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
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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (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 |
|---|---|---|---|
| GB848423804A GB8423804D0 (en) | 1984-09-20 | 1984-09-20 | Chemical process |
| GB8423804 | 1984-09-20 |
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 PT PT81161A patent/PT81161B/en not_active IP Right Cessation
- 1985-09-19 FI FI853599A patent/FI853599L/en not_active Application Discontinuation
- 1985-09-19 AT AT2740/85A patent/AT392639B/en not_active IP Right Cessation
- 1985-09-19 ES ES547108A patent/ES8604918A1/en not_active Expired
- 1985-09-19 GB GB08523178A patent/GB2164647B/en not_active Expired
- 1985-09-19 DK DK426085A patent/DK426085A/en not_active Application Discontinuation
- 1985-09-19 IT IT48572/85A patent/IT1200117B/en active
- 1985-09-19 JP JP60207694A patent/JPS61106566A/en active Pending
- 1985-09-19 KR KR1019850006858A patent/KR870001166B1/en not_active IP Right Cessation
- 1985-09-19 GR GR852283A patent/GR852283B/el unknown
- 1985-09-20 CA CA000491180A patent/CA1237440A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FI853599A0 (en) | 1985-09-19 |
| GB8523178D0 (en) | 1985-10-23 |
| ES8604918A1 (en) | 1986-02-16 |
| AT392639B (en) | 1991-05-10 |
| PT81161A (en) | 1985-10-01 |
| IT1200117B (en) | 1989-01-05 |
| PT81161B (en) | 1988-01-22 |
| ES547108A0 (en) | 1986-02-16 |
| DK426085D0 (en) | 1985-09-19 |
| DK426085A (en) | 1986-03-21 |
| IT8548572A0 (en) | 1985-09-19 |
| KR860002488A (en) | 1986-04-26 |
| GR852283B (en) | 1985-12-23 |
| ATA274085A (en) | 1990-10-15 |
| KR870001166B1 (en) | 1987-06-15 |
| FI853599L (en) | 1986-03-21 |
| GB2164647A (en) | 1986-03-26 |
| GB8423804D0 (en) | 1984-10-24 |
| GB2164647B (en) | 1988-02-03 |
| JPS61106566A (en) | 1986-05-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |