GB2164647A - Process for the preparation of a furan derivative - Google Patents
Process for the preparation of a furan derivative Download PDFInfo
- Publication number
- GB2164647A GB2164647A GB08523178A GB8523178A GB2164647A GB 2164647 A GB2164647 A GB 2164647A GB 08523178 A GB08523178 A GB 08523178A GB 8523178 A GB8523178 A GB 8523178A GB 2164647 A GB2164647 A GB 2164647A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methyl
- formula
- salt
- carried out
- alkali metal
- 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
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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
Abstract
Ranitidine is prepared by treating the compound <IMAGE> in which R represents H or preferably methyl with a methylating agent such as a methyl halide, dimethyl sulphate or a methyl sulphonic ester. The reaction may be carried out in the presence of a base or an alkali metal methylsulphinylmethide salt. The starting material (II) is readily obtainable in pure crystalline form and the process does not involve evolution of thiol.
Description
SPECIFICATION
Process 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)
which is known as ranitidine is disclosed in British Patent Specification No. 1565966 as a potent and selective H2- antagonist.
The present invention provides a novel and useful process for the preparation of ranitidine of formula (I) which comprises treating a compound of formula (II)
in which R represents a hydrogen atom or a methyl group with a methylating agent. Suitable methylating agents include methyl halides such as methyl bromide or methyl iodide, dimethylsulphate 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 methysulphinylmethide.
Suitable bases include carbonates e.g. sodium carbonate or potassium carbonate, bicarbonates 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, NaCH2S(O)CH3, this is conveniently prepared in situ from an alkali metal hydride such as sodium hydride and dimethylsulphoxide.
When the compound of formula (II) is reacted with 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. Alternatively, when an organic base is used, this may conveniently also be employed as the solvent for the reaction.
The reaction involving the alkali metal methylsulphinylmethide salt may also be carried out in the presence of a solvent, suitable solvents including dimethylsulphoxide or an ether eg tetrahydrofuran.
The 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 (II) in which R represents a methyl group.
If desired the furan derivative of formula (I) once obtained may be converted into an acid addition 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), eg an alcohol such as ethanol 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 advantage 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 following examples in which temperatures are in "C and hplc refers to high performance liquid chromatography.
Example 1 N-[2-[[5-[(Dimethylamino)methyl7-2-furanylmethylythio]ethyly -N'-methyl-2-nitro- 1,1-ethenediamine (a) A mixture of sodium hydride (70% dispersion in oil, 0.15g) 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-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (1.29) (Compound A) in dimethylsulphoxide (10ml) was added dropwise followed by the addition of iodomethane (0.27ml) in dimethylsulphoxide (10ml) and the solution was stirred at 200, 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 separated and the aqueous layer further extracted with dichioromethane (2x50ml). The combined dichloromethane extracts were washed with brine, dried (Na2CO3) and evaporated and the residue (1.59) was chromatographed on silica [Merck
No. 7734, 8091 using dichloromethane: ethanol:0.88 ammonia 75:8:1 as eluent to give the title compound (0.179). N.m.r. and l.r. spectroscopy showed that this sample was consistent with the title compound prepared according to the method of Example 15 in British Patent Specification No. 1565966.
(b) Similarly, sodium hydride (60% dispersion in oil, 0.449), dimethylsulphoxide (60ml), Compound A (1.5g) and methyl tosylate (1.029) gave a product which was shown by hpic to contain about 157mg of the title compound.
(c) Similarly, sodium hydride (60% dispersion in oil, 0.449), dimethylsulphoxide (80ml), Compound A (1.5g) and dimethylsulphate (0.76ml) gave a product which was shown by hplc to contain about 157mg of the title compound.
Example 2 N-J24f16-[{Dimeth ylamino)m eth ylj-2-furan yIJm ethylithiol-eth yll-N'-methvl-2-nitro- 1, 1-ethenediamine
(a) N-[-2-[[[5-[(methylamino)methyl]-2-furanyl]methyl]-thio]ethyl]-N'-methyi-2-nitrow ethenediamine hydrochloride (Compound B) (1.33g) and potassium carbonate (0.55g) in methanol (25ml) were treated with iodomethane (0.56g) at 0-4" for 5h and then at room temperature for a further 17h. The reaction mixture was shown by hplc to contain 211 mug of the title compound.
(b) Similarly, Compound B (0.549), triethylamine (0.339), methanol (12ml) and iodomethane (0.1my) gave a mixture which was shown by hpic to contain about 50mg of the title compound.
(c) Similarly, Compound B (0.54g), pyridine (0.19g), methanol (12ml) and iodomethane (0.1my) gave a mixture which was shown by hplc to contain about 50mg of the title compound.
(d) Similarly, Compound A (0.549), methanol (12ml) and iodomethane (0.1my) 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 formula (I)
which comprises treating a compound of formula (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.
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 any of claims 1 to 3 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, potassium bicarbonate, pyridine or triethylamine.
6. A process as claimed in any of claims 1 to 3 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 any of claims 1 to 7 carried out at a temperature of 0 to 50"C.
9. A process as claimed in any of claims 1 to 8 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 (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848423804A GB8423804D0 (en) | 1984-09-20 | 1984-09-20 | Chemical process |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8523178D0 GB8523178D0 (en) | 1985-10-23 |
| GB2164647A true GB2164647A (en) | 1986-03-26 |
| GB2164647B GB2164647B (en) | 1988-02-03 |
Family
ID=10567015
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848423804A Pending GB8423804D0 (en) | 1984-09-20 | 1984-09-20 | Chemical process |
| GB08523178A Expired GB2164647B (en) | 1984-09-20 | 1985-09-19 | Process for the preparation of a furan derivative |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848423804A Pending GB8423804D0 (en) | 1984-09-20 | 1984-09-20 | Chemical process |
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) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| GB2132615A (en) * | 1982-12-08 | 1984-07-11 | Degussa | New ethene diamine and guanidine derivatives |
-
1984
- 1984-09-20 GB GB848423804A patent/GB8423804D0/en active Pending
-
1985
- 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 GR GR852283A patent/GR852283B/el unknown
- 1985-09-19 AT AT2740/85A patent/AT392639B/en not_active IP Right Cessation
- 1985-09-19 PT PT81161A patent/PT81161B/en not_active IP Right Cessation
- 1985-09-19 GB GB08523178A patent/GB2164647B/en not_active Expired
- 1985-09-19 KR KR1019850006858A patent/KR870001166B1/en not_active IP Right Cessation
- 1985-09-19 FI FI853599A patent/FI853599L/en not_active Application Discontinuation
- 1985-09-19 JP JP60207694A patent/JPS61106566A/en active Pending
- 1985-09-19 ES ES547108A patent/ES8604918A1/en not_active Expired
- 1985-09-20 CA CA000491180A patent/CA1237440A/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| GB2132615A (en) * | 1982-12-08 | 1984-07-11 | Degussa | New ethene diamine and guanidine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| PT81161A (en) | 1985-10-01 |
| AT392639B (en) | 1991-05-10 |
| JPS61106566A (en) | 1986-05-24 |
| KR870001166B1 (en) | 1987-06-15 |
| GR852283B (en) | 1985-12-23 |
| ES547108A0 (en) | 1986-02-16 |
| PT81161B (en) | 1988-01-22 |
| KR860002488A (en) | 1986-04-26 |
| CA1237440A (en) | 1988-05-31 |
| DK426085A (en) | 1986-03-21 |
| GB2164647B (en) | 1988-02-03 |
| ATA274085A (en) | 1990-10-15 |
| GB8423804D0 (en) | 1984-10-24 |
| GB8523178D0 (en) | 1985-10-23 |
| DK426085D0 (en) | 1985-09-19 |
| ES8604918A1 (en) | 1986-02-16 |
| IT8548572A0 (en) | 1985-09-19 |
| IT1200117B (en) | 1989-01-05 |
| FI853599A0 (en) | 1985-09-19 |
| FI853599L (en) | 1986-03-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930919 |