WO2005028459A1 - Preparation method for quetiapine - Google Patents

Preparation method for quetiapine Download PDF

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Publication number
WO2005028459A1
WO2005028459A1 PCT/FI2004/000561 FI2004000561W WO2005028459A1 WO 2005028459 A1 WO2005028459 A1 WO 2005028459A1 FI 2004000561 W FI2004000561 W FI 2004000561W WO 2005028459 A1 WO2005028459 A1 WO 2005028459A1
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Prior art keywords
compound
ethyl
formula
hydroxyethoxy
piperazine
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Application number
PCT/FI2004/000561
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French (fr)
Inventor
Leif Hilden
Arne Grumann
Soini Huhta
Petteri Rummakko
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Fermion Oy
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Priority to US50498203P priority Critical
Priority to US60/504,982 priority
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Publication of WO2005028459A1 publication Critical patent/WO2005028459A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215Radicals derived from nitrogen analogues of carbonic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D281/00Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02Seven-membered rings
    • C07D281/04Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12Seven-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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention discloses a process for the preparation of quetiapine, which comprises the ring closure and deprotection of a compound of the formula (I), as well as novel intermediates in the process.

Description

PREPARATION OF QUETIAPINE
Field of the invention
1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]diben2θ[b,f]-l,4-thiazepine (I) is a well established drug substance known under the INN name quetiapine.
Figure imgf000002_0001
I It is used as an antipsychotic or neuroleptic. The present invention provides an economical alternative method for the preparation of quetiapine in high yield and purity. Further objects of the invention are novel intermediates useful in the process according to the invention.
Background of the invention
Several methods for the preparation of quetiapine are known, as disclosed in e.g. GB 8607684, GB 8705574, and WO 01/55125. The known methods involve reacting a halo derivative (e.g. iminochloride) of dibenzo[b,f][l,4]-thiazepin-l 1(10- H)-one with l-[2-(hydroxyethoxy)-ethyl]piperazine; reacting the aforementioned halo derivative with piperazine and reacting the resulting intermediate with a haloethoxyethanol; and reacting a haloethylpiperazinylthiazepine derivative with ethylene glycol.
Summary of the invention
According to the present invention, the target compound I is obtained by cyclizing a compound of formula II
Figure imgf000002_0002
II wherein PG represents a protective group, and subsequently removing the protective group.
The compound of formula II is prepared either a) by attaching the protective group PG to the hydroxyl group of compound III
Figure imgf000003_0001
Ill which may be prepared by a one pot reaction involving 2- phenylsulfanylphenylamine, l-[2-(hydroxyethoxy)-ethyl]piperazine and a coupling agent, e.g. phosgene or equivalent; or
b) by attaching the protective group to the hydroxyl group of l-[2-(hydroxyethoxy)- ethyl]piperazine prior to reaction with 2-phenylsulfanylphenylamine and the coupling agent.
Further objects of the invention are the novel intermediates III, IV and V:
Figure imgf000003_0002
Disclosure of the invention
2-phenylsulfanylphenylamine maybe prepared e.g. by reacting l-chloro-2- nitrobenzene with benzenethiol and catalytically reducing the nitro group, e.g. as disclosed in the literature. According to the method of the present invention, compound III or IV is obtained without isolation of intermediates by allowing 2- phenylsulfanylphenylamine to react with a carbonyl compound VI
Figure imgf000004_0001
VI
wherein Rl and R2 may independently be halo, p-nitrophenyl, imidazolyl or -OR wherein R is alkyl or aryl, and adding l-[2-(hydroxyethoxy)-ethyl]piperazine either as such or with a protective group on the hydroxy group. Preferred carbonyl compoumds VI include phosgene, diphosgene, triphosgene, (p-nitro)phenylchloroformate, methylchloroformate, dimethyl carbonate and carbonyldi-imidazole. Preferred protective groups inlude ethers and esters, e.g. benzoyl, acetyl, benzyl and tetrahydropyryl.
The reaction of 2-phenylsulfanylphenylamine with the compound of formula VI is preferably carried out in a suitable solvent; preferably toluene, but other aromatic and aliphatic hydrocarbons, also chlorinated derivatives, may be used. The reaction temperature may range from - 50 °C to 25 °C. The subsequent reaction with protected or unprotected l-[2-(hydroxyethoxy)-ethyl]piperazine is preferably carried out at - 10 °C to 25 °C in the presence of a base, preferably triethylamine but other bases, e.g. other tertiary amines, may be used.
In the case l-[2-(hydroxyethoxy)-ethyl]piperazine is used in the above step without a protective group, the protective group PG is subsequently introduced to yield compound II. Preferably, benzoyl chloride is used; other alternatives include acid chlorides and anhydrides, as well as ether-forming reagents. The reaction is preferably carried out at a temperature of 0- 100 °C, preferably at ambient temperature.
Compound TJ is cyclized by treatment with a ring closure agent. Such agents include phosphorus oxychloride, phosphorus pentoxide and polyphosphoric acid. An advantageous reagent is a mixture of phosphorus oxychloride and phosphorus pentoxide, preferably using an excess of phosphorus oxychloride as a solvent. Possible co-solvents are aliphatic or aromatic hydrocarbons, preferably toluene, as well as chlorinated hydrocarbons. The preferable temperature ranges from 50 to 130 °C, preferably about 80 - 100 °C.
Following cyclization, the protective group on the hydroxyl moiety is removed to produce the target compound I, which can be further transferred to a pharmaceutically acceptable salt thereof. If the protective group is susceptible to hydrolysis in basic conditions, sodium hydroxide in ethanol at 20 - 100 °C is preferably used.
Examples
Example 1. 4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2- phenylsulfanyl-phenyl)-amide
The reaction was carried out without isolation of intermediates in a one pot synthesis. Toluene (30 ml) and phosgene solution (20% in xylene, 9.1 ml, 17.16 mmol) were charged into a reaction flask. The mixture was cooled to -50°C. A mixture of 2-phenylsulfanylphenylamine (3 g, 14.9 mmol), triethylamine (2.4 ml, 17.1 mmol) and toluene (5 ml) was charged into the reaction flask at -50°C during 5 min. The mixture was allowed to reach room temperature and it was stirred at room temperature for 1.5 h. Then the reaction mixture was added to another reaction flask at -10-0 °C, containing the cooled mixture of l-[2-(hydroxyethoxy)-ethyl]- piperazine, triethylamine (2.7 ml) and toluene (20 ml). The reaction mixture was stirred at room temperature for 1.5 h. Precipitated triethylamine hydrochloride was filtered off. The resulting toluene solution was washed twice with saturated NaCl- water (10 ml), dried with K2CO3 and evaporated in vacuo. The yield of 4-[2-(2- hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)-amide was 4.76 g. 1H NMR (CDC13). 2.35 (4H, m), 2.53 (2H, t), 3.34 (4H, t), 3.60 (4H, m), 3.67 (2H, t), 7.0-7.63 (9H, m). 13C NMR (CDC13). 43.5, 52.8, 57.7, 61.8, 67.7, 72.4, 115.3, 118.4, 122.8, 125.4, 126.1, 126.3, 126.4, 127.8, 128.9, 129.2, 131.2, 141.2, 153.9 Example 2. Benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-l-yl]- ethoxy} -ethyl ester
4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl- phenyl)-amide (4 g, 10 mmol), triethylamine (2 ml, 15 mmol) and toluene (50 ml) were charged into a reaction flask. Benzoyl chloride (1.7 g, 12 mmol) in toluene (5 ml) was added at 0-10 °C. The mixture was stirred for 16 h at 20 °C. Cold water (50 ml) and 1 M NaOH (10 ml) were added. The mixture was stirred for 20 min. The water phase was separated. The organic phase was washed with saturated NaCl solution (25 ml) and evaporated in vacuo. The yield of benzoic acid 2-{2-[4-(2- phenylsulfanyl-phenylcarbamoyl)piperazin-l-yl]-ethoxy}-ethyl ester was 4.91 g. 1H NMR (CDC13). 2.35 (4H, m), 2.54 (2H, m), 3.28 (4H, m), 3.63 (2H, ), 3.77 (2H, m), 4.47 (2, m), 7.0-8.3 (14H, m). 13C NMR (CDCI3). 43.7, 53.0, 57.6, 63.9, 68.9, 69.0, 118.4, 119.8, 122.7, 126.5, 127.1, 129.2, 129.3, 129.6, 130.0, 131.0, 133.1, 135.6, 136.0, 136.5, 140.1, 141.3, 154.0, 166.4
Example 3. Benzoic acid 2-[2-(4-dibenzo[b,fj[l,4]-thiazepin-ll-yl-piperazin-l-yl]- ethoxy] -ethyl ester
Benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-l-yl]-ethoxy}- ethyl ester (2 g, 3.96 mmol), phosphorus oxychloride (15 ml) and phosphorus pentoxide (2 g) were charged into a reaction flask. Then the mixture was stirred at 90 °C for 19 h. Phosphorus oxychloride was evaporated in vacuo. Dichlorometane (20 ml) and ice-water (20 ml) were added to the residue. NaHCO3 was added until the pH was 7-8. The organic phase was separated, washed with saturated NaCl- water (10 ml), dried with Na2SO4 and evaporated. Yield of benzoic acid 2-[2-(4- dibenzo[b,f][l,4]-thiazepin-l l-yl-piperazin-l-yl]-ethoxy]-ethyl ester 1.53 g. 1H NMR (CDCI3). 2.52-2.67 (6H, m), 3.67-3.80 (8H, m), 4.47 (2H, m), 6.90-8.0 (13H, m). 13C NMR (CDCI3). 46.1, 53.4, 63.7, 68.9, 69.0, 69.1, 122.7, 125.4, 127.1, 128.2, 128.4, 129.0, 129.1, 129.2, 129.6, 129.7, 130.0, 130.7, 131.1, 132.1, 133.0, 134.1, 139.8, 160.7, 166.5 Example 4. Quetiapine
Benzoic acid 2-[2-(4-dibenzo[b,fJ[l,4]-thiazepin-l l-yl-piperazin-l-yl]-ethoxy]- ethyl ester (1.5 g, 2.97 mmol), ethanol (10 ml) and 50% NaOH (1 ml) were charged into a reaction flask. Then the mixture was stirred at 80 °C for 2 h. The reaction mixture was evaporated in vacuo. Ethyl acetate (20 ml) and saturated NaCl-water (15 ml) were added to the residue. The water phase was separated. To the organic phase was added 1 M HC1 (10 ml). To the combined water phase was added 50% NaOH until the pH was 12 and saturated NaCl- water (10 ml). The alkaline water phase was extracted twice with ethyl acetate (10 ml). The combined organic phase was washed with saturated NaCl- water (10 ml), dried with Na2SO4 and evaporated. Yield of quetiapine 0.93 g.

Claims

What is claimed is:
1. A method for the preparation of the compound of formula I
Figure imgf000008_0001
by treating a compound of the general formula II
Figure imgf000008_0002
II
wherein PG is a protective group, with a ring closure agent to produce a compound of formula VII
Figure imgf000008_0003
VII and removing the protective group to produce compound I.
2. The method of claim 1, wherein PG is benzoyl.
3. The method of claim 1, wherein the ring closure agent is phosphorus oxychloride and phosphorus pentoxide.
4. The method of claim 1, wherein the compound of formula II is prepared by reaction between 2-phenylsulfanylphenylamine, a compound of formula VI
Figure imgf000009_0001
VI wherein Rl and R2 may independently be halo, p-nitrophenyl, imidazolyl or -OR wherein R is alkyl or aryl; and a) l-[2-(hydroxyethoxy)-ethyl]piperazine, whereby the protective group PG in formula II is subsequently attached; b) an O-protected derivative of l-[2-(hydroxyethoxy)-ethyl]piperazine.
5. 4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)- amide
6. Benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-l-yl]-ethoxy}- ethyl ester
7. Benzoic acid 2-[2-(4-dibenzo[b,f][l,4]-thiazepin-ll-yl-piperazin-l-yl]-ethoxy]- ethyl ester
PCT/FI2004/000561 2003-09-23 2004-09-23 Preparation method for quetiapine WO2005028459A1 (en)

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US10/572,370 US7858777B2 (en) 2003-09-23 2004-09-23 Preparation method for quetiapine
DE602004031129T DE602004031129D1 (en) 2003-09-23 2004-09-23 PROCESS FOR THE PREPARATION OF QUETIAPIN
CA002538866A CA2538866A1 (en) 2003-09-23 2004-09-23 Preparation of quetiapine
JP2006526654A JP2007505865A (en) 2003-09-23 2004-09-23 Manufacture of quetiapine
AT04767075T AT496038T (en) 2003-09-23 2004-09-23 PROCESS FOR THE PREPARATION OF QUETIAPIN
EP04767075A EP1664009B1 (en) 2003-09-23 2004-09-23 Preparation method for quetiapine

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
WO2010100623A1 (en) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Process for the preparation of quetiapine fumarate
US8101597B2 (en) 2007-05-07 2012-01-24 Actavis Group Ptc Ehf Quetiapine salts and their polymorphs
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003235435A1 (en) * 2002-03-20 2003-10-08 Teva Pharmaceutical Industries Ltd. Crystalline forms of quetiapine hemifumarate
PT1664007E (en) * 2003-09-23 2010-02-15 Fermion Oy Preparation of quetiapine
WO2008121415A2 (en) * 2007-03-29 2008-10-09 Teva Pharmaceutical Industries Ltd. Improved process for preparing quetiapine fumarate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3539573A (en) * 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
EP0240228A1 (en) * 1986-03-27 1987-10-07 Ici Americas Inc. Thiazepine compounds
EP0282236A1 (en) * 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Process for the preparation of a thiazepine compound
WO2001055125A1 (en) * 2000-01-25 2001-08-02 EGIS Gyógyszergyár Rt. A process for the preparation of quetiapine and intermediates therefor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA979441A (en) * 1967-02-27 1975-12-09 American Cyanamid Company 11-(piperazinyl) dibenz (b,f) (1,4) oxazepines and analogous thiazepines
US3458516A (en) * 1968-02-16 1969-07-29 American Cyanamid Co 11-(piperazinyl)dibenz(b,f)(1,4)oxazepines and analogous thiazepines
PT1664007E (en) 2003-09-23 2010-02-15 Fermion Oy Preparation of quetiapine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3539573A (en) * 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
EP0240228A1 (en) * 1986-03-27 1987-10-07 Ici Americas Inc. Thiazepine compounds
EP0282236A1 (en) * 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Process for the preparation of a thiazepine compound
WO2001055125A1 (en) * 2000-01-25 2001-08-02 EGIS Gyógyszergyár Rt. A process for the preparation of quetiapine and intermediates therefor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WARAWA E J ET AL: "Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, 1 February 2001 (2001-02-01), pages 372 - 389, XP002213291, ISSN: 0022-2623 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
US8101597B2 (en) 2007-05-07 2012-01-24 Actavis Group Ptc Ehf Quetiapine salts and their polymorphs
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine
WO2010100623A1 (en) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Process for the preparation of quetiapine fumarate

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AT496038T (en) 2011-02-15
EP1664009A1 (en) 2006-06-07
EP1664009B1 (en) 2011-01-19
US20070111986A1 (en) 2007-05-17
US7858777B2 (en) 2010-12-28
JP2007505865A (en) 2007-03-15
DE602004031129D1 (en) 2011-03-03

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