WO2000029400A2 - Procedure for synthesis of n-[2[[[5- [(dialkilamino) methyl]-2- furanyl] methyl]thyo] ethyl]-n'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides - Google Patents
Procedure for synthesis of n-[2[[[5- [(dialkilamino) methyl]-2- furanyl] methyl]thyo] ethyl]-n'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides Download PDFInfo
- Publication number
- WO2000029400A2 WO2000029400A2 PCT/YU1999/000011 YU9900011W WO0029400A2 WO 2000029400 A2 WO2000029400 A2 WO 2000029400A2 YU 9900011 W YU9900011 W YU 9900011W WO 0029400 A2 WO0029400 A2 WO 0029400A2
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- WIPO (PCT)
- Prior art keywords
- methyl
- formula
- furanyl
- ethyl
- compound
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- 0 C*C=*(C)NC Chemical compound C*C=*(C)NC 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Definitions
- Suggested invention is related to the area of organic chemical technology, specificly to the process of obtaining of therapeutically active products N-2[[[5- [ (dialkylamino) methyl] - 2 -furanyl] methyl] thio] ethyl] - N - alkyl - 2-nitro 1, 1 alkenediamine of formula (I) and their hydrochlorides of formula (II),
- R l5 R 2 and R 3 are alkyl groups (C1-C 4 ), and X is nitro-alkene group, which are applied in pharmaceutical industry as blockers of histamine H 2 receptors.
- X is nitro-alkene group, which are applied in pharmaceutical industry as blockers of histamine H 2 receptors.
- One of them which is well known is N—[2[[[[5- [(dimethylamino)methyl]-2- furanyl] methyl] thio] ethyl] - N ⁇ -methyl-2-nitro- 1,1-ethendiamine (Ranitidine), as well as its hydrochloride (Ranitidine hydrochloride).
- This invention has solved the problem of using of [2[[[5-[(dimethylamino)methyl-2-furanyl] methyl] thio] -ethanamine (Cistofur base), which is unstable, viscous, difficult for supplying, using [2[[[5- [(dimethylamino)methyl-2-furanyl] methyl] thio] -ethanamine hydrochloride (Cistofur hidrochloride) which is stable and exists on the market as a powdered substance.
- ES 495, 493 recomends the process for obtaining of Ranitidine, where in the first phase 2[[(2-furanyl)]methyl]thio]ethanoamine reacts with 1,1- bis(methylthio)-2-nitroethen, and in further reaction with methylamine, N-[2- [[(2-furanyl)methyl]thio]ethyl]-N"-methyl-2-nitro-l ,1-ethendiamine is obtained, which at the end reacts with formaldehyde and dimethilamine and gives desired product.
- the process according to this invention avoids the defaults of the known processes, primarily of the process given in patent Ger. off. DE 2, 734, 070.
- the simpler way for obtaining of N-[2[[[5-[(dialkylamino)methyl]-2- furanyl] methyl] thio] ethyl] -N ⁇ -alkyl-2-nitro 1, 1 alkendiamine of formula (I) and their hydrochlorides of formula (II) is provided, as well as usage of cheaper fundamental substances with higher level of their utilization.
- Reaction is carried out with agitation and heating for 3,5 hours at 45-50°C, afterwards the temperature is elevated and reaction mixture is under the reflux for 30 minutes, get cooled and formed N-[2[[[[-5- [(dimethylamino)methyl]-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro 1,1 ethendiamine is extracted with chloroform.
- Chloroform layer is washed with water, passed through anhydrous sodium sulphate, treated with activated char-coal, filtered and evaporated to the constant mass at 45°C.
- Oily base is resuspended at the room temperature in 4-methyl pentane-2- on 1 : 2-5 (m/v) and with agitation and cooling, crystalization is carried out.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention is related to the procedure for obtaining of the therapeutically active N-[2[[[5-[(dialkylamino methyl]-2-furanyl] methyl] thio] ethyl]-N'-alky-2-nitro1,1 alkenediamines) of formula (I) and their hydrochlorides of formula (II), where R1, R2 and R3 are alkyl groups (C1-C4), and X is nitro-alkenic group by reaction of 2[[[5-[(dimethylamino-methyl-2-furanyl]methyl]thio]-ethanamine-hydrochloride) and N-methyl-1(methylthio-2-nitroethenamine) in the aqueous environment at the mild temperature.
Description
PROCEDURE FOR SYNTHESIS OF
N-[2[[[5-[(dialkylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N^-alkyl-2- nitrol,l alkenediamines and their hydrochlorides
Field of technique to which the invention belongs
Suggested invention is related to the area of organic chemical technology, specificly to the process of obtaining of therapeutically active products N-2[[[5- [ (dialkylamino) methyl] - 2 -furanyl] methyl] thio] ethyl] - N - alkyl - 2-nitro 1, 1 alkenediamine of formula (I) and their hydrochlorides of formula (II),
Technical problem
There was a need to find a new, technologically better process for production of furanic derivatives, primarily Ranitidine and its hydrochloride, with high yield and high purity, which enables their application in pharmaceutical industry, wherein it is used for curing of ulcus duodendi and as hstamine antagonists (H2 receptors). This invention has solved the problem of
using of [2[[[5-[(dimethylamino)methyl-2-furanyl] methyl] thio] -ethanamine (Cistofur base), which is unstable, viscous, difficult for supplying, using [2[[[5- [(dimethylamino)methyl-2-furanyl] methyl] thio] -ethanamine hydrochloride (Cistofur hidrochloride) which is stable and exists on the market as a powdered substance.
Condition of technique
There are several known processes for synthetical production of Ranitidine and its hydrochloride.
Thus, a process for poduction of Ranitidine is described in ES 497, 386 where the fundamental substances are chlorhydrate 5-(dimethylamino)methyl-2- chlormethylfuran and N-(2-mercaptoethyl)- N"-methyl-2-nitro-l,l- ethendiamine. The reaction is carried out in methanol in presence of sodium or potassium hydroxide.
American patent US 4, 347, 191 provides the process for obtaining of 5- dimethylaminomethyl-2-furanmethanol starting from 2-furanmethanol.
In Spanish patent ES 500, 986 a process for obtaining of furanic derivatives is described and according to it 5-dimethylaminomethyl-furan-2- methanol is converted to 5-(dimethylamino)methyl-2-chlormethylfuran in the form of chlorhydrate. In inert environment, obtained product is converted to corresponding mercaptan which, by means of condensation, with previously prepared 2-(2-hidroxyethylamine)-2,2-bis-dimethylthio-nitroethylene gives the final product.
Ger. off. DE 2, 734, 070 describes te procedure for synthesis of Ranitidine, and according to it, Ranitidine is obtained by reaction of N-methyl- l-(methylthio)-2-nitroethenamine (1) with 2-[[[5-(dimethylamino)-methyl-2- furanyl]-methyl]-thio]-ethanamine (2). The reaction is carried out by instillation of compound (2) into aqueous suspension of compound (1) at temperature of 45-
50°C for 4-5 hours, reaction continues for 3,5 hours and after that the temperature increases while the reaction mixture is under the reflux for 30 minutes. Removing of water is carried out by azeotropic distillation while products of degradation are formed for the reason of increased temperature, which significantly lowers the yield and quality of obtained Ranitidine.
In ES 496, 919 the process for obtaining of alkyl-furan is described, which with scondary amine gives 5-dialkylaminomethyl-2-mercaptomethyl- furan. The compound obtained this way is converted to thioether by reaction with N-alkyl-N -2-bromethyl-urea, which is finally nitrated.
ES 495, 493 recomends the process for obtaining of Ranitidine, where in the first phase 2[[(2-furanyl)]methyl]thio]ethanoamine reacts with 1,1- bis(methylthio)-2-nitroethen, and in further reaction with methylamine, N-[2- [[(2-furanyl)methyl]thio]ethyl]-N"-methyl-2-nitro-l ,1-ethendiamine is obtained, which at the end reacts with formaldehyde and dimethilamine and gives desired product.
There are processes described in literature, according to which Ranitidine can be obtained from the corresponding aldehyde (EP 0055625) or by methylation of corresponding isothiourea, and then by nitration of obtained compound (EP 0055626) or it can be obtained starting from the corresponding thiol and nitro derivative.
In the Swiss patent CH 650,505 synthesis of Ranitidine from cistofur and l-nitro-2,2-bis-(methylthioethan) is suggested.
According to DOS 74071 Ranitdine is obtained by reaction of 5- (dimethylamino)-methyl-2-furyl-mercaptan with l-methylamino-r-(2 chloroethylamino)-2-nitroethan.
Description of solution of the technical problem with examples of performance
The process according to this invention avoids the defaults of the known processes, primarily of the process given in patent Ger. off. DE 2, 734, 070. The simpler way for obtaining of N-[2[[[5-[(dialkylamino)methyl]-2- furanyl] methyl] thio] ethyl] -N^-alkyl-2-nitro 1, 1 alkendiamine of formula (I) and their hydrochlorides of formula (II) is provided, as well as usage of cheaper fundamental substances with higher level of their utilization.
In fact, by the process according to the invention, specificly realized is the derivative: N-[2[[[5-[(dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N - methyl-2-nitro 1, 1 ethendiamine of formula (I-a), with the following characteristics:
-structural formula
-molecular formula: C13H22N403S -molecular weight: 314,24 -melting point: 67-70°C and its hydrochloride of formula (II-a), with the following characteristics: -structural formula
-molecular formula: Cι3H22N403S x HC1 -molecular weight: 350,86 -melting point: 134-140°C.
The advantages of the suggested process are:
-the simplicity of the process of performance,
-instillation time is reduced to 20 to 60 minutes,
-instillation is carried out at the room temperature,
-using of intermediates (III) in the form of hydrochloride, which is more stable than the basic form and more available,
-avoiding azeotropic distillation,
-good yield and high quality of products,
-formed salts which are derived from the starting intermediates do not have any influence on the further course of the reaction as well as on the quality of the final product of formula (Il-a).
The suggested process is primarily regarded to the synthesis of Ranitidine where 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine hydrochloride of formula (III) in excess of 10-30%
without prior conversion to base (which simplifies the process of synthesis itself) in presence of aqueous solution of bases such as: NaOH, NH4OH, KOH, and primarily NaOH, is instillated at the room temperature, for 20-60 minutes (which is significantly shorter time in comparison to other processes) into the aqueous suspension of the compound N-methyl-1 -(methylthio)-2- nitroethenamine of formula (IV) with releasing of methyl mercaptan.
After heating, extraction with an organic solvent is carried out (which avoids removing of water by azeotropic distillation), organic layer is treated with
activated char-coal, washed with water (while formed salts derived from the starting intermediates are removed and do not have any influence on the further course of the reaction and on quality of the final product). After that, evaporation, crystalization and filtration are carried out, and finally, wanted compound N-[2[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl] -N^- methyl-2-nitro 1, 1 ethendiamine of formula (I-a) is obtained.
Hydrochlorination of the compound of formula (I-a) gives desired product N-[2[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N^-methyl-2- nitro 1, 1 ethendiamine hydrochloride of formula (Il-a), which is characterized by good yield, exceptionally high purity and high quality of the product.
The following examples are given for illustration.
Example 1.
N-[2[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio] ethyl] -N -methyl-2- nitro 1,1 ethendiamine of formula (I-a)
Solution of 41,33g (0,165 mol) of 2-[[[5-(dimethylamino)-methyl-2- furanyl]methyl]thio]-ethanamine-hydrochloride, 12g (0,3mol) of sodium hydroxide and water, is instillated at the room temperature for 30 minutes into aqueous suspension of 22,2g (0,15 mol) N-methyl-l-(methylthio)-2- nitroethenamine. Reaction is carried out with agitation and heating for 3,5 hours at 45-50°C, afterwards the temperature is elevated and reaction mixture is under the reflux for 30 minutes, get cooled and formed N-[2[[[-5- [(dimethylamino)methyl]-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro 1,1 ethendiamine is extracted with chloroform.
Chloroform layer is washed with water, passed through anhydrous sodium sulphate, treated with activated char-coal, filtered and evaporated to the constant mass at 45°C.
Oily base is resuspended at the room temperature in 4-methyl pentane-2- on 1 : 2-5 (m/v) and with agitation and cooling, crystalization is carried out.
After filtration and drying, 38,5g of N-[2[[[-5-[(dimethylamino)methyl]- 2furanyl]methyl]thio] ethyl] -N^-methyl-2-nitro 1, 1 ethendiamine of formula (I-a) is obtained, as almost white powder, melting point 67-70°C (yield 74,25%).
Example 2.
N- [2 [[ [-5- [(dimethylamino)methyl]-2-furanyl] methyl] thio] ethyl] -N^-methyl-2- nitro 1,1 ethendiamine hydrochloride of formula (Il-a)
Dissolve 8,169g (0,026 mol) of compound of formula (I-a) in ethanolic solution containing 0,026 equivalents of hydrogen chloride. Formed Ranitidine chloride is precipitated by instillation of ethyl acetate with cooling and agitating. After crystalization (2 hours) the precipitate is filtered, washed with ethyl acetate and dryed at 50°C. 7,94g (0,0226 mol) of the compound (Il-a) is obtained as almost white powder, characterized with high pharmacopoeic purity, with melting point Tt=134-140°C (yield 87,03%).
Claims
1. Process for obtaining of N-[2[[[5-[(dialkylamino)methyl]-2- furanyl] methyl] thio] ethyl] -N -alkyl-2-nitro 1,1 alkendiamine of formula (I)
as well as its hydrochloride of formula (Il-a)
without prior conversion to the base, in an excess of 10-30% in presence of water solution of the bases such as: NaOH, NH4OH, KOH, and primarily NaOH is instillated at the room temperature for 20-60 minutes, which significantly shortens the duration of the process, into the aqueous suspension of the compound (IV),
2. The procedure, according to the claim 1, marked by the fact that wanted compound of formula (I-a) is separated from the aqueous phase by extraction with organic solvents such as: chloroform, ethyl acetate, acetone, primarily chloroform, whereafter the chloroform layer is treated with activated char-coal and evaporated in vacuum.
3. The procedure, according to the claims from 1 to 3, marked by the fact that the obtained product is resuspended in 4-methylpentane-2- on 1 : 2 (m/v) and after crystalization and hydrochlorination gives desired product of formula (Il-a), characterized with high pharmacopoeic purity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU14798/00A AU1479800A (en) | 1998-11-19 | 1999-11-18 | Procedure for synthesis of N-(2(((5-((dialkilamino) methyl)-2- furanyl) methyl)thyo) ethyl)-N'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YUP-525/98 | 1998-11-19 | ||
| YU52598A YU52598A (en) | 1998-11-19 | 1998-11-19 | Procedure for synthesis of n-[2[[[5-[ (dialkylamino)methyl] -2-furanil]methyl]thi0]etyl]-n'-alkyl-2-nitro 1,1 alkendiamine and its hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000029400A2 true WO2000029400A2 (en) | 2000-05-25 |
| WO2000029400A3 WO2000029400A3 (en) | 2000-07-20 |
Family
ID=25550316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/YU1999/000011 WO2000029400A2 (en) | 1998-11-19 | 1999-11-18 | Procedure for synthesis of n-[2[[[5- [(dialkilamino) methyl]-2- furanyl] methyl]thyo] ethyl]-n'- alkyl-2-nitro1,1 alkenediamines and their hydrochlorides |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU1479800A (en) |
| WO (1) | WO2000029400A2 (en) |
| YU (1) | YU52598A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382922A (en) * | 2017-08-03 | 2017-11-24 | 江苏汉斯通药业有限公司 | The preparation method of high-transmittance ranitidine hydrochloride |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2734070A1 (en) * | 1976-08-04 | 1978-02-09 | Allen & Hanburys Ltd | AMINOALKYLFURA DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| EP0055625A1 (en) * | 1980-12-30 | 1982-07-07 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| CH642072A5 (en) * | 1976-08-04 | 1984-03-30 | Allen & Hanburys Ltd | Process for the preparation of aminoalkylfuran derivatives |
| GB2160204A (en) * | 1984-06-15 | 1985-12-18 | Glaxo Group Ltd | Preparation of N-methyl-1-alkylthio-2-nitroethenamines |
| EP0697411A1 (en) * | 1994-06-24 | 1996-02-21 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
-
1998
- 1998-11-19 YU YU52598A patent/YU52598A/en unknown
-
1999
- 1999-11-18 AU AU14798/00A patent/AU1479800A/en not_active Abandoned
- 1999-11-18 WO PCT/YU1999/000011 patent/WO2000029400A2/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2734070A1 (en) * | 1976-08-04 | 1978-02-09 | Allen & Hanburys Ltd | AMINOALKYLFURA DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| CH642072A5 (en) * | 1976-08-04 | 1984-03-30 | Allen & Hanburys Ltd | Process for the preparation of aminoalkylfuran derivatives |
| EP0055625A1 (en) * | 1980-12-30 | 1982-07-07 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| GB2160204A (en) * | 1984-06-15 | 1985-12-18 | Glaxo Group Ltd | Preparation of N-methyl-1-alkylthio-2-nitroethenamines |
| EP0697411A1 (en) * | 1994-06-24 | 1996-02-21 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1479800A (en) | 2000-06-05 |
| YU52598A (en) | 2001-05-28 |
| WO2000029400A3 (en) | 2000-07-20 |
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