CS221818B2 - Method of making the derivatives of the 1-/cyclohexyl/-4-aryl-4-piperidine with the cyano group and aryl group,bound in position 4 cyclohexyl ring - Google Patents

Method of making the derivatives of the 1-/cyclohexyl/-4-aryl-4-piperidine with the cyano group and aryl group,bound in position 4 cyclohexyl ring Download PDF

Info

Publication number: CS221818B2
Authority: CS; Czechoslovakia
Prior art keywords: parts; formula; group; acid; reaction
Prior art date: 1980-01-24

Application number

CS81435A

Other languages

Czech (cs)

English (en)

Inventor

Raymond Stokbroex

Marcel Luyckx

Joannes Willwms

Original Assignee

Janssen Pharmaceutica Nv

Priority date (The priority date 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 date listed.)

1980-01-24

Filing date

1981-01-21

Publication date

1983-04-29

1981-01-21 Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv

1983-04-29 Publication of CS221818B2 publication Critical patent/CS221818B2/cs

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125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title claims abstract description 11
125000003118 aryl group Chemical group 0.000 title claims abstract description 7
125000004093 cyano group Chemical group *C#N 0.000 title claims abstract description 7
238000004519 manufacturing process Methods 0.000 title 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 44
LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 100
239000000203 mixture Substances 0.000 claims description 66
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
-1 (1-pyrrolidinyl) - Chemical class 0.000 claims description 57
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 50
239000002253 acid Substances 0.000 claims description 45
238000006243 chemical reaction Methods 0.000 claims description 36
239000003054 catalyst Substances 0.000 claims description 35
238000003756 stirring Methods 0.000 claims description 28
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
239000011541 reaction mixture Substances 0.000 claims description 27
238000000034 method Methods 0.000 claims description 26
229910052739 hydrogen Inorganic materials 0.000 claims description 22
239000001257 hydrogen Substances 0.000 claims description 22
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 21
150000003839 salts Chemical class 0.000 claims description 19
229910052763 palladium Inorganic materials 0.000 claims description 17
125000000217 alkyl group Chemical group 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
239000002904 solvent Substances 0.000 claims description 13
238000010992 reflux Methods 0.000 claims description 12
239000000376 reactant Substances 0.000 claims description 11
229910052697 platinum Inorganic materials 0.000 claims description 10
239000007858 starting material Substances 0.000 claims description 10
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
238000006460 hydrolysis reaction Methods 0.000 claims description 9
238000010438 heat treatment Methods 0.000 claims description 8
230000007062 hydrolysis Effects 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
238000002360 preparation method Methods 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 7
150000002367 halogens Chemical class 0.000 claims description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
239000003960 organic solvent Substances 0.000 claims description 7
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 5
150000004820 halides Chemical group 0.000 claims description 5
150000001412 amines Chemical class 0.000 claims description 4
JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
125000006418 4-methylphenylsulfonyl group Chemical group 0.000 claims description 3
238000007126 N-alkylation reaction Methods 0.000 claims description 3
125000003545 alkoxy group Chemical group 0.000 claims description 3
125000004432 carbon atom Chemical group C* 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
239000003513 alkali Substances 0.000 claims description 2
239000012298 atmosphere Substances 0.000 claims description 2
125000004122 cyclic group Chemical group 0.000 claims description 2
150000008282 halocarbons Chemical class 0.000 claims description 2
229930195733 hydrocarbon Natural products 0.000 claims description 2
150000002576 ketones Chemical class 0.000 claims description 2
150000002825 nitriles Chemical class 0.000 claims description 2
150000003053 piperidines Chemical class 0.000 claims description 2
125000001424 substituent group Chemical group 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims 2
125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
125000002431 aminoalkoxy group Chemical group 0.000 claims 1
125000004429 atom Chemical group 0.000 claims 1
229910052799 carbon Inorganic materials 0.000 claims 1
238000007036 catalytic synthesis reaction Methods 0.000 claims 1
238000003776 cleavage reaction Methods 0.000 claims 1
125000004663 dialkyl amino group Chemical group 0.000 claims 1
AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 claims 1
150000004678 hydrides Chemical class 0.000 claims 1
150000002430 hydrocarbons Chemical class 0.000 claims 1
239000012442 inert solvent Substances 0.000 claims 1
229910052751 metal Inorganic materials 0.000 claims 1
239000002184 metal Substances 0.000 claims 1
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
231100000252 nontoxic Toxicity 0.000 claims 1
230000003000 nontoxic effect Effects 0.000 claims 1
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
230000007017 scission Effects 0.000 claims 1
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
230000001387 anti-histamine Effects 0.000 abstract description 4
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
239000000243 solution Substances 0.000 description 53
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
239000000047 product Substances 0.000 description 31
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
238000009835 boiling Methods 0.000 description 20
239000000706 filtrate Substances 0.000 description 20
239000003480 eluent Substances 0.000 description 19
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
239000000284 extract Substances 0.000 description 12
229960001701 chloroform Drugs 0.000 description 11
238000002844 melting Methods 0.000 description 11
230000008018 melting Effects 0.000 description 11
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
239000003610 charcoal Substances 0.000 description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
235000011114 ammonium hydroxide Nutrition 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
239000008346 aqueous phase Substances 0.000 description 7
150000002148 esters Chemical class 0.000 description 7
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
238000001816 cooling Methods 0.000 description 6
239000012458 free base Substances 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
238000006845 Michael addition reaction Methods 0.000 description 5
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
239000000908 ammonium hydroxide Substances 0.000 description 5
239000002585 base Substances 0.000 description 5
239000004927 clay Substances 0.000 description 5
229920002055 compound 48/80 Polymers 0.000 description 5
150000002431 hydrogen Chemical class 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000008194 pharmaceutical composition Substances 0.000 description 5
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
239000001632 sodium acetate Substances 0.000 description 5
235000017281 sodium acetate Nutrition 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
241000700159 Rattus Species 0.000 description 4
150000007513 acids Chemical class 0.000 description 4
150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
230000000694 effects Effects 0.000 description 4
125000004494 ethyl ester group Chemical group 0.000 description 4
239000010410 layer Substances 0.000 description 4
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
239000007787 solid Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
239000003826 tablet Substances 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
239000000739 antihistaminic agent Substances 0.000 description 3
CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
239000002775 capsule Substances 0.000 description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
239000000460 chlorine Substances 0.000 description 3
125000001309 chloro group Chemical group Cl* 0.000 description 3
238000004440 column chromatography Methods 0.000 description 3
150000004292 cyclic ethers Chemical class 0.000 description 3
239000002552 dosage form Substances 0.000 description 3
230000032050 esterification Effects 0.000 description 3
238000005886 esterification reaction Methods 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
125000001153 fluoro group Chemical group F* 0.000 description 3
239000007791 liquid phase Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
239000012071 phase Substances 0.000 description 3
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
229930192474 thiophene Natural products 0.000 description 3
YSULUXOLTMBSFF-UHFFFAOYSA-N (4-fluoro-2-methylphenyl)methanol Chemical compound CC1=CC(F)=CC=C1CO YSULUXOLTMBSFF-UHFFFAOYSA-N 0.000 description 2
125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
BFBFYOBHZSATCK-UHFFFAOYSA-N 4-(2-fluorophenyl)-3-methyl-1-(4-methylphenyl)sulfonylpiperidine-4-carboxylic acid Chemical compound CC1CN(S(=O)(=O)C=2C=CC(C)=CC=2)CCC1(C(O)=O)C1=CC=CC=C1F BFBFYOBHZSATCK-UHFFFAOYSA-N 0.000 description 2
YYFWRAUDAXLUTQ-UHFFFAOYSA-N 4-(3-chloro-2-methylphenyl)-1-(4-methylphenyl)sulfonylpiperidine-4-carbonyl chloride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CCC(C=2C(=C(Cl)C=CC=2)C)(C(Cl)=O)CC1 YYFWRAUDAXLUTQ-UHFFFAOYSA-N 0.000 description 2
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
239000005711 Benzoic acid Substances 0.000 description 2
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
239000005977 Ethylene Substances 0.000 description 2
XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
241000755093 Gaidropsarus vulgaris Species 0.000 description 2
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
241001611408 Nebo Species 0.000 description 2
DZZGGKPKWGPNJA-UHFFFAOYSA-N Normeperidinicacid Chemical class C=1C=CC=CC=1C1(C(=O)O)CCNCC1 DZZGGKPKWGPNJA-UHFFFAOYSA-N 0.000 description 2
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
241001648319 Toronia toru Species 0.000 description 2
125000002723 alicyclic group Chemical group 0.000 description 2
XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
238000007112 amidation reaction Methods 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
238000010533 azeotropic distillation Methods 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
230000037396 body weight Effects 0.000 description 2
239000000969 carrier Substances 0.000 description 2
230000003197 catalytic effect Effects 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
239000003937 drug carrier Substances 0.000 description 2
238000010828 elution Methods 0.000 description 2
150000002081 enamines Chemical class 0.000 description 2
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
239000005457 ice water Substances 0.000 description 2
SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical class OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
239000007788 liquid Substances 0.000 description 2
239000011777 magnesium Substances 0.000 description 2
ZOSKCBSQEITOCV-UHFFFAOYSA-N methanesulfonic acid;dihydrochloride Chemical compound Cl.Cl.CS(O)(=O)=O ZOSKCBSQEITOCV-UHFFFAOYSA-N 0.000 description 2
238000002156 mixing Methods 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
239000003921 oil Substances 0.000 description 2
XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
239000006187 pill Substances 0.000 description 2
235000011056 potassium acetate Nutrition 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
239000000843 powder Substances 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
238000010956 selective crystallization Methods 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
FNWWTNNFZGBMEM-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-oxocyclohexane-1-carbonitrile Chemical compound C1=CC(F)=CC=C1C1(C#N)CCC(=O)CC1 FNWWTNNFZGBMEM-UHFFFAOYSA-N 0.000 description 1
DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
RJPNVPITBYXBNB-UHFFFAOYSA-N 1-bromo-4-fluoro-2-methylbenzene Chemical compound CC1=CC(F)=CC=C1Br RJPNVPITBYXBNB-UHFFFAOYSA-N 0.000 description 1
WSWPHHNIHLTAHB-UHFFFAOYSA-N 1-ethoxy-4-methylbenzene Chemical compound CCOC1=CC=C(C)C=C1 WSWPHHNIHLTAHB-UHFFFAOYSA-N 0.000 description 1
HYFLWBNQFMXCPA-UHFFFAOYSA-N 1-ethyl-2-methylbenzene Chemical compound CCC1=CC=CC=C1C HYFLWBNQFMXCPA-UHFFFAOYSA-N 0.000 description 1
VJARIBGMDPJLCL-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=C(CC#N)C(Cl)=C1 VJARIBGMDPJLCL-UHFFFAOYSA-N 0.000 description 1
QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
- 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
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Hydrogenated Pyridines (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

CS81435A 1980-01-24 1981-01-21 Method of making the derivatives of the 1-/cyclohexyl/-4-aryl-4-piperidine with the cyano group and aryl group,bound in position 4 cyclohexyl ring CS221818B2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US11492480A	1980-01-24	1980-01-24
US06/191,631 US4369184A (en)	1980-01-24	1980-09-29	1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives

Publications (1)

Publication Number	Publication Date
CS221818B2 true CS221818B2 (en)	1983-04-29

Family

ID=26812674

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CS81435A CS221818B2 (en)	1980-01-24	1981-01-21	Method of making the derivatives of the 1-/cyclohexyl/-4-aryl-4-piperidine with the cyano group and aryl group,bound in position 4 cyclohexyl ring

Country Status (25)

Country	Link
US (1)	US4369184A (da)
EP (1)	EP0034415B1 (da)
AU (1)	AU538130B2 (da)
BG (2)	BG35465A3 (da)
CA (1)	CA1187080A (da)
CS (1)	CS221818B2 (da)
DE (1)	DE3163787D1 (da)
DK (1)	DK152670C (da)
ES (2)	ES8204421A1 (da)
FI (1)	FI76562C (da)
GR (1)	GR71898B (da)
HK (1)	HK81088A (da)
HU (1)	HU183293B (da)
IE (1)	IE50706B1 (da)
IL (1)	IL61968A (da)
LU (1)	LU88220I2 (da)
MA (1)	MA19046A1 (da)
MY (1)	MY8700593A (da)
NL (1)	NL930017I2 (da)
NO (1)	NO1994012I1 (da)
NZ (1)	NZ196117A (da)
PH (1)	PH16611A (da)
PL (2)	PL127679B1 (da)
SU (1)	SU1230467A3 (da)
YU (1)	YU48446B (da)

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JPS6322584A (ja) *	1986-07-15	1988-01-30	Senjiyu Seiyaku Kk	１−ハイドロキシ−５−オキソ−５Ｈ−ピリド〔３，２−ａ〕フエノキサジン−３−カルボン酸エステル類
DE4108527A1 (de) *	1991-03-15	1992-09-17	Basf Ag	Neue 1-(4-cyano-4-aryl-cyclohexyl)piperazine, ihre herstellung und verwendung
SE9400447D0 (sv) *	1994-02-11	1994-02-11	Astra Ab	New compounds
WO1995025518A1 (en) *	1994-03-18	1995-09-28	Ciba-Geigy Ag	Aqueous solution of levocabastine for ophthalmic use
US5661163A (en)	1995-06-07	1997-08-26	Merck & Co., Inc.	Alpha-1a adrenergic receptor antagonists
JP2000509374A (ja)	1996-04-19	2000-07-25	アルファセラピュティックコーポレイション	凍結乾燥した血液タンパク質のウイルス不活性化方法
US6267986B1 (en)	1999-09-24	2001-07-31	Ranbaxy Laboratories Limited	Process for the preparation of a controlled drug delivery system containing pseudoephedrine and a long acting antihistamine
US20020146409A1 (en) *	2001-01-30	2002-10-10	Herring Steven W.	Methods for stabilizing lyophilized blood proteins
PL373433A1 (en) *	2002-08-30	2005-08-22	Altana Pharma Ag	The use of the combination of ciclesonide and antihistamines for the treatment of allergic rhinitis
EP1976513B1 (en) *	2006-01-06	2016-08-24	Sunovion Pharmaceuticals Inc.	Cycloalkylamines as monoamine reuptake inhibitors
NZ573174A (en)	2006-06-01	2012-01-12	Msd Consumer Care Inc	Sustained release pharmaceutical dosage form containing phenylephrine
CN104161736A (zh)	2006-06-01	2014-11-26	Msd消费保健品公司	包含去氧肾上腺素的缓释药物制剂
AU2008343045A1 (en) *	2007-12-21	2009-07-09	Msd Consumer Care, Inc.	Enhancing photostabilization of oxymetazoline
CN104039321B (zh)	2011-11-18	2017-02-22	赫普泰雅治疗有限公司	药物化合物
GB201404922D0 (en)	2014-03-19	2014-04-30	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201513743D0 (en)	2015-08-03	2015-09-16	Heptares Therapeutics Ltd	Muscarinic agonists
GB201519352D0 (en)	2015-11-02	2015-12-16	Heptares Therapeutics Ltd	Pharmaceutical compounds
US10259787B2 (en)	2016-10-14	2019-04-16	Heptares Therapeutics Limited	Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
GB201617454D0 (en)	2016-10-14	2016-11-30	Heptares Therapeutics Limited	Pharmaceutical compounds
GB201810239D0 (en)	2018-06-22	2018-08-08	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201819960D0 (en)	2018-12-07	2019-01-23	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201819961D0 (en)	2018-12-07	2019-01-23	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB202020191D0 (en)	2020-12-18	2021-02-03	Heptares Therapeutics Ltd	Pharmaceutical compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE1206436B (de) *	1957-07-05	1965-12-09	Janssen Pharmaceutica Nv	Verfahren zur Herstellung von Derivaten von 2, 2-Diaryl-4-(4'-phenyl-piperidino)-butyronitrilen
NL127792C (da) *	1965-06-29

1980
- 1980-09-29 US US06/191,631 patent/US4369184A/en not_active Expired - Lifetime
1981
- 1981-01-08 GR GR63814A patent/GR71898B/el unknown
- 1981-01-16 AU AU66255/81A patent/AU538130B2/en not_active Expired
- 1981-01-21 CS CS81435A patent/CS221818B2/cs unknown
- 1981-01-22 DK DK029381A patent/DK152670C/da not_active IP Right Cessation
- 1981-01-22 PH PH25120A patent/PH16611A/en unknown
- 1981-01-22 MA MA19247A patent/MA19046A1/fr unknown
- 1981-01-23 FI FI810193A patent/FI76562C/fi not_active IP Right Cessation
- 1981-01-23 BG BG050518A patent/BG35465A3/xx unknown
- 1981-01-23 HU HU81148A patent/HU183293B/hu unknown
- 1981-01-23 YU YU18381A patent/YU48446B/sh unknown
- 1981-01-23 ES ES498793A patent/ES8204421A1/es not_active Expired
- 1981-01-23 DE DE8181300313T patent/DE3163787D1/de not_active Expired
- 1981-01-23 EP EP81300313A patent/EP0034415B1/en not_active Expired
- 1981-01-23 LU LU88220C patent/LU88220I2/xx unknown
- 1981-01-23 IE IE125/81A patent/IE50706B1/en not_active IP Right Cessation
- 1981-01-23 IL IL61968A patent/IL61968A/xx not_active IP Right Cessation
- 1981-01-23 CA CA000369180A patent/CA1187080A/en not_active Expired
- 1981-01-23 PL PL1981229365A patent/PL127679B1/pl unknown
- 1981-01-23 PL PL1981233921A patent/PL127483B1/pl unknown
- 1981-01-23 SU SU813233002A patent/SU1230467A3/ru active
- 1981-01-26 NZ NZ196117A patent/NZ196117A/en unknown
- 1981-12-30 ES ES508441A patent/ES508441A0/es active Granted
1987
- 1987-12-30 MY MY593/87A patent/MY8700593A/xx unknown
1988
- 1988-10-06 HK HK810/88A patent/HK81088A/en not_active IP Right Cessation
1993
- 1993-03-02 NL NL930017C patent/NL930017I2/nl unknown
- 1993-06-16 BG BG097872A patent/BG60472B2/bg unknown
1994
- 1994-08-30 NO NO1994012C patent/NO1994012I1/no unknown

Also Published As

Publication number	Publication date
YU48446B (sh)	1998-07-10
CA1187080A (en)	1985-05-14
NL930017I1 (nl)	1993-05-03
GR71898B (da)	1983-08-11
SU1230467A3 (ru)	1986-05-07
HK81088A (en)	1988-10-14
ES8307219A1 (es)	1983-07-01
MA19046A1 (fr)	1981-10-01
PH16611A (en)	1983-11-24
ES508441A0 (es)	1983-07-01
DE3163787D1 (en)	1984-07-05
LU88220I2 (da)	1994-02-03
FI76562C (fi)	1988-11-10
PL233921A1 (da)	1982-06-21
IE810125L (en)	1981-07-24
PL127483B1 (en)	1983-10-31
BG60472B2 (bg)	1995-04-28
NO1994012I1 (no)	1994-08-30
AU538130B2 (en)	1984-08-02
HU183293B (en)	1984-04-28
NL930017I2 (nl)	1993-07-16
IL61968A0 (en)	1981-02-27
BG35465A3 (en)	1984-04-15
MY8700593A (en)	1987-12-31
PL229365A1 (da)	1982-03-29
YU18381A (en)	1983-10-31
IL61968A (en)	1984-09-30
FI810193L (fi)	1981-07-25
DK29381A (da)	1981-07-25
EP0034415B1 (en)	1984-05-30
FI76562B (fi)	1988-07-29
ES498793A0 (es)	1982-05-01
DK152670C (da)	1988-08-22
US4369184A (en)	1983-01-18
PL127679B1 (en)	1983-11-30
ES8204421A1 (es)	1982-05-01
DK152670B (da)	1988-04-11
EP0034415A1 (en)	1981-08-26
NZ196117A (en)	1984-05-31
IE50706B1 (en)	1986-06-25
AU6625581A (en)	1981-07-30

Publication	Publication Date	Title
JP3056321B2 (ja)	2000-06-26	ピペリジン誘導体
AU2001242744B2 (en)	2005-07-21	Diphenylalkylamine derivatives useful as opioid delta receptor ligands
BG60472B2 (bg)	1995-04-28	Производни на 1-(циклохексил или циклохексенил)-4-арил-4- пиперидинкарбоксилова киселина
HU179734B (en)	1982-12-28	Process for producing pharmaceutically effective new n-2 above-bracket-1,2,3,4-tetrahydro-8-quinolyl-bracket closed-sulfonyl-l-arginine-amides
EA007225B1 (ru)	2006-08-25	Производные n-[фенил(пиперидин-2-ил)метил]бензамида и их применение в терапии
EP0258755A1 (en)	1988-03-09	Alpha-alkyl-4-amino-3-quinoline-methanols and 1-(4-aralkylamino-3-quinolinyl) alkanones, a process for their preparation and their use as medicaments
EP0040639A1 (en)	1981-12-02	Isoxazole derivatives
JPS63146874A (ja)	1988-06-18	インドール誘導体
HUP0501016A2 (en)	2006-02-28	(s)-4-amino-5-chloro-2-methoxy-n-{1-[1-(2-tetrahydrofurylcarbonyl)-4-piperidinylmethyl]-4-piperidinyl}benzamide, process for the preparation thereof pharmaceutical composition containing the same and intermediate therefor
HU187777B (en)	1986-02-28	Process for preparing pyrrolidine derivatives
EP0068331B1 (en)	1986-01-15	Tetrahydrofuran compounds and analogs thereof
US3974158A (en)	1976-08-10	2-(Substituted anilino)methylmorpholines
US5102882A (en)	1992-04-07	Pyroglutamide derivatives
HU202211B (en)	1991-02-28	Process for producing new imidazoline derivatives and pharmaceutical compositions containing them as active components
SU1093251A3 (ru)	1984-05-15	Способ получени производных 4 @ -пиридо(1,2-а)пиримидин-4-она или их фармацевтически приемлемых кислотно-аддитивных солей
HU182941B (en)	1984-03-28	Process for preparing new n-oxacyclyl-alkyl-piperidines further pharmaceutical compositions containing these compounds
FI71936B (fi)	1986-11-28	Foerfarande foer framstaellning av neuroleptiskt aktiva 2-substituerade-8-fluor-5-(4-fluorfenyl)-2,3,4,4a 5,9b-hexahydro-4a 9b-trans-1h-pyrido/4,3-b/indolderivat
JPH04226959A (ja)	1992-08-17	Ｎ−置換トリフルオロメチルフェニルテトラヒドロピリジンおよびこれを含む薬剤組成物
KR870001681B1 (ko)	1987-09-22	히단토인 유도체의 제조방법
US4029786A (en)	1977-06-14	Morpholine derivatives for treating depression
CH644364A5 (de)	1984-07-31	4-(naphthalinyloxy)piperidin-derivate.
US4002618A (en)	1977-01-11	2,2-Diphenyl-5-(4-substituted-piperidino)-3-trans-pentenenitriles
US3037982A (en)	1962-06-05	Phenylpiperazinylalkyl propionanilides
KR950007591B1 (ko)	1995-07-12	피로글루타미드 유도체
US4622327A (en)	1986-11-11	2H-azeto[2,1-a]-isoquinoline derivatives and pharmaceutical compositions containing them