IE39896L - Pyridine derivatives - Google Patents

Pyridine derivatives

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Publication number
IE39896L
IE39896L IE741220A IE122074A IE39896L IE 39896 L IE39896 L IE 39896L IE 741220 A IE741220 A IE 741220A IE 122074 A IE122074 A IE 122074A IE 39896 L IE39896 L IE 39896L
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IE
Ireland
Prior art keywords
compound
methyl
formula
hydroxy
preparing
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IE741220A
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IE39896B1 (en
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Merck & Co Inc
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Publication of IE39896L publication Critical patent/IE39896L/en
Publication of IE39896B1 publication Critical patent/IE39896B1/en

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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
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    • 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
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    • 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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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
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    • C07D497/04—Ortho-condensed systems
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

1473591 Vinylic and acetylenic pyridines and their N-oxides MERCK & CO Inc 11 June 1974 [15 June 1973 18 April 1974 26 April 1974] 25858/74 Headings C2C and C2P The invention comprises novel compounds (I) and their pharmaceutically acceptable salts, in which m is 0 or 1; x is 0, 1, 2 or 3; A is or -C# C-, where R<SP>7</SP> is hydrogen, chlorine or fluorine; each of R<SP>1</SP> and R<SP>2</SP> is hydrogen or C 1-3 alkyl; R<SP>3</SP> is (a) hydrogen, (b) -SO 3 H, (c) -PO 3 H 2 , (d) amidino, (e) N-(C 1-4 alkyl) 2 , (f) -CH 2 CH(NH 2 )COOH, (g) ethoxycarbonylmethyl, (h) where E represents (1) adamantyl, (2) C 3-8 cycloalkyl, (3) C 1-5 alkoxy, (4) C 2-6 alkyl, (5) N- (C 1-4 alkyl) 2 , (6) phenyl, (7) 2-acetoxyphenyl, (8) 2 - hydroxy - 4 - (2,4 - difluorophenyl)- phenyl, (9) 3 - chloro - 4 - allyloxybenzyl, (10) α - methyl - 4 - isobutylbenzyl, (11) α- methyl - 3 - phenoxybenzyl, (12) α - methyl - 3- benzoylbenzyl, (13) 1 - (6 - methoxynaphth - 2- yl)ethyl, (14) α - methyl - 3 - fluoro - 4 - phenylbenzyl, (15) 2 - (3 - chloro - 4 - cyclohexylbenzoyl)ethyl, (16) 2 - (3 - trifluoromethylanilino)phenyl, (17) 2 - (2,3 - dimethylanilino)- phenyl, (18) 2 - (2,6 - dichloro - 3 - methylanilino)phenyl, (19) 2 - (3 - trifluoromethylanilino - 3 - pyridyl, (20) 2 - (2 - methyl - 3- chloroanilino)-3-pyridyl, or (i) where G represents (1) C 1-4 alkoxy, (2) -S- (alkali metal) or (3) wherein L represents (1) -(CH 2 ) 1-5 -, (2) phenylene, or (3) (m) -S-R<SP>8</SP>, wherein R<SP>8</SP> represents (1) -C(CH 3 ) 2 CH(NH 2 )COOH, (2) C 1-5 alkyl, (3) C 2-5 alkenyl, (4) phenyl-C 1-3 alkyl, (5) phenyl, (6) C 2-5 alkynyl, (7) 2-carboxyphenyl, or (8) R<SP>4</SP> is hydrogen, C 1-3 alkyl, phenyl, chloro, carboxy, C 1-3 alkoxycarbonyl, fluoro; and R is (a) C 1-3 alkyl, (b) hydroxy, (c) (d) hydroxy-C 1-3 alkyl; and (e) when one R is hydroxy adjacent to the group, the oxygen and sulphur thereof may be joined together through a group of formula wherein R<SP>5</SP> and R<SP>5</SP>α are the same or different and each is hydrogen, C 1-6 alkyl, phenyl, dimethylphenyl, or difluorophenyl, or taken together, R<SP>5</SP> and R<SP>5</SP>α represent =O or =S. When R<SP>3</SP> is -SO 3 H and -PO 3 H 2 the compounds exist as internal salts (Ia) and (Ib) and cyclic isomers of certain of the compounds (I) are also described, e.g. as shown in the relationship between (Ic) and (Id) Many standard methods are described for preparing the novel compounds. In particular, 2- methyl - 3 - hydroxy - 5 - vinyl - 4 - pyridylmethylthio-phosphonic acid internal salt is made by acidifying sodium 2 - methyl - 3 - hydroxy - 5- vinyl - 4 - pyridylmethylthiophosphorothioate which is itself obtained by interacting trisodium phosphorothioate and 2-methyl-3-hydroxy - 4 - chloromethyl - 5 - vinylpyridine hydrochloride. Salts (of ylide type) from triphenylphosphine and 2-methyl-3-hydroxy-4- acetylthiomethyl - 5 - chloromethylpyridine, 2- methyl - 3 - hydroxy - 4 - mercaptomethyl - 5- chloromethylpyridine, bis - [2 - methyl - 3- hydroxy - 5 - chloromethylpyridin - 4 - methyl]- disulphide or 2 - methyl - 3 - acetoxy - 4- acetylthiomethyl - 5 - chloromethylpyridine are obtained by interacting triphenylphosphine and the stated pyridine compound. Pharmaceutical preparations having antiinflammatory action and especially suitable for treating rheumatoid arthritis contain (I) as active ingredient. Administration is orally, parenterally, rectally or topically. [GB1473591A]

Description

39896 This invention is concerned with novel mercaptoalkyl-pyridines and derivatives thereof carrying a nuclear unsaturated substituent, methods for their preparation, a method of treating non-human rheumatoid arthritis and related inflammatory diseases with the novel compounds and pharmaceutical compositions containing these novel compounds as active ingredient.
More particularly, the invention provides novel compounds of structural formula: 1 R x C SR 3 I i R 2 (0) m and theii pnarmaceutically acceptable salts, in which m is 0 3 9 8 9 G or 1; x is O, 1, 2 or 3; A is -C1I=C- or -CsC- , where R7 '7 R 1 2 is hydrogen, chlorine or fluorine; each of R and R is nydrogen or Cj_3 alkyl; R^ is (a) hydrogen, (b) -SOjH, (c) -PO^Hj, (d) amidino, 5 (c) -N(Cj__4 alkyl)2, (f) -ClIjCH (NH2) COOH, (g) ethoxycarbonylmethyl, O II (h) -C-K, where E represents (1) adamantyl, (2) cycloalkyl, (3) alkoxy, (4) C2_6 alkyl, (5) alkyl)2, (6) phenyl, (7) 2-acotoxyphcny1, I') (8) 2-hytlroxy-4-(2,4-tli-fluoroplii;nyl)phony 1, {')) 3- cliloro-4-allyloxybonzyl, (lO) <»-mcthyl-4-isobutyl-benzyl, (11) a-methyl-3-phenoxybenzyl, (12) a-methyl-3-benzoylbenzyl, (13) 1-(6-methoxynaphth-2-yl)ethyl, (14) cx-methyl-3-fluoro-4-phenylbenzyl, (15) 2-(3-15 chloro-4-cyclohexylbenzoyl)ethyl, (16) 2—(3— trifluoromethylanilino)phenyl, (17) 2-(2,3- dimethyl-anilinojphenyl, (18) 2-(2,6-dichloro-3-methylanilino)-phenyl, (19) 2-(3-trifluoromethylanilino-3-pyridyl, (20) 2-(2-methyl-3-chloroanilino)-3-pyridyl, or o 1 11 (i) -C-S- j— Rx, (j) -CMIICII2C02(C1_4 alkyl) 20 S II (k) -C-G, where G represents (1) C^_4 alkoxy, - 3 - 39896 (2) -S(alkali metal) or ^1 A-R4 O II (1) -C-(L) O or 0 Rl l-"-S4"^+- V wherein L I2 j, (0)m represents (1) -(Cl^)^-, (2) phenylene, or / \ Q Q (3) ~N^ ^N-, (m) -S-R , wherein R represents (1) -C(CH3)2CH(NH2)COOH, (2) C1-5 alkyl, (3) C2_5 alkenyl, (4) phenyl-C^_.j alkyl, (5) phenyl, (6) C2-5 alkynyl, (7) 2-carboxy-phenyl, or (8) CH2OH 10 R A-R4 (n) -S-C N ■ R2 X (0)m Rx. (o)-(S)1_3-C - 4 - 39896 (p) -CNH2 ; 4 R is hydrogen, alkyl, phenyl, chloro, carboxy, alkoxycarbonyl, fluoro; and R is (a) alkyl, (b) hydroxy, O (c) -O-C-E , (d) hydroxy-C^_2 alkyl; and (e) when one R is hydroxy adjacent to the R1 I -C-SH group, the oxygen and sulfur I R2 lo thereof may be joined together through a group of formula: „5 C R5 a wherein R"* and R~* are the same or different and a each is hydrogen, C^_g alkyl, phenyl, dimethyl-15 phenyl, or difluorophenyl, or taken together, R"* and R^ represent =0 or =S.
A preferred embodiment of this invention is th^ 4 compound described above wherein the -AR group and the R1 I 3 -C-SR group are alternatively in the 4 and 5-positions la Rz - 5 - 39896 of the pyridine ring.
A still more preferred embodiment is the compound of structural formula: A-R and especially wherein A-R represents -CH=C".12> R represents hydroxy or C2_fi alkanoyloxy, and R3 represents hydrogen, -S03H, C2_6 alkanoyl, or A-R or a pharmaceutically acceptable salt thereof. 10 Of particular importance are the compounds: 2-methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine; 2-methyl-3-acetoxy-4-acetylthiomethy1-5-vinylpyridine; 2-methyl-3-hydroxy-4-acetylthiomethy1-5-vinylpyridine; 2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethylthiosulfuric acid; 15 3-ethoxycarbonyloxy-4-ethoxycarbonylthiomethy1-2-methy1-5- vinylpyridine; and bis/2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl7disulfide or a pharmaceutically acceptable salt thereof. - 6 - 3 9 8 9 G In the above descriptions R3 has been defined in part as -SO^H and ~po3"2 to facilitate description. It is understood that molecules within these descriptions actually exist as internal salts, having structures such as R4-A R1 R4-A r1 I C — SPO^H and Rx -0- C sso3e N ^ | j| ^ R Bunte salt The Uunto salts, as well as having utility against rheumatoid .irlhrltls, are valuable intermediates in the synthesis oL the disulfides. Thus, these liunte salts form another embodiment of this invention.
Certain of the other compounds described above can and do exist as isomers and cyclic internal condensation products, for example: ho ch3 ch3 and such cyclic isomers are considered to be within the scope of the invention.
The pharmaceutically acceptable salts include those prepared from mineral and organic acids commonly used in the pharmaceutical art, such as hydrochloric, hydrobromic, sulfuric, nitric, maleic, fumaric, tartaric or succinic acids as well as alkali metal salts of the mercaptans, and the thiophosphoric acid and thiosulfuric acid analogues described above, and divalent metallic complexes. 3 9 8 0 G It is well known that the mercapto group is subject to reaction with aldehydes and ketones t® form hemimercaptals and hemimercaptoles. It is similarly known. Field el al., J. Med. Chem. 12, 624-628 (1969) that many of these hemimer-5 captals and hemimcrcaptolcs prepared from biologically activc incrcaptans servo as "latcntiating" derivatives, or as chemical modifications of biologically active compounds to form new compounds, which upon in vivo enzymatic or chemical transformation will liberate the parent compounds. Latentiation may lO also provide means of favorably influencing absorption, transport, distribution, localization, metabolism, toxicity, and duration of action, as well as stability. Included with the group of aldehydes and ketones suitable for this purpose arc chloral, hexafluoro-acetone, acetone, benzaldehyde, 15 pyruvate, and ketomalonate. Since latentiation of mercapto groups by this means is known in the art, these latentiating derivatives are considered to be within the scope of the novel method of treatment and novel compounds of this invention.
Another means of latentiation is by addition of the 20 thiols of this invention to a,B-unsaturated acids such as maleic acid and cinnamic acid as described by Srivistava et al., in J. Med. Chem., lj>, 428-429 (1973).
Latentiation may also be achieved by substitution of the mercapto hydrogen with a l-methyl-4-nitroimidazol-5-yl 25 group, as in azathioprine, or a pivaloyloxymethyl group.
In spite of the extensive antiinflammatory research in the past two decades, there is still an obvious need for an effective and well tolerated agent for the treatment of rheumatoid arthritis. Conventional non-steroidal antiinflam-30 matory-analgesic-antipyretic agents, such as aspirin and many - 8 - 3 9 8 9 G experimental new drugs under clinical evaluation, are mostly effective in providing symptomatic relief of the acute syndrome only. As a consequence, the anti-rheumatic actions of two old remedies, viz. gold and D-penicillamine, in spite of their potential side-effects, have received renewed interest in the past few years. The clinical efficacy of both drugs was reconfirmed by well-controlled multi-center clinical studies. Several rheumatologists have expressed the opinion that a superior D-penicillamine-like compound would be a valuable contribution to medicine in this important field.
Novel mercaptoalkyl pyridines falling within the scope of Formula I have been found to possess an important degree of anti-rheumatoid arthritis activity. In accordance with the present invention, rheumatoid arthritis and related inflammatory diseases are treated in non-human animals by the administration of an effective amount of a compound of Formula I. For this purpose the compound may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal, intraarticular, injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, compounds of the invention have been found to be effective in the treatment of humans.
The pharmaceutical compositions containing the compound of the present invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions :i a 8 a (> intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more sweetening agents, flavoring agents, coloring agents and/or 5 preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert lO diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic 15 acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl 20 distearate may be included.
Formulations for oral use may also be presented as hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules in 25 which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active mater.als in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, 30 for example sodium carboxymethylcellulose, methylcellulose, - lO - 3 9 8 9 8 hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, which may be a naturally-occurring phosphatide, for example lecithin, condensation products of an alkylene 5 oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols, for example hcptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene lO sorbitol moi.o-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan mono-oleato. The said aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl £-15 hydroxy benzoate, one or more coloring agents, one or more flavoriny agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, 20 oilve oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a Ihiekenlinj agent, for ex.unple beeswax, hard paraffin or cctyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral 25 preparation. These compositions may be preserved by the addition of an anti-oxidant such as as;cor5>ic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or 30 wetting agent, suspending agent and one or more preservatives. - 11 - Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan mono-oleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents are water, Ringer's solution, isotonic sodium chloride - 12 - 39800 solution, and sterile fixed oils, including synthetic mono-glycerides or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, containing the anti-inflammatory agents are used.
Dosage levels of from 0.5 mg. to 140 mg. per kilogram of body weight per day arc useful in the treatment of the above-indicated conditions (25 mg. to 7 gms. per patient per day). For example, inflammation is effectively treated and antipyretic and analgesic activity manifested by the administration of O.l to SO my, preferably 1 mg to 15 mg, of the compound per kilogram of body weight per day (5 mg to 3.5 gms, and preferably 50 mg to 1 g per patient per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from 5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from 25 mg to 500 mg of active ingredient.
It 9 8 9 6 It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound, the age, body weight, general health, sex, diet, time of adminis-5 tration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The novel compounds of this invention are generally prepared from known pyridine derivatives. 10 The method of preparation will depend upon the nature of the substituents in the final product desired.
Thus, when R3 is to be -SO^H, the compounds are prepared by reacting a compound of general formula: 1 0 A 15 in which m, x, A, R, R , R , R and Q are as defined herein with sodium thiosulfate.
This product can be further treated to produce other compounds of the present invention. Thus, treatment of a compound in which R3 is -SO^H 20 (a) with an alkali metal hydroxide and a compound of formula 8 3 ft ft R SH produces a compound in which R is -SR , where R is as defined above; (b) with a reducing agent produces a compound in which R3 is hydrogen; - 14 - 3 9 8 9 U (c) treatment (1) with an alkali metal hydroxide, optionally in the presence of a compound of formula: 'm (2) with a mineral acid. (3) with Na2S or Na2S2» (4) with iodine, produces a compound in which R3 is: 12 d in which m, x, A, R, R , R and R* are as defined above, the lo values depending on the starting material and nature or reagents used to effect tho reaction.
To produce a compound in which R3 is -CS-SMe or 12 4 in which Me is an alkali metal and x, A, R, R , R and R are 15 as defined above, a compound having the formula (A) set forth above is reacted with an alkali metal trithloc.jrbon.it'-. - 15 - 3 9 8 9 G If the resulting product is reacted with an alkali or an acid, a compound in which R3 is hydrogen results.
A compound in which R3 is hydrogen can also be prepared by reaction of a compound having formula (A) (1) with thiourea or a potassium C1-4 alkyl xanthogenate, followed by an alkali metal hydroxide or a reducing agent; (2) with a potassium thioacyloate followed by an alkali; or (3) with an alkali metal hydrosulfide; or by reduction of a compound in which R3 is l°>m ■» jk in which m, x, A, R, R , R and R are as defined above. The latter compounds can be produced not only by the methods indicated above but also by reaction of a compound of formula (A) with (1) thiourea, followed by an alkali metal hydroxide and an oxidizing agent; (2) a potassium alkyl xanthogenate, followed by ammonium hydroxide, or by ammonium hydroxide and an oxidizing agent; or (3) Na2S2; or by reaction of a compound of general formula: - 16 - 3 0 8 !) g (B) 1 2 in which the CR R Oil substitucnt is in the 2, 4 or 6 position and the OH group is adjacent to it and A, R, R*, R2, R4, x and m are as defined above, with P2S5* 5 Reaction of a compound of Formula (A) (1) with trisodium phosphorothioate and a mineral acid results in a compound in which R3 is -PO^^; (2) with a potassium thioacyloate results in a compound in which R3 is acyl; l<) (3) with ethyl mercaptoacetatc results in a compound in which R3 is ethoxycarbonylmothy1; (4) with cysteine results in a compound in which R3 is g-carboxy-B-aminoethyl.
Reaction of a compound of Formula (B) above with carbon 15 disulfide and an alkali metal hydroxide results in a compound in which R3 is hydrogen.
When Q in the compound of Formula (A) is mercapto, the compound can be reacted (1) with cyanogen bromide and a di(C^_4 alkyl)amine to 20 produce a compound in which R3 is alkyl)2; (2) vith a compound of formula ii-CO'Cl, K-COMir or (li• CO) 20 to producc a compound in which R3 is -COli, where K is as defined above; (3) with phosgene to produce a compound in which R is - 17 - 39806 12 4 in which A, R, R , R , R , x and ra are as defined above; (4) with phosgene and a alkyl aminoacetate to produce a compound in which R3 is N-^C^ alkoxy) carbonyl7~ methylcarbamoyl; (5) with phosgene and ammonia to produce a compound in which R3 is carbamoyl; (6) with a compound of formula Cl-CO-L -C0-C1 or Br- z CO-Lz~CO-Br to produce a compound in which R3 is 10 12 4 in which A, R, R,R,R,x and m are as defined above and L is -(C^Jy (where y is an integer from 1 to 5), phenylene or 1,4-piperazindiyl and z is O or 1; (7) with o-carboxyphenyl o-carboxybenzenethiolsulfonate 15 to produce a compound in which R3 is 2-carboxyphenylthio; (8) with thiamine-S-monooxide to produce a compound in which R3 is 18 - 3 9 8 9 G ch. ch, ch2oh (9) with sulfur dichloride and sulfur monochloride to 3 . produce a compound in which R is „1 a-r -(S>w— ? 12 4 In which A, R, R , K , R , x and in ;in; as doflneil above anil w is 2 or 3; or (10) with an oxidizing agent to produce a compound in which R3 is -s-c 10 A in which m, x, A, R, R , R and R are as defined above. - 19 - 3 9 8 9 G The present invention also provides a method of preparing a compound of general formula: .5 .S \ l(x-l) or a pharmaceutically acceptable salt thereof, in which A, R, R*", R2, R4, R"*, R^, x and m are as defined above and the ends of the oxamethylcnethiamethylene chain are attached to adjacent carbon atoms of the pyridine ring, that comprises reacting a compound of formula: (x-1) 10 in which the hydroxy and mercaptomethyl groups are attached to adjacent carbon atoms of the pyridine ring with a compound of 5 5 5 5 formula R^-CO-R when R and R^ are separate or with phosgene or thiophosgene. - 20 - 3 9 8 9 G Preferred compounds in accordance with the present invention are prepared by appropriate choice of reagent. Thus, 2-methyl-3-hydroxy-4-raercaptomethyl-5-vinylpyridine and its pharmaceutically acceptable salts are prepared 5 (a) by treating a compound of formula: in which R*^ is hydrogen or C2-6 a^'canoyl» (i.e. a 2-meth/l-3-(hydroxy or C2_g alkanoyloxy)-4-hydroxyinethyl-5-viny1-pyridine), with CS2 and alkali; or lO (b) by treating a compound of formula: or Il2SCO(C1_4 alkyl) H=CH„ 21 3 9 8 9 6 in which is as defined above with an alkali or a reducing agent.
The 2-methy1-3-(hydroxy or C2_g alkanoyloxy)-4-hydroxy-methyl-5-vinylpyridine is itself prepared by reducing a 5 compound of formula: or a /2-methy1-3-(hydroxy or C2_6 alkanoyloxy)-5-vinyl-4-pyridyi7" A compound of structural formula: O O II II CH2 S C (L)0 or 1 C s CI12 H_C=HC ^ OH XX ch3 or a pharmaceutically acceptable salt thereof, where h is 10 -(CH2)i_5~ phenylene, or 1,4-piperazindiyl is prepared by treating 2-methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine with a compound of formula X'.C0.{L)^ Qr ^.CO.X' where each X' is chlorine or bromine.
Practical methods of carrying out the various processes 15 of the present invention will now be set forth. - 28 - 3989 (i Where the final product has a free a-mercaptoalkyl group in 2, 4 or 6 position and is adjacent to a hydroxy1 substituent such as in 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, it is readily formed by dissolving the corresponding a-hydroxyalkyl compound in a Cj_5 alkanol, preferably ethanol, containing an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, treating the solution with carbon disulfide and heating for 2-8 hours at a temperature from 50°C. to reflux, followed by acidification of the cooled mixture. Isolation is accomplished by standard techniques such as concentration to dryness and extraction with a solvent.
An alternative procedure for producing a free >»-mercaptoalkyl group irrespective of its location on the pyridine nucleus is the removal of protective groups from a preformed thio compound. For example, S-acyl compounds, such as the S-benzoyl, .ire converted to the free mercapto by recognized hydrolytic procedures, for example by saponification with dilute alkali at from room temperature to 75°C.
The mercaptoalkyl group in any position may also be prepared by first converting the corresponding hydroxyalkyl group to the chloromethyl or bromoethyl by heating at from 50°C. to reflux temperature for 1-4 hours with thionyl chloride or with concentrated hydrobromic acid respectively. The resulting halo methyl compound is then treated in one of two alternative procedures. (a) The halomethyl compound in aqueous solution is treated with a alkyl alkali metal xanthogenate, such as ethyl potassium xanthogenate, at 5-10°C. for 1-4 days, and l.ho xantliaLo product is oxtracted with a solvent such as ether - 29 - 39896 and reduced with lithium aluminium hydride or sodium boro-hydride. Alternatively, the xanthate can be converted to mercapto by heating at 50°C. to reflux with aqueous alcoholic alkali such as sodium or potassium hydroxide. (b) The halomethyl compound is heated in a alkanol such as methanol, with thiourea at SO°C. to reflux for 1-4 hours. The isothioureide is then heated at 50°C. to reflux in water or a alkanol such as ethanol containing an alkali metal hydroxide such as sodium or potassium hydroxide, preferably in an inert atmosphere such as nitrogen. Alternatively, the thioureide may be reduced with lithium aluminium hydride or lithium borohydride as previously described.
The Bunte salts of the mercaptoalkyl compounds of this invention are prepared from the corresponding chloro- or bromomcthyl compounds and sodium thlosulfate in aqueous alcohol by warming tho mixture at from SO°C. to reflux for a period ot from a few minutes to 2 hours.
These Bunte salts, as well as being useful in the novel method of treatment, find utility as an intermediate compound in producing the disulfides, both symmetrical and unsymmetrical, and also to the free mercaptomethyl compoii-.ds.
The mercaptomethyl compounds are obtained from the Bunte salts by reduction with lithium aluminium hydride or sodium borohydride at -10° to 10°C. in an inert organic solvent, such as tetrahydrofuran or mixtures of tetrahydrofuran and ether.
Disulfides are obtained from the Bunte salts by mixing at 20-100°C. approximately molar equivalents of a Bunte salt and a sulfhydryl compound such as penicillamine or an alkyl-mercaptan, or a mercaptomethyl pyridine of this invention such as 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, with - 30 - 3 U 8 D (> an aqueous alkali metal hydroxide such as sodium or potassium hydroxide.
Alternatively, a Bunte salt, such as that of 2-methyl-3-hydroxy-4-raercaptomethyl-5-vinylpyridine, is converted to 5 the symmetrical disulfide such as bis^7-methyl-3-hydroxy-5- vinylpyridyl-4-methyf7disulfide by various procedures: (a) by treating it with aqueous alkali or dilute mineral acid at 20-100°C.; (b) by treating it with Na2S2 in an aqueous alkanol at 20-100°C. for 3-24 hours; (c) by treating it with Na2S in lO an aqueous alkanol at 20-100°C. for a period of a few minutes to 4 hours; or (d) by treating it with iodine at ambient temperature in an aqueous alkanol for 8-24 hours.
Another procedure for obtaining symmetrical disulfides such as bis^3:-methyl-3-hydroxy-5-vinylpyridyl-4-methyr7di-15 sulfide is by treating a hydroxyalkyl compound such as 2-methyl- 3-hydroxy-4-hydroxymethylpyridine with phosphorus pentasulfide in a solvent such as pyridine at a temperature from 50°C to reflux for 2-10 hours followed by acidification and further heating for 1-4 hours. 20 A further procedure for obtaining symmetrical disulfides such as bis/2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl7di-sulfide is by treating an isothiuronium salt such as 2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl isothiuronium salt at a temperature of 10°C to room temperature with dilute aqueous 25 caustic alkali such as 5-15% (w/v) sodium hydroxide and aqueous hydrogen peroxide for .i period of ,-j f«:w minute:; to 2 hours.
Similarly, an Isothiuronium salt can be converted Lo .i disulfide by substituting sodium tetrathionate in the above reaction, followed by acidification to about pH 5-7. 30 Tho alkyl xanthogenates of this invention such as 2- - 31 - 39890 methyl-3-hydroxy-5-vinylpyridyl-4-methyl ethyl xanthogenate are also converted to disulfides by treatment with ammonium hydroxide and slow addition of hydrogen peroxide at 0°-15°C. in aqueous alkanolic solution for 1-5 hours. 5 An additional procedure for preparing the symmetrical disulfides of this invention such as bis^T-methyl-3-hydroxy-5-vinylpyridyl-4-methyl7disulfide is by treating a compound of formula: lO where Q is a facile leaving group such as chloro, bromo, iodo, inethanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy, with sodium sulfide (Na2S2>. The reaction is conducted in aqueous alkanol at about room temperature although temperature is not critical for 2-24 hours. 15 The disulfide dimers may also be prepared from the corresponding monomer xanthate by treating it for 12 hours to 4 days at room temperature with concentrated ammonium hydroxide.
Another method of preparing the disulfide dimers involves oxidation of the corresponding monomer by bubbling 20 air through a solution of the monomer in dilute ammonium hydroxide at 20-50°C. for 15-30 hours, or in an organic solvent at 20-50°c for periods of 1-4 days.
Alternatively, the monomer may be oxidized with a per- - 32 - 3380 G acid such as m-chloroperbenzoic acid, peracetic acid, perpht-halic acid, sodium hypochlorite, iodine, or hydrogen peroxide in aqueous solution at 0-15°C.
As well as being a final product, a disulfide is 5 frequently used as a convenient means of protecting the mer capto group while manipulating other functional groups on the molecule. In this case, the monomer is subsequently obtained by reduction. Useful reducing systems are lithium aluminium hydride in ether at room temperature for 1-20 hours; zinc in lO hydrochloric acid; zinc in acetic acid; and tin in hydrochloric acid.
Another type of derivative found useful both as a final product and as particularly useful protective groups because they tie up both a hydroxyl group and a vicinal hydroxymethyl 15 or mercaptomethyl, are cyclic ketals and acetals. They are prepared by treating, for example, a 3-hydroxy-4-mercapto-mcthyl compound with a carbonyl compound such as acetone or benzaldehyde saturated with hydrogen chloride at -5°C. to +5°C. for 2-6 hours. 20 A typical derivative is: 3 9 8 9 0 Where the desired product is in the form of its N-oxide, the oxygen must be introduced before the mercapto group, as the latter is subject to oxidation. The N-oxides are usually prepared by treating a pyridine-free base with 5 a peracid as m-chloroperbcnzoic acid at room temperature in an inert solvent such as chloroform, or methylene chloride for a period of 16-4 3 hours.
Another type of cyclic compound has the formula: lO where R^ and R^ taken together, represent =0 or =S. These cyclic compounds are prepared simply by adding phosgene or thiophosgene in an inert solvent such as pyridine benzene, chloroform or tetrahydrofuran to a solution of the free mercapto compound in a sim^ar solvent at -5 to +10°C. and 15 then leaving at room temperature overnight.
Certain other useful end products are considered as biological equivalents of the mercaptomethyl compounds.
One such is the thiophosphoric acid prepared by treating a chloroalkyl compound with trisodium phosphoro-20 thioate in aqueous solution at about 0°C. and leaving the mixture for 10-20 hours at 0-10°C. followed by acidification.
Another type of useful end product is the S-ester or carbamoyl compound. These are generally formed by treating the - 34 - 39800 mcrcaptoalkyl compound with an acylating compound such as a carboxylie anhydride or carboxylic chloride or a carbamoyl chloride in an inert organic solvent such as tetrahydrofuran with or without the presenco of an acid acceptor such as 5 pyridine or triethylamino or the pyridine nitrogen of the \ substrate itself. Where the substrate carries a free hydroxyl group as woll as the mercaptoalkyl group, it too may become acylated. However, by control of the amount of acylating agent, either the S-acyl or the 0,S-diacyl compound can be lo obtained. The reaction is conducted at room temperature to reflux temperature for 1 hour to 2 days.
Related acylating procedures conducted generally as described above for the normal acylation involves the use of reagents having dual acyl groups such as isophthaloyl 15 chloride, N,N'-dichlorcarbonylpiperazine, phosgene, oxalyl chloride, glutaryl chloride, succinyl chloride, or pentane-dicarbonyl chloride, which result in symmetrical dicarbo-thioates.
Phosgene is also a useful reagent for preparing S-20 carbamates. By using an excess of phosgene and adding a mercaptoalkylpyridine dropwise followed by evaporation of exccss of phosgene and treatment with an amino compound such as ammonia or an amino acid ester at room temperature for 3-24 hours. 25 The compounds, where R3 is - 35 - 39 896 12 -c-s-crr <°>m are prepared by treating a chloro- or bromoalkylpyridine with disodium trithiocarbonate in a alkanol at 10-50°C. for 1-6 hours. 5 Similarly prepared are compounds in which R3 is S II -C-S(alkali :netal). In this case the solvent is preferably an aqueous alkanol, and an excess of the alkali metal trithiocarbonate is used. After adjustment of the pH to 6.2-6.5 with dilute acid, the product precipitates. 10 Another type of useful end product is a sulfenamide of formula: r2 » I ri-C-SN(C1_4 alkyl)2 These are prepared by treating the mercaptoalkyl compounds with thiocyanogen in an inert solvent such as ether. The resulting - 36 - 39896 precipitate is then treated with di(C^_4 alkyl) amine for 1/2 to 3 hours.
Related to the previously described disulfides is the disulfide represented by the partial structural formula: coon This compound is prepared by treating a mcrcaptoalkyl compound witJi o-ciirboxyphcnyl o-carboxybcnzcnethlol-sulfonate in a C^_,. .tik-inol for 4-24 hours at 10-50°C.
An alternative procedure for the preparation of S-acyl compounds is by treatment of a corresponding halomethyl compound with an alkali metal thioacyl compound such as potassium thiobenzoate in an inert solvent such as an aqueous alkanol at a temperature from room temperature to 100°C. for 1/2 to 3 hours.
Another novel unsymmetrical disulfide is that prepared from a mercaptoalkyl compound of this invention and thiamine-S-monoxide by suspending the latter in water and adding the former slowly with stirring. After 1/2 or 3 hours at a temperature of from room temperature to 50°C., the mixture is filtered, and the product is extracted from the filtrate.
The compounds in which R3 is -CH2C02Et and -Cl^CHtNH)-CO2II are prepared by treating a bromo- or chloromethyl-pyridine with ethyl mercaptoacetate or cysteine respectively in a C^_^ alkanol and in the presence of a strong base such as a sodium alkoxide in sufficient quantity both to react with - 37 - 39890 any acidic functional groups such as a nuclear hydroxyl on the pyridine ring or the carboxyl group of cysteine and to neutralize the HBr or IIC1 produced in the condensation reaction. 5 As well as the disulfides described above, polysulfides, particularly the tri- and tetra- sulfides, are a further embodiment of this invention. They are prepared by forming an alkali metal salt of the sulfhydryl group by treating one of the mercaptomethyl pyridines of this invention in an aprotic lO solvent such as dimethyl foimaraide or dimethyl sulfoxide with an alkali metal hydride such as sodium hydride or an alkali metal organic compound such as n-butyl lithium or sodium phenyl, at -1G°C. to +10°C., followed by treatment of the alkali metal sulfide with sulfur dichloride (SC^) or sulfur 15 monochloride (S2CI2) for 5-24 hours. The reaction is quenched by addition of water and the trisulfide or tetrasulfide respectively is isolated by extraction.
If the mercaptoalkyl compound in the above reaction carries a free hydroxyl or other functional group that could 20 participate in reaction with the reagents, it is advisable to protect it with a standard blocking group such as benzyl.
The novel compounds of this invention also carry an alkenyl or alkynyl substituent. The alkenyl is generally prepared from the corresponding formylpyridine by means of u 25 standard Wittig reagent, for example, triphenylmethylphosp- honium bromide in the presence of a strong base such as sodium hydride in a solvent such as dimethyl sulfoxide. The reaction is best conducted in the cold, below about 25°C. followed by leaving at room temperature for prolonged periods 30 such as 1-3 days or by heating at temperatures of 40-90°C. - 38 - 3 9 8 9 G for 1 to 7 hours.
Where the vinyl substituent carries more than one halo substituents, reactions related to the Wittig reaction are used which involve preparation of the Wittig reagent in situ. Por example, the dichlorovinyl and chlorofluorovinyl groups are introduced by treating a pyridine aldehyde with a mixture of triphenylphosphine, potassium t-butoxide and chloroform or dichlorofluoromethane at 40-50°C. for 2-7 hours. The difluorovinyl analog is prepared by treating the pyridineal-dehyde with triphenylphosphine and sodium chlorodifluoro-acetate in monoglyme or diglyme at 60-lOO°C. for 16-48 hours.
Alternatively, the alkenyl group may be prepared from a formylpyridine by first subjecting it to a Grignard reaction under standard conditions to form an o-hydroxyalkylpyridine followed by thermal dehydration of the a-hydroxy compouna by refluxing in a high boiling solvent such as diethyleneglycol dimethyl ether (diglyme).
The alkynyl analogs are readily prepared from the corresponding alkenyl compounds by addition of bromine across the double bond by simply adding bromine dropwise to the alkene in an inert solvent such as chloroform preferably at O-20°C., followed by double dehydrobromination. The dehydrobromination occurs on heating the dibromo compound in alcoholic alkali such as alcoholic potassium hydroxide.
Additional processes for the preparation of certain of the particularly important compounds of this invention follow.
One of the processes of this invention is illustrated by: - 39 - 3 d 8 9 g II The process comprises treating either Compound I or Compound II with a strong base such as with an alkali metal amide, tor example sodamide or potassium amide in liquid 5 ammonia at -5 to -35°C for 15 minutes to 2 hours, followed by evaporation of the ammonia, solution of the solid residue in water and adjusting to neutrality.
Other strong bases which may be employed are alkali metal hydroxides, alkali metal alkoxides and alkali metal lO alkyls, alkali metal aryls, alkali metal hydrides, Grignard reagents, alkali metal alkyl amides (e.g. lithium diisopropyl amide.) The starting materials (I and II) for use in the novel process can be prepared by condensation of 4-methyl-5-ethoxy-15 oxazole with 2,5-dihydro-2-methylthiophene or 3,6-dihydro-2H-thiopyran, respectively, by heating in a sealed tube with trichloroacetic acid at about 140°C for 20 to 40 hours.
Another process is illustrated as follows: - 40 - 3 9 8 9 0 (Ci_5alkyl)0.
Cll, n SR' cii=ch, wherein R is hydrogen, alkanoyl, (e.g. acetyl) or - S and R*° is hydrogen, alkanoyl or -SCl^ ch2=hc OH CH, "N 5 The process comprises warming at 50 C to reflux temperature for lO to 30 hours a mixture of the two reagents in an inert organic solvent such as benzene, toluene or chloro-benzene, in the presence of a strong organic acid such as trichloroacetic acid, benzenesulfonic acid, toluensauifonic 10 acid or methanesulfonic acid.
The starting material, 5-mercapto-l,3-pentadiene, is prepared from 5-bromo-l,3-pentadiene by heating it with thiourea at reflux in 95% ethanol, followed by treating the resulting thiuronium bromid- with alkali. After acidification, 15 the separated oily product is distilled.
The other starting material, 5-alkanoylthio-l,3-pentadiene, is prepared by acylating the mercapto compound with an alkanoic anhydride and triethylamine at 130°C for about 3 hours. 20 The third starting material, bis/1,3-pentadiene-5-yl/- disulfide, is prepared by bubbling air through a mixture of - 41 - 39896 5-mercapto-l,3-pentadiene in ammonium hydroxide solution. Another process is illustrated as follows: R1^ CH- 11 12 wherein R represents hydrogen or alkanoyl; R represents hydrogen, alkanoyl or -S-CH. 10 R13 represents hydrogen, alkanoyl, or is Cli2=CH SCH. and B is a function which on reduction results in the vinyl function and includes /\ -CH - CH2, / \ -CH - CH S and -CHCH.
V„ 2 15 The cyclic oxide and sulfide are reduced with triethylphosphite by heating at 50°C. to reflux approximately equimolar amounts of the triethylphosphite and the epoxide or episulfide for 1 to 5 hours.
Alternatively, the epoxides and episulfides can be - 42 - 39 B9G reduced to the vinyl group with magnesium amalgam in the presence of magnesium bromide by heating the mixture in an inert organic solvent such as a high boiling ether, for example, 1,2-dimethoxyethane or diethylene glycol dimethyl ether at 50°C. to lOO°C. Magnesium complexes are then destroyed with aqueous ammonium chloride solution. This reaction goes through an intermediate of partial structure OMgBr I rr \ "2 other useful reducing agents lor converting the epoxide lo .ind episullidc to the vinyl group .ire Cr (ClO^^ ^nd ethylene diamine in dimethylformamide; zinc and acetic acid; a mixture of zinc, sodium iodide, sodium acetate and acetic acid; a mixture of triphenylphosphine, triphenylborane in ether at 70°C; triphenylphosphine at 180°C. and potassium selenocyanate in 15 methanol.
The acetylenic side chain is readily reduced to the vinyl group by catalytic hydrogenation with a Lindlar catalyst, or palladium on barium sulfate in the presence of an organic-base such as quinoline in a C1_^ alkanol such as methanol. 20 Other useful reagents for reducing the acetylenic group to vinyl are hydrogen and nickel acetate; electrolysis with lithium chloride and methylamine; chromium sulfate in dimethylformamide; sodium borohydride and boron trifluoride etherate in diglyme; diisobutyl aluminum hydride in benzene; 25 lithium aluminum hydride in diglyme at about 120°C and diboron tetrachloride. - 43 - :i 9 8 U G The starting materials are prepared according to the following reaction sequences: ch2oh 110- CH -CHO 3^N ^ C>12SH no - Cli.
Clio cs2/KOII Ethyl orthoformate ;h2oh 0 IICl HO > ClI(OC2H5)2 CH, CH2SAc CHO © CBr4/(C6H5)3P © n-butyl lithium ch3s-cii2 CH2SAc AcO CH.
CH2SAc > cech AcO CH 3 — KSCN CH2SAc AcO O / \ CH-CH. - 44 - 3989U cu2su ilO c»2sh -CHO O II e CH^S-Cllj •N' CH ■» 3"S. o / \ ch-c11. (1) CUr4/(C6II5)3P/Zn (2) n-butyl lithium V h2sii c:i.
-C"Cii N" V /»7 KSCN V CH2SH no— ch.
N S / \ CII-CII. xT ZQ7 V CU2—S S CII- no-1 CH O <> s \ / \ -CH-CH2Cll2-CH- Cll / N^— C,,3 C«Kn 11., S S Cll H-CH_dlUCH l-CH- - 45 - 39 8 y c The preparation of these intermediates and the novel process of this invention are described in the examples that follow.
Another process is illustrated as follows: R14S CH. ,14 CH.
CH=CH- CH2SH HO CH.
CH=CH- 14 wherein R is an acid and/or alkali labile protecting group such as acyl or tetrahydropyranyl or, wherein the groups taken together, represent a group of the formula: >15 \ / ,16 lO wherein R^"* and R^ can be the same or different and represent hydrogen, alkyl, aryl or aralkyL, or taken together represent =0 or =S.
The process involves treating the starting material in aqueous, alkanolic or aqueous alkanolic solution with a mineral 15 acid such as hydrochloric, hydrobromic or sulfuric acid or a strong organic acid such as trichloroacetic, toluenesulfonic, benzenesulfonic or methanesulfonic acid usually at an elevated temperature such as 50°C to reflux temperature until hydrolysis is complete, followed by cooling and isolation of 20 the acid addition salt of the product. - 46 - 3 9 8 9 G 14 Alternatively where the protecting groups R are alkali labile such as O-acyl and S-acyl, they are readily removed by dissolving the starting material in a alkanol containing aqueous caustic solution such as sodium or *> potassium hydroxide at a final concentration of 1 to 3 normal. It is preferable to deaerate the mixture by bubbling nitrogen through it. The reaction is conducted at room temperature to reflux temperature for 2 to 24 hours. After cooling the mixture is acidified to about pH 3 and the acid lo salt of the product i3 isolated.
Another process is illustrated as follows: CII = CII..
^ IT * ^ ^ c!l, 17 18 wherein R is hydrogen or alkanoyl; R is hydrogen, alkanoyl or -SCH dhc 19 and R is hydrogen, alkanoyl or -S-CH h2c=hc 3 U 8 1) G In essence, the process comprises converting an aldehyde function to a vinyl function or in other words exchanging a carbonyl oxygen for a methylene group and is accomplished by means of a carbonylolefination reaction involving a variety 5 of reagents such as methylene dilithium, methylene magnesium; methylene magnesium halides such as methylene magnesium bromide or iodide and phosphorous compounds such as triphenyl methyl-phosphonium bromide, a-lithio methylphosphonic acid bis(dimethylamide), a-lithio dimethyl methylphosphonothioate, 10 a-N-dilithio-methane sulfinyl-p-toluidine, phenylthiomethyl lithium, methylene zinc, methylene mercuric halides and bis/" trimethylsilyl7methyl lithium. In the above reagents lithium can be replaced by sodium as the metal compcnent.
The reactions comprise treating the aldehyde compound 15 with the metallic reagent in an inert solvent such as tetrahydrofuran and dimethylsulfoxide under anhydrous conditions for 1 to 6 hours at room temperature to reflux temperature.
A further alternative process for preparing tlu? final product comprises converting a compound of tho formula: © 20 wherein R is hydrogen or alkanoyl of up to 6 carbon atoms 21 (especially acetyl); R is hydrogen, alkanoyl of up to 6 carbon atoms (especially acetyl) or - 48 - •' ?> H i) (j ch2s- wherein M is -C1I=CH_ or -Cll-CH,; and X, and X, are each II *1 X2 hydrogen, hydroxy, wherein R22 is alkyl (preferably Cx_5 alkyl) or aryl (preferably plienyl or substituted phenyl) Lor example, such as tosylate or mesylate; or halo (chloro, bromo, iodo, fluoro), preferably chloro and especially (•:-chloro; one and no more than one of and X7 is hydrogen a: any one time to the desired product by dehydrohalogerut .Ion, denyJrosulfonylation or dehydration.
The dehydroha logenat ion or denydrosu 1 f ony ! al 101. be carried out under well known conditions such as • in.,- i :i t.!\e presence of an inert solvent or is r.iore usually is done, with the addition of a base as well. Accordingly, Compound i is heated in the presence of an alkali or alkali r.etal base ■ r organic base. Bases such as calcium carbonate, sodium carbonate, barium carbonate or their corresponding hydro:-; i u-s may be suitably used. Also, the solvent may act as the base a '-•.ell. Accordingly, not only solvents sucli as dimethy L f ormawi .i tetrahydrofuran and dimethylsulfoxide Miay be used, bur. also basic solvents such as pyridine and .N'-N-dimethyianil ine. Thr-amount of base employed is not critical, but it is preferred to use at least one equivalent of base per equivalent of Compound 3. The reaction is suitably carried out at ttanpor 1 of i roiii to the reflux temperature of the s"! vent and preferably between IOO-] 20°C until Liio react i on is sub:: La nr. 3 . ■ - 4 9 - 3 9 8 9 6 complete.
Compound 3 may be suitably prepared from the corresponding alpha or beta hydroxyethyl compound under normal conditions used to convert a hydroxy group to a halo or sulfonyl group. Accordingly, for example, the hydroxyethyl compound may be reacted with a thionyl halide (preferably thionyl chloride) at below or above room temperature and preferably between 25-50°C until the reaction is substantially completed. In place of the thionyl halide, one may also use other halogen donor compounds such as stannic chloride in the presence of HC1 gas, sulfuryl chloride or phosphorous 22 pentachloride. When X is to be R SO^, the reaction is similarly carried out by employing an aryl or alkylsulfonyl halide such as methanesulfonyl chloride or toluenesulfonyl chloride. The beta hydroxyethyl compound may be prepared from the corresponding 3-aldehyde by reaction of said compound with a methyl magnesium halide or metal lithium compound in the presence of any non-hydroxylic solvent, at a temperature of from 0°C to reflux and preferably from 20-30°C. The metal complex thus formed may be neutralized under acid conditions. For such purposes, mineral acids, organic acids and preferably ammonium halides may be used.
The alpha hydroxyethyl compound may be prepared from the corresponding hydroxymethyl compound by first converting the hydroxy group to the halo group as previously described for the conversion of a hydroxy to a halo group. The halomethyl compound is then reacted at elevated temperatures in the picisence of magnesium with paraformaldehyde and the subsequent metal complex thus formed is cleaved in the presence of an acid to yield the a-hydroxyethyl compound. - 50 - 3 9 8 y G In the dehydration reaction, one goes directly from the alpha or beta hydroxyethyl compound to the final product without first forming the 3-haloethyl compound. The alpha or beta hydroxyethyl compound may be thermally dehydrated in tlu; presence of a variety of reagents such as potassium hydroyen sulfate, aluminium oxide and silica gel in a manner known per :>e. The process described above may bo shown by the following Clow sheet: l<21o ('I! 22 en su Clio r21o > 22 C11 -SR I on I II o v:ii r; © A 1 <:\i .:Ji< V cMv-s-ir K < ' Ch CH--CM -OI-C'.!., <- ^ N 'J y' 1 " > CH , © 10 ^ further iitorn.it ivo pre :ess tor preparing tho t Lii.il product:; comprises rentrtLng an ylide of the foiLowing ! urinal.: with lorma Idohyde: CU,SH 24 r2°o 1-- cll=p ys jx Cll xliorcm i r, hydrogen or alkanoyl •• •: up to o car: 'jii at !'•;> (esp.-cialiy aoot.yl), R24 is hy.Irogon, ilkmoyL or op f .• b uirlion atoms (.'Specially icetyl.} or a -iioup of t:.o f '): ; ■: • i 1 . i: 398DG C»2"S- wherein Y is -CH=P+03X or -CI^CHj, X is halogen and 0 is phenyl, substituted phenyl, or alkyl.
The reaction is carried out with formaldehyde in the presence of a base and, if desired, a solvent. The type of base is not critical and, accordingly, can be organic, aliphatic, metal organic, metal oxide, heterocyclic or inorganic bases. Such bases as N-butyl lithium, trialkylamincs (triethylamine), ter-aralkylamines, alkali and alkaline earth alkoxides such as sodium methoxide, potassium ethoxide and calcium methoxide; alkali and alkaline earth bases such as sodium, potassium, calcium, lithium carbonates, bicarbonates, hydroxides and oxides. Examples of such bases are solium bicarbonate, calcium carl>onate, sodium bicarbonate, lithium carbonate, sodium hydroxide, and potassium hydroxide. Th^ reaction is preferably carried out in a solvent. The solvent may be inert or a basic solvent which may be used in place of an additional base, if desired. Any solvent may be employed which renders sufficient solubility to the reactants to cause reaction. For example, such solvents as aromatic solvents (benzene, toluene), heterocyclic (tetrahydrofuran, dioxane), aliphatic (hexane, methylene dichloride, dimethylformamide), alkanols (methanol, isopropanol, as well as water and mixtures of water and water soluble organic solvents. It is preferred, however, to employ non-hydroxylic organic solvents or water 398DG unci especially water- The mole ratio of base to ylide and formaldehyde is not critical but is preferably about a one to one ratio, although one may use ratios of from 0.5:3 up to 3:0.5 of ylide to formaldehyde and at least 0.5:1 of base to formaldehyde or more base when it is used as the solvent as well.
The reaction may be suitably carried out at a temperature of from 15°C to the reflux temperature of the system and preferably from 50°C to 10G°C for a period of time* i .» substantially complete the reaction.
The ylide compound is prepared from the corresponding •j-h.i lomethy! compound by reaction of said compound with a i. i ry 1 phosph i ne , particularly triphenylphosphine in an inert solvent ,il. ' • I •'va Li *d 11 Miii n* la I ,ur<. One may use non- i : y«l i < )xy 1 i c . ,lvents a:', toluene, ethylacet ite, hexane, tnd i <■!. i ahydrofuran. Tho reaction is carried out at elevated t emperaturos, preferably between 50°C to tho rei lux temper..* a the system tor a period of time sufficient to substanti.« 1 • complete the reaction. The reaction time is dependent upon the reactants and temperature and, therefore, usually between 1 and Ion hours, '''lie '>-ha 1 oiuethy I compound, in turn, is prepared from tho hydroxyi'iethy 1 compound as described herein.
In Lhe l-Jxamplos, which follow, temper.itures ,'iri: on : he Cent iiirade seale, parts are by wei'jhl , mesh s i /.es are b.:;. andard:;, and the compositions ol ;olvnl I", i x Mi re- •: ire .jivm on a volume i>a5;i.s. ; :x imp i l.
.! - Me thy 1 - 3 -1 lyo roxy-'l -He reapLome t hy 1 - j - i 1; y 1. py r i ■ i i no !Iy I :■a na : ! • • ..top A: Preparation ol i , I t -d i -<>- i sopr« >py 1 ide.ne d-'riv it. i ve 3 9 8 9 6 of 2-methvl-3-hvdroxv-4-hydroxvmethyl-5-vinvl-pyrldine 67 ml. of n-butyl lithium (1.9 M in n-hexane) was run into a stirred suspension of triphenylmethylphosphonium bromide (42.7 g., 0.12 M) at room temperature in tetrahydro-5 furan (300 ml.) under nitrogen. To this stirred solution a solution of the 3,4a-di-0-isopropylidene derivative of 2-methyl 3-hydroxy-4-hydroxymethyl-5-formylpyridine (24.7 gm. O.H9 M) in tetrahydrofuran (300 ml.) was added dropwise over 1 hour. The reaction mixture was left for 1 hour at room temperature lO and then refluxed for 4 hours.
The solution was evaporated to dryness first under house pump vacuum and then high vacuum at 30-50°C. The red-oily product was triturated with 400 ml. ether. Solid triphenylphosphine oxide was filtered off (17.O gm.) and the ethereal 15 filtrate was extracted with 2 x 200 ml. saturated sodium bisulfite solution and evaporated to dryness to give a reddish-yellow oil. The product was used in the next step.
Step B: Preparation of 2-methyl-3-hydroxy-4-hydroxymethyl-5- vinylpyridine hydrochlor de 20 A solution of the red oil obtained above (25 gm. 0.122 M) was stirred in 2.5 N hydrochloric acid (500 ml.) and aceton.i (500 ml.) at reflux under nitrogen for 1.5 hours. The acetone was distilled off to a temperature of 90° and the cooled solution was extracted with ethyl acetate (3 x 400 ml.). 25 The aqueous layer was poured into excess of saturated aqueous sodium bicarbonate solution (700 ml.).
The aqueous layer was extracted with ethyl acetate (1 x 400 ml.). The organic solution was dried (MgSO^), filtered and evaporated to give an off-white solid recrystallizable 30 from ethyl acetate, m.p. 164-166°. 9.4 gm. - 54 - 3 9 8 i) (j Stop C: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl- 5-vinylpyridine hydrochloride In a 1-liter 3-necked flask equipped with nitrogen inle tube, a thermometer and additional funnel on top of a condense were placed 530 ml. of 90-4 ethanol and 53.4 gm. of NaOli. After solution was complete, 50 ym. of product from Step U was added To the resulting solution (under N2> was added 30 ml. of CS2 dropwise over a period of about 1/2 hour with stirring at 10-1 r>°. The resulting mixture was then stirred for 1/2 hour at 20°, then cooled to about 15°C., an additional 20 ml. of CS^ wai added dropwise and the mixture was rcfluxed for 4 hours. Tho mixture was then cooled to about lO°C. and concentrated lie I wa: .aided unLil the pll remained .jL 2. (About 80 ml. requiied). TIil-fixture was kept in an ice bath overnight, and conccntrated under reduced pressure (bath temperature 20°) to remove the ethanol. The resulting material was added (N.; alinos) to a cold stirred suspension of 120 gm. of NallCO-j in 1 liter of water. The organic material was extracted with 3 x 300 mi. of ethyl acetate (air excluded as much as possible). The combine-: extracts were dried (MgSO^), filtered and concentrated under reduced pressure. The residue was purified by chromatography using about I kg. of Sic>2 (liaker) and ethyl acetate as the eluant. The appropriate fractions (as determined by tic-KtOAc dev) were combined and concentrated to an appropriate volume giving the white crystalline free base. 1st. crop. in.p. L15-117C (33 gm.). Crop 2, in.p. 114-ll(i° (t> gin) An.il. Cqll .
C.i led: C, '") 0. G 6; 11, 6.12; N, 7.73; S. 17.7 1'ound: C, 'S 9 . (> 4 ; 11, 6.35; N, 7.26; S, 17.30.
It. was converted to tho hydrochloride by the following 3 9 8 9 G procedure: The free base (39 gm.) was dissolved in 500 ml. of dry T1IF and, with stirring, dry HC1 was admitted keeping the temperature below 25° until a slight excess was present. The 5 resulting white precipitate was collected, washed with tetrahydrofuran and dried under vac. m.p. 149-152°, wt 45 g.
Anal. C9H12ClNOS, m.w. 217.7 Calcd: C, 49.65; H, 5.56; N, 6.44; S, 14.73.
Found: C, 49.87; H, 5.82; N, 6.44; S, 15.10. lO By the procedure substantially as described in Example 1, but substituting for the triphenylmethylphosphonium bromide used in Step A thereof, equivalent amounts of triphenylethyl-phosphonium bromide, triphenylbenzylphosphonium bromide and triphenylchloromethylphosphonium bromide, there are prepared in 15 sequence, respectively.
Step A: 3,4a-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxyraethyl-5-(1-propenyl)pyridine (oil, 35% yield) ; 3,4u-di-0-isopropylidene derivative of 2-methyl-3-20 hydroxy-4-hydroxymethyl-5-styrylpyridine; and 3,4a-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl) pyridine.
Step B: 2-methyl-3-hydroxy-4-hydroxymethy1-5-(1-propenyl)-pyridine hydrochloride (100% yield); 25 2-methyl-3-hydroxy-4-hydroxyinethyl-5-styrylpyridine hydrochloride; and 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)-pyridine hydrochloride.
Step C: 2-mev.hyl-3-hydroxy-4-mercaptomethyl-5- (1-propenyl)-30 pyridine hydrochloride (60% yield, m.p. 175-178°C); - 56 - 3 9 8 u i; 2-iaoLhy l-3-hydroxy-4-morcaptomethy l-'j-sty ry 1 py r idi iu; hydrochloride (m.p. 190-195°C.); and 2-mcthyl-3-hydroxy-4-mercaptomethyl-5-(2-chlorovinyl) pyridine hydrochloride.
Example 2 2-Methyl-3-llydroxy-4-Mercaptomethylpyridine-5-Acrylie Acid Hydrochlor ide A mixLure of 1.23 ml. of boiling ethanol and I i I t ered 11< > t . evaporation <>l the. extract gave a syrup which wau crystallized from c!i loroform-cther to give 2-methyl-3-tiyd roxy- 4 -me reap tome thy Ipy r id inu-5-acry 1 i c acid hydrochlor ide, m.p. 227-22 8°C.
Example 3 2-Methyl-3-Hydroxy-4-Viny1-5-benzoylthiomethylpyridine :itep A: Preparation of 3,4u-di-0-isopropyliJene derivative of 2-methyl-3-hydroxy-4-hydroxymethy 1-5-ben::oy 1 - thiomethylpyr i dine 'l'o a :>tirred solution of 80 g. of tho 3,4.t-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxy-moUiyl-5-chloromethylpyr idine in 1 liter of ethanol under nitrogen there was added 96 g. of potassium thiobenzoate in 2f)U ml. of water over 30 minutes. After 1 hour, the ethanol was evaporated at 40°C. and the aqueous solution was extracted witii 3 9 8 0 g 4 x 300 ml. of ethyl acetate. The extract was washed with 1 x 75 ml. of water, dried over maonesium sulfate and concentrated to dryness to give 116 g. of 3,4a-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-benzoyl-5 thiomethylpyridine, m.p. 74-77°C.
Step B; Preparation of 2-methyl-3-hydroxy-4-hydroxymethyl-5-benzoylthiomethylpyridine The product from Step A was dissolved in 1 liter of ethanol and was treated with 1 liter of 2.5 N hydrochloric lO acid. The mixture was heated cn a steam bath for 30 minutes.
The ethanol was evaporated at 60°C. and the aqueous solution was poured into excess of sodium bicarbonate solution. The precipitate was collectcd and dried to yive 48 g. of 2-inethyl-3-liydroxy-4-hy-bcnzoy I thiome thy Ipy rid ine, m.p. 174-l'j 177° .
Step C: Preparation of 2-methyl-3-hydroxy-4-formyl-5-benzoylthiomethylpyrIdine A solution of the lOg. of the product from Step 13 in 300 ml. of hot chloroform was treated with 100 g. of 20 manganese dioxide. After 1/2 hour of stirring, the mixture was filtered and the filtrate was evaporated to dryness to yive 9.2 g. of 2-methyl-3-hydroxy-4-formyl-5-benzoylthio-methylpyridine, m.p. 127-130°C.
Step P: Preparation of 2-methyl-3-acetoxy-4-formyl-5-25 benzoylthiomethylpyridine A mixture of 11 y. of product from Step C, 4.62 g. of acetic anhydride, 4.62 y. of triethylamine, and 30 ml. of - 58 - 39SD li dry tetrahydrofuran was left at room temperature for 1.5 hours and evaporated at 20° to a small volume. The residue was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated to dryness to give 12.3 g. of 5 2-inethyl-3-acetoxy-4-formyl-5-benzoylthlomethylpyridine, m.p. 128-130°C. (dec.).
Step K: Preparation of 2-methyl-3-acetoxy-4-(1-hydroxyethyl)-5-benzoylthiomethylpyridine To a stirred suspension of the aldehyde (6.58 g.) lo in tetrahydrofuran (200 inl.), methyl magnesium bromide (0.02 mole; 6 inl. of 3.6 M in tetrahydrofuran) (b.6 ml.) was added dropwise and the mixture was stirred overnight at room temperature. Tho reaction was poured into 5GO ml. of an ice-water solution of ammonium chloride (!<)•) gm.), stirred for a lr> few minutes and extracted well with ether (4 x 300 ml.) . The combined extracts were washed with water, dried over magnesium sultate, I i ll.orod and evaporated to give .in oil which was used directly in the next stop.
Stop !■': 1'reparation of 2 -n.ethy l-3-hy>lroxy-4-viny 1 - 5-( bon/.oy 1 tli iomeLhy I pyr id ine Tho product from Step t; (2 gm.) was added to diglymo and refluxed 3 hours. The mixture was evaporated to dryness to give 2-methy1-3-nydroxy-4-viny1-5-benzoylthiomethyIpyridine. This material was purified by chromatography on 800 gm. of silica gel by elution with lOs methanol in chloroform (v/v) .
Kxample 4 2 Methy1-3-Hydroxy-4-Viny1-5-MercaptomethyIpyridine - 59 - 3980g A mixture of 1 g. of 2-methyl-3-hydroxy-4-vinyl-5-bcnzoylthioinethylpyridine, 10 ml. of tetrahydrofuran and lO ml. of 2.5 N aqueous sodium hydroxide was left at room temperature overnight. The solution was acidified to about pli 5 6 with hydrochloric acid and then adjusted to pH 7.5 with solid sodium bicarbonate. The mixture was extracted with 3 x lOO ml. of ethyl acetate:isopropanol (9:1 v/v). The extract was dried over magnesium sulfate and concentrated to an oil which crystallized on trituration with ether to give 175 mg. lO of 2-methyl-3-hydroxy-4-vinyl-5-mercaptomethylpyridine, m.p. 130-140°C.
Example 5 2-Methyl-3-Hydroxy-4-Acetylthiomethy1-5-Vinylpyridine A mixture of 2.54 g. of 2-methyl-3-hydroxy-4-15 mercaptomethyl-5-vinylpyridine hydrochloride, 120 ml. of anhydrous tetrahydrofuran, 3.82 ml. of triethylamine, and 1.32 ml. of acetic anhydride was left overnight at room temperature. After evaporation to dryness, the residue was dissolved in ethyl acetate, extracted with aqueous sodium 20 bicarbonate solution, dried over magnesium sulfate, and evaporated to dryness. After trituration with ether, the residue crystallized to give 0.8 g. of 2-methyl-3-hydroxy-4-acetylthiomethyl-5-vinylpyridine, m.p. 130-132°C.
Example 6 25 2-Methyl-3-Acetoxy-4-Acetylthiomethyl-5-Vinylpyridine A mixture of 680 mg. of acetic anhydride and 10 ml. - 60 - j a o >i u of tetrahydrofuran was added slowly to 653 mg. of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 20 ml. of tetrahydrofuran at 10°C. After stirring for one hour at room temperature, the mixture was evaporated to dryness. The residue 5 was triturated with a mixture of 20 ml. of ethyl acetate and 20 ml. of water. The ethyl acetate was separated, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from cyclohexane to give 2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, m.p. 72-73°C. The same lo product is obtained by starting with the S-acetate product of Example 5.
Example 7 3-o-4a-S-Benzylidene Derivative of 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine 15 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine (1 g.) was dissolved in tetrahydrofuran and stirred at 0°C. with 900 mg. of benzaldehyde while gaseous hydrogen chloride was introduced over a 2 hour period. After leaving overnight at room temperature, the mixture was evaporated to dryness. The 20 residue was taken up in water, poured onto excess of solid sodium bicarbonate and extracted with ethyl acetate. The extract was dried and evaporated to dryness, and the residue was chromatographed on silica gel by elution with tetrahydrofuran to give 220 mg. of 3-0-4>»-S-benzylidene derivative of 2-methyl-25 3-hydroxy-4-morcaptomethyl-5-vinylpyrtdinir (oil).
Similarly prepared were the 3-0-4 Following the procedure of Example 8 but substituting for the ethylchloroformate used therein, equivalent amounts of adamantanoyl chloride, cyclopropylcarbonyl chloride, 2-acetoxysalicyloyl chloride, benzoyl chloride, 2-hydroxy-4-(2,3-difluorophenyl)benzoyl chloride, 3-chloro-4-allyloxyphenyl-acetyl chloride, a-methyl-4-isobutylphenylacetyl chloride, a-methyl-3-phenoxyphenylacetyl chloride, -x-methyl-3-benzoyl-phenylacetyl chloride, a-methyl-6-methoxynaphth-2-ylacetyl chloride, a-methyl-3-fluoro-4-phenylphenylacetyl chloride, 4-(3-chloro-4-cyclohexylphenyl)-4-ketobutyryl chloride, 2 —(3— trifluoromethylanilino)benzoyl chloride, 2-(2,3-dimethylanil-ino)benzoyl chloride, 2-{2,6-dichloro-3-methylanilino)benzoyl - 62 - :»u s i) u chloride, 2-(3-trifluoromethylanilino)nicotinoyl chloride, and 2-(2-methyl-3-chloroanilino)nicotinoyl chloride, there are produced respectively the S-mono- and 0,S-di- adamantanoyl, cyclopropanoyl, 2-acetoxybenzoyl, benzoyl, 2-hydroxy-4-(2,4-difluorophenyl)benzoyl, 3-chloro-4-allyloxyphenyl-acetyl, u-methyl-4-isobutylphenylacetyl, a-methyl-3-phenoxy-phenylacetyl, a-methyl-3-benzoylphenylacctyl, a-methyl-6-methoxynaphth-2-ylacetyl, m-methyl-3-fluoro-4-phenylpheny1-.icety1, 4-(3-chloro-4-cyclohexylpheny1)-4-kctobutyry1, 2 - (3-Lri £luoromethylanilino)benzoyl, 2-(2,3-dimethylani1ino)bcnzoy1, 2-(2,6-dichloro-3-methy1ani1ino)benzoyl, 2-(3-trifluoromothy1-.in i 1 i no) n icot inoy I .mil 2 - ( 2-me thy I -3-cii loroani 1 ino) n icot inoy ! Jor ivatives of 2-methyl-3-hydroxy-4-mercaptomet.hyl-5-v iny L-pyr idine. l-'ul iowiny tiie procedure of Example 8 but substituting tor the 2-me thy l-3-hydroxy-4-mercaptoine thy 1-5-v iny lpyridine used therein an equivalent amount of 2-methyl-3-hydroxy-4-mercaptomethy1-5-ethynylpyridine (Example 9) there are produced 2-methyl-3-ethoxycnrbonyloxy-4-ethoxycarbony1thiomethy1-5-ethyny lpyr id ine; 2-ine thy 1-3-hydroxy-4-ethoxycarbony 1 thiome thy 1-5-othynyl-pyr idine; 2-methy1-3-adnmantanoyloxy-4-adamantanoylthiomethy1-5-ethyny Ipyridine; 2-me thy l-3-hydroxy-4 -adamantanoyl thiomethyl-5-ethynyLpyr id ine ; 2 -methyl - 3-cyclopropanoy loxy-4 -cyclopropanoyl tli iomethy 1.-5-ethynylpyr idine; 2-methy1-3-hydroxy-4-cyclopropanoylthiomethy1-5-ethyny1pyri-d i ne; 39800 2-methyl-3-(2-acetoxybenzoyloxy)-4-(2-acetoxybenzoylthio-methyl)-5-ethynylpyridine; and 2-methyl-3-hydroxy-.4- (2-acetoxybenzoyl thiome thy 1) -5-ethynyl-pyridlne. 5 Example 9 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Ethynylpyridine Hydrochloride Step A: Preparation of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(1.2-dibromoethyl)pyridine lO Bromine (320 mg.) was added over 10 minutes to a stirred suspension of 320 mg. of 2-methyl-3-hydroxy-4-hydroxy-methyl-5-vinylpyridine in chloroform at 10°C. After being stirred for lO minutes, the mixture was evaporated to an oil.
Step B: Preparation of 2-methyl-3-hydroxy-4-hydroxymethyl-5-15 ethynylpyridine The oily product from Step A was refluxed in 15 ml. of 10% (w/v) ethanolic potassium hydroxide under nitrogen for lO minutes. After cooling the solvent was evaporated. The residue was extracted with 2 x 20 ml. of hot isopropanol which 20 was then filtered and evaporated to give solid 2-methyl-3-hydroxy-4-hydroxymethy1-5-ethynylpyridine, m.p. 170-171°C.
Step C: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine hydrochloride The product from Step B (3.26 g.) was treated with 25 1.6 g. of sodium hydroxide and 3 ml. of carbon disulfide according to the procedure described in Example 1, Step C, to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine hydrochloride, m.p. 114-126°C. (dec.). - 64 - 3989 g Example IP 2-Methvl-3-Hydroxy-4-(1-mercaptoethyl)-5-Vinylpyridine Step A; Preparation of 2-methyl-3-hydroxy-4-formyl-5- vinylpyridine 5 A solution of 10 g. of 2-methyl-3-hydroxy-4- hydroxymethyl-5-vinylpyridine in 300 ml. of hot chloroform was treated with lOO g. of manganese dioxide. After 1/2 hour of stirring, the mixture was filtered and the filtrate was evaporated to dryness to give 2-methyl-3-hydroxy-4-formyl-5- lO vinylpyridine.
Step B: Preparation of 2-methyl-3-hydroxy-4-(l-hydroxyethyl)-5-vinylpyridine To a stirred suspension of the aldehyde (0.2 mole) in tetrahydrofuran (200 ml.), methyl magnesium chloride (0.44 15 mole; 3.35 M in tetrahydrofuran) (13.2 ml.) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 500 ml. of an ice-water solution of ammonium chloride (lOO gm.), stirred for a few minutes and extracted well with ether (4 x 300 ml.). The 20 combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to give an oil which was used directly in the next step.
Step C: Preparation of 2-methyl-3-hydroxy-4-(1-mercaptoethyl)-5-vinylpyridine 25 The product of Step B was converted by the procedure of Example 1, Step C, to 2-methyl-3-hydroxy-4-(1-mercaptoethyl) -5-vinylpyridine. - 65 - 39 BO 6 Example 11 2-Methyl-3-Hydroxy-4-(2-mercaptobut-2-yl)-S-Vinylpyridine Step A: Preparation of 2-methyl-3-hydroxy-4-acetyl-5- vlnylpyrldine 5 To 750 ml. of dry methylene chloride containing 47.S ml. of dry pyridine was added with stirring and cooling 29.6 g. of chromium trioxide. The mixture was left for 20 minutes at room temperature and then treated with a solution of 10.96 g. of the product from Example 10, Step B, in 250 ml. lO of dry methylene chloride over 15 minutes. After one hour at room temperature, the reaction mixture was filtered and the residue was washed with 2 x lOO ml. of methylene chloride. Tho methylene chloride filtrates were extracted with 3 x 500 ml. of 5% (w/w) aqueous sodium hydroxide solution, dried over 15 magnesium sulfate and evaporated to dryness. The residue was crystallized from hexane to give 2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine.
Step B; Preparation of 2-methyl-3-hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine 20 A solution of 3.93 g. of the product from Step A in 200 ml. of tetrahydrofuran was treated dropwise with 110% excess of ethyl magnesium bromide in tetrahydrofuran. After leaving for 2 days at ambient temperature the reaction was quenched on ice-water (lOO ml.) containing lO g. of ammonium 25 chloride. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 2-methyl-3-hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine, which was used directly in the next step. - 66 - 3 9 8 0 G Step C; Preparation of 2-methyl-3-hydroxy-4-(2-mercaptobut-2-yl)-5-vinylpyridine The product of Step B was converted by the procedure of Kxamplc 1, Step C, to 2-riethyl-3-hydroxy-4-(2-mercaptobut-5 2-yI)-5-vinylpyridine.
Example 12 2-Viny1-3-Hydroxy-4-Mercaptomethyl-5-llydroxymethyIpyridine Step A: I'reparation of ethyl u-formy 1 -u-Eormamidoacctfttc diothylacetal 11 > A solution of ethyl u-forinyl- i-formainido acctatc (I equivalent) in 200 ml. anhydrous ethanol is saturated with dry hydrogen chloride at G°C. The solution is allowed to reach room temperature and is left for 16 hours. The solution is then concentrated under reduced pressure to yield the desired I rj acetyl as an oil.
Step U: Preparation of 4-farmy 1-5-ethoxyoxnzole diethyl acetal A 2 liter flask is charged with 340 ml. anhydrous chloroform and 142 gm. phosphorus pentoxide. To this stirred 1-'" mixture, a solution of 0.5 mole ethyl u-forinyl-'i-foririumido- acctate diethyl acetal in 200 ml. chloroform is added over lo minutes. The reaction is then maintained under gentle reflux for 6 hours. To the cooled reaction mixture is added 750 ml. 20i potassium hydroxide solution with good agitation over 1.5 2'j hours. After addition is complete, it is left for 30-00 minutes at room temperature. The layers are separated, and the aqueous phase is extracted with fresh chloroform (2 x 200 ml.). - 67 - 39800 The combined chloroform extracts are dried over anhydrous magnesium sulfate. After solvent removal, the residual oil is distilled at reduced pressure to afford the desired oxazole.
Step C: Preparation of diethyl 2-formyl-3-hydroxypyridine- 4,5-dicarboxylate diethyl acetal A mixture of 31 gm. (0.2 m) diethyl malcatc and O.l m of oxazole from Step A is charged to a flask and heated to 110-115°C. for 4 hours. The mixture is cooled and 20 ml. of a 25% solution of dry hydrogen chloride in absolute ethanol is added. Then 300 ml. ether is introduced and after cooling overnight, the crystalline hydrochloride is isolated. The corresponding free base is obtained by introducing the hydrochloride into excess of aqueous sodium bicarbonate, followed by chloroform extraction. The chloroform extracts, after magnesium sulfate drying, are concentrated at reduced pressure affording the desired free base.
Step D: Preparation of 2-formyl-3-hydroxy-4,5-dihydroxy- methylpyridine hydrochloride A flask is charged with 1.14 gm. (0.03 m) lithium aluminum hydride and 50 ml. anhydrous ether. After cooling a solution of O.Ol m. of the diester from Step C in 5 ml. ether is added dropwise with stirring. The reaction mixture is then maintained under gentle reflux for 6 hours. Then the reaction mixture is cooled, and 100 ml. ice-water added dropwise with stirring. Then carbon dioxide gas is introduced for 30 minutes. The resulting solid is collected by filtration, and stirred with lOO ml. aqueous ethanol (1:1). Carbon dioxide gas is again introduced for 30 minutes. After filtration, the solids are - 68 - 3 D 8 u i; washed with hot ethanol (3 x 50 ml.). All filtrates and washings are combined, acidified with hydrochloric acid, warmed for 30 minutes at 50°C., and evaporated to dryness at reduced pressure. Extraction of the residue with hot 5 ethanol (4 x 25 ml.), followed by filtration and evaporation, gives the crude dicarhinol.
Step K: Preparation of 2-formyl-3-acetoxy-4-acetoxymethyl- 5-acetoxyniethylpyridine A solution of one equivalent of 2-formyl-3-hydroxy-lo 4,5-dihydroxymethylpyridine hydrochloride in 400 ml. anhydrous tetrahydrofuran is treated with four equivalents of triethylamine and left for one hour at room temperature. Then three equivalents of acetic anhydride are introduced, and the reaction mixture is left for 4 hours at room temperature. The lb reaction mixture is concentrated under reduced pressure to a gum. This is treated with a mixture of 300 ml. of diethyl ether and 300 ml. of distilled water. After shaking well, the layers are separated and the ethereal layer is dried over magnesium sulfate. After evaporation to dryness, the desired triacetate 2o is obtained as a viscous oil.
Step F: Preparation of 2-vinyl-3-hydroxy-4,5-dihydroxymothy1-pyridine hydrochloride A 2 liter flask is charged with one equivalent of methyl triphenylphosphonium chloride and 600 ml. of anhydrous 25 diethyl ether. This solution is cooled to 0°C. and one equivalent of n-butyllithium in hexane is introduced over a thirty minute period under nitrogen. When addition is complete, t.Uc solution is left for an additional 30 minutes at ')-5°C. Then 69 - 3 9 8 9 G a solution of one equivalent of 2-formyl-3-acetoxy-4,5-diacutoxymethyl pyridine in 250 ml. of anhydrous ether is added dropwise with stirring over an one hour period. The reaction mixture is then left for 16 hours at room temperature/ 5 and is then cooled to 0°C. and filtered. The filtrate is concentrated to dryness under reduced pressure and treated with a mixture of 500 ml. of 2.5 N hydrochloric acid and 300 ml. of ethyl acetate. After shaking well, the organic phase is separated and discarded. The aqueous phase is extracted with 2 lO more 300 ml. portions of ethyl acetate and these too are discarded. The aqueous phase is then refluxed with stirring under nitrogen for 3 hours and after cooling is poured onto excess of aqueous sodium bicarbonate. The crude, solid, free base is isolated by filtration end air dried. This crude solid 15 is taken up into 300 ml. dry tetrahydrofuran and saturated with dry hydrogen chloride at 0°C. Then 300 ml. dry diethyl ether is introduced and the desired hydrochloride crystallized. It is isolated by filtration and dried in vacuo.
Step G; Preparation of 2-vinyl-3-hydroxy-4-mercaptomethyl-5-20 hydroxymethylpyrldlne The product from Step F is treated with sodium hydroxide and carbon disulfide as described in Example 1, Step C, to produce 2-vinyl-3-hydroxy-4-mercaptomethyl-5-hydroxy-me thylpyridine. 25 Example 13 2-Methyl-3-Hydroxy-4-Mercaptom2thy l-5-llyiJroxyinothyl-6-Vinylpyrldine Step A: Preparation of N-acryloylalanine ethyl ester - 7o - 3 9 8 9 U To 0.5 mole of alanine ethyl ester hydrochloride in 500 ml. of benzene is added 0.5 moles of acryloyl chloride. To this stirred mixture is added portionwise 0.6 moles of anhydrous sodium carbonate. The reaction mixture is then ri refluxed for 1 hour, stirred for an additional 2 hours and filtered, and the filtrate is concentrated to give N-acryloyl-alanine ethyl ester.
Step U: Preparation of >-cthoxy-4-mcthvl-2-vlnyloxazolc To a suspension of l.o mole of phosphorus pentoxide lo in )iK) ml. ol" dry chloroform is added dropwise wiLli stirring • i solul ion <>l moli- ol" N-.icry I oy I .i I .in i n<: ethyl ester. The reaction mixture is heated at gentle ret lux for 5 hours and tnen cooled. To the cooled mixture is added with rapid stirring 7'.jO ml. of 2oA aqueous potassium hydroxide. After stirring at I'> room temperature for 1 hour, the chloroform layer is separated and the aqueous layer extracted with 2 :< 200 ml. of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, and concentrated Ln vacuo to yield 5-ethoxy-4-methyl-2-vinyloxa7.ole. 2'» Step C: Preparation of dim..thyl 2-methyl-3-hydroxy-6- vinylpyridine 4,5-dlcarboxylate A mixture of 0.2 mole of dimethyl maleate and O.l mole of 5-ethoxy-4-inethyl-2-vinyloxazole is heated at 110-115°C. for 4 hours. The reaction mixture is cooled and 20 ml. of a 2rj'l. solution of hydrogen chloride (dry) in > I ut e - met.h.ino I added. Addit ion ol ether to the cooled reaction I'li.xl.uie precipitates the hydrochloride salt of tin; product. The free base is obtained by dissolving the hydrochloride salt in a minimum volume of water, adding solid sodium bicarbonate to pi! - 71 - 3 9 8 9 G 6.5 to 7.0 and extracting with chloroform. The combined chloroform extracts are dried over sodium sulfate and concentrated ii» vacuo to give dimethyl 2-methyl-3-hydroxy-6-vinylpyridine 4,5-dicarboxylate. 5 Step D: Preparation of 2-methyl-3-hydroxy-4,5-di(hydroxy- methyl)-6-vlnylpyridine To a suspension of 0.15 mole of lithium aluminium hydride in 250 ml. of ether is added dropwise with stirring a solution of 0.05 mole of dimethyl 2-methyl-3-hydroxy-6-lO vinylpyridine 4,5-dicarboxylate in 150 ml. of ether. The mixture is refluxed for 6 hours and stirred overnight at room temperature. The reaction is cooled and lOO ml. of water added dropwise with stirring. The resulting mixture is saturated with carbon dioxide for 30 minutes and then filtered. The 15 precipitate is stirred with 250 ml. of cthanol-water (1:1) and saturated again with carbon dioxide and filtered. The solid is then extracted twice with lOO ml. of boiling ethanol. The combined filtrates are evaporated to dryness _in vacuo. The residue is extracted 5 times with lOO ml. of boiling ethanol. 20 The combined extracts are filtered and evaporated to dryness to give 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)-6-vinyl-pyridine.
Step E: Preparation of 2-methyl-3-hydroxy-4-mercaptcmethyl- 5-hydroxymethy1-6-vinylpyridine 25 Treatment of the product of Step D with sodium hydroxide and carbon disulfide by the procedure described in Example 1, Step C, yields 2-methyl-3-hydroxy-4-mercaptomethyl- 5-hydroxymethy1-6-vinylpyridine. - 72 - 3 0 8 0 U Example 14 Uunte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vlnylpyritlinc __ Step A: Preparation of 2-methyl-3-hydroxy-4-chloromethy 1 5 5-vinyl pyridine hydrochlorido A mixture of 1.65 g. of 2-methyl-3-hydroxy-4-hydroxymethy1-5-vinylpyridine hydrochloride, 1 ml. of thionyl chloride and 20 ml. of tetrahydrofuran is refluxed 6 hours. After cooling, the precipitate is collected on a filter, washed lo with ether and dried to give 2-methyl-3-hydroxy-4-chloromethyl- 5-vinyl pyridine hydrochloride.
Stop 1!: ('reparation of Bunte salt of 2-methyl-3-hydroxy-4-mcrcaptomethy1-5-vinylpyrid ine A solution of 20 g. of sodium thiosulfate penta-15 hydrate in IS ml. of water is added to a solution of 18 y. of 2 -inethy l-3-hydroxy-4 -chloromethy1-5-v iny lpyr idi ne hyd roch1->>ride in 1<*> ml. of 507. ethanol. The mixture is heated for one hour at 75°C., cooled and evaporated Lo dryness to yive the liunLe :.;a 11 of 2-mothy 1-3-hydroxy-4-mercaptomethy 1 -5-2<> v i ny 1 py r id i ne , m.p. Ir)8-200°C.
Example 15 2-Methy1-3-Hydroxy-4-Mercaptomethyl-5-VinyIpyridine Mixed Disulfide with penicillamine, Pihydrochloride The Bunte salt (O.Ol inole) from Example 14, o.ol 25 mole of penicillamine and 3 molecular equivalents of sodium hydroxide (2.5 :\i aqueous solution) are warmed together on a steam bath tor 2 hours. After cooling the mixture is extracted with 2 x 50 ml. of ethyl acetate. The extract is dried over - 73 - magnesium sulfate and concentrated to dryness. The residue is taken up in tetrahydrofuran and treated with hydrogen chloride to precipitate the dihydrochloride of 2-methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine mixed disulfide with penicillamine.
Example 16 2-Methyl-3-Hydroxy-5-Vinyl-4-Pyridylmethylthiophosphonic Aci d Step A: Preparation of sodium 2-methyl-3-hydroxy-5-vinyl-4- pyridylmethylthiophosphorothioate Trisodium phosphorothioate (1.8 g., 0.01 mole) in water (5 ml.) is run into a solution of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride (O.Ol mole) in water (15 ml.) at 0°. The solution is stirred overnight at 10°. The solution is diluted with methanol and the solid sodium 2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthiophosphorothioate is filtered off.
Step B: Preparation of 2-methyl-3-hydroxy-5-vinyl-4- pyridylmethylthiophosphonic acid The product from Step A (O.Ol mole) in water (40 ml.) is acidified to pH 1 with dilute hydrochloric acid, and kept there for 20 minutes. Methanol is added to precipitate the subject compound as an internal salt.
Example 17 2-Methyl-4-Mercaptomethyl-5-Vinylpyridine Step A: Preparation of 2-methyl-4-acetoxymethyl-5- hydroxymethylpyridine - 74 - 3 9 8 9 G 2-Methyl-4,5-di(hydroxymethyl)pyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.1 mole) at room temperature overniyht. The pyridine is evaporated and the residue is dissolved in lO ml. water and extracted with 5 2 x 30 ml. of chloroform. After drying over magnesium sulfate, the chloroform is evaporated and the residue is chromato-yraphed on a silica gel column using benzene-ethanol as eluate. By this precedure is obtained: (1) 2-methyl-4-acetoxy-5-hydroxymethylpyridine; lO (2) 2-methyl-4-hydroxymethyl-5-acetoxymethylpyridine; (3) 2-methy1-4,5-d L(acctoxymethyl)pyridine.
Step B: Preparation of 2-niethyl-4-acetoxymethyl-5-formy1- pyridine This product is prepared by oxidation of 2-methyl-15 4-acetoxymetnyl-5-hydroxymethylpyridine (from Step A) with chromium trioxide in pyridine by the procedure substantially .is described in Example 11, Step A.
Step C: Preparation of 2-methyl-4-acetoxymethyl-5-viny 1- pyridine 2u This product is prepared from the product of Step I! by means of a Wittig reaction using triphenylmethylphosphonium bromide as reagent and the procedure substantially as described in Example 1, Step A.
Stop I): Preparation of 2-methyl-4-hydroxymethyl-5-vinyl-2'j pyr id ino The product from Step C (0.00 mole) is stirred in .in aqueous alcoholic solution (1:1) of 2.5 N sodium hydroxide (40 ml.) at room temperature for 4 hours. The mixture is - 75 - 39890 concentrated to dryness. The residue is dissolved in 20 ml. of water, acidified with acetic acid and neutralized with sodium bicarbonate. The precipitate is collected and dried to give 2-methyl-4-hydroxymethyl-5-vinylpyridine. 5 Step E: Preparation of 2-methyl-4-mercaptomethyl-5- vinylpyridlne The above product, O.l mole, is dissolved in lOO ml. of tetrahydrofuran and O.l role of thionyl chloride introduced. After 3 hours at reflux, the reaction mixture is lO cooled and the desired intermediate 4-chloromethyl compound is isolated by filtration.
The 4-chloromethyl compound (O.l mole) in lOO ml. of absolute ethanol is added dropwise to a solution of 0.35 equivalents potassium ethylxanthate in 200 ml. of water at O-15 5°C., at such a rate that the temperature docs not exceed lo°C.
After the addition, tho reaction mixture is left for one hour at 5-10°C. and 4 hours at room temperature. The reaction mixture is quenched on 150 ml. of ether and shaken well. After separation, the ethereal layer is dried over magnesium sulfate 20 and evaporated ^n vacuo to afford 4-ethylxanthatomethyl intermediate.
The xanthate in 200 ml. of tetrahydrofuran:ether (3:1 .•/v) is added to excess of lithium aluminium hydride under ethex and nitrogen at 0°C. over 30 minutes. After being stirred 25 one hour at room temperature, it is poured into a mixture of tetrahydrofuran and saturated ammonium chloride solution. The aqueous layer is separated and extracted with 2 x 400 ml. of tetrahydrofuran. The combined tetrahydrofuran solutions are dried and evaporated to dryness to give 2-methyl-4-mercapto- - 76 - 3980(3 iiiethy I. -5-v i ny I pyr id i no.
Example 18 2-Mcthyl-4-Vinyl-5-Hcrcaptomethylpyricline By the procedure substantially as described in !> Example 17, Steps B, C, D, E, but substituting for the 2-methyl-4-acetoxymethyl-5-hydroxymethylpyridine used in Kx.imple 17, Step B, an equivalent amount of 2-methyl-4-hydroxymethyl-!>-acetoxyjnethylpyridine, there arc produced sequentiaIly, lo 2-methy1-4-formy1-5-acetoxymethylpyridine, 2-methy1-4-viny1-5-acetoxymcthylpyridine, 2-methyl-4-vinyl-5-hydroxymothylpyridine, and 2-methy1-4-viny1-5-mercaptomethyIpyridine.
Kxample 19 I2-Vii»yl-'j-Morcaptomethy 1 pyridine :;i i'|i A: It«-p.ir.it i i>n o I nu■ thy I-<»-nn'l.liy I n i c<>t. i i>• 11 «• O-MothylnicoL inic acid (O.l mole) is refluxed in loo ml. of methanol saturated with gaseous hydrogen chloride for I hour and then evaporated to dryness. The residue is 20 stirred saturated with aqueous sodium bicarbonate solution and the product is extracted into chloroform. The chloroform extract is dried and concentrated to dryness to yive nioLliy) 6-methy Inicot inatc.
Step B: Preparation of 2-methyl-5-hydroxymethylpyridine 2rj Methyl 6-methyInicotinate (0.05 mole) is stirred in dry tetr.ihydrof uran (50 ml.) at 10°C. while solid lithium - 77 - 3 9 8 9 0 aluminum hydride (0.0125 mole) is added over one hour. Water (10 ml.) is added with stirring, and the mixture is concentrated to dryness. The residue is extracted several times with hot isopropanol and the combined extracts are filtered and 5 concentrated to dryness to give 2-methyl-5-hydroxymethyl- pyridine.
Step C: Preparation of 2-methyl-5-acetoxymethylpyridine 2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0. 15 mole) at room temperature overnight. The mixture is concentrated to dryness, and the residue is dissolved in 70 ml. of water and extracted with 3 x 25 ml. of chloroform. After drying over sulfate, the chloroform is concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine.
Step D: Preparation of 2-methyl-5-acetoxymethylpyridine-N-oxide 2-Methyl-5-acetoxymethylpyridine (0.05 mole) is stirred in 50 ml. of chloroform at 15°C. while chloroperbenzoic acid (0.06 mole) is added over 10 min. The solution is 20 extracted with saturated sodium bicarbonate solution (3 x 20 ml.) and 2 x 20 ml. of water. The chloroform is dried over magnesium sulfate, and concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine-N-oxide.
Step E: Preparation of 2,5-di(acetoxymethyl)pyridine 25 2-Methyl-5-acetoxymethylpyridine-' -oxide (0.05 mc_3) is refluxed in 50 ml. of acetic anhydride for two hours and then evaporated to dryness. The residue is fractionally distilled under high vacuum to obtain 2,5-di(acetoxymethyl)-pyridine. lO 15 - 78 - 3 9 8 0 0 Stop F: Preparation of 2.5-di(hydroxymcthyl)pyridine 2,5-Di(acetoxymethyl)pyridine (0.05 mole) is reduced with lithium aluminium hydride (0.025 mole) in tetrahydrofuran (50 ml.) at 0°C. with stirring. After one hour, water is added 5 to decompose excess of hydride, and the mixture is concentrated to dryness. The residue is extracted with hot isopropanol (2 x 60 ml.) and the extract is concentrated to dryness to give 2,5-di(hydroxymethyl) pyridine.
Step G; Preparation of 2-formyl-5-hydroxymethylpyridine lo 2,5-Di(hydroxymethyl)pyridine (10 g.) in 300 ml. of hot chloroform is treated with lOO g. of manganese dioxide. After half an hour of stirring, the mixture is filtered and the filtrate is evaporated to dryness to give 2-formyl-5-hydroxymethylpyridine.
IS Step II: Preparation of 2-formy l-5-cl» loromethy Ipy r id ine hydrochloride 2-Formyl-5-hydroxymt:tiiylpyrid ine (O.l mole) in lOO mi. of tetrahydrofuran is treated with O.ll mole of thionyl chloride, and the mixture is refluxed for 3 hours. The product, 2o 2-formyl-5-chloromethylpyridine hydrochloride is collected by 1i1Lralion from the cooled reaction mixture.
Step 1: Preparation of 2-di (methoxy)inethyl-5-chloromethyl-pyridine hydrochloride A mixture of o.1 mole of 2-formyl-5-chloromethyl 25 pyridine hydrochloride and 250 ml. of methanol that has been saturated with hydrogen chloride is stirred overnight at room temperature. The reaction mixture is then concentrated in vacuo to give 5-chloromethyl-2-di(methoxy)methylpyridine hydrochloride. - 79 - 39890 Step J: Preparation of bis^Z-formyl-5-pyridylmethy£7 disulfide ______ a solution of O.l mole of 2-di (met".ioxy)methyl-5-chloromethylpyridine in absolute alcohol (ISO ml.) is added 5 dropwise at 10-15°C. over 20 minutes, to a suspension of 6 g. of sodium sulfide (^282) in 50 ml. of absolute alcohol. The mixture is stirred at room temperature for half an hour and then for 15 minutes at 40-50°C. and is poured into 800 ml. of water. The mixture is extracted with ether and the extract is lo dried over magnesium sulfate and concentrated to an oil. The oil is dissolved in 80 ml. of IN hydrochloric acid and heated for 20 min. at 40°C. The mixture is cooled, its pH is adjusted to 7 with sodium bicarbonate and the mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and 15 concentrated to dryness to give bis/2-formyl-5-pyridylmethyl7-disulfide.
Step K: Preparation of bis/2-vinyl-5-pyridylmethyl7disulfide By the process of k'xample 1, Step A, but using as starting materials bis/7-formyl-5-pyridylmethyl7clisulf ide and 20 triphenylmethylphosphonium bromide, there is produced bis^J-viny1-5-pyridylmethyl7disulfide.
Stop L: Preparation of 2-Vinyl-5-mercaptomethylpyridine To a suspension of 0.2 gm. of lithium aluminium hydride in lOO ml. of dry tetrahydrofuran was added 0.004 mole 25 of bis^T-vinyl-5-pyridylmethyI7disulfide. The reaction mixture was stirred for 3 hours at 0-5°. At this time there was added to the reaction mixture lOO ml. of benzene, 50 ml. of water, and 20 gm. ammonium chloride. The organic layer was separated - 80 - :i a 8 <) ii and tlie aqueous layer extracted twice with 50 ml. of benzene. The combined benzene extracts were washed well with water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (250 gm.) and elution with ether 5 gave 2-vinyl-5-mercaptomethylpyridine.
Example 2Q 2-Methyl-3-Hydroxy -4-Mercaptomethyl-5-VinyIpyridine-N-Oxlde Hydrochloride Step A: Preparation of 3,4u-di-0-isopropylidene derivative lo of pyridoxine N-oxide The 3,4n-di-0-isopropylidene derivative of pyridoxine (0.05 mole) is stirred in 50 ml. of chloroform at 15°C while m-chloroperbenzoic acid (0.06 mole) is added over lO minuter,. The solution is extracted with saturated sodium bicarbonate 15 solution (3 x 20 ml.) and water (2 x 20 ml.). The chloroform layer is dried over magnesium sulfate and concentrated to dryness to give the 3, 4tt-di-0-isopropy I idene derivative ol pyridoxine N-oxide.
Step B: Preparation of 3,4u-di-0-isopropylidene derivative 20 of 2-methyl-3-hydroxy-4-hydroxymethylpyridine-5- aldehyde-N-oxide To 75 ml. of dry methylene chloride containing 4.7'< ml. or dry pyridine is added with stirring and cooling 2.')G g. of chromium trioxide. The mixture is left for 20 minutes 25 at room temperature and then treated with a solution of 1 . of the product from Step A in 25 ml. of dry methylene chloride over 15 minutes. After one hour at room temperature, tli ■ mixture is filtered and the residue washed wit n 2 x lo ml. ol - 81 - 3 9 8 9 6 methylene chloride. The combined filtrates are extracted with 3 x 50 ml. of 5% (w/v) aqueous sodium hydroxide solution, dried over magnesium sulfate and evaporated no dryness to give 3,4a-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-aldehyde-N-oxide.
Step C; Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine-N-oxide hydrochlorldo By the procedure of Example 1, Steps A, B, and C, using as starting material 3,4a-di-0-isopropylidene derivative of 2-methy1-3-hydroxy-4-hydroxymethylpyridine-5-aldehyde-N-oxide and triphenylmethylphosphonium bromide, there are produced in sequence: 3,4u-di-0-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine-N-oxide, 2-methyl-3-hydroxy-4-hydroxymethy1-5-vinylpyridine-N-oxide hydrochloride, and 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine-N-oxide hydrochloride.
Example 21 Bis/2-methyl-3-hydroxy-5-vinvl-4-pyridylmethyl7disulfide 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride (9 g.) is dissolved in 50 ml. water and treated with 2 N ammonium hydroxide to about pH 9. Air is bubbled through the solution for 24 hours. The precipitated bis/T-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl7disulfide is collected on a filter and dried, m.p. 178-180° (dec.). - 82 - 3980 u Example 22 Uis/T-methyl-3-hydroxy-5-vinyl-4-pyridylmethyr7disulfide 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride (4.36 g.) is dissolved in 40 ml. of water at 5 2-7°C. under a nitrogen atmosphere. To this solution there is added 2.0 ml. of 30i hydrogen peroxide over 2 mins. while maintaining the temperature at 2-7°C. After 30 minutes, stirring at this temperature, the mixture is filtered and, under nitrogen, the filtrate is stirred with excess of lo saturated sodium bicarbonate solution at 2°C. for 10 minutes.
The mixture is filtered quickly and the filter cake washed with 2 x 4o ml. of acetonitrile. The solids are dried over phosphorus pentoxide to give 1.5 g. of bis/2-metliy1-3-hydroxy-5-vinyl-4-pyridylmethyl7disulfide, m.p. >300°. The rnonohydrate 15 has m.p. 178-180°C.
Eximple 23 2-Hethy 1-3-Hydroxy-4-Mereaptomethy1-5-VinyIpyr id ine Step A: Preparation of ?-methyl-3-hydroxy-4-benzoylthio-methy1-5-vinyIpyridine To a stirred solution of 65 g. of 2-methy 1-3-hydroxy-4-chloromethyl-5-vinylpyridine in I liter of ethanol under nitrogen there is added 96 g. of potassium thiobenzoate in 2UO ml. of water over 30 minutes. After 1 hour, the ethanol is evaporated at 4G°C. and the aqueous solution is extracted 25 with 4 x 300 ml. of ethyl acetate. The extract is washed with 1 x 75 ml. of water, dried over magnesium sulfate and concentrated to dryness to give 2-methyl-3-hydroxy-4-benzoy1thiomethy1-5-vinylpyridine. - 83 - 39806 Step D: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl- 5-vinylpyridine A mixture of 1 g. of 2-methyl-3-hydroxy-4-benzoylthiomethy 1-5-vinylpyridine, 10 ml. of tetrahydrofuran, 5 and 10 ml. of 2.5 N aqueous sodium hydroxide is left at room temperature overnight. The solution is acidified to a pH of about 6 with hydrochloric acid and the pll then adjusted to 7.5 with solid sodium bicarbonate. The mixture is extracted with 3 x lOO ml. of ethyl-acetate: isopropanol (9:1 v/v). The 10 extract is dried over magnesium sulfate and concentrated to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.
Example 24 2-Methyl-3-Hydroxy-4-Mercapt-ome thy 1-5-Viny lpyr idine 2-Methyl-3-hydroxy-4-hydroxymethy 1-5-vinylpyridine, 15 O.l mole, is dissolved in lOO ml. of tetrahydrofuran and 0.1 mole of thionyl chloride introduced. After 3 hours reflux, the reaction mixture is cooled and the desired 4-chloromethyl intermediate compound is isolated by filtration.
The 4-chloromethyl compound (O.l mole) in lOO ml. of 20 absolute ethanol is added dropwise to a solution of 0.35 equivalents potassium ethylxanthate in 200 ml. of water at 0-5°C., at such a rate that the temperature does not exceed lO°C. After addition, the reaction is left for one hour at 5-10°C. and 4 hours at room temperature. The reaction mixture 25 is quenched on 150 ml. of ether and shaken \ell. After separation, the ethereal layer is dried over magnesium sulfate and evaporated in vacuo to afford the 4-ethylxanthatomethyl intermediate compound. - 84 - 39890 Tho xanthate in 200 ml. of tetrahydrofuran:other (3:1 v/v) is added to excess of lithium aluminium hydride under oilier aiul n LI. r«njon al •>"('. over Jo minutes. Alter beinq stirred for one hour at room temperature, it is poured into 5 a mixture of tetrahydrofuran and saturated ammonium chloride solution. The aqueous layer is separated and extracted with 2 x 400 ml. of tetrahydrofuran. The combined tetrahydrofuran solutions are dried and evaporated to dryness to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. lo Example 25 2-Methyl-3-llydroxy-4-Mercaptomethyl- 5-Viny lpyr idine Hydro-cli lor ide Step A: Preparation of 2-methyl-3-hydroxy-4-isothioureido- methy1-5-vinylpyridine 15 A mixture of 21.O g. of 2-methyl-3-hydroxy-4- chloromethyl-5-vinylpyridine, 6.74 g. of thiourea, and 200 ml. of ethar.ol is refluxed for 3 hours. The mixture is cooled and filtered and the solids were washed with ether to give 2-inotliyl -3-hydroxy-4- isoth ioureidomethy 1-5-viny Ipy rid ine 20 hydrochloride.
Stop U: Preparation of 2-methyl-3-hydroxy-4-inercaptomethy 1-5-vinylpyridine hydrochloride A mixture of 9.0 g. of the isothioureido compound of Step A, and 60 ml. of 6.5'A (w/v) potassium hydroxide is 25 refluxed for 4 hours. A black solid is filtered off, and the filtrate acidified with acetic acid and evaporated to dryness. Tho residue is extracted with 40 ml. of water and 200 ml. of other. The aqueous phase is separated, acidified with 85 - 39896 concentrated hydrochloric acid, basified with sodium bicarbonate solution and extracted with ethyl acetate. Evaporation to dryness gives 2-methyl-3-hydroxy-4-mercapcomethyl-5-vinylpyridine hydrochloride. 5 Example 26 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine The isothioureido compound from Example 25, Step A, (O.l mole) in 200 ml. of tetrahydrofuran:ether (3:1 v/v) is added to an excess of lithium aluminium hydride under ether 10 and nitrogen at 0°C. over 30 minutes. After being stirred for one hour at room temperature, it is poured into a mixture of tetrahydrofuran and saturated ammonium chloride solution. The aqueous layer is separated and extracted with 2 x 400 ml. of tetrahydrofuran. The combined tetrahydrofuran solutions are 15 dried and evaporated to dryness to give 2-methyl-3-hydroxy-4-mercaptomethyl-5- vinylpyridine.
Example 27 2-Methy1-3-Hydroxy-4-Mcrcaptomethyl-5-Vinylpyridine The Uunte salt of 2-methyl-3-hydroxy-4-mercapto-20 methyl-5-vinylpyridine (O.l mole) in 200 ml. of tetrahydro-furan:ether (3:1 v/v) is added to an excess of lithium aluminium hydride under ether and nitrogen at 0°C. over 30 minutes. After being stirred for one hour at room temperature, it is poured into a mixture of tetrahydrofuran and saturated 2 5 ammonium chloride solution. The aqueous layer is separated and extracted with 2 x 400 ml. of tetrahydrofuran. The combined tetrahydrofuran solutions are dried and evaporated to dryness - 86 - 3 9 8 9 G to yive 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine.
Example 28 Bis^2:-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl7Disulfide dihydrochloride 5 The xanthate product (0.05 mole) from Example 24 in 50 ml. of concentrated ammonium hydroxide and lOO ml. of ethanol is stirred overnight at room temperature. The oily residue is extracted into 2 x lOO ml. of methylene chloride and dried over magnesium sulfate. The solution is filtered lo and treated with dry gaseous hydrogen chloride Example 29 I'« Mi s/T-Motliy I -3-llydroxy-5-Viny 1 -4-1'yr idy lino thy I/l)i su I f i do i) ihydroch lor ide The Uunte salt of 2-methyl-3-hydroxy-4-mercapto-methyl-5-vinylpyridine (O.l mole) is refluxed for 18 hours with 1 N sulfuric acid. The mixture is concentrated to dryness, 20 the residue is taken up in isopropanol and the solution is filtered and again evaporated to an oil. The oil is treated with aqueous sodium bicarbonate solution. The resulting solid is collected, dissolved in isopropanol and treated with gaseous hydrogen chloride. Addition of other causes crystalli-25 nation of bis/2~methyl-3-hydroxy-5-viny 1 -4-pyridy lmotlty disulf ide d i hydrochlor ido. - 87 - 3 9 8 9 G Example 30 2-Methyl-3-Hydroxv-4-Mercaptomethy1-5-Vinylpyridine To a suspension of 0.2 gm. of lithium aluminium hydride in lOO ml. of dry tetrahydrofuran is added 0.004 5 mole of bis^7-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl7~ disulfide. The reaction mixture is stirred for 3 hours at 0-5°. At this time there is added to the reaction mixture lOO ml. of benzene, 50 ml. of water, and 20 gm. ammonium chloride. The organic layer is separated and the aqueous lO layer extracted 2 times with 50 ml. of benzene. The combined benzene extracts are washed well with water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (250 gm.) and elution with ether gives 2-methyi- 3-hydroxy-4-mercaptomethyl-5-vinylpyridine. 15 Example 31 o-Carboxyphenyl 2-methyl-3-hydroxy-5-vinylpyrid-4-yl-methyl Disulfide To a solution of 0.02 mole of o-carboxyphenyl o-carboxybenzenethiolsulfonate in 200 ml. of 95% ethanol is 20 added 0.02 mole of finely powdered 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. The reaction mixture is stirred overnight at room temperature and the resulting precipitate filtered to yield o-carboxyphenyl 2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl disulfide. 25 Similarly prepared is o-carboxyphinyl 2-methyl- 3-hydroxy-5-ethynylpyrid-4-ylmethyl disulfide.
Example 32 S,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl)- - 88 - 3 9 8 9 0 carbonodithioate Pihydrochloride To an ice-cooled solution of 4.5 gm. of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of dry pyridine is added dropwise 10 ml. of a 12.5% solution 5 of phosgene in benzene. Tho reaction mixture is allowed to come to room temperature and stirred for three hours after which time it is concentrated iii vacuo. The residue is extracted and partitioned between benzene and saturated sodium bicarbonate solution. The benzene layer is separated. It) washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographe 1 on 250 gm. of silica gel. Elution with ether gives S,S'-bis (2-methyl-3-hydroxy-5-v iny1-4-pyr idylmethy1)carbonodithioate Similarly prepared is S, 3'-bi s (2-m >thy 1 - 3-hydroxy-l r> 5-ethynyl-4-pyridylmethyl) oarbonod i th ioa te di hydroch lor ide .
Example 3 3 S,S'-bis(2-niethyl-3-hydrox/-5-viny1-4-pyridylmethyl) I,3-ben/.ened icarboth io.ite To a solution of 4.S ym. (O.Q2 mole) of 2-niethyl-20 3-hydroxy-4-inercaptomethyl-5-vinylpyridine in 50 ml. of pyridine and 50 ml. of chloroform is added dropwise with stirring a solution of 2.0 gm. (O.Ol mole) of isophthaloyl dichloride in 50 nil. of chloroform. The reaction mixture is stirred overnight at room temperature and then concentrated 25 jji vacuo. The residue is extracted between benzene and saturated sodium bicarbonate solution. The benzene layer is separated, washed with water, dried over sodium sulfate and concentrated _in vacuo to give an oil. Chromatography on 1,000 - 89 - 3 9 8 9 G gm. of silica gel and elution with ether affords S,S'-bis{2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl) 1,3-benzenedicarb-othioate.
Similarly prepared is S,S'-bis(2-methyl-3-hydroxy-5-ethynyl-4-pyridylmethyl) 1,3-benzenedicarbothioate.
Example 34 Ethyl N-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthio-carbonyl)qlycinate To a well stirred mixture of 20 ml. of 12.5% phosgene in benzene and 50 ml. of benzene is added dropwise a solution of 2.5 gm. (O.Ol moles) of 2-methyl-3-hydroxy- 4-mercaptomethyl-5-vinylpyridine in 25 ml. of benzene. The reaction mixture is stirred for 3 hours and then purged with nitrogen for 1 hour to remove any unreacted phosgene. The reaction mixture is then concentrated _i_n vacuo to give a gummy solid. To the above is added 5.6 gm. (0.04 moles) of ethyl glycinate and lOO ml. of dry dioxane. The mixture is stirred and 6 ml. of triethylamine added. After stirring overnight a1 room temperature, the mixture is concentrated in vacuo and the residue extracted and partitioned between ether and saturated sodium bicarbonate solution. The ethereal layer is separated, washed with water, dried over sodium sulfate and concentrated to give crude product. Chromatography on 900 gm. of silica gel and elution with ether gives ethyl N-(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethylthio-carbonyl)glycinate.
Similarly prepared is ethyl N-(2-methyl-3-hydroxy- 5-ethyny1-4-pyridylmethylthiocarbonyl)glycinate. - 90 - 3 9 8 9 C Example 35 N,N'-Diethyl 2-mcthyl-3-hydroxy-5-vinylpyrld-4-yl-methylsulfenamide To a suspension of 9.5 gm. of lead thlocyanate in 5 200 ml. of dry ether which had been cooled to o-5°, is added dropwise 3.7 gm. of bromine dissolved in 25 ml. of carbon tetrachloride. The reaction mixture is stirred for 30 minutes after the addition is complete. The supernatant liquid which contains the thiocyanogen, is decanted into a 10 1-liter flask equipped with a mechanical stirrer and ether is added to make 500 ml. of solution. A solution of 4.5 gm. of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of ether is added dropwise. A heavy precipitate forms immediately and the reaction mixture is stirred for 30 15 minutes after the addition is complete. Diethylamine (15 ml.) is then added and the reaction mixture allowed to come to room temperature. After 1 hour 200 ml. of benzene and 250 ml. of saturated sodium bicarbonate are added. The organic layer is separated, washed with water, dried over sodium sulfate 20 and concentrated to give an oil. Chromatography on 600 gm. of silica gel and elution with 50% ether in petroleum ether gives N,N'-diethyl 2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl-sulfenamide as an oil.
Similarly prepared is N,N-diethyl 2-methyl-3-hydroxy-25 5-ethynylpyrid-4-ylmethylsulfenamide.
Example 36 4-Dimethylaminocarbonylthiomethy1-3-Hydroxy-2-Methyl-5-Vinylpyridine - 91 - 3 9 8 9 l> To a mixture of 7.4 gm. (0.04 m) of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. dry pyridine and 50 ml. of chloroform is added diopwise with stirring a solution of 3.25 gm. (0.3 m) of dimethyl-5 carbamoyl chloridc in SO ml. of chloroform.
The reaction mixture is stirred for 3 hours after the addition is completed, and then concentrated i_n vacuo. The residue is extracted and partitioned between ether-benzene 1:1 and saturated sodium bicarbonate solution. The ^0 organic phase is separated, washed well with water, dried over sodium sulfate, and concentrated in vacuo to give crude material. Chromatography on 900 gm. of silica gel gives 4-dimethylaminocarbonylthiomethyl-3-hydroxy-2-methy1-5-vinylpyridine . 15 Similarly prepared is 4-dimethylaminocarbonylthio me thy l-3-hydroxy-2-me thy 1-5-ethyny lpyr idine.
Example 37 S,S'-Bis(2-methyl-3-hydroxy-5-vinyl-4-pyridyImethy1) 1,4-piperazinedicarbothioate Dihydrochloride 20 To a solution of 4.50 gm. (0.02 m) of 2-methyl-3- hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of pyridine and 50 ml. of chloroform is added all at once as a solid 2.1 gm. (O.Ol m) of N,N•-dichlorocarbonyl piperazine. The reaction mixture is then stirred at room temperature 2 5 for 4 hours, concentrated in vacuo and extracted between chloroform and saturated sodium bicarbonate solution. The aqueous layer is separated and extracted two times with chloroform. The combined chloroform extracts are washed with - 92 - 3980 U water, dried and concentrated to an oil which gradually crystallizes. Recrystallizatlon from methanol gives S,S'-bis(2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl) 1,4-pipera-zinedicarbothioate dihydrochloride.
Similarly prepared is S,S'-bis(2-methyl-3-hydroxy-5-cthyny-4-pyridylmethyl) 1,4-piperazinedicarbothioate dihydrochloride.
Example 38 2-Methyl-3-llydroxv-4-Carbamoylthiomethy1-5-Vinylpyridine Employing the procedure of Example 34 but substituting for the ethyl glycinate used therein, an equivalent amount of ammonia, there is produced 2-methyl-3-hydroxy-4-iMrhamoyIthiomethy1-5-vinylpyridine.
Kxample 3') 2-Methy1-3-Hydroxy-4-Mercapuomethy1-5-(2,2-d ichloroviny1)-pyridine Hydrochloride Step A; Preparation of 5-(2,2-dichloroviny1)-2,2,8- trimethyl-4H-1, 3-dioxino/"4, 5-c/pyridine To a well stirred ice-cooled mixture of O.l mole of triphenylphosphine and O.l mole of potassium t-butoxide in 250 ml. of heptane is added over thirty minutes a mixture of o.l mole of chloroform in 200 ml. of heptane. The resulting mixture is concentrated in vacuo at 15-2o' to a volume of about lOO ml. and a solution of O.l mole of 2,2,8-tr imethy1-411-1,3-diox ino/4 ,5-c/pyridino-5-carboxul-doliyde in 25o ml. of heptane is added. The reaction mixture 39890 was heated at 40-50° for 5 hours, then cooled, filtered, and concentrated vacuo to give crude product. Chromatography on silica gel and elution with mixtures of ether and petroleum ether (10-50%) gives pure 5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4U-l,3-dioxino/H,5-c7pyridine.
Step B: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl- 5-(2,2-dichlorovinyl)pyridine hydrochloride Using the procedure of Example 1, Steps B and C, for hydrolysis of the isopropylidene group and formation of the mercapto group, there is produced 2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-dichloro"inyl)pyridine hydrochloride.
When dichlorofluoromethane is used in place of chloroform in Step A of the above procedure, there is obtained 5- (2-chloro-2-f luorovinyl) -2,2,8-1 rime thy 1-411-1, 3-dioxino^ , 5-c7pyridine, which upon hydrolysis and treatment with carbon disulfide as in Step B, there is produced 2-methy1-3-hydroxy-4-mercaptomethyl-5-(2-chloro-2-fluorovinyl)pyridine hydrochloride.
Example 40 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-(2,2-difluorovinyl)-pyridine Hydrochloride Step A: Preparation of 5-(2,2-difluorovinyl)-2,2,8-trimethyl- 4H-1,3-dioxino/^ ,5-c7pyridine A mixture of O.l mole of 2,2,8-trimethyl-4H-l,3-dioxinoZ3,5-c7pyridine-5-carboxaldehyde, O.ll mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoro-acetate in lOO ml. of diglyme is heated under nitrogen at 90° - 94 - U980o for 24 hours. The reaction mixture is then filtered and concentratcd iji vacuo. Chromatography of tho residue on •silica ycl and elution wiLli mixtures of other and petroleum other (10-50%) gives 5-(2,2-difluorovinyl)-2,2,8-trimethyl-5 411-1,3-dioxino^4,5-c7pyridine.
Step B: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-(2,2-difluorovinyl)pyridine hydrochloride Using the procedure of Example 1, Steps B and C, for hydrolysis of the isopropylidene group and formation of lo tho mercapto group, there is produced 2-methyl-3-hydroxy-4- iiii; reap tome thy l-5-(2,2-di£ luorovinyl) pyr i d inc hydroch lor ide .
Example 41 Preparation of the compound of formula: cll,, Cll3\^, N v^-"'NH2.IIBr ^ciio ch2n s — scu2 M cli3 ch2ch2ou ch3 15 Thiamine-S-monoxido is suspended in 12()nil. of water and 1.83 g. of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinyl-pyridine is added over 5 min. After being stirred for 1 hour, the mixture is filtereJ and the filtrate is extracted with n-butanol. The <_::tract is washed with water and dried over 2o magnesium sulfate. The dried solution is acidified with 484 - 95 - 3 9 8 1) G hydrobromic acid in acetic acid, and evaporated to dryness. The residue is recrystallized from ethanol to give the desired product.
Example 42 5 Preparation of Mixed Disulfides Using the procedure of Example IS, but substituting for the penicillamine an equivalent amount of ethylthiol allylthiol, benzythiol or thiophenol, there is produced respectively {2-methyl-3-hydroxy-5-vinylpyridy1-4-methyl) lO (ethyl)disuIf ide, 12-methy1-3-hydroxy-5-vinylpyridy1-4-methyl) (allyl)disulfide, (2-methyl-3-hydroxy-5-vinylpyridy1-4-methyl) (benzyl)disulfide, or (2-methyl-3-hydroxy-5-vinyl-pyridy1-4-methyl) (phenyl)disulfide.
Example 43 15 8-Methyl-2-Oxo-5-Vinyl-4H-l,3-Thioxino/S»5-g7Pyridine To a mixture of O.Ol of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. chloroform and 50 ml. pyridine is added at O to 5° a solution of 0.022 moles of phosgene in benzene. The reaction mixture is allowed to 20 warm to room temperature and is stirred overnight. The reaction mixture is then concentrated iji vacuo and excess of saturated sodium bicarbonate solution is added. The resulting solid is collected by filtration. Chromatography on silica gel and elution with methanol in chloroform (1-5%) gives 25 8-methyl-2-oxo-5-vinyl-4II-l, 3-thioxino^ , 5-c7pyridine.
When thiophosgene is used in place of phosgene in the above example,8-methyl-2-thiono-4H-l,3-dioxino/3,5-c/-pyridinc is obtained. - 96 - U989o Example 44 Sodium(2-methyl-3-hydroxy-5-vinyl-4-pyridyl) Methyl Tr ithiocarbonate 2-Methyl-3-hydroxy-4-chloromethy1-5-vinyIpyridine 5 (2o g.) is suspended in water/methanol (100:25 v/v) and treated with disodium trithiocarbonate (33%) (45 g.). The mixture is stirred at 5C°C. for 4 hours under nitrogen and adjusted to pli 6.2-6.5 with dilute acid. The precipitate is reerystal1ized from DMF/wnter to give sodium (2-metliyl-3-1<> hydroxy-5-vinyl-4-pyridyl) methyl trithiocarbonate.
Example 4 5 Bis/2-methyl-3-hydroxy-5-vinylpyridy1-4-methy Tr i thiocarbonate To a solution of 2-methyl-3-hydroxy-4-chioromethy1 15 5-vinylpyridine (9 g.) in methanol (lOO ml.) is added 22t sodium trithiocurbonate (17.5 ml.) at 20°C. The mixture is kept at 20°C. for 3 hours. The precipitate is collected, washed with water and hot ethanol, and dried and recrystal-Lized from l)MF to give bis/JJ-methyl-3-hydroxy-5-vinylpyridy 1 2o 4-methyl7trithiocarbonate.
Example 46 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine Hydrochloride The product from Example 45 (10 g.), methanol, 25 (200 ml.) and 10% NaOlI solution (50 ml.) are refluxed for lO hours. The mixture is neutralized to pll 5-7 with dilute hydrochloric acid, and extracted with ethyl acetate. The - 97 - 3 0 B 0 G extract is concentrated to dryness, and the residue is chromatographed on silica gel by elution with ethyl acetate. The ethyl acetate solution is concentrated to dryness and the residue is taken up in THF and treated with gaseous 5 hydrogen chloride to precipitate 2-methyl-3-hydroxy-4- mercaptomethyl-5-vinylpyridine hydrochloride.
Example 47 S,S' -bis/2-methyl-3-hydroxy-5-vinyl-4-pyridylmethy_l7-l, 3-Propylenedicarbothioate ; lO By the procedure of Example 33, but substituting for the isophthaloyldichloride used therein, an equivalent amount of glutaroyl chloride, there is produced S,S'-bis/5-methyl-3-hydroxy-5-vinyl-4-pyridylmethyi7-l,3-propylenedi-carbothioate. 15 Similarly, by using oxalyl chloride, malonyl - i i chloride, succinyl chloride or pentane dicarbonyl chloride, there are produced respectively: S,S' -bis/T:-methyl-3-hydroxy-5-vinyl-4-pyridylmethyi7di-carbothioate. 20 S,S' -bis/2"-methy 1-3-hydroxy-5-viny 1-4-pyr idy Imethy l7me thy 1-enedicarbothioate.
S, S'-bis/2*-me thyl-3-hydroxy-5-vinyl-4-pyridy Imethy l7-l, 2-ethylenedicarbothioate, and S,S* -bis/2-methyl-3-hydroxy-5-vinyl-4-pyridyImethy 1/-1,5-25 pentamethylenedicarbothioate.
Example 48 4-Ethoxycarbony Imethy Ithiomethyl-3-Hydroxy-2-Me thy 1-5-Vinyl Pyridine - 98 - 39800 To an ice-cold mixture of O.Ol mole of ethyl mercaptoacetatc and 0.02 mole of sodium ethoxide in lOO ml. ethanol under nitrogen is added a solution of 4-bromomethyl- 3-hydroxy-2-methyl-5-vinylpyridine hydrobromide in SO ml. 5 of ethanol. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo and taken up between ethyl acetate and water. The organic layer is separated, washed well with water, dried and concentrated. Chromatography of the residue on silica gel followed by elution with mixtures lO of ether and petroleum ether (10-50%), gives 4-ethoxycarbon-ylmethylthiomethyl-3-hydroxy-2-methyl-5-vinyl pyridine.
Example 40 4-(2-Amino-2-carboxyethyIthiomethyl)-3-Hydroxy-2-Methy1-5-Vinylpyridinc 15 Using O.Ol mole of cysteine and 0.03 mole of sodium meLhoxide in the procedure of Example 4 8, is obtained after appropriate workup, 4-(2-amino-2-carboxyethylthiomethy1)-3-hydroxy-2-methy1-5-vinyIpyridine.
Example 5Q 20 Bis/2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl7Disulfide To a mixture of 0.035 mole of sodium sulfide nonahydrate and 0.034 mole of S in 50 ml. of water is added with stirring 0.02 mole of 4-bromomethyl-3-hydroxy-2-methyl- 5-vinylpyridine hydrobromide in SO ml. H2o. The reaction 25 mixture is stirred overnight and then filtered to isolate crude product and sulfur. The precipitate is extracted with 8'A aqueous hydrochloric acid, filtered, and the filtrate then - ')") - :i 9 8 01> neutralized with sodium bicarbonate. The resulting precipitate is filtered to give bis^J-methyl-3-hydroxy-5-vinylpyridyl-4-methyf7disulfide.
Example 51 5 Bis^!Pmethyl-3-hydroxy-5-vinylpyridyl-4-methy £?trisulfide Step A: Preparation of 2-methyl-3-benzyloxy-4-hydroxy-me thy 1-5-viny lpyr idine To a mixture of O.l mole of 3-hydroxy-4-hydroxy-methyl-2-methy1-5-vinylpyridine in 500 ml. of acetone and lO 25 gm. potassium carbonate is added O.ll mole of benzyl chloride. The reaction mixture is stirred overnight, filtered, and the acetone removed i£ vacuo to yield 2-methy1-3-benzyloxy-4-hydroxymethy1-5-vinylpyridine.
Step B: Preparation of 2-methyl-3-benzyloxy-4-chloromethyl-15 5-v iny lpyr idine To a solution of O.l mole of 3-benzyloxy-4-hydroxy-methyl-2-methyl-5-vinylpyridine in 500 ml. of benzene is added dropwise with cooling a solution of O.ll mole of thionyl chloride in 50 ml. benzene. The reaction mixture is stirred 2O for 1 hour and then filtered to give 2-methyl-3-benzyloxy-4- chloromethy1-5-vinylpyridine.
Stop C: Preparation of 2-methyl-3~benzyloxy-4-mercaptomethyl-5-vinylpyridine To a well stirred solution of O.ll mole of thiourea 25 in 250 ml. methanol, under N2 is added O.l mole of 3- benzyloxy-4-chloromethy1-2-methy1-5-vinylpyridine hydrochloride. The mixture is refluxed for 1 hour and then cooled. A solution of 0.4 mole of sodium hydroxide in 50 ml. of water is - lOO - 3980u added, and tlic resulting mixture refluxed for 30 minutes. After concentration iji vacuo the reaction mixture is taken up between benzene and water and enough acetic acid added to neutralize tho mixture. The organic layer is separated, r> washed well with water, dried, and concentrated to give 2- moLhy1-3-benzyloxy-4-mereaptomethy1-5-vinyIpyridino.
Step D; Preparation of bis23"-methyl-3-benzyloxy-5- vinylpyridyl-4-methyI7trisulfide To O.Ol mole of sodium hydride in 50 ml. dry lO dimethylformamide under nitrogen at 0-5° is added 0.01 mole of 2-methy1-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine in lo ml. of diinethylforin.iniide. When the evolution of hydrogen li.is censed, O.OOS mole ol* sulfur dichloride is added. The reaction mixture is stirred overnight, poured into benzeno-15 ice-water, dried and concentrated. Chromatography on silica gel and elution with mixtures of other and petroleum ether (l0-80'4) gives bis/2-methyl-3-benzyloxy-5-vinylpyridyl-4-methyl7trisulf ide.
Step K: Preparation of bis/]n-methyl-3-hydroxy-5-viny1-2o pyridyl-4-methyl7trisulfide A mixture of O.Ol mole bis(3-benzyloxy-2-methyl-5-vinylpyridyl-4-methyl)trisulfide in lO ml. concentrated hydrochloric acid and 20 mi. acetic acid is heated for 2 hour: at 60°. The reaction mixture is concentrated _in vacuo and 2 5 taken up between benzene-ether (1:1) and saturated sodium bicarbonate solution. The organic layer is separated, washed with water, dried and concentrated in vacuo to yield bis/2"-methyl-3-hydroxy-5-vinylpyridyl-4-methyiy trisulf ide. - lOl 39896 Example 52 Bis£F-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl7Tetrasulfide Following the procedure substantially as described in Example 51, Steps D and E, but substituting for the sul£ur 5 dichloride used in Step D, an equimolar amount of sulfur monochloride, there is produced in turn, bis/?-methyl-3-benzyloxy-5-vinylpyridyl-4-methyf7tetrasulfide and bis£f-methyl-3-hydroxy-5-vinylpyridyl-4-methyl7tetrasulfIde.
Example 53 10 Bis^T-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methy][7Disulfide The Bunte salt of 2-methyl-3-hydroxy-4-mercapto-methyl-5-vinylpyridine (2.6 g.) is dissolved in a solution of 1.9 g. 2-methyl-3-hydroxy-4-mercaptoir.ethyl-5-vinyl-pyridine in 16 ml. of 10% (w/v) sodium hydroxide solution. 15 The pll is adjusted to 6.5 with dilute hydrochloric acid. The precipitate is collected, washed with water, acetone and ether and dried to give bis^-methyl-3-hydroxy-5-vinyl-pyridyl-4-methy^disulfide.
Example 54 20 Bis//2"-methyl-3-hydroxy-5-vinylpyridyl-4-methyl7Disulf ide A solution of 3.3 g. of the Bunte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 50 ml. of 60% (v/v) aqueous methanol is treated with 0.85 g. of sodium sulfide. (^282) in 5 ml. of water with stirring for 25 3 hours. The solution is stored at room temperature for 16 hours. The precipitate is collected, washed with water, - 102 - 39800 acetone nnd other and dried to give bls/2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl/disulfide.
Substituting for the 0.85 g. of Na2S2 used in the above example, 1.2 g. of Na2S.9H20, the same result is 5 accomplished.
Example 55 Bis/2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl7Disulfide A solution of 12.2 g. of the Bunte salt of 2-methy1-3-hydroxy-4-mercaptomethyl-5-vinylpyridine in 200 ml. of 50% 10 (v/v) aqueous methanol is treated with 6.4 g. of iodine and the mixture is stirred at room temperature for 16 hours. The precipitate is collected, washed with water, acetone and ether, and dried to give bis/2-methyl-3-hydroxy-5-vinyl-pyridyl-4-methyX/disulfide. 15 Example 56 Bis/2-Methyl-3-Hydroxy-5—Vinylpyridy1-4-Methy1/Disulfide A solution of 4.9 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine in 250 ml. of pyridine is treated with 2.5 g. of freshly prepared P2S5 Powder and the mixture 20 is refluxed for 4 hours. The solvent is removed under reduced pressure. To the residue is added 200 ml. of 2.5 N hydrochloric acid and the mixture is refluxed for 2 hours. After cooling, it is poured into saturated sodium bicarbonate solution. The precipitate is collected, washed with water, acetone and ether, 25 and dried to give bis/2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl/disulfide. - 103 - 39800 Example 57 Bls/7:-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyr7Disulf ide A solution of 10 g. of 2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl?.sothiuronium bromide in 35 ml. of 5 methanol and 15 ml. of water is treated with 50 ml. of 10% (w/v) aqueous sodium hydroxide solution. 8.0 g. of 10% aqueous hydrogen peroxide is added at 20°C. and the mixture ir stirred for 5 minutes and then neutralized with 10% hydrochloric acid solution. The precipitate is collected, 10 washed with water, acetone and ether, and dried to give bis£T-methyl-3-hydroxy-5-vinylpyridyl-4-methy^disulfide.
Example 58 Uis£2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl_7Disulf ide A mixture of 77.8 g. of 2-methyl-3-hydroxy-5-vinylpyridyl-4-methylisothiuronium bromide in 250 ml. water, 27 g. of sodium tetrathionate in 500 ml. of water, and 350 ml. of 4N sodium hydroxide solution is stirred at room temperature for 30 mins. Hydrochloric acid (4N) is added to pH 6. The precipitate is collected, washed with water, acetone and ether, and dried to give bis/2~methyl-3-hydroxy-5-vinylpyridyl-4-methyl/dlsulfide.
Example 59 Bis/2-Methyl-3-Hydroxy-5-Vinylpyridyl-4-Methyl7Disulf ide A mixture of 36.5 g. of 2-methyl-3-hydroxy-5-25 vinyl-4-pyridylmethyl ethyl xanthogenate in 730 ml. of methanol and 365 ml. of concentrated ammonium hydroxide is - 104 - 15 20 3980G cooled to 5°C. and treated with 190 ml. of 3% hydrogen peroxide solution dropwise over 30-45 minutes. After stirring 2 hours at 2-5°C., the precipitate is collected, washed with water, acetone and ether and dried to give bis/J"-methyl-3-5 hydroxy-5-vinylpyridyl-4-methyl7disulfide.
Example 60 Bis^2*-Me thy l-3-Hydroxy-5-Vinylpyr idy l-4-Methyl7Disul fide Step A: Preparation of 2-methyl-3-hydroxy-4-methane-sulfonyloxymethy1-5-vinylpyridine lo A mixture of 0.1 mole of 2-methyl-3-hydroxy-4- hydroxymethyl-5-vinylpyridine and 0.1 mole of methane-sulfonyl chloride in lOO ml. of dry pyridine is held one hour at roo.u temperature and then evaporated i_n vacuo Lo about lO ml. This residue is partitioned between lOO nil. of 15 chloroform and lOO ml. of saturated aqueous sodium bicarbonate solution. The organic phase is separated, washed with water, dried, filtered, and concentrated to dryness to y i ve 2-methy L-3-hydroxy-4-metiianesul f ony loxyinethy 1-5-v i ny l-pyridine. 20 Step B: Preparation of bis/_2-methyl-3-hydroxy-5-vinyl-pyridy1-4-methy1/disulfide The residue from Step A is taken up in lOO ml. of 60% (v/v) aqueous methanol and treated with O.l mole of Na2S2 in lO ml. of water. After stirring 16 hours at room 25 temperature the precipitate is collected, washed with water, acetone and ether and dried to give bis^2*-methyl-3-hydroxy-5_vinylpyridyl-4-methyl7disulfide. - 105 - 39 8 9 G Example 61 A mixture of 250.parts of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride and 25 parts of lactose is granulated with a suitable amount of water, and to this is added lOO parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60°C. The dry granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration.
The specific mercaptomethylpyridine used in the foregoing example may be replaced by 25, lOO, 250 or 500 parts of other mercaptoalkylpyridines of this invention to produce cablets suitable for oral administration according to the method of this invention.
Example 62 A mixture of 50 parts of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride, 3 parts of the calcium salt of lignin sulfonic acid, and 237 parts of water is ball-milled until the size of substantially all of particles is less than lO microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethyl-cellulose and 0.9 parts of the butyl ester of p-hydroxy-benzoic acid in 300 parts of water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes.
Example 63 A mixture of 250 parts of 2-methyl-3-hydroxy-4-vinyl- - 106 - 39 89g 5-mercaptomethylpyridine, 200 parts of maize starch, and 30 parts of nltjlnit: acid is mixed with .1 sufficient quantity «»L" lov. aqueous paste of m.ii/.e starch, and granulated. The granules are dried in a current of warm air, and the dry 5 granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.
Example 64 A mixture of 500 parts 2-methyl-3-hydroxy-4-mercapto-li) methyl-5-ethynylpyridine, 60 parts maize starch, and 20 parts of gum acacia is granulated with a sufficient quantity of water. The mass is passed through a 12-mesh screen, and the granules are dried in a current of warm air. The dry granules are passed through a 16-mesh screen, mixed with 5 15 parts of magnesium stearate and compressed into tablet form suitable for oral administration.
Example 65 (1) Tablets - 10,000 scored tablets for oral use, each containing 500 mg. of active ingredient are prepared 20 from the following ingredients: Gm. 2-methyl-3-hydroxy-4-mercapto- 5000 methyl-5-(1-propenyl)pyridine hydrochlor ide 25 Starch, U.S.P. 350 Talc, U.S.P. 250 Calcium stearate 35 The powdered mercaptoniethylpyridine is granulated - 107 - 3 9 8 9 G with a 4% w./v. aqueous solution of methylcellulose U.S.P. (1500 cps.). To the dried granules is added a mixture of the remainder of the ingredients and the final mixture compressed into tablets of appropriate weight. 5 (2) Capsules - 10,000 two-piece hard gelatine capsules for oral use, each containing 250 mg. of active ingredient are prepared from the following ingredients: GM. 2-methyl-3-hydroxy-4-mercapto- 2500 10 methylpyridine-5-acrylic acid Lactose, U.S.P. 1000 Starch, U.S.P. 300 Talc, U.S.P. 65 Calcium stearate 25 15 The powdered mercaptomethyl compound is mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner. Capsules containing lO, 25, 50, and 100 mg. of active ingredient are also prepared by substituting lOO, 20 250, 500, and lOOO gin. for 2500 gm. in the above formulation. (3) Soft elastic capsules - One-piece soft elastic capsules for oral use, each containing 500 mg. of active material are prepared in the usual manner by first dispersing the powdered active material in sufficient 25 corn oil to render the material capsulatable. (4) Aqueous suspension - An aqueous suspension for oral use containing in each 5 ml., lgm. of active ingredient is prepared from the following ingredients: - 108 - 3989 u GM. 3-0-4u-S-benzylidine dorIvn- Livc of 2-iiii,Lliy l-3-liyilroxy-4- 2 merc.iptouicLliy 1 -5-viny I py r l»l Iihj 5 Mcthylparaben, U.S.P. 7.5 Propylparaben, U.S.P. 2.5 Saccharin sodium 12.5 Glycerin 3000 Tragacanth powder lO lO Orange oil flavor lO t'.n. & C. orange dye 7.5 Dcionized water, q.s. 10,000 ml.
Example 66 2-Methyl-3-Hydroxy-4-Mercaptomethyl-5-Vinylpyridine 15 A solution obtained by reacting 0.4 mole sodium with alsolute alcohol is saturated by passing in hydrogen sulfide for 5 hours. There is then added in portions 0.05 mole of 4-chloromethyl-3-hydroxy-2-methyl-5-vinylpyridine hydrochloride and the mixture is stirred overnight at room 2o temperature with hydrogen sulfide slowly bubbled through the mixture. The reaction mixture is then concentrated _in vacuo and taken up between ethyl acetate and water containing acetic acid. The ethyl-acetate layer is removed, dried over sodium sulfate and concentrated to give 2-methyl-3-hydroxy-2 5 4-mercaptomethy1-5-vinylpyridine.
The above reaction can be carried out using any other alkali metal hydrosulfide in place of the sodium hydrosul-fide to obtain the product. - 109 - 3 9 8 9 6 Similarly, the corresponding 4-bromomethyl may be used in place of the 4-chloromethyl compound above to obtain the desired mercapto compound.
Example 67 5 2-Methyl-3-hydroxy-4-mercaptomethy 1-5-viny lpyr idine hydro chloride Step A; Preparation of 3-methylthieno/J,4-^7-6-methyl-7- pyridinol A mixture of 20.0 g. of 4-methyl-5-ethoxy oxazole, lO 14.0 g. of 2,5-dihydro-2-methylthiophene and 400 mg. of trichloroacetic acid is prepared in a sealed tube and heated at 140°C for 24 hours. The tube is cooled and opened, and the reaction mixture slurried with 1 liter of chloroform. The insoluble solid is collectcd by flltr.it ion and chromato-15 graphed on silica gel. The crude product is eluted with ethyl acetate and crystallized from methanol to cjive pure 3-methyl-thieno /3,4-c7~6-methyl-7-pyridinol.
Step U; Preparation of 2-methyl-3-hydroxy-4-mercapto- methy1-5-vinylpyridine hydrochloride 20 The 3-methylthieno^3,4-c7-6-methyl-7-pyridinol (20.0 g.) is added to a solution of 15.0 g. of potassium amide in 400 ml. of liquid ammonia at -50 to -33°C. The reaction mixture is stirred for 30 minutes and then the ammonia is allowed to evaporate. The residue is dissolved in 200 ml. of 25 water and the pH of the solution is carefully adjusted to 7 by addition of 2N aqueous hydrochloric acid. The precipitated oil is taken up in ethyl acetate and chromatographed on - 110 - 3 9 8 9 o silica gel. The product is eluted by ethyl acetate and recovered by evaporation of the solvent, and the residue is taken up in tetrahydrofuran and treated with gaseous hydrogen chloride to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride, melting point 149-152°C.
Example 68 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride Step A: Preparation of lll-thiopyrano/T.3-c7-7-methy 1-8- pyr idinol A mixture of 20.0 g. of 4-methyl-5-ethoxy oxazole, 14.0 ij. of 3,6-dihydro-2II-thiopyran and 400 mg. of trichloroacetic acid is heated in a sealed tube at 140°C for 40 hours. The tube is cooled, opened, and the reaction mixture slurried with 1 liter of chloroform. The insoluble solid is collected by filtration and chroma toy rapiied on silica gol. The crude product is elutcd with ethyl acetate and crystallized from methanol to give lll-thiopyrano/J", 3-c7-7-methyl-8-pyridinol.
Step B: Preparation of 2-methyl-3-hydroxy-4-inercaptomethy1-5-vinylpyridine hydrochloride Following the procedure of Example 67, Step B, but substituting for the 3-methylthieno£J,4-c7~6-methyl-7-pyridinol used therein an equivalent amount of lH-thio-pyrano/4",3-c7-7-methyl-8-pyridinol, there is produced 2-methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride, melting point 149-152°C.
- Ill - 39896 Example 69 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride ' Step A; Preparation of 5-mercapto-l,3-pentadlene 5 A mixture of 147.O g. of 5-bromo-l,3-pentadiene 76.O g. of thiourea and 250 ml. of 95% ethanol is refluxed for 3 hours. The solvent is removed under reduced pressure and the residual thiuronium bromide complex is stirred in a solution of 60.O g. of sodium hydroxide in 400 ml. of water. 10 On acidification with dilute hydrochloric acid and cooling, the thiol separates as an oil which is removed from the aqueous layer, washed with 300 ml. of water and dried over magnesium sulfate. The crude product is vacuum distilled to give 5-mercapto-l,3-pentadiene. 15 Step B: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride A solution of 20.O g. of 4-methyl-5-ethoxy oxazole, 14.O g. of 5-mercapto-l,3-pentadiene, 400 mg. of trichloroacetic acid and 200 ml. of toluene is refluxed for 20 hours. The reaction mixture is cooled, filtered to remove insolubles and concentrated almost to dryness. The residue is chromato-graphed on silica gel and the product eluted by ethyl acetate. Crystallization from chloroform gives 4-mercaptomethyl-2-methyl-5-vinyl-3-pyridinol. This material is dissolved in tetrahydrofuran and treated with gaseous hydrogen chloride causing precipitation of 2-methyl-3-hyilroxy-4-mercaptomethy1-5-vinylpyridino hydrochloride, mcltin Step B: Preparation of 2-methyl-3-hydroxy-4-acetylthio- methy1-5-vinylpyridine By the procedure described in Example 69 Step B 15 but substituting for the 5-mercapto-l,3-pentadiene an equivalent amount of 5-acetylthio-l,3-pentadiene and eliminating conversion to the hydrochloride salt, there is produced 2-methyl-3-hydroxy-4-acetylthioraethyl-5-vinylpyridine, melting point 130-132°C. 20 Example 71 bis/If-Methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl7-disulfide Step A: Preparation of bis/I",3-pentadiene-5-yI7-d:.sulfide 5-Mercapto-l,3-pentadiene (0.05 mole) is added to lOO ml. of 501 aqueous ethanol and sufficient ammonium 25 hydroxide to br-.ng it to pH 9. Air is bubbled through the mixture for 24 hours. The excess ammonia and ethanol is - 113 - 3 9 8 9 G evaporated under reduced pressure. The precipitated oil is taken up in ethyl acetate, dried over magnesium sulfate and concentrated to oily bis^T",3-pentadiene-5-yl7-disulfide.
Step B; bis^"-Methyl-3-hydroxy-5-vinylpyrid-4-yImethyI7~ 5 disulfide By the procedure described in Example 69, Step B but substituting for the 5-mercapto-l,3-pentadiene an equal amount by weight of bis£T,3-pentadiene-5-yl7-disulfide and eliminating comversion to the free base, there is produced lO bis/7t-Methyl-3-hydroxy-5-vinylpyrid-4-yImethy 17~disulfide, melting point >300°C.
Example 72 2-Methyl-3-acetoxy-4-acetyIthiomethyl-5-vinylpyridine Step A: Preparation of pyridoxal diethylacetal 15 Pyridoxal (O.Ol mole) is refluxed with 0.15 mole of ethyl orthoformate and a trace of £-toluenesulfonic acid in lOO ml. of methanol for 3 hours. The cooled mixture is poured into excess of saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the extract 20 is dried over sodium sulfate and concentrated to dryness to give a residue of pyridoxal diethylacetal.
Step B; Preparation of 4-mercapto-5-pyridoxal hydrochloride The residue from Step A is dissolved in 125 ml. of ethanol containing 3 g. of potassium hy'roxide. After the 25 mixture has been stirred for 10 minutes, 5 ml. of carbon disulfide is added and the mixture is refluxed for 4 hours. The cooled mixture is acidified to about pH 3 with hydroch- - 114 - 3 a s y u loric acid and the mixture is warmed at 50°C for 30 minutes. The mixture is concentratcd to dryness and the residue is extracted with 2 x lOO ml. of hot ethanol and the extract is concentrated to dryness to give 4-mercapto-5-pyridoxal hydro-S chloride.
Step C; Preparation of 2-methyl-3-acetoxy-4-acetyl-thiomethyl-5-formyl pyridine A mixture of 2 y. of acetic anhydride in So ml. of tetrahydrofuran is added slowly to the product from Step lo U, dissolved in lOO ml. of tetrahydrofuran and 0.7 g. of triethylomino at lO°C. After stirring 1 hour at room temperature, the mixture is evaporated to dryness. The residue is triturated with a mixture of SO ml. of ethyl acetate and SO ml. of water. The ethyl acetate is separated, dried over IS magnesium sulfate and evaporated to dryness to yive 2-methyl- J-acetoxy-4-acetylthiomethy 1-S-formyIpyr idine.
Step D: Preparation of 2-methyl-3-acetoxy-4-acety1thio-- methylpyridine-5-ethylene oxide Dimethyloxosulfonium methylide is prepared by 2O refluxiny a mixture of 0.04 mole of sodium hydride, 5.12 g. (0.04 mole) of trimethyloxosulfonium chloride ar.d 30 ml. of dry tetrahydrofuran under nitrogen until the evolution of hydrogen ceases (around 2 hours). With the reaction mixture held at 55°C, a solution of (0.03 mole) 10.5 g. of the 25 product from Step C in 30 ml. of tetrahydrofuran is slowly added dropwise with stirring over a period of 1.5 hours and the reaction mixture is stirred at 55°C for an additional, hour. The reaction mixture is concentrated under reduced -115- 3 9 8 9 G pressure to a volume of about 10 ml. and 50 ml. of water is added and then extracted with 3 x 50 ml. of ether. The combined organic fractions are washed with aqueous sodium bisulfite solution and then dried with anhydrous sodium 5 sulfate. Evaporation of the solvent gives 2-methyl-3-acetoxy- 4-acetylthiomethylpyridlne-5-ethylene oxide.
Step E: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methvl-5-vlnylpyrldlne A mixture of 7.3 g. (0.02 mole) of the product lO from Step D, 11.O g. of magnesium bromide and 0.02 g. atom of magnesium amalgam in 50 ml. of 1,2-dimethoxyethane is refluxed under nitrogen for 1.6 hour. The mixture is cooled to room temperature and is treated with lOO ml. of ether and 30 ml. of saturated ammonium chloride solution. The aqueous 15 layer is separated and then extracted twice with 50 ml. of ether. The combined organic fractions are dried with anhydrous sodium sulfate. The solvent is evaporated to give the crude product which is recrystallized from cyclohexane to give 2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, 20 melting point 72-73°C.
Example 73 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride Following the procedure of Example 72, Steps D 25 and E but substituting for the 2-methyl-3-acetoxy-4-acetyl- thiomethyl-5-formylpyridine used in Step D an equivalent amount of 2-methyl-3-hydroxy-4-mercaptomethyl-5-formy1-pyridine and using two additional equivalents of sodium - 116 - :i u 8 u o hydride in Step E, there are produced in turn 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-ethylene oxide and 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, which on conversion to the hydrochloride salt gives 2-methyl-3-hydroxy-5 4-mercaptomethyl-5-vinylpyrldine hydrochloride, melting point 149-152°C. lo Example 74 2-Methyl-3-acetoxy-4-acetyIthiomethyl-5-vinylpyridine Step A; Preparation of 2-methyl-3-acetoxy-4-acetylthio- methylpyrldine-5-ethylene episulfide To a well stirred solution containing 1.9 g. (0.02 mole) of potassium thiocyanate in 5 ml. of water is added 3.9 g. (0.02 mole) of 2-methyl-3-acetoxy-4-acetyl-tliiomethylpyridine-5-ethylene oxide. The turbid solution Is 15 stirred at 25°C overnight. Tlie aqueous layer is separated, and set aside and the organic layer is treated with a second aqueous solution of potassium thiocyanate (1 g. in 5 ml. of water) as described for another 5 hours. The aqueous layer is separated and combined with the first aqueous phase and 2o these combined aqueous phases are extracted with three portions of 20 ml. of ethyl acetate. The ethyl acetate extracts and the organic phase are combined, dried over anhydrous calcium chloride and the solvent is evaporated to give 2-methyl-3-acetoxy-4-acetylthiomethyIpyridine-5-ethylene episulfide. 25 Step B: Preparation of 2-methyl-3-acetoxy-4-acetylthio- me thy 1-5-viny lpyr idine A mixture of (0.02 mole) of the product from Step A and 3.3 g. (0.02 mole) of triethyl phosphate is heated at - 117 - 3 9 8 0 G reflux for 2 hours. The reaction mixture is then cooled to room temperature and treated with 30 ml. of ethyl acetate and 100 ml. of 2.5N hydrochloric acid. The ethyl acetate layer is separated. The aqueous solution is washed once with 20 ml. of ether and then neutralized with 2N sodium hydroxide solution to pH 5. The aqueous solution is extracted with three 50-ml. portions of ethyl acetate. The combined organic fractions are dried with anhydrous sodium sulfate. The solvent i . evaporated and the residue is chromatographed on silica gel with ethyl acetate to give 2-methyl-3-acetoxy-4-acetyl-thiomethyl-5-vinylpyridine, melting point 72-73°C.
Example 75 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydrochloride By the procedure of Example 74, but substituting for the 2-methyl-3-acetoxy-4-acetylthiomethylpyridine-5-ethylene oxide an equivalent amount of 2-methy1-3-hydroxy- 4-mercaptomethylpyridine-5-ethylene oxide, there are produced in turn 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-ethylene episulfide and 2-methyl-3-hydroxy-4-mercaptomethyl- 5-vinylpyridine hydrochloride, melting point 149-152°C.
Example 76 2-Methy1-3-acetoxy-4-acetylthiomethy1-5-vinylpyridine Step A: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methy1-5-ethynyIpyridine A solution of 0.02 mole of 2-methyl-3-acetoxy-4-acetylthiomethy1-5-formylpyridine in 50 ml. of methylene - 118 - 39896 chloride Is treated with 26.5 g. of carbon tetrabromide, 1 g. of zinc dust and 10.3 g. of triphenylphosphine at 25°C for 1 hour. Pentane, 200 ml., is added to the reaction mixture. The insoluble materials are filtered off. The organic 5 filtrate is evaporated under reduced pressure to give the dibromo olefin which is treated directly with (0.08 mole) of n-butyl lithium in 50 ml. of tetrahydrofuran at -78°C for 1 hour and at 25°C for another hour. The reaction is quenched by addition of 20 ml. of water and the pll of the lO aqueous layer is adjusted to 5. Ethyl acetate (80 ml.) is added. After mixing, the organic layer is separated, washed with 30 ml. of aqueous sodium bisulfite solution and water, and dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is chromatographed using silica lr> yel and ethyl acetate as elucnt to give 2-methyl-3-acetoxy- 4-acety1thiomethy1-5-ethynylpyridine.
Step D; Preparation of 2-ro»»thyl-3-acetoxy-4-acetylthio-methy1-5-vinylpyridine A solution of (O.Ol mole) of 2-methyl-3-acetoxy-20 4-acetylthiomethyl-5-ethynylpyridine in 15 ml. of methanol is treated with 0.06 g. of 5% palladium-on-barium sulfate and 0.06 y. of pure quinoline. After O.Ol mole of hydrogen has been consumed, the catalyst is removed by filtration.
After evaporation of the methanol, there is obtained 2-methyI-25 3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, melting point 72-73°C.
Example 77 2-Methyl-3-hydroxy-4-mereaptomethyI-5-vinylpyridine hydroch loride . . - 119 - 39896 By the procedure of Example 76, but substituting for the 2-methyl-3-acetoxy-4-acetylthlomethyl-5-formyl-pyridine an equivalent amount of 2-methyl-3-hydroxy-4-mercaptomethyl-5-formylpyrldine, there are produced in turn 5 2-methyl-3-hydroxy-4-mercaptoraethyl-5-ethynylpyridine and 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. The latter product is taken up in tetrahydrofuran and treated with gaseous hydrogen chloride, which causes precipitation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine lO hydrochloride, melting point 149-152°C.
Example 78 Bis/T-methyl-3-hydroxy-5-vinylpyridin-4-methyl7disulfide By treating each of (1) 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-ethyleneoxide from Example 73; 15 (2) 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-ethylene episulfide from Example 75 and (3) 2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynylpyridine from Example 77 with alcoholic ammonia at pH 9 or above and bubbling air or oxygen through the mixture for about 24 hours, there are produced 20 respectively: (4) bis^2-methyl-3-hydroxy-5-ethcxiranylpyrid-4-ylmethyl7~disulfide; (5) bis/jT-methyl-S-hydroxy-S-ethyl-enethiitanylpyrid-4-ylmethyI7-disulfide and (6) bis/J-methyl- 3-hydroxy-5-ethynylpyrid-4-ylmethyi7-disulfide.
Treatment of these products, (4), (5) and (6) 25 according to the procedures described in Example 72, Step E; Example 74, Step B and Example 76, Step B, respectively, produces in each case bis/2-methyl-3-hydroxy-5-vinylpyridin- 4-methyl/disulfide, m.p. >300°C. - 120 - 3980U Example 79 2-Methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine hydro-chloride The 3,4a-0,S-benzylidene derivative of 2-methyl-5 3-hydroxy-4-mercaptomethyl-5-vinylpyridine (O.Oi mole) is dissolved in lOO ml. o£ 2.5N hydrochloric acid and heated at 90°C for 1 hour. After cooling the mixture is extracted well with ether and the extracts are discarded. The aqueous phase is concentrated to dryness and the residue is crystal-lo lized from cyclohexane to give 2-methyl-3-hydroxy-4- mercaptomethyl-5-vinylpyridine hydrochloride, melting point 14<)-152°C.
Example 80 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinyIpyridine hydro-15 chloride 2-Methy1-3-tetrahydropyranyloxy-4-tetrahydropyran-ylthioinethyl-5-vinylpyridine 5.6 g. (0.016 inole) is treated with 172 mg. (l.O mmole) of £-toluenesulfonic acid in 200 ml. methanol at room temperature for 2 hours. Methanol is 20 evaporated off under reduced pressure. The residue is treated with lOO ml. of ethyl acetate. The organic solution is washed with 10'4 sodium bicarbonato solution and water and then dried with anhydrous sodium acetate. Crude product is obtained after removal of the solvent. Column chromatography with silica gel 25 and ethyl acetate as eluent gives pure 2-methyl-3-hydroxy- 4-mercaptomethyl-5-vinylpyridine which on solution in tetrahydrofuran and treatment with dry gaseous hydrogen chloride provides 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinyIpyridine hydrochloride, melting point 149-152°C. - 121 - 39896 Example 81 2-Methyl-3-hydroxy-4-mercaptoraethyl-5-vinylpyridine hydrochloride A mixture of 80 ml. of ethanol and 20 ml. of 2N 5 sodium hydroxide solution is deaerated by bubbling nitrogen through it. To the solution is added O.Ol mole of 2-methyl- 3-acetoxy-4-acetylthiomethyl-5-vinylpyridine and the mixture is heated on a steam bath for 3 hours. After cooling, the mixture is made strongly acid with hydrochloric acid and then lo concentrated to dryness. The residue is extracted several times with hot cyclohexane. The combined cyclohexane extracts are concentrated by evaporation at atmospheric pressure to incipient cloudiness and then cooled. The precipitate is collected to give 2-methyl-3-hydroxy-4-mercaptomethyl-5-15 vinylpyridine hydrochloride, melting point 149-152°C.
Example 82 2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydro-chloride To a stirred suspension of 4.86 g. (0.09 mole) of 20 sodium methoxide in 54 ml. of hexamethylphosphoramide (HMPA) is added 4.8 g. (0.03 mole) of bis-(trimethylsilyl) methane at 60°C under an atmosphere of nitrogen. The resulting yellow solution is stirred for 2 hours and then treated with 1.83 g. of 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-aldehyde. 25 The mixture is allowed to stand for 12 hours and treated with lOO ml. of ethyl acetate and 80 ml. of water. The pll of the aqueous layer is adjusted to 5. After mixing, the organic layer is separated and washed four times with 50 ml. of water and - 122 - 3 9 8 9 o dried witli anhydrous sodium sulfate. After evaporation of the solvent and chromatography on silica gel with ethyl acetate as eluent and conversion to the hydrochloride salt, there is obtained 2-methyl-3-hydroxy-4-mercaptomethyl-5-5 vinylpyridinc hydrochloride, melting point 149-152°C.
Example 83 2-Methyl-3-acetoxy-4-acetylthiomethy1-5-vinylpyridine Magnesium turnings (600 mg.) in 15 ml. of dry tetrahydrofuran and a trace of iodine are placed in a flask lo equipped wi Lh 2oo g. ol" ice and the pll adjusted to 5 t.o 7 with hydrochloric acid. The aqueous mixture is extracted with benzene and back-extracted with 2.5N hydrochloric acid. The acid extract is concentrated to dryness and the residue is recrysta11izod from cyclohexane to yive 2-methyl-3-acet.oxy-4-acety lthio-20 methyl-5-vinylpyridine, melting point 72-73°C.
Example 84 bis^2-Methyl-3-hydroxy-5-vinylpyridine-4-methy27~disulfide Step A: Preparation of 4-mercaptopyridoxal diethylacctal Pyridoxal diethylacetal (O.Ol mole) is dissolved in 25 125 ml. of ethanol containing 3 g. of potassium hydroxide.
After the mixture has been stirred for lO minutes, 5 rnl. of carbon disulfide is added and the mixture is refluxed for 4 - 123 - 3980g hours. The cooled mixture is neutralized with dilute hydrochloric acid. The mixture is concentrated to a small volume in vacuo and the residue is partitioned between water and ethyl acetate. The ethyl acetate is separated, dried over anhydrous 5 aodium Sulfate and concentrated to dryness.
Step B; Preparation of bis25-methyl-3-hydroxy-5-formyl- pyridyl-4-methyt7-dlsulfide The residue from Step A is taken up in 100 ml. of ethanol and treated with 25 ml. of concentrated ammonia. Air 10 is bubbled through the mixture for 24 hours at room temperature lixcess of ammonia and most of the ethanol is evaporated under reduced pressure and the mixture is neutralized with 2.5N hydrochloric acid and warmed on the steam bath for 30 minutes. The solution is concentrated to dryness and the residue is 15 crystallized from ethyl acetate to give bis/T-methyl-3-hydroxy-5-formylpyridyl-4-methyi7"disulfide.
Step C: Preparation of bis^7-methyl-3-hydroxy-5-vinyl-pyridyl-4-methy17-disulfide A mixture of SO ml. of dimethyl sulfoxide and 5 gm. 20 of sodium hydride emulsion (50%) (O.l mole) is heated to 70-85°C on a steam bath under nitrogen. When evolution of hydrogen ceases, a solution of 37 gm. of triphenylethyl-phosphonium bromide in warm dimethyl sulfoxide is added drop-wise while the temperature is maintained at 10-20°C. Thirty 25 minutes after the addition is complete, a solution of 18.2 gm. of bis/2-methy1-3-hydroxy-5-formylpyridy1-4-methyl/disulfide in warm dimethyl sulfoxide is added, and the mixture is stirred for 16 hours at ambient temperature. It is then poured into - 124 - 39800 water and the resulting precipitate is collected on a filter and washed with acetonitrile. The solids are dried over phosphorous pentoxide to give bis/5^-methyl-3-hydroxy-5-vinylpyridyl-4-methy!7-disulfide, melting point >300°C.
Example 85 2-Methyl-3-acetoxy-4-acetylthiomethy1-5-a-hydroxyethy1-pyridlne Step A: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl- 5-chloromethylpyridine 20 y. of the 3,4u-0,S-isopropy 1 idene dor iv.iL i ve of 2-methyI-3-hydroxy-4-mercaptomethyl-5-hydroxymethylpyridine is dissolved in 50 ml. of thionyl chloride. After one hour at room temperature, the thionyl chloride is removed at the aspirator. The residue (the corresponding 5-chloromethyl compound) is refluxed with a mixture of 400 ml. of 2.5N IIC1 and 4(H) ml. of acetone for 1.5 hours. The acetone is distilled ol'l" until the bath temperature reaches 00°C. The cooled solution is extracted with 3 x 300 ml. of ethyl acetate. The aqueous layer is poured into 700 ml. of saturated aqueous sodium bicarbonate and extracted with 3 x 300 ml. of ethyl-acetate. The ethyl acetate layer is dried over magnesium sulfate and evaporated to give 2-methyl-3-hydroxy-4-mercapto-5-chloromethylpyridine.
Step B; Preparation of 2-methyl-3-ace^.oxy-4-acetylthio-methy1-5-chloromethylpyridine 20 y. of the product from Step A above is dissolved in 50 ml. of acetic anhydride. After half an hour at 25°C, the - 125 - 30896 the reaction mixture is poured into 200 ml. of ice water and filtered to isolate the desired product, 2-methyl-3-acetoxy- 4-acety1thioraethy1-5-chloromethylpyridine.
The corresponding 3-hydroxy-4-acetylthiomethyl 5 compound may be prepared by using 0.08 mole of acetic anhydride in 50 ml. of THF in the above example.
Step C: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methyl-S-a-hydroxyethylpyridine O.l mole of the compound from step B is dissolved lO in 200 ml. of THF in the presence of O.l mole of magnesium turnings. After the magnesium has dissolved, 0.1 mole of paraformaldehyde is added. After refluxing for 1 hour, the mixture is poured over 500 grams of ice and water containing 50 grams of ammonium chloride. The mixture is then extracted 15 with ethyl acetate and is evaporated to give the crude product.
Similarly, the 3-hydroxy-4-acetylthiomethyl compound from Step B above may be used in Step C to give 2-methyl-3-hydroxy-4-acetylthiomethyl-5-a-hydroxyethylpyridine.
Similarly, when an equivalent amount of the product 20 from Step A is used in place of the product from Step B, in Step C there is obtained 2-methyl-3-hydroxy-4-mercaptomethyl- 5-n-hydroxyethylpyridine.
Example 86 bis/7^-Methy1-3-hydroxy-5-a-hydroxyethylpyridine-4-methy£7-25 disulfide Step A; Preparation of bis/)P-methyl-3-hydroxy-5-chloro-methy lpyr idy 1-4-methyl]?-disulfide 0.1 mole of 2-methyl-3-hydroxy-4-mercaptomethyl-5- - 126 - U989G chloromethylpyridine is slurried into 200 ml. of water and to this is added 250 ml. of O.l N I1C1. To the solution thus formed is added 0.1 mole of H2O2 and after half an hour at 25°C, the mixture is poured into 200 ml. of saturated 5 aqueous sodium bicarbonate. The reaction mixture is stirred and filtered, and the cake is washed with water and dried over magnesium sulfate to yield bis^J"-methyl-3-hydroxy-5-chloro-methylpyridyl-4-methy^disulf ide.
Step B; Preparation of bis/5"-methyl-3-hydroxy-5-lO a~hydroxvethylpyridyl"4-methvt7disulfide The product from Step A above is reacted in accordance with Step C of Example 85 to give the tiesired compound.
Example 87 15 2-Methyl-3-acetoxy-4-acetylthiomethy1-5-vinyIpyridine Step A: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methyl-5-B-hydroxyethylpyridine To a solution of 0.1 mole of 2-methyl-3-acetoxy-4-acetylthiomethyl-5-formylpyridine dissolved in 200 ml. of 20 anhydrous tetrahydrofuran (T1IF) is added O.l mole of methyl- magnesium bromide in THF, maintaining the temperature at 0°c. After warming to 25°C for 1 hour, the mixture is poured over 500 grams of ice and water containing 50 grams of ammonium chloride. On removal of the THF, the product separates. ,5 Step B: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methyl-5-P.-chloroethylpyridine 20 g. of the product from Step A above is dissolved in 50 ml. of thionyl chloride. After 1 hour at room temperature, - 127 - 3 9 8 9 0 the thionyl chloride is removed at the aspirator and 300 ml. of ethyl acetate is added. This solution is added to 200 ml. of saturated sodium bicarbonate and extracted with 3 x 300 ml. of ethyl acetate. The ethyl acetate layer is dried over 5 magnesium sulfate and evaporated to give 2-methy1-3-acetoxy- 4-acetylthiomethyl-5-(J-chloroethylpyridine.
Step C: Preparation of 2-methyl-3-acetoxy-4-acetylthio- methyl-5-vinylpyridlne hydrochloride To the crude product from Step B above is added 30 lO ml. of THF and to this is added lO grams of calcium carbonate and the slurry heated to 110°C for two hours. The salts are then removed by filtration. Evaporation of the solvent leaves a solid residue of 2-methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridine, melting point 72-73°C. 15 Similarly when an equivalent amount of 2-methyl-3- hydroxy-4-acetylthiomethyl-5-formylpyridine, 2-methyl-3-hydroxy-4-mercapto-5-formylpyridine or bis£2-methyl-3-hydroxy- 5-rormylpyrlc!yl-4-methy£7disulfido is used in plneo of 2-methyl-3-acetoxy-4-acetylthiomethyl-5-formylpyridine in 20 Example 87 A above the product reacted in accordance with Examples 87 B and 87 C, there is obtained 2-methy1-3-hydroxy-4-acetylthioraethyl-5-vinylpyridine, melting point 130-132°C; 2-methyl-3-hydroxy-4-mercapto-5-vinylpyridinef melting point 115-117°C or bis^?-methyl-3-hydroxy-5-vinylpyridyl-4-methyI7- 25 disulfide, melting point >300°C.
Similarly when an equivalent amount of 2-methyl-3-acetoxy-4-acetylthiomethyl-5-o-hydroxyethylpyridine; 2-methy1- 3-hydroxy-4-acetylthiomethyl-5-a-hydroxyethylpyridine; 2-methyl-3-hydroxy-4-mercapto-5-a-hydroxyethylpyridine or - 128 - 3 9 8 'J G bis/^mothyl-3-hydroxy-5-u-hydroxye thy lpyr idyl-4-me thy 17" disulfide is used in place of 2-methyl-3-acetoxy-4-acetyl-thiomethyl-5-B-hydroxyethylpyridine in Example 87 B above and the product reacted in accordance with Example 87 C above, there is obtained the corresponding 5-vinylpyridine compound.
Similarly when an equivalent amount of toluene sulfonyl chloride or methanesulfonyl chloride is used in place of thionyl chloride in Example 87 B above and the tosylate or mesylate thus formed is reacted in accordance with Example 87 C above, there is obtained 2-methyl-3-aeetoxy-4-acetylthioinethyl-5-vinylpyridine, melting point 72-73°C.
Example 88 Tin* s.ilL from triphenylphosphine and 2-methyl-3-aeetwxy-4-. iceLy 1 Mi iomoI hy I-5-eh Loromethy lpyr ill ine A reaction mixture of O.l mole of 2-methy1-3-acetoxy-4-acetylthiomothyl-5-chloromethylpyridine, 500 ml. of benzene and O.l mole of triphenylphosphine are refluxed for 72 hours. The slurry thus obtained is cooled to 25°C ar.d filtered and the cake is dried under slight vacuum to yield the desired compound.
Similarly when an equivalent amount of 2-methyl-3-hydroxy-4-acetylthiomethyl-S-chloromethylpyridine, 2-methyl-3-hydroxy-4-mercaptomethy1-5-chloromethylpyridine or bis/2-metliy 1 -3-hydroxy-5-ch lor< imethy Lpyr idy L-4 -inethy f^-di :;u 1 f Lili.* is used in place of 2-ineUiy 1 -3-acetoxy-4-.icety 1 thiomet.hy 1 -'i-cli loromethylpyridine in tho above example, there is obtained the corresponding salt of triphenylphosphine and the mentioned compound. - 129 - 3 9 8 0 G Example 89 2-Methyl-3-acetoxy-4-acetylthlomethyl-5-vinylpyridine To 0.1 mole of the product from Example 88 In 200 ml. of THF is added O.l mole of 1.9M n-butyllithium in hexane followed by 0.1 mole of paraformaldehyde over half an hour. The reaction is stirred for 3 hours and then refluxed for 4 hours. The reaction mixture is then evaporated to dryness under vacuum. The product is triturated with 200 ml. of ether and the inorganic salt and solid triphenylphosphine oxide filtered off. The ethereal filtrate is then evaporated to yield the desired product.
Similarly when an equivalent amount of triethylamine is used in place of n-butyl lithium, there is obtained the desired product.
Similarly when an equivalent amount of the other pyridine compounds obtained from Example 88 are used in place of the starting material of Example 89, there are obtained 2-methyl-3-hydroxy-4-acetylthiomethy1-5-vinylpyridine, 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine (which is converted to the hydrochloride by bubbling HC1 gas through the ethereal solution) and bis/2-methyl-3-hydroxy-5-vinylpyridyl-4— methy|7disulfide.
Example 90 2-Methyl-3-acetoxy-4-acetylthiomethyl-5-vinylpyridlne O.1 mole of the salt from triphenylphosphine and 2-methy1-3-acetoxy-4-acetylthiomethy1-5-chloromethy1-pyridine is suspended in aqueous 40% formalin (lOO ml.) and added to lOO ml. of 10% aqueous sodium carbonate with stirring. - 130 - 39890 After one hour, the reaction mixture is adjusted to a pll of 6 with IN ltd and extracted with 4 x SOO ml. of ethylacotatc. The ethyl acetate extract is then evaporated to yield the crude product. The product is purified by chromatography over 5 silica gel using ethyl acetate as eluent.
Similarly when an equivalent amount of the other salts obtained from Example 88 are used in place of the starting material above, there are obtained 2-methyl-3-hydroxy- 4-acetylthiomethy1-5-vinylpyridine, 2-methyl-3-hydroxy-4-lO mercaptomethyl-5-vinylpyridine and bisZiF-methyl-3-hydroxy- 5-vinylpyridyl-4-methy^disulfide. - 131 - U 9 8 9 G

Claims (1)

1. CLAIMS: - 1. A compound of structural formula: or a pharmaceutically acceptable salt thereof, in which m is 5 O or 1; x is O, 1, 2 or 3; A is -CH=C- or -C=C- where R7 b is hydrogen, chlorine, or fluorine; 1 2 each of R and R is hydrogen or alkyl; R^ is (a) hydrogen, (b) -SO^H, (c) -PO^Hj, (d) amid ino, (e) ~N(C1_^ alkyl)2» (f) -CH2CH(NH2)COOH, (g) ethoxycarbon-lO ylmethyl, O II (h) -C-B, where E represents (1) adamantyl, (2) cycloalkyl, (3) C1-5 alkoxy, (4) C2_6 alkyl, (5) -n0 or —c s—CH2 h=ch- h2c=hc - 138 - 3989 0 or a pharmaceutically acceptablc salt thereof, where L is -(CH,). phenylene, or -N^ ^N-. W 18. Bis^2-methyl-3-hydroxy-5-vinylpvridyl-4-methyl7 disulfide or a pharmaceutically acccptable salt thereof. 19. Bis/Z-methyl-3-hydroxy-5-vinylpyridyl-4-methyl7 disulfide or sulfate salt thereof. 20. A method of preparing a compound of general formula ch2sh ch=ch- or a pharmaceutically acceptable salt thereof that comprises lo treating a compound of for.aula: ch2oh m=cii_ ,11 • in which R is hydrogen or C2_g alkanoyl with C^2 and alkali. 21. A method of preparing a compound of general formula: ch2sh ch=ch- - 139 - :t 9 8 9 G or a pharmaceutically acceptable salt thereof that comprises treating a compound of formula: nh y \ nh. h=ch_ in which R11 is as defined in Claim 20 with an alkali or a reducing agent. 22. A method of preparing a compound of general formula ch2sh ch=ch_ or a pharmaceutically acceptable salt thereof that comprises treating a compound of formula: S lO Cll2SCO(C1_4 alkyl) ii=C1I_ in which R** is as defined in Claim 20 with an alkali or a reducing igent. - 140 - 39890 23. A method of preparing a compound of formula: ch2sh rx10 XT ch=ch. ch3 or a pharmaceutically acccptable salt thereof, in which R11 is as defined in Claim 20, that comprises reducing a compound of formula: ch2sso3h R1X0 CH. XT" 24. A method of preparing a compound of general formula lO ch=ch„ or a pharmaceutically acceptable salt thereof, in which is as defined in Claim 20 and R13 is C2_6 alkanoyl, that comprises acylating a compound of formula: ch2sh ch=ch_ - 141 - 3 9 8 9 G 25. A method of preparing a compound of formula: h2sh R^O ch. ch=c!i- or a pharmaceutically acceptable salt thereof, in which R^ is as defined in Claim 20, that comprises reducing a compound of formula: ch=ch. *3 N""3 26. A method of preparing a compound of general formula 10 ch=ch- ch2=ch *3 ^"3 or a pharmaceutically acceptable salt thereof that comprises treating a compound of formula: ch2sso3h ch=ch. - 142 - 3 9 8 9 G in which R^"*" is as defined in Claim 20 with acid or alkali. 27. A method of preparing a compound of general formula CH. H Cll. or a pharmaccutically acccptable salt thereof that comprises treating a compound of formula: S II CII2SCO(C1_4 alkyl) H=CH~ in which R*^ is as defined in Claim 20 with ammonium hydroxide. 28. A method of preparing a compound of general formula R1X0 CIl. ,11 CH- 3 V"'3 11 or a pharmaceutically acceptable salt thereof, in which R is as defined in Claim 20 that comprises treating a compound o formula: - 143 - 39896 ch2sh ch=ch- with an oxidizing agent. 29. A method of preparing a compound of general formula ch. r110- ^£H=CH2 c»2=cii n' CH, CH, 11 or a pharmaceutically acceptable salt thereof, in which R is as defined in Claim 20 that comprises treating a compound of formula: ;il=CH. lO where Q is chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or 2,4-dinitrobenzoy-loxy, with sodium disulfide. 30. A method of preparing a compound of general formula: - 144 - 39890 or a pharmaceutically acceptable salt thereof, that comprises treating a compound of formula: S in which R11 is as defined in Claim 20 with an alkali. 31. A method of preparing a compound of general formula or a pharmaceutically acceptable salt thereof, that comprises treating a compound of formula: with an alkali metal hydroxide and a compound of formula: - 145 - 39800 R11© CH, ch2sh ch=ch. where, in the formulae, R*"*" is as defined in Claim 20. 32. A method of preparing a compound of general formula ho ch. ch- *3 —3 or a pharmaceutically acceptable salt thereof, that comprises treating a compound of formula: ch2sso3h ch=ch. CH, in which R11 is as defined in Claim 20 with Na2S2 or Na2S. 33. A method of preparing a compound of general formula - 146 - 3 9 8 0 0 a phainnaceutically acceptable salt thereof, in which R** as defined in Claim 20 that comprises treating a compound formula: 5 with iodine. 34. A method of preparing a compound of general formula: or a pharmaccutically acccptable salt thereof, in which R11 is as defined in Claim 20 that comprises treating a compound lo of formula: with P2S5* 35. A method of preparing a compound of general formul.i: or is of - 147 - 3 9 8 9 c or a pharmaceutically acceptable salt thereof, that comprises 5 in which R*^ is as defined in Claim 20 with an alkali metal hydroxide and an oxidizing agent. 36. A method of preparing a compound of general formula or a pharmaceutically acceptable salt thereof, that comprises lO treating a compound of formula: S II CH2-S-C-0(C1_4 alkyl) CH=CH_ in which R is as defined in Claim 20 with ammonium hydroxide - 148 - 3 9 8 9 l> and an oxidizing agent. 37. A method of preparing a compound of formula: O II CH2SC-E CH=CH- lo or □ pharmaceutically acceptable salt thereof, where R is O hydroxy or -O-D-E and E is as defined in Claim 1, that comprises treating 2-methyl-3-hydroxy-4-mercaptomethy1-5-vinylpyridine with a compound of formula E.CO.Cl, E.CO.Br or (E.CO)jO. 38. A method of preparing a compound of formula: R, R~ H=CH- or a pharmaceutically acceptable salt thereof, in which R^ and R(^ are as defined in Claim 1, that comprises treating 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine with a compound of formula: c=o 15 39. A method of preparing a compound of formula: - 149 - 39 8 U G or a pharmaceutically acceptable salt thereof, in which X is 0 or S, that comprises treating 2-.uethyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine with carbonyl chloride or 5 thiocarbonyl chloride. 40. A method of preparing a compound of formula: Q or a pharmaceutically acceptable salt, thereof, in which R is -C{CH3)2CH(NH2)-COOH, C1-5 alkyl, C2_5 alkenyl, phenyl-C1_3 10 alkyl, phenyl, C2_^ alkynyl, or 2-carboxyphenyl, that comprises treating a compound of formula: O with a compound of formula HS-R . - 15o - 'j'JSiiii 41. A method of preparing a compound of structural formula: \ or .1 pharmaceutically acccptable salt thereof, whore I. Is 5 phenylene, or 1,4-piperaz inil iy 1 that comprises t. reat ing 2-metliyl-3-liydroxy-4-mercaptomethy 1-5-viny lpyr idine with a compound of formula XjC0.(l»>0 ^.CO.X' where each X' is cli lor ine or bromine. 42. A method of preparin-j a compound as claimed in I') Claim I in which U3 is — S'* II, tli.it <~<>ni|>i i :;i;s read i 11 • j i i:< >mp< >111 h I ol iji.-neral lormula: (<)) m in which m, x, A, R, R^, R2 and R^ are as defined in Claim 1 and Q is as defined in Claim 29, with sodium thiosulfate. 15 43. A method of preparing a compound as claimed in 3 8 8 Claim 1 in which R is -SR , wnere R is as defined in Claim 1, that comprises reacting a compound having the formula set - 151 39 8 9 G forth in Claim 42 with sodium thiosulfate, followed by an ft alkali metal hydroxide and a compound of formula R SH. 44. A method of preparing a compound as claimed in Claim 1 in which R3 is 12 4 in which m, x. A, R, R , R and R are as defined in Claim 1 that comprises reacting a compound having the formula set forth in Claim 42 with sodium thiosulfate, followed by an alkali metal hydroxide and a compound of formula: (0)m 45. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 with sodium thiosulfate, followed by an alkali metal hydroxide 15 or a mineral acid. 46. A method of preparing a compound as claimed in Claim 1 in which R3 is hydrogen, that comprises reacting a compound having the formula set forth in Claim 42 with sodium thiosulfate, followed by a reducing agent. - 152 - 39891* 47. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 with sodium thiosulfate, followed by Na2S2 or Na2S. 48. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 with sodium thiosulfate, followed by iodine. 49. A method of preparing a compound as claimed in Claim 1 in which R3 is hydrogen, that comprises reacting a compound having the formula set forth in Claim 42 with an alkali metal trithiocarbonate followed by an alkali or an acid. 50. A method of preparing a compound as claimed in Claim 1 in which R3 is -CS-SMe and 10 A in which Me is an alkali metal and x» A, R, R , R and R are as defined in Claim 1, that comprises reacting a compound having the formula set forth in Claim 42 with an alkali metal trithiocarbonate. 51. A method of preparing a compound as claimed in Claim 1 in which R3 is -PO^l^, that comprises reacting a compound having the formula set forth in Claim 42 with trisodium phosphorothioate and a mineral acid. 52. A method of preparing a compound as claimed in Claim 3 1 in which R is hydrogen, that comprises reacting a compound - 153 - 3 9 8 0 0 having the formula set forth in Claim 42 with thiourea or a potassium alkyl xanthogenate, followed by an alkali metal hydroxide or a reducing agent. 53. A method of preparing a compound as claimed in 5 Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 with thiourea, followed by an alkali metal hydroxide and an oxidizing agent. 54. A method of preparing a compound as claimed in 10 Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 with a potassium C^_4 alkyl xanthogenate, followed by ammonium hydroxide, or by ammonium hydroxide and an oxidizing agent. 55. A method of preparing a compound as claimed in 15 Claim 1 in which R3 is acyl, that comprises reacting a compound having the formula set forth in Claim 42 with a potassium thioacyloate. 56. A method of preparing a compound as claimed in Claim 1 in which R3 is hydrogen, that comprises reacting a 20 compound having the formula set forth in Claim 42 with a potassium thioacyloate followed by an alkali. 57. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 42 25 with Na2S2» 58. A method of preparing a compound as claimed in Claim 1 in which R3 is ethoxycarbonylmethyl, that comprises reacting a compound having the formula set forth in Claim 42 with ethyl mercaptoacetate. - 154 - A'JSDii 59. A method of preparing a compound as claimed in Claim 1 in which R3 is R-carboxy-0-aminocthyl, that comprises reacting a compound having the formula set forth in Claim 42 with cysteine. 5 60. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound of general formula: (<>)m 1 2 in which the CR R OH substituent is in the 2, 4 or 6 position 12 4 lo and the OH group is adjacent to it and A, R, R , R , R , x and m are as defined in Claim 1, with P2S5' 61. A method of preparing a compound as claimed in Claim 1 in which R3 is hydrogen, that comprises reacting a compound having the formula set forth in Claim 60 with carbon disulfide I') and an alkali metal hydroxide. 62. A method of preparing a compound as claimed in Claim 1 in which R3 is COE, where li is as defined in Claim 1, that comprises reacting a compound of general formula: - 155 - 3 9 8 9 G 12 4 in which A, R, R , R , R , x and m are as defined in Claim 1 with a compound of formula E.CO.Cl, E.CO.Br or (E.C0)20. 63. A method of preparing a compound as claimed in Claim 1 in which R3 is ~NtC^_ij alkyl) 2, that comprises reacting a 5 compound having the formula set forth in Claim 62 with cyanogen bromide and a di(C^_^ alkyl)amine. 64. A method of preparing a compound as claimed in Claim 1 in which R3 is 12 4 10 where A, R, R , R , R , x and m are as defined in Claim 1, that comprises reacting a compound having the formula set forth in Claim 62 with phosgene. 65. A method of preparing a compound as claimed in Claim 1 in which R3 is N-/Tc^_jj alkyl)carbonyl7methylcarbamoyl, that 15 comprises reacting a compound having the formula set forth in Claim 62 with phosgene and a C^_^ alkyl aminoacetate. 66. A method of preparing a compound as claimed in Claim 1 in which R3 is carbamoyl, that comprises reacting a compound having the formula set forth in Claim 62 with phosgene and 20 ammonia. 67. A method of preparing a compound as claimed in Claim 1 in which R3 is - 156 - 3 9 8 9 G (O)m 12 4 where A, R, R , R , R , x and m are as defined in Claim 1 and L is ~(CH0)y { where % is an integer from 1 to 5,) phenylene or 1,4-piperazindiyl, and z is O or 1 that comprises 5 reacting a compound having the formula set forth in Claim 62 with a compound of formula Cl-CO-Lz~CO-Cl or Br-CO-Lz~CO-Br. 68. A method of preparing a compound as claimed in Claim 1 in which R3 is 2-carboxyphenylthio, that comprises reacting a compound having the formula set forth in Claim 62 lo with o-carboxyphenyl o-carboxybenzenethiolsulfonate. 69. A method of preparing a compound as claimed in Claim 1 in which R3 is CH201i that comprises reacting a compound having the formula set 15 forth in Claim 62 with thiamine-S-monoxide. 70. A method of preparing a compound as claimed in Claim 1 in which R3 is 157 - 398DU 12 4 where A, R, R , R , R , x and m are as defined in Claim 1 and w is 2 or 3, that comprises reacting a compound having the formula set forth in Claim 62 with sulfur dichloride 5 and sulfur monochloride. 71. A method of preparing a compound as claimed in Claim 1 in which R3 is as defined in Claim 44, that comprises reacting a compound having the formula set forth in Claim 62 with an oxidizing agent. lO 72. A method of preparing a compound of general formula: or a pharmaceutically acceptable salt thereof, in which A, R, 1 2 4 5 5 R , R , R , R , Ra, x and m are as defined in Claim 1 and the ends of the oxamethylenethiamethylene chain are attached to 15 adjacent carbon atoms of the pyridine ring, that comprises reacting a compound of formula - 158 - 3 9 8 0 i> in which the hydroxy and mercaptomethyl groups are attached to adjacent carbon atoms of the pyridine ring with a compound of formula R^-CO-R"* when R^ and R^ are separate or with phosgene 5 or thiophosgene. 73. A method of preparing a compound as claimed in Claim 1 in which R3 is hydrogen, that comprises reducing a compound in which K3 is as defined in Claim 44. 74. A method of preparing a compound as claimed in Claim 12 to 71, 7 3 and 74, as applied to the preparation of a compound 15 ol formula: or or a pharmaceutically acceptable salt thereof. 76. A method as claimed in Claim 60,as applied to the preparation of a compound of general formula: - 159 - or 10 l(x-l) (x-l) or a pharmaceutically acceptable salt thereof. 77. A method as claimed in Claim 72, as applied to the preparation of a compound of general formula: R(x-1) or (x-l) V 0 X (0)m or a pharmaceutically acceptable salt thereof. 78. A method as claimed in Claim 75, as applied to the preparation of a compound of formula: SR~ A-R - 160 - 3 9 8 9 0 or a pharmaceutically acceptable salt thereof. 79. A method as claimed in Claim 76, as applied to the preparation of a compound of general formula: or a pharmaceutically acceptable salt thereof. 80. A method as claimed in Claim 77, as applied to the preparation of a compound of general formula: ,5 A-R 81. A method as claimed in Claim 78, as applied to the preparation of a compound of general formula: SR" C1I=CII. 82. A method as claimed in Claim 79, as applied to tho preparation of a compound of general formula: - 161 - s s h r 3 ch=ch2 ch2=ch h 3 83. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinyl-pyridine or a pharmaceutically acceptable salt thereof. 84. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid or a pharmaceutically acceptable salt thereof. 85. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-(1-propenyl)pyridine or a pharmaceutically acceptable salt thereof. 86. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-ethynyl-pyridine or a pharmaceutically acceptable salt thereof. 87. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-styryl-pyridine or a pharmaceutically acceptable salt thereof. 88. A method as claimed in Claim 78 as applied to the preparation of 2-methyl-3-hydroxy-4-vinyl-5-mercaptomethyl-pyridine or a pharmaceutically acceptable salt thereof. 89. A method of preparing a compound of formula: H Cm !H=CH 2 3 - 162 - 3 9 8 0 0 or a pharmaceutically acccptable salt thereof, comprising the ring opening ol" a compound of formula: or salt thereof. 90. A nethod of preparing a compound of structural formula H=CH. where R*® is hydrogen, alkanoyl, or -SCH. that comprises treating a compound of formula: (C1_5 alkyl) O Cll. with a compound of formula - 163 3989G cd where R is hydrogen, alkanoyl, or 91. A method of preparing a compound of formula: or pharmaceutically acceptable salt thereof, where R** is 13 hydrogen or alkanoyl, and R is hydrogen, alkanoyl, or that comprises reducing a compound of formula: where R11 is hydrogen or alkanoyl; R*"2 is hydrogen, alkanoyl, or - 164 - U 9 8 t) G b and lo I'j A A B is -CH-CH2, -CH-CH2, or -C=CH. 02. A method as claimed in Claim 91 as applied to the preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinyl-pyridine or a pharmaceutically acceptable salt thereof. 93. A method as claimed in Claim 91 as applied to the preparation of 2-methyl-3-acetoxy-4-acetylthiomethyl-5-v i ny 1 pyr id i in* or a phnrui.icmiL leal ly acc«*ptabli' salt. Llicrcol". 04. A method of pr«:p.ir 1 n
IE1220/74A 1973-06-15 1974-06-11 Vinylic and acetylenic pyridines and their n-oxides IE39896B1 (en)

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US3290319A (en) * 1965-02-26 1966-12-06 Bristol Myers Co Substituted carbamates of pyridine 2, 6-dimethanethiols
US3591584A (en) * 1968-08-27 1971-07-06 Pfizer Benzothiazine dioxides
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IE39896B1 (en) 1979-01-31
GB1473591A (en) 1977-05-18
NO144569C (en) 1981-09-23
JPS59511B2 (en) 1984-01-07
SE411208B (en) 1979-12-10
NL7407212A (en) 1974-12-17
DK148594C (en) 1986-01-27
SE7711211L (en) 1977-10-06
JPS5040574A (en) 1975-04-14
SE426170B (en) 1982-12-13
AU6976574A (en) 1975-12-04
LU70318A1 (en) 1975-03-06
ZM9274A1 (en) 1976-02-23
FI167474A (en) 1974-12-16
FR2233055A1 (en) 1975-01-10
IL44958A (en) 1978-09-29
SE7406972L (en) 1974-12-16
NL187395C (en) 1991-09-16
DK290274A (en) 1975-02-10
IL44958A0 (en) 1974-09-10
CA1021342A (en) 1977-11-22
CH605764A5 (en) 1978-10-13
DK148594B (en) 1985-08-12
FR2233055B1 (en) 1977-11-04
ES427187A1 (en) 1977-01-01
NO741962L (en) 1975-01-13
DE2428470C2 (en) 1988-10-13
NO144569B (en) 1981-06-15
NL187395B (en) 1991-04-16
EG11578A (en) 1978-03-29
DE2428470A1 (en) 1975-01-23

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