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
Links
- 150000003222 pyridines Chemical class 0.000 title claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title 1
- 239000005864 Sulphur Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 9
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 9
- 239000011701 zinc Substances 0.000 claims abstract description 8
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 5
- VGWRNXUFWFDSCH-UHFFFAOYSA-N 4-(ethylaminomethyl)-2-methyl-5-(methylsulfanylmethyl)pyridin-3-ol Chemical compound CCNCC1=C(CSC)C=NC(C)=C1O VGWRNXUFWFDSCH-UHFFFAOYSA-N 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- -1 pyridine compound Chemical class 0.000 description 5
- HVEICIWLYSSSDN-UHFFFAOYSA-N 4-(aminomethyl)-2-methyl-5-(methylsulfanylmethyl)pyridin-3-ol Chemical compound CC1=NC=C(C(=C1O)CN)CSC HVEICIWLYSSSDN-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 229960000443 hydrochloric acid Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- RADLENWZROEWLP-UHFFFAOYSA-N 3-hydroxy-2-methyl-5-(methylsulfanylmethyl)pyridine-4-carbaldehyde Chemical compound CC1=NC=C(C(=C1O)C=O)CSC RADLENWZROEWLP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ABHXVRQHPLALCY-UHFFFAOYSA-N 4-(ethyliminomethyl)-2-methyl-5-(methylsulfanylmethyl)pyridin-3-ol Chemical compound CC1=NC=C(C(=C1O)C=NCC)CSC ABHXVRQHPLALCY-UHFFFAOYSA-N 0.000 description 1
- NJNQLQVJRHTLGM-UHFFFAOYSA-N 4-[(ethylideneamino)methyl]-2-methyl-5-(methylsulfanylmethyl)pyridin-3-ol Chemical compound CC1=NC=C(C(=C1O)CN=CC)CSC NJNQLQVJRHTLGM-UHFFFAOYSA-N 0.000 description 1
- AIYWGDYVMBTAHH-UHFFFAOYSA-N 4-[2-(ethylamino)ethyl]-2-methyl-5-(methylsulfanylmethyl)pyridin-3-ol Chemical compound CCNCCC1=C(CSC)C=NC(C)=C1O AIYWGDYVMBTAHH-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- 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 BE BE7000717A patent/BE833984A/en not_active IP Right Cessation
- 1975-09-29 GB GB3973975A patent/GB1461068A/en not_active Expired
- 1975-09-30 AT AT746775A patent/AT350568B/en not_active IP Right Cessation
- 1975-09-30 FR FR7529902A patent/FR2286818A1/en active Granted
- 1975-10-01 CH CH1274375A patent/CH602650A5/xx not_active IP Right Cessation
- 1975-10-01 LU LU73493A patent/LU73493A1/xx unknown
- 1975-10-01 CA CA236,795A patent/CA1068710A/en not_active Expired
- 1975-10-01 SE SE7511011A patent/SE7511011L/en unknown
- 1975-10-01 YU YU02470/75A patent/YU247075A/en unknown
- 1975-10-01 IE IE2148/75A patent/IE41740B1/en unknown
- 1975-10-01 DK DK442975A patent/DK442975A/en unknown
- 1975-10-01 CS CS756634A patent/CS188253B2/en unknown
- 1975-10-02 ES ES441425A patent/ES441425A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| LU73493A1 (en) | 1977-05-24 |
| YU247075A (en) | 1982-05-31 |
| CH602650A5 (en) | 1978-07-31 |
| FR2286818A1 (en) | 1976-04-30 |
| FR2286818B1 (en) | 1979-01-05 |
| CA1068710A (en) | 1979-12-25 |
| DK442975A (en) | 1976-04-03 |
| DE2447053A1 (en) | 1976-04-08 |
| AT350568B (en) | 1979-06-11 |
| JPS5141364A (en) | 1976-04-07 |
| CS188253B2 (en) | 1979-02-28 |
| SE7511011L (en) | 1976-04-05 |
| ATA746775A (en) | 1978-11-15 |
| BE833984A (en) | 1976-03-29 |
| NL7511253A (en) | 1976-04-06 |
| GB1461068A (en) | 1977-01-13 |
| ES441425A1 (en) | 1977-07-01 |
| IE41740L (en) | 1976-04-02 |
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