IE41740B1 - Preperation of a sulphur-containing pyridine derivative - Google Patents
Preperation of a sulphur-containing pyridine derivativeInfo
- Publication number
- IE41740B1 IE41740B1 IE2148/75A IE214875A IE41740B1 IE 41740 B1 IE41740 B1 IE 41740B1 IE 2148/75 A IE2148/75 A IE 2148/75A IE 214875 A IE214875 A IE 214875A IE 41740 B1 IE41740 B1 IE 41740B1
- Authority
- IE
- Ireland
- Prior art keywords
- process according
- acid
- carried out
- temperature
- hydrogenation
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1461068 2-Methyl-3-hydroxy-4-ethylaminomethyl - 5 - methylthiomethyl - pyridine MERCK PATENT GmbH 29 Sept 1975 [2 Oct 1974] 39739/75 Heading C2C The invention comprises a process for the preparation of 2 - methyl - 3 - hydroxy - 4- ethylaminomethyl - 5 - methylthiomethylpyridine, wherein a pyridine derivative of the general formula in which R signifies -CH=N-CH 2 - or -CH 2 -N=CH-, or a salt thereof, is reacted with sodium borohydride or with zinc and an acid or with hydrogen in the presence of Raney nickel.
Description
Tho present invention is concerned with a new and advantageous process for the preparation of 2-methyl-3hydroxy-4-ethylaminomethyl-5-methylthiomethyl-pyridine and of its acid-addition salts.
2-Methyl-3-hydroxy-4—ethylaminoethyl-5-methylthiomethyl-pyridine and its acid-addition salts are described and claimed in our British Patent Specification Mb.1,263,370
This pyridine compound and its salts have valuable pharmacological properties and can, therefore, be used in pharmaceutical compositions. In particular, they have a favourable action on the electroencephalogram.
Some processes for the preparation of these compounds are already known. However, they suffer from certain disadvantages: some of them do not give very pure products and, in some cases, the yields obtained are unsatisfactory.
lie have now found that these compounds can be obtained by a new process in very high yields and excellent purity.
Thus, according to the present invention, there is provided a process for the preparation of 2-raethyl-3hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine, wherein a pyridine derivative of the general formula:-
in which R signifies -CH=H-CH2- or -0H2-H=CH-, or a salt thereof, is reacted with sodium borohydride or with zinc and an acid or with hydrogen in the presence of Haney nickel,
-241740
The pyridine derivatives of general formula (I) are the Schiff’s bases 2-methyl~5-hydroxy-4-ethyliminomethyl-5-methylthiomethyl-pyridine (la) and 2-methyl-3hydroxy-4-ethylideneaminomethyl-5-methylthiomethyl5 pyridine (Ih). Compound Ia is known; it can easily he obtained from 2-methyl-3-hydroxy-4-formyl~5-methylthiomethylpyridine and ethylamine. Compound lb can be obtained from 2-methyl-3-hydroxy-4-aminomethyl-5-methylthiomethylpyridine and acetaldehyde.
io The reduction with sodium borohydride can be carried out in the presence of an inert solvent and preferably in the presence of water and/or an alcohol, such as methanol or ethanol. The reaction temperature can be from about 0 to 50°C. and preferably from 10 to 30°0.
In the case of the reduction with zinc and an acid, the zinc is advantageously used in the form of zinc dust.
The acid used is preferably an aliphatic carboxylic acid containing up to 4 carbon atoms, especially acetic acid but also formic acid, propionic acid or butyric acid, or
2o is a mineral acid, such as hydrochloric acid or sulphuric acid. in this case, the reaction can be carried out at a temperature of from about 20 to about 100°0. and preferably of from 40 to 70°C.
Hydrogenation with Raney nickel is preferably carried 2S out under acidic, neutral or basic conditions in the presence of an inert solvent, such as an alcohol, for example methanol or ethanol, or an ester, for example, ethyl acetate, or a carboxylic acid, for example formic acid, acetic acid or propionic acid, or an ether, for 10 example tetrahydrofuran or dioxan. The hydrogenation can
-341740 be carried out at a temperature of from about -20 to +15O°C. and preferably of from ambient temperature to +100°C. and at pressures of from 1 to 100 and preferably of from 1 to 10 ats.
According to an especially advantageous embodiment of the process of the present invention, the starting material of general formula (i) is prepared in. situ from an appropriate aldehyde and an appropriate amine, followed by reduction in the manner described above, without isolation.
The desired product obtained, when in the form of the free base, can, if desired, be converted with an acid in the usual way into the corresponding acid-addition salt, For this purpose, there can be used those acids 15 which give physiologically-compatible salts. Thus, there can be used inorganic acids, for example, sulphuric acid, nitric acid, a hydrohalic acid, such as hydrochloric acid or hydrobromic acid, a phosphoric acid, such as orthophosphoric acid or sulphamic acid, as well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- and polybasic carboxylic or sulphonic acids, for example, formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulphonic acid, ethane-disulphonic acid, 2-hydroxyethane-sulphonic acid, benzene-sulphonic acid, p-toluene-sulphonic acid or a naphthalene-mono- or disulphonic acid.
-441740
The free base can, if desired, be liberated from one of its salts by treatment with a strong base, for example, sodium or potassium hydroxide or 3odium or potassium carbonate.
The process acoording to the invention gives the desired base and its acid-addition salts in very high yields and in a very pure form which is practically free from by-products. The compounds so obtained can be used directly, without further purification, to the preparation of pharmaceutical compositions.
The following Examples are given for the purpose of illustrating the present invention:Example 1.
22.4 g. 2-methyl-3-hydroxy-4-ethyliminomethyl-5methylthiomethyl-pyridine (Ila; m.p. 45°0·; obtainable from 2-methyl-3-hydroxy-4-formyl-5-methylthiomethylpyridine and ethylamine) are dissolved in 100 ml. methanol and 3.7 g. sodium borohydride are added thereto portionwise, with cooling. Subsequently, the reaction mixture is filtered and the filtrate is acidified with ethanolie hydrochloric acid, while cooling, and then mixed viith diethyl ether. The 2-methyl-3-hydroxy-4-ethylarainomethyl5-methylthiomethyl-pyridine dihydrochloride obtained is filtered off with suction, washed with ether, dried and recrystallised from methanol/diethyl ether; m.p. 245°C. The product obtained is thin layer chromatographically pure. The yield is quantitative.
The same product is obtained in an analogous manner from 2-methyl-3-hydroxy-4-ethylideneaminomethyl-5-methylthiomethyl-pyridine (lib).
-5Example) 2.
19.7 β. 2-methyI-3-hydroxy-4-forniyl-5-methylthiomethyl-pyridine are dissolved in 200 ml. ethanol, 20 ml. ethylamine are added thereto and the reaction mixture is boiled briefly. After cooling, a further 6 ml. ethylamine are added thereto. The reaction mixture is then evaporated, the crude IXa obtained is dissolved in 100 ml. ethanol and
3.7 g. sodium borohydride are introduced portionwise, while cooling, whereafter the reaction mixture is worked 10 up analogously to Example 1 to give I-dihydrochloride;
m.p. 245°C.
The same compound is obtained by the reaction of
2-methyl-3-hydroxy-4-aminomethyl-5-methylthiomethylpyridine with acetaldehyde and subsequent reduction of l5 the crude lib obtained.
Example 3.
19.7 g. 2-methyl-3-hydroxy-4-forrnyl-5-methylthiomethyl-pyridine and 26 ml. ethylamine are dissolved in 200 ml. methanol, followed by boiling for 15 minutes.
2o The reaction mixture is then evaporated and the crude
Ila obtained is dissolved in 650 ml. acetic acid. 32.5 g. zinc dust are added thereto over the course of 5 minutes.
The reaction mixture is heated to 70°C. and then oooled to 40°C. and a further 32.5 g. zinc dust added, whereafter 25 it is again heated to 70°C., then cooled to 40°C. and a further 32.5 g. zinc dust added. After brief heating to 50°C., the reaction mixture is cooled, filtered and the filtrate evaporated, acidified with ethanolic hydrochloric
- acid and the I-dihydrochloride obtained after the addition 30 of diethyl ether, filtered off with suction and recrystallised from methanol/diethyl ether; m.p. 245°C.
-641740
The same compound is obtained by the reaction of 2-methyl-3-hydroxy-4-aminomethyl-5-methylthiomethylpyridine with acetaldehyde and subsequent reduction of the crude lib obtained.
Example 4.
197 g. 2-methyl-3-hydroxy-4-formyl-5-methylthiomethyl-pyridine are dissolved in 2000 ml. methanol, 195 g ethylamine are added thereto and the reaction mixture is boiled for a few minutes, then cooled and a further 60 g.
lo ethylamine added thereto. The solution so obtained is hydrogenated in the presence of 40 g. Raney nickel at 3 ats. pressure and 20°C. for 3 hours. The reaction mixture is then filtered and the filtrate is evaporated and worked up analogously to Example 1 to give a quantit15 ative yield of I-dihydrochloride; m.p. 245°C·
The same compound is obtained by the reaction of
2-methyl-3-hydroxy-4-aminomethyl-5-methylthiomethylpyridine with acetaldehyde and subsequent reduction of the crude lib obtained.
Claims (23)
1. What we claim is :1. A process for the preparation of
2. -methyl-
3. -hydroxy4-ethylaminomethyl-5-methylthiomethyl-pyridine, wherein a pyridine derivative of the general formula:- in which R signifies -GH=IJ-0H 2 - or -CH 2 -N=0H-, or a salt thereof, is reacted with sodium borohydride or with zinc and an acid or with hydrogen in the presence of Raney nickel. lo 2. A process according to claim 1, wherein the reaction with sodium borohydride is carried out in an inert solvent. 3· A process according to claim 2, wherein the inert solvent is water and/or an alcohol.
4. A process according to claim 3, wherein the alcohol 15 is methanol or ethanol.
5. A process according to any of the preceding claims, wherein the reaction with sodium borohydride is carried out at a temperature of from 0 to 50°C.
6. A process according to claim 5, wherein the reaction 20 with.sodium borohydride is carried out at a temperature of from 10 to 30°G.
7. A process according to claim 1, wherein the zinc is used in the form of zinc dust.
8. A process according to claim 1 or 7, wherein the 25 acid used is an aliphatic carboxylic acid containing up to 4 carbon atoms or a mineral acid. -841740
9. A prooess according to claim 8, wherein the acid used is formic aoid, acetic acid, propionic acid, butyric acid, hydrochloric acid or sulphuric acid.
10. A prooess according to any of claims 1 and 7 to 9, 5 wherein the reaction with zinc is carried out at a temperature of from 20 to 100°0.
11. A process according to claim 10, wherein the reaction with zinc is carried out at a temperature of from 40 to 70°C. lo
12. , A process according to claim 1, wherein the hydrogenation using Raney nickel is carried out in an acid, neutral or basic medium.
13. A process according to claim 12, wherein the hydrogenation is carried out in an inert solvent. ls
14. A process according to claim 13, wherein the inert solvent is an alcohol, an ester, a carboxylic aoid or an ether.
15. A process according to any of claims 1 and 12 to 14, wherein the hydrogenation is carried out at a temperature 20 of from -20 to +150°C.
16. A process according to claim 15, wherein the hydrogenation is carried out at a temperature of from ambient temperature to +100°C.
17. A process according to any of claims 1 and 12 to 16, 25 wherein the hydrogenation is carried out at a pressure of from 1 to 100 ats.
18. A process according to claim 17, wherein the hydrogenation is carried out at a pressure of from 1 to 10 ats.
19. A process according to any of the preceding claims, 30 wherein the pyridine derivative used as starting material 941740 is prepared in. situ from an appropriate aldehyde and an appropriate amine and further reacted without isolation.
20. A process according to any of the preceding claims wherein, when the product is obtained in the fora of a 5 base, it is reacted with an inorganic or organic acid to give a physiologically-compatible salt. .
21. A process according to any of claims 1 to 19, wherein, when the product is obtained in the form of a salt, it is reacted with a strong base to give the free θ pyridine base.·
22. A process according to any of the preceding claims substantially as hereinbefore described and exemplified.
23. 2-Methyl-3-hydroxy-4-ethylaminomethyl-5-methylthiomethyl-pyridine and the acid-addition salts thereof, 5 whenever prepared by the process according to any of claims 1 to 22.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742447053 DE2447053A1 (en) | 1974-10-02 | 1974-10-02 | PROCESS FOR THE PRODUCTION OF A SULFUR-CONTAINING PYRIDINE DERIVATIVE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE41740L IE41740L (en) | 1976-04-02 |
| IE41740B1 true IE41740B1 (en) | 1980-03-12 |
Family
ID=5927359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2148/75A IE41740B1 (en) | 1974-10-02 | 1975-10-01 | Preperation of a sulphur-containing pyridine derivative |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5141364A (en) |
| AT (1) | AT350568B (en) |
| BE (1) | BE833984A (en) |
| CA (1) | CA1068710A (en) |
| CH (1) | CH602650A5 (en) |
| CS (1) | CS188253B2 (en) |
| DE (1) | DE2447053A1 (en) |
| DK (1) | DK442975A (en) |
| ES (1) | ES441425A1 (en) |
| FR (1) | FR2286818A1 (en) |
| GB (1) | GB1461068A (en) |
| IE (1) | IE41740B1 (en) |
| LU (1) | LU73493A1 (en) |
| NL (1) | NL7511253A (en) |
| SE (1) | SE7511011L (en) |
| YU (1) | YU247075A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5843271B2 (en) * | 1977-05-02 | 1983-09-26 | 凸版印刷株式会社 | Decorative material manufacturing method |
| JPS56127484A (en) * | 1980-03-12 | 1981-10-06 | Toppan Printing Co Ltd | Manufacture of facing material having remarkable cubic effect |
| JP2668591B2 (en) * | 1990-03-30 | 1997-10-27 | 日本デコール株式会社 | Manufacturing method of decorative sheet |
| JP4046253B2 (en) | 1998-05-20 | 2008-02-13 | 大日本印刷株式会社 | Synchronized embossed decorative sheet and method for producing the same |
| JP4268261B2 (en) | 1999-05-12 | 2009-05-27 | 大日本印刷株式会社 | Cosmetic material and method for producing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH61A (en) * | 1889-01-08 | Grusonwerk Ag | Clamping device for cannons | |
| US2540946A (en) * | 1947-12-18 | 1951-02-06 | Merck & Co Inc | Pyridoxal-histamine and processes for preparing the same |
-
1974
- 1974-10-02 DE DE19742447053 patent/DE2447053A1/en not_active Ceased
- 1974-11-18 JP JP49132109A patent/JPS5141364A/ja active Pending
-
1975
- 1975-09-24 NL NL7511253A patent/NL7511253A/en not_active Application Discontinuation
- 1975-09-29 GB GB3973975A patent/GB1461068A/en not_active Expired
- 1975-09-29 BE BE7000717A patent/BE833984A/en not_active IP Right Cessation
- 1975-09-30 FR FR7529902A patent/FR2286818A1/en active Granted
- 1975-09-30 AT AT746775A patent/AT350568B/en not_active IP Right Cessation
- 1975-10-01 CA CA236,795A patent/CA1068710A/en not_active Expired
- 1975-10-01 YU YU02470/75A patent/YU247075A/en unknown
- 1975-10-01 CS CS756634A patent/CS188253B2/en unknown
- 1975-10-01 DK DK442975A patent/DK442975A/en unknown
- 1975-10-01 IE IE2148/75A patent/IE41740B1/en unknown
- 1975-10-01 LU LU73493A patent/LU73493A1/xx unknown
- 1975-10-01 CH CH1274375A patent/CH602650A5/xx not_active IP Right Cessation
- 1975-10-01 SE SE7511011A patent/SE7511011L/en unknown
- 1975-10-02 ES ES441425A patent/ES441425A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH602650A5 (en) | 1978-07-31 |
| LU73493A1 (en) | 1977-05-24 |
| ATA746775A (en) | 1978-11-15 |
| NL7511253A (en) | 1976-04-06 |
| JPS5141364A (en) | 1976-04-07 |
| CA1068710A (en) | 1979-12-25 |
| CS188253B2 (en) | 1979-02-28 |
| IE41740L (en) | 1976-04-02 |
| DE2447053A1 (en) | 1976-04-08 |
| DK442975A (en) | 1976-04-03 |
| FR2286818B1 (en) | 1979-01-05 |
| ES441425A1 (en) | 1977-07-01 |
| SE7511011L (en) | 1976-04-05 |
| GB1461068A (en) | 1977-01-13 |
| AT350568B (en) | 1979-06-11 |
| BE833984A (en) | 1976-03-29 |
| YU247075A (en) | 1982-05-31 |
| FR2286818A1 (en) | 1976-04-30 |
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