IE58606B1 - Preparation of amine derivatives - Google Patents
Preparation of amine derivativesInfo
- Publication number
- IE58606B1 IE58606B1 IE148485A IE148485A IE58606B1 IE 58606 B1 IE58606 B1 IE 58606B1 IE 148485 A IE148485 A IE 148485A IE 148485 A IE148485 A IE 148485A IE 58606 B1 IE58606 B1 IE 58606B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- methyl
- preparation
- nitromethane
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Electromechanical Clocks (AREA)
Abstract
Compounds of formula (II> in which R1 is C1-4 alkyl, preferably methyl, are prepared by reaction of a compound of formula (I> where Q is hydrogen or a cation derived from a suitable base with a suitable alkylating agent such as an alkyl halide or a dialkyl sulphate. The compound of formula (II) may be converted into a histamine H2-antagonist containing an -NHC(=CHNO2)NHCH3 end group, e.g. ranitidine, by reaction with an appropriate amine. The compound of formula (I) (compounds where Q is H or alkali metal are said to be novel) may be prepared by reaction of methyl isothiocyanate with the carbanion of nitromethane (preferably generated in situ by reaction of nitromethane with a suitable base) in the presence of dimethyl sulphoxide as solvent, Q representing the cation derived from the base used to produce the carbanion of nitromethane.
Description
The present invention relates to the preparation of amine derivatives. N-Methyl-1-alkylthio-2-nitroethenamine derivatives are useful as intermediates for the preparation of ranitidine and other histamine H ?-ant.npon i. s ts containing the -NHC(=ΓΗΝΟ2)MHCH^ end group, such as nizatidine.
Such intermediates have previously been prepared by direct displacement of a single alkylthio group in 2,2bisaIkylthio-1-nitroethenc derivatives by reaction with methylamine. However this reaction suffers from a lack of selectivity and provides N-methy1-1-alky 1thio-2-nitroethenes contaminated with both unreacted starting material and the bis-aminated side product 2,2-bismethylamino-1-nitroethene .
British Patent Specification 1421792 discloses the preparation of compounds of formula NHR in which X and Ύ, which may be the same or different, each represent hydrogen, nitro, cyano, or SC^Ar (where Ar is optionally substituted phenyl), except that X and Y cannot 2 both represent hydrogen, R represents lower alkyl and R represents lower alkyl or aralkyl, by the following reaction sequence: CH2XY S c CHXY C The substituted methane CH^XT is said to be reacted with the isothiocyanate ester after treatment with a strong base such as sodium hydride or sodium hydroxide. In the only specific example of this reaction which is disclosed, methyl isothiocyanate is reacted with malononitrile in the presence of sodium hydride and dimethylformamide. The second stage of the reaction is carried out by adding methyl iodide in dimethylformamide.
Chem. Ber. 100 591-604(1967) discloses the reaction of phenyl isothiocyanate with nitromethane and also discloses that the reaction should be carried out in the presence of sodium hydride in dimethylformamide. The reaction is followed by methylation with methyl iodide tc produce N-phenyl-1-methylthio-2-nitroethenamine.
The use of sodium hydride in dimethylformamide as taught by the documents referred to above is unsuitable for large scale preparations in view of the known hazards associated with the combination of these reagents.
The present invention provides a process preparation of a compound of formula (I) for the (I) wherein Q is hydrogen or a cation derived from a suitable 5 base which comprises reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulphoxide as solvent, optionally in the presence of a cosolvent. The carbanion of nitromethane is generated in situ from nitromethane by reaction with the base. The compound of formula (I) wherein Q is a hydrogen atom may be prepared from the compound of formula (I) in which Q is a cation by addition of one equivalent of a suitable acid.
The compound of formula (I) may be treated with an appropriate alkylating agent such as an alkyl halide (e.g* methyl bromide or methyl iodide) or a dialkyl sulphate (e.g. dimethyl sulphate), to produce an N-methyl-l-alkylthio-2nitro-ethenamine derivative of formula (II) RnS c=chno2 (II) ch3nh wherein R is a alkyl group, preferably methyl.
It has now surprisingly been found that formation of the compound of formula (I) and thus production of the N-methy1- 1-a iky Jthio-2-nitroethanamine derivatives of formula (II) takes place in particularly good yield, provided that the reaction between methyl isothiocyanate and the carbanion of nitromethane is carried out in dimethyl sulphoxide as a solvent, optionally in the presence of a co-solvent. Thus when the reaction of methyl isothiocyanate with nitromethane is carried out in the presence of sodium hydride as base the yield increases from 22% when dimethylformamide is used as solvent to 59% when dimethyl sulphoxide is used as solvent.
Preferably the compound of formula (I) is reacted in situ with the alkylating agent and in this case the reaction will also generally be carried out in the same solvent medium. Λ preferred process, according to the invention for pre pa rsi ng N-me thy 1 - 1 - a Iky I. th io-2-n i t roe thorium i ne de r i va t i ves of formula (II) comprises reacting methyl isothiocyanate with the carbanion of nitromethane to give the compound of formula (I) in situ followed by alkylation with an appropriate alkylating agent as referred to above, the reaction being carried out in the presence of dimethyl sulphoxide as solvent, optionally in the presence of a co-solvent. Suitable cosolvents, the choice of which depends on the base used, include aprotic solvents (such as dimethylformamide and Nmethylpyrrolidinone) and water.
A particular embodiment of this process involves methylation of the compound of formula (I) prepared in situ using a suitable methylating agent such as methyl iodide or dimethyl sulphate to give N-methyl-l-methylthio-2-nitroethenamine,i.e. the compound of formula (II) where R^ is methyl.
The compounds of formula (I) can exist in tautomeric forms and formula (I) is intended to include all such forms.
The process of the present invention gives N-methyl-1alkylthio-2-nitroethenamines of formula (II) in good yield and in a form that may be used to prepare compounds such as ranitidine without further purification. This, process, which uses cheap simple and commercially available starting materials, may in general be carried out safely on a large scale and under mild conditions. The process of the invention is particularly applicable to the preparation of Nmethyl-l-methylthio-2-nitroethenamine.
Conveniently the carbanion of nitromethane is prepared in situ by treating nitromethane with a suitable base. Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or alkali metal alkoxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tert-butoxide. Alkali metal hydroxides are preferred and when the base is an alkali metal hydroxide it may be added as an aqueous solution.
Where subsequent- reaction with the alkylating agent is carried out on the compound of formula (1) prepared in -°1 itu then the same solvent medium will generally be used for the alkylation reaction.
The temperature of the reaction is conveniently within the range 0-50°C, and the reaction is preferably carried out at room temperature.
According to a further aspect, the invention provides a process for the preparation of compounds, particularly histamine antagonists, containing an -NHC (=CHNC>2) NHCH^ end group which comprises reacting an N-methy1-1-a Iky1thio-2-nitroethenamine derivative of formula (II), prepared as described above, with an appropriate amine. Thus, in accordance with this aspect of the invention, ranitidine may be prepared from 2-[L5(N,N-dimethylaminomethyl)-2-furanmethylthio]ethylamino as the am i ne, preferably using N-methyl-1-methylthio-2-nitrcethenamine as the compound of formula (II). The reaction may be carried out in a solvent such as water, optionally with heating.
The invention is illustrated but in no way limited by the following Examples: Example J N-Methyl-1-methylthio-2-nitroethenamine (i) Nitromethane (1.2 5 q) was added over 1 min. to a suspension of flake potassium hydroxide (1.15 q) in di5 methyl sulphoxide (containinq 7.5% water) (18ml). A solution of methy1isothiocyanate (1.5q) in dimethyl sulphoxide (containinq 7.5% water) (2.5ml) was added over 2 min. keepinq the temperature at 20-26°. The solution was stirred for a further 0.5h at room temperature and methyl iodide (3.19q) added dropwise over 2 min. keepinq the temperature at 22-24°. Stirrinq was continued for lh. at room temperature, and the solution was then diluted with water (200ml) and extracted with dichloromethane.
The combined extracts were washed with water, evaporated to dryness, and the residue was crystallised from 2-propanol to qive the title compound (1.5q), Y49.4% m.p. 113-116.5°. (ii) Nitromethane (1.32q) in dimethyl sulphoxide (containinq 7.5% water) (5ml) was added over 5 min. at. 0-5° to sodium hydride (0.52q) in dimethyl su.lnhnxide (containinq 7.5% water (20ml). The mixture wag allowed to warm to room temperature and after a further 30 min. methyl isothiocyanate (1.58q) in dimethyl suinhoxide (containinq 7.5% water) (5ml) was added over 5 min.
The mixture was treated with methyl iodide (3.07q) in dimethyl sulphoxide (containing 7.5?0 water) (5ml) keepinq the temperature below 30°, and the resulting solution was stirred overniqht. The solvent was removed, water (50ml) j was added to the residue and the mixture was worked up accordinq to the procedure in Example l(i) to give the title compound (1.88q), Y58.7%. m.p. 112-114°. (iii) Nitromethane (0.62g) was added dropwise over 2 min. to a suspension of potassium tert-butoxide (l.lg) in l0 dry dimethyl sulphoxide (9ml) under an atmosphere of nitrogen with the temperature kept at 20-25°. The mixture was stirred for 10 min. and a solution of methyl isothiocyanate (0.715g) in dimethyl sulphoxide (containing 7.5 λ water) (3ml) was added dropwise over 2 in in. Stirring 15 was continued for 0.5h at room temperature and then methyl iodide (1.5 2 q) was added dropwise over 2 min. with the temperature kept at 20-25°. The solution was stirred at room temperature for 2h. , diluted with water (100ml) and worked up accordinq to the procedure in Example l(i) to 20 give the title compound (0.96g) , Y66.1% m.p. 113-115.5°. (iv) According to the procedure in Example l(iii), but replacing potnssium tert-butoxide with sodium hydroxide (1.6g), nitromethane (2.44q) in dimethyl sulphoxide (containing 7.5% water) (35ml) and methyl isothiocyanate (2.92 g) in dimethyl sulphoxide (containing 7.5% water) (5ml) followed by alkylation with methyl iodide (6.25g) gave the title compound (2.64q), Y44.5%. m.p. 113-116°.
Example 2 N-Methyl-l-methylthio-2-nitroethenamine Potassium hydroxide (20.88g) in water (12.4ml) was added to a stirred solution of methyl isothiocyanate (27.22g) and nitromethane (22.75g) in dimethyl sulphoxide (185ml), keeping the temperature at 10-15°. Stirrinq was continued for 60 min. at 10-15° then the solution was divided into 2 equal portions (each 120ml). (i) The first portion was stirred at 10-15° while dimethyl sulphate (17.62ml) was added over 15 min. stirring was continued for 30 min. then water (9Dm I ) was added and the mixture was worked up according to the nrocedure in Example l(i) to give the title compound (12.45 g ) , Y 4 5.1% . m.p. 112.5 114°. (ii) The second portion was treated with methyl iodide (11.66ml) and worked up in the same manner to give the title compound (14.61q ) , Y5 2.9%. m.p. 112.5 - 114°.
Example 3 N-Methyl-l-methylthio-2-nitroethenamine Nitromethane (1.05q) and methyl isothiocyanate (1.26g) in dry dimethyl sulphoxide (6.71g) was added over 70 min. to a stirred suspension of sodium hydride (0.41q) in dimethylformamide (4.3ml) with the temperature kept below 25°. Stirring was continued for 3h. then methyl iodide (2.45g) was added over 15 min. keening the temperature below 30°. The resulting solution was stirred for 30 min., water (9ml.) was added and the solution was worked up according to the procedure in Example l(i) to qive the title compound. (1.30q),Y50.8%. m.p. 113.5-115.5°.
Example 4 N-Methyl-l-methylthio-2-nitroethenainine Nitromethane (22.7g) was added over P mi'i. In a stirred suspension of flake potassium hydroxide (2 Π.P 6 o) in ίο dimethyl s 111ρ h oxide (157.5ml) and water (6.4ml) keepinq the temperature at 15-20°. A solution of methyl isothiocyanate (27.19 q) in dimethyl sulphoxide (27ml) and water (1ml) was added dropwise over 20 min. keepinq the temperature at 15-25°. Stirrinq was continued for a further lh. at room temperature and methyl iodide (52.78q) was added over 10 min. keeping the temperature at 15-20°. The resulting mixture was stirred for a further lh. at room temperature then water (178ml) was added and the mixture was worked up accordinq to the procedure in Example 1 (i) to qive the title compound (25.68q), Y46.6%. m.p .113-116°.
Example 5 N-[2-[5-(Dimethylamino)methyl-2-furanylmethylthio]ethyl]15 Nl-methyl-2-nitro-l,l-ethenediamine A solution of 2-[5-(N,N-dimethy1 aminomethy1 )-2-furanme t h y 11 h i o ] e t h y 1 am i n e (32.lq) in water (25ml) was added dropwise over 4h. to a stirred solution of N-methyl-1methy1thio-2-nitroethenamine (23q) in water (40ml) at 50°.
The reaction mixture was heated at 50° fur ·< further 2h. and then heated to 90°. Methyl isobutyl ketone (150ml) was added to the solution and the water remnved by azeotropic distillation. The solution was cooled at 60° and charcoal (l.5g) added. The mixture was filtered, the charcoal residue washed with methyl isobutyl ketone (50ml) and the combined filtrate and washinqs were cooled to 0°. The title compound (39q) m.p.68-70° crystallised and was f iltered off .
Claims (20)
1. A process for the preparation of a compound of formula (I) CHpm c=chno 2 (I, 5 wherein Q is a hydrogen or a cation derived from a suitable base which comprises reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulphoxide as solvent, the carbanion of nitromethane having been generated in situ from nitromethane and the base, and 10 optionally treating the compound in which Q is a cation with a suitable acid to generate the compound in which Q is hydrogen.
2. A process as claimed in claim 1, wherein dimethyl sulphoxide is used together with a co-solvent. 15
3. A process as claimed in claim 1 or 2, wherein the base is an alkali metal hydroxide.
4. A process as claimed in claim 3, wherein the base is an alkali metal hydroxide used as an aqueous solution.
5. A process as claimed in claim 3 or 4, wherein the 20 alkali metal hydroxide is potassium hydroxide.
6. A process as claimed in claim 1 or 2, wherein the base is an alkali metal hydride or an alkali metal alkoxide.
7. A process as claimed in claim 6, wherein the base is sodium hydride or potassium tert-butoxide.
8. λ process for the preparation of an N-methyl-alkylthio-2-nitroethenamine derivative of formula (II, c=chno 2 (II) wherein Ri is a Οχ_4 alkyl group, which comprises preparing a compound of formula (I) as defined in claim 1 by a process as claimed in any of claims 1 to 7 and subsequently reacting the compound of formula (I) with a suitable alkylating agent to produce the N-methyl-l-alkylthio-2-nitroethenamine derivative of formula (II).
9. A process as claimed in claim 8, wherein the reaction with the alkylating agent is carried out on the compound of formula (I) prepared in situ*
10. A process as claimed in claim 8 or 9, wherein the alkylating agent is an alkyl halide or a dialkyl sulphate.
11. A process as claimed in any of claims 8 to 10 for the preparation of the compound of formula (II) in which Κχ is methyl, wherein the alkylating agent is methyl iodide or dimethyl sulphate.
12. A process for the preparation of a compound containing an -NHC(-CHNO2)NHCH3 end group which comprises preparing an N-methyl-l-alkylthio-2-nitroethenamine derivative of formula (II) as defined in claim 8 by a method as claimed in any of claims 8 to 11, and subsequently reacting the derivative of formula (II) with a suitable amine.
13. λ process as claimed in claim 12, wherein the compound containing an —NHC(“CHNO 2 )NHCH3 end group is ranitidine and the amine is 2-[5-(N,N-dimethylaminomethyl)-2furanmethylthio)ethylamine.
14. a process as claimed in claim 13, wherein the compound of formula (II) is N-methyl-l-methylthio-2-nitroethenamine.
15. A process according to claim 1 for the preparation of a compound of formula (I) given and defined in claim 1, substantially as hereinbefore described and exemplified.
16. A compound of formula (I) given and defined in claim 1, whenever prepared by a process claimed in any one of claims 1-7 and 15.
17. A process according to claim 8 for the preparation of an N-methyl-alkylthio-2-nitroethenamine derivative of formula (II) given and defined in claim 8, substantially as hereinbefore described and exemplified.
18. An N-methyl-alkylthio-2-nitroethenamine derivative of formula (II) given and defined in claim 8, whenever prepared by a process claimed in any one of claims 8-11 and 17.
19. A process according to claim 12 for the preparation of a compound containing an -NHC(=CHNO 2 )NHCH^ end group, substantially as hereinbefore described and exemplified.
20. A compound containing an -NHC(=CHNO 2 )NHCH^ end group, whenever prepared by a process claimed in any one of claims 12 - 14 and 19.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848415254A GB8415254D0 (en) | 1984-06-15 | 1984-06-15 | Amine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE851484L IE851484L (en) | 1986-01-15 |
| IE58606B1 true IE58606B1 (en) | 1993-10-20 |
Family
ID=10562466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE148485A IE58606B1 (en) | 1984-06-15 | 1985-06-14 | Preparation of amine derivatives |
Country Status (22)
| Country | Link |
|---|---|
| JP (2) | JPH0643382B2 (en) |
| KR (1) | KR870002019B1 (en) |
| AT (1) | AT395974B (en) |
| BE (1) | BE902655A (en) |
| CA (1) | CA1256454A (en) |
| CH (1) | CH667871A5 (en) |
| DE (1) | DE3521456A1 (en) |
| DK (1) | DK170067B1 (en) |
| ES (1) | ES8705359A1 (en) |
| FI (1) | FI82239C (en) |
| FR (1) | FR2565972B1 (en) |
| GB (2) | GB8415254D0 (en) |
| HU (1) | HU198179B (en) |
| IE (1) | IE58606B1 (en) |
| IL (1) | IL75523A (en) |
| IT (1) | IT1209960B (en) |
| NL (1) | NL8501727A (en) |
| NO (1) | NO162461C (en) |
| PT (1) | PT80643B (en) |
| SE (1) | SE462913B (en) |
| SG (1) | SG92590G (en) |
| ZA (1) | ZA854502B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU9203905D0 (en) * | 1989-04-05 | 1993-04-28 | Glaxo Group Ltd | Method for producing ranitidine |
| EP0396830B1 (en) * | 1989-05-10 | 1993-10-27 | Council of Scientific and Industrial Research | An improved process for the preparation of 1-substituted amino-1-substituted thio-2-nitro alkenes |
| US5686588A (en) * | 1995-08-16 | 1997-11-11 | Yoo; Seo Hong | Amine acid salt compounds and process for the production thereof |
| YU52598A (en) * | 1998-11-19 | 2001-05-28 | D.D. Zdravlje- sektor za istraživanje i razvoj | Procedure for synthesis of n-[2[[[5-[ (dialkylamino)methyl] -2-furanil]methyl]thi0]etyl]-n'-alkyl-2-nitro 1,1 alkendiamine and its hydrochloride |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1421792A (en) * | 1973-05-17 | 1976-01-21 | Smith Kline French Lab | Heterocyclic substituted-1, 1-diamino-ethylene derivatives methods for their preparation and compositions containing them |
| GB1554153A (en) * | 1975-05-15 | 1979-10-17 | Smith Kline French Lab | Process for making 2-amino-2-alkylthionitroethylenes |
| GB1565966A (en) | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
-
1984
- 1984-06-15 GB GB848415254A patent/GB8415254D0/en active Pending
-
1985
- 1985-06-13 IT IT8548213A patent/IT1209960B/en active
- 1985-06-14 PT PT80643A patent/PT80643B/en not_active IP Right Cessation
- 1985-06-14 KR KR1019850004197A patent/KR870002019B1/en not_active IP Right Cessation
- 1985-06-14 NO NO852418A patent/NO162461C/en not_active IP Right Cessation
- 1985-06-14 IE IE148485A patent/IE58606B1/en not_active IP Right Cessation
- 1985-06-14 BE BE0/215184A patent/BE902655A/en not_active IP Right Cessation
- 1985-06-14 FI FI852366A patent/FI82239C/en active IP Right Grant
- 1985-06-14 DK DK270585A patent/DK170067B1/en not_active IP Right Cessation
- 1985-06-14 AT AT0178085A patent/AT395974B/en active
- 1985-06-14 CA CA000484041A patent/CA1256454A/en not_active Expired
- 1985-06-14 ZA ZA854502A patent/ZA854502B/en unknown
- 1985-06-14 DE DE19853521456 patent/DE3521456A1/en active Granted
- 1985-06-14 FR FR858509049A patent/FR2565972B1/en not_active Expired
- 1985-06-14 HU HU852367A patent/HU198179B/en not_active IP Right Cessation
- 1985-06-14 GB GB08515195A patent/GB2160204B/en not_active Expired
- 1985-06-14 ES ES544214A patent/ES8705359A1/en not_active Expired
- 1985-06-14 NL NL8501727A patent/NL8501727A/en not_active IP Right Cessation
- 1985-06-14 IL IL75523A patent/IL75523A/en not_active IP Right Cessation
- 1985-06-14 SE SE8502973A patent/SE462913B/en not_active IP Right Cessation
- 1985-06-14 CH CH2530/85A patent/CH667871A5/en not_active IP Right Cessation
- 1985-06-15 JP JP60130673A patent/JPH0643382B2/en not_active Expired - Fee Related
-
1990
- 1990-11-13 SG SG925/90A patent/SG92590G/en unknown
-
1993
- 1993-09-16 JP JP5230589A patent/JPH06102656B2/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |