WO1991008197A1 - Improved method of preparing an intermediate for the manufacture of bambuterol - Google Patents
Improved method of preparing an intermediate for the manufacture of bambuterol Download PDFInfo
- Publication number
- WO1991008197A1 WO1991008197A1 PCT/SE1990/000792 SE9000792W WO9108197A1 WO 1991008197 A1 WO1991008197 A1 WO 1991008197A1 SE 9000792 W SE9000792 W SE 9000792W WO 9108197 A1 WO9108197 A1 WO 9108197A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- potassium carbonate
- acetophenone
- improved method
- pyridine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960003060 bambuterol Drugs 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940093499 ethyl acetate Drugs 0.000 claims abstract description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 6
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 6
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940043232 butyl acetate Drugs 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019439 ethyl acetate Nutrition 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 5
- 125000006414 CCl Chemical group ClC* 0.000 claims 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 6
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 0 *C(Oc1cc(C(*)=O)cc(*=*)c1)=* Chemical compound *C(Oc1cc(C(*)=O)cc(*=*)c1)=* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- JGFUVCOUEFNHMG-UHFFFAOYSA-N [Br].C(C)O.C(C)(=O)OCC Chemical compound [Br].C(C)O.C(C)(=O)OCC JGFUVCOUEFNHMG-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
Definitions
- the present invention relates to an improved method for the preparation of an intermediate for bambuterol, i.e. for the preparation of 2'-bromo-3,5-di[N,N-dimethyl- ⁇ arba oyloxy]acetophenone, having the formula
- DMCC N,N-dimeth ⁇ lcarbamo ⁇ lchloride
- the object of the invention is to provide an improved method for the preparation of the intermediate 2'-bromo- 3,5-di-[N,N-dimethylcarbamoyloxy]acetophenone (1) for the production of bambuterol avoiding the use of pyridine and methylene chloride as solvents and eliminating the separation problems in the work-up step.
- potassium carbonate having a crystal water content of 11 - 13 % is used. This might be achieved by using a mixture of crystallized and calcinated potassium carbonate, resulting in a easily stirred two-phase system. Calcinated potassium carbonate (completely dry) gives a slow and non-complete reaction, and the addition of water to the calcinated potassium carbonate results in a sticky mass which is difficult to stir. Further, free water should not be present in the reaction mixture because of the risk of hydrolysis of the reactants.
- the bromination step which according to the invention first involves the addition of HBr, preferably dissolved in ethanol, and a second step charging with bromine, Br-, has the advantage that the bromination will proceed calmly. When bromination is performed directly with bromine, the reaction will start very slowly and at a certain point it will proceed vigorously and will be hard to control.
- pyridine will act both as base and solvent.
- pyridine will only be present in catalytic amounts.
- the pyridine will initially take up the hydrochloric acid formed, which then will be transferred to the potassium carbonate, which is consumed.
- crystallized potassium carbonate is used as the base.
- the water will released slowly and the base will be slowly consumed by the hydrochloric acid, which is first taken up and then transferred from the catalytic amount of pyridine present in the reaction mixture.
- the crystallized potassium carbonate contains about 1.5 moles of H-O which corresponds to about 16 %.
- the optimum water content is 11 - 13 %, and this content is obtained using a mixture of calcinated potassium carbonate and crystallized potassium carbonate.
- the crystal slurry is cooled to - 14 ⁇ 2°C and the crystals are collected on a filter and washed with 12 g (15 ml) cold (-14°C) ethanol. The crystals are dried at 40°C in vacuum.
- the yield is about 20.7 g (75 %).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Fats And Perfumes (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/741,424 US5200551A (en) | 1989-12-01 | 1990-11-20 | Method of preparing an intermediate for the manufacture of bambuterol |
EP91900394A EP0456799B1 (en) | 1989-12-01 | 1990-11-29 | Improved method of preparing an intermediate for the manufacture of bambuterol |
DE69009461T DE69009461T2 (en) | 1989-12-01 | 1990-11-29 | IMPROVED METHOD FOR THE PRODUCTION OF AN INTERMEDIATE PRODUCT FOR THE PREPARATION OF BAMBUTEROL. |
NO912853A NO174804B (en) | 1989-12-01 | 1991-07-19 | Process for the preparation of an intermediate for the preparation of bambuterol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8904064-6 | 1989-12-01 | ||
SE8904064A SE8904064D0 (en) | 1989-12-01 | 1989-12-01 | IMPROVED METHOD OF PREPARING AND INTERMEDIATE FOR THE MANUFACTURE OF BAMBUTEROL |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991008197A1 true WO1991008197A1 (en) | 1991-06-13 |
Family
ID=20377664
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1990/000792 WO1991008197A1 (en) | 1989-12-01 | 1990-11-29 | Improved method of preparing an intermediate for the manufacture of bambuterol |
Country Status (14)
Country | Link |
---|---|
US (1) | US5200551A (en) |
EP (1) | EP0456799B1 (en) |
JP (1) | JPH04503218A (en) |
AT (1) | ATE106388T1 (en) |
AU (1) | AU630013B2 (en) |
CA (1) | CA2045554A1 (en) |
DE (1) | DE69009461T2 (en) |
DK (1) | DK0456799T3 (en) |
ES (1) | ES2054483T3 (en) |
IE (1) | IE65994B1 (en) |
NO (1) | NO174804B (en) |
PT (1) | PT96051B (en) |
SE (1) | SE8904064D0 (en) |
WO (1) | WO1991008197A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4954886B2 (en) * | 2004-11-08 | 2012-06-20 | エムキュア ファーマシューティカルズ リミテッド | Efficient process for producing (S) -3-[(1-dimethylamino) ethyl] -phenyl-N-ethyl-N-methyl-carbamic acid |
ES2301439B1 (en) * | 2005-08-31 | 2009-05-01 | Universidad De Malaga | USE OF MICOSPORINE TYPE AMINO ACID (M-GLY) AS AN ANTIOXIDANT OR ADDITIVE IN FOOD PRODUCTS. |
KR100701743B1 (en) | 2005-10-05 | 2007-03-29 | 주식회사 라이트팜텍 | Novel Making Proces of the Bambuterol |
CN102617404A (en) * | 2012-04-06 | 2012-08-01 | 张长利 | Preparation processes of bambuterol hydrochloride and intermediate thereof |
CN104262202B (en) * | 2014-09-12 | 2016-12-07 | 广东东阳光药业有限公司 | The preparation technology of bambuterol intermediate |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1173753A (en) * | 1964-12-18 | 1969-12-10 | Schering Ag | Novel m-(Carbamoyloxy) Compounds |
US4451663A (en) * | 1980-07-09 | 1984-05-29 | Aktiebolaget Draco | Carbamate intermediates for bronchospasmolytics |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3441108A1 (en) * | 1984-11-10 | 1986-05-15 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING O- (1-METHOXY-2-CHLORINE) -ETHOXYPHENYL-N-METHYLCARBAMATE |
US4925971A (en) * | 1987-12-08 | 1990-05-15 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for producing aliphatic o-arylurethanes |
-
1989
- 1989-12-01 SE SE8904064A patent/SE8904064D0/en unknown
-
1990
- 1990-11-20 US US07/741,424 patent/US5200551A/en not_active Expired - Fee Related
- 1990-11-26 IE IE424790A patent/IE65994B1/en not_active IP Right Cessation
- 1990-11-29 ES ES91900394T patent/ES2054483T3/en not_active Expired - Lifetime
- 1990-11-29 AU AU68981/91A patent/AU630013B2/en not_active Ceased
- 1990-11-29 AT AT91900394T patent/ATE106388T1/en not_active IP Right Cessation
- 1990-11-29 CA CA002045554A patent/CA2045554A1/en not_active Abandoned
- 1990-11-29 EP EP91900394A patent/EP0456799B1/en not_active Expired - Lifetime
- 1990-11-29 WO PCT/SE1990/000792 patent/WO1991008197A1/en active IP Right Grant
- 1990-11-29 DK DK91900394.7T patent/DK0456799T3/en active
- 1990-11-29 DE DE69009461T patent/DE69009461T2/en not_active Expired - Fee Related
- 1990-11-29 JP JP3501014A patent/JPH04503218A/en active Pending
- 1990-11-30 PT PT96051A patent/PT96051B/en not_active IP Right Cessation
-
1991
- 1991-07-19 NO NO912853A patent/NO174804B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1173753A (en) * | 1964-12-18 | 1969-12-10 | Schering Ag | Novel m-(Carbamoyloxy) Compounds |
US4451663A (en) * | 1980-07-09 | 1984-05-29 | Aktiebolaget Draco | Carbamate intermediates for bronchospasmolytics |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
CN106187820B (en) * | 2016-07-02 | 2017-09-19 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
Also Published As
Publication number | Publication date |
---|---|
EP0456799B1 (en) | 1994-06-01 |
ATE106388T1 (en) | 1994-06-15 |
NO174804C (en) | 1994-07-13 |
CA2045554A1 (en) | 1991-06-02 |
NO912853L (en) | 1991-07-19 |
SE8904064D0 (en) | 1989-12-01 |
PT96051A (en) | 1991-09-13 |
US5200551A (en) | 1993-04-06 |
DE69009461T2 (en) | 1994-10-13 |
NO912853D0 (en) | 1991-07-19 |
EP0456799A1 (en) | 1991-11-21 |
DE69009461D1 (en) | 1994-07-07 |
ES2054483T3 (en) | 1994-08-01 |
DK0456799T3 (en) | 1994-10-03 |
JPH04503218A (en) | 1992-06-11 |
AU630013B2 (en) | 1992-10-15 |
NO174804B (en) | 1994-04-05 |
IE904247A1 (en) | 1991-06-05 |
PT96051B (en) | 1998-02-27 |
AU6898191A (en) | 1991-06-26 |
IE65994B1 (en) | 1995-11-29 |
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