NO173094B - PROCEDURE FOR THE PREPARATION OF RANITIDIN - Google Patents
PROCEDURE FOR THE PREPARATION OF RANITIDIN Download PDFInfo
- Publication number
- NO173094B NO173094B NO892040A NO892040A NO173094B NO 173094 B NO173094 B NO 173094B NO 892040 A NO892040 A NO 892040A NO 892040 A NO892040 A NO 892040A NO 173094 B NO173094 B NO 173094B
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- Norway
- Prior art keywords
- methyl
- compound
- water
- nitromethane
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 7
- VMXUWOKSQNHOCA-UHFFFAOYSA-N N1'-[2-[[5-[(dimethylamino)methyl]-2-furanyl]methylthio]ethyl]-N1-methyl-2-nitroethene-1,1-diamine Chemical compound [O-][N+](=O)C=C(NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UHFFFAOYSA-N 0.000 title claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 15
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 claims description 12
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- 150000001768 cations Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YQFHPXZGXNYYLD-UHFFFAOYSA-N n-methyl-1-methylsulfanyl-2-nitroethenamine Chemical compound CNC(SC)=C[N+]([O-])=O YQFHPXZGXNYYLD-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- -1 2-[5-(dimethylamino)methyl-2-furanylmethylthio]ethyl Chemical group 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Peptides Or Proteins (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av ranitidin, det vil si N-[2-[5-(dimetylairtino)metyl-2-furanylmetyltio]etyl]-N'-metyl-2-nitro-l,1-etendiamin. The present invention relates to a method for the production of ranitidine, that is N-[2-[5-(dimethylairtino)methyl-2-furanylmethylthio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine.
Fremstillingen skjer ifølge oppfinnelsen ved at The production takes place according to the invention by
a) metylisotiocyanat omsettes med karbanionet av nitrometan i nærvær av dimetylsulfoksyd som oppløsningsmiddel, eventuelt a) methyl isothiocyanate is reacted with the carbanion of nitromethane in the presence of dimethyl sulfoxide as solvent, optionally
i nærvær av et medoppløsningsmiddel, idet karbanionet av nitrometan er dannet in situ fra nitrometan og en egnet base, for å danne en forbindelse med formel (I) in the presence of a cosolvent, the carbanion of nitromethane being formed in situ from nitromethane and a suitable base, to form a compound of formula (I)
hvor Q' er et kation avledet fra basen, og where Q' is a cation derived from the base, and
forbindelsen hvor Q' er et kation, behandles eventuelt med en egnet syre for å danne forbindelsen med formel I hvor Q' er hydrogen, b) den fremstilte forbindelse hvor Q' er hydrogen eller et kation, Cx-A alkyleres for å danne et N-metyl-l-alkyltio-2-nitroetenamin-derivat, og c) nevnte N-metyl-l-alkyltio-2-nitroetenamin-derivat med formel I hvor Q' er en C x. 4 alkylgruppe, omsettes med 2-[5-(N,N-dimetylaminometyl)-2-furanmetyltio]etylamin. the compound where Q' is a cation is optionally treated with a suitable acid to form the compound of formula I where Q' is hydrogen, b) the compound prepared where Q' is hydrogen or a cation, Cx-A is alkylated to form a N -methyl-1-alkylthio-2-nitroethenamine derivative, and c) said N-methyl-1-alkylthio-2-nitroethenamine derivative of formula I where Q' is a C x. 4 alkyl group, is reacted with 2-[5-(N,N-dimethylaminomethyl)-2-furanmethylthio]ethylamine.
I trinn b) fremstilles og i trinn c) anvendes fortrinnsvis N-metyl-l-metyltio-2-nitroetenamin anvendes som forbindelsen med formel (I). Omsetningen kan utføres i et oppløsningsmiddel så som vann, eventuelt med oppvarming. In step b) is prepared and in step c) is preferably used N-methyl-1-methylthio-2-nitroethenamine is used as the compound of formula (I). The reaction can be carried out in a solvent such as water, optionally with heating.
Det følgende eksempel skal tjene til å illustrere oppfinnelsen ytterligere. The following example shall serve to further illustrate the invention.
EKSEMPEL EXAMPLE
1) N- metyl- l- metyltio- 2- nitroetenamin 1) N- methyl- 1- methylthio- 2- nitroethenamine
(i) Nitrometan (1,25 g) ble i løpet av 1 minutt satt til en suspensjon av flakformig kaliumhydroksyd (1,15 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (18 ml). En oppløsning av metylisotiocyanat (1,5 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (2,5 ml) ble tilsatt i løpet av 2 minutter mens temperaturen ble holdt ved 20 - 26°C. Oppløsningen ble omrørt i ytterligere 0,5 time ved romtemperatur, og metyljodid (3,19 g) ble tilsatt dråpevis over 2 minutter, mens temperaturen ble holdt ved 22 - 24°C. Omrøringen ble fortsatt i 1 time ved romtemperatur, og oppløsningen ble derefter fortynnet med vann (2 00 ml) og ekstrahert med diklormatan. De samlede ekstrakter ble vasket med vann, inndampet til tørrhet, og residuet ble krystallisert fra 2-propanol for å gi tittelforbindelsen (1,5 g), utbytte 49,4% smp. 113 - 116-C. (ii) Nitrometan (1,32 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (5 ml) ble i løpet av 5 minutter ved 0 - 5°C satt til natriumhydrid (0,52 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (20 ml). Blandingen fikk oppvarmes til romtemperatur, og efter ytterligere 30 minutter ble metylisotiocyanat (1,58 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (5 ml) tilsatt i løpet av 5 minutter. (i) Nitromethane (1.25 g) was added over 1 minute to a suspension of flaky potassium hydroxide (1.15 g) in dimethyl sulfoxide (containing 7.5% water) (18 ml). A solution of methyl isothiocyanate (1.5 g) in dimethyl sulfoxide (containing 7.5% water) (2.5 mL) was added over 2 minutes while maintaining the temperature at 20-26°C. The solution was stirred for an additional 0.5 hour at room temperature, and methyl iodide (3.19 g) was added dropwise over 2 minutes, while maintaining the temperature at 22-24°C. Stirring was continued for 1 hour at room temperature, and the solution was then diluted with water (200 mL) and extracted with dichloromethane. The combined extracts were washed with water, evaporated to dryness, and the residue crystallized from 2-propanol to give the title compound (1.5 g), yield 49.4% m.p. 113 - 116-C. (ii) Nitromethane (1.32 g) in dimethyl sulfoxide (containing 7.5% water) (5 ml) was added to sodium hydride (0.52 g) in dimethyl sulfoxide (containing 7 .5% water) (20 ml). The mixture was allowed to warm to room temperature, and after a further 30 minutes, methyl isothiocyanate (1.58 g) in dimethyl sulfoxide (containing 7.5% water) (5 ml) was added over 5 minutes.
Blandingen ble behandlet med metyljodid (3,07 g) i dimetylsulfoksyd (inneholdende 7,5 % vann) (5 ml), mens temperaturen ble holdt under 30°C, og den resulterende oppløsning ble omrørt natten over. Oppløsningsmidlet ble fjernet, vann (50 ml) ble satt til residuet, og blandingen ble opparbeidet i henhold til fremgangsmåten i alternativ (i) for å gi tittelforbindelsen (1,88 g), utbytte 58,7%, smp. 112 - 114 °C. The mixture was treated with methyl iodide (3.07 g) in dimethyl sulfoxide (containing 7.5% water) (5 mL) while maintaining the temperature below 30°C, and the resulting solution was stirred overnight. The solvent was removed, water (50 ml) was added to the residue and the mixture was worked up according to the procedure of option (i) to give the title compound (1.88 g), yield 58.7%, m.p. 112 - 114 °C.
(iii) Nitrometan (0,62 g) ble satt dråpevis i løpet av 2 minutter til en suspensjon av kalium-tert-butoksyd (1,1 g) i tørt dimetylsulfoksyd (9 ml) under en atmosfære av nitrogen mens temperaturen ble holdt ved 2 0 - 25°C. Blandingen ble omrørt i 10 minutter, og en oppløsning av metylisotiocyanat (0,715 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (3 ml) ble tilsatt dråpevis over 2 minutter. Omrøring ble fortsatt i 0,5 time ved romtemperatur, og derefter ble metyljodid (1,52 (iii) Nitromethane (0.62 g) was added dropwise over 2 min to a suspension of potassium tert-butoxide (1.1 g) in dry dimethyl sulfoxide (9 mL) under an atmosphere of nitrogen while maintaining the temperature at 20 - 25°C. The mixture was stirred for 10 minutes, and a solution of methyl isothiocyanate (0.715 g) in dimethyl sulfoxide (containing 7.5% water) (3 ml) was added dropwise over 2 minutes. Stirring was continued for 0.5 h at room temperature, and then methyl iodide (1.52
g) tilsatt dråpevis over 2 minutter mens temperaturen ble holdt ved 2 0 - 25°C. Oppløsningen ble omrørt ved romtemperatur g) added dropwise over 2 minutes while the temperature was maintained at 20 - 25°C. The solution was stirred at room temperature
i 2 timer, fortynnet med vann (100 ml) og opparbeidet i henhold til fremgangsmåten ifølge eksempel l(i) for å gi tittelforbindelsen (0,96 g), utbytte 66,1%, smp. 113 - 115,5°C. for 2 hours, diluted with water (100 ml) and worked up according to the procedure of Example 1(i) to give the title compound (0.96 g), yield 66.1%, m.p. 113 - 115.5°C.
(iv) I henhold til fremgangsmåten ifølge alternativ (iii), men ved å erstatte kalium-tert-butoksyd med natriumhydroksyd (1,6 (iv) According to the method according to alternative (iii), but by replacing potassium tert-butoxide with sodium hydroxide (1.6
g) ga nitrometan (2,44 g) i dimetylsulfoksyd (inneholdende 7,5% vann) (35 ml) og metylisotiocyanat (2,92 g) i g) gave nitromethane (2.44 g) in dimethyl sulfoxide (containing 7.5% water) (35 mL) and methyl isothiocyanate (2.92 g) in
dimetylsulfoksyd (inneholdende 7,5% vann) (5 ml) fulgt av alkylering med metyljodid (6,25 g), tittelforbindelsen (2,64 dimethyl sulfoxide (containing 7.5% water) (5 mL) followed by alkylation with methyl iodide (6.25 g), the title compound (2.64
g), utbytte 44,5%, smp. 113 - 116°C. g), yield 44.5%, m.p. 113 - 116°C.
2) N- f 2- [ 5- ( dimetvlamino) metyl- 2- furanylmetyltio] etyl"| - N' - 2) N-f 2-[5-(dimethylamino)methyl-2-furanylmethylthio]ethyl"| - N' -
metyl- 2- nitro- l, l- etendiamin methyl-2-nitro-l,l-ethenediamine
En oppløsning av 2-[5-(N,N-dimetylaminometyl)-2-furan-metyl-tio]etylamin (32,1 g) i vann (25 ml) ble satt dråpevis over 4 timer til en omrørt oppløsning av N-metyl-l-metyltio-2-nitroetenamin (23 g) i vann (40 ml) ved 50°C. Reaksjonsbland-ingene ble oppvarmet ved 50°C i ytterligere 2 timer og ble derefter oppvarmet til 90°C. Metylisobutylketon (150 ml) ble satt til oppløsningen, og vannet ble fjernet ved azeotropisk destillasjon. Oppløsningen ble avkjølt til 60°C, og trekull (1,5 g) ble tilsatt. Blandingen ble filtrert, trekullresten ble vasket med metylisobutylketon (50 ml), og de samlede filtrater og vaskevæsker ble avkjølt til 0°C. Tittelforbindelsen (39 g), smp. 60-70°C, krystalliserte og ble frafiltrert. A solution of 2-[5-(N,N-dimethylaminomethyl)-2-furan-methyl-thio]ethylamine (32.1 g) in water (25 ml) was added dropwise over 4 hours to a stirred solution of N- methyl-1-methylthio-2-nitroethenamine (23 g) in water (40 ml) at 50°C. The reaction mixtures were heated at 50°C for an additional 2 hours and then heated to 90°C. Methyl isobutyl ketone (150 mL) was added to the solution and the water was removed by azeotropic distillation. The solution was cooled to 60°C and charcoal (1.5 g) was added. The mixture was filtered, the charcoal residue was washed with methyl isobutyl ketone (50 mL), and the combined filtrates and washings were cooled to 0°C. The title compound (39 g), m.p. 60-70°C, crystallized and was filtered off.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO892040A NO173094C (en) | 1984-06-15 | 1989-05-22 | PROCEDURE FOR THE PREPARATION OF RANITIDIN |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB848415254A GB8415254D0 (en) | 1984-06-15 | 1984-06-15 | Amine derivatives |
NO852418A NO162461C (en) | 1984-06-15 | 1985-06-14 | PROCEDURE FOR THE PREPARATION OF AMINE DERIVATIVES. |
NO892040A NO173094C (en) | 1984-06-15 | 1989-05-22 | PROCEDURE FOR THE PREPARATION OF RANITIDIN |
Publications (4)
Publication Number | Publication Date |
---|---|
NO892040L NO892040L (en) | 1985-12-16 |
NO892040D0 NO892040D0 (en) | 1989-05-22 |
NO173094B true NO173094B (en) | 1993-07-19 |
NO173094C NO173094C (en) | 1993-10-27 |
Family
ID=27262388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO892040A NO173094C (en) | 1984-06-15 | 1989-05-22 | PROCEDURE FOR THE PREPARATION OF RANITIDIN |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO173094C (en) |
-
1989
- 1989-05-22 NO NO892040A patent/NO173094C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO892040D0 (en) | 1989-05-22 |
NO892040L (en) | 1985-12-16 |
NO173094C (en) | 1993-10-27 |
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