WO2002040460A1 - A process for the preparation of 2-[phenothiazin-10-yl] ethyl methane sulphonate - Google Patents
A process for the preparation of 2-[phenothiazin-10-yl] ethyl methane sulphonate Download PDFInfo
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- WO2002040460A1 WO2002040460A1 PCT/IN2001/000201 IN0100201W WO0240460A1 WO 2002040460 A1 WO2002040460 A1 WO 2002040460A1 IN 0100201 W IN0100201 W IN 0100201W WO 0240460 A1 WO0240460 A1 WO 0240460A1
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- Prior art keywords
- formula
- phenothiazin
- preparation
- ethanol
- reaction
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- LNXZDZDPYBPHAM-UHFFFAOYSA-N 10-propylphenothiazine Chemical compound C1=CC=C2N(CCC)C3=CC=CC=C3SC2=C1 LNXZDZDPYBPHAM-UHFFFAOYSA-N 0.000 title claims description 6
- FMENRHNHBUWRMN-UHFFFAOYSA-N 2-phenothiazin-10-ylethanol Chemical compound C1=CC=C2N(CCO)C3=CC=CC=C3SC2=C1 FMENRHNHBUWRMN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 6
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 5
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 5
- 238000007796 conventional method Methods 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229950000688 phenothiazine Drugs 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 238000007126 N-alkylation reaction Methods 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- 238000003328 mesylation reaction Methods 0.000 claims 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 abstract description 4
- ONVGBCNKVCPJCI-UHFFFAOYSA-N 3-(10h-phenothiazin-10-ium-10-yl)propane-1-sulfonate Chemical compound C1=CC=C2N(CCCS(=O)(=O)O)C3=CC=CC=C3SC2=C1 ONVGBCNKVCPJCI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000003756 stirring Methods 0.000 description 17
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- YBKKHNAVGOALIQ-UHFFFAOYSA-N 2-phenothiazin-10-ylethyl methanesulfonate Chemical compound C1=CC=C2N(CCOS(=O)(=O)C)C3=CC=CC=C3SC2=C1 YBKKHNAVGOALIQ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 5
- 229940117927 ethylene oxide Drugs 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 1
- 229910018954 NaNH2 Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/26—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom without other substituents attached to the ring system
Definitions
- the present invention relates to a process for the preparation of 2- [phenothiazin-10-yl]ethylmethane sulphonate of the formula (1).
- the compound of formula (1) is an intermediate for the preparation of many pharmaceutically active compounds.
- Ethyleneoxide used for N-alkylation of lOH-phenothiazine of the formula (2) is a low boiling solvent and will polymerise easily into polyethylene oxide, which poses handling problem in bulk quantities.
- the reaction is carried out using moisture sensitive pyrophoric reagents such as NaNH 2 , which needs careful handling.
- Ethylene oxide or ethylene carbonate used for N-alkylation of phenothiazine of the formula (2) can lead to radical polymerization, which poses handling problem in bulk quantities.
- it is essential to have a commercially viable, cost effective, high yielding process for preparing the compound of formula (1).
- the main objective of the present invention is therefore to provide an improved process for the preparation of 2-[phenothiazin-10-yl]ethylmethane sulphonate of the formula (1).
- Another objective of the present invention is to provide an improved l o process for the preparation of 2-[phenothiazin- 10-yl] ethylmethane sulphonate of the formula (1), avoiding pyrophoric reagents, thereby making the process easy to operate in commercial scales .
- the objective of the present invention has been achieved by employing polar aprotic solvents such as DMF, DMSO, DMAc and the like and avoiding 15 column chromatography.
- the present invention provides a process for the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1), which
- N-alkylation lOH-phenothiazine of the formula (2) with 2-haloethanol of formula (8) wherein X represents halogen atom such as chlorine, fluorine, bromine or iodine in step (i) may be carried out in the presence of polar aprotic solvents such as DMF, DMSO, DMAc and the like in the presence of nucleophilic organic or inorganic bases such as sodium hydride, t-BuOH, and sodium methoxide.
- the yield of the resultant, 2-[phenothiazin-10-yl]ethanol of the formula (4) is in the order of 57-66 % and purity of 99 %.
- This compound can be used directly for the next step without purification involving column chromatography, thereby saving the time and cost.
- the reaction of 2- [phenothiazin-10-yl]ethanol of the formula (4) with methane sulfonyl chloride may be carried out in the presence of solvent such as DCM, DCE, toluene and the like and a base such as triethylamine, tributylamine and the like.
- the final compound namely 2- [phenothiazin-10-yl] ethylmethane sulfonate of the formula (1) is obtained in quantitative yield and purity of 99 %.
- the invention is described in the example given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
- Step (I) 2-[Phenothiazin-10-vnethanol of the formula (4)
- Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N 2 atmosphere with stirring.
- DMF 200 ml was added to the washed sodium hydride, freed from oil and toluene.
- lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min.
- Step (ii 2- rPhenothiazin-lO-yl] ethylmethane sulfonate of the formula (I) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenothiazin-10-y ⁇ ]ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N 2 atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N 2 atmosphere in about 10 min. at room temperature under stirring.
- Methane sulfonyl chloride (107 g, ⁇ 73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min.
- the reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC.
- Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min.
- the organic layer was separated, washed with DM water (3 x 300 ml), dried over Na SO 4 and was concentrated under reduced pressure in a rotavapor to a volume of ⁇ 600 ml. Petroleum ether ( ⁇ 600 ml) was added to a cone, solution of organic layer at 10-15 °C under stirring.
- Step (i) 2-rPhenothiazin-lO-ynethanol of the formula (4)
- Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N 2 atmosphere with stirring.
- DMF 200 ml was added to the washed sodium hydride, freed from oil and toluene.
- lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature.
- Step (ii) 2- [Phenothiazin-10-yl] ethyl methane sulfonate of formula (1)
- 2-[phenothiazin-10-yl]ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N atmosphere with stirring.
- Triethylamine 113.4 g, 157 ml was added portion wise under N 2 atmosphere in about 10 min. at room temperature under stirring.
- Methane sulfonyl chloride (107 g, ⁇ 73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min.
- the reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC.
- Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min.
- the organic layer was separated, washed with DM water (3 x 300 ml), dried over Na SO 4 and was concentrated under reduced pressure in a rotavapor to a volume of ⁇ 600 ml. Petroleum ether ( ⁇ 600 ml) was added to a cone, solution of organic layer at 10-15 °C under stirring.
- Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N 2 atmosphere with stirring.
- DMF 200 ml was added to the washed sodium hydride, freed from oil and toluene.
- lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature.
- the process does not require the use of expensive reagents and dry solvents, thereby making the process safe and economical.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
A process for the preparation of 2-[phenothiazin-10-yl]ethylmethane sulphonate of the formula (1) which comprises : N-alkylating the 10H-phenothiazine with 2-haloethanol in the presence of a polar aprotic solvent and a nucleophilic organic or inorganic base to get 2-[phenothiazin-10-yl]ethanol, mesylating the 2-[phenothiazin-10-yl]ethanol to the compound of formula (1) by treating with methane sulphonyl chloride in the presence of an organic base and an organic solvent and isolating the compound of formula (1) by conventional methods.
Description
A PROCESS FOR THE PREPARATION OF 2-[PHENOTHIAZIN-10- YL] ETHYL METHANE SULPHONATE
Field of the invention
The present invention relates to a process for the preparation of 2- [phenothiazin-10-yl]ethylmethane sulphonate of the formula (1).
Several synthetic processes have been reported for the preparation of 2- [phenothiazin-10-yl]ethanol of the formula (4), which is an important intermediate in the preparation of 2-[phenothiazin-10-yl]ethylmethane sulphonate of formula (1).
In our international publication No. WO 98/52946, we have disclosed the compound of formula (I) and its preparation from 2-[phenothiazin-10- yl]ethanol of the formula (4).
B. Dahlbom [Swed. 129, 842 (1950), Acta. Chem. Scand. 6, 310 (1952)], described the preparation of 2-[phenothiazin-10-yl]ethanol of the formula (4) by reaction of lOH-phenothiazine of the formula (2) with ethylene oxide in presence of condensing agent such as alkali amides, PhONa, or EtCO2Li in toluene. The reaction is shown in scheme- 1 below :
Scheme - 1
This process has the following drawbacks :
• Ethyleneoxide used for N-alkylation of lOH-phenothiazine of the formula (2) is a low boiling solvent and will polymerise easily into polyethylene oxide, which poses handling problem in bulk quantities.
• The reaction is carried out using moisture sensitive pyrophoric reagents such as NaNH2, which needs careful handling.
M.G. Canquil, A Casadorall and M.E. Casadovall (Bull. Soc. Chim., France, 1566 (I960)] described the process for preparation of 2-[phenothiazin-10- yfjethanol of the formula (4) by initial fusion reaction of 10-H-phenothiazine of the formula (2) with Lithium metal, followed by reaction of 10-lithiophenic thiazine with ethyleneoxide. The reaction is shown in scheme-2 below :
Scheme-2
K. Hiroyoshi [Japan, 73, 33, 755 (1974), CA. 81 : 261835] described the process for the preparation of 2-[phenothiazin-10-yl]ethanol by fusion reaction of lOH-phenothiazine of the formula (2) with ethylene carbonate at 200 °C . The reaction is shown in scheme-3 below :
Scheme-3
O. Saburo, U. Koji [Japan Kokai, 74, 40, 675 (1974), CA 82 : 170988p (1975)] described the process for the preparation of 2-[phenothiazin-10- yfjethanol of the formula (4) by initial fusion reaction of lOH-phenothiazine of the formula (2) with KOH at 30 °C, followed by reaction of potassium salt of phenothiazine with ethylene oxide in xylene medium. The reaction is shown in scheme-4 below :
Scheme-4
The processes described in the above schemes have the following drawbacks.
• The reactions are carried out at very high temperatures ranging from 200-300 °C, which is very difficult for scale-up operations and also from safety point of view.
• At very high temperature charring of the RM was observed, affecting the yield.
• Ethylene oxide or ethylene carbonate used for N-alkylation of phenothiazine of the formula (2) can lead to radical polymerization, which poses handling problem in bulk quantities.
In view of the importance of the compound of formula (1), it is essential to have a commercially viable, cost effective, high yielding process for preparing the compound of formula (1).
5 Objective of the invention
The main objective of the present invention is therefore to provide an improved process for the preparation of 2-[phenothiazin-10-yl]ethylmethane sulphonate of the formula (1).
Another objective of the present invention is to provide an improved l o process for the preparation of 2-[phenothiazin- 10-yl] ethylmethane sulphonate of the formula (1), avoiding pyrophoric reagents, thereby making the process easy to operate in commercial scales .
The objective of the present invention has been achieved by employing polar aprotic solvents such as DMF, DMSO, DMAc and the like and avoiding 15 column chromatography.
Detailed description of the Invention
Accordingly, the present invention provides a process for the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1), which
20 comprises : i). N-alkylating the lOH-phenothiazine of the formula (2) with 2- haloethanol of the formula (8) where X represents halogen atom such as fluorine, chlorine, bromine or iodine in the presence of a polar aprotic solvent and a nucleophilic organic or inorganic base to get 2-[phenothiazin-10-
25 yl]ethanol of the formula (4), ii). mesylating the 2-[phenothiazin-10-yl]ethanol of the formula (4) obtained in step (i) to yield compound of formula (1) by treating with methane sulphonyl chloride in the presence of an organic base and an organic solvent and
iii). isolating the compound of formula (1) by conventional methods.
The reaction is shown in scheme-5 below :
Scheme-5
The N-alkylation lOH-phenothiazine of the formula (2) with 2-haloethanol of formula (8) wherein X represents halogen atom such as chlorine, fluorine, bromine or iodine in step (i) may be carried out in the presence of polar aprotic solvents such as DMF, DMSO, DMAc and the like in the presence of nucleophilic organic or inorganic bases such as sodium hydride, t-BuOH, and sodium methoxide. The yield of the resultant, 2-[phenothiazin-10-yl]ethanol of the formula (4) is in the order of 57-66 % and purity of 99 %. This compound can be used directly for the next step without purification involving column chromatography, thereby saving the time and cost. The reaction of 2- [phenothiazin-10-yl]ethanol of the formula (4) with methane sulfonyl chloride may be carried out in the presence of solvent such as DCM, DCE, toluene and the like and a base such as triethylamine, tributylamine and the like. The final compound namely 2- [phenothiazin-10-yl] ethylmethane sulfonate of the formula (1) is obtained in quantitative yield and purity of 99 %.
The invention is described in the example given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example- 1
Step (I) 2-[Phenothiazin-10-vnethanol of the formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. 2-Chloroethanol (87.3 g) in DMF (50 ml) was added at 50-60 °C in about 1 h\ After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C / 150 mm till no more drops of toluene were observed. The residue was distilled in high vacuum to afford 2-phenothiazin-10- yl]ethanol of the formula (4) as light brown oil, b.p. 210 °C, (weighs about 72- 85 g, yield : 58-64%, purity 99% by HPLC). The IR, 1H-NMR data are consistent with assigned structure.
Step (ii 2- rPhenothiazin-lO-yl] ethylmethane sulfonate of the formula (I) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenothiazin-10-yι]ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N2 atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g, ~ 73 ml) was added to the reaction
mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC. Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na SO4 and was concentrated under reduced pressure in a rotavapor to a volume of ~ 600 ml. Petroleum ether (~ 600 ml) was added to a cone, solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2-[phenothiazin-10- yl)ethyl methane sulfonate of the formula (1), m.p. 113-115°C (weighs about 222 g, Yield : 95%, Purity 99% by HPLC). The IR, 1H NMR data are consistent with assigned structure.
Example 2
Step (i) : 2-rPhenothiazin-lO-ynethanol of the formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature. 2-Bromoethanol (137 g) in DMF (50 ml) was added dropwise at room temperature in about 4 h under N2 atmosphere with stirring. After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C / 150 mm till no more drops of toluene were observed. The residue was distilled in high vacuum to afford 2-phenothiazin-10- yijethanol of the formula (4) as light brown oil, b.p. 210 °C (weighs about 75
g, yield 60%, purity 99% by HPLC). The IR, 1H NMR data are consistent with the assigned structure.
Step (ii) 2- [Phenothiazin-10-yl] ethyl methane sulfonate of formula (1) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenothiazin-10-yl]ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g, ~ 73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC. Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na SO4 and was concentrated under reduced pressure in a rotavapor to a volume of ~ 600 ml. Petroleum ether (~ 600 ml) was added to a cone, solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2-[phenothiazin-10- yl)ethyl methane sulfonate of the formula (1), .p. 113-115°C (weighs about 222 g, Yield : 95%, Purity 99% by HPLC). The IR, 1H NMR data are consistent with assigned structure.
Example 3
Step (i) 2- [Phenothiazin-10-yl] ethanol of the formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature.
2-Iodoethanol (171 g, ~ 78 ml) in DMF (50 ml) was added dropwise at room temperature in about 15 h under stirring N2 atmosphere. After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C / 150 mm till no more drops of toluene were observed. The residue was distilled in high vacuum to afford the 2-[phenothiazin-10- yljethanol of the formula (4) as light brown oil, b.p. 210 °C, (weighs about 70 g, yield 56 %, purity 99 % by HPLC). The IR, 1H NMR data are consistent with the assigned structure.
Step (ii) 2- [Phenothiazin-10-yl] ethylmethane sulfonate of the formula (1)
In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenothiazin-10-yl]ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N2 atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g, ~ 73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC. Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na2SO and was concentrated under reduced pressure in a rotavapor to a volume of ~ 600 ml. Petroleum ether (~ 600 ml) was added to a cone, solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2-[phenothiazin-10- yl)ethyl methane sulfonate of the formula (1), m.p. 113-115°C (weighs about
222 g, Yield : 95%, Purity 99% by HPLC). The IR, 1H NMR data are consistent with assigned structure.
Advantages of the Invention • The process does not require the use of expensive reagents and dry solvents, thereby making the process safe and economical.
• The purification by column chromatography is totally avoided resulting in further economy of the process.
• The time required for the completion of the reaction is reduced drastically, the overall yield and purity of the product is enhanced thereby making the process commercially economical.
• The process is commercially viable and can be employed for the easy and quick preparation of the compounds of formula (1).
Claims
1. A process for the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1)
2. The process as claimed in claim 1, wherein the N-alkylation in step (i) is carried out in the presence of polar aprotic solvents selected from DMF,
DMSO or DMAc.
3. The process as claimed in claims 1 and 2, wherein the nucleophilic organic or inorganic base used in step (i) is selected from BuOK, sodium methoxide or sodium hydride.
4. The process as claimed in claims 1 to 3, wherein the mesylation in step (ii)is carried out in the presence of solvent selected from DCM, toluene or dichloroethane.
5. The process as claimed in claims 1 to 4, wherein the base used in step (ii) is selected from triethylamine or tributylamine.
6. A process for the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1) substantially as herein described with reference to the examples.
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| AU2002221030A AU2002221030A1 (en) | 2000-11-17 | 2001-11-15 | A process for the preparation of 2-(phenothiazin-10-yl) ethyl methane sulphonate |
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| WO2012066048A1 (en) * | 2010-11-16 | 2012-05-24 | Solvay Sa | Rechargeable metal or metal-ion cell |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998052946A1 (en) * | 1997-12-02 | 1998-11-26 | Dr. Reddy's Research Foundation | Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension |
-
2001
- 2001-11-15 AU AU2002221030A patent/AU2002221030A1/en not_active Abandoned
- 2001-11-15 WO PCT/IN2001/000201 patent/WO2002040460A1/en not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998052946A1 (en) * | 1997-12-02 | 1998-11-26 | Dr. Reddy's Research Foundation | Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension |
Non-Patent Citations (4)
| Title |
|---|
| G. BIDAN: "N-(hydroxyalkyl)pyrroles: precursors for the synthesis of polypyrroles bearing active centres", TETRAHEDRON LETTERS., vol. 26, no. 6, 1985, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 735 - 736, XP002190141, ISSN: 0040-4039 * |
| J. J. D'AMICO ET AL: "Derivatives of 3-(2-hydroxyethyl)-2-benzothiazolinone and related compounds", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 25, 1988, HETEROCORPORATION. PROVO., US, pages 1601 - 1605, XP002190140, ISSN: 0022-152X * |
| J.J. D'AMICO ET AL: "Carbamates, thiolcarbamates, dithiocarbamates and thiocarbamates derived from 2-benzothiazolinone and benzoxazolinone", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 26, 1989, HETEROCORPORATION. PROVO., US, pages 655 - 660, XP002190142, ISSN: 0022-152X * |
| TIERNEY M.T. ET AL: "Synthesis and characterization of fluorenone-, anthraquinone-, and phenothiazine-labeled oligodeoxynucleotides: 5'-probes for DNA redox chemistry", JOURNAL OF ORGANIC CHEMISTRY., vol. 65, no. 17, 25 August 2000 (2000-08-25), AMERICAN CHEMICAL SOCIETY. EASTON., US, pages 5355 - 5359, XP002190139, ISSN: 0022-3263 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012066048A1 (en) * | 2010-11-16 | 2012-05-24 | Solvay Sa | Rechargeable metal or metal-ion cell |
| US9203080B2 (en) | 2010-11-16 | 2015-12-01 | Solvay Sa | Rechargeable metal or metal-ion cell |
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