CA1237440A - Process for the preparation of a furan derivative - Google Patents
Process for the preparation of a furan derivativeInfo
- Publication number
- CA1237440A CA1237440A CA000491180A CA491180A CA1237440A CA 1237440 A CA1237440 A CA 1237440A CA 000491180 A CA000491180 A CA 000491180A CA 491180 A CA491180 A CA 491180A CA 1237440 A CA1237440 A CA 1237440A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- salt
- alkali metal
- carried out
- formula
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 150000002240 furans Chemical class 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000002585 base Substances 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 5
- -1 methyl halide Chemical class 0.000 claims abstract description 5
- 239000012022 methylating agents Substances 0.000 claims abstract description 5
- 229960000620 ranitidine Drugs 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 229940086542 triethylamine Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 150000003573 thiols Chemical class 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VMXUWOKSQNHOCA-UKTHLTGXSA-N ranitidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UKTHLTGXSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- C07D307/38—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
ABSTRACT
Process for the Preparation of a Furan Derivative Ranitidine is prepared by treating the compound (II)
Process for the Preparation of a Furan Derivative Ranitidine is prepared by treating the compound (II)
Description
~3~
Proces__For the Preparation of a furan derivative _ _ .
This invention relates to a process for the preparation of a furan derivative.
The furan derivative of formula (I) t~
/~ 1CI~Nn2 (I) Me2NCH2 0 CH2SC~2CH2NHCNHMe which is known as ranitidine is disclosed in ~ritish Patent Specification No. 1565966 as a potent and selective H2- antagonist.
lOThe present invention provides a novel and useFul process for the preparation of ranitidine of formula (I) which comprises treating a compound oF formula (II) 15RHNCH2 CH2SCH2CH2NHCNHMe (II) in which R represents a hydrogen atom or a methyl qroup with a methylating agent. Suitable methylating agents include methyl halides such as methyl bromide or methyl iodide, di~ethylsulphate or Methyl sulphonic esters such as methyl methanesulphonate or methyl p-toluene-sulphonate.
The reaction may optionally be carried out in the presence of a base or a salt such as an alkali metal methy1sulphinylmethide.
Proces__For the Preparation of a furan derivative _ _ .
This invention relates to a process for the preparation of a furan derivative.
The furan derivative of formula (I) t~
/~ 1CI~Nn2 (I) Me2NCH2 0 CH2SC~2CH2NHCNHMe which is known as ranitidine is disclosed in ~ritish Patent Specification No. 1565966 as a potent and selective H2- antagonist.
lOThe present invention provides a novel and useFul process for the preparation of ranitidine of formula (I) which comprises treating a compound oF formula (II) 15RHNCH2 CH2SCH2CH2NHCNHMe (II) in which R represents a hydrogen atom or a methyl qroup with a methylating agent. Suitable methylating agents include methyl halides such as methyl bromide or methyl iodide, di~ethylsulphate or Methyl sulphonic esters such as methyl methanesulphonate or methyl p-toluene-sulphonate.
The reaction may optionally be carried out in the presence of a base or a salt such as an alkali metal methy1sulphinylmethide.
- 2 - ~ ~37~
Suitable bases include carbonates e.~. sodium carbonate or potassium carbonate, bicarbunates e.g. sodium bicarbonate or potassium bicarbonate or organic bases such as pyridine or triethylamine.
When the reaction is carried out in the presence of a base the compound of formula (II) may conveniently be used in the form of an acid addition salt such as a hydrochloride salt.
When the reaction is carried out in the presence of an alkali metal methylsulphinylmethide salt, such as the potassium salt or more particularly the sodium salt, NaCI-12S(O)CH3, this is conveniently prepared in situ from an alkali metal hydride such as sodium hyclride and dimethylsulphoxide.
When the compound of formula (II) is reacted ~lith the methylating agent alone or in the presence of a base, the reaction may be carried out in an aprotic solvent such as an amide eg dimethylformamide or N-methylpyrrolidone, or acetonitrile, or an alcohol e.g. methanol or ethanol, or a ketone eg methyl ethyl ketone. ~lternatively, when an organic base is used, this may conveniently also be employed as the solvent for the reaction.
The reaction involvinq the alkali metal methyl-sulphinylmethide salt may also he carriecl out in the presence of a solvent, suitàble solvents includinq dimethylsulphoxide or an ether eg tetrahydrof~lran.
~ 3 - ~ ~3~4~
rhe methylation reaction is conveniently carried out at a temperature of from 0 to 50, preferably at room temperature.
A preferred process according to the present invention involves preparing ranitidine of formula (I) by methylating a compound of formula (Il) in which R
represents a methyl group.
If desired the furan derivative of formula (I) once obtained may be converted into an acid addltion salt, eg a hydrochloride, using conventional methods. Thus for example, appropriate quantities of the free base of formula (I) and an acid, eg hydrochloric acid, may be mixed in a suitable solvent(s), eq an alcohol such as sthanol or isopropanol, or an ester such as ethyl acetate.
The process of the present invention is advantageous - in that the starting material of formula (II) is readily obtainable in a pure crystalline form. Furthermore, the process has the advantage that there is no evolution of thiol. This is a significant advantaqe since it is necessary to prevent the release of thiol into the environment and this requires the use of specialised equipment which is expensive to run.
The invention is illustrated but not limited by the followinq examples in which temperatures are in C and hplc refers to hiqh perFormance liquid chromato~raohy.
Suitable bases include carbonates e.~. sodium carbonate or potassium carbonate, bicarbunates e.g. sodium bicarbonate or potassium bicarbonate or organic bases such as pyridine or triethylamine.
When the reaction is carried out in the presence of a base the compound of formula (II) may conveniently be used in the form of an acid addition salt such as a hydrochloride salt.
When the reaction is carried out in the presence of an alkali metal methylsulphinylmethide salt, such as the potassium salt or more particularly the sodium salt, NaCI-12S(O)CH3, this is conveniently prepared in situ from an alkali metal hydride such as sodium hyclride and dimethylsulphoxide.
When the compound of formula (II) is reacted ~lith the methylating agent alone or in the presence of a base, the reaction may be carried out in an aprotic solvent such as an amide eg dimethylformamide or N-methylpyrrolidone, or acetonitrile, or an alcohol e.g. methanol or ethanol, or a ketone eg methyl ethyl ketone. ~lternatively, when an organic base is used, this may conveniently also be employed as the solvent for the reaction.
The reaction involvinq the alkali metal methyl-sulphinylmethide salt may also he carriecl out in the presence of a solvent, suitàble solvents includinq dimethylsulphoxide or an ether eg tetrahydrof~lran.
~ 3 - ~ ~3~4~
rhe methylation reaction is conveniently carried out at a temperature of from 0 to 50, preferably at room temperature.
A preferred process according to the present invention involves preparing ranitidine of formula (I) by methylating a compound of formula (Il) in which R
represents a methyl group.
If desired the furan derivative of formula (I) once obtained may be converted into an acid addltion salt, eg a hydrochloride, using conventional methods. Thus for example, appropriate quantities of the free base of formula (I) and an acid, eg hydrochloric acid, may be mixed in a suitable solvent(s), eq an alcohol such as sthanol or isopropanol, or an ester such as ethyl acetate.
The process of the present invention is advantageous - in that the starting material of formula (II) is readily obtainable in a pure crystalline form. Furthermore, the process has the advantage that there is no evolution of thiol. This is a significant advantaqe since it is necessary to prevent the release of thiol into the environment and this requires the use of specialised equipment which is expensive to run.
The invention is illustrated but not limited by the followinq examples in which temperatures are in C and hplc refers to hiqh perFormance liquid chromato~raohy.
3~49L~
Example 1 N-[2-[[5-[(Dimethylamino)methy1]-2-furanylmethyl]thio]
ethyl] -N'-methyl-2-nitr:o-1 7?-ethenediamine (a) A mixture of sodium hydride (70O dispersion in oil, 0.159) and dry dimethylsulphoxide (30ml) was heated at 70-75 for 0.75h under nitrogen. On cooling to 20 a solution oF N-[2-[[5-[(methylamino)methyl]-2-Furanyl-methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ether1ediamine (1.2~) (Compound A) in dimethylsulphoxide (10ml) was added dropwise fnllowed by the addition of iodomethane (0.27ml) in dimethylsulpho`xide (10ml) and the so]ution was stirred at 20, under nitrogen, for 18h. Water (10ml) was added and the mixture was evaporated in vacuo. The residue was partitioned between dichloromethane (50ml) and 2N aqueous sodium carbonate (50ml). The dichloromethane layer was separateo and the aqueous layer further extracted with dichloromethane (2x50ml). The combined dichloromethane extracts were washed with brine, dried (Na2C03) and evaporated and the residue (1.59) was chromatographed on 2b silica [~lerck No. 7734, 809] using dichloromethane:
ethanol:O.88 ammonia 75:n:1 as eluent to qive the title (0.179). N.m.r. and I.r. spectroscopy showed that this sample was consistent with the title compound 374~L~
prepared according to the method oF Example 15 in British Patent Specification No. 1565966.
(b) Similarly, sodium hydride (60o dispersion in oil, 0.449), dimethylsulphoxide (60ml), Compound A (1.5g) and methyl tosylate (1.02g) gave a product which was shown by hplc to contain about 157mg of the title compound.
(~) Similarly, sodium hydride (60no dispersion in oil, - 0.449), dimethylsulphoxide (80ml), Cornpound A (1.59) anrl dimethylsulphate (0.76ml) gave a product which was shown by hplc to contain about 157mg of the title compound~
Example 2 N-[2-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]-ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (a) N-[2-[[[5-[(methylamino)methyl]-2-furanyl~methyl~-thio] ethyl]-N'-methyl-2-nitro-1,1-ethenediamine hydrochloride (Compound B) (1.33g) and potassium carbonate (0.559) in methanol (25ml) were treated with iodomethane ~0 (0.5~9) at 0-4 for 5h and then at room temperature for a further 17h. The reaction mixture was stlown by hplc to to contain 211mg of the title compound.
~2~7~
(b) Similarly, Compound 8 ~0.54g), triethylamine (0.339), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mg o~ the title compound.
(c) Similarly, Compound B (0.54q), pyridine (0.199), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mq of the title compound.
(d) Similarly, Compound A (0.549), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mg of the title compound.
Example 1 N-[2-[[5-[(Dimethylamino)methy1]-2-furanylmethyl]thio]
ethyl] -N'-methyl-2-nitr:o-1 7?-ethenediamine (a) A mixture of sodium hydride (70O dispersion in oil, 0.159) and dry dimethylsulphoxide (30ml) was heated at 70-75 for 0.75h under nitrogen. On cooling to 20 a solution oF N-[2-[[5-[(methylamino)methyl]-2-Furanyl-methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ether1ediamine (1.2~) (Compound A) in dimethylsulphoxide (10ml) was added dropwise fnllowed by the addition of iodomethane (0.27ml) in dimethylsulpho`xide (10ml) and the so]ution was stirred at 20, under nitrogen, for 18h. Water (10ml) was added and the mixture was evaporated in vacuo. The residue was partitioned between dichloromethane (50ml) and 2N aqueous sodium carbonate (50ml). The dichloromethane layer was separateo and the aqueous layer further extracted with dichloromethane (2x50ml). The combined dichloromethane extracts were washed with brine, dried (Na2C03) and evaporated and the residue (1.59) was chromatographed on 2b silica [~lerck No. 7734, 809] using dichloromethane:
ethanol:O.88 ammonia 75:n:1 as eluent to qive the title (0.179). N.m.r. and I.r. spectroscopy showed that this sample was consistent with the title compound 374~L~
prepared according to the method oF Example 15 in British Patent Specification No. 1565966.
(b) Similarly, sodium hydride (60o dispersion in oil, 0.449), dimethylsulphoxide (60ml), Compound A (1.5g) and methyl tosylate (1.02g) gave a product which was shown by hplc to contain about 157mg of the title compound.
(~) Similarly, sodium hydride (60no dispersion in oil, - 0.449), dimethylsulphoxide (80ml), Cornpound A (1.59) anrl dimethylsulphate (0.76ml) gave a product which was shown by hplc to contain about 157mg of the title compound~
Example 2 N-[2-[[[5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]-ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (a) N-[2-[[[5-[(methylamino)methyl]-2-furanyl~methyl~-thio] ethyl]-N'-methyl-2-nitro-1,1-ethenediamine hydrochloride (Compound B) (1.33g) and potassium carbonate (0.559) in methanol (25ml) were treated with iodomethane ~0 (0.5~9) at 0-4 for 5h and then at room temperature for a further 17h. The reaction mixture was stlown by hplc to to contain 211mg of the title compound.
~2~7~
(b) Similarly, Compound 8 ~0.54g), triethylamine (0.339), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mg o~ the title compound.
(c) Similarly, Compound B (0.54q), pyridine (0.199), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mq of the title compound.
(d) Similarly, Compound A (0.549), methanol (12ml) and iodomethane (0.1ml) gave a mixture which was shown by hplc to contain about 50mg of the title compound.
Claims (10)
1. A process for the preparation of ranitidine of the formula (I) (I) which comprises treating a compound of the general formula (II) (II) in which R represents a hydrogen atom or a methyl group, with a methylating agent.
2. A process as claimed in claim 1 in which R
represents a methyl group.
represents a methyl group.
3. A process as claimed in claim 1 or 2 in which the methylating agent is a methyl halide, dimethyl sulphate or a methyl sulphonic ester.
4. A process as claimed in claim 1 carried out in the presence of a base.
5. A process as claimed in claim 4 wherein the base is sodium carbonate, potassium carbonate, sodium bicarbonate, postassium bicarbonate, pyridine or triethyl amine.
6. A process as claimed in claim 1 carried out in the presence of an alkali metal methylsulphinyl methide salt.
7. A process as claimed in claim 6 in which the alkali metal methylsulphinylmethide salt is prepared in situ from an alkali metal hydride and dimethylsulphoxide.
8. A process as claimed in claim 1, claim 2 or claim 4 carried out at a temperature of 0 to 50°C.
9. A process as claimed in claim 1 in which the furan derivative of formula (I) is subsequently converted into an acid addition salt.
10. A process as claimed in claim 9 in which the acid addition salt is the hydrochloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8423804 | 1984-09-20 | ||
| GB848423804A GB8423804D0 (en) | 1984-09-20 | 1984-09-20 | Chemical process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1237440A true CA1237440A (en) | 1988-05-31 |
Family
ID=10567015
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000491180A Expired CA1237440A (en) | 1984-09-20 | 1985-09-20 | Process for the preparation of a furan derivative |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS61106566A (en) |
| KR (1) | KR870001166B1 (en) |
| AT (1) | AT392639B (en) |
| CA (1) | CA1237440A (en) |
| DK (1) | DK426085A (en) |
| ES (1) | ES8604918A1 (en) |
| FI (1) | FI853599L (en) |
| GB (2) | GB8423804D0 (en) |
| GR (1) | GR852283B (en) |
| IT (1) | IT1200117B (en) |
| PT (1) | PT81161B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| NL8303965A (en) * | 1982-12-08 | 1984-07-02 | Degussa | NEW FOOD DIAMINE AND GUANIDINE DERIVATIVES; METHOD FOR PREPARING THEREOF MEDICINES CONTAINING THEM; METHOD FOR PREPARING SUCH MEDICINES; APPLICATION OF THE COMPOUNDS FOR THE PREPARATION OF MEDICINAL PRODUCTS AND IN MEDICINE. |
-
1984
- 1984-09-20 GB GB848423804A patent/GB8423804D0/en active Pending
-
1985
- 1985-09-19 ES ES547108A patent/ES8604918A1/en not_active Expired
- 1985-09-19 IT IT48572/85A patent/IT1200117B/en active
- 1985-09-19 FI FI853599A patent/FI853599L/en not_active Application Discontinuation
- 1985-09-19 PT PT81161A patent/PT81161B/en not_active IP Right Cessation
- 1985-09-19 DK DK426085A patent/DK426085A/en not_active Application Discontinuation
- 1985-09-19 KR KR1019850006858A patent/KR870001166B1/en not_active Expired
- 1985-09-19 JP JP60207694A patent/JPS61106566A/en active Pending
- 1985-09-19 GR GR852283A patent/GR852283B/el unknown
- 1985-09-19 GB GB08523178A patent/GB2164647B/en not_active Expired
- 1985-09-19 AT AT2740/85A patent/AT392639B/en not_active IP Right Cessation
- 1985-09-20 CA CA000491180A patent/CA1237440A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT81161A (en) | 1985-10-01 |
| FI853599A7 (en) | 1986-03-21 |
| GB8423804D0 (en) | 1984-10-24 |
| FI853599L (en) | 1986-03-21 |
| ES8604918A1 (en) | 1986-02-16 |
| DK426085A (en) | 1986-03-21 |
| AT392639B (en) | 1991-05-10 |
| KR860002488A (en) | 1986-04-26 |
| KR870001166B1 (en) | 1987-06-15 |
| JPS61106566A (en) | 1986-05-24 |
| GB8523178D0 (en) | 1985-10-23 |
| PT81161B (en) | 1988-01-22 |
| GR852283B (en) | 1985-12-23 |
| IT1200117B (en) | 1989-01-05 |
| ATA274085A (en) | 1990-10-15 |
| DK426085D0 (en) | 1985-09-19 |
| FI853599A0 (en) | 1985-09-19 |
| GB2164647A (en) | 1986-03-26 |
| GB2164647B (en) | 1988-02-03 |
| IT8548572A0 (en) | 1985-09-19 |
| ES547108A0 (en) | 1986-02-16 |
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