JP2013502462A - 神経刺激性ピペラジンの合成 - Google Patents
神経刺激性ピペラジンの合成 Download PDFInfo
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- JP2013502462A JP2013502462A JP2012526928A JP2012526928A JP2013502462A JP 2013502462 A JP2013502462 A JP 2013502462A JP 2012526928 A JP2012526928 A JP 2012526928A JP 2012526928 A JP2012526928 A JP 2012526928A JP 2013502462 A JP2013502462 A JP 2013502462A
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- compound
- formula
- reaction
- piperazine
- alkyl
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 239000007822 coupling agent Substances 0.000 claims description 6
- 238000005897 peptide coupling reaction Methods 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 58
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 6
- 229960003512 nicotinic acid Drugs 0.000 abstract description 6
- 235000001968 nicotinic acid Nutrition 0.000 abstract description 6
- 239000011664 nicotinic acid Substances 0.000 abstract description 6
- 150000004885 piperazines Chemical class 0.000 abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000000926 neurological effect Effects 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 17
- 229940011051 isopropyl acetate Drugs 0.000 description 17
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 17
- 239000002002 slurry Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 239000007789 gas Substances 0.000 description 10
- -1 hydrohalide Chemical compound 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 6
- 229940073608 benzyl chloride Drugs 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 238000005574 benzylation reaction Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000004766 neurogenesis Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001595 flow curve Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 1
- NTSFJZORNYYLFW-UHFFFAOYSA-N 4-methylbenzenesulfonyl bromide Chemical compound CC1=CC=C(S(Br)(=O)=O)C=C1 NTSFJZORNYYLFW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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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 description 1
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- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
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- 125000002541 furyl group Chemical group 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 230000001537 neural effect Effects 0.000 description 1
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- 125000000627 niacin group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Abstract
Description
本願は、2009年8月24日に出願された米国仮特許出願第61/236,477号の優先権を主張し、この米国仮特許出願の内容は、本明細書中に参考として援用される。
本発明は、神経発生剤として有用な化合物およびその塩に対する合成法に関する。より具体的には、本発明はベンジルおよびニコチン酸部分とカップリングされた二置換型ピペラジンを調製するための方法に関する。
本明細書において引用により援用される特許文献1は、神経発生剤として、本明細書にその合成が記載されている化合物のクラスを含むさまざまな化合物を記載している。すなわち、本発明の方法に従って調製される化合物は、ヒト海馬の多能性幹細胞/前駆細胞およびニューロン前駆体の増殖/分化によって神経発生を促進することから利益を得るさまざまな状態の処置に有用である。こうした状態は、アルツハイマー病、軽度認知障害、認知症、発作、外傷性脳損傷、脊髄損傷、統合失調症などを含む。本発明によって提供される合成法は、ベンジルピペラジンなどの規制物質の使用を回避する。
R1はアルキルであり、
R2はHまたはアルキルであり、
R3およびR4の各々は独立にアルキル、アルケニル、ハロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、NR2、SR、またはORであり、ここでRはアルキルまたはアリールであり、
nは0、1または2であり、
mは0、1、2または3であり、
この方法は、次式の化合物、すなわち
次式の化合物、すなわち
次式の化合物、すなわち
次式の化合物、すなわち
その後この保護基を除去するか、または非保護ピペラジンを用いて一方の窒素と選択的にカップリングさせることによって得られてもよい。保護基を用いる反応は、ペプチドカップリング剤の存在下で式(4)の化合物を保護ピペラジンと接触させる(contracting)ことによって行なわれてもよいし、式(4)の化合物を対応するハロゲン化ベンゾイルに転化し、弱塩基の存在下で保護ピペラジンを加えることによって行なわれてもよい。
工程1Bによる3EPrの調製
A.クロロニコチン酸(5.0g、31.7mmol)を丸底フラスコに入れ、続いてトルエン(無水、40mL)およびDMF(120μL、0.05当量)を入れた。その結果得られたスラリーを55℃に加熱し、次いで塩化チオニル(4.6mL、2.0当量)を5分間にわたって滴下して加えた。スラリーを55℃にて3時間撹拌し、その間に気体の発生が観察されて、混合物が均質になった。サンプルを取ってトリエチルアミンを含むメタノール中でクエンチすることによって、HPLC分析のためのメチルエステルを得た。HPLCによる分析は、酸塩化物への転化が完了していることを示した。フラスコを蒸留のために適合させて、加熱して還流させた。約20mLの溶媒が除去されてから、溶液を周囲温度まで冷却した。別のフラスコにN−Boc−ピペラジン(7.1g、1.2当量)、アセトニトリル(30mL、6体積(vol))、およびトリエチルアミン(13.3mL、3.0当量)を入れた。わずかな吸熱がみられた。次いで酸塩化物の調製溶液を、内部温度を35℃より下に維持するような速度で加えた。その結果得られたスラリーを周囲温度にて1時間撹拌した。HPLCによる分析は、反応が完了していることを示した。反応混合物を飽和NaHCO3溶液(20mL)でクエンチし、水層を酢酸イソプロピル(20mL)で抽出した。有機層を合わせて水(10mL)で洗浄した。水洗浄物のHPLC分析は、生成物がいくらか水層に失われていることを示した。有機層を約2体積に濃縮し、次いでヘプタン(50mL)を加えて沈殿を誘導した。その結果得られたスラリーを周囲温度にて30分間撹拌し、0〜5℃に1時間冷却し、濾過して、ヘプタンで洗浄した。次いで湿ったケークを真空下で一晩乾燥させて、9.85gの3EPr[MDM−W−1(14)、収率95%、HPLCによる99.8面積%]を薄黄色の固体として得た。
脱保護(工程2)
A.実施例1または実施例2において調製された3EPrの1gを、50℃にて2当量のHClおよび5〜6NのTF2−プロパノールで処理した。反応は6時間以内に完了することが見出された(fond to)。
1Eへの転化(工程3および4)
A.実施例3で調製した3Eの粗サンプルをTFAと複合体化させて(complexed)ベンズアルデヒドと反応させ、生成物をカラムクロマトグラフィ(2〜6%メタノール/DCM)によって精製した。生成物を含む画分を集め、減圧下で溶媒を除去して、化合物2Gを濃い油として得た。1H NMRは指定された構造に一致した。2Eは油であったため、3Eは2工程のテレスコーピング方法(telescoped method)で化合物1Eに転化された。
スキーム1の完全な実行
A.2−クロロニコチン酸の50gサンプルを、トリエチルアミン(2当量)およびTBTU(1.4当量)の存在下でN−Bocピペラジン(1.2当量)によって処理した。この反応はIPAc(300mL、6体積)中で、周囲温度にて行なった。12時間後にHPLC分析によって反応の完了を判断した。濾過および水性処理の後、真空下でIPAc抽出物を180gに減らした(重量比で約1:1 IPAc/生成物)。
リン酸塩の調製
A.添加漏斗と、還流凝縮器と、熱電対と、オーバーヘッドスターラーとを備えた22Lの3つ首の丸底フラスコを加熱マントルに入れた。フラスコにエタノール(7.9L、Pharmco lot#0802062)を入れ、続いて脱イオン水(420mL)を入れた。次に1E(700g、2.1mol)をその反応器に入れ、得られた混合物を75℃に加熱した。エタノール中のH3PO4の1M溶液(4.5L、4.5mol、2.1当量)を、30分間にわたって急速な流れとして加えた。その結果得られた混合物を15分間撹拌し、1E・H3PO4(0.5g)を再結晶化のためのシードとして加えた。その結果得られた透明な溶液を、20℃/hの速度で周囲温度まで冷却した。
MDM−W−128:1.25当量のH3PO4、12体積の、EtOH中の5%水
MDM−W−130:1.0当量のH3PO4、12体積のEtOH
MDM−W−131:1.0当量のH3PO4、12体積の、EtOH中の5%水
各反応物を70℃に加熱し、1Eリン酸塩をシードとして加え[0.1wt%、DAJ−F−40(2)]、20℃/時間の速度で20℃に冷却した。その結果得られた濃いスラリーを一晩撹拌し、濾過し(EtOHで洗浄しながら)、一定の重量になるまで乾燥した。これらの反応の結果を表1に示す。一般的に、EtOH中の5%水を用いた反応から得られたスラリーの方が管理しやすかった。
リン酸塩形成スクリーニング
Claims (10)
- 次式の化合物、すなわち
であって、ここで
R1はアルキルであり、
R2はHまたはアルキルであり、
R3およびR4の各々は独立にアルキル、アルケニル、ハロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、NR2、SR、またはORであり、ここでRはアルキルまたはアリールであり、
nは0、1または2であり、
mは0、1、2または3である化合物を合成するための方法であって、
該方法は、次式の化合物、すなわち
であって、ここでR3、R4、mおよびnは式(1)において定義されたものと同様であり、Lは脱離基である化合物を、
次式の化合物、すなわち
であって、ここでR1およびR2は式(1)において定義されたものと同様である化合物と反応させる工程を含む、方法。 - mおよびnは0である、請求項1から3のいずれか1項に記載の方法。
- R3および/またはR4はアルキルである、請求項1から3のいずれか1項に記載の方法。
- LおよびL’は独立にハロ、OTsまたはOTfである、請求項1から3のいずれか1項に記載の方法。
- PrはBocまたはFmocである、請求項1から3のいずれか1項に記載の方法。
- LおよびL’は独立にハロである、請求項1から3のいずれか1項に記載の方法。
- 前記式(1)の化合物を薬学的に許容される塩に転化する工程をさらに含む、請求項1に記載の方法。
- 前記塩はリン酸塩である、請求項9に記載の方法。
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JP7204640B2 (ja) | 2016-09-12 | 2023-01-16 | ニューラルステム・インコーポレーテッド | 糖尿病に関連する神経障害の改善 |
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