GB2053900A - 6,8-Dibromo-1,4-dihydro-2H- 3,1-benzoxazine-2-one and the production of bromhexin - Google Patents
6,8-Dibromo-1,4-dihydro-2H- 3,1-benzoxazine-2-one and the production of bromhexin Download PDFInfo
- Publication number
- GB2053900A GB2053900A GB8017619A GB8017619A GB2053900A GB 2053900 A GB2053900 A GB 2053900A GB 8017619 A GB8017619 A GB 8017619A GB 8017619 A GB8017619 A GB 8017619A GB 2053900 A GB2053900 A GB 2053900A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dihydro
- bromhexin
- dibromo
- benzoxazin
- production
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- RQJFMNQNCRVVFJ-UHFFFAOYSA-N 6,8-dibromo-1,4-dihydro-3,1-benzoxazin-2-one Chemical compound N1C(=O)OCC2=CC(Br)=CC(Br)=C21 RQJFMNQNCRVVFJ-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims abstract description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- SYZIUAAQNFJPJY-UHFFFAOYSA-N 1,4-dihydro-3,1-benzoxazin-2-one Chemical compound C1=CC=C2COC(=O)NC2=C1 SYZIUAAQNFJPJY-UHFFFAOYSA-N 0.000 claims abstract description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 238000009835 boiling Methods 0.000 abstract description 2
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011083 clear filtration Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- XJINZNWPEQMMBV-UHFFFAOYSA-N n-methylhexan-1-amine Chemical compound CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
N-(2-amino-3,5-dibromobenzyl)- N-methyl-cyclohexylamine, the hydrochloride of which has the formula <IMAGE> is prepared by brominating 1,4- dihydro-2H-3,1-benzoxazin-2-one with free bromine to form the hitherto unknown intermediate 6,8-dibromo- 1,4-dihydro-2H-3,1-benzoxazin-2- one, and reacting this with N-methyl- cyclohexylamine to bromhexin. Preferably, the reaction takes place by heating in N-monomethylformamide to the boiling point of the latter.
Description
SPECIFICATION
Process for the production of bromhexin
The invention relates to a novel process for the production of bromhexin, a non-proprietory name for N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine, which is a known compound having a mucolytic and cough-relieving effect, and to an intermediate for use in the process.
Different methods of producing bromhexin are known and described in the Danish Patents Nos.
101,066,101,301, 101 795, and 119,408, in the Danish published patent specifications Nos.
135,499,135,574, and 135,680, and DE-OS 2,273,193.
These known methods have disadvantages either in the form of needing temporary protective measures for non-reacting substituents or in difficultly accessible starting materials or costly reduction agents, and common to all of them is that the disadvantages result in reduced yields.
The object of the invention is to provide a process for the production of bromhexin, in which the said disadvantages are avoided, and the bromhexin is recovered in a high yield and extremely pure.
In the process of the invention, 1 ,4-dihydro-2H-3,1 -benzoxazin-2-one is reacted with free bromine to give 6,8-dibromo-1 ,4-dihydro-2H-3,1 -benzoxazin-2-one, which is then reacted with N-methylcyclohexylamine to form bromhexin, the latter being recovered as an acid addition salt from the reaction mixture.
The reactions take place according to the following scheme of reactions:
The starting material I is a known compound, which can be prepared from o-aminobenzyl alcohol by condensation with for example phosgene.
The hitherto unknown intermediate II is a white, crystalline compound being slightly soluble in water and melting at 21 8-2200C.
In a preferred embodiment of the process, the reaction with N-methylhexylamine according to the invention takes place in solution in N-monomethylformamide, since hereby a yield of up to-90% is obtained by the reaction.
The process of the invention is illustrated by the following Examples.
EXAMPLE 1
To a solution of 9.0 g (0.0604 mole) of 1 ,4-dihydro-2H-3,1-benzoxazin-2-one in 40 ml of glacial acetic acid were added 60.9 g (0.38 mole) of bromine, whereby the temperature increased from 240 to 740 C. The reaction mixture was left to cool to room temperature and was then poured into 500 ml of water, whereby a precipitation of the brominated benzoxazinone took place. The precipitate was filtered off and washed on the filter, first with water, then with a weak solution of sodium hydrogen sulphite and finally with hexane.
The excess bromine could be recovered from the parent lye and washwater by distillation.
The yield of the brominated benzoxazinone was 16.5 g (0.0537 mole), corresponding to 89% of the theoretical yield. The melting point was 21 8-2200C, and thin layer chromatography showed no impurities.
A mixture of 3.07 g (0.010 mole) of the recovered 6,8-dibromo-1 ,4-dihydro-2H-3,1 -benzoxazin2-one and 4.52 g (0.040 mole) of N-methyl-cyclohexylamine in 10 ml of N-monomethylformamide was heated with stirring and refluxing for 2 hours on a 210"C hot oil bath. After cooling, the mixture was poured into 70 ml of water, and concentrated hydrochloric acid was added until acid reaction.
By cooling in ice-water with stirring, N-(2-amino-3,5-dibromobenzyl)-N-methyl cyclohexylammonium chloride (bromhexin hydrochloride) crystallized and was filtered off after one hour, washed with water, and dried. The yield was 3.7 g (8.97 millimoles), corresponding to 89.7% of the theoretical yield. The melting point was 232-233.50C, and the compound was analytically pure.
EXAMPLE 2
A mixture of 1.65 g (5.4 millimoles) of the 6,8-dibromo-1 ,4-dihydro-2H-3,1 -benzoxazin-2-one of
Example 1 and 2.4 g (21 millimoles) of N-methyl-cyclohexylamine in 10 ml of diethyleneglycol was heated for 20 hours with stirring and refluxing on a 21 00C hot oil bath. After cooling, 150 ml of water were added, and then hydrochloric acid was added until acid reaction, after which the mixture was heated to reflux temperature. To the boiling mixture were added 10 ml of ethanol and active carbon, after which clear filtration at reflux temperature was carried out.
The filtrate was cooled in ice-water, whereby N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylammonium chloride crystallized. The compound was filtered off and washed with water. The yield of the analytically pure compound was 1.1 g (2.67 millimoles), corresponding to 49.4% of the theoretical yield.
Claims (4)
1. Process for the production of bromhexin, in which 1,4-dihydro-2H-3,1 -benzoxazin-2-one is reacted with free bromine to form 6,8-dibromo-l ,4-dihydro-2H-3.1 -benzoxazin-2-one, which is then reacted with N-methyl-cyclohexylamine to form bromhexin, which is recovered from the reaction mixture as an acid addition salt.
2. The process of claim 1, in which the reaction with N-methyl-cyclohexylamine takes place in solution in N-monomethylformamide.
3. 6,8-Dibromo- 1 ,4-dihydro-2H-3, 1 -benzoxazin-2-one.
4. Process for the production of bromhexin, substantially as herein described in Example 1 or
Example 2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK230179A DK145718C (en) | 1979-06-01 | 1979-06-01 | DIBROME COMPOUND USE AS INTERMEDIATE IN THE PREPARATION OF N- (2-AMINO-3,5-DIBROMBENZYL) -N-METYLCYCLOHEXYLAMINE |
| DK230079A DK145714C (en) | 1979-06-01 | 1979-06-01 | METHOD FOR PREPARING N- (2-AMINO-3,5-DIBROMBENZYL) -N-METYLYCYLOHEXYLAMINE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2053900A true GB2053900A (en) | 1981-02-11 |
| GB2053900B GB2053900B (en) | 1983-04-20 |
Family
ID=26066477
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8017619A Expired GB2053900B (en) | 1979-06-01 | 1980-05-29 | 6,8-dibromo-1,4-dihydro-2h-3,1-benzoxazine-2-one and the production of bromhexin |
Country Status (11)
| Country | Link |
|---|---|
| AT (1) | AT371800B (en) |
| CH (1) | CH642617A5 (en) |
| DE (1) | DE3020604A1 (en) |
| ES (1) | ES492005A0 (en) |
| FI (1) | FI68808C (en) |
| GB (1) | GB2053900B (en) |
| IE (1) | IE49820B1 (en) |
| KE (1) | KE3302A (en) |
| NL (1) | NL8003153A (en) |
| NO (2) | NO148372C (en) |
| SE (1) | SE433847B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775316A (en) * | 2012-08-17 | 2012-11-14 | 夏智红 | Bromhexine hydrochloride compound and medicine composition thereof |
| CN102924295A (en) * | 2012-10-09 | 2013-02-13 | 石家庄东方药业有限公司 | Bromhexine hydrochloride crystal as well as preparation method and application of crystal |
| CN103145564A (en) * | 2013-03-15 | 2013-06-12 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2881955B1 (en) | 2005-02-11 | 2007-05-11 | Oreal | COSMETIC NANOEMULSION CONTAINING HYDROXYL UREA COMPOUND |
-
1980
- 1980-05-23 IE IE1081/80A patent/IE49820B1/en unknown
- 1980-05-23 SE SE8003874A patent/SE433847B/en not_active IP Right Cessation
- 1980-05-27 FI FI801705A patent/FI68808C/en not_active IP Right Cessation
- 1980-05-29 GB GB8017619A patent/GB2053900B/en not_active Expired
- 1980-05-30 DE DE19803020604 patent/DE3020604A1/en not_active Withdrawn
- 1980-05-30 AT AT0288580A patent/AT371800B/en not_active IP Right Cessation
- 1980-05-30 CH CH423780A patent/CH642617A5/en not_active IP Right Cessation
- 1980-05-30 ES ES492005A patent/ES492005A0/en active Granted
- 1980-05-30 NO NO801617A patent/NO148372C/en unknown
- 1980-05-30 NL NL8003153A patent/NL8003153A/en not_active Application Discontinuation
-
1982
- 1982-11-26 NO NO823977A patent/NO148415C/en unknown
-
1983
- 1983-07-11 KE KE3302A patent/KE3302A/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775316A (en) * | 2012-08-17 | 2012-11-14 | 夏智红 | Bromhexine hydrochloride compound and medicine composition thereof |
| CN102775316B (en) * | 2012-08-17 | 2013-06-12 | 夏智红 | Bromhexine hydrochloride compound and medicine composition thereof |
| CN102924295A (en) * | 2012-10-09 | 2013-02-13 | 石家庄东方药业有限公司 | Bromhexine hydrochloride crystal as well as preparation method and application of crystal |
| CN102924295B (en) * | 2012-10-09 | 2014-10-29 | 石家庄东方药业有限公司 | Bromhexine hydrochloride crystal as well as preparation method and application of crystal |
| CN103145564A (en) * | 2013-03-15 | 2013-06-12 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
| CN103145564B (en) * | 2013-03-15 | 2014-06-18 | 湖北美林药业有限公司 | Bromhexine hydrochloride compound and pharmaceutical composition thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CH642617A5 (en) | 1984-04-30 |
| NO823977L (en) | 1980-12-02 |
| SE8003874L (en) | 1980-12-02 |
| NL8003153A (en) | 1980-12-03 |
| FI801705A (en) | 1980-12-02 |
| NO148415B (en) | 1983-06-27 |
| AT371800B (en) | 1983-07-25 |
| FI68808B (en) | 1985-07-31 |
| KE3302A (en) | 1983-08-19 |
| ATA288580A (en) | 1982-12-15 |
| GB2053900B (en) | 1983-04-20 |
| ES8104185A1 (en) | 1981-04-01 |
| FI68808C (en) | 1985-11-11 |
| ES492005A0 (en) | 1981-04-01 |
| NO801617L (en) | 1980-12-02 |
| SE433847B (en) | 1984-06-18 |
| NO148415C (en) | 1983-10-12 |
| IE49820B1 (en) | 1985-12-25 |
| DE3020604A1 (en) | 1980-12-11 |
| NO148372B (en) | 1983-06-20 |
| IE801081L (en) | 1980-12-01 |
| NO148372C (en) | 1983-09-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |