water mixture was added slowly. After further stirring, the product was filtered off, washed with water and acetone. The wet solid was then dried to afford dibenzo [b,fj[l,4] thiazepine-1 l-(10H)-one in 83 % (176 g) yield. Melting range-259 -260 °C
1H NMR (CDC13), δ = 7.14 (t, J = 7.5 Hz, 4H), 7.23 (d, J = 7.8 Hz, 1H), 7.33-7.38 (m, 1H), 7.41- 7.57 (m, 1H), 7-67 -7.69 (m, 1H), 10.7 (br s, lH)
13C NMR (CDCI3), δ = 122.6, 126.0, 128.7, 129.7, 130.2, 131.8, 131.9, 132.2, 133.0, 137.0, 137.4, 139.4, 169.9;
Method B
To phosphorous pentoxide (P2O5) 22.5 g (0. 159 mole), methane sulfonic acid 100 mL (1.54 mole) was added at ambient temperature. The suspension was heated to 120 °C with stirring. The clear solution was cooled to 80°C and phenyl 2-(phenyIthio)- phenylcarbamate 50 g (0.15 mole) was added in one lot with stirring. The temperature was raised to 100-105 °C and maintained for about 3 h, after which, by-products phenylmesylate and excess acid were distilled under reduced pressure. To the residue obtained, ice-water mixture was added slowly. After further stirring, the product was filtered off, washed with water and acetone. The wet solid was then dried to afford dibenzo[b,fJ[l,4]thiazepine-l l-(10H)-one in 81 % (28 g) yield.
Example: 3
Preparation of dibenzo[b,f| [1,4] thiazepine-1 l-(10H)-one (IB)
2-Amino diphenylsulfide 500 g (2.49 mole) was dissolved in toluene and was cooled to 5 °C. To the stirred solution was added phenylchloroformate 187.7 mL (1.49 mole) in toluene over a period of 1 h. Additional phenylchloroformate 187.7 mL (1.49 mole) in toluene, an aqueous solution (1.25 L) of sodium hydroxide 74.6 g (1.865 mole) and sodium carbonate 224.12 g (2.114 mole) were added simultaneously over a period of 1 h. After the addition was completed, the reaction mixture was further stirred at ambient temperature for 1 h. The organic layer was separated and washed with dil. HC1. Further the organic layer was washed with water. Toluene was distilled off under vacuum and the phenyl 2-(phenylthio)-phenylcarbamate was stored at 100°C. In a separate round bottomed flask phosphorous pentoxide 385.8 g (2.74 mole) and methanesulfonic acid 1.13 L (17.41 mole) were mixed at ambient temperature. The suspension was heated to 120 °C with stirring. The clear solution was cooled to 80 °C and it was added with stirring to the phenyl 2-(phenylthio)-phenylcarbamate which was maintained at 100°C. The temperature was raised to 105 - 110 °C and maintained for about 3 h. After allowing the reaction mixture to cool to ambient temperature, ice-water mixture was added slowly. After further stirring, the product was filtered off, washed with water and acetone. The wet solid was then dried to afford dibenzo[b,fJ[l,4]thiazepine-l l-(10H)-one in 81.7 % (461.6 g) yield. Melting range-259 -260 °C
Example 4
Cyclization of Example 2"
Figure imgf000012_0001
2A 2B
Yield: 76%
1H NMR (DMSO-de), δ = 2.29 (s, 3H), 7.11-7.15 (m, 1H), 7.21-7.41 (m, 4H), 7.49-7.55 (m, 2H), 10.7 (br s, 1H).
13 C NMR (DMSO-de), 6 = 20.3, 123.1, 125.2, 129.2, 129.6, 131.4, 131.5, 132.3, 1232.5, 132.9, 137.6, 138.6, 139.9, 168.4.
Melting range: 217-220 °C
Example 5
Cyclization e 2"
Figure imgf000012_0002
Yield: 72%
1H NMR (DMSO-de), δ = 2.21 (s, 3H), 7.18-7.32 (m, 1H), 7.26-7.31 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 10.7 (br s, 1H)
13C NMR (DMSO-de), δ = 20.3, 122.5, 125.0, 123.0, 131.3, 131.6, 132.2, 132.8, 133.6, 133.7, 137.2, 139.0, 141.5, 168.1
Melting range: 235-238 °C
Example 6
Cyclization of 4A to 4B was performed by using "Method A" described in "Example 2" 0163
Figure imgf000013_0001
4A 4B
Yield: 78%
1H NMR (DMSO-de), δ = 7.26-7.29 (m, 2H), 7.47 -7.61 (m, 4H), 7.68 - 7.71 (m, 1H) 10.75 (br s, 1H)
13 C NMR (DMSO-de), δ = 122.5, 125.1, 127.6, 129.1, 131.3, 131.4, 132.2, 133.8, 133.9, 135.6, 137.6, 141.3, 168.1
Melting range: 276-288 °C.

Claims

We Claim:
1. A process for preparation of dibenzothiazepinone compound of Formula I,
Figure imgf000014_0001
Formula I
said process comprising, reacting a compound of Formula II
Figure imgf000014_0002
Formula II
in presence of an acid catalyst comprising phosphorus pentoxide and methanesulfonic acid; to obtain dibenzothiazepinone compound of Formula I; wherein
Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of H, OH, F, CI, Br, I, -ORa, -SRa, -N02, -CN, unsubstituted or substituted Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted 03.7 cycloalkyl, unsubstituted or substituted Ci^ fluoroalkyl or perfluoroalky, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
wherein Ra is selected from H, Ci-6 linear or branched alkyl, unsubstituted or substituted benzyl, C3-7 cycloalkyl, C|-6 fluoroalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;
R9 is -ORb, wherein Rb is selected from the group consisting of Ci- linear or branched alkyl, substituted or unsubstituted benzyl, C3-7 cycloalkyl, Ci-6 fluoroalkyl or perfluoroalkyl, aryl and heteroaryl.
2. The process as claimed in claim 1, wherein the acid catalyst comprises phosphorus pentoxide and methanesulfonic acid in a molar ratio of 1 : 1 to 1 : 15.
3. The process as claimed in claim 2, wherein the molar ratio of phosphorus pentoxide and methanesulfonic acid is preferably in the ratio range of 1 :6 to 1:10.
4. The process as claimed in claim 1, wherein each of Rl, R2, R3, R4, R5, R6, R7 and R8 is H.
5. The process as claimed in claim 1 , wherein Rb is phenyl.
6. The process as claimed in claim 1, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is in the ratio range of 1:1:1 to 10:1:15.
7. The process as claimed in claim 1, wherein the molar ratio of phosphorus pentoxide: compound of "Formula II": methanesulfonic acid is preferably in the ratio range of 1 : 1 :6 to 3 : 1 : 10.
8. A process for preparation of a dibenzomiazepinone compound of Formula I, said process comprising:
mixing phosphorous pentoxide and methanesulfonic acid in a molar ratio of 1:1 to 1 : 15 at a temperature range of 20 °C to 80 °C to obtain a mixture,
heating and stirring the mixture at a temperature range of 80 °C to 150 °C, cooling the heated mixture to 80 °C to 20 °C to obtain an acid catalyst, mixing compound of Formula II and the acid catalyst to obtain a reaction mixture
raising temperature of the reaction mixture to 80°C to 120°C for a time period of 2 hour to 6 hour.
adding ice-water mixture to the reaction mixture to obtain a product, filtering the product, and
washing the product with water and acetone to obtain the compound of
Formula I.
9. The process as claimed in claim 8 optionally comprising:
heating compound of Formula II at a temperature range of 95 °C to 105 °C before mixing with the acid catalyst.
10. A process as claimed in any one of claim 1 to 9, for use in the preparation of a dibenzothiazepinone compound which is a key intermediate for the preparation of quetiapine or its derivatives.
PCT/IN2011/000163 2010-03-29 2011-03-10 Process for preparation of dibenzothiazepinone compounds WO2011121602A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447615A (en) * 2014-02-28 2015-03-25 广东东阳光药业有限公司 Preparation method of quetiapine intermediate

Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0282236A1 (en) 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Process for the preparation of a thiazepine compound
WO2004047722A2 (en) 2002-11-28 2004-06-10 Sk Corporation METHOD OF PREPARING 10H-DIBENZO[b,f][1,4]THIAZEPIN-11-ONE

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Publication number Priority date Publication date Assignee Title
EP0282236A1 (en) 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Process for the preparation of a thiazepine compound
WO2004047722A2 (en) 2002-11-28 2004-06-10 Sk Corporation METHOD OF PREPARING 10H-DIBENZO[b,f][1,4]THIAZEPIN-11-ONE

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Title
HELV. CHIM. ACTA, vol. 48, 1965, pages 336
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PHILIP E. EATON, GLENN R. CARLSON, JAMES T. LEE: "Phosphorus pentoxide-methanesulfonic acid. Convenient alternative to polyphosphoric acid", JOURNAL OF ORGANIC CHEMISTRY, vol. 38, 1973, pages 4071 - 4073, XP002650385, DOI: 10.1021/jo00987a028 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447615A (en) * 2014-02-28 2015-03-25 广东东阳光药业有限公司 Preparation method of quetiapine intermediate

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