NZ761473B2 - Trans-isomeric heterocyclic compounds and preparation thereof - Google Patents
Trans-isomeric heterocyclic compounds and preparation thereof Download PDFInfo
- Publication number
- NZ761473B2 NZ761473B2 NZ761473A NZ76147318A NZ761473B2 NZ 761473 B2 NZ761473 B2 NZ 761473B2 NZ 761473 A NZ761473 A NZ 761473A NZ 76147318 A NZ76147318 A NZ 76147318A NZ 761473 B2 NZ761473 B2 NZ 761473B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- acid
- trans
- pharmaceutically acceptable
- formula
- substituted
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 50
- -1 3,5-disubstituted pyridine Chemical class 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000011780 sodium chloride Substances 0.000 claims abstract description 36
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000012442 inert solvent Substances 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 150000001924 cycloalkanes Chemical class 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 230000002378 acidificating Effects 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 8
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- LLHKCFNBLRBOGN-UHFFFAOYSA-N Propylene glycol methyl ether acetate Chemical compound COCC(C)OC(C)=O LLHKCFNBLRBOGN-UHFFFAOYSA-N 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- KQNPFQTWMSNSAP-UHFFFAOYSA-N Isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N diguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 125000003441 thioacyl group Chemical group 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- 229910052723 transition metal Inorganic materials 0.000 claims description 4
- 150000003624 transition metals Chemical class 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N (+)-tartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- WXNXCEHXYPACJF-SSDOTTSWSA-N (2R)-2-acetamido-4-methylpentanoic acid Chemical compound CC(C)C[C@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-SSDOTTSWSA-N 0.000 claims description 3
- LINPSOODYGSBAH-HZPDHXFCSA-N (2R,3R)-2,3-dibenzoyloxy-4-(dimethylamino)-4-oxobutanoic acid Chemical compound O([C@@H](C(=O)N(C)C)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 LINPSOODYGSBAH-HZPDHXFCSA-N 0.000 claims description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2R,3R)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 3
- LJFJPDHXAWVDSA-DVOMOZLQSA-N 2-[(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexyl]oxycarbonylbenzoic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C1=CC=CC=C1C(O)=O LJFJPDHXAWVDSA-DVOMOZLQSA-N 0.000 claims description 3
- JDRMYOQETPMYQX-UHFFFAOYSA-M 4-methoxy-4-oxobutanoate Chemical compound COC(=O)CCC([O-])=O JDRMYOQETPMYQX-UHFFFAOYSA-M 0.000 claims description 3
- KXGVEGMKQFWNSR-LLQZFEROSA-N Deoxycholic acid Chemical group C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 3
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 3
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4S)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 claims description 3
- 229960003964 deoxycholic acid Drugs 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- LSPHULWDVZXLIL-LDWIPMOCSA-N (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 2
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 claims description 2
- HEFNNWSXXWATRW-JTQLQIEISA-N (2S)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 2
- CILPHQCEVYJUDN-UHFFFAOYSA-N 2-(5-methyl-2-propan-2-ylcyclohexyl)oxyacetic acid Chemical compound CC(C)C1CCC(C)CC1OCC(O)=O CILPHQCEVYJUDN-UHFFFAOYSA-N 0.000 claims description 2
- VCFKXWGKKDZMPO-LLVKDONJSA-N 2-[[(1R)-1-phenylethyl]carbamoyl]benzoic acid Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1C(O)=O VCFKXWGKKDZMPO-LLVKDONJSA-N 0.000 claims description 2
- WUEKFTPKHWMMIP-SECBINFHSA-N 4-oxo-4-[[(1R)-1-phenylethyl]amino]butanoic acid Chemical compound OC(=O)CCC(=O)N[C@H](C)C1=CC=CC=C1 WUEKFTPKHWMMIP-SECBINFHSA-N 0.000 claims description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 claims description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N Pyroglutamic acid Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- UUDLQDCYDSATCH-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;hydrate Chemical compound O.OC(=O)C(O)C(O)C(O)=O UUDLQDCYDSATCH-UHFFFAOYSA-N 0.000 claims 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N Tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 17
- 230000003287 optical Effects 0.000 description 13
- 150000003053 piperidines Chemical class 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000707 stereoselective Effects 0.000 description 7
- BCCUXBGEPLKSEX-UHFFFAOYSA-N 5-methylpyridine-3-carboxamide Chemical compound CC1=CN=CC(C(N)=O)=C1 BCCUXBGEPLKSEX-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
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- 239000001257 hydrogen Substances 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 3
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- 125000005843 halogen group Chemical group 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
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- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940114148 picric acid Drugs 0.000 description 1
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Provided is a trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof, in which R1is C1-C5alkyl or C3-C5cycloalkyl. The trans-isomeric compound has a trans:cis ratio of at least 70:30. Further provided is a method for preparing the trans-isomeric compound. Method of preparation includes hydrogenation of 3,5-disubstituted pyridine, in the presence of a palladium catalyst. of preparation includes hydrogenation of 3,5-disubstituted pyridine, in the presence of a palladium catalyst.
Description
TRANS-ISOMERIC HETEROCYCLIC COMPOUNDS AND PREPARATION
THEREOF
TECHNICAL FIELD
The present disclosure relates to trans-isomeric heterocyclic compounds, i.e.,
piperidines, and a method of preparing the stereo-specific isomers.
BACKGROUND
Some heterocyclic compounds, e.g., piperidines, possess pharmaceutical activity.
It has been reported that their pharmaceutical activity, as well as safety, varies based on
the stereochemical configurations of the substituents on the piperidine ring. See, e.g.,
Pharmacia, 1989, 25(4), 311-336. Thus, effective synthesis of piperidines with high
stereo-selectivity is of great importance.
Methods for preparing cis/trans mixtures of piperidines, e.g., piperidine
carboxamide, are well known in the field. See, e.g., DeNinno et al., Bioorganic and
Medicinal Letters, 2011, 21, 3095-3098, and Gancia et al., . Yet,
conventional methods produce either non-stereo selective isomers or mainly cis-isomers.
There is a need to develop a new method for preparing trans-isomeric piperidines.
SUMMARY
An aspect of the present disclosure is a method of preparing a trans-isomeric
compound of formula (I) below or a pharmaceutically acceptable salt thereof:
(I).
The method, unexpectedly producing trans-isomeric piperidines in high yield and
high stereo-selectivity, includes the step of hydrogenating a compound of formula (II)
below or a pharmaceutically acceptable salt thereof:
N (II),
with a palladium catalyst in the presence of an inert solvent to obtain a trans-isomeric
compound of formula (I) having a trans:cis ratio of at least 70:30 (up to 99.9:0.1) or a
pharmaceutically acceptable salt thereof, in which R in formulas (I) and (II) is C -C
1 1 5
alkyl or C -C cycloalkyl.
The above-described method can further include a resolution step, which is
performed via optical resolution of the trans-isomeric compound with an acidic resolving
agent. This process can provide an optically enriched enantiomer of the trans-isomeric
compound of formula (I) or a pharmaceutically acceptable salt thereof. The acidic
resolving agent can be in R-form or S-form. If needed, the enantiomer thus obtained can
be recrystallized with a recrystallization solvent.
Another aspect of this disclosure is a trans-isomeric compound of formula (I)
below or a pharmaceutically acceptable salt thereof:
H (I),
in which R is C -C alkyl or C -C cycloalkyl and the trans-isomeric compound in an
1 1 5 3 5
isomeric compound mixture has a trans:cis ratio of at least 70:30. In an embodiment, R
is C -C alkyl, e.g., methyl.
The trans-isomeric compound of formula (I) can be in the form of (3S, 5S)-
configuration, i.e., formula (Ia) shown below, or (3R, 5R)-configuration, i.e., formula (Ib)
also shown below:
NH NH
H (Ia) H (Ib).
The term “C -C alkyl” herein refers to a straight or branched chain hydrocarbon
radical containing 1 to 5 carbon atoms. Examples of C -C alkyl include, but are not
limited to, methyl, ethyl, propyl, and isopropyl. The term “C -C cycloalkyl” refers to a
saturated, cyclic hydrocarbon moiety containing 3 to 5 carbon atoms. Examples of C -C
cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.
Alkyl and cycloalkyl mentioned herein include both substituted and unsubstituted
moieties, unless specified otherwise. Possible substituents on alkyl and cycloalkyl
include, but are not limited to, amino, hydroxyl, halo, thio, acylamino, aminoacyl,
aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl,
acyloxy, carboxyl, and carboxylic ester.
A further aspect of this disclosure is a trans-isomeric compound of formula (I)
prepared by the method described above.
In another aspect of this disclosure is a trans-isomeric compound of formula (I)
below or a pharmaceutically acceptable salt thereof:
(I),
wherein R is a substituted or unsubstituted C -C alkyl or a substituted or unsubstituted
1 1 5
C -C cycloalkyl and the trans-isomeric compound in an isomeric compound mixture has
a trans:cis ratio of at least 70:30, and
wherein the substituted alkyl or the substituted cycloalkyl is substituted with a
substituent selected from the group consisting of amino, hydroxyl, halo, thio, acylamino,
aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl,
thioacyl, acyloxy, carboxyl, and carboxylic ester.
In another aspect of the present invention is a method of preparing a trans-
isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof:
H (I),
the method comprising hydrogenating a compound of formula (II) below or a
pharmaceutically acceptable salt thereof:
(II),
with a palladium catalyst in the presence of an inert solvent to obtain the trans-isomeric
compound of formula (I) having a trans:cis ratio of at least 70:30 or the pharmaceutically
acceptable salt thereof, wherein R of formulas (I) and (II) is a substituted or
unsubstituted C -C alkyl or a substituted or unsubstituted C -C cycloalkyl, and wherein
1 5 3 5
the substituted alkyl or the substituted cycloalkyl is substituted with a substituent selected
from the group consisting of amino, hydroxyl, halo, thio, acylamino, aminoacyl,
aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl,
acyloxy, carboxyl, and carboxylic ester.
The details of the disclosure are set forth in the description below. Other features
and objects of the disclosure will be apparent from the following detailed description of
several embodiments, and also from the appending claims.
DETAILED DESCRIPTION
Disclosed first in detail herein is a trans-isomeric compound of formula (I),
reproduced below, or a pharmaceutically acceptable salt thereof:
H (I).
In this formula, R is C -C alkyl or C -C cycloalkyl. In some embodiments, R
1 1 5 3 5 1
is C -C alkyl, e.g., methyl, ethyl, and isopropyl. In some embodiments, the trans-
isomeric compound has a trans:cis ratio of at least 70:30, e.g., 80:20, 90:10, and 99:1.
The trans-isomeric compound can be present as a pure enantiomer. An exemplary
enantiomer is in the form of (3S, 5S)-configuration of formula (Ia) shown in the
SUMMARY section above or a pharmaceutically acceptable salt thereof, or in the form
of (3R, 5R)-configuration of formula (Ib), also shown in the SUMMARY section above,
or a pharmaceutically acceptable salt thereof.
The term “pharmaceutically acceptable salt” refers to an acid or base salt of a
compound of this disclosure. In some embodiments, the pharmaceutically acceptable
salts include acid addition salts that can be formed by reacting the compound with a
pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid,
hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid,
propionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, lactic acid, malic
acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid,
aspartic acid, and glutamic acid.
The compounds described above include the compounds themselves, as well as
their salts, prodrugs, polymorphs, stereoisomers and solvates, if applicable. A salt, for
example, can be formed between an anion and a positively charged group (e.g., amino)
on a compound having one of the above formulas. Suitable anions include chloride,
bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate,
acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and
maleate. Likewise, a salt can also be formed between a cation and a negatively charged
group (e.g., carboxylate) on a compound having one of the above formulas. Suitable
cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an
ammonium cation such as tetramethylammonium ion. The compounds also include those
salts containing quaternary nitrogen atoms. For calculation simplicity, unless otherwise
stated, the weight of a compound mentioned herein refers to that of the free base form of
that compound. Examples of prodrugs include esters and other pharmaceutically
acceptable derivatives, which, upon administration to a subject, are capable of providing
active compounds. A solvate refers to a complex formed between an active compound
and a pharmaceutically acceptable solvent. Examples of the pharmaceutically acceptable
solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
Also within the scope of this disclosure is a method of preparing a trans-isomeric
compound of formula (I) or a pharmaceutically acceptable salt thereof.
To reiterate, the method includes hydrogenating a compound of formula (II),
shown in the SUMMARY section above, with a palladium catalyst in the presence of an
inert solvent to stereo-selectively produce a trans-isomeric compound of formula (I)
having a trans:cis ratio of at least 70:30 or a pharmaceutically acceptable salt thereof.
The stereo-selective hydrogenation of the compound of formula (II) is conducted
in the presence of a palladium catalyst at a suitable pressure using a variety of solvents.
The trans:cis ratios are determined by nuclear magnetic resonance (NMR) spectroscopy.
The palladium catalyst includes one or more palladium compounds, such as
Pd(OH) /C, Pd/C, Pd(OAc) , Pd/Al O , or a combination thereof. In other embodiments,
2 2 2 3
it may contain another transition metal catalyst, e.g., Pt/C and Rh/C. The content of
palladium in the palladium catalyst can be about 0.01 wt% to about 30 wt%, or about 0.1
wt% to about 25 wt%, or about 1 wt% to about 20 wt%, or about 2 wt% to about 20 wt%,
or about 5 wt% to about 20 wt%.
Examples of the inert solvent include, but are not limited to, H O, a C -C ester
2 1 10
(e.g., ethyl acetate and methyl acetate), a C -C cycloalkane (e.g., cyclopropane,
3 10
cyclobutane, cyclopentane, and cyclohexane), tetrahydrofuran (THF),
dimethylformamide (DMF), acetonitrile, a C -C alcohol (e.g., methanol, ethanol, n-
1 10
propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, propylene
glycol, and butylene glycol), an alkylene glycol monoalkyl ether (e.g., propylene glycol
monomethyl ether, propylene glycol monoethyl ether, and propylene glycol monopropyl
ether), an alkylene glycol monoalkyl ether carboxylate (e.g., propylene glycol
monomethyl ether acetate, propylene glycol monoethyl ether acetate, and propylene
glycol monopropyl ether acetate), an amide-based solvent (e.g., N,N-dimethylacetamide
and N,N-dimethylformamide), an organic acid (e.g., a C -C carboxylic acid and a C -
1 10 1
C sulfonic acid), and combinations thereof. In an embodiment, an inert solvent can
contain two or more C -C esters, two or more C -C cycloalkanes, and the like. In
1 10 3 10
other embodiments, an inert solvent can contain one or more inorganic acids (e.g.,
hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid).
In one embodiment, the inert solvent is H O, a C -C ester, a C -C cycloalkane,
2 1 5 3 6
THF, DMF, acetonitrile, a C -C alcohol, propylene glycol monomethyl ether, propylene
glycol monomethyl ether acetate, N,N-dimethylacetamide, a C -C carboxylic acid (e.g.,
formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, difluoroacetic acid,
trifluoroacetic acid, and a combination thereof), a C -C sulfonic acid (e.g.,
methanesulfonic acid), or a combination thereof, and in other embodiments, containing
one or more inorganic acids of hydrochloric acid, sulfuric acid, phosphoric acid, and
nitric acid. In another embodiment, the inert solvent is H O, a C -C ester, a C -C
2 1 5 3 6
cycloalkane, THF, DMF, a C -C alcohol, propylene glycol monomethyl ether, propylene
glycol monomethyl ether acetate, N,N-dimethylacetamide, a C -C carboxylic acid, a C -
1 5 1
C sulfonic acid, or a combination thereof, and in other embodiments, containing
hydrochloric acid. In still other embodiments, the inert solvents are H O, methanol
(MeOH), ethanol (EtOH), isopropanol (i-PrOH), ethyl acetate, formic acid, acetic acid,
methanesulfonic acid, and a combination thereof, and in some embodiments, containing
hydrochloric acid.
Unexpectedly, the inert solvent containing an inorganic acid (e.g., hydrochloric
acid, sulfuric acid, phosphoric acid, and nitric acid) is capable of providing extremely
high stereo-selectivity of trans-isomeric piperidines. As examples, the inert solvent is an
organic acid or a combination of the organic acid with one or more of the following
solvents: H O, a C -C ester, a C -C cycloalkane, THF, DMF, acetonitrile, an alkylene
2 1 10 3 10
glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an amide-based
solvent, a C -C alcohol, and an inorganic acid. In one embodiment, the inert solvent is
1 10
a C -C carboxylic acid, a C -C sulfonic acid, or a combination thereof, or further
1 5 1 5
combined with one or more solvents of H O, a C -C ester, a C -C cycloalkane, THF,
2 1 10 3 10
DMF, acetonitrile, an alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl
ether carboxylate, an amide-based solvent, a C -C alcohol, and an inorganic acid. In
1 10
another embodiment, the inert solvent is formic acid, acetic acid, propionic acid, butyric
acid, isobutyric acid, or a combination thereof, or further combined with one or more
solvents of H O, a C -C ester, a C -C cycloalkane, THF, DMF, acetonitrile, an
2 1 10 3 10
alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an
amide-based solvent, a C -C sulfonic acid, a C -C alcohol, and an inorganic acid.
1 10 1 10
Also unexpectedly, the inert solvent containing an organic acid (e.g., a C -C
carboxylic acid and a C -C sulfonic acid) can produce extremely high stereo-selectivity
of trans-isomeric piperidines. As examples, the inert solvent is a C -C ester, a C -C
1 5 3 6
cycloalkane, THF, DMF, acetonitrile, a C -C alcohol, propylene glycol monomethyl
ether, propylene glycol monomethyl ether acetate, N,N-dimethylacetamide, a C -C
carboxylic acid, a C -C sulfonic acid, or a combination thereof, or further combined with
H O.
In an embodiment, the hydrogenation reaction is carried out at 10-100 C, e.g.,
o o o o o
-80 C, 20-70 C, 20-60 C, 20-50 C, and 25-45 C. As examples, it is carried out at
o o o o o o o o
C, 30 C, 35 C, 40 C, 45 C, 50 C, 55 C, or 60 C.
The hydrogenation reaction can be carried out under a hydrogen pressure of 1-60
bar, 5-50 bar, 10-40 bar, 15-30 bar, or 15-25 bar.
The hydrogenation reaction time varies within a wide range, e.g., 1-80 hours,
depending on the palladium catalyst, the hydrogen pressure, the reaction temperature, and
the hydrogenation facility used. Completion of the hydrogenation reaction can be
confirmed by NMR. After completion, purification can be effected by filtration,
concentration under reduced pressure, and distillation. In an embodiment, the trans-
isomeric piperidine thus obtained can be converted into a salt form, if needed.
In an exemplary method, the hydrogenation reaction is carried out at 25-45 C
under a hydrogen pressure of 15-25 bar.
In some embodiments, by performing the method, trans-isomeric piperidine is
obtained with a trans:cis ratio of 70:30 to 99.9:0.1 (e.g., 70:30 to 99:1, 70:30 to 95:5,
70:30 to 90:10, 75:25 to 99.9:0.1, 75:25 to 95:5, 75:25 to 90:10, 80:20 to 99.9:0.1, 80:20
to 99: 1, 80:20 to 95:5, 80:20 to 90:10, 85:15 to 99.9:0.1, 85:15 to 99: 1, 85:15 to 95:5,
and 85:15 to 90:10).
The preparation method described above can further include a resolution step,
which is performed via optical resolution of the trans-isomeric piperidine thus obtained
with an acidic resolving agent. This step provides an optically enriched enantiomer of
the trans-isomeric compound of formula (I), i.e., (3S, 5S)- or (3R, 5R)-configuration
enantiomer, or a pharmaceutically acceptable salt thereof in high yield and high purity.
The acidic resolving agent can be in R-form or S-form. The enantiomer thus obtained
can be further recrystallized with a recrystallization solvent.
The term “acidic resolving agent” refers to an acidic compound that can lead to
the precipitation of a diastereomer containing a suitable enantiomer in high chemical and
optical yields.
Shown below is the optical resolution reaction:
(3S,5S)-configuration, salt (Ia)
acidic resolving agent
(3R,5R)-configuration, salt (Ib)
in which R is C -C alkyl or C -C cycloalkyl. Two salt forms of the optical isomers
1 1 5 3 5
containing (3S, 5S)-configuration Ia and (3R, 5R)-configuration Ib can each be obtained
by optical resolution of the trans-isomeric compound of formula (I) with an acidic
resolving agent.
The enantiomeric excess value (i.e., “ee value”) of one enantiomer ((3S, 5S)-
configuration Ia or (3R, 5R)-configuration Ib) is 70-100 %, 80-100 %, 90-100 %, 95-100
%, 99-100 %, 70-99.9 %, 80-99.9 %, 85-99.9 %, 90-99.9 %, 95-99.9 %, or 99-99.9 %. In
general, the term “ee value” is the difference between the amounts of each of the
enantiomers present in a mixture, relative to the total amount of the compound in the
mixture expressed as percentage (×100%).
The acidic resolving agent can be deoxycholic acid, (-)-2,3:4,6-di-o-
isopropylideneketo-L-gulonic acid monohydrate, D-(-)-quinic acid, L-pyroglutamic
acid, (-)-monomethylsuccinate, N-acetyl-D-(+)-leucine, N-acetyl-L-methionine, (R)-(+)-
N-(1-phenylethyl)succinamic acid, (S)-(+)oxetetrahydrofurancarboxylic acid, (R)-
(+)-N-(1-phenylethyl)phthalamic acid, (-)-mono-(1R)-menthyl phthalate, (-)-
menthyloxyacetic acid, (S)-(+)-mandelic acid, L-(+)-tartaric acid, D-(+)-camphoric acid,
(-)-dibenzoyl-L-tartaric acid anhydrous, (-)-dibenzoyl-L-tartaric acid monohydrate, (-)-
O,O'-dibenzoyl-L-tartaric acid mono (dimethylamide), D-(+)camphorsulfonic acid,
L-(+)-lactic acid, L-(-)-malic acid, (-)-O,O'-di-p-toluoyl-L-tartaric acid, (R)-(-)-naproxen,
or (S)-ibuprofen.
Note that both R-form and S-form of an acidic resolving agent, e.g., (R)-(-)-
naproxen and (S)-(+)-naproxen, can be used to acquire a high ee value.
In one embodiment, the acidic resolving agent is deoxycholic acid, D-(-)-quinic
acid, (-)-monomethylsuccinate, N-acetyl-D-(+)-leucine, N-acetyl-L-methionine, (-)-
mono-(1R)-menthyl phthalate, (-)-dibenzoyl-L-tartaric acid anhydrous, (-)-O,O'-
dibenzoyl-L-tartaric acid mono(dimethylamide), D-(+)camphorsulfonic acid, L-(+)-
lactic acid, or (R)-(-)-naproxen.
The optical resolution can be carried out in the presence of an inert solvent. Use
of the inert solvent is well known in the art and varies depending on the type of the
starting racemic trans-isomer of a piperidine compound and the resolving agent used.
The inert solvent for optical resolution can be H O, a C -C ester (e.g., ethyl
2 1 10
acetate and methyl acetate), a C -C cycloalkane (e.g., cyclohexane), THF, DMF,
3 10
acetonitrile, a C -C alcohol (e.g., MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, and i-
1 10
BuOH), an alkylene glycol monoalkyl ether (e.g., propylene glycol monomethyl ether,
propylene glycol monoethyl ether, and propylene glycol monopropyl ether), an alkylene
glycol monoalkyl ether carboxylate (e.g., propylene glycol monomethyl ether acetate,
propylene glycol monoethyl ether acetate, and propylene glycol monopropyl ether
acetate), an amide-based solvent (e.g., N,N-dimethylacetamide and N,N-
dimethylformamide), or a combination thereof.
In one embodiment, the inert solvent is H O, acetonitrile, ethyl acetate, C -C
2 1 3
alcohol, or a combination thereof. In another embodiment, the inert solvent is
acetonitrile.
In one embodiment, the ratio of the inert solvent to a reaction substrate is not
particularly restricted. For example, the solvent can be used in an amount 0.5 to 100
times the weight of the substrate.
The temperature for optical resolution varies depending on the type of the starting
material, the resolving agent, and the solvent used. For example, the reaction is
performed at 20-60 C (e.g., 30-50 C).
The optical resolution described above can further include a step of
recrystallization of (3S, 5S)-configuration (Ia) or (3R, 5R)-configuration (Ib) with a
recrystallization solvent to form a product with high optical purity.
The recrystallization solvent can be H O, a C -C ester (e.g., ethyl acetate and
2 1 10
methyl acetate), a C -C cycloalkane (e.g., cyclohexane), THF, DMF, acetonitrile, a C -
3 10 1
C alcohol (e.g., MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, and i-BuOH), an alkylene
glycol monoalkyl ether (e.g., propylene glycol monomethyl ether, propylene glycol
monoethyl ether, and propylene glycol monopropyl ether), an alkylene glycol monoalkyl
ether carboxylate (e.g., propylene glycol monomethyl ether acetate, propylene glycol
monoethyl ether acetate, and propylene glycol monopropyl ether acetate), an amide-based
solvent (e.g., N,N-dimethylacetamide and N,N-dimethylformamide), or a combination
thereof. In one embodiment, an anti-solvent can also be employed during
recrystallization. The term “anti-solvent” herein refers to a solvent in which a crystalline
compound has limited or poor solubility. Examples of the anti-solvent include, but are
not limited to, ethyl acetate, acetone, methyl ethyl ketone, toluene, isopropyl acetate, and
t-butyl methyl ether.
Without further elaboration, it is believed that one skilled in the art can, based on
the above description, utilize the present disclosure to its fullest extent. The following
examples are, therefore, to be construed as merely illustrative, and not limitative of the
remainder of the disclosure in any way whatsoever. The publications cited herein are
incorporated by reference in their entirety.
EXAMPLE 1: Stereo-selective hydrogenation of the 5-methyl-nicotinamide
(III) (IV)
TABLE 1
Stereo-selective hydrogenation
Group Catalyst Solvent Ratio (trans:cis)
C1 5 wt% Rh/C EtOH/MeOH 46:54
C2 5 wt% Pt/C EtOH/MeOH/MsOH 53:47
E1 10 wt% Pd/C EtOH 73:27
E2 10 wt% Pd/C EtOH/MeOH/MsOH 78:22
E3 4 wt% Pd/C & 1 wt% Pt/C EtOH/MeOH/MsOH 77:23
E4 10 wt% Pd(OH) /C AcOH 75:25
E5 20 wt% Pd(OH) /C i-PrOH 77:23
E6 20 wt% Pd(OH) /C H O/EtOAc 78:22
As shown in the above reaction and Table 1, a magnetically-stirred autoclave was
charged with 5-methyl-nicotinamide, i.e., Compound (III), different inert solvents, and
transition metal catalysts to afford trans-isomeric Compound (IV). The autoclave was
pressurized with H at 15 bar and stirred at 45 C. Thereafter, a sample of the contents in
the autoclave was analyzed by NMR.
Table 1 indicates that use of a non-palladium catalyst, i.e., Rh/C or Pt/C, resulted
in a trans:cis ratio of 46:54 to 53:47 (Groups C1 and C2). In other words, no significant
selectivity of diastereoisomers was observed. Unexpectedly, when using a palladium
catalyst, the hydrogenation of compound (III) steoro-selectively produced compound (IV)
favoring the formation of the trans-isomer with a trans:cis ratio of 73:27 to 78:22 (Groups
E1 to E6).
These results indicate that hydrogenation using a palladium catalyst favorably
produced trans-isomeric piperidines.
EXAMPLE 2: Stereo-selective hydrogenation of 5-methyl-nicotinamide in the presence
of formic acid and Pd(OH) /C
An autoclave was charged with 5-methyl-nicotinamide (200 g), Pd(OH) /C (20
wt%, 55 g), and 2 L of formic acid under a gentle steam of nitrogen. The autoclave was
closed and flushed 3 times with nitrogen and 2 times with hydrogen under a continuous
stirring. The hydrogenation reaction, performed at 40 C under a H -pressure of 20 bar,
was stirred until completion. Subsequently, the reaction mixture was filtered and
concentrated to give 520 g of a crude product. The trans:cis ratio of the crude product
was determined to be 85:15.
The crude product was dissolved in 3 L of 2-propanol and treated dropwise with a
1M solution of hydrochloric acid in diethyl ether. A hydrochloride salt was formed and
isolated. Results from NMR analysis of the salt follow:
H-NMR (DMSO-d6, 400MHz) ppm: 8.61 (br s, 2H), 7.74 (br s, 1H), 7.25 (br s, 1H),
3.23, 3.03 (ABq, J = 11.0 Hz, 2H), 2.85 (d, J = 11.6 Hz, 1H), 2.75-2.77 (m, 1H), 2.53-
2.56 (m, 1H), 1.85-1.92 (m, 2H), 1.48-1.55 (m, 1H), 0.91 (d, J = 6.3 Hz, 3H); C-NMR
(DMSO-d6, 75MHz) ppm: 175.27, 48.30, 43.62, 35.11, 32.84, 25.02, 18.05; MS(ESI):
m/z = 165.1(M+Na ).
EXAMPLE 3: Stereo-selective hydrogenation of 5-methyl-nicotinamide in the presence
of HCl, H O/MeOH, and Pd/C
An autoclave was charged with 5-methyl-nicotinamide (15.6 g), hydrochloric acid
(1.0 equivalent), H O (40 mL), MeOH (56 mL), and Pd/C (10 wt% on C, 0.5 g) under a
gentle steam of nitrogen. The autoclave was closed and flushed 3 times with nitrogen
and 2 times with hydrogen under a continuous stirring. The hydrogenation reaction was
performed at 25 C under a H -pressure of 20 bar and constant stirring. Subsequently, the
reaction mixture was filtered and washed with H O/MeOH. The filtrate was concentrated
and dried under vacuum to give a trans-isomeric piperidine with a trans:cis ratio of 89:11.
EXAMPLE 4: Optical resolution with (S)-(+)-Naproxen
Referring to the reaction above, 115 mg of (S)-(+)-naproxen and 142 mg of
racemic trans-isomeric compound (IV) were dissolved in 3 mL of acetonitrile under
heating at 50 C. The solution was allowed to stand overnight at a room temperature (rt).
The resulting mixture was filtered and washed with acetonitrile to afford a white crystal
of (3R, 5R)-configuration of the (S)-naproxen salt of compound (IV) (yield 43%; ee
value 90%).
EXAMPLE 5: Optical resolution with (R)-(-)-Naproxen
Referring to the reaction above, 1.26 g of (R)-(-)-naproxen and 1.56 g of racemic
trans-isomeric compound (IV) were dissolved in 22 mL of acetonitrile under heating at
50 C. The solution thus obtained was allowed to stand overnight at a room temperature
(rt). The resulting mixture was filtered and washed with acetonitrile to afford a crystal of
(3S, 5S)-configuration of the (R)-naproxen salt of compound (IV) (yield 42%; ee value
96.8%). The crystal was also recrystallized from acetonitrile and isopropanol (yield
66.7%; ee value 99.9%). Results from NMR analysis of the salt follow:
H-NMR (methanol-d4, 300MHz) ppm: 7.61 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 2.7 Hz,
1H), 7.41 (m, 0.5H), 7.38 (m, 0.5H), 7.08 (m, 1H), 7.00 (d, J = 2.4 Hz, 0.5H), 6.97 (d, J =
2.4 Hz, 0.5H), 3.78 (s, 3H), 3.62 (q, J = 7.2 Hz, 1H), 3.21-3.24 (m, 2H), 2.95-3.00 (m,
1H), 2.67-2.73 (m, 2H), 2.30 (t, J = 12.0 Hz, 1H), 1.79-1.88 (m, 2H), 1.36 (d, J = 7.5 Hz,
3H), 1.34-1.35 (m, 1H), 0.78 (d, J = 6.6 Hz, 3H); C-NMR (methanol-d4, 75MHz) ppm:
183.43, 178.88, 158.86, 140.66, 134.93, 130.61, 130.26, 128.10, 127.80, 126.65, 119.68,
111.53, 106.67, 55.83, 50.97, 45.83, 37.43, 34.96, 26.84, 20.01, 18.75; MS (ESI): m/z =
165.1 (M +Na).
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any
combination. Each feature disclosed in this specification may be replaced by an
alternative feature serving the same, equivalent or similar purpose. Thus, unless
expressly stated otherwise, each feature disclosed is only an example of a series of
equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the
characteristics of the present disclosure, and without departing from the spirit and scope
thereof, can make various changes and modifications of the disclosure to adapt it to
various usage and conditions. Thus, other embodiments are also within the scope of the
following claims.
Claims (22)
1. A trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof: 5 H (I), wherein R is a substituted or unsubstituted C -C alkyl or a substituted or 1 1 5 unsubstituted C -C cycloalkyl and the trans-isomeric compound in an isomeric compound mixture has a trans:cis ratio of at least 70:30, and wherein the substituted alkyl or the substituted cycloalkyl is substituted with a 10 substituent selected from the group consisting of amino, hydroxyl, halo, thio, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester.
2. The trans-isomeric compound of claim 1, wherein R is C -C alkyl. 1 1 5
3. The trans-isomeric compound of claim 2, wherein R is methyl.
4. The trans-isomeric compound of claim 1 being present in a form of (3S, 5S)-configuration of formula (Ia) below or a pharmaceutically acceptable salt thereof: 20 (Ia).
5. The trans-isomeric compound of claim 1 being present in a form of (3R, 5R)-configuration of formula (Ib) below or a pharmaceutically acceptable salt thereof: H (Ib).
6. A method of preparing a trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof: 5 H (I), the method comprising hydrogenating a compound of formula (II) below or a pharmaceutically acceptable salt thereof: N (II), with a palladium catalyst in the presence of an inert solvent to obtain the trans-isomeric 10 compound of formula (I) having a trans:cis ratio of at least 70:30 or the pharmaceutically acceptable salt thereof, wherein R of formulas (I) and (II) is a substituted or unsubstituted C -C alkyl or a substituted or unsubstituted C -C cycloalkyl, and wherein 1 5 3 5 the substituted alkyl or the substituted cycloalkyl is substituted with a substituent selected from the group consisting of amino, hydroxyl, halo, thio, acylamino, aminoacyl, 15 aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester.
7. The method of claim 6, further comprising resolving the trans-isomeric compound or the pharmaceutically acceptable salt thereof with an acidic resolving agent 20 to obtain an enantiomer of the trans-isomeric compound or the pharmaceutically acceptable salt thereof, wherein the enantiomer is present in a form of (3S, 5S)- configuration of formula (Ia) below or (3R, 5R)-configuration of formula (Ib) below: NH NH H (Ia) H (Ib).
8. The method of claim 6, wherein R is C -C alkyl. 1 1 5
9. The method of claim 8, wherein R is methyl.
10. The method of claim 6, wherein thepalladium catalyst is Pd(OH) /C, Pd/C, Pd(OAc) , Pd/Al O , or a combination thereof, and the content of palladium in the 2 2 3 10 palladium catalyst is 0.01 wt% to 30 wt%.
11. The method of claim 10, further comprising providing an additional transition metal catalyst. 15
12. The method of claim 11, wherein the additional transition metal catalyst is Pt/C or Rh/C.
13. The method of claim 6, wherein the inert solvent is H O, a C -C ester, a 2 1 10 C -C cycloalkane, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, a 3 10 20 C -C alcohol, an alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether 1 10 carboxylate, an amide-based solvent, an organic acid, or a combination thereof.
14. The method of claim 13, wherein the inert solvent is combined with one or more inorganic acids.
15. The method of claim 6, wherein the inert solvent is H O, a C -C ester, a 2 1 5 C -C cycloalkane, THF, DMF, a C -C alcohol, propylene glycol monomethyl ether, 3 6 1 5 propylene glycol monomethyl ether acetate, N,N-dimethylacetamide, a C -C carboxylic acid, a C -C sulfonic acid, or a combination thereof.
16. The method of claim 15, wherein the inert solvent is H O, methanol, ethanol, isopropanol, formic acid, acetic acid, ethyl acetate, methanesulfonic acid, or a combination thereof.
17. The method of claim 16, wherein the inert solvent is combined with hydrochloric acid.
18. The method of claim 6, wherein the inert solvent is an organic acid or a 10 combination of the organic acid with one or more solvents selected from the group consisting of H O, a C -C ester, a C -C cycloalkane, THF, DMF, acetonitrile, an 2 1 10 3 10 alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an amide-based solvent, a C -C alcohol, and an inorganic acid. 1 10 15
19. The method of claim 18, wherein the organic acid is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, or a combination thereof.
20. The method of claim 7, wherein the acidic resolving agent is deoxycholic acid, (-)-2,3:4,6-di-o-isopropylideneketo-L-gulonic acid monohydrate, D-(-)-quinic 20 acid, L-pyroglutamic acid, (-)-monomethylsuccinate, N-acetyl-D-(+)-leucine, N-acetyl-L- methionine, (R)-(+)-N-(1-phenylethyl)succinamic acid, (S)-(+)oxe tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-phenylethyl)phthalamic acid, (-)-mono- (1R)-menthyl phthalate, (-)-menthyloxyacetic acid, (S)-(+)-mandelic acid, L-(+)-tartaric acid, D-(+)-camphoric acid, (-)-dibenzoyl-L-tartaric acid anhydrous, (-)-dibenzoyl-L- 25 tartaric acid monohydrate, (-)-O,O'-dibenzoyl-L-tartaric acid mono (dimethylamide), D- (+)camphorsulfonic acid, L-(+)-lactic acid, L-(-)-malic acid, (-)-O,O'-di-p-toluoyl-L- tartaric acid, (R)-(-)-naproxen, (S)-ibuprofen, or a R-form or S-form thereof.
21. The method of claim 7, further comprising recrystallizing the (3S, 5S)- 30 configuration enantiomer or the (3R, 5R)-configuration enantiomer with a recrystallization solvent.
22. The method of claim 21, wherein the recrystallization solvent is H O, a C1-C10 ester, a C3-C10 cycloalkane, THF, DMF, acetonitrile, a C1-C10 alcohol, or a combination thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/674,937 | 2017-08-11 | ||
US15/674,937 US10377714B2 (en) | 2017-08-11 | 2017-08-11 | Trans-isomeric heterocyclic compounds and preparation thereof |
PCT/IB2018/001044 WO2019048923A2 (en) | 2017-08-11 | 2018-08-10 | Trans-isomeric heterocyclic compounds and preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ761473A NZ761473A (en) | 2021-09-24 |
NZ761473B2 true NZ761473B2 (en) | 2022-01-06 |
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