JP6862354B2 - ナイトロジェンマスタード誘導体の調製方法 - Google Patents
ナイトロジェンマスタード誘導体の調製方法 Download PDFInfo
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- JP6862354B2 JP6862354B2 JP2017558492A JP2017558492A JP6862354B2 JP 6862354 B2 JP6862354 B2 JP 6862354B2 JP 2017558492 A JP2017558492 A JP 2017558492A JP 2017558492 A JP2017558492 A JP 2017558492A JP 6862354 B2 JP6862354 B2 JP 6862354B2
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- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 277
- -1 methyloxycarbonyl Chemical group 0.000 claims description 172
- 238000000034 method Methods 0.000 claims description 141
- 150000003839 salts Chemical class 0.000 claims description 86
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- 239000003638 chemical reducing agent Substances 0.000 claims description 50
- 229940106681 chloroacetic acid Drugs 0.000 claims description 48
- 238000004519 manufacturing process Methods 0.000 claims description 44
- 125000006239 protecting group Chemical group 0.000 claims description 43
- 239000003054 catalyst Substances 0.000 claims description 27
- 239000000872 buffer Substances 0.000 claims description 13
- 229940089960 chloroacetate Drugs 0.000 claims description 10
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical group [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims description 7
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 7
- 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 claims description 6
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910000085 borane Inorganic materials 0.000 claims description 5
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002879 Lewis base Substances 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000000499 3-oxazolines Chemical class 0.000 claims 3
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 2
- 239000006172 buffering agent Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 79
- 239000000047 product Substances 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 34
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 30
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 25
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 24
- 229960001924 melphalan Drugs 0.000 description 24
- ZCMWSKHHXLCVHI-VROPFNGYSA-N ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(=CC=1)N(CCCl)CCCl)C1=CC=C(F)C=C1 ZCMWSKHHXLCVHI-VROPFNGYSA-N 0.000 description 22
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 230000008569 process Effects 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 16
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 125000004494 ethyl ester group Chemical group 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- XLQWJXJJLULKSL-UHFFFAOYSA-N n-methyl-n-(pentyliminomethylideneamino)methanamine;hydrochloride Chemical compound Cl.CCCCCN=C=NN(C)C XLQWJXJJLULKSL-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 0 CCOC([C@](Cc(cc1)ccc1F)C(C([C@](Cc1ccc(*)cc1)*=C)=O)=C)=O Chemical compound CCOC([C@](Cc(cc1)ccc1F)C(C([C@](Cc1ccc(*)cc1)*=C)=O)=C)=O 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical class ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 235000008729 phenylalanine Nutrition 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
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- 230000008878 coupling Effects 0.000 description 2
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- 229940127089 cytotoxic agent Drugs 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- 229950009924 melphalan flufenamide Drugs 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012066 reaction slurry Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
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- 238000012369 In process control Methods 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
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- SUYHVQFAQPEJLE-UHFFFAOYSA-L magnesium;2-chloroacetate Chemical compound [Mg+2].[O-]C(=O)CCl.[O-]C(=O)CCl SUYHVQFAQPEJLE-UHFFFAOYSA-L 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- ROSJKFFLIXTTAW-UHFFFAOYSA-N n,n-bis(2-chloroethyl)aniline Chemical compound ClCCN(CCCl)C1=CC=CC=C1 ROSJKFFLIXTTAW-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- KPFSGNRRZMYZPH-UHFFFAOYSA-M potassium;2-chloroacetate Chemical compound [K+].[O-]C(=O)CCl KPFSGNRRZMYZPH-UHFFFAOYSA-M 0.000 description 1
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- 238000004886 process control Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
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- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/06—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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Description
この方法は、化合物(II):
を含み、
式中、PGは保護基であり、Rは、適切に保護された形のOHであるか、または
この方法は、上記の化合物(III)の製造のための方法を行うこと、および、さらに、化合物(III)を脱保護して、化合物(I)またはその塩を生成することを含み、
式中、Rは、任意に適切に保護された形のOHであるか、または
この方法は、化合物(IV):
式中、PGは保護基である。
この方法は、化合物(VI):
式中、PGは保護基であり、Rは、任意に適切に保護された形のOHであるか、または、
式中、YはNH2またはNO2であり、PGは保護基である。
この方法は、次の工程:
(c)化合物(II):
を含み、
式中、PGは保護基であり、Rは、適切に保護された形のOHであるか、または
この方法は、次の工程:
(c)化合物(IIb)
を含み、
式中、PGは保護基である。
この方法は、次の工程:
(c)化合物(IIa):
を含み、
式中、Rは、適切に保護された形のOHであるか、または
この方法は、次の工程:
(c)化合物(IIc):
を含む。
ここで、PGおよびRは、工程(c)に関して上で定義された通りである。
(a)化合物(IV):
を含み、式中、PGは、工程(c)に関して上で定義された通りである、化合物(VIb)の製造のための方法も提供する。
(a)化合物(IVc):
を含む。
(b)化合物(IV):
を含む、化合物(II)の製造のための本発明の方法を提供し、
式中、PGは、工程(c)に関して上で定義された通りであり、Rは、任意に適切に保護された形のOHであるか、または、
(b)化合物(VIa):
を含み得、
式中、Rは、任意に適切に保護された形のOHであるか、または
(b)化合物(VIb)を、還元剤と、例えばH2/Pd/Cと反応させて、化合物(IIb)を得ること、
を含み得、
式中、PGは、工程(c)に関して上で定義された通りである。
(b)化合物(VIc)を、還元剤と、例えばH2/Pd/Cと反応させて、化合物(IIc)を得ること、
を含み得る。
(b)化合物(VI)を還元剤と反応させることを含む、化合物(II)の製造のためのプロセス;
(c)化合物(II)を、クロロ酢酸と、還元剤の存在下に反応させることを含む、化合物(III)、または脱保護されたその生成物、または脱保護されたその生成物の塩の製造のためのプロセス;および/または
(d)化合物(III)を脱保護して、化合物(I)またはその塩を生成することを含む、化合物(I)、またはその塩の製造のためのプロセス;
の1つ以上を含む方法を提供し、
式中、PGは保護基であり、Rは、任意に適切に保護された形のOHであるか、または
(a)化合物(IV)を化合物(V)と反応させることを含む、化合物(VIb)の製造のためのプロセス;および/または
(b)化合物(VIb)を還元剤と反応させることを含む、化合物(IIb)の製造のためのプロセス;および/または
(c)化合物(IIb)を、クロロ酢酸と、還元剤の存在下に反応させることを含む、化合物(IIIb)、または脱保護されたその生成物の製造のためのプロセス;および/または
(d)化合物(IIIb)を脱保護して、化合物(Ib)またはその塩を生成することを含む、化合物(Ib)またはその塩の製造のためのプロセス;
の1つ以上を含む方法を提供し、
ここで、PGは、ステップ(c)に関して上で定義された通りである。
(c)化合物(XI):
を含む。
一般的な実験の詳細
特に断わらなければ、全ての試薬/溶媒は、市販品製造業者から購入され、さらなる精製なしに使用された。
化合物(VIc)の合成
1H-NMR (300 MHz, DMSO-D6) δ 8.48 (広幅なd, 1H, J=7.5 Hz), 8.16 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=9 Hz), 7.28 (2H, dd, J=8,7, 8.1 Hz), 7.12-7.02 (3H, m), 4.49 (1H, dd, J=14.4, 7.2 Hz), 4.32-4.24 (1 H, m), 4.04 (2H, dd, J=14.4, 7.2 Hz), 3.08-2.95 (3H,m), 2.84 (1H, dd, J=13.2, 10.8 Hz), 1.27 (s, 9H), 1.11 (3H, t, J=7.2Hz)
13C-NMR (75 MHz, DMSO-D6) δ 171.4 (C=O), 171.2 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.2 (C=O), 146.6 (C), 146.2 (C), 133.1 (C), 131.1 (2炭素, CH, d, J=8.3 Hz), 130.6 (2炭素, CH), 123.1 (C), 114.9 (2炭素, CH, J=20.4 Hz), 78.1 (C), 60.6 (CH2), 55.1 (CH), 53.6 (CH), 37.3 (CH2), 35.9 (CH2), 28.0 (3炭素, CH3), 14.0 (CH3)
例2
化合物(IIc)の合成
1H-NMR (300 MHz, DMSO-D6) δ 8.26 (1H, d, J=7.5Hz), 7.26 (dd, 2H, J=8.1, 5.7 Hz), 7.09 (2H, t, J=8.7 Hz), 6.86 (2H, d, J=8.1 Hz), 6.71 (1H, d, J=8.7 Hz), 6.45 (1H, d, J=8.1 Hz), 4.87 (2H, s), 4.45 (1H, dd, J=14.4, 7.5 Hz), 4.07-4.00 (3H, m), 3.06-2.91 (2H, m), 2.71 (1H, dd, J=13.8, 3.9 Hz), 2.54-2.46 (1H, m), 1.31 (s, 9H), 1.11 (3H, t, J=6.9 Hz).
13C-NMR (75 MHz, DMSO-D6) δ 171.4 (C=O), 171.2 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.1 (C=O), 146.9 (C), 133.2 (C, d, J=3.0 Hz), 131.1 (2炭素, CH, d, J=8.3 Hz), 129.5 (2炭素, CH), 124.8 (C), 114.8 (2炭素, CH, J=21.1 Hz), 113.6 (2炭素, CH), 77.9 (C), 60.5 (CH2), 56.0 (CH), 53.5 (CH), 36.7 (CH2), 35.9 (CH2), 28.1 (3炭素, CH3), 13.9 (CH3)
本発明者等は、粗化合物(VIc)または再晶析した化合物(VIc)(純度:99.1面積%)を出発材料として用い、また、様々な反応条件、例えば、H2の圧力、Pd/Cの重量/重量%、溶媒および温度を変えて、例2を数回、繰り返した。再晶析された化合物(VIc)を出発材料として用いたとき、粗生成物純度(97.2面積%)は、粗化合物(VIc)を用いたとき(この場合、粗生成物純度は、一般に95〜96面積%である)より僅かに高かった。最終収率および純度も、粗化合物(VIc)から出発したときより僅かに高い(98〜98.5面積%)。
化合物(IIIc)の調製
(i)クロロ酢酸塩の存在下にBH3SMe2を用いて行う
1H-NMR (300 MHz, DMSO-D6) δ 8.30 (1H, d, J=7.8 Hz), 7.26 (2H, dd, J=8.1, 6 Hz), 7.09-7.05 (3H, m), 6.79 (1H, d, J=8.9 Hz), 6.63 (2H, d, J=8.4 Hz), 4.49-4.42 (1H, dd, J=14.7, 7.5 Hz), 4.07-3.99 (3H, m), 3.68 (8H, s), 3.06-2.91 (2H, m), 2.76 (1H, dd, J=13.8, 4.2 Hz), 2.56 (1H, m), 1.29 (9H, s), 1.1 (3H, t, J=6.6 Hz)
13C-NMR (75 MHz, DMSO-D6) δ 172.1 (C=O), 171.3 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.2 (C=O), 144.7 (C), 133.2 (C, d, J=3.0 Hz), 131.1 (2炭素, CH, d, J=7.5 Hz), 130.2 (2炭素, CH), 126.1 (C), 114.9 (2炭素, CH, J=21.1 Hz), 111.6 (2炭素, CH), 78.0 (C), 60.6 (CH2), 55.9 (CH), 53.5 (CH), 52.2 (CH2), 41.2 (CH2), 36.4 (CH2), 35.9 (CH2), 28.1 (3炭素, CH3), 14.0 (CH3)
(ii)クロロ酢酸塩の存在下にBH3SMe2を用いて行う
オーバーヘッド攪拌機を有する0.5Lの乾燥した反応器に、化合物(IIc)(7.5g、15.84mmol)を、続いて2−MeTHF(150mL)を入れた。混合物を、45℃に加熱して、透明な溶液にした。溶液を4℃に冷却し、クロロ酢酸(38.9g、411.8mmol)を加え、続いて、TI=5〜13℃で、クロロ酢酸ナトリウム塩(18.4g、158.4mmol)を加えた。次いで、BH3SMe2溶液(15.6g、205.9mmol、19.5mL)を90分かけて添加した。添加後、反応温度を、TI=20〜25℃に調節し、この温度に達した後、5時間保った。反応を、TI=15〜25℃で、水(150g、8333mmol、150mL)により、水相のpH=3.5で、ゆっくりとクエンチし、TI=6℃で、攪拌しないで一夜放置した。生成物である化合物(IIIc)は、有機相に析出していたが、攪拌しながら、温度をTI=35℃に調節すると、2つの透明な相が生成した。放置して相分離させ、水相を除去した。有機相を、20%NaCl(aq)で3回洗った。3つの水相のpHは、1.7、1.1、および1.1であった。第3の水相の除去の後、有機相を丸底フラスコに移し、その半分の体積にエバポレータで濃縮した。生成物である化合物(IIIc)が析出し始め、6℃で19時間放置して、生成物スラリーを十分に析出させた。スラリーをフィルターで収集し、丸底フラスコおよびフィルターケーキを、2−MeTHF:n−ヘプタン(2×40mL)で洗い、続いて、TJ=35℃で高真空下に乾燥すると、8.3g(87.6%)の未補正収量で、白色粗生成物である化合物(IIIc)を生成した。HPLCによる純度は99.4面積%。
磁気攪拌子を有する100mLの乾燥した丸底フラスコに、ゆっくりとした窒素流の下で、化合物(IIc)(0.75g,1.58mmol)を、続いて、無水テトラヒドロフラン(6mL)、クロロ酢酸(3.89g、41.2mmol)、およびクロロ酢酸ナトリウム塩(1.84g、15.8mmol)を入れた。TI=5〜13℃で、1MのBH3THF溶液(20.6mmol、20.6mL)を、30分かけて添加した。添加後、反応温度を、TI=23〜28℃の間に調節し、この温度に達した後、2時間保った。インプロセスコントロール試料(HPLC)が、反応の未完了を示したので、ジャケットの温度を、TJ=40℃に設定し、内部温度がTI=40℃に達したとき、この温度に2時間、反応物を保ち、その時点で、インプロセス試料(HPLC)は、6.7面積%の出発材料、7.1%のアシル化付加物(不純物)および84.1%の化合物(IIIc)を示した。TI=23℃で、反応を進め、4日間放置し、その後、エタノール(2.4g、3mL)でゆっくりとクエンチした。水(100mL)を加え、1MのK2CO3水溶液で、pHを7に調節した。反応物スラリーをフィルターで収集し、反応容器およびフィルターケーキを水(2×20mL)で洗い、続いて、TJ=35℃で、高真空下に乾燥すると、0.85g(89.6%)の未補正収量で、無色の粗生成物を生成した。HPLCによる純度は94.3面積%であり、1つの主要な不純物は、3.8面積%の、出発材料のクロロアセチル化付加物に帰属された。
磁気攪拌子を有する100mLの乾燥した丸底フラスコに、ゆっくりとした窒素流の下で、化合物(IIc)(0.75グラム、1.58mmol)を、続いて、無水テトラヒドロフラン(6mL)およびクロロ酢酸(3.89g、41.2mmol)を入れた。TI=5〜16℃で、BH3SMe2(1.56g、20.6mmol、2.0mL)の溶液を、30分かけて添加した。添加後、反応温度を、TI=25℃に調節し、この温度に達した後、2.5時間保った。プロセスコントロール試料(HPLC)は、化合物(IIIc)のBoc−脱保護形であるメルフルフェン(化合物(Ib)を、66面積%で示した。反応を、エタノール(2.9g、3.7mL)で、ゆっくりとクエンチした。反応物のpHを、1MのK2CO3水溶液で、pH=8に調節し、続いて、EtOAc(40mL)を加えた。層分離させ、水層を、EtOAc(50mL)で再抽出した。有機層を合わせ、<30mbar、35℃で、減量して油状物とした。油状物を、EtOAc(30mL)から2回、再蒸留精製し、残留物を、TJ=23℃/5mbarで乾燥すると、1.6gの茶色がかった油状物が残された。化合物(Ib)のHPLCによる純度は、66.1面積%であった。
塩酸塩としての化合物(Ib)の調製
1H-NMR (300 MHz, MeOH-D4) δ 7.26 (2H, dd, J=8.4, 8.1 Hz), 7.17 (2H, d, J=8.4 Hz), 7.02 (2H, dd, J=9, 8.4 Hz), 6.74 (2H, d, J=8.4 Hz), 4.69 (1H, dd, J=7.8, 6.3 Hz), 4.15 (2H, dd, J=14.1, 7.2 Hz), 4.04 (1H, dd, J=8.4, 5.4 Hz), 3.76 (4H, dd, J=6.3, 6 Hz), 3.67 (4H, dd, 6.6, 5.7 Hz), 3.17 (2H, dd, J=14.4, 6 Hz), 3.06-2.88 (2H, m), 1.22 (3H, t, J=7.2 Hz)
13C-NMR (75 MHz, MeOH-D4) δ 172.2 (C=O), 169.8 (C=O), 163.4 (C-F, d, J=244.5 Hz), 147.4 (C), 133.9 (C, d, J=3 Hz), 132.1 (2炭素, CH, d, J=7.5 Hz), 131.8 (2炭素, CH), 123.4 (C), 116.2 (2炭素, CH, d, J=21.9 Hz), 113.7 (2炭素, CH), 62.6 (CH2), 55.6 (CH), 55.5 (CH), 54.3 (CH2), 41.6 (CH2), 37.6 (CH2), 37.6 (CH2), 14.5 (CH3)
例4は、酢酸エチルの存在下に、1.3Mから2.5MまでHClの濃度を変えて、また6℃から室温まで温度を変えて、成功裏に繰り返された。
以下に、出願当初の特許請求の範囲に記載された発明を付記する。
[1] 化合物(III):
化合物(II):
式中、PGは保護基であり、Rは、適切に保護された形のOHであるか、または、
[2] 前記方法が、ボラン、ボラン−ルイス塩基錯体、ボロヒドリド、メタルヒドリド、および、金属触媒の存在下のH 2 からなる群から選択される還元剤の存在下に行われる、[1]に記載の方法。
[3] 前記還元剤が、BH 3 、またはボランジメチルスルフィドである、[2]に記載の方法。
[4] PGが、メチルオキシカルボニル、エチルオキシカルボニル、9−フルオレニルメチルオキシカルボニル、t−ブチルオキシカルボニル、ベンジルオキシカルボニル、p−メトキシベンジルオキシカルボニル、1−アダマンチルオキシカルボニル、p−ブロモベンジルオキシカルボニル、トリフルオロアセチル、クロロアセチル、フェニルアセチル、ベンズアセチル、p−トルエンスルホニル、2−ニトロベンゼンスルホニル、t−ブチルスルホニル、2−または4−ニトロベンゼンスルホニル、2,4−ジニトロベンゼンスルホニル、および、2−ナフタレンスルホニルからなる群から選択される、[1]から[3]のいずれかに記載の方法。
[5] PGが、t−ブチルオキシカルボニルである、[4]に記載の方法。
[6] 前記方法が、3から50℃の範囲の、例えば4から45℃の範囲の温度で行われる、[1]から[5]のいずれかに記載の方法。
[7] 前記方法が、5から40℃の範囲の温度で行われる、[1]から[6]のいずれかに記載の方法。
[8] 前記方法が、緩衝剤の存在下に行われる、[1]から[7]のいずれかに記載の方法。
[9] 前記緩衝剤が、クロロ酢酸塩である、例えばクロロ酢酸ナトリウムである、[8]に記載の方法。
[10] クロロ酢酸:クロロ酢酸塩のモル比が、2:1から5:1である、[9]に記載の方法。
[11] 化合物(II):クロロ酢酸塩のモル比が、1:7から1:20である、[9]または[10]に記載の方法。
[12] Rが、
[13] 化合物(III)の塩または化合物(III)の脱保護された生成物の塩の製造のための方法であって、[1]から[12]のいずれかに記載の方法および塩を生成する工程を、例えば塩酸塩を生成する工程を含む、方法。
[14] 化合物(II)が、化合物(VI):
式中、PGは、化合物(II)に関して定義された通りであり、Rは、任意に適切に保護された形のOHであるか、または、
[15] 前記還元剤が、水素および触媒である、例えばH 2 /Pd/Cである、[14]に記載の方法。
[16] Rが、
式中、PGは、化合物(II)に関して定義された通りである、[14]または[15]に記載の方法。
[17] 化合物(I):
[1]から[16]のいずれかに記載の方法を行うこと、および、さらに、化合物(III)を脱保護して、化合物(I)またはその塩を生成することを含み、
式中、Rは、任意に適切に保護された形のOHであるか、または、
[18] 化合物(I)が、化合物(Ib):
[19] 化合物(I)の塩の製造のための方法であって、[17]または[18]に記載の方法および塩を生成する工程を、例えば、塩酸塩を生成する工程を含む、方法。
[20] 前記方法が、化合物(Ib)の塩酸塩:
[21] 化合物(VIb):
化合物(IV):
式中、PGは保護基である、方法。
[22] 化合物(II):
式中、PGは保護基であり、Rは、任意に適切に保護された形のOHであるか、または、
[23] 前記還元剤が、水素および触媒である、例えばH 2 /Pd/Cである、[22]に記載の方法。
[24] 次の構造:
式中、YはNH 2 またはNO 2 であり、PGは保護基である化合物。
[25] PGが、t−ブチルオキシカルボニルである、[24]に記載の化合物。
Claims (21)
- 化合物(III):
化合物(II):
式中、PGは、メチルオキシカルボニル、エチルオキシカルボニル、9-フルオレニルメチルオキシカルボニル、t-ブチルオキシカルボニル、ベンジルオキシカルボニル、p-メトキシベンジルオキシカルボニル、1-アダマンチルオキシカルボニル、p-ブロモベンジルオキシカルボニル、トリフルオロアセチル、クロロアセチル、フェニルアセチル、ベンズアセチル、p-トルエンスルホニル、2-ニトロベンゼンスルホニル、t-ブチルスルホニル、2-または4-ニトロベンゼンスルホニル、2,4-ジニトロベンゼンスルホニル、および、2-ナフタレンスルホニルからなる群から選択される保護基であり、
Rは、適切に保護された形のOHであるか、または、
- 前記方法が、ボラン、ボラン−ルイス塩基錯体、ボロヒドリド、メタルヒドリド、および、金属触媒の存在下のH2からなる群から選択される還元剤の存在下に行われる、請求項1に記載の方法。
- 前記還元剤が、BH3、またはボランジメチルスルフィドである、請求項2に記載の方法。
- PGが、t-ブチルオキシカルボニルである、請求項1から3のいずれか一項に記載の方法。
- 前記方法が、3から50℃の範囲の、例えば4から45℃の範囲の温度で行われる、請求項1から4のいずれか一項に記載の方法。
- 前記方法が、5から40℃の範囲の温度で行われる、請求項1から5のいずれか一項に記載の方法。
- 前記緩衝剤が、クロロ酢酸塩である、例えばクロロ酢酸ナトリウムである、請求項1から6のいずれか一項に記載の方法。
- クロロ酢酸:クロロ酢酸塩のモル比が、2:1から5:1である、請求項7に記載の方法。
- 化合物(II):クロロ酢酸塩のモル比が、1:7から1:20である、請求項7または8に記載の方法。
- 化合物(III)の塩または化合物(III)の脱保護された生成物の塩の製造のための方法であって、請求項1から10のいずれか一項に記載の方法および塩を生成する工程を、例えば塩酸塩を生成する工程を含む、方法。
- 化合物(II)が、化合物(VI):
式中、PGは、化合物(II)に関して定義された通りであり、Rは、任意に適切に保護された形のOHであるか、または、
であり、前記適切に保護された形は、メチルエステル、メトキシメチルエステル、9-フルオレニルメチルエステル、t-ブチルエステル、ベンジルエステル、ジフェニルメチルエステル、トリフェニルメチルエステル、2,6-ジメチルフェニルエステル、トリメチルシリルエステル、トリエチルシリルエステル、2-(トリメチルシリル)エトキシメチルエステル、2-(トリメチルシリル)エチルエステル、S-t-ブチルエステル、および、2-アルキル-1,3-オキサゾリンからなる群から選択される、請求項1から11のいずれか一項に記載の方法。 - 前記還元剤が、水素および触媒である、例えばH2/Pd/Cである、請求項12に記載の方法。
- 化合物(I):
請求項1から14のいずれか一項に記載の方法を行うこと、および、さらに、化合物(III)を脱保護して、化合物(I)またはその塩を生成することを含み、
式中、Rは、任意に適切に保護された形のOHであるか、または、
- 前記方法が、化合物(I)の塩の製造のための方法である、請求項15または16に記載の方法。
- 化合物(VIb):
化合物(IV):
式中、PGは、メチルオキシカルボニル、エチルオキシカルボニル、9-フルオレニルメチルオキシカルボニル、t-ブチルオキシカルボニル、ベンジルオキシカルボニル、p-メトキシベンジルオキシカルボニル、1-アダマンチルオキシカルボニル、p-ブロモベンジルオキシカルボニル、トリフルオロアセチル、クロロアセチル、フェニルアセチル、ベンズアセチル、p-トルエンスルホニル、2-ニトロベンゼンスルホニル、t-ブチルスルホニル、2-または4-ニトロベンゼンスルホニル、2,4-ジニトロベンゼンスルホニル、および、2-ナフタレンスルホニルからなる群から選択される保護基である、方法。 - 次の構造:
式中、YはNH2またはNO2であり、PGは、メチルオキシカルボニル、エチルオキシカルボニル、9-フルオレニルメチルオキシカルボニル、t-ブチルオキシカルボニル、ベンジルオキシカルボニル、p-メトキシベンジルオキシカルボニル、1-アダマンチルオキシカルボニル、p-ブロモベンジルオキシカルボニル、トリフルオロアセチル、クロロアセチル、フェニルアセチル、ベンズアセチル、p-トルエンスルホニル、2-ニトロベンゼンスルホニル、t-ブチルスルホニル、2-または4-ニトロベンゼンスルホニル、2,4-ジニトロベンゼンスルホニル、および、2-ナフタレンスルホニルからなる群から選択される保護基である化合物。 - PGが、t-ブチルオキシカルボニルである、請求項20に記載の化合物。
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