WO2008152434A1 - Synthesis for the preparation of quetiapine - Google Patents
Synthesis for the preparation of quetiapine Download PDFInfo
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- WO2008152434A1 WO2008152434A1 PCT/HU2008/000067 HU2008000067W WO2008152434A1 WO 2008152434 A1 WO2008152434 A1 WO 2008152434A1 HU 2008000067 W HU2008000067 W HU 2008000067W WO 2008152434 A1 WO2008152434 A1 WO 2008152434A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- thiazepine
- quetiapine
- compound
- ethoxy
- Prior art date
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- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229960004431 quetiapine Drugs 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- -1 11-chlorodibenzo[b,f][1,4]thiazepine compound Chemical class 0.000 claims abstract description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 6
- 239000001530 fumaric acid Substances 0.000 claims abstract description 6
- 239000012442 inert solvent Substances 0.000 claims abstract description 6
- 238000002955 isolation Methods 0.000 claims abstract description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 6
- JCYZKOJFYMJJTJ-UHFFFAOYSA-N 2-(2-piperazine-1,4-diium-1-ylethoxy)ethanol;dichloride Chemical compound Cl.Cl.OCCOCCN1CCNCC1 JCYZKOJFYMJJTJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZEGOHKKKKMDYSR-UHFFFAOYSA-N 8h-benzo[b][1,4]benzothiazepin-7-one Chemical compound C1=NC2=CC=CC=C2SC2=C1C(=O)CC=C2 ZEGOHKKKKMDYSR-UHFFFAOYSA-N 0.000 claims abstract description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 31
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 15
- 239000012071 phase Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000004237 preparative chromatography Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JKWULZOMUNJJTK-UHFFFAOYSA-N 1-ethoxy-1-piperazin-1-ylethanol;hydrate;dihydrochloride Chemical compound O.Cl.Cl.CCOC(C)(O)N1CCNCC1 JKWULZOMUNJJTK-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- POOHNCPQYPMWKZ-UHFFFAOYSA-N thiazepine;hydrochloride Chemical compound Cl.S1C=CC=CC=N1 POOHNCPQYPMWKZ-UHFFFAOYSA-N 0.000 description 2
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 description 1
- ZIFBRTNTVHUJOI-UHFFFAOYSA-N 1-ethoxy-1-piperazin-1-ylethanol dihydrochloride Chemical compound Cl.Cl.N1(CCNCC1)C(C)(O)OCC ZIFBRTNTVHUJOI-UHFFFAOYSA-N 0.000 description 1
- ZFOZNNFYECYUQB-UHFFFAOYSA-N 6-chlorobenzo[b][1,4]benzothiazepine Chemical compound ClC1=NC2=CC=CC=C2SC2=CC=CC=C12 ZFOZNNFYECYUQB-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- KOXIVMUITVOLHH-UHFFFAOYSA-N chlorobenzene methylsulfinylmethane Chemical compound ClC1=CC=CC=C1.CS(=O)C KOXIVMUITVOLHH-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
Classifications
-
- 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 desired salt of compound of formula (I) was obtained by dissolving the quetiapine base in another organic solvent, followed by salt formation which is isolated by filtration.
- aqueous phase was extracted with 50 ml (45 g) of ethyl acetate.
- the unified organic phases were washed with 2x50 ml of water and 50 ml of 15 % NaCI solution.
- the obtained crystal suspension was stirred for 30 minutes at 58-62 0 C and then it was cooled to 0-5 0 C and stirred for further 2 hours at this temperature.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Process for the synthesis of 2-[2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-piperazine-1-yl)-ethoxy]-ethanol of formula (I) (quetiapine) by reacting the 1-oxodibenzo-[b,f][1,4]thiazepine of formula (II) with phosphorus oxychloride by d) using 1-6 molequivalent of phosphorus oxychloride in an inert solvent and the obtained 11-chlorodibenzo[b,f][1,4]thiazepine compound of formula (IV) without isolation; e) is reacted further in an inert solvent in the presence of a base with 2-[2-(1-piperazinyl)-ethoxy]-ethanol dihydrochloride of formula (III a) or dihydrochloride monohydrate of formula (III b), in the mixture of an inert non-polar and dipolar aprotic solvent; f) in desired case the isolated quetiapine base of formula (I) is reacted with fumaric acid to form the hemifumarate salt thereof.
Description
Synthesis for the preparation of quetiapine
The invention relates to a process for the synthesis of the known drug of formula (I). The chemical name of compound (I) is 2-[2-(4-dibenzo[b,f][1 ,4]thiazepine-11-yl- piperazine-1-yl)-ethoxy]-ethanol, the INN name thereof is quetiapine.
The compound (I) is synthesized by reacting 1-oxodibenzo-[b,f][1 ,4]thiazepine of formula (II) with 2-[2-(1-piperazinyl)-ethoxy]-ethanol dihydrochloride of formula (III a) or dihydrochloride monohydrate of formula (III b).
H — N N. _OH
III. b.
I. a.
IV.
The synthesis of quetiapine of formula (I) is described first in EP 240228 Patent of
ICI. According to the description 11-chlorodibenzo[b,f][1 ,4]thiazepine so called: iminochloride compound of formula (IV) is prepared from dibenzo-[b,f][1 ,4]-thiazepine-11-on, so called dibenzo-thiazepine ketone of formula (II) by reacting with excess of phosphorus oxychloride for 6 hours, which is used for solvent as well.
The isolation of compound of formula (IV) is very difficult. The excess of phosphorus oxychloride was distilled out, the obtained residue was extracted with toluene and water. Then the toluene was evaporated to give the crude iminochloride compound of formula (IV). Thereafter the obtained compound of formula (IV) was refluxed in xilol with 2-[2-
(1-piperazinyl)-ethoxy]-ethanol of compound of formula (III) for 30 hours.
The reaction mixture was extracted with aqueous NaOH solution and diethyl- ether. The extract of diethyl-ether was treated with aqueous HCI1 followed by addition of sodium carbonate and extraction with methylene chloride to give the product in methylene chloride solution. The evaporation of the methylene chloride solution resulted a viscous oil. The quetiapine base of formula (I) was obtained by preparative chromatography. The pharmaceutically acceptable salt thereof was produced by salt formation.
- This process is quite complicated, time consuming, the solvent requirement thereof is high and it has the following problems in large scale production: - The big access of phosphorus oxychloride could be removed only by distillation.
This process is very corrosive and it requires special equipment.
- The extraction of the residue with water is quite difficult even in laboratory scale, because the iminochloride compound of formula (IV) is water sensitive and it can be hydrolyzed easily to the starting compound of dibenzo-thiazepine ketone of formula (II). - It is very difficult to carry out this reaction in large scale, since the evaporation requires special equipment.
The reaction of iminochloride compound of formula (IV) with the 2-[2-(1- piperazinyl)-ethoxy]-ethanol of compound of formula (III) takes extremely long time: 30 hours.
The reaction was carried out at high, reflux temperature (at the boiling point of xilol) which caused serious tar precipitation. For this reason the isolation of the product in good quality required multistep water-solution extraction of the evaporation residue.
The preparative chromatography needs high amount of solvent. The quetiapine base of formula (I) was obtained by evaporation from the dilute solution of preparative chromatography.
The desired salt of compound of formula (I) was obtained by dissolving the quetiapine base in another organic solvent, followed by salt formation which is isolated by filtration.
Int. Pat. Appl. No. WO 2006 113425 of TEVA describes the reaction of the compound of formula (IV) with the base of formula (III) in xilol, toluene or in another high boiling point alcohol e.g.: n-buthanol or the mixture thereof in the presence of a catalyst, preferably potassium iodide and a base.
After the reaction was completed, the quetiapine base is obtained by evaporation. The desired salt of compound of formula (I) was formed by salt formation.
The disadvantage of the reaction is that the starting material of formula (IV) can be prepared and purified only with difficulties. The compound of formula (IV) was reacted with the base of formula (III) with long (20-40 hours) reaction time.
Further disadvantage of the process of TEVA is that the purity of the obtained quetiapine base is only about 90 %. There is no data for the purity of the isolated salt.
The aim of our invention is to elaborate an improved process, which eliminates the disadvantages of the known procedures and according to which high quality product can be obtained by simple technology and which is appropriate for large scale production.
The invention relates to a process for the synthesis of 2-[2-(4- dibenzo[b,f][1 ,4]thiazepine-11-yl-piperazine-1-yl)-ethoxy]-ethanol of formula (I) (quetiapine) by reacting the 1-oxodibenzo-[b,f][1 ,4]thiazepine of formula (II) with phosphorus oxychloride by
a) using 1-6 molequivalent of phosphorus oxychloride in an inert solvent and the obtained 11-chlorodibenzo[b,f][1,4]thiazepine compound of formula (IV) without isolation
b) is reacted further in an inert solvent in the presence of a base with 2-[2-(1- piperazinyl)-ethoxy]-ethanol dihydrochloride of formula (III a) or dihydrochloride monohydrate of formula (III b), in the mixture of an inert non-polar and dipolar aprotic solvent
c) in desired case the isolated quetiapine base of formula (I) is reacted with fumaric acid to form the hemifumarate salt thereof.
It was surprisingly found that using inert non-polar solvent for the conversion of dibenzo-thiazepine ketone of formula (II) to the iminochloride compound of formula (IV) can be carried out also with 1-6 molequivalent of phosphorus oxychloride.
Then to the reaction mixture water was added forming the iminochloride compound of formula (IV) in an inert, non-polar solvent quantitatively without hydrolysis.
The compound of formula (IV) is so pure that the isolation of the compound of formula (IV) is not necessary.
Moreover it was surprisingly found that the reaction of the iminochloride compound of formula (IV) with 2-[2-(1-piperazinyl)-ethoxy]-ethanol dihydrochloride of formula
(III a) or dihydrochloride monohydrate of formula (III b) in the mixture of an inert non-polar and dipolar aprotic solvent in the presence of a base e.g.: sodium carbonate at 85-90 0C required less reaction time: 6-8 hours.
After the reaction was completed the mixture was cooled down, diluted with water and extracted with a solvent.
In desired case the salt formation is carried out in an appropriate solvent used for the extraction e.g. ethyl acetate.
According to the process of the invention the salt of formula (I) can be isolated by filtration with pharmaceutical quality, high purity and in very good yield.
The amount of phosphorus oxychloride is preferably 4-5 mol equivalent.
The inert non-polar solvent is preferably chlorobenzene.
The dipolar aprotic solvent is preferably dimethyl sulphoxide.
The quetiapine compound of formula (I) can be produced from the prepared - but not isolated - iminochloride compound of formula (IV) of high purity in the mixture of preferable chlorobenzene - dimethyl sulphoxide solvents with mild alkylating conditions without by- products.
The obtained quetiapine product of formula (I) has high HPLC purity, the amount of impurities is less than 0.3 % and the amount of individual impurities are less then 0.1%.
The invention is illustrated by the following non limiting examples:
Example 1
Synthesis of (2-[2-(4-Dibenzo[b,f][1,4]thiazepine-11-yl-piperazine-1-yl)-ethoxy]-ethanol (I) hemifumarate salt
In a flask 11.3 g (0.05 mol) of thiazepine-keton of formula (II) and 2.9 g (0.023 mol) of N,N-dimethylaniline was added dropwise to 75 ml (83 g) of chlorbenzene in dry N2 atmosphere with stirring.
The solution was cooled below 15 °C and 34.0 g (0.22 mol) of phosphorus oxychloride was added to it in such a way that the temperature of the reaction remained below 15 0C.
The reaction was warmed to 95-100 0C and stirred at this temperature for 3 hours (after 2-2.5 hours a homogenous solution was obtained).
After the reaction was completed the solution was cooled to 0-5 0C and it was added to the mixture of 200 ml of water and 75 ml of chlorobenzene in such a way that the temperature of the reaction remained below 10 0C.
After stirring the phases were separated, the water phase was extracted with 40 ml of chlorobenzene and the unified organic phases were washed with 50 ml of water.
After separation of the phases the chlorobenzene solution was concentrated by evaporation in vacuum to 50 ml.
To the obtained 50 ml chlorobenzene solution of thiazepine-chloride of formula (IV) 130 ml of dimethyl-sulphoxide, 13.6 g (0.055 mol) of piperazinyl-ethoxy-ethanol
dihydrochloride of formula (lll.a) and 32 g (0.29 mol) of sodium carbonate was added in N2 atmosphere.
The alkylation reaction was completed at 85-90 0C in 6-8 hours with vigorous stirring.
Then the solution was cooled to 20-25 0C, 450 ml of water and 160 ml of ethyl acetate was added to it.
After separation of the phases the aqueous phase was extracted with 50 ml (45 g) of ethyl acetate. The unified organic phases were washed with 2x50 ml of water and 50 ml of 15 % NaCI solution.
To the ethyl acetate solution in four portion altogether 3.4 g (0.029 mol) of fumaric acid was added at 58-62 0C.
The salt formation begins in 2-3 minutes, the obtained crystal suspension was stirred for 30 minutes at 58-62 0C and then it was cooled to 0-5 0C and stirred for further 2 hours at this temperature.
The precipitated crystals were filtered, washed with 2x10 ml 0-5 0C of water and dried.
25.3 g (wet), 19.8 g (dried) of the title compound was obtained in 90 % yield. HPLC purity: 99.91 %.
Example 2
Synthesis of (2-[2-(4-Dibenzo[b,f][1,4]thiazepine-11-yl-piperazine-1-yl)-ethoxy]-ethanol (I) hemifumarate salt In a flask 11.3 g (0.05 mol) of thiazepine-keton of formula (II) and 2.9 g (0.023 mol) of
N,N-dimethylaniline was added to 75 ml (83 g) of chlorobenzene dropwise in dry N2 atmosphere with stirring.
The solution was cooled below 15 0C and 34.0 g (0.22 mol) of phosphorus oxychloride was added to it in such a way that the temperature of the reaction remained below 15 0C.
The reaction was warmed to 95-100 0C and stirred at this temperature for 3 hours (after 2-2.5 hours a homogenous solution was obtained).
After the reaction was completed the solution was cooled to 0-5 0C and it was added to the mixture of 200 ml of water and 75 ml of chlorobenzene in such a way that the temperature of the reaction remained below 10 0C.
After stirring the phases were separated, the water phase was extracted with 40 ml of chlorobenzene and the unified organic phases were washed with 50 ml of water.
After separation of the phases the chlorobenzene solution was concentrated by evaporation in vacuum to 50 ml.
To the obtained 50 ml chlorobenzene solution of thiazepine-chloride of formula (IV) 130 ml of dimethyl-sulphoxide, 14.6 g (0.055 mol) of piperazinyl-ethoxy-ethanol dihydrochloride monohydrate of formula (lll.b) and 32 g (0.29 mol) of sodium carbonate was added in N2 atmosphere.
The alkylation reaction was completed at 85-90 0C in 6-8 hours with vigorous stirring.
Then the solution was cooled to 20-25 0C, 450 ml of water and 160 ml of ethyl acetate was added.
After separation of the phases the aqueous phase was extracted with 50 ml (45 g) of ethyl acetate. The unified organic phases were washed with 2x50 ml of water and 50 ml of 15 % NaCI solution.
To the ethyl acetate solution in four portion altogether 3.4 g (0.029 mol) of fumaric acid was added at 58-62 0C.
The salt formation begins in 2-3 minutes, the obtained crystal suspension was stirred for 30 minutes at 58-62 0C and then it was cooled to 0-5 0C and stirred for further 2 hours at this temperature.
The precipitated crystals were filtered, washed with 2x10 ml 0-5 0C of water and dried.
26.2 g (wet), 20.2 g (dried) of the title compound was obtained in 91.8 % yield. HPLC purity: 99.90 %.
Example 3
Synthesis of (2-[2-(4-Dibenzo[b,f][1,4]thiazepine-11-yI-piperazine-1-yl)-ethoxy]-ethanol (I) hemifumarate salt
In a 50 litre of autoclave 4 kg (17.6 mol) of thiazepine-keton of formula (II) and 1000 g (8.25 mol) of N,N-dimethylaniline was added dropwise to 26.5 I of chlorbenzene in dry N2 atmosphere with stirring.
The solution was cooled below 15 0C and 12 kg (78.3 mol) of phosphorus oxychloride was added to it in such a way that the temperature of the reaction remained below 15 0C.
The reaction was warmed to 95-100 0C and stirred at this temperature for 3 hours (after 2-2.5 hours a homogenous solution was obtained).
After the reaction was completed the solution was cooled to 0-5 0C and it was added to the cooled mixture of 71 I of water and 26.5 I of chlorobenzene in such a way that the temperature of the reaction remained below 10 0C.
After stirring for 30 minutes the phases were separated, the water phase was extracted with 14 I of chlorobenzene and the unified organic phases were washed with 18 I of water.
After separation of the phases the chlorobenzene solution was concentrated by evaporation in vacuum to 17 I.
To the obtained chlorobenzene solution 46 I (50.6 kg) of dimethyl-sulphoxide, 5.13 kg (20.7 mol) of piperazinyl-ethoxy-ethanol dihydrochloride monohydrate of formula (lll.b) and 11.3 kg (106.6 mol) of sodium carbonate was added.
The alkylation reaction was completed at 85-90 0C in 6-8 hours with vigorous stirring.
Then the solution was cooled to 20-25 0C and it was added to the mixture of 160 I of water and 57 I of ethyl acetate. After separation the aqueous phase was extracted with 18 I of ethyl acetate. The unified organic phases were washed with 2x18 I of water and 20 I of 15 % NaCI solution.
To the ethyl acetate solution in four portion altogether 1.22 kg (10.3 mol) of fumaric acid was added at 58-62 0C.
The obtained crystal suspension was stirred for 30 minutes at 58-62 0C and then it was cooled to 0-5 0C and stirred for further 2 hours at this temperature.
The precipitated crystals were filtered, washed with 2x5 I 0-5 0C of ethyl acetate and dried at max. 50 0C.
9.1 kg (without drying), 7.21 kg (after drying) of the title compound was obtained in 93 % yield. HPLC purity: 99.92 %.
HPLC purity study of the fumarate salt of quetiapine compound of formula (I)
HPLC conditions:
Column: YMC-Pack Pro C18 150 x 4.6 mm, 5μm Temperature of sample holder: 25 0C Temperature of the column: 45 0C Flow rate: 1.0 ml/minutes
Volume of the injection: 10 μl Detection: UV 252 nm
Eluent:
• A: 50 ml of methanol + 50 ml of acetonitrile + 900 ml of buffer
• B: 450 ml of methanol + 450 ml of acetonitrile + 100 ml of buffer Buffer: In 1000 ml water 1.2 ml of cc. H3PO4, pH=6.6 (+0.05) with triethyl-amine.
Gradient: time (minute) B%
0 50
20 90 35 90
36 50
45 50
Claims
1. Process for the synthesis of 2-[2-(4-dibenzo[b,fJ[1 ,4]thiazepine-11 -yl-piperazine-1 -yl)- ethoxy]-ethanol of formula (I) (quetiapine) by reacting the 1-oxodibenzo- [b,f][1 ,4]thiazepine of formula (II) with phosphorus oxychloride characterized by a) using 1-6 molequivalent of phosphorus oxychloride in an inert solvent and the obtained 11-chlorodibenzo[b,f][1 ,4]thiazepine compound of formula (IV) without isolation b) is reacted further in an inert solvent in the presence of a base with 2-[2-(1- piperazinyl)-ethoxy]-ethanol dihydrochloride of formula (III a) or dihydrochloride monohydrate of formula (III b) in the mixture of an inert non-polar and dipolar aprotic solvent c) in desired case the isolated quetiapine base of formula (I) is reacted with fumaric acid to form the hemifumarate salt thereof.
,O H
H N H N NU
2HCI .2HCI .H 20
II. b.
2. Process according to claim 1 characterized by using 4-5 mol equivalent of phosphorus oxychloride
3. Process according to claim 1 characterized by using chlorobenzene as inert non- polar solvent.
4. Process according to claim 1 characterized by using dimethyl sulphoxide as dipolar aprotic solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0700411A HU230144B1 (en) | 2007-06-12 | 2007-06-12 | Process for producing quetiapine |
| HUP0700411 | 2007-06-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008152434A1 true WO2008152434A1 (en) | 2008-12-18 |
Family
ID=89987581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2008/000067 WO2008152434A1 (en) | 2007-06-12 | 2008-06-11 | Synthesis for the preparation of quetiapine |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HU230144B1 (en) |
| WO (1) | WO2008152434A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100623A1 (en) | 2009-03-04 | 2010-09-10 | Ranbaxy Laboratories Limited | Process for the preparation of quetiapine fumarate |
| CN103724294A (en) * | 2012-10-12 | 2014-04-16 | 无锡乾浩生物医药有限公司 | Novel preparation method of quetiapine |
| CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0240228A1 (en) * | 1986-03-27 | 1987-10-07 | Ici Americas Inc. | Thiazepine compounds |
| WO2006113425A1 (en) * | 2005-04-14 | 2006-10-26 | Teva Pharmaceutical Industries Ltd. | Process for preparing quetiapine fumarate |
| WO2006117700A2 (en) * | 2005-04-21 | 2006-11-09 | Medichem, S.A. | Process for preparing quetiapine and quetiapine fumarate |
| WO2007020011A1 (en) * | 2005-08-12 | 2007-02-22 | Sandoz Ag | Processes for the preparation of thiazepines |
-
2007
- 2007-06-12 HU HU0700411A patent/HU230144B1/en unknown
-
2008
- 2008-06-11 WO PCT/HU2008/000067 patent/WO2008152434A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0240228A1 (en) * | 1986-03-27 | 1987-10-07 | Ici Americas Inc. | Thiazepine compounds |
| WO2006113425A1 (en) * | 2005-04-14 | 2006-10-26 | Teva Pharmaceutical Industries Ltd. | Process for preparing quetiapine fumarate |
| WO2006117700A2 (en) * | 2005-04-21 | 2006-11-09 | Medichem, S.A. | Process for preparing quetiapine and quetiapine fumarate |
| WO2007020011A1 (en) * | 2005-08-12 | 2007-02-22 | Sandoz Ag | Processes for the preparation of thiazepines |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100623A1 (en) | 2009-03-04 | 2010-09-10 | Ranbaxy Laboratories Limited | Process for the preparation of quetiapine fumarate |
| CN103724294A (en) * | 2012-10-12 | 2014-04-16 | 无锡乾浩生物医药有限公司 | Novel preparation method of quetiapine |
| CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
| CN114181172B (en) * | 2021-12-27 | 2023-12-22 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
Also Published As
| Publication number | Publication date |
|---|---|
| HU230144B1 (en) | 2015-09-28 |
| HU0700411D0 (en) | 2007-08-28 |
| HUP0700411A2 (en) | 2009-01-28 |
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