KR20110015449A - 아르포르모테롤의 합성방법 - Google Patents
아르포르모테롤의 합성방법 Download PDFInfo
- Publication number
- KR20110015449A KR20110015449A KR1020107029606A KR20107029606A KR20110015449A KR 20110015449 A KR20110015449 A KR 20110015449A KR 1020107029606 A KR1020107029606 A KR 1020107029606A KR 20107029606 A KR20107029606 A KR 20107029606A KR 20110015449 A KR20110015449 A KR 20110015449A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- formula
- acid
- salt
- diastereomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- BPZSYCZIITTYBL-YJYMSZOUSA-N R-Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 title claims description 21
- 229960001692 arformoterol Drugs 0.000 title description 10
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 201
- 238000000034 method Methods 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 239000003054 catalyst Substances 0.000 claims abstract description 56
- 239000002253 acid Substances 0.000 claims abstract description 48
- 230000008569 process Effects 0.000 claims abstract description 45
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 38
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 31
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 claims abstract description 29
- 230000009467 reduction Effects 0.000 claims abstract description 22
- 238000006722 reduction reaction Methods 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 18
- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 13
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 11
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 7
- 150000002466 imines Chemical class 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- 235000002639 sodium chloride Nutrition 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 36
- 229960002848 formoterol Drugs 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 33
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 29
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 230000002829 reductive effect Effects 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 16
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 16
- 150000008040 ionic compounds Chemical class 0.000 claims description 15
- 229910052763 palladium Inorganic materials 0.000 claims description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 229910052697 platinum Inorganic materials 0.000 claims description 13
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 10
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
- 239000007868 Raney catalyst Substances 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000004927 clay Substances 0.000 claims description 6
- 229910052570 clay Inorganic materials 0.000 claims description 6
- 229910000510 noble metal Inorganic materials 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 5
- 229910000085 borane Inorganic materials 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 239000010948 rhodium Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- QNRXNRGSOJZINA-MRVPVSSYSA-N (2r)-2,3-dihydro-1h-indole-2-carboxylic acid Chemical class C1=CC=C2N[C@@H](C(=O)O)CC2=C1 QNRXNRGSOJZINA-MRVPVSSYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 3
- VCDGSBJCRYTLNU-CJGYBVCLSA-N 9-[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]-9-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1B2[C@@H]1C[C@@H](C2(C)C)C[C@@H]2[C@H]1C VCDGSBJCRYTLNU-CJGYBVCLSA-N 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- XEXFVRMLYUDDJY-UHFFFAOYSA-N azane;hydrate;hydrochloride Chemical compound [NH4+].[NH4+].[OH-].[Cl-] XEXFVRMLYUDDJY-UHFFFAOYSA-N 0.000 claims description 3
- NGPGDYLVALNKEG-UHFFFAOYSA-N azanium;azane;2,3,4-trihydroxy-4-oxobutanoate Chemical compound [NH4+].[NH4+].[O-]C(=O)C(O)C(O)C([O-])=O NGPGDYLVALNKEG-UHFFFAOYSA-N 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- PSEHHVRCDVOTID-VMAIWCPRSA-N chloro-bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@H]([C@@H]1C)B(Cl)[C@H]2[C@H](C)[C@]3(C[C@@](C2)(C3(C)C)[H])[H])[C@@]2([H])C(C)(C)[C@]1([H])C2 PSEHHVRCDVOTID-VMAIWCPRSA-N 0.000 claims description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 3
- FDTUVFSBEYKVAP-UHFFFAOYSA-N formic acid;pyridine Chemical compound OC=O.C1=CC=NC=C1 FDTUVFSBEYKVAP-UHFFFAOYSA-N 0.000 claims description 3
- 230000022244 formylation Effects 0.000 claims description 3
- 238000006170 formylation reaction Methods 0.000 claims description 3
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- 229960003975 potassium Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000001508 potassium citrate Substances 0.000 claims description 3
- 229960002635 potassium citrate Drugs 0.000 claims description 3
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 3
- 235000011082 potassium citrates Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 3
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- 239000011343 solid material Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 claims description 3
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 2
- 229910010082 LiAlH Inorganic materials 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 150000001983 dialkylethers Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000002608 ionic liquid Substances 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 229940043279 diisopropylamine Drugs 0.000 claims 1
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 description 58
- 125000000217 alkyl group Chemical group 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 29
- 125000003118 aryl group Chemical group 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 7
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- CVGPWMGXKOKNFD-UHFFFAOYSA-N n-benzyl-1-(4-methoxyphenyl)propan-2-amine Chemical compound C1=CC(OC)=CC=C1CC(C)NCC1=CC=CC=C1 CVGPWMGXKOKNFD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
- C07C217/86—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
-
- 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
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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| KR20110015449A (ko) | 2008-06-02 | 2011-02-15 | 시플라 리미티드 | 아르포르모테롤의 합성방법 |
| US20110313199A1 (en) * | 2008-12-26 | 2011-12-22 | Actavis Group Ptc Ehf | processes for preparing substantially pure arformoterol and its intermediates |
| EP2348013A1 (en) | 2010-01-25 | 2011-07-27 | Inke, S.A. | Process for preparation of intermediates of arformoterol |
| MX355697B (es) | 2010-04-12 | 2018-04-27 | Supernus Pharmaceuticals Inc | Métodos para producir sales de viloxazina y polimorfos novedosos de las mismas. |
| MX2014011576A (es) * | 2012-04-11 | 2014-11-21 | Cipla Ltd | Composicion farmaceutica. |
| CN103664677A (zh) * | 2012-09-05 | 2014-03-26 | 中山大学 | 一种(r,r)-福莫特罗酒石酸盐的不对称合成方法 |
| CN106518690A (zh) * | 2016-09-21 | 2017-03-22 | 北京万全德众医药生物技术有限公司 | 酒石酸阿福特罗重要中间体的一种制备方法 |
| CN106565527A (zh) * | 2016-11-02 | 2017-04-19 | 北京万全德众医药生物技术有限公司 | 一种酒石酸阿福特罗甲酰胺中间体的制备方法 |
| CN107673957B (zh) * | 2017-10-13 | 2020-10-23 | 河北工业大学 | 一种酸碱双功能离子液体催化低碳醛羟醛自缩合反应的方法 |
| CN109627173A (zh) * | 2019-01-19 | 2019-04-16 | 西南石油大学 | 一种氢转移选择性还原腈类制备仲胺的方法 |
| CN112574055B (zh) * | 2019-09-30 | 2024-07-09 | 天津天药药业股份有限公司 | 福莫特罗及其药用盐的制备方法及应用 |
| CN113717060B (zh) * | 2021-09-03 | 2024-03-15 | 成都新恒创药业有限公司 | 一种去甲肾上腺素及其重酒石酸盐的合成方法 |
| CN115873909B (zh) * | 2022-12-06 | 2023-08-11 | 天津法莫西生物医药科技有限公司 | 一种阿福特罗手性中间体的制备方法 |
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| US3994974A (en) * | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
| JP3167705B2 (ja) * | 1990-05-21 | 2001-05-21 | 広栄化学工業株式会社 | 3―(n―ベンジル―n―アルコキシカルボニルアルキルアミノ)プロピオン酸エステルの製法 |
| WO1995012572A1 (en) | 1993-11-04 | 1995-05-11 | Abbott Laboratories | Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase |
| SE9404080L (sv) | 1993-12-28 | 1995-06-29 | Ciba Geigy Ag | Förfarande för framställning av en optiskt ren enantiomer av formoterol |
| EP0938467B1 (en) * | 1996-11-11 | 2002-06-12 | Sepracor, Inc. | Process for the preparation of optically pure isomers of formoterol |
| US6040344A (en) * | 1996-11-11 | 2000-03-21 | Sepracor Inc. | Formoterol process |
| US5965622A (en) * | 1998-06-23 | 1999-10-12 | Sepracor Inc. | Desformoterol and process for its preparation |
| JP2000239237A (ja) * | 1999-02-19 | 2000-09-05 | Yamanouchi Pharmaceut Co Ltd | 光学活性化合物の結晶及びその製法 |
| JP2002255910A (ja) * | 2001-02-27 | 2002-09-11 | Nippon Kayaku Co Ltd | 1,1ービス(3−アミノー4ーヒドロキシフェニル)シクロアルカン類の製造方法 |
| GB0118238D0 (en) * | 2001-07-26 | 2001-09-19 | Smithkline Beecham Plc | Medicaments |
| GB2380996A (en) | 2001-09-19 | 2003-04-23 | Novartis Ag | Hydroxy-nitrobenzene derivatives useful in the preparation of formoterol |
| CN1805926A (zh) * | 2003-05-05 | 2006-07-19 | 兰贝克赛实验室有限公司 | 二苯基氮杂环丁酮衍生物的反式异构体的制备方法 |
| GB0407908D0 (en) | 2004-04-07 | 2004-05-12 | Univ York | Ionic liquids |
| JP4924034B2 (ja) | 2004-05-24 | 2012-04-25 | 和光純薬工業株式会社 | イオン性液体担持クラウン化合物 |
| WO2008035380A2 (en) | 2006-09-19 | 2008-03-27 | Natco Pharma Limited | An improved process for the preparation of high purity formoterol and its pharmaceutically acceptable salts |
| KR20110015449A (ko) | 2008-06-02 | 2011-02-15 | 시플라 리미티드 | 아르포르모테롤의 합성방법 |
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2009
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- 2009-06-02 CA CA2724882A patent/CA2724882A1/en not_active Abandoned
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2014
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| CA2724882A1 (en) | 2009-12-10 |
| JP2011523658A (ja) | 2011-08-18 |
| EP2285770A1 (en) | 2011-02-23 |
| AU2009253877B2 (en) | 2013-09-12 |
| NZ589497A (en) | 2012-09-28 |
| US20110166237A1 (en) | 2011-07-07 |
| ES2539947T3 (es) | 2015-07-07 |
| EP2285770B1 (en) | 2015-05-20 |
| AU2009253877A1 (en) | 2009-12-10 |
| ZA201008222B (en) | 2011-07-27 |
| JP2015063529A (ja) | 2015-04-09 |
| US9029421B2 (en) | 2015-05-12 |
| WO2009147383A1 (en) | 2009-12-10 |
| US20150210629A1 (en) | 2015-07-30 |
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