WO2008068600A2 - An improved process for the preparation of zaleplo - Google Patents
An improved process for the preparation of zaleplo Download PDFInfo
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- WO2008068600A2 WO2008068600A2 PCT/IB2007/003787 IB2007003787W WO2008068600A2 WO 2008068600 A2 WO2008068600 A2 WO 2008068600A2 IB 2007003787 W IB2007003787 W IB 2007003787W WO 2008068600 A2 WO2008068600 A2 WO 2008068600A2
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- WO
- WIPO (PCT)
- Prior art keywords
- zaleplon
- formula
- process according
- aliphatic amine
- acetic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 claims abstract description 53
- 229960004010 zaleplon Drugs 0.000 claims abstract description 52
- 238000000746 purification Methods 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 229960000583 acetic acid Drugs 0.000 claims description 14
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000003139 primary aliphatic amines Chemical group 0.000 claims 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims 1
- QNCMDFVHPFYZNK-UHFFFAOYSA-N butan-1-ol;2-methylpropan-1-ol Chemical compound CCCCO.CC(C)CO QNCMDFVHPFYZNK-UHFFFAOYSA-N 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000932 sedative agent Substances 0.000 abstract description 3
- 230000001624 sedative effect Effects 0.000 abstract description 3
- 239000002249 anxiolytic agent Substances 0.000 abstract description 2
- 230000000949 anxiolytic effect Effects 0.000 abstract description 2
- 239000003158 myorelaxant agent Substances 0.000 abstract description 2
- 210000002027 skeletal muscle Anatomy 0.000 abstract description 2
- -1 aliphatic alcohols Chemical class 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- 229940121985 Non-benzodiazepine hypnotic Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- FZSDJRKAWHMQFF-UHFFFAOYSA-N n-[3-[3-(dimethylamino)prop-2-enoyl]phenyl]-n-ethylacetamide;hydrochloride Chemical compound Cl.CCN(C(C)=O)C1=CC=CC(C(=O)C=CN(C)C)=C1 FZSDJRKAWHMQFF-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940061368 sonata Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to an improved process for the preparation of
- Zaleplon N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (Zaleplon) of formula (I), more particularly the present invention relates to a method for the purification of Zaleplon of formula (I), which is useful in medicine as an anxiolytic, sedative and skeletal muscle relaxing agent.
- Zaleplon is chemically known as N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7- yl)phenyl]-N-ethylacetamide is a non-benzodiazepine hypnotic from the pyrazolopyrimidine class and has the following structural formula:
- Zaleplon is useful as a sedative and hypnotics agent, and it is marketed as
- Zaleplon was first reported in US Patent No. 4,626,538 (henceforth '538). According to the teachings of '538 patent, Zaleplon is prepared by the reaction of 3-dimethylamino- l-(3-N-ethyl-N-acetylaminophenyl)-2-propen- 1 -one with 3-amino- pyrazole-4-carbonitrile in glacial acetic acid at a reflux temperature. The method described in '538 patent solvent glacial acetic acid is removed by distillation, which leads to the degradation of product, formation of impurities and reduction in yield moreover it involves additional step and longer reaction time.
- the PCT Publication No. WO 2005/073235 A2 describes a process for the preparation of Zaleplon containing less than 0.2% impurities by reaction of 3-amino-4- pyrazol-carbonitrile with equi-molar amount of N- ⁇ 3-[3-(dimethylamino)-l-oxo-2- propenyl]phenyl ⁇ -N-ethyl-acetamide hydrochloride in the presence of aliphatic alcohols or a mixture of water and aliphatic alcohols at a pH of 3.0-3. 5.
- the main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in good yield and high chemical purity.
- Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which minimizes the steps and would be easy to implement on commercial scale.
- Still another objective of the present invention is to provide a method for the purification of a compound of formula (I), which would result higher chemical purity of a compound of formula (I).
- the present invention provides an improved process for the preparation of Zaleplon (I), comprising the steps of;
- the present invention further provides another improved process for the preparation of Zaleplon (I), comprising the steps of;
- the present invention provides a process by which Zaleplon is prepared from 3-amino-4-cyanopyrazole and 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one in glacial acetic acid without distilling out the acetic acid.
- organic solvent employed for dissolving Zaleplon is selected from the group consisting of dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride and the like, most preferably dichloromethane.
- anti-solvent solvent employed for precipitating Zaleplon is selected form straight, branched or cyclo alkane, which is selected from hexane, n-heptane or cyclo hexane and the like, most preferably n- heptane.
- the present invention provides a process for purification of Zaleplon. Accordingly the Zaleplon dissolved using alcoholic solvent and the resultant solution treated with organic amine. The process of reacting the alcoholic solution with organic amine, preferably aliphatic primary amine removes the undesired by-products and pure Zaleplon is obtained by cooling the reaction mass to below 15° C.
- aliphatic primary amine used is preferably methylamine, ethyl amine and n-propyl amine; most preferably aqueous methylamine; and alcoholic solvent used is selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
- all the steps are preferably performed at a temperature in the range of (-) 10 0 C to reflux temperature of the solvent used.
- the starting materials are prepared according to the literature available in the prior art.
- Example 2 In a reaction vessel, glacial acetic acid (150 mL) and 3-amino-4-cyanopyrazole
- Zaleplon 38 g obtained according to the example 3, was dissolved in dichloromethane (190 mL) under stirring to get a clear solution. The solution was charcoalized, and the filtrate concentrated up to 5 volumes at 4O 0 C. The concentrated mass was cooled to 25 to 30 0 C and n-heptane (247 mL) added and stirred for 60 to 90 mins. Filtration followed by washing with n-heptane (76 mL) and drying under vacuum afforded pure Zaleplon (30 g; purity by HPLC not less than 99.7%).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an improved process for the preparation of N-[3-(3-cyanopyrazolo[ 1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (Zaleplon) of formula (I), more particularly the present invention relates to a method for the purification of Zaleplon of formula (I), which is useful in medicine as an anxiolytic, sedative and skeletal muscle relaxing agent. Formula (I)
Description
ANIMPROVED PROCESS FORTHE PREPARATION OF ZALEPLON
Field of the Invention
The present invention relates to an improved process for the preparation of
N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (Zaleplon) of formula (I), more particularly the present invention relates to a method for the purification of Zaleplon of formula (I), which is useful in medicine as an anxiolytic, sedative and skeletal muscle relaxing agent.
Background of the Invention
Zaleplon is chemically known as N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7- yl)phenyl]-N-ethylacetamide is a non-benzodiazepine hypnotic from the pyrazolopyrimidine class and has the following structural formula:
(I)
Zaleplon is useful as a sedative and hypnotics agent, and it is marketed as
Sonata® by Wyeth Pharmaceuticals.
Zaleplon was first reported in US Patent No. 4,626,538 (henceforth '538). According to the teachings of '538 patent, Zaleplon is prepared by the reaction of
3-dimethylamino- l-(3-N-ethyl-N-acetylaminophenyl)-2-propen- 1 -one with 3-amino- pyrazole-4-carbonitrile in glacial acetic acid at a reflux temperature. The method described in '538 patent solvent glacial acetic acid is removed by distillation, which leads to the degradation of product, formation of impurities and reduction in yield moreover it involves additional step and longer reaction time.
US Patent No. 5,714,607 (henceforth '607) describes a process for the preparation of Zaleplon by reaction of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one with 3-amino-pyrazole-4-carbonitrile in a mixture of water and acetic acid. As reported in US 7,057,041 reaction carried out under the condition described in '607 resulted in Zaleplon contaminated with a side product, N- [3-(3-cyanopyrazolol[ 1 ,5-a]pyrimidine-5-yl)phenyl]-N-ethylacetamide. The formation of this by-product creates a serious technological problem in the industrial scale production of Zaleplon intended for use as an active ingredient in pharmaceutical formulations.
The PCT Publication No. WO 2005/073235 A2 describes a process for the preparation of Zaleplon containing less than 0.2% impurities by reaction of 3-amino-4- pyrazol-carbonitrile with equi-molar amount of N-{3-[3-(dimethylamino)-l-oxo-2- propenyl]phenyl}-N-ethyl-acetamide hydrochloride in the presence of aliphatic alcohols or a mixture of water and aliphatic alcohols at a pH of 3.0-3. 5.
While certain processes of Zaleplon preparation are known, but still there is a continuing need for simple and improved processes for the preparation of Zaleplon. We focused our research to develop a process, which reduces the formation of impurity / by-product, improves the quality and yield of product. The proposed process has advantages of simple operations, high yield and suitable for industrial production over the processes described in the related prior arts.
Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in good yield and high chemical purity.
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which minimizes the steps and would be easy to implement on commercial scale.
Still another objective of the present invention is to provide a method for the purification of a compound of formula (I), which would result higher chemical purity of a compound of formula (I).
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Zaleplon (I), comprising the steps of;
a) condensing 3-amino-4-cyanopyrazole of formula (III) with 3-dimethylamino-l- (3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one of formula (II) in glacial acetic acid;
b) mixing the reaction mixture with an organic solvent without distillation of acetic acid; c) washing the organic layer with water; d) precipitating with an anti-solvent to get Zaleplon of formula (I); and
e) optionally purifying Zaleplon by dissolving in an organic solvent and precipitating by adding an anti-solvent to obtain pure Zaleplon of formula (I).
Alternatively the present invention further provides another improved process for the preparation of Zaleplon (I), comprising the steps of;
a) condensing 3-amino-4-cyanopyrazole of formula (III) with 3-dimethylamino- 1 -(3 -N-ethyl-N-acetylaminophenyO-Z-propen- 1 -one of formula (II) in glacial acetic acid;
b) optionally cooling the reaction mixture; c) adding water to the reaction mixture; d) isolating Zaleplon by filtration; e) treating an alcoholic solution of Zaleplon with an aliphatic amine; f) optionally charcoalizing the solution obtained from step (e); g) cooling and isolating the Zaleplon of formula (I); and h) optionally purifying Zaleplon of formula (I) by dissolving in an organic solvent and precipitating by adding an anti-solvent to obtain pure Zaleplon of formula
(I)-
The process is shown in the scheme given below:
Before Purification
PURIFICATION
(D (Purified Zaleplon)
After Purification
Description of the Invention
Accordingly, the present invention provides a process by which Zaleplon is prepared from 3-amino-4-cyanopyrazole and 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one in glacial acetic acid without distilling out the acetic acid.
In an embodiment of the present invention, organic solvent employed for dissolving Zaleplon is selected from the group consisting of dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride and the like, most preferably dichloromethane.
In another embodiment of the present invention, anti-solvent solvent employed for precipitating Zaleplon is selected form straight, branched or cyclo alkane, which is selected from hexane, n-heptane or cyclo hexane and the like, most preferably n- heptane.
In an embodiment of the present invention, the present invention provides a process for purification of Zaleplon. Accordingly the Zaleplon dissolved using alcoholic solvent and the resultant solution treated with organic amine. The process of reacting the alcoholic solution with organic amine, preferably aliphatic primary amine removes the undesired by-products and pure Zaleplon is obtained by cooling the reaction mass to below 15° C.
In another embodiment of the present invention, aliphatic primary amine used is preferably methylamine, ethyl amine and n-propyl amine; most preferably aqueous methylamine; and alcoholic solvent used is selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 100C to reflux temperature of the solvent used.
In the present invention the starting materials are prepared according to the literature available in the prior art.
The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.
Example (1)
In a reaction vessel, glacial acetic acid (75 mL) and 3-amino-4-cyanopyrazole (15.56 g) were taken, the contents heated to 800C to 850C and 3-dimethylamino-l-(3-N- ethyl-N-acetylaminophenyl)-2-propen-l-one (25 g) was added. The reaction mass was stirred at the same temperature till the completion of the reaction. After completion of the reaction the reaction mass was cooled to 250C to 350C, dichloromethane added and stirred. The reaction mass was washed with water followed by sodium carbonate solution. To the organic layer n-heptane (150 mL) was added and stirred for 30 to 45 min. The solid was filtered and suck dried to obtain of crude Zaleplon as a wet cake (20 g)-
Crude Zaleplon (20 g) was dissolved in six volume of dichloromethane in a reaction vessel at 250C to 300C. n-Heptane (120 mL) was added to the solution of
dichloromethane and stirred for 45 to 60 min. The solid was filtered and dried under vaccum to obtain pure Zaleplon (H g; purity by HPLC not less than 99.72%).
Example (2) In a reaction vessel, glacial acetic acid (150 mL) and 3-amino-4-cyanopyrazole
(27 g) were taken, and the contents heated to 800C to 900C. A solution of 3-dimethylamino-l-(3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one (50 g) in glacial acetic acid (100 mL) was added, maintained at 8O0C to 900C for 3 to 5 hrs and then cooled to 500C to 600C. After completion of the reaction water was added, material filtered and washed with water. The material was dried under vacuum to obtain crude Zaleplon (43 g).
Example (3)
In a reaction vessel, crude Zaleplon (50 g) obtained according to the example 2, was added to methanol (1000 mL) and the contents heated at 45°C to 5O0C until a clear solution was obtained. Aqueous methylamine solution was added to the solution and maintained at 45°C to 500C for 5 to 6 hrs. The solution was charcoalized, and the filrate concentrated under vacuum until it reached 6 volumes. The reaction mass was cooled and maintained at 5 to 100C for 30 to 45 min, filtered, washed with cold methanol and dried to obtain pure Zaleplon (42 g; purity by HPLC not less than 99.3).
Example (4)
In a reaction vessel, Zaleplon (38 g) obtained according to the example 3, was dissolved in dichloromethane (190 mL) under stirring to get a clear solution. The solution was charcoalized, and the filtrate concentrated up to 5 volumes at 4O0C. The concentrated mass was cooled to 25 to 300C and n-heptane (247 mL) added and stirred for 60 to 90 mins. Filtration followed by washing with n-heptane (76 mL) and drying under vacuum afforded pure Zaleplon (30 g; purity by HPLC not less than 99.7%).
Claims
We Claim:
(I) A process for the preparation of Zaleplon of formula (I), comprising the steps of;
a) condensing 3-amino-4-cyanopyrazole of formula (III) with 3-dimethylamino- 1 -(3-N-ethyl-N-acetylaminophenyl)-2-propen- 1 -one of formula (II) in glacial acetic acid;
b) optionally cooling the reaction mixture; c) adding water to the reaction mixture; d) isolating Zaleplon by filtration; e) treating an alcoholic solution of Zaleplon with an aliphatic amine; f) optionally charcoalizing the solution obtained from step (e); and g) isolating the Zaleplon of formula (I).
(2) A process for the purification of Zaleplon of formula (I), comprising the steps of; a) treating an alcoholic solution of Zaleplon with an aliphatic amine; b) optionally charcoalizing the solution obtained from step (a); and c) isolating the Zaleplon of formula (I).
(3) A process according to claim no. 1 or 2 wherein the said alcoholic solution of Zaleplon is prepared by dissolving Zaleplon in an alcoholic solvent selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n- butanol isobutanol, tertiary butanol, or mixtures thereof; most preferably methanol.
(4) A process according to claim 1 or 2, wherein the said aliphatic amine is primary aliphatic amine.
(5) A process according to claim 4, wherein the said primary aliphatic amine is selected from methylamine, ethylamine, n-butyl amine or n-propyl amine; most preferably aqueous methylamine.
(6) A process according to claim 1 or 2, wherein the Zaleplon is isolated from reaction mass by cooling the reaction mass.
(7) A process for the preparation of Zaleplon of formula (I), comprising the steps of;
(I) a) condensing 3-amino-4-cyanopyrazole of formula (III) with 3-dimethylamino-l- (3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one of formula (II) in glacial acetic acid;
(II) (III)
b) mixing the reaction mixture with an organic solvent; c) washing the organic layer with water; and
d) precipitating with an anti-solvent to get Zaleplon of formula (I); wherein the improvement consists of treating the reaction mixture with organic solvent without distillation of acetic acid.
(8) A process according to claim no. 7, wherein the said organic solvent used in step (d) is selected from the group consisting of dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride or mixtures thereof.
(9) A process according to claim no. 7, wherein the said anti-solvent used in step (d) is selected from hexane, n-heptane or cyclohexane or mixtures thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2255CH2006 | 2006-12-06 | ||
| IN2255/CHE/2006 | 2006-12-06 | ||
| IN701/CHE/2007 | 2007-04-03 | ||
| IN701CH2007 | 2007-04-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008068600A2 true WO2008068600A2 (en) | 2008-06-12 |
| WO2008068600A3 WO2008068600A3 (en) | 2008-08-07 |
Family
ID=39492679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2007/003787 WO2008068600A2 (en) | 2006-12-06 | 2007-12-06 | An improved process for the preparation of zaleplo |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008068600A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622615A (en) * | 2015-12-30 | 2016-06-01 | 上海天慈国际药业有限公司 | Novel method for synthesizing zaleplon |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0208846A1 (en) * | 1983-06-23 | 1987-01-21 | American Cyanamid Company | [7-(3-Disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines |
| EP0776898A1 (en) * | 1995-12-01 | 1997-06-04 | American Cyanamid Company | Process improvement in the synthesis of N-[3-(3-cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl-acetamide |
-
2007
- 2007-12-06 WO PCT/IB2007/003787 patent/WO2008068600A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0208846A1 (en) * | 1983-06-23 | 1987-01-21 | American Cyanamid Company | [7-(3-Disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines |
| EP0776898A1 (en) * | 1995-12-01 | 1997-06-04 | American Cyanamid Company | Process improvement in the synthesis of N-[3-(3-cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl-acetamide |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622615A (en) * | 2015-12-30 | 2016-06-01 | 上海天慈国际药业有限公司 | Novel method for synthesizing zaleplon |
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| WO2008068600A3 (en) | 2008-08-07 |
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