CA1071634A - Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivatives - Google Patents
Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivativesInfo
- Publication number
- CA1071634A CA1071634A CA254,573A CA254573A CA1071634A CA 1071634 A CA1071634 A CA 1071634A CA 254573 A CA254573 A CA 254573A CA 1071634 A CA1071634 A CA 1071634A
- Authority
- CA
- Canada
- Prior art keywords
- tetrahydro
- formula
- thieno
- pyridine derivatives
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003222 pyridines Chemical class 0.000 title claims description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- OJYDKYKQCVPTFG-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-c]pyridine Chemical class C1N=CC=C2SCCC21 OJYDKYKQCVPTFG-UHFFFAOYSA-N 0.000 claims abstract 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract 3
- DKASUYIOUPPQSY-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[2,3-c]pyridine Chemical class C1C=NC=C2SCCC21 DKASUYIOUPPQSY-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 29
- -1 alkoxy radical Chemical class 0.000 abstract description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 11
- 125000003118 aryl group Chemical group 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000003367 polycyclic group Chemical group 0.000 abstract description 2
- 241000694408 Isomeris Species 0.000 abstract 1
- 150000005840 aryl radicals Chemical class 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229920006324 polyoxymethylene Polymers 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 101150067506 dinB gene Proteins 0.000 description 1
- 101150028435 dinB2 gene Proteins 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- SAALQYKUFCIMHR-UHFFFAOYSA-N propan-2-ol;2-propan-2-yloxypropane Chemical compound CC(C)O.CC(C)OC(C)C SAALQYKUFCIMHR-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PROCESS FOR THE PREPARATION OF TETRAHYDRO-THIENO[3,2-C]-AND [2,3-C]PYRIDINE DERIVATIVES.
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of tetrahydro-thieno [3,2-c]pyridine derivatives of the formula (Ia) and their isomeris tetrahydro-thieno [2,3-c]pyridine derivatives in which R1 represents hydrogen, a lower alkyl or alkoxy radical, an aryl radical or an aralkyl radical; R2 and R3 represent hydrogen, halogen, a lower alkyl or alkoxy group, a di(loweralkyl)amino, nitro, cyano or acetamido group or, together with the phenyl nucleus to which they are attached, form a polycyclic aromatic ring, comprising reacting a tetrahydrothieno[3,2-c]pyridine derivative of the formula:
(IIa) or a derivative of its isomer, tetrahydro[2,3-c]pyridine, with formaldehyde H-CHO and a phenol of the formula:
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of tetrahydro-thieno [3,2-c]pyridine derivatives of the formula (Ia) and their isomeris tetrahydro-thieno [2,3-c]pyridine derivatives in which R1 represents hydrogen, a lower alkyl or alkoxy radical, an aryl radical or an aralkyl radical; R2 and R3 represent hydrogen, halogen, a lower alkyl or alkoxy group, a di(loweralkyl)amino, nitro, cyano or acetamido group or, together with the phenyl nucleus to which they are attached, form a polycyclic aromatic ring, comprising reacting a tetrahydrothieno[3,2-c]pyridine derivative of the formula:
(IIa) or a derivative of its isomer, tetrahydro[2,3-c]pyridine, with formaldehyde H-CHO and a phenol of the formula:
Description
~ ~ 7 ~ ~ ~ 4 This invention relates to a new process for the preparation of tetrahydro-thieno ~,2- ~pyridine derivatives of the formula:
OH
R1 ~ Rz (la) and their isomers, tetrahydro-thieno ~,3- ~pyridine deriva-tives of the formula:
~n CH2~ (1~) in which the hydroxyl group OH is at 2- or 4-position; Rl represents hydrogen, a lower alkyl or alkoxy radical, an aryl ; 10 radical or an aralkyl radical; R2 and R3 represent each hydro-gen, halogen, a lower alkyl or alkoxy radical, a di-(lower-alkyl)amino, nitro, cyano or acetamido radical or, together with the phenyl nucleus to which they are attached, Form a polycyclic aromatic ring, R2 and R3 being at 3-, 4-, 5- or 6-position when OH is at 2-position and being at 3- and 5-positions and other than hydrogen when OH is at 4-position.
Said compounds possess valuable therapeutic proper-ties and, in addition, are useful intermediates in the prepa-ration of derivatives used both in the chemical and pharma-; 20 ceutical industries.
4,5,6,7-Tetrahydro-thieno ~,2- ~pyridine derivatives have already been described, together with a process for their preparation, in Canadian Patent 1,038,871 and its division Canadian Patent 1,042,299. Said process comprises condensing a compound of the forrnula:
B -N
OH
R1 ~ Rz (la) and their isomers, tetrahydro-thieno ~,3- ~pyridine deriva-tives of the formula:
~n CH2~ (1~) in which the hydroxyl group OH is at 2- or 4-position; Rl represents hydrogen, a lower alkyl or alkoxy radical, an aryl ; 10 radical or an aralkyl radical; R2 and R3 represent each hydro-gen, halogen, a lower alkyl or alkoxy radical, a di-(lower-alkyl)amino, nitro, cyano or acetamido radical or, together with the phenyl nucleus to which they are attached, Form a polycyclic aromatic ring, R2 and R3 being at 3-, 4-, 5- or 6-position when OH is at 2-position and being at 3- and 5-positions and other than hydrogen when OH is at 4-position.
Said compounds possess valuable therapeutic proper-ties and, in addition, are useful intermediates in the prepa-ration of derivatives used both in the chemical and pharma-; 20 ceutical industries.
4,5,6,7-Tetrahydro-thieno ~,2- ~pyridine derivatives have already been described, together with a process for their preparation, in Canadian Patent 1,038,871 and its division Canadian Patent 1,042,299. Said process comprises condensing a compound of the forrnula:
B -N
- 2 ~ ~ 7 ~ ~ 3 ~
in which the radicals A and B represent each at least an atom or group selected from hydrogen, halogen, lower alkyl, lower alkoxy, nitro and amino, with a halide of the formula Hal-R in which Hal represents a halogen atom and R represents an optionally substituted alkyl, aryl or aralkyl radical, to give a pyridinium salt of the formula:
A
B ~ ~ - R, Hal~3 and subsequently hydrogenating said pyridinium salt to give a derivative of the formula (I):
A
B ~ N - R
4,5,6,7-Tetrahydro-thieno ~ ,3- ~pyridine derivatives have also been prepared by an analogous process (Canadian Patent Appln. n 255,299, filed June 21, 1976, by Applicant).
This process, however, is expensive and delicate in that it requires numerous difficult procedures.
In addition, use of this preparation process makes it difficult to obtain derivatives having on the nitrogen atom a benzyl radical carrying a hydroxyl group at 2- or 4-position.
Indeed, to obtain derivatives of such type according to said process, ;t is necessary to proceed via the methoxylated derivat;ve which is subsequently hydrolyzed.
Therefore, the object of the present invention is to provide a simple process for the preparation, in good yields, of derivatives of the formula (Ia) or their isomers of the formula (Ib) in which the phenyl nucleus carries a hydroxy group at 2- or 4-position.
The process of this invention comprises reacting a tetra-~i ~
.
: , ' - ' ' ' . ., ' :. . ' ., , ' ' ', .: .
~ 7~63~
hydrothieno ~,2-c7pyridine derivative of the formula:
~ (IIa) or a derivative of its isomer, tetrahydro~ ~3 _7pyridi~e, of the formula: R1 ~ ~ H ~IIb) in which R1 has the above described meanings, with formaldehyde . H-C~0 and a phenol of the formula qH
~ R2 (III~
in which R2 and R3 have the above-defined meanings, to give the desired derivative of the formula (Ia) or (Ib).
The (Mannich type) reaction occurs Q~ one of the ortho-positions of the phenol, when it is free~ When both ortho-positions are occupied, the reaction occurs at the para-position.
Thus~ in the case of phe~ols in which at least one of the positions ortho to 0~ is free~ the Mannich reaction occurs at said free ortho-positions 0~
N~ 2 ~ ~ N ~ n2 + HCH0 + ~ ~~~ S R3 radicals R2 and R3 occupying optionally 3-9 4-~ 5- or 6-positions in the derivative of the ~ormula (Ia) or (Ib).
The sa~e reaction occurs ~lith unsubstituted phenol~ and with polycyclic phenols such a~ ~naphthol~ for example.
In the case of phenols carr~i~g both substituent~ R2 and R3 ... . ... . ..
~(~7~63~
at o~tho-position to the OH ~adical, the reaction occurs at para-position:
~2 33 c~z ~oll The condensation reaction o~ thi~ invention is advantageously conducted within a medium consisting of an organic solvent such as ethanol, propanol or dioxan. The reaction is advantageously effected in the hot~ at a temperature bet~een 50C and the boiling temperature of the solvent used, best results being obtained at temperatures o~ about 80C.
It is preferred to effect the reaction with oonst~nt stirring, during a period of time of 2-20 hours.
Formaldehyde or its different polymerization products9 such as polyoxymethylene9 may be used for the reaction.
Purification of the desired deriYative is effected either by recrystallization from an organic s-olvent, or after conversion to a salt, by washing, drying and optionally recrystallization from an organic solvent.
The following non-limiting Examples are give~ to illustrate the p~esent invention.
EXA~LE 1 Preparation of 5-(3,5-dimethyl~4-hydroxy benzyl)-4,5~6,7-tetrahydro thieno~ 92-_7pyridine A mixture of 4~5,6,7-tetrahydro-thie~o~,2_~ pyridi~e (6~1 g;
44 mmoles)9 2,6-dimethyl-phenol (5~4 g; 44 mmoles)9 polyoxymethyle~e (2.7 Bi 90 ~mole~) and dioxan (50 cc) is stirred at 80C duri~g 3 hours~ A~ter concentration in ~acuo, the residue is recrystallized .
.. ~ : . .. . .
.. . .
.
~ ,, -: .
in which the radicals A and B represent each at least an atom or group selected from hydrogen, halogen, lower alkyl, lower alkoxy, nitro and amino, with a halide of the formula Hal-R in which Hal represents a halogen atom and R represents an optionally substituted alkyl, aryl or aralkyl radical, to give a pyridinium salt of the formula:
A
B ~ ~ - R, Hal~3 and subsequently hydrogenating said pyridinium salt to give a derivative of the formula (I):
A
B ~ N - R
4,5,6,7-Tetrahydro-thieno ~ ,3- ~pyridine derivatives have also been prepared by an analogous process (Canadian Patent Appln. n 255,299, filed June 21, 1976, by Applicant).
This process, however, is expensive and delicate in that it requires numerous difficult procedures.
In addition, use of this preparation process makes it difficult to obtain derivatives having on the nitrogen atom a benzyl radical carrying a hydroxyl group at 2- or 4-position.
Indeed, to obtain derivatives of such type according to said process, ;t is necessary to proceed via the methoxylated derivat;ve which is subsequently hydrolyzed.
Therefore, the object of the present invention is to provide a simple process for the preparation, in good yields, of derivatives of the formula (Ia) or their isomers of the formula (Ib) in which the phenyl nucleus carries a hydroxy group at 2- or 4-position.
The process of this invention comprises reacting a tetra-~i ~
.
: , ' - ' ' ' . ., ' :. . ' ., , ' ' ', .: .
~ 7~63~
hydrothieno ~,2-c7pyridine derivative of the formula:
~ (IIa) or a derivative of its isomer, tetrahydro~ ~3 _7pyridi~e, of the formula: R1 ~ ~ H ~IIb) in which R1 has the above described meanings, with formaldehyde . H-C~0 and a phenol of the formula qH
~ R2 (III~
in which R2 and R3 have the above-defined meanings, to give the desired derivative of the formula (Ia) or (Ib).
The (Mannich type) reaction occurs Q~ one of the ortho-positions of the phenol, when it is free~ When both ortho-positions are occupied, the reaction occurs at the para-position.
Thus~ in the case of phe~ols in which at least one of the positions ortho to 0~ is free~ the Mannich reaction occurs at said free ortho-positions 0~
N~ 2 ~ ~ N ~ n2 + HCH0 + ~ ~~~ S R3 radicals R2 and R3 occupying optionally 3-9 4-~ 5- or 6-positions in the derivative of the ~ormula (Ia) or (Ib).
The sa~e reaction occurs ~lith unsubstituted phenol~ and with polycyclic phenols such a~ ~naphthol~ for example.
In the case of phenols carr~i~g both substituent~ R2 and R3 ... . ... . ..
~(~7~63~
at o~tho-position to the OH ~adical, the reaction occurs at para-position:
~2 33 c~z ~oll The condensation reaction o~ thi~ invention is advantageously conducted within a medium consisting of an organic solvent such as ethanol, propanol or dioxan. The reaction is advantageously effected in the hot~ at a temperature bet~een 50C and the boiling temperature of the solvent used, best results being obtained at temperatures o~ about 80C.
It is preferred to effect the reaction with oonst~nt stirring, during a period of time of 2-20 hours.
Formaldehyde or its different polymerization products9 such as polyoxymethylene9 may be used for the reaction.
Purification of the desired deriYative is effected either by recrystallization from an organic s-olvent, or after conversion to a salt, by washing, drying and optionally recrystallization from an organic solvent.
The following non-limiting Examples are give~ to illustrate the p~esent invention.
EXA~LE 1 Preparation of 5-(3,5-dimethyl~4-hydroxy benzyl)-4,5~6,7-tetrahydro thieno~ 92-_7pyridine A mixture of 4~5,6,7-tetrahydro-thie~o~,2_~ pyridi~e (6~1 g;
44 mmoles)9 2,6-dimethyl-phenol (5~4 g; 44 mmoles)9 polyoxymethyle~e (2.7 Bi 90 ~mole~) and dioxan (50 cc) is stirred at 80C duri~g 3 hours~ A~ter concentration in ~acuo, the residue is recrystallized .
.. ~ : . .. . .
.. . .
.
~ ,, -: .
3~1 from ethanol-isopropanol (M.p. = 158C; yield: 4 .
Preparation o~ 5-(2~hydroxy-5~nitro-benzyl3-6-methyl-4,5,6~7_ tetrahydro--thie:no~,3 ~ 2--c7pyridine A mixture of 6-methyl-4,5,6~7-tetrahydro-thieno~ ,2-c7_ pyridine (6.3 g; 41 mmoles), p-nitro-phenol (5.7 B; 41 mmoles) 7 polyoxymethylene (2D5 g; 83 mmoles) and dioxan (50 CC) iS sti~rPd at 80C during 4 hours. After concentration in vacuo~ the residue is dissolved in ether and then treated with 0.5 equivalent oxalic acid in ethanol solution. The resulting semi-oxalate is filtered, ~ashed with boiling methanol-water (1:3)J filtered again and dried (M.p. = 214C; yield: 27%).
EXA~
Preparation o~ 6-(2-hydroxy-5-chloro-benzyl3-7-methyl-475,6,7-tetrahydro-thieno~3 -c7pyr i dinP
A mixture of 7-methyl-4,5,6,7--tetrahydro-thieno~ 73-_7-pyridine (6~0 g; 39.2 mmoles), p-chlorophenol (5~05 g; 39~2 mmoles)~
polyoxymethylene (2.36 g; 78.5 mmoles) and dio~an (70 cc3 is stirred at 80C during 15 hours~ After concentration in vacuo~
the resiaue is taken up into 2N hydrochloric acid~ The aqueous phase is ext~acted with ether, made basic with concentrated ammonia and again extracted with methylene chloride. The organic ext~acts are washed With water~ dried o~er sodium sul~ate and concentrated in Yacuo. The residue is treated with 0.5 equivalent oxalir acid in ethanol solutionD The resulti~g semi-oxalate is fil-tered and recrystallized ~rom ethanol-dimethyl ~ormamide (M~po = 170C;
yield: 38%)~
EXA~LE 4 Preparation of 6-(2-hydroxy--5-cyano~benzyl)-4,5,6,7-.
. : . - . :
~7~63~
tetrahydro-thieno ~,3-_7pyridine A mixture of 4,5,677-tetrahydro-thieno~93-~ py~idine (1 g;
7,2 mmoles)9 p-cyano-phenol (95% purity; 0.9 g; 7~2 mmoles)~
polyoxymethylene (0.43 g; 14.4 mmoles) and dioxan (20 oc) is stirred at 80C during 4 hours. After concentration in vacuo, the residue is taken up i~to 2N hydrochloric acid. The aqueous phase is extracted with ether, made basie with concentrated ammonia and again extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sul~ate and concentrated in ~acuo. The residue is recrystallized from isopropyl ether-isopropanol (M.p. 134C; yield: 23~).
Using the proeedures described in the preceding Examples, the following compounds are obtained:
5-(2-Hydroxy-5-methoxy-benzyl)-4,5,697-tetrahydro-thieno~ ,2-~7-pyridine White crystals; M.p. = 90C
5-(2-Hydroxy-5-nitro-benzyl)-4,5,6,7-tetrahydro-thieno~2-o7-pyridine Yellow cryst~ls; M p. = 160C.
EXA~LE 7 5-(2-Hydroxy-3-methoxy-benzyl)-4,596,7-tetrahydro-thieno~ ,2-~ _ pyridine White crystals; M.p~ = 84C.
5-(5-Chloro-2-hydr~y-be~zyl)-495,6,7-tetrahydro-thieno~,2-c7_ pyridine White erystals; M.p. _ 82_85C.
~ 7 l~t~
5-(5-Chloro-2~hydroxy-benzyl)-6-methyl-4, 5, 6,7-tetrahydro-thienoL3~2-c7pyridine 7 se~i-oxalate White c~ystals; M.p~ = 200C.
5-(5-Fluoro-2-hydroxy-benzyl)-4,5,6,7-tet~ahydro-thieno~,2-c7-pyridine Pale yello~ crystals; M.p. _ 92C.
5-o-Hydroxybenzyl-4~5~6~7-tetrahydro-thieno~ ,2-~ pyridine, semi-oxalat~
White crystals; M.p. = 216C.
5-(2-~ydroxy-3-methyl-benzyl)~4,5,6,7-tetrahydro-thieno~ ,2ec7_ pyridine, semi-oxalate, semi-hydrate White crystals; M.p~ = 198C
5-(3-Acetamido-2-hydroxy-benzyl)-4,5,6,7-thieno~,2-c7pyridine White crystals; M.p. = 154C.
6-(S-Chloro-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~ ,3__7_ pyridine White crystals; M.p. = 222C.
EXA~LE 15 6-(3~4-Dichloro-2-hydroxy-benzyl)-495,6,7-tetrahydro-thieno~,3_~7_ pyridine White crystals; M.p. = 153C~
: EXAMPLE 16 6-(2-Hydroxy-5-nitro-benzyl)-4,5~6~7-tetrahydro-~hieno~l3-c)-~ 8 --.
3~
pyridine Iellow crystals; M.p. = 159C.
6-(3~5-Dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~,3-c7py~idine Ivory crystals; M p. = 118C.
6-(2-Hydroxy-3-isopropyl-benzyl~-495,6~7-tetrahydro-thieno~ ,3-c7pyridine Very pale yellow crystals; M.p. = 101C.
.
6-(2-Hydroxy-5-methyl-benzyl)~4,5~6,7-tetrahydro-thieno~,3-_7pyridine~ semi-oxalate, æemi-hydrate Very pale yellow crystals9 M.p. = 196C.
EXAMPLE _ 6-(4-Dimethylami~o-2-hydroxy-benzyl)-4~596,7-tetrahydro-thieno~ ,3-_7pyridine Pink orystals; M.p. = 140C.
6-o-Hydroxybenzyl-4~5,697-tetrahydro-thieno~,3-c7pyridine Beige crystals; Mop~ = 98C.
..
6~ ydroxynaphthyl-methyl)-4,5~6,7-tet~ahydro-thieno~,3-c7 pyridine Pale yellow crystals; M~p~ = 150C
EXA~LE 23 5-(3,5-Dichloro-4-hydroxy~benzyl)-4~5~6,7-tetrahydro-thieno~,2-c7pyridine White crystals; M.p. = 170C.
_ g _ ... : .
Preparation o~ 5-(2~hydroxy-5~nitro-benzyl3-6-methyl-4,5,6~7_ tetrahydro--thie:no~,3 ~ 2--c7pyridine A mixture of 6-methyl-4,5,6~7-tetrahydro-thieno~ ,2-c7_ pyridine (6.3 g; 41 mmoles), p-nitro-phenol (5.7 B; 41 mmoles) 7 polyoxymethylene (2D5 g; 83 mmoles) and dioxan (50 CC) iS sti~rPd at 80C during 4 hours. After concentration in vacuo~ the residue is dissolved in ether and then treated with 0.5 equivalent oxalic acid in ethanol solution. The resulting semi-oxalate is filtered, ~ashed with boiling methanol-water (1:3)J filtered again and dried (M.p. = 214C; yield: 27%).
EXA~
Preparation o~ 6-(2-hydroxy-5-chloro-benzyl3-7-methyl-475,6,7-tetrahydro-thieno~3 -c7pyr i dinP
A mixture of 7-methyl-4,5,6,7--tetrahydro-thieno~ 73-_7-pyridine (6~0 g; 39.2 mmoles), p-chlorophenol (5~05 g; 39~2 mmoles)~
polyoxymethylene (2.36 g; 78.5 mmoles) and dio~an (70 cc3 is stirred at 80C during 15 hours~ After concentration in vacuo~
the resiaue is taken up into 2N hydrochloric acid~ The aqueous phase is ext~acted with ether, made basic with concentrated ammonia and again extracted with methylene chloride. The organic ext~acts are washed With water~ dried o~er sodium sul~ate and concentrated in Yacuo. The residue is treated with 0.5 equivalent oxalir acid in ethanol solutionD The resulti~g semi-oxalate is fil-tered and recrystallized ~rom ethanol-dimethyl ~ormamide (M~po = 170C;
yield: 38%)~
EXA~LE 4 Preparation of 6-(2-hydroxy--5-cyano~benzyl)-4,5,6,7-.
. : . - . :
~7~63~
tetrahydro-thieno ~,3-_7pyridine A mixture of 4,5,677-tetrahydro-thieno~93-~ py~idine (1 g;
7,2 mmoles)9 p-cyano-phenol (95% purity; 0.9 g; 7~2 mmoles)~
polyoxymethylene (0.43 g; 14.4 mmoles) and dioxan (20 oc) is stirred at 80C during 4 hours. After concentration in vacuo, the residue is taken up i~to 2N hydrochloric acid. The aqueous phase is extracted with ether, made basie with concentrated ammonia and again extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sul~ate and concentrated in ~acuo. The residue is recrystallized from isopropyl ether-isopropanol (M.p. 134C; yield: 23~).
Using the proeedures described in the preceding Examples, the following compounds are obtained:
5-(2-Hydroxy-5-methoxy-benzyl)-4,5,697-tetrahydro-thieno~ ,2-~7-pyridine White crystals; M.p. = 90C
5-(2-Hydroxy-5-nitro-benzyl)-4,5,6,7-tetrahydro-thieno~2-o7-pyridine Yellow cryst~ls; M p. = 160C.
EXA~LE 7 5-(2-Hydroxy-3-methoxy-benzyl)-4,596,7-tetrahydro-thieno~ ,2-~ _ pyridine White crystals; M.p~ = 84C.
5-(5-Chloro-2-hydr~y-be~zyl)-495,6,7-tetrahydro-thieno~,2-c7_ pyridine White erystals; M.p. _ 82_85C.
~ 7 l~t~
5-(5-Chloro-2~hydroxy-benzyl)-6-methyl-4, 5, 6,7-tetrahydro-thienoL3~2-c7pyridine 7 se~i-oxalate White c~ystals; M.p~ = 200C.
5-(5-Fluoro-2-hydroxy-benzyl)-4,5,6,7-tet~ahydro-thieno~,2-c7-pyridine Pale yello~ crystals; M.p. _ 92C.
5-o-Hydroxybenzyl-4~5~6~7-tetrahydro-thieno~ ,2-~ pyridine, semi-oxalat~
White crystals; M.p. = 216C.
5-(2-~ydroxy-3-methyl-benzyl)~4,5,6,7-tetrahydro-thieno~ ,2ec7_ pyridine, semi-oxalate, semi-hydrate White crystals; M.p~ = 198C
5-(3-Acetamido-2-hydroxy-benzyl)-4,5,6,7-thieno~,2-c7pyridine White crystals; M.p. = 154C.
6-(S-Chloro-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~ ,3__7_ pyridine White crystals; M.p. = 222C.
EXA~LE 15 6-(3~4-Dichloro-2-hydroxy-benzyl)-495,6,7-tetrahydro-thieno~,3_~7_ pyridine White crystals; M.p. = 153C~
: EXAMPLE 16 6-(2-Hydroxy-5-nitro-benzyl)-4,5~6~7-tetrahydro-~hieno~l3-c)-~ 8 --.
3~
pyridine Iellow crystals; M.p. = 159C.
6-(3~5-Dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno~,3-c7py~idine Ivory crystals; M p. = 118C.
6-(2-Hydroxy-3-isopropyl-benzyl~-495,6~7-tetrahydro-thieno~ ,3-c7pyridine Very pale yellow crystals; M.p. = 101C.
.
6-(2-Hydroxy-5-methyl-benzyl)~4,5~6,7-tetrahydro-thieno~,3-_7pyridine~ semi-oxalate, æemi-hydrate Very pale yellow crystals9 M.p. = 196C.
EXAMPLE _ 6-(4-Dimethylami~o-2-hydroxy-benzyl)-4~596,7-tetrahydro-thieno~ ,3-_7pyridine Pink orystals; M.p. = 140C.
6-o-Hydroxybenzyl-4~5,697-tetrahydro-thieno~,3-c7pyridine Beige crystals; Mop~ = 98C.
..
6~ ydroxynaphthyl-methyl)-4,5~6,7-tet~ahydro-thieno~,3-c7 pyridine Pale yellow crystals; M~p~ = 150C
EXA~LE 23 5-(3,5-Dichloro-4-hydroxy~benzyl)-4~5~6,7-tetrahydro-thieno~,2-c7pyridine White crystals; M.p. = 170C.
_ g _ ... : .
Claims (6)
1. Process for the preparation of derivatives selected from the group consisting of the tetrahydro-thieno-[3,2-c]pyridine derivatives of the formula:
(Ia) and their isomeric pyridine derivatives of the formula:
(Ib) in which the hydroxyl radical is at a position selected from the 2- and 4-positions; R1 is selected from the group con-sisting of hydrogen and a lower alkyl radical having 1 to 4 carbon atoms; R2 and R3, when taken individually, are each selected from the group consisting of hydrogen, halogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical having 1 to 4 carbon atoms, a di(loweralkyl)amino radical wherein the alkyl has 1 to 4 carbon atoms, nitro, cyano and acetamido and R2 and R3 when taken together form a fused benzene ring, R2 and R3 being at a position selected from the 3-, 4-, 5- and 6-positions when OH is at 2-position and being at the 3- and 5-positions and other than hydrogen when OH is at 4-position, comprising heating a derivative selected from the group consisting of the tetrahydro-thieno-[3,2-c]pyridine derivatives of the formula:
(IIa) and their isomeric tetrahydrothieno [2,3-c]pyridine derivatives of the formula:
(IIb) in which R1 has the above-defined meanings, with formaldehyde H-CHO and a phenol of the formula:
(III) in which R2 and R3 have the above-defined meanings, to give the desired derivative selected from the pyridine derivatives of the formulae (Ia) and (Ib).
(Ia) and their isomeric pyridine derivatives of the formula:
(Ib) in which the hydroxyl radical is at a position selected from the 2- and 4-positions; R1 is selected from the group con-sisting of hydrogen and a lower alkyl radical having 1 to 4 carbon atoms; R2 and R3, when taken individually, are each selected from the group consisting of hydrogen, halogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical having 1 to 4 carbon atoms, a di(loweralkyl)amino radical wherein the alkyl has 1 to 4 carbon atoms, nitro, cyano and acetamido and R2 and R3 when taken together form a fused benzene ring, R2 and R3 being at a position selected from the 3-, 4-, 5- and 6-positions when OH is at 2-position and being at the 3- and 5-positions and other than hydrogen when OH is at 4-position, comprising heating a derivative selected from the group consisting of the tetrahydro-thieno-[3,2-c]pyridine derivatives of the formula:
(IIa) and their isomeric tetrahydrothieno [2,3-c]pyridine derivatives of the formula:
(IIb) in which R1 has the above-defined meanings, with formaldehyde H-CHO and a phenol of the formula:
(III) in which R2 and R3 have the above-defined meanings, to give the desired derivative selected from the pyridine derivatives of the formulae (Ia) and (Ib).
2. Process as claimed in claim 1, wherein the reaction is effected within an organic solvent.
3. Process as claimed in claim 2, wherein said organic solvent is selected from the group consisting of ethanol, propanol and dioxan.
4. Process as claimed in claim 2, wherein the reaction is effected at a temperature between 50°C and the boiling temperature of the solvent.
5. Process as claimed in claim 2, wherein the reaction is effected with stirring, during a period of time of 2-20 hours.
6. The tetrahydro-thieno [3,2-c]pyridine derivatives of the formula:
(Ia) and their isomeric pyridine derivatives of the formula:
(Ib) in which the hydroxyl radical is at a position selected from the 2- and 4-positions, R1 is selected from the group con-sisting of hydrogen and a lower alkyl radical having 1 to 4 carbon atoms, R2 and R3, when taken individually, are each selected from the group consisting of hydrogen, halogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical having 1 to 4 carbon atoms, a di(loweralkyl)amino radical wherein the alkyl has 1 to 4 carbon atoms, nitro, cyano and acetamido and R2 and R3 when taken together form a fused benzene ring, R2 and R3 being at a position selected from the 3-, 4-, 5- and 6-positions when OH is at 2-position and being at the 3- and 5-positions and other than hydrogen when OH is at 4-position, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
(Ia) and their isomeric pyridine derivatives of the formula:
(Ib) in which the hydroxyl radical is at a position selected from the 2- and 4-positions, R1 is selected from the group con-sisting of hydrogen and a lower alkyl radical having 1 to 4 carbon atoms, R2 and R3, when taken individually, are each selected from the group consisting of hydrogen, halogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower alkoxy radical having 1 to 4 carbon atoms, a di(loweralkyl)amino radical wherein the alkyl has 1 to 4 carbon atoms, nitro, cyano and acetamido and R2 and R3 when taken together form a fused benzene ring, R2 and R3 being at a position selected from the 3-, 4-, 5- and 6-positions when OH is at 2-position and being at the 3- and 5-positions and other than hydrogen when OH is at 4-position, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7521549A FR2317303A1 (en) | 1975-07-09 | 1975-07-09 | PROCESS FOR PREPARING TETRAHYDROTHIENO (3,2-C) AND (2,3-C) PYRIDINE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071634A true CA1071634A (en) | 1980-02-12 |
Family
ID=9157715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA254,573A Expired CA1071634A (en) | 1975-07-09 | 1976-06-10 | Process for the preparation of tetrahydro-thieno (3, 2-c) - and (2, 3-c) pyridine derivatives |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5236691A (en) |
| AR (1) | AR211019A1 (en) |
| AT (1) | AT348526B (en) |
| BE (1) | BE843822A (en) |
| CA (1) | CA1071634A (en) |
| CH (1) | CH609349A5 (en) |
| DD (1) | DD125081A5 (en) |
| DE (1) | DE2630474A1 (en) |
| DK (1) | DK141333B (en) |
| ES (1) | ES448404A1 (en) |
| FR (1) | FR2317303A1 (en) |
| GB (1) | GB1544093A (en) |
| GR (1) | GR59812B (en) |
| HU (1) | HU172280B (en) |
| IE (1) | IE42821B1 (en) |
| IL (1) | IL49641A (en) |
| LU (1) | LU74674A1 (en) |
| MX (1) | MX3224E (en) |
| NL (1) | NL7605362A (en) |
| PH (1) | PH12311A (en) |
| PL (1) | PL100685B1 (en) |
| PT (1) | PT65072B (en) |
| SE (1) | SE421699B (en) |
| SU (1) | SU628819A3 (en) |
| YU (1) | YU40137B (en) |
| ZA (1) | ZA763219B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5665315A (en) * | 1979-11-02 | 1981-06-03 | Nec Corp | Magnetic recording and inspecting system |
| DE3736664A1 (en) * | 1987-10-29 | 1989-05-11 | Boehringer Ingelheim Kg | TETRAHYDRO-FURO- AND -THIENO (2,3-C) PYRIDINE, THEIR USE AS A MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
| NZ233654A (en) * | 1989-05-18 | 1993-02-25 | Bristol Myers Squibb Co | 2-aminomethyl-5-aminophenol derivatives; hair dye compositions containing them |
-
1975
- 1975-07-09 FR FR7521549A patent/FR2317303A1/en active Granted
-
1976
- 1976-03-31 LU LU74674A patent/LU74674A1/xx unknown
- 1976-04-01 CH CH404576A patent/CH609349A5/en not_active IP Right Cessation
- 1976-04-21 GR GR50593A patent/GR59812B/en unknown
- 1976-04-23 YU YU1030/76A patent/YU40137B/en unknown
- 1976-05-06 PT PT65072A patent/PT65072B/en unknown
- 1976-05-19 NL NL7605362A patent/NL7605362A/en not_active Application Discontinuation
- 1976-05-21 IE IE1079/76A patent/IE42821B1/en unknown
- 1976-05-24 IL IL49641A patent/IL49641A/en unknown
- 1976-05-31 ES ES448404A patent/ES448404A1/en not_active Expired
- 1976-06-01 ZA ZA763219A patent/ZA763219B/en unknown
- 1976-06-03 AR AR263501A patent/AR211019A1/en active
- 1976-06-09 SU SU762366005A patent/SU628819A3/en active
- 1976-06-10 CA CA254,573A patent/CA1071634A/en not_active Expired
- 1976-06-16 MX MX000320U patent/MX3224E/en unknown
- 1976-07-01 DK DK297876AA patent/DK141333B/en not_active IP Right Cessation
- 1976-07-01 PH PH7618641A patent/PH12311A/en unknown
- 1976-07-05 AT AT489876A patent/AT348526B/en not_active IP Right Cessation
- 1976-07-06 BE BE168664A patent/BE843822A/en not_active IP Right Cessation
- 1976-07-07 SE SE7607762A patent/SE421699B/en not_active IP Right Cessation
- 1976-07-07 DE DE19762630474 patent/DE2630474A1/en active Pending
- 1976-07-07 DD DD193745A patent/DD125081A5/xx unknown
- 1976-07-08 GB GB28511/76A patent/GB1544093A/en not_active Expired
- 1976-07-08 PL PL1976191016A patent/PL100685B1/en unknown
- 1976-07-08 JP JP51081441A patent/JPS5236691A/en active Granted
- 1976-07-09 HU HU76PA00001255A patent/HU172280B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT65072A (en) | 1976-06-01 |
| DD125081A5 (en) | 1977-03-30 |
| HU172280B (en) | 1978-07-28 |
| YU40137B (en) | 1985-08-31 |
| SE421699B (en) | 1982-01-25 |
| IE42821B1 (en) | 1980-10-22 |
| ZA763219B (en) | 1977-05-25 |
| DK141333C (en) | 1980-08-25 |
| MX3224E (en) | 1980-07-28 |
| JPS5236691A (en) | 1977-03-22 |
| YU103076A (en) | 1982-02-28 |
| PL100685B1 (en) | 1978-10-31 |
| FR2317303B1 (en) | 1977-12-16 |
| PT65072B (en) | 1977-09-13 |
| FR2317303A1 (en) | 1977-02-04 |
| IE42821L (en) | 1977-01-09 |
| GR59812B (en) | 1978-03-01 |
| GB1544093A (en) | 1979-04-11 |
| DK141333B (en) | 1980-02-25 |
| BE843822A (en) | 1977-01-06 |
| DE2630474A1 (en) | 1977-01-13 |
| ES448404A1 (en) | 1977-07-01 |
| SU628819A3 (en) | 1978-10-15 |
| IL49641A0 (en) | 1976-07-30 |
| IL49641A (en) | 1978-08-31 |
| AT348526B (en) | 1979-02-26 |
| AR211019A1 (en) | 1977-10-14 |
| ATA489876A (en) | 1978-07-15 |
| JPS5310077B2 (en) | 1978-04-11 |
| PH12311A (en) | 1979-01-16 |
| DK297876A (en) | 1977-01-10 |
| SE7607762L (en) | 1977-01-10 |
| LU74674A1 (en) | 1976-09-01 |
| NL7605362A (en) | 1977-01-11 |
| CH609349A5 (en) | 1979-02-28 |
| AU1568676A (en) | 1977-03-31 |
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