AP937A - Stereospecific preparation of chiral 1-aryl-and 1-heteroaryl-2-substituted ethyl-2-amines. - Google Patents
Stereospecific preparation of chiral 1-aryl-and 1-heteroaryl-2-substituted ethyl-2-amines. Download PDFInfo
- Publication number
- AP937A AP937A APAP/P/1999/001476A AP9901476A AP937A AP 937 A AP937 A AP 937A AP 9901476 A AP9901476 A AP 9901476A AP 937 A AP937 A AP 937A
- Authority
- AP
- ARIPO
- Prior art keywords
- optionally substituted
- compound
- reacting
- formula
- substituted aryl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 10
- 230000000707 stereoselective effect Effects 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 28
- -1 2-amino-2-substituted ethyl Chemical group 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910003002 lithium salt Inorganic materials 0.000 claims description 13
- 159000000002 lithium salts Chemical class 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 150000002642 lithium compounds Chemical class 0.000 claims description 10
- 150000008064 anhydrides Chemical class 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002516 radical scavenger Substances 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 150000001541 aziridines Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical group CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 4
- GXLVXAJNTZHIJO-GNFRJPFZSA-N [Li+].ClC1=C(SC=C1)[C@@]1(CS(=O)(=O)[NH-])C(C=CC=C1)CCCC Chemical compound [Li+].ClC1=C(SC=C1)[C@@]1(CS(=O)(=O)[NH-])C(C=CC=C1)CCCC GXLVXAJNTZHIJO-GNFRJPFZSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Chemical group O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000011282 treatment Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 244000309464 bull Species 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 150000003461 sulfonyl halides Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical group CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000002253 anti-ischaemic effect Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- GVWIBAQTEVKJFP-ZCFIWIBFSA-N (2r)-1-(3-chlorothiophen-2-yl)butan-2-amine Chemical compound CC[C@@H](N)CC=1SC=CC=1Cl GVWIBAQTEVKJFP-ZCFIWIBFSA-N 0.000 description 1
- JCBPETKZIGVZRE-SCSAIBSYSA-N (2r)-2-aminobutan-1-ol Chemical compound CC[C@@H](N)CO JCBPETKZIGVZRE-SCSAIBSYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QUBJDMPBDURTJT-UHFFFAOYSA-N 3-chlorothiophene Chemical compound ClC=1C=CSC=1 QUBJDMPBDURTJT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- IDGQXGPQOGUGIX-VIFPVBQESA-N O-BENZYL-l-SERINE Chemical compound OC(=O)[C@@H](N)COCC1=CC=CC=C1 IDGQXGPQOGUGIX-VIFPVBQESA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- KWBHRQPXEXPYCY-XCOGQXMVSA-N [Li+].ClC1=C(SC=C1)[C@@]1(CS(=O)(=O)[NH-])C(C=CC=C1)CCCC.ClC1=C(SC=C1)C[C@@H](CC)N Chemical compound [Li+].ClC1=C(SC=C1)[C@@]1(CS(=O)(=O)[NH-])C(C=CC=C1)CCCC.ClC1=C(SC=C1)C[C@@H](CC)N KWBHRQPXEXPYCY-XCOGQXMVSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003243 anti-lipolytic effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- LKMCJXXOBRCATQ-UHFFFAOYSA-N benzylsulfanylbenzene Chemical compound C=1C=CC=CC=1CSC1=CC=CC=C1 LKMCJXXOBRCATQ-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 239000012659 cardioprotective agent Substances 0.000 description 1
- 229940045200 cardioprotective agent Drugs 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- SZNYYWIUQFZLLT-UHFFFAOYSA-N isopropylmethyl ether Natural products CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- VYGSFTVYZHNGBU-UHFFFAOYSA-N trichloromethanesulfonic acid Chemical compound OS(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940030010 trimethoxybenzene Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
- C07D203/24—Sulfur atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention is directed to methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2-position, and to intermediates to the substituted ethyl-2-amines.
Description
STEREOSPECIFIC PREPARATION OF CHIRAL 1-ARYL- AND 1-HETEROARYL-2-SUBSTITUTED ETHYL-2-AMINES
FIELD OF THE INVENTION
This invention is directed to methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2position.
C The invention is directed also to intermediates to the substituted ethyl-2-amines.
The substituted ethyl-2-amines, and intermediate compounds thereto, are useful as intermediates in the synthesis of cardiovascular agents, including antihypertensive agents, anti-ischemic agents, cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and antilipolytic agents which reduce plasma lipid levels, serum triglyceride i 7 levels, and plasma cholesterol levels.
For example, the substituted ethyl-2-amines are useful as intermediates in the preparation of antihypertensive and anti-ischemic heterocyclyl adenosine derivatives and analogues as disclosed in U.S. Patent 5,364,862. They are useful also in the preparation of N9-cyclopentyl-substituted adenine derivatives reported to be adenosine receptor ligands, and useful in cardiovascular conditions such as hypertension, thrombosis and atherosclerosis, and also in central nervous system conditions comprising psychotic conditions such as schizophrenia, and convulsive disorders such as epilepsy, as disclosed in U.S. Patent 4,954,504. They are useful also in the preparation of N-6 and 5'-N substituted carboxamidoadenosine derivatives which have beneficial cardiovascular and antihypertensive activity as reported in U.S. Patent 5,310,731.
REPORTED DEVELOPMENTS
Stereospecific preparation of chiral optionally substituted heteroaryl-2-substituted ethyl 2aniines by reaction of heteroaryl anions with 2-substituted ethylene oxides, and subsequent stereospecific conversion of the resulting chiral ethyl alcohol to the amine has been reported by Spada et al., in U.S.
Patent 5,364,862.
Facilitation of acidolytic cleavage reactions, for example the removal of various protecting groups, in the presence of electrophilic scavengers has been reported. Deprotection of Nc’-mesitylene-2sulfonylarginine is reported by Yajima et al., Chem. Pharm. Bull. 26 (12) 3752-3757 (1978). Removal of the protecting group of O-benzyl serine, threonine, and tyrosine, and deprotection of Ne35 benzyloxycarbonyllysine is reported by Kiso et al., Chem. Pharm. Bull. 28 (2) 673-676 (1980).
Deprotection procedures for the p-toluenesulfonyl and p-methoxybenzenesulfonyl groups from the N'’function of histidine is reported by and Kitagawa et al., Chem. Pharm. Bull. 28 (3) 926-931 (1980).
AP/P/ 9 9 / 0 1 4 76
AP 00937
SUMMARY OF THE INVENTION
The present invention is directed to methods for stereospecifically preparing [(1-optionally substituted aryl)- or (1-optionally substituted heteroaryl)]-2-substituted ethyl-2-amines, having chirality at the 2-position, comprising reacting a 2-amino-2-substituted ethyl alcohol, having chirality at the 25 position, with an [(optionally substituted aryl)- or (trihalomethyl) sulfonyl]- halide or anhydride in the presence of a base to form an [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position.
DETAILED DESCRIPTION
As used above, and throughout the description of this invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Aryl means phenyl or naphthyl.
Optionally substituted aryl means an aryl group which be substituted with one or more aryl group substituents. Examples of aryl group substituents include alkyl, alkoxy, amino, aryl, heteroaryl, trihalomethyl, nitro, carboxy, carboalkoxy, carboxyalkyl, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, or carbamoyl. Preferred aryl group substituents include halo, hydroxy, alkyl, aryl, alkoxy, trihalomethyl, cyano, nitro, and alkylmercaptyl.
Heteroaryl means about a 4 to about a 10 membered aromatic ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinolinyl, quinazolinyl, imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, and benzothiazolyl. A preferred heteroaryl group is thienyl.
Optionally substituted heteroaryl means that the heteroaryl group may be substituted by one or more aryl group substituents. Examples of heteroaryl group substituents include alkoxy, alkylamino, aryl, carbalkoxy, carbamoyl, cyano, halo, heteroaryl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl or nitro. Preferred heteroaryl group substituents include halo, hydroxy, alkyl, aryl, alkoxy, trihalomethyl, cyano, nitro, and alkylmercaptyl.
Halogen (halo, halide) means chlorine (chloro, chloride), fluorine (fluoro, fluoride), bromine (bromo, bromide) or iodine (iodo, iodide).
Alkyl means a saturated aliphatic hydrocarbon group which may be straight or branched and 30 having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups may be straight or branched and have about 1 to about 10 carbon atoms in the chain. Lower alkyl means an alkyl group which may be straight or branched having about 1 to about 6 carbon atoms, such as methyl, ethyl, propyl or tert-butyl. Branched means that a lower alkyl group is attached to a linear alkyl chain.
Aralkyl means an alkyl group substituted by an aryl group. Optionally substituted aralkyl means that the aryl group of the aralkyl group may be substituted with one or more aryl group substituents.
AP/P/ 9 9/01476
AP 00937
Heteroaralkyl means an alkyl group substituted by a heteroaryl group. Optionally substituted heteroaralkyl means that the heteroaryl group or the heteroaralkyl group may be substituted with one or more aryl group substituents.
Electrophilic scavenger means an agent that can have a promoting effect on acidolytic 5 cleavage reactions, for example, as described by Yajima et al., Chem. Pharm. Bull. 26 (12) 3752-3757 (1978), Kiso et al., Chem. Pharm. Bull. 28 (2) 673-676 (1980), and Kitagawa et al., Chem. Pharm. Bull. 28 (3) 926-931 (1980).
An embodiment according to the invention is directed to a reaction of a 2-amino-2-substituted ethyl alcohol with a sulfonyl halide or anhydride, preferably in the presence of an aprotic organic solvent. Aprotic organic solvents which are suitable for the reaction include aprotic organic ethers, aromatic hydrocarbons, heteroaromatic hydrocarbons, aliphatic hydrocarbons, and aprotic organic amides. More particularly, examples of suitable aprotic organic solvents include diethyl ether, tert-butyl methyl ether, isopropyl methyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, and dioxan. In a special embodiment of methods according to the invention, the preferred aprotic organic solvent is tert15 butyl methyl ether.
The reaction with the sulfonyl halide or anhydride takes place preferably at a temperature range from about 25°C to about 90°C; more preferably from about 25°C to about 40°C.
Suitable sulfonyl halides and anhydrides include phenyl-, tol-4-yl-, 2,4,6-trimethylphenyl-, 2,4dimethylphenyl-, 4-methoxyphenyl-, 4-nitrophenyl-, 4-bromophenyl-, naphth-l-yl-, naphth-2-yl-, and trifluoromethyl- sulfonyl chloride and anhydride. In a special embodiment of methods according to the invention, a preferred sulfonyl chloride is p-toluenesulfonyl chloride (i.e., tol-4-yl sulfonyl chloride).
According to the invention, the reaction of the 2-amino-2-substituted ethyl alcohol with the sulfonyl halide or anhydride takes place in the presence of a base. Bases which are suitable for the reaction include aqueous alkali metal hydroxides, aqueous alkali metal carbonates, and aprotic organic amines. More particularly, examples of suitable alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide; examples of suitable alkali metal carbonates include potassium carbonate, sodium carbonate, and cesium carbonate; and examples of suitable aprotic organic amines include triethylamine, diisopropyl ethyl amine, N-methylmorpholine, and pyridine. In a special embodiment of methods according to the invention, a preferred base is aqueous sodium hydroxide.
Another embodiment according to the invention is directed to the reaction of the [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position, which is formed from the reaction of the 2-amino-2-substituted ethyl alcohol with the sulfonyl halide or anhydride, with an [(optionally substituted aryl)- or (optionally substituted heteroaryl)] lithium compound to form the lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]35 1- [(optionally substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2-position. In a special embodiment of the invention, the lithium salt formed in the reaction is isolated as a solid.
AP/P/ 9 9 / 0 1 4 76
ΑΡ 0 0 9 3 7
Organolithium compounds may exist as tetramers, hexamers, and higher aggregates in hydrocarbon and ether solvents, as described, for example, by Carey, F.A., and Sundberg, Richard J.,
Advanced Organic Chemistry, Plenum Press, New York (2d ed. 1984), and Fraenkel et al., J. Am. Chem.
Soc. 102, 3345 (1980). Formation by methods according to the invention of such aggregates of the lithium salts, and the aggregates so-formed are contemplated by and included in the invention.
The reaction to form lithium salt takes place preferably in an aprotic organic solvent. Aprotic organic solvents which are suitable for the reaction include aprotic organic ethers, aliphatic hydrocarbons, and aromatic hydrocarbons. In a special embodiment of methods according to the invention, a preferred aprotic organic solvent is an aprotic organic ether and, more particularly, tert-butyl methyl ether.
The formation of the lithium salt takes place preferably at about -80°C to about 50°C; more preferably at about -40°C to about 50°C.
Yet another embodiment according to the invention is directed to the treatment of the lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]-l- [(optionally substituted aryl)15 or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2-position with one or more strong acids in the presence of an electrophilic scavenger. This treatment takes place preferably at a temperature range of about 45°C to about reflux.
Strong acids which are suitable for the treatment include methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, trichloromethane sulfonic acid, trichloroacetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid. In a special embodiment of the invention, the treatment takes place preferably in a mixture of strong acids; more preferably in a mixture of methanesulfonic acid and trifluoroacetic acid.
Electrophilic scavengers which are suitable for the treatment include anisole, thioanisole, diphenyldisulfide, phenylbenzylsulfide, trimethoxybenzene, m-cresol, and 1,2-ethanediol. In a special embodiment according to the invention, a preferred electrophilic scavenger is thioanisole.
A preferred embodiment according to the invention is a method for preparing a compound of
Formula I, nh2
Formula I
AP/P/ 9 9/01476 wherein * indicates a chiral carbon atom,
R, is optionally substituted aryl, or optionally substituted heteroaryl; and
R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, comprising reacting a compound of Formula II
AP 00937
NH2
Formula II
OH with a compound of Formula III
R2-SO,-R'
Formula III wherein
R' is halo or OSO2R2; and
R2 is optionally substituted aryl, or trihalomethyl, in the presence of a base to form an aziridine compound of Formula IV.
Formula IV
A further preferred embodiment of the present invention is the method of preparing a compound of Formula I wherein R, is optionally substituted heteroaryl; more preferably R, is 3-chlorothien-2-yl.
Another further preferred embodiment of the invention is the method for preparing the 15 compound of Formula I wherein R3 is alkyl; more preferably R3 is ethyl.
Another preferred embodiment according to the invention is a method for preparing a compound of Formula I, comprising reacting the aziridine of Formula IV with a compound of formula Li-R, to form a lithium compound of Formula V,
L VI 0 / 6 6 /d/dV ___-Li
N
Formula V or an aggregate thereof.
Another preferred embodiment according to the invention is a method for preparing a compound of Formula I, comprising treating the lithium compound of Formula V with a strong acid or mixture of strong acids in the presence of an electrophilic scavenger.
Preferred embodiments according to the invention are illustrated in Scheme I.
AP 00937 nh2 /SO2R2
Fk /N
R2-S02-R'
-►
Base r3
RrLi v
1) Acid,
Electrophilic R2SO2-\^ ^\J\ NH2 Scavenger N
Scheme I
If it is necessary or desirable to prevent cross-reaction between chemically active substituents (for example, any aryl or heteroaryl group substituents) during the reactions or treatments of the methods according to the invention, the substituents may be protected by standard blocking groups which may be subsequently removed or retained, as required, by known methods to afford the desired product (see, for example, Green, Protective Groups in Organic Synthesis, Wiley, New York (1982)). Selective protection or deprotection also may be necessary or desirable to allow conversion or removal of existing substituents, or to allow subsequent reaction to afford the final desired product.
The present invention is directed also to intermediates to [(1-optionally substituted aryl)- or (1optionally substituted heteroaryl)]-2-substituted ethyl-2-amines.
A compound embodiment according to the invention is the [(N-arylsulfonyl)- or (Ntrihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position, formed by the reaction of the of the 2-amino-2-substituted ethyl alcohol with the sulfonyl halide or anhydride according to the method of the invention. A preferred embodiment of said aziridine is the compound of Formula IV. A special embodiment of said aziridine includes l-p-toluenesulfonyl-2(R)-ethylaziridine.
Another compound embodiment according invention is the lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]-l- [(optionally substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2-position formed by the reaction of the aziridine with an [(optionally substituted aryl)- or (optionally substituted heteroaryl)] lithium compound according to the method of the invention. A preferred embodiment of this lithium salt is the compound of Formula V. A special embodiment of the lithium salt includes is (R)-l-(3chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt.
The present invention is further explained, but is in no way limited, by the following examples.
L V 1 0 / 6 6 /d/dV
EXAMPLE 1
AP 00937
Preparation of l-p-toluenesulfonyl-2(R)-ethylaziridine
R-(-)-2-amino-1 -butanol (99.96 g,105 mL) and tert-butyl methyl ether (TBME) (277g, 366 mL) are combined under a nitrogen atmosphere. This mixture is stirred for several minutes and 10 N aqueous sodium hydroxide (449 mL) is added over a period of about 10 minutes. The reaction mixture is cooled to below 10°C and a solution of p-toluene sulfonyl chloride (TsCl) (464 g) in TBME (711 g) is added over a period of about 50 minutes, maintaining the temperature of the reaction mixture at or below 32°C. After the addition is complete, the mixture is stirred for about 30 minutes at 40°C, and water (900 mL) is added while cooling the mixture to 25°C. The layers are separated and the organic layer washed sequentially with water (150 g) and 25% aqueous sodium chloride solution (300 g). Toluene (450 g) is
T added to the organic layer, and the mixture distilled under reduced pressure, maintaining the temperature of the mixture at or below 45°C, until the water content of the mixture is below about 0.1%. The resulting solution is used, without further treatment, for the preparation described in Example 2.
EXAMPLE 2
Preparation of (R)-1-(3-chiorothien-2-yl)-2-butyltoluenesulfonamide lithium salt
Under a nitrogen atmosphere, a solution of 3-chlorothiophene (48.75 g) in TBME (291 g) is cooled to -10°C, and 2.5 M n-butyllithium in hexanes (151.3 mL) is added at such a rate that the reaction temperature is maintained between 0 and 5° C. After the addition is complete, the mixture is cooled to 5°C and l-p-toluenesulfonyl-2(R)-ethylaziridine (74.1 g, as a 56.9 % (w/w) solution in TBME) is added at such a rate to maintain the temperature of the reaction mixture below 9°C (during which time a solid precipitates). After about 5 minutes the mixture is cooled to 0° C and the precipitate is collected by vacuum filtration, washed with 0°C TBME (60 mL), and dried in vacuo at about 40°C, to give (R)-1-(3chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt, m.p. 372°C (dec.). MS (FAB), m/z 350, 352 (100%), 'HNMR (200 M/zz, DMSO) δ 0.8 (t, 3H); 2.25 (s, 3H); 6.85 (d, 1H); 7.05 (d, 2H), 7.35 (d, 2H).
EXAMPLE 3
Preparation of (R)-l-(3-chlorothien-2-yl)-2-aminobutane (R)-l-(3-chlorothien-2-yl)-2-butyltoluenesulfonamide lithium salt (120 g) is added in one portion to trifluoroacetic acid (470 g) in a vessel equipped with a condenser and mechanical stirrer. The temperature of the mixture rose from about 25 °C to about 60°C. As the resulting solution is cooling, thioanisole (85.2 g) is added, followed by methanesulfonic acid (65.9 g). The reaction mixture is heated at 80°C for about six hours. The mixture is cooled to 18°C and toluene (600 mL) is added. 6M aqueous sodium hydroxide solution (820 mL) is then added portionwise, with stirring, maintaining the reaction temperature below 60°C. The layers are separated and the organic phase is washed with water until the pH of the wash is 9, then brine. The organic solution is cooled to 18°C and toluene (200 mL) is added followed concentrated hydrochloric acid (42 mL). The resulting slurry is distilled at about 47°C at 180 mm Hg to azeotropically remove water. After about 200 mL of toluene/water had been removed the mixture is cooled to 40°C, allowed to come to atmospheric pressure, then cooled to 15°C over a 1 hour
AP/P/ 9 9/01476
AP 00937 period. The solids which precipitate are collected by vacuum filtration, washed with 60 mL of toluene and dried in vacuo to give (R)-l-(3-chlorothien-2-yl)-2-aminobutane as the hydrochloride salt, m.p. 137.6°C. MS (El), m/z 190, 192 (10%); ‘HNMR (200 Mfe, DMSO) 8 0.9 (t, 3H); 1.6 (m, 2H); 7.05 (d, 1H); 7.6 (d, 2H), 8.35 (s, 2H).
Claims (28)
- WHAT IS CLAIMED IS:1. A method for stereospecifically preparing a [(1-optionally substituted aryl)- or (1-optionally5 substituted heteroaryl)]-2-substituted ethyl-2-amine, having chirality at the 2-position, comprising reacting a 2-amino-2-substituted ethyl alcohol, having chirality at the 2-position, with an [(optionally substituted aryl)- or (trihalomethyl) sulfonyl]- halide or anhydride in the presence of a base to form an [(N-arylsulfonyl)- or (N-trihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position.
- 2. A method according to claim 1 further comprising reacting said aziridine with an [(optionally i' substituted aryl)- or (optionally substituted heteroaryl)] lithium compound to form the lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]-l- [(optionally substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having chirality at the 2-position.
- 3. A method according to claim 2 further comprising treating said lithium salt with one or more strong acids in the presence of an electrophilic scavenger.15
- 4. A method according to claim 1 for preparing a compound of formula nh2 wherein * indicates a chiral carbon atom,20 R, is optionally substituted aryl, or optionally substituted heteroaryl; andR3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; comprising reacting a compound of formula nh2AP/P/ 9 9 / 0 1 4 7 625 with a compound of formula R2-SO2-R’ whereinR1 is halo or OSO2R2; andR2 is optionally substituted aryl, or trihalomethyl,30 in the presence of a base to form an aziridine compound of formula ,SO2R2Xjz r,AP 00937
- 5. A method according to claim 4 further comprising reacting said aziridine compound with a compound of formula Li-R,, to form a lithium compound of formulaR2SO2\^ /'Ll N r3 , or an aggregate thereof.
- 6. A method according to claim 5 further comprising treating said lithium compound with a strong5 acid or mixture of strong acids in the presence of an electrophilic scavenger.
- 7. A method according to claim 4 wherein said reacting occurs in an aprotic organic solvent.
- 8. A method according to claim 7 wherein said aprotic organic solvent is tert-butyl methyl ether.
- 9. A method according to claim 4 wherein R2-SO2-R' is p-toluenesulfonyl chloride.12,A method according to claim 4 wherein said reacting occurs at about 25°C to about 90°C.A method according to claim 4 wherein said reacting occurs at about 25°C to about 40°C.A method according to claim 4 wherein said base is selected from the group consisting of an aqueous alkali metal hydroxide, an aqueous alkali metal carbonate, and an aprotic organic amine.
- 13. A method according to claim 4 wherein said base is aqueous sodium hydroxide.
- 14. A method according to claim 4 wherein R! is optionally substituted heteroaryl.
- 15 15. A method according to claim 14 wherein R, is 3-chlorothien-2-yl.
- 16. A method according to claim 4 wherein R3 is alkyl.
- 17. A method according to claim 16 wherein R3 is ethyl.
- 18. A method according to claim 5 wherein said reacting said aziridine compound occurs in a solvent selected from the group consisting of an aprotic organic ether, aliphatic hydrocarbon, and an20 aromatic hydrocarbon.
- 19. A method according to claim 18 wherein said reacting said aziridine compound occurs in tertbutyl methyl ether.
- 20. A method according to claim 5 further comprising isolating said lithium compound as a solid.
- 21. A method according to claim 5 wherein said reacting occurs at about25 -80°C to about 50°C.
- 22. A method according to claim 21 wherein said reacting occurs at about -40°C to about 50°C.
- 23. A method according to claim 6 wherein said mixture of strong acids comprises methanesulfonic acid and trifluoroacetic acid.30
- 24. A method according to claim 6 wherein said electrophilic scavenger is thioanisole.
- 25. A method according to claim 6 wherein said treating occurs at about 45°C to about reflux.
- 26. The [(N-arylsulfonyl)- or (N-frihalomethylsulfonyl)]-2-substituted aziridine having chirality at the 2-position according to claim 1.
- 27. The aziridine compound according to claim 4 of formulaAP/P/ 9 9 / 0 1 4 76Ap 00937
- 28. A compound according to claim 27 which is l-p-toluenesulfonyl-2(R)-ethylaziridine.
- 29. The lithium salt of an [(N-optionally substituted aryl)- or (N-trihalomethyl)sulfonyl]-l[(optionally substituted aryl)- or (optionally substituted heteroaryl)]-2-substituted alkyl-2-amine having5 chirality at the 2-position according to claim 2.
- 30. The lithium compound according to claim 5 of formulaR2SO2X. Li N 3 , or an aggregate thereof.
- 31. A lithium compound according to claim 30 which is (R)-l-(3-chlorothien-2-yl)-2butyltoluenesulfonamide lithium salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2600596P | 1996-09-12 | 1996-09-12 | |
| PCT/US1997/015729 WO1998011064A1 (en) | 1996-09-12 | 1997-09-10 | Stereospecific preparation of chiral 1-aryl- and 1-heteroaryl-2-substituted ethyl-2-amines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9901476A0 AP9901476A0 (en) | 1999-03-31 |
| AP937A true AP937A (en) | 2001-02-07 |
Family
ID=21829300
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1999/001476A AP937A (en) | 1996-09-12 | 1997-09-10 | Stereospecific preparation of chiral 1-aryl-and 1-heteroaryl-2-substituted ethyl-2-amines. |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US6127550A (en) |
| EP (1) | EP0942900A4 (en) |
| JP (1) | JP2001501922A (en) |
| KR (1) | KR100317871B1 (en) |
| CN (2) | CN1112354C (en) |
| AP (1) | AP937A (en) |
| AU (1) | AU732332B2 (en) |
| BG (1) | BG103259A (en) |
| BR (1) | BR9711466A (en) |
| CA (1) | CA2265886A1 (en) |
| EA (1) | EA001364B1 (en) |
| HU (1) | HUP0000219A3 (en) |
| IL (1) | IL128813A0 (en) |
| NO (1) | NO991023L (en) |
| OA (1) | OA10991A (en) |
| PL (1) | PL331933A1 (en) |
| SK (1) | SK26999A3 (en) |
| UA (1) | UA54451C2 (en) |
| WO (1) | WO1998011064A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU225504B1 (en) * | 1997-05-13 | 2007-01-29 | Sanofi Aventis | Novel halophenyl-(2-(2-thienyl)-ethylamino)-acetonitriles and process for producing them |
| CN1383427A (en) | 1998-12-31 | 2002-12-04 | 阿温蒂斯药物公司 | Process for preparing N6-substituted deaza-adenosine derivatives |
| KR100426030B1 (en) * | 2000-07-22 | 2004-04-03 | (주) 한켐 | Chirality conversion method in lactone sugar compounds |
| KR100440461B1 (en) * | 2000-08-19 | 2004-07-15 | (주) 한켐 | Process for the preparation of L-ribose using 1,4-lactone |
| KR100433179B1 (en) * | 2001-11-10 | 2004-05-27 | 주식회사 삼천리제약 | Method for Producing 2-Deoxy-L-ribose |
| CN100506919C (en) * | 2006-02-23 | 2009-07-01 | 中国科学院化学研究所 | Method for Chiral Induction of Achiral Cyanine Dye Aggregates Using Human Serum Protein |
| WO2018225851A1 (en) | 2017-06-09 | 2018-12-13 | 中外製薬株式会社 | Method for synthesizing peptide containing n-substituted amino acid |
| JP7568510B2 (en) * | 2018-11-30 | 2024-10-16 | 中外製薬株式会社 | Method for deprotecting peptide compounds or amide compounds, method for removing resin in solid-phase reaction, and method for producing peptide compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3431152A (en) * | 1967-03-23 | 1969-03-04 | American Cyanamid Co | Compositions containing aromatic sulfonyl aziridine as curing agents |
| US4933470A (en) * | 1987-10-05 | 1990-06-12 | Neorx Corporation | Method of synthesis of vicinal diamines |
| SG80526A1 (en) * | 1990-09-25 | 2001-05-22 | Rhone Poulenc Rorer Int | Compounds having antihypertensive and anti- ischemic properies |
-
1997
- 1997-09-10 CA CA002265886A patent/CA2265886A1/en not_active Abandoned
- 1997-09-10 KR KR1019997001970A patent/KR100317871B1/en not_active Expired - Fee Related
- 1997-09-10 AU AU42562/97A patent/AU732332B2/en not_active Ceased
- 1997-09-10 HU HU0000219A patent/HUP0000219A3/en unknown
- 1997-09-10 BR BR9711466A patent/BR9711466A/en active Search and Examination
- 1997-09-10 EP EP97940882A patent/EP0942900A4/en not_active Withdrawn
- 1997-09-10 AP APAP/P/1999/001476A patent/AP937A/en active
- 1997-09-10 IL IL12881397A patent/IL128813A0/en not_active IP Right Cessation
- 1997-09-10 CN CN97197895A patent/CN1112354C/en not_active Expired - Fee Related
- 1997-09-10 JP JP10513724A patent/JP2001501922A/en not_active Ceased
- 1997-09-10 EA EA199900281A patent/EA001364B1/en not_active IP Right Cessation
- 1997-09-10 WO PCT/US1997/015729 patent/WO1998011064A1/en not_active Ceased
- 1997-09-10 SK SK269-99A patent/SK26999A3/en unknown
- 1997-09-10 PL PL97331933A patent/PL331933A1/en unknown
- 1997-10-09 UA UA99042043A patent/UA54451C2/en unknown
-
1999
- 1999-03-02 NO NO991023A patent/NO991023L/en not_active Application Discontinuation
- 1999-03-10 OA OA9900052A patent/OA10991A/en unknown
- 1999-03-11 US US09/266,641 patent/US6127550A/en not_active Expired - Fee Related
- 1999-03-17 BG BG103259A patent/BG103259A/en unknown
- 1999-10-25 US US09/426,403 patent/US6433172B1/en not_active Expired - Fee Related
-
2001
- 2001-12-20 CN CN01143342A patent/CN1388119A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| NONE * |
Also Published As
| Publication number | Publication date |
|---|---|
| SK26999A3 (en) | 1999-10-08 |
| NO991023D0 (en) | 1999-03-02 |
| JP2001501922A (en) | 2001-02-13 |
| KR20000036007A (en) | 2000-06-26 |
| EA001364B1 (en) | 2001-02-26 |
| OA10991A (en) | 2001-11-07 |
| US6127550A (en) | 2000-10-03 |
| CN1112354C (en) | 2003-06-25 |
| BR9711466A (en) | 1999-08-24 |
| AU732332B2 (en) | 2001-04-12 |
| KR100317871B1 (en) | 2002-01-18 |
| EP0942900A1 (en) | 1999-09-22 |
| HUP0000219A3 (en) | 2001-04-28 |
| CN1388119A (en) | 2003-01-01 |
| AU4256297A (en) | 1998-04-02 |
| CA2265886A1 (en) | 1998-03-19 |
| US6433172B1 (en) | 2002-08-13 |
| AP9901476A0 (en) | 1999-03-31 |
| CN1230176A (en) | 1999-09-29 |
| PL331933A1 (en) | 1999-08-16 |
| NO991023L (en) | 1999-03-02 |
| UA54451C2 (en) | 2003-03-17 |
| EA199900281A1 (en) | 1999-08-26 |
| IL128813A0 (en) | 2000-01-31 |
| HK1022296A1 (en) | 2000-08-04 |
| BG103259A (en) | 2000-02-29 |
| HUP0000219A2 (en) | 2000-12-28 |
| WO1998011064A1 (en) | 1998-03-19 |
| EP0942900A4 (en) | 2004-08-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101379154B1 (en) | Carbonyl asymmetric alkylation | |
| AP937A (en) | Stereospecific preparation of chiral 1-aryl-and 1-heteroaryl-2-substituted ethyl-2-amines. | |
| JP2008525486A (en) | Method for producing substituted piperidine | |
| US6458963B1 (en) | Process for preparing eprosartan using regioselective protection of 2,4-disubstituted-imidazole intermediates | |
| JP2002534430A (en) | Process for producing N6-substituted deazaadenosine derivatives | |
| JPH08503195A (en) | Tartronic acids, their acetalic ethers and O-esters | |
| US7109352B2 (en) | Process for producing optically active amino acid derivatives | |
| WO1992015562A2 (en) | Preparation of omega-substituted alkanamide | |
| HK1022296B (en) | Stereospecific preparation of chiral 1-aryl-and 1-heteroaryl-2-sustituted ethyl-2-amines | |
| US7122696B2 (en) | Processes for preparation of N-protected-β-amino alcohols and N-protected-β-amino epoxides | |
| US4697013A (en) | Condensed as-triazine derivatives | |
| CZ72199A3 (en) | Stereospecific preparation of chiral 1-aryl- and 1-heteroaryl-2-substituted ethyl-2-amines | |
| KR20020047255A (en) | Process for preparing oxazolines from tetrahydrofurans | |
| JP2002523490A (en) | Method for producing N-protected azetidine-2-carboxylic acids (AzeOHs) | |
| US5981757A (en) | Nizatidine preparation | |
| US6207834B1 (en) | Process for producing piperidinecarboxylic acid amide derivatives | |
| JP2002506430A (en) | Method for producing chiral 3,4-dehydroproline | |
| MXPA99007536A (en) | Process for preparing eprosartan | |
| KR20010043046A (en) | Process for the preparation of methyl(2s)-2-[(3r)-3-(n-[tert-butyloxycarbonyl]-amino)-2-oxopyrrolidin-1-yl]propionate |