WO2005028457A1 - Preparation of quetiapine - Google Patents

Preparation of quetiapine Download PDF

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WO2005028457A1
WO2005028457A1 PCT/FI2004/000559 FI2004000559W WO2005028457A1 WO 2005028457 A1 WO2005028457 A1 WO 2005028457A1 FI 2004000559 W FI2004000559 W FI 2004000559W WO 2005028457 A1 WO2005028457 A1 WO 2005028457A1
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Prior art keywords
ethyl
ethoxy
mixture
compound
bis
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PCT/FI2004/000559
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French (fr)
Inventor
Arne Grumann
Soini Huhta
Petteri Rummakko
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Fermion Oy
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Priority to US60/504,983 priority
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    • 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
    • C07D417/02Heterocyclic 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 two hetero rings
    • C07D417/12Heterocyclic 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 two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • 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
    • C07D309/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10Oxygen atoms
    • C07D309/12Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

Abstract

The present invention discloses a process for the preparation of quetiapine, which comprises the reaction of dibenzo[b,f][1,4]thiazepin-11-ylamine with a compound of the general formula (II) 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]dibenzo[b,fJ-l,4-thiazepine is a well established drug substance known under the INN name quetiapine. 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 I are known, as disclosed in e.g. GB 8607684, GB 8705574, and WO 01/55125.
Figure imgf000002_0001
Known methods include reacting a halo derivative (e.g. iminochloride) of dibenzo[b,fj[l,4]-thiazepin-l l(10-H)-one with l-(hydroxyethoxyethyl)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 prepared by reacting dibenzo[b,f][l,4]thiazepin-ll-ylamine with a compound of the general formula II:
Figure imgf000003_0001
II wherein PG is a is a hydroxyl protecting group selected from the group consisting of acetyl, benzoyl, pivaloyl, methoxymethyl, benzyl, 4-methoxybenzyl, allyl, tetrahydropyranyl, silyl, alkyl carbonate, aryl carbonate, aralkyl carbonate, benzyl carbonate, allylsulfonyl, benzylsulfonyl, toluenesulfonyl; preferably PG is methoxymethyl, benzyl, tetrahydropyryl or acyl; LG is a suitable leaving group selected from halogen, trifluoromethyl, O-p-toluenesulfonyl and O-methylsulfonyl, preferably halogen, most preferably chloro, to produce a compound of formula III
Figure imgf000003_0002
III and subsequently removing the protecting group to produce quetiapine.
Further objects of the invention are the novel intermediates IV, V, VI, VII, VIII and IX:
Figure imgf000003_0003
V VI
Figure imgf000003_0004
vπi rv
Figure imgf000004_0001
Disclosure of the invention
Dibenzo[b,f][l,4]thiazepin~l 1-ylamine may be prepared e.g. according to J.Heterocyclic Chem., 34, 465 (1997) from 2-aminothiophenol and 2- chlorobenzonitrile. According to one embodiment of the present invention, the compound of formula II is [2-(2-benzyloxy-ethoxy)-ethyl]bis-(2-chloroethyl)amine VI. Thus intermediate VII is produced:
Figure imgf000004_0002
Preferably, the debenzylation step is carried out with a suitable Lewis acid, preferably boron trichloride, or alternatively using catalytic hydrogenation.
According to another embodiment of the invention, the compound according to formula II is bis(2-chloroethyl)-{2-[2-(tetrahydropyran-2-yloxy)ethoxy]ethyl}amine TV, whereby intermediate IX above, which can be deprotected to product I, is obtained. [2-(2-benzyloxy-ethoxy)-ethyl]bis-(2-chloroethyl)amine VI may be prepared starting from (2-chloro-ethoxymethylbenzene) by reacting it with triethanolamine to obtain a dihydroxy compound. Preferably, the reaction is carried out without a solvent at a temperature of 20 -160 °C. Instead of (2-chloro-ethoxymethylbenzene), derivatives with alternative leaving groups at the 2-site may be used, e.g. other halogens, O-p-toluenesulfonyl or O-methanesulfonyl.
An alternative route to intermediate TJ involves the reaction between a compound of the general formula XI PG--. ^\ ^,C "LG
XI wherein PG and LG are defined as above, and diethanolamine to yield an intermediate of formula XII:
Figure imgf000005_0001
XII According to a preferable embodiment, this alternative route involves reacting [2- (2-chloro-ethoxy)-ethoxymethyl]benzene TV (obtained from bromomethylbenzene and 2-(2-chloro-ethoxy)-ethanol) with diethanolamine:
Figure imgf000005_0002
IV V
The resulting diol V may be converted to the dichloro derivative VI, preferably using thionyl chloride.
Coupling of dibenzo[b,fj[l,4]thiazepin-l 1-ylamine with the relevant compound of formula II and removal of the protective group yields the target compound I. Compounds VTJ and IX may be obtained by treating dibenzo[b,fJ[l,4]thiazepin-l 1- ylamine X with sodium hydride in DMF, adding the relevant substrate and isolating the reaction product. Debenzylation with boron trichloride or removal of the THP group in acid conditions, respectively, yields quetiapine I, which can be further reacted to a pharmaceutically acceptable salt thereof.
Examples
Example 1. 2-[[(2-benzyloxy-ethoxy)-ethyl]bis-(2-hydroxyethyl)amino]ethanol
Triethanolamine (150 ml, 1 mol) was charged into a reaction flask and warmed to 60 °C. 60% sodium hydride (16 g, 0.4 mol) was added in small portions at 60-100 °C. The mixture was stirred for 30 min. at 60-100 °C. (2-chloroethoxymethyl)- benzene (60 g, 0.35 mol) and potassium iodide (0.1 g) were added. The mixture was warmed for 6 h at 140 °C. The mixture was cooled to 30 °C. 10% NaCl-water (300 ml) was added, and the obtained solution was washed with a mixture of 80 ml hexane and 20 ml toluene. The water phase was extracted twice with ethyl acetate (150 ml and 50 ml). The combined organic phase was washed twice with 10% NaCl-water (100 ml and 50 ml). The organic phase was dried with K2CO3 and evaporated. The product 6 was a yellowish oil which was used without further purification. Yield of 2-[[(2-benzyloxy-ethoxy)-ethyl]bis-(2-hydroxyethyl)- amino]ethanol: 62 g.
1H NMR (CDC13) 2.7 (6H, m), 3.59 (10H, m), 4.55 (2H, s), 7.3 (5H, m). 13C NMR (CDC13) 53.9, 57.3, 59.8, 69.2, 69.8, 69.9, 73.3, 127.57, 127.65, 127.72, 127.87, 138.0.
Example 2. [2-(2-benzyloxy-ethoxy)-ethyl]bis-(2-chloroethyl)amine, hydrochloride
2-[[(2-benzyloxy-ethoxy)-ethyl]bis-(2-hydroxyethyl)amino]ethanol (60 g, 0.21 mol), toluene (300 ml) and dimethylformamide (2 ml) were charged into a reaction flask. Thionyl chloride (100 ml) was added. The mixture was stirred at reflux for 4 h. 100 ml was distilled off. The reaction mixture was slowly added to water (200 ml) at 20-50°C. The toluene phase was separated.
The water phase was extracted twice with dichloromethane (150 ml and 30 ml). The solvent was evaporated and the residue (36 g) was dissolved in ethyl acetate (200 ml). The solution was cooled to 0 °C and the precipitated product was filtered, washed with cold ethyl acetate and dried. Yield of [2-(2-benzyloxy-ethoxy)- ethyl]bis-(2-chloroethyl)amine as hydrochloride 15.8 g . 1H NMR (CDCI3) 2.45-3.70 (10H, m), 4.0 (6H, m), 4.54 (2H, s), 7.30-7.38 (5H, m), 13.1 (1H, s). 13C NMR (CDCI3) 36.7, 53.0, 55.2, 65.2, 69.2, 70.7, 73.4, 127.83, 127.93, 128.0, 128.46, 128.53, 137.82.
Example 3. ll-{4-[2-(2-benzyloxy-ethoxy)ethyl]-piperazin-l-yl}- dibenzo[b,f][l,4]thiazepine
Dibenzo[b,f][l,4]thiazepin-l l-ylamine (9.3 g, 0.041 mol) and dimethylformamide
(40 ml) were charged into a reaction flask. 60% sodium hydride (5 g, 0.12 mol) was added in small portions. The mixture was stirred for 15 min. at 40 °C. The mixture was cooled to 20 °C and [2-(2-benzyloxy-ethoxy)-ethyl]bis-(2-chloroethyl)amine hydrochloride (15 g, 0.042 mol) was added. The mixture was warmed for 5 h at 80
°C. The solvent was distilled off under reduced pressure. The residue was dissolved into dichloromethane (80 ml) and water (100 ml). The water phase was separated.
The organic phase was dried with K2CO3 and evaporated, the residue being 17.7 g
(91,2%). Purification: The residue (12 g) was cromatographed on silica gel eluating with ethyl acetate - triethylamine (96:4), yield 7.9 g (65.8%).
1H NMR (CDCI3) 2.51-2.67 (6H, m), 3.53-3.67 (10H, m), 4.55 (2H, s), 6.87-7.51
(13H, m)
13C NMR (CDCI3) 46.1, 57.8, 69.0, 69.1, 69.5, 70.5, 73.2, 122.7, 125.3, 127.6, 128.0, 128.2, 128.3, 129.0, 129.1, 130.7, 131.6, 132.1, 132.2, 132.7, 134.2, 138.3,
139.9, 149.0, 160.7. Example 4. Quetiapine
11 - {4-[2-(2-benzyloxy-ethoxy)ethyl] -piperazin- 1 -yl} -dibenzo[b,fJ [ 1 ,4]thiazepine (0.2 g, 0.422 mmol) and toluene (5 ml) were charged into a reaction flask. The mixture was cooled to -5 °C. 1 M BC13 in xylene (1 ml) was added and the reaction mixture was allowed to warm to room temperature and stirred 2 h at ambient temperature. A mixture of triethylamine (2 ml) and methanol (5 ml) was added. After 10 min. of stirring, 1 M NaOH (1 ml) and saturated NaCl-water (2 ml) were added. The organic phase was separated and evaporated. Yield of quetiapine 0.15 g.
Using tetrahydropyran as OH-protective group:
Example 5. 2-((2-hydroxy-ethyl)- {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-ethyl} - amino)-ethanol
2-(2-chloro-ethoxy)-ethanol (25 g, 0.2 mol), dichlorometane (50 ml) and Amberlyst H-15 (1 g) were charged into a reaction flask. 2,3-dihydropyran (25 ml, 0.3 mol) was added during 15 minutes. The mixture was stirred for 17 h at 25 °C. Amberlyst H-15 was filtered off and dichlorometane was evaporated in vacuo. To the residue were added diethanolamine (50 g), Na2CO3 (20 g), Nal (1 g), TB ABr (0.1 g) and DMF (60 ml). The mixture was stirred for 5 h at 140 °C. DMF was evaporated in vacuo. Ethyl acetate (100 ml) and 10 % NaCl-water (100 ml) were added. The mixture was stirred for 5 min. and the water phase was separated. The organic phase was washed with 10 % NaCl-water (100 ml), dried with Na CO3 and evaporated in vacuo. Yield 43.9 g.
The product was used without further purification.
Example 6. Bis-(2-chloro-ethyl)- {2-[2-(tetrahydropyran-2-yloxy]-ethyl}-amine
2-((2-hydroxy-ethyl)- {2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl} -amino)- ethanol ( 9 g, 0.03 mol), dichlorometane (50 ml) and triphenylphosphine (18.4 g, 0.07 mol) were charged into a reaction flask. The mixture was cooled to 0 °C, and N-chlorosuccinimide (9.3 g (0.07 mol) was added in small portions at 0-20 °C. The mixture was stirred for 17 h at 25 °C. Dichlorometane was evaporated in vacuo. To the residue was added hexane (100 ml) and 10 % K2CO -water (20 ml). The mixture was stirred for 10 min. and the insoluble material was filtered off. The organic phase was evaporated in vacuo. Yield of 2 7.7 g . 13C NMR (CDC13) 19.5, 26.4, 30.6, 42.0, 54.3, 57.2, 62.2, 66.7, 70.1, 70.2, 99.0.
Example 7. 1 l-(4-{2-[2-(tetrahydro-pyran-2-yloxy-)ethoxy]-ethyl}-piperazin-l-yl)- dibenzo[b,f] [ 1 ,4]thiazepine
Dibenzo[b,fJ[l,4]thiazepin-l 1-ylamine (0.11 g, 0.5 mmol), bis-(2-chloro-ethyl)-{2- [2-(tetrahydropyran-2-yloxy]-ethyl}-amine (0.3 g) and dimethylformamide (1 ml) were charged into a reaction flask. 60% sodium hydride (0.1 g) was added in small portions. The mixture was stirred for 30 min. at 50 °C. The mixture was warmed for 3.5 h at 105 °C. The mixture was cooled to 20 °C and water (3 ml) was added. The water phase was decanted, and the precipitated product was dissolved into ethyl acetate (5 ml). The solution was washed with water (2 ml). The solvent was distilled under reduced pressure. The residue was used further without purification. Yield 0.24 g. 13C NMR (CDC13) 19.5, 25.4, 30.6, 45.6, 45.7, 57.7, 62.2, 66.6, 68.8, 70.4, 98.9, 122.8, 125.3, 126.9, 129.0, 129.1, 130.7, 131.9, 131.95, 133.6, 134.2, 140.0, 149.0, 160.7
Example 8. Quetiapine
11 -(4- {2-[2-(tetrahydro-pyran-2-yloxy-)ethoxy] -ethyl} -piperazin- 1 -yl)-dibenzo- [b,f][l,4]thiazepine (0.24 g, 0.5 mmol), methanol (2 ml) and 30% HC1 (1 ml) were charged into a reaction flask. The mixture was stirred 2 h at 50°C and the methanol was evaporated. The residue was dissolved in water (3 ml). The solution was washed with ethyl acetate (3 ml). To the water phase was added 50% NaOH (1 ml) and the product was extracted with ethyl acetate (5 ml). The ethyl acetate phase was washed with saturated NaCl-water (3 ml), and the organic phase was evaporated. Yield 0.16 g.

Claims

What is claimed is:
1. A method for the preparation of the compound of formula I
Figure imgf000010_0001
by reacting the compound of formula X
Figure imgf000010_0002
X with a compound of the general formula II
Figure imgf000010_0003
II
wherein PG is a suitable protective group, and LG is a leaving group selected from the group consisting of halo, trifluoromethyl, O-p-toluenesulfonyl and O- methylsulfonyl, to yield a compound of the general formula III
Figure imgf000010_0004
in
and removing the protective group PG.
2. The method of claim 1, wherein LG is chloro.
3. The method of claim 1, wherein PG is selected from the group consisting of benzyl, tetrahydropyryl, methoxymethyl and acyl.
4. The method of claim 1, wherein PG is benzyl.
5. The method of claim 4, wherein the benzyl group is removed using boron trichloride.
6. The method of claim 1, wherein PG is tetrahydropyryl.
7. 2-[[(2-benzyloxy-ethoxy)-ethyl]bis-(2-hydroxyethyl)amino]ethanol.
8. [2-(2-benzyloxy-ethoxy)-ethyl]bis-(2-chloroethyl)amine.
9. 11- {4-[2-(2-benzyloxy-ethoxy)ethyl]-piperazin- 1-yl} -dibenzo[b,f] [ 1 ,4] thiazepine.
10. 2-((2-hydroxy-ethyl)-{2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-ethyl}-amino)- ethanol.
11. Bis-(2-chloro-ethyl)- {2-[2-(tetrahydropyran-2-yloxy]-ethyl} -amine.
12. ll-{4-[2-(2-tetrahydropyran-2-yloxy)-ethoxy)ethyl]-piperazin-l-yl}- dibenzo [b,f] [ 1 ,4]thiazepine.
PCT/FI2004/000559 2003-09-23 2004-09-23 Preparation of quetiapine WO2005028457A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095529A1 (en) * 2008-01-31 2009-08-06 Fermion Oy A process for the preparation of quetiapine
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
DE202009018024U1 (en) 2008-08-01 2010-12-09 Krka Tovarna Zdravil, D.D., Novo Mesto Quetiapine composition
US8101597B2 (en) 2007-05-07 2012-01-24 Actavis Group Ptc Ehf Quetiapine salts and their polymorphs
CN103304515A (en) * 2012-03-07 2013-09-18 华东师范大学 Method for preparing 11-amino dibenzo [b, f] [1,4] thiazepine
CN111492046A (en) * 2017-12-20 2020-08-04 亨斯迈石油化学有限责任公司 Aromatic-based polyetheramine alkoxylates

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Cited By (8)

* 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
WO2009095529A1 (en) * 2008-01-31 2009-08-06 Fermion Oy A process for the preparation of quetiapine
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine
DE202009018024U1 (en) 2008-08-01 2010-12-09 Krka Tovarna Zdravil, D.D., Novo Mesto Quetiapine composition
WO2010100623A1 (en) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Process for the preparation of quetiapine fumarate
CN103304515A (en) * 2012-03-07 2013-09-18 华东师范大学 Method for preparing 11-amino dibenzo [b, f] [1,4] thiazepine
CN111492046A (en) * 2017-12-20 2020-08-04 亨斯迈石油化学有限责任公司 Aromatic-based polyetheramine alkoxylates

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