CA2055189A1 - Process for preparing 1-{2-¬ (5-dimethyllaminomethyl-2-furyl) -methylthio)-ethyl)-amino-1-methylamino-2-nitroethylene - Google Patents
Process for preparing 1-{2-¬ (5-dimethyllaminomethyl-2-furyl) -methylthio)-ethyl)-amino-1-methylamino-2-nitroethyleneInfo
- Publication number
- CA2055189A1 CA2055189A1 CA002055189A CA2055189A CA2055189A1 CA 2055189 A1 CA2055189 A1 CA 2055189A1 CA 002055189 A CA002055189 A CA 002055189A CA 2055189 A CA2055189 A CA 2055189A CA 2055189 A1 CA2055189 A1 CA 2055189A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- furyl
- methylthio
- ethyl
- nitroethylene
- 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
Classifications
-
- 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
- C07D307/36—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
Abstract The invention relates to a new process for preparing 1-{2-[(5-dimethylaminomethyl-2-furyl)-methylthio]-ethyl}--amino-1-methylamino-2-nitroethylene of the formula (I) (I) (generic name: ranitidine), which comprises reacting the diketene imine derivative of formula (II) (II) with methylamine.
The most important advantage of the invention consists in that ranitidine can be prepared in a yield of more than 90 % in an outstanding quality by a simple procedure.
The most important advantage of the invention consists in that ranitidine can be prepared in a yield of more than 90 % in an outstanding quality by a simple procedure.
Description
2 ~
PROCESS FOR PREPARING 1 {2-~(5-DIM~THYL~MINOM~THYL-2-FURYL)-~M~THYLTHI03-~T~YL}~ANINO l-METHYLAMINO-2-NIT~OETHYLEN~
The invention relates to a new process for preparing 1-{2-[(5-dimethylaminomethyl-2~furyl)-methylthio] ethyl~--amino-1~methylaminoD2-nitroethylene of the formula (I) \ N-CH ~ CH2- S- CH2-c~l?~ C NH C~3 (I) ,. _ (generic name: ranitidine).
It is known that, being a highly effective H-2 receptor antagonist, the compound of formula (I) i5 the active ingredient of several outstanding medicaments being useful against gastric and duodenal ulcers.
The preparation of the compound of formula (I) in three dif~erent ways was first described in the British patent specification No. 1,565,966. However, these processes should be carried out thruogh a high number of steps to give a rather low yield and in addition, combrous methods of purification are needed to obtain a pure product.
A4793-67-SZO/KmO
~0~8~
A~ter the compound of formula (I) had become an important drug, novel processes were developed for its preparation in addition to those mentioned above. Today more than 10 ranitidine processes are known each o~ which involves, however, some drawbacks. A part of the processes start from the corresponding thiol derivative (see e.g.
United States patent specifications Nos. 4,497,961 and 4,~40,93~), howe~er, these methods require a reactant containing a nitro group ~e.y. an aziridine derivative), which is rather difficult to prepare.
An ingenious method was published in the European patent applications Nos. 0,055,625 and 0,219,225, where the dimethylaminomethyl group attached to 2 position of the furan cycle was introduced in the final step of the synthesis. The disadvantage of these methods consists therein that, due to various side reactions, the last: step results in a surprisingly low yield.
From various other types of syntheses the Hungarian patent specification No. 196,979 deserves accentuation, according to which the compound of formula (I) can be prepared through a compound supposed to be a ketena imine.
This compound was not isolated and its chemical properties were not defined. The reaction was carried out in an extremely dilute solution (5 g/360 ml of solvent) and a sig-nificant amount (reaching 50 ~ of the weight of the productobtained) of silver nitrate was used. According to the examples of this specification an in SltU prepared ketene imine deriYative was obtained by the treatment of a 2 ~
methylthio-nitro derivative with silver nitrate and under effect of methylamine, which then directly gave crude rani-tidine without isolation. The yield of recrystallized rani-tidine as calculated for the methylthio nitro compound was not higher than 58 to 73 %.
Thus, the aim o~ the pres0nt invention is to provide a process, which is use~ul to prepare the aimed ranitidine final product in a high yield and simple way on an industrial - scale.
The invention is based on the recognition that the aimecl purpo~e can very ef~ectively be achieved in a one-step reac-tion from a novel diketene imine compound unknown up to the present to give ranitidine in a nearly lOO % yield.
Namely, it has been found during our investigations that the diketene imine derivative of Xormula ~II), , N Cll2 ~ C~i2 S (C~-l2)2- N -c-- Cl-l- NO
Cl-l~ ~ (II) ~ 1`1--Cl-12 ~ ,~ C~-12 -S--(C)-12~2--Nl-l--C~ C--N02 Cl-13 ,, .. , .. ~ .. .. .
(chemically 1 {2-[(5~N,N-dimethylaminomethyl-2-furyl)-methyl-thio]-ethyl}-2-{2-[(5-N,N-dimethylaminomethyl-2-furyl)-methylthio]-1-ethylamino}-3-nitro-4-nitromethyl0ne-2-azetine;
hereinafter abbreviated: diketene imine derivative~, which is 2 ~
easy to produce from cysteamine hydrochloride and a fur~uryl derivative, can excellently be reacted with methylamine in a defined mole ratio to give ranitidine base with an out-standing quality in a simple reaction occurring at room temperature.
Thus, the present invention relates to a process for the peparation of 1-{2-[(5~dimethylaminomethyl-2-furyl)-methyl-thio]ethyl}-amino-l-methylamino-2-nitroethylene of the formula ~I), which comprises reacting the diketene imine com-pound of formula (II) with methylamine.
Methylamine is used in gaseou~ form or in aqueoussolution, preferably at a temperature between 0 C and 70 C.
According to a pre~ered embodiment of the invention the diketene imine derivative of formula ~II) is reacted with 10 moles of 40 % by weight aqueous methylamine at a temperature between 20 C and 25 C. The reaction mixture obtained is clarified, filtered and extracted. The compound of formula (I), i.e. ranitidine is directly or indirectly isolated from the organic phase.
The most impor~ant advanta~e o~ the present invention consists kherein that the aimed compound of formula (I) can be prepared in a yield over so % by u5ing a very simple technologic procedure. The base thus prepared can simply be transformed to its ~alt.
The invention is illustrated in detail ~y the following non-limiting E~amples.
~ample ~
.5 g (0.015 mol) of the diketene imine derivative of 2 ~ 8 9 formula (II) are dissolved in 30 ml of water and 41 g (0.5 mol) of 40 % aqueous methylamine solution are added at room temperature during 15 minutes. After stirring for 1 hour the mixture is clarified with 0.5 g o~ celite and 0.5 g of activated carbon at room temperature for 15 minutes and then filtered. The ~iltrate is extracted with 40 ml and then twice with 20 ml of chloroform each. After drying the combined extract over anhydrous sodium sulfate the drying agent is filtered o~f, the solvent is evaporated and the oily residue is recrystallized from 35 ml of ethyl acetate to obtain 9 g (9~ %) of 1-~2 C(5-dimethylaminomethyl 2-furyl)methylthio]-ethyl}-amino-1-methylamino-2-nitroethylene, m.p.: 71-73 C.
This product does not contain any contamination which can be identified on thin layer chromatogram (TLC~ o ~cample 2 The process described in Exalmple 1 is followed, except that gaseous methylamine is ~lowly introduced to the aqueous solution of the diketene imine derivative at room temperature until the reaction of the diketene imine becomes complete~
(This can be shown by thin layer chromatography by using a developing systen containing acetone~ethyl acetate/ammonium hydroxide in 5:5:1 ratio.) In this way ranitidine is obtained in a yield of 9.1 g (95.5 %), m.p.: 71-73 C. This product contains no TLC-detectable contamination.
~ mple 3 A) The process described in Example 1 is followed, ~xcept that only 8 g (0.1 mol) o~ 40 % aqueous methylamine are used ~or the reaction and the reaction mixture is stirred 205~9 for 2 hours after addition. Ranitidine is obtained in a yielcl of 8.9 g (93-~ %)-B) The wet crystals of the ranitidine bas~ are dissolvedin 30 ml of ethanol and the solution is stirred with 0.5 g of celite and 0.5 g of activated carbon at room temperature for 30 minutes. After filtering off the clarifying agent, the filtrate is acidified to a pH value of 5 to 6 by adding 30 %
ethanolic hydrogen chloride solution. After cooling (in a - bath of 0 C) under stirring the product precipitatesO After filtering the product is washed with 10 ml of ethanol main-tained below 5 C. The ethanol used for washing can be employed as a medium for the next batch. In this way ~.05 g ~76.1 %) of ranitidine hydrochloride are obtained.
E~ampl* 4 The process of Example 1 can be carrried out in such a way that the oily product obtaine!d after evaporating chloro-form is dissolved in 30 ml of absO ethanol and the pH value of the solution is adjusted to a value of 5 to 6 by adding concentrated ethanolic hydrogen chloride solution. After inoculation, the solution is stirred at 5 to 10 C for 1 hour. The crystalline precipitate is filtered, washed with ethanol, cooled to 5 C and then dried under reduced pressure at room temperature to yield 9.4 g (89 %) of ranitidine hydrochloride.
E~ample 5 On carrying out the process of Exampla 4 on a 1000-fold scale 950 g (89.g %) of ranitidine hydrochloride are ob-tained.
PROCESS FOR PREPARING 1 {2-~(5-DIM~THYL~MINOM~THYL-2-FURYL)-~M~THYLTHI03-~T~YL}~ANINO l-METHYLAMINO-2-NIT~OETHYLEN~
The invention relates to a new process for preparing 1-{2-[(5-dimethylaminomethyl-2~furyl)-methylthio] ethyl~--amino-1~methylaminoD2-nitroethylene of the formula (I) \ N-CH ~ CH2- S- CH2-c~l?~ C NH C~3 (I) ,. _ (generic name: ranitidine).
It is known that, being a highly effective H-2 receptor antagonist, the compound of formula (I) i5 the active ingredient of several outstanding medicaments being useful against gastric and duodenal ulcers.
The preparation of the compound of formula (I) in three dif~erent ways was first described in the British patent specification No. 1,565,966. However, these processes should be carried out thruogh a high number of steps to give a rather low yield and in addition, combrous methods of purification are needed to obtain a pure product.
A4793-67-SZO/KmO
~0~8~
A~ter the compound of formula (I) had become an important drug, novel processes were developed for its preparation in addition to those mentioned above. Today more than 10 ranitidine processes are known each o~ which involves, however, some drawbacks. A part of the processes start from the corresponding thiol derivative (see e.g.
United States patent specifications Nos. 4,497,961 and 4,~40,93~), howe~er, these methods require a reactant containing a nitro group ~e.y. an aziridine derivative), which is rather difficult to prepare.
An ingenious method was published in the European patent applications Nos. 0,055,625 and 0,219,225, where the dimethylaminomethyl group attached to 2 position of the furan cycle was introduced in the final step of the synthesis. The disadvantage of these methods consists therein that, due to various side reactions, the last: step results in a surprisingly low yield.
From various other types of syntheses the Hungarian patent specification No. 196,979 deserves accentuation, according to which the compound of formula (I) can be prepared through a compound supposed to be a ketena imine.
This compound was not isolated and its chemical properties were not defined. The reaction was carried out in an extremely dilute solution (5 g/360 ml of solvent) and a sig-nificant amount (reaching 50 ~ of the weight of the productobtained) of silver nitrate was used. According to the examples of this specification an in SltU prepared ketene imine deriYative was obtained by the treatment of a 2 ~
methylthio-nitro derivative with silver nitrate and under effect of methylamine, which then directly gave crude rani-tidine without isolation. The yield of recrystallized rani-tidine as calculated for the methylthio nitro compound was not higher than 58 to 73 %.
Thus, the aim o~ the pres0nt invention is to provide a process, which is use~ul to prepare the aimed ranitidine final product in a high yield and simple way on an industrial - scale.
The invention is based on the recognition that the aimecl purpo~e can very ef~ectively be achieved in a one-step reac-tion from a novel diketene imine compound unknown up to the present to give ranitidine in a nearly lOO % yield.
Namely, it has been found during our investigations that the diketene imine derivative of Xormula ~II), , N Cll2 ~ C~i2 S (C~-l2)2- N -c-- Cl-l- NO
Cl-l~ ~ (II) ~ 1`1--Cl-12 ~ ,~ C~-12 -S--(C)-12~2--Nl-l--C~ C--N02 Cl-13 ,, .. , .. ~ .. .. .
(chemically 1 {2-[(5~N,N-dimethylaminomethyl-2-furyl)-methyl-thio]-ethyl}-2-{2-[(5-N,N-dimethylaminomethyl-2-furyl)-methylthio]-1-ethylamino}-3-nitro-4-nitromethyl0ne-2-azetine;
hereinafter abbreviated: diketene imine derivative~, which is 2 ~
easy to produce from cysteamine hydrochloride and a fur~uryl derivative, can excellently be reacted with methylamine in a defined mole ratio to give ranitidine base with an out-standing quality in a simple reaction occurring at room temperature.
Thus, the present invention relates to a process for the peparation of 1-{2-[(5~dimethylaminomethyl-2-furyl)-methyl-thio]ethyl}-amino-l-methylamino-2-nitroethylene of the formula ~I), which comprises reacting the diketene imine com-pound of formula (II) with methylamine.
Methylamine is used in gaseou~ form or in aqueoussolution, preferably at a temperature between 0 C and 70 C.
According to a pre~ered embodiment of the invention the diketene imine derivative of formula ~II) is reacted with 10 moles of 40 % by weight aqueous methylamine at a temperature between 20 C and 25 C. The reaction mixture obtained is clarified, filtered and extracted. The compound of formula (I), i.e. ranitidine is directly or indirectly isolated from the organic phase.
The most impor~ant advanta~e o~ the present invention consists kherein that the aimed compound of formula (I) can be prepared in a yield over so % by u5ing a very simple technologic procedure. The base thus prepared can simply be transformed to its ~alt.
The invention is illustrated in detail ~y the following non-limiting E~amples.
~ample ~
.5 g (0.015 mol) of the diketene imine derivative of 2 ~ 8 9 formula (II) are dissolved in 30 ml of water and 41 g (0.5 mol) of 40 % aqueous methylamine solution are added at room temperature during 15 minutes. After stirring for 1 hour the mixture is clarified with 0.5 g o~ celite and 0.5 g of activated carbon at room temperature for 15 minutes and then filtered. The ~iltrate is extracted with 40 ml and then twice with 20 ml of chloroform each. After drying the combined extract over anhydrous sodium sulfate the drying agent is filtered o~f, the solvent is evaporated and the oily residue is recrystallized from 35 ml of ethyl acetate to obtain 9 g (9~ %) of 1-~2 C(5-dimethylaminomethyl 2-furyl)methylthio]-ethyl}-amino-1-methylamino-2-nitroethylene, m.p.: 71-73 C.
This product does not contain any contamination which can be identified on thin layer chromatogram (TLC~ o ~cample 2 The process described in Exalmple 1 is followed, except that gaseous methylamine is ~lowly introduced to the aqueous solution of the diketene imine derivative at room temperature until the reaction of the diketene imine becomes complete~
(This can be shown by thin layer chromatography by using a developing systen containing acetone~ethyl acetate/ammonium hydroxide in 5:5:1 ratio.) In this way ranitidine is obtained in a yield of 9.1 g (95.5 %), m.p.: 71-73 C. This product contains no TLC-detectable contamination.
~ mple 3 A) The process described in Example 1 is followed, ~xcept that only 8 g (0.1 mol) o~ 40 % aqueous methylamine are used ~or the reaction and the reaction mixture is stirred 205~9 for 2 hours after addition. Ranitidine is obtained in a yielcl of 8.9 g (93-~ %)-B) The wet crystals of the ranitidine bas~ are dissolvedin 30 ml of ethanol and the solution is stirred with 0.5 g of celite and 0.5 g of activated carbon at room temperature for 30 minutes. After filtering off the clarifying agent, the filtrate is acidified to a pH value of 5 to 6 by adding 30 %
ethanolic hydrogen chloride solution. After cooling (in a - bath of 0 C) under stirring the product precipitatesO After filtering the product is washed with 10 ml of ethanol main-tained below 5 C. The ethanol used for washing can be employed as a medium for the next batch. In this way ~.05 g ~76.1 %) of ranitidine hydrochloride are obtained.
E~ampl* 4 The process of Example 1 can be carrried out in such a way that the oily product obtaine!d after evaporating chloro-form is dissolved in 30 ml of absO ethanol and the pH value of the solution is adjusted to a value of 5 to 6 by adding concentrated ethanolic hydrogen chloride solution. After inoculation, the solution is stirred at 5 to 10 C for 1 hour. The crystalline precipitate is filtered, washed with ethanol, cooled to 5 C and then dried under reduced pressure at room temperature to yield 9.4 g (89 %) of ranitidine hydrochloride.
E~ample 5 On carrying out the process of Exampla 4 on a 1000-fold scale 950 g (89.g %) of ranitidine hydrochloride are ob-tained.
Claims (5)
1. A process for the preparation of 1-{2-[(5--dimethylaminomethyl-2-furyl)-methylthio]-ethyl}-amino-1--methylamino-2-nitroethylene of the formula (I) (I) which comprises reacting the diketene imine derivative of formula (II) (II) with methylamine.
2. The process as claimed in claim 1, which comprises using methylamine in gaseous form or in an aqueous solution.
3. The process as claimed in claim 1, which comprises carrying out the reaction at a temperature between 0 °C and 70 °C
4. The process as claimed in claim 1, which comprises reacting the diketene imine derivative of formula (II) with 2.2 to 35 moles of 20 to 50 % by weight aqueous methylamine solution at room temperature.
5. The process as claimed in claim 1, which comprises using 10 moles of 40 % by weight of aqueous methylamine solution in the reaction.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU907074A HU207308B (en) | 1990-11-09 | 1990-11-09 | Process for producing 1- /2-/5-/dimethyl-amino-methyl/-2-/furyl-methyl-thio/-ethyl//- -amino-1-/methyl-amino-2-nitro-ethylene |
| HU7074/90 | 1990-11-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2055189A1 true CA2055189A1 (en) | 1992-05-10 |
| CA2055189C CA2055189C (en) | 1992-05-10 |
Family
ID=10972142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002055189A Granted CA2055189A1 (en) | 1990-11-09 | 1991-11-08 | Process for preparing 1-{2-¬ (5-dimethyllaminomethyl-2-furyl) -methylthio)-ethyl)-amino-1-methylamino-2-nitroethylene |
Country Status (16)
| Country | Link |
|---|---|
| KR (1) | KR920009813A (en) |
| CN (1) | CN1061968A (en) |
| AR (1) | AR248017A1 (en) |
| AT (1) | AT400146B (en) |
| CA (1) | CA2055189A1 (en) |
| CZ (1) | CZ280197B6 (en) |
| DK (1) | DK184291A (en) |
| ES (1) | ES2036479B1 (en) |
| FI (1) | FI915265A (en) |
| GR (1) | GR1002225B (en) |
| HU (1) | HU207308B (en) |
| NO (1) | NO179208C (en) |
| PL (1) | PL166616B1 (en) |
| PT (1) | PT99470A (en) |
| RU (1) | RU2032681C1 (en) |
| YU (1) | YU177391A (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2115111B (en) * | 1982-01-25 | 1987-01-14 | Ava Int Corp | Fail safe gate valves and actuators therefor |
| ES543966A0 (en) * | 1982-11-22 | 1986-03-01 | Medichem Sa | PROCEDURE FOR THE PREPARATION OF N- (2 - ((((5- (DIMETILA-MINO) -METIL-2-FURANIL) METHYL) THIO) ETIL) -N'-METHYL-2-NITRO-1,1- ETENDIAMINE |
| YU42819B (en) * | 1982-11-22 | 1988-12-31 | Lek Tovarna Farmacevtskih | Process for preparing n-/2-///5-(dimethyl-amino)-methyl-2-furanyl/methyl/thio/ethyl-n'-methyl-2-nitro-1,1-ethene diamine |
| PT79699B (en) * | 1983-12-22 | 1986-12-10 | Pfizer | Process for preparing quinolone inotropic agents |
| HU196979B (en) * | 1985-01-11 | 1989-02-28 | Gyogyszerkutato Intezet | Process for producing basic thioether and salt |
| ES8603706A1 (en) * | 1985-06-12 | 1986-01-16 | Medichem Sa | Nitro:ethylidene di:amine deriv. |
-
1990
- 1990-11-09 HU HU907074A patent/HU207308B/en not_active IP Right Cessation
-
1991
- 1991-11-06 RU SU915010152A patent/RU2032681C1/en active
- 1991-11-06 AT AT0220391A patent/AT400146B/en not_active IP Right Cessation
- 1991-11-07 GR GR910100451A patent/GR1002225B/en unknown
- 1991-11-07 YU YU177391A patent/YU177391A/en unknown
- 1991-11-08 CA CA002055189A patent/CA2055189A1/en active Granted
- 1991-11-08 PL PL91292327A patent/PL166616B1/en unknown
- 1991-11-08 AR AR91321118A patent/AR248017A1/en active
- 1991-11-08 CZ CS913403A patent/CZ280197B6/en unknown
- 1991-11-08 FI FI915265A patent/FI915265A/en not_active Application Discontinuation
- 1991-11-08 PT PT99470A patent/PT99470A/en not_active Application Discontinuation
- 1991-11-08 DK DK184291A patent/DK184291A/en unknown
- 1991-11-08 NO NO914376A patent/NO179208C/en unknown
- 1991-11-08 ES ES9102480A patent/ES2036479B1/en not_active Expired - Lifetime
- 1991-11-09 CN CN91110542A patent/CN1061968A/en active Pending
- 1991-11-09 KR KR1019910019914A patent/KR920009813A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO914376L (en) | 1992-05-11 |
| NO179208C (en) | 1996-08-28 |
| NO914376D0 (en) | 1991-11-08 |
| GR1002225B (en) | 1996-04-18 |
| PT99470A (en) | 1992-10-30 |
| KR920009813A (en) | 1992-06-25 |
| AR248017A1 (en) | 1995-05-31 |
| ATA220391A (en) | 1995-02-15 |
| FI915265A (en) | 1992-05-10 |
| HUT59916A (en) | 1992-07-28 |
| HU907074D0 (en) | 1991-05-28 |
| GR910100451A (en) | 1992-10-08 |
| AT400146B (en) | 1995-10-25 |
| YU177391A (en) | 1994-01-20 |
| RU2032681C1 (en) | 1995-04-10 |
| ES2036479A1 (en) | 1993-05-16 |
| ES2036479B1 (en) | 1993-12-16 |
| HU207308B (en) | 1993-03-29 |
| FI915265A0 (en) | 1991-11-08 |
| CZ280197B6 (en) | 1995-11-15 |
| DK184291A (en) | 1992-05-10 |
| PL166616B1 (en) | 1995-06-30 |
| CS340391A3 (en) | 1992-05-13 |
| CA2055189C (en) | 1992-05-10 |
| DK184291D0 (en) | 1991-11-08 |
| CN1061968A (en) | 1992-06-17 |
| PL292327A1 (en) | 1992-07-13 |
| NO179208B (en) | 1996-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kim et al. | Monosubstituted guanidines from primary amines and aminoiminomethanesulfonic acid | |
| IE48532B1 (en) | Process for preparing h2-receptor antagonist cimetidine | |
| KR920002295B1 (en) | Process for the preparation of pyrrolidone derivatives | |
| CA2055189A1 (en) | Process for preparing 1-{2-¬ (5-dimethyllaminomethyl-2-furyl) -methylthio)-ethyl)-amino-1-methylamino-2-nitroethylene | |
| EP0260588B1 (en) | Process for the preparation of alpha-N-[(hypoxanthin-9-yl)-pentyloxycarbonyl]-arginine | |
| SU1122222A3 (en) | Method of obtaining cymetidine | |
| US5099067A (en) | Use of ammonium formate as a hydrogen transfer reagent for reduction of chiral nitro compounds with retention of configuration | |
| JP2578797B2 (en) | Method for producing N- (sulfonylmethyl) formamides | |
| KR100196343B1 (en) | Process for the preparation of (2-chloro-pyridin-5-yl-methyl)-ethylendiamine | |
| US4275216A (en) | Process for preparing 4(5)-hydroxymethyl 5(4)-lower alkyl imidazoles | |
| US4623730A (en) | Processes for preparing 4-amino-3-imidazolin-2-one and (2-methoxy-2-iminoethyl)urea | |
| SU862822A3 (en) | Method of preparing n-cyano-n'-methyl-n"-/2-((4-methyl-5-imidazolyl)-methylthio)-ethyl/-guanidine | |
| Papoutsis et al. | Phenyliodonium derivatives from 4‐aminocoumarin and their reactivity | |
| SU561513A3 (en) | The method of obtaining piperazine derivatives or their salts | |
| JP2682713B2 (en) | Production of optically active tetrahydrofuran | |
| US4585880A (en) | Process for the preparation of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxyacetic acid | |
| US4892956A (en) | 5-cyano-4,5-dihydro-3,4-dicarboxypyrazole derivatives | |
| EP0276574B1 (en) | Alpha-acyloxyketone derivatives | |
| JPS622588B2 (en) | ||
| SU1627081A3 (en) | Process for preparation of hydroxydipraphenon and its pharmacologic available salts | |
| JPH033668B2 (en) | ||
| JPS636063B2 (en) | ||
| EP0429619B1 (en) | New process for the preparation of phenyl-guanidine derivatives | |
| FI66590B (en) | PROCEDURE FOR FRAMSTATION OF AV 5'-ALKANOYLAMINO-2 '- (2-HYDROXI-3-ISOPROPYLAMINOPROPOXY) -ACETOFENONE | |
| JPS5914468B2 (en) | Method for producing 5-methyl-2-furfural |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |