MXPA96003967A - Synthesis of prototypes for ren inhibitors - Google Patents
Synthesis of prototypes for ren inhibitorsInfo
- Publication number
- MXPA96003967A MXPA96003967A MXPA/A/1996/003967A MX9603967A MXPA96003967A MX PA96003967 A MXPA96003967 A MX PA96003967A MX 9603967 A MX9603967 A MX 9603967A MX PA96003967 A MXPA96003967 A MX PA96003967A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- percent
- compound
- milliliters
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title claims description 5
- 230000015572 biosynthetic process Effects 0.000 title claims description 4
- 230000002194 synthesizing Effects 0.000 title claims description 3
- 241000282941 Rangifer tarandus Species 0.000 title 1
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 43
- -1 2-carbamoyl-2-methylpropyl Chemical group 0.000 claims abstract description 40
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 14
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 10
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 150000003140 primary amides Chemical class 0.000 claims abstract description 7
- 150000001925 cycloalkenes Chemical class 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 150000003334 secondary amides Chemical class 0.000 claims abstract description 6
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940086526 Renin-inhibitors Drugs 0.000 claims abstract description 4
- 150000002390 heteroarenes Chemical class 0.000 claims abstract description 4
- 239000002461 renin inhibitor Substances 0.000 claims abstract description 4
- 239000000543 intermediate Substances 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 16
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- ZFTFAPZRGNKQPU-UHFFFAOYSA-L carboxylato carbonate Chemical compound [O-]C(=O)OC([O-])=O ZFTFAPZRGNKQPU-UHFFFAOYSA-L 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000004030 hiv protease inhibitor Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 102100000775 REN Human genes 0.000 abstract description 3
- 108090000783 Renin Proteins 0.000 abstract description 3
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 abstract 1
- 238000007040 multi-step synthesis reaction Methods 0.000 abstract 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 36
- 101700043453 chch-3 Proteins 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 239000000203 mixture Substances 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 16
- 239000008079 hexane Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 125000000471 iminomethylidene group Chemical group [H]N=C=* 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000010409 thin film Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 101700067048 CDC13 Proteins 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- MSZJEPVVQWJCIF-UHFFFAOYSA-N butylazanide Chemical compound CCCC[NH-] MSZJEPVVQWJCIF-UHFFFAOYSA-N 0.000 description 4
- 150000002374 hemiaminals Chemical class 0.000 description 4
- 150000003951 lactams Chemical class 0.000 description 4
- 150000002596 lactones Chemical group 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- ORWYRWWVDCYOMK-HBZPZAIKSA-N Angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 3
- 102400000344 Angiotensin-1 Human genes 0.000 description 3
- 101800000734 Angiotensin-1 Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- ILBCDLOQMRDXLN-UHFFFAOYSA-N furan-2-yloxy(trimethyl)silane Chemical compound C[Si](C)(C)OC1=CC=CO1 ILBCDLOQMRDXLN-UHFFFAOYSA-N 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-Propanediol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 229950006323 Angiotensin ii Drugs 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II dizwitterion Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 101710027499 Os03g0268000 Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- MKFJRRMYWGERCT-UHFFFAOYSA-N bihapten 1 dimethyl ether Chemical compound COC1=CC=CC(CCCCCCCCCC2OC(=O)C(=C)C2)=C1OC MKFJRRMYWGERCT-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000707 stereoselective Effects 0.000 description 2
- QISRRCVJTQSICP-KOLCDFICSA-N (2S,3R)-3-methyl-2-phenyl-3,4-dihydro-2H-pyrrole Chemical compound C[C@@H]1CC=N[C@@H]1C1=CC=CC=C1 QISRRCVJTQSICP-KOLCDFICSA-N 0.000 description 1
- CKGJWXGCQYJRGY-LDYMZIIASA-N (4R,5R)-4-methyl-5-phenyloxolan-2-one Chemical compound C[C@@H]1CC(=O)O[C@H]1C1=CC=CC=C1 CKGJWXGCQYJRGY-LDYMZIIASA-N 0.000 description 1
- JSCZDGQZCVPSFP-KCJUWKMLSA-N (4R,5S)-4-methyl-5-phenylpyrrolidin-2-one Chemical compound C[C@@H]1CC(=O)N[C@@H]1C1=CC=CC=C1 JSCZDGQZCVPSFP-KCJUWKMLSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- FWTJDTQXENOXPC-UHFFFAOYSA-N 3-benzyloxolan-2-one Chemical compound O=C1OCCC1CC1=CC=CC=C1 FWTJDTQXENOXPC-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- RAFGELQLHMBRHD-SLEZCNMESA-N Bixin Chemical compound COC(=O)\C=C\C(\C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C(O)=O RAFGELQLHMBRHD-SLEZCNMESA-N 0.000 description 1
- 101700065604 CDC12 Proteins 0.000 description 1
- 102100000129 CHURC1 Human genes 0.000 description 1
- 101710014631 CHURC1 Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- NALBLJLOBICXRH-UHFFFAOYSA-N Dinitrogen monohydride Chemical compound N=[N] NALBLJLOBICXRH-UHFFFAOYSA-N 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
- 239000007832 Na2SO4 Substances 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- JXYRIQRQKAUQIY-UHFFFAOYSA-N acetic acid;oxolane Chemical compound CC(O)=O.C1CCOC1 JXYRIQRQKAUQIY-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- YAGCIXJCAUGCGI-UHFFFAOYSA-N butoxycarbonyl butyl carbonate Chemical group CCCCOC(=O)OC(=O)OCCCC YAGCIXJCAUGCGI-UHFFFAOYSA-N 0.000 description 1
- 125000005242 carbamoyl alkyl group Chemical group 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 210000003622 mature neutrocyte Anatomy 0.000 description 1
- XXGJRAFLOAKNCC-UHFFFAOYSA-N methane;molecular hydrogen Chemical compound C.[H][H] XXGJRAFLOAKNCC-UHFFFAOYSA-N 0.000 description 1
- SKJLTONJBDORJV-INIZCTEOSA-N methyl (2S)-2-phenyl-2-(phenylmethoxymethoxy)acetate Chemical compound O([C@H](C(=O)OC)C=1C=CC=CC=1)COCC1=CC=CC=C1 SKJLTONJBDORJV-INIZCTEOSA-N 0.000 description 1
- ITATYELQCJRCCK-UHFFFAOYSA-N methyl 2-hydroxy-2-phenylacetate Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Abstract
Renin prototype inhibitors are prepared having the general structure: (I) where n is from 0 to 3 inclusive, A are either hydrogen atoms, or together they are a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy, wherein the identity of the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms, R2 and R3 are independently alkyl of 1 to 4 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms, or an aliphatic substituent such as, for example, butyl, 2-morpholinoethyl, or 2-carbamoyl-2-methylpropyl, R5 is selected from aromatics, substituted aromatics, and heteroaromatics , substituted or unsubstituted cycloalkyls, cycloalkenes having from 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives such as 3-methoxypropyloxy, alkyl derivatives of primary and secondary amides, through a novel multi-step synthesis. These compounds are valuable intermediates for the manufacture of pharmaceutical products such as renin inhibitors and V protease inhibitors.
Description
SYNTHESIS OF PROTOTYPES FOR INHIBITORS OF RENIÑA
The present invention relates to the field of biological activity related to the similar enzymatic and chemical specific decomposition of angintensinogen by "separation in angiotensin-I, and then in angiotensin-I I, which SP couples with the receptors that initiate the activity hi It has been known for a long time to use compounds with similar chemical properties and a general stereochemical conformation, either as substitutes for activators, to produce positive effects or to block specific receptors to avoid effects. In practice, despite massive advances in the knowledge of the conformational structure of chemical compounds, the exact conformation of a particular compound, its chemical synthesis, and its biological properties can not be predicted with confidence. present invention, the compounds provided are important intermediates for the fabric of inhibitors of renin prototypes. Renin inhibitors prevent the production of angiotensin-II, a potent vasoconstrictor and, therefore, are potent antihypertensive agents. The basic action of renin is as shown below in the present, first dissociating the angiotensinogen to provide a specific fragment (angiotensin I), and then subdivided into a second specific fragment (angiotensin II), which is coupled with the appropriate receptor for Start biological activity:
Renina
Asp-Arg-Val yr-lleu-His-Pro-Phe-H¡s-Leu al-lleu-Val-lleu-H¡s--
Angiotensin converting enzyme Asp-Arg-Val-Tyr-lleu-His-Pro-P e-His-Leu
Asp-Arg-Val-Tyr-lleu-His-Pro-P e
Recipient of A-II Biological Activity
The present invention contemplates a novel stereoselective chemical synthesis of compounds such as of the general formula I:
Although the invention will be described and will be specifically referred to as it relates to these compounds and their processes, the principles of this invention are equally applicable to similar compounds and processes, and according to the same, it will be understood that the invention is not limited to such compounds and processes.
BACKGROUND AND PREVIOUS TECHNIQUE The antecedent is that of stereospecific synthetic organic chemistry, a voluminous and ever-expanding field, where it is a full-time occupation to keep informed of general trends, especially in areas related to human medical application. The applicant does not know of any prior art related to the specific matter described herein. A principal objective of the invention is to develop novel compounds, suitable as prototypes for renin inhibitors. It is a related main objective, to synthesize these novel compounds through novel chemical processes. It is a subsidiary objective to devise practical synthetic schemes for preparing novel compounds. It is an additional subsidiary objective to prepare the novel compounds as stereoisomerically pure as practical. It is an additional objective to characterize all the compounds thus prepared, as completely as possible. Other objects may be readily appreciated by practitioners skilled in the art, from the following description, appended claims, and accompanying drawings and figures.
DESCRIPTION OF THE INVENTION In a broad aspect, the invention relates to a chemical compound having the structure:
where n is from 0 to 3 inclusive, A are either either hydrogen atoms, or they are together a single carbon-nitrogen bond, R, is hydrogen, or hydrocarbylcarboxy, wherein the hydrocarbyl identity is selected from of the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms. Rj and R-? they are independently alkyl of 1 to -U carbon atoms. R. is alkyl of 1 to 6 carbon atoms or a substituent of an aliphatic character. R- is selected from aromatic groups. substituted aromatics, and heteroaromatics, cycloalkyl those substituted or insituted. cycloalkenes having from 3 to 8 carbon atoms. the substituents being selected from alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives. primary and secondary amides and alkyl derivatives. The alkyl derivatives of primary and secondary amides are, for example, primary and secondary carbamoylalkyl groups. Preferably n is 0. Aliphatic substitute substitutes are, for example, butyl, 2-morpholinoethyl, or 2-carbamoyl-2-methylpropyl. The alkoxy derivatives are, for example, alkoxyalkoxy groups such as 3-methoxypropyloxy. Both A taken together can form a single carbon-nitrogen bond. In one variation, Rj is preferably alkylcarboxy, and the alkyl group has from 1 to 6 carbon atoms. A preferred compound is tertiary butyl tertiary acid ester (1S ^ S ^ R ^ 'R.SS -SI ^' - butylcarbamoyl-J-1-hydroxy-butyl] -3-methyl-2-phenyl-pyrrolidin-1-carboxylic acid. Another preferred compound is pyrrolidine (1 'S, 2S, 3R, 3' R, 5S) -5 - [(3'-butylcarbamoyl) -l'-hydroxy-butyl] -3-methyl-2-phenolic. Rj is preferably aralkylcarboxy, and the aralkyl group has from 7 to 10 carbon atoms.A preferred compound is benzyl acid ester
(1S, 2S, 3R, 3'R, 5S) -5 - [(3'-butylcarbamoyl) -l'-hydroxy-butyl] -3-methyl-1-2-phenyl-pyrrole idin-1-carboxylic acid. Both A can be hydrogen, when R ^ is preferably alkylcarboxy and the aralkyl group has from 1 to 7 carbon atoms. A preferred compound is butyl amide of (2R, aS, 5S, 7R) -5- [[1,1-di-methylethyl) carboni-1] amino] -4-hydraxy-2,7-dimethyl-8-phenyl- octanaic Another preferred compound is (2R, 4S, 5S.7R) -5-amino-4-h? Drax? -2,7-dimethyl-8-phenyl-octanoic butyl acid amide. In another broad aspect, the present invention relates to processes for the preparation of a first chemical compound of the structure:
where n is 0 to 3 inclusive. A are either either hydrogen atoms, or they form a single carbon-nitrogen bond, R. is hydrogen, or hydrocarbon lcarboxi. wherein the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, Ro and R-j are independently alkyl of 1 to -I carbon atoms, R *. is alkyl of 1 to 6 carbon atoms or an aliphatic substituent such as, for example, butyl. 2-morpholipoethyl, or 2-carbamo? 1-2-met? I gave it. R ^ is selected from aromatic groups. substituted aromatics, and heteroaromatics, cycloalkyl substituted or unsubstituted. cycloalkenes having from 3 to 8 carbon atoms, the substituents being selected from alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives such as 3-ethoxypropyloxy, and alkyl derivatives of secondary primary amides. The processes include a step selected from the group consisting of: (a) hydrogenolysis of a second compound of the above formula, wherein both A together form a single carbon-nitrogen bond, and R, is alkylcarboxy, wherein the alkyl has from 1 to 6 carbon atoms, in the presence of PdCOH ^ / C; (b) hydrogeropolysis of a third compound of the above formula, wherein both A together form a single carbon-nitrogen bond, and R, is aralkylcarboxy, wherein the aralkyl has from 7 to 10 carbon atoms, in the presence of PdCPH C, and dialkyl dicarbonate, wherein both alkyl groups of the dicarbonate are identical and have from 1 to 6 carbon atoms; and (c) treatment of a fourth compound having the structure:
where n is 0 to 3 inclusive. R; is hydrocarbylcarboxy wherein the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms. j and R-s are independently alkyl of 1 to 4 carbon atoms, with RgNHAlMej, wherein R, is alkyl of 1 to 6 carbon atoms. Preferably n is O, in both formulas. A preferred process of claim 14 comprises the step of hydrogenolysis of the second compound. Another preferred compound comprises the step of hydrogenolysis of the third compound. A further preferred process comprises the step of treating the fourth compound, wherein in a preferred step, Rj is alkylcarboxy, the alkyl group having 1 to 6 carbon atoms. Alternatively, R can be aralkylcarboxy, the aralkyl having 7 to 10 carbon atoms. OR
BRIEF DESCRIPTION OF THE FIGURES AND ATTACHED SCHEMES Scheme 1 indicates a first synthetic route of the invention.
DESCRIPTION OF THE PREFERRED MODALITIES The chemical formulas of some compounds of the invention are illustrated hereinafter:
2a, R = E3oc; 2b, Cbz hydrophobic domain 2c, R = H 3b, R = H
The chemical formula of a first and a second compound of the invention is illustrated below:
The detailed steps of a synthetic route from mandelate of (S) -methyl 4 to the starting precursors, tertiary butyl ester of (2S, 3R) -3-methyl-5-oxo-2-phenyl-pyrrolidine-1-carboxylic acid 12, and (2S, 3R) -3-methyl-2-phenyl-3,4-dihydro-2H-pyrrole 14, are as follows:
i- 4, R = H 6 l? - 5, R = Bom, [aJ0 + 1 19 '(c- = 1 24) Ialp + 85 * (c = 1.55) 96: 4, diastereomeric proportion 27)
12, R = Boc, [a] D -4.6 ° (0 = 0.835), mp = 74-75 ° C 13, R = H, [a] D -27o0 (c = 1055), mp = 105-106 ° C
a) PhCH2OCH2Cl (Bom-Cl), i-Pr2EtN, CH2C12, 100 hours, 83 percent; b) i, DIBAL-H, toluene, -78 ° C, 3.5 hours; ii, MeOH, -78 ° C, 30 minutes; iii, methyltriphenylphosphoranylidene acetate, room temperature, 20 minutes, 75 percent trans, 6 percent cis; c) MeaCu ia .3TMSC1, THF, -78 ° C, 2H; d) TMSBr, Ch2Cl2, -23 ° C to room temperature, 72 percent for steps (c) and (d); e) i, 0.5N NaOH, MeOH, 0 ° C to room temperature, 2 hours; ii, 1 N HCl; iii CH2N2Et20, EtOAc, 0 ° C, 98 percent; f) (PhO) 2P (0) N3 DEAD, PPh3, THf, 0 ° C to room temperature, 16 hours, 89 percent;
g) 1,3-propanediol, i-Pr2EtN, MeOH, room temperature, 18 hours, 86 percent; h) (Boc) 20, i-Pr2EtN, DMPA, CHr, Cl2, room temperature, 24 hours, 99 percent; i) DIBAL-H, toluene, -78 ° C, 1 hour; ii, MeOH, -78 ° C, 20 minutes, 77 percent; j) PPh3, toluene, 16 hours.
This route starts from methyl mandelate 4, where the hydroxyl is protected by forming a (benzyloxy ethyl) acetal of Brom 5 with a yield of 83 percent. The carbon chain is then extended to give the homolog of phenyl trans-2-butenoic acid 6 by the effective insertion of a trans double bond, with a yield of 75 percent, with 6 percent of the cis-6 isomer being methylated then to give the unpurified 7, as a 94: 6 mixture of the diastereoisomers, including 5 percent of the deconjugated product, and a crude yield of about 96 percent. Crude 7 is cyclized to lactone 8, phenylmethyldihydrofuranone, in a yield of 72 percent (from 6). The 8 was converted to the equivalent hydroxymethyl ester 9 by hydrolysis and methylation in 98 percent yield. The 9 was converted to the equivalent azide ester 10 with a yield of 89 percent, as a diastereoisomeric mixture of 96: 4. The 10 in one route is cyclized to lactam 11. methyl pyrrolidinone with an 86 percent yield, followed by protection of the amino hydrogen with 1-carboxybutyl ester to give 12 with a 99 percent yield. In an alternative route, the 10 is converted to the equivalent aldehyde of azide 13 with a yield of 77 percent, and then cyclized to imine 14, methyl-f-enyl-dihydro-H-pyrrole. The detailed steps of a subsequent synthetic route, starting from 12 to the butyl acid amide (2R.4S, 5S.7R) -5- [[1,1-dimethyl ethoxy) carbonyl] amino] are illustrated below. -4-hydroxy-2,7-dimet i-8-phenyloctanoic acid 3a.
p.f. 143-14J "c: 2a. [A] 0-79.9 ° (c = 1-0.5) 3a.la] D-17.r (c = 1.47) p.f.83-84 ° C
a) i, D1BAL-H, toluene, -78 ° C. 4 hours; ii. MeOH ,. -78 ° C. 30 minutes, 72 percent; b) CSA, MeOH, room temperature. 1 hour, 100 percent; c) 2- (trimethylsilyloxy) furan, BF3.Et, 0; CH-, C12, -78 ° C. 1 hour, treoreritro = 6: 1, 98 percent; d) 10 percent Pd-C, H-¿(1 atm), EtOAc. room temperature. 1 hour, 93 percent; e) i, (TMS) 2NLi, THF, -78CC, 40 minutes; ii. MeJ, -78 ° C, 90 minutes, -50 ° C, 1 hour; iii, AcOH-THF, 67 percent; f) BuNHAlMe, CHjClj, room temperature, 7 hours, 76 percent; g) 20 percent Pd (0H) 2; H2 (3.9 Kg / cm2), EtOH / EtOAc (2: 3). room temperature, 48 hours, 73 percent.
This route begins with the protected lactam 12. whose amido-carbonyl is effectively reduced in hydroxyl to hemiaminal 15a, as a mixture of anomers and rotamers with a yield of 72 percent. This is then methylated to give the 16th, as a mixture of four isomers, with a 100 percent yield. This compound is then treated by effectively displacing / replacing methoxy, with the substituted furan, to form an unsaturated lactone ring, to give 17a, with a 98 percent yield, of an isomeric ratio of threo: erythro of 6: 1 . The pure erythro 17a is crystallized as a mixture of rotamers. The 17a is hydrogenated by saturating the furan / lactone double bond to yield 93 percent of the 18a as a mixture of two rotamers. The saturated lactone ring of lßa is methylated, and 67 percent of the desired monomethyl 19a, and 15 percent of the dimethyl lactone are obtained. The 19th crystalline is analyzed by X-rays. The lactone ring is opened by the formation of the butyl amide to give the 2a with a yield of 76 percent. The pyrrolidone ring is then hydrogenolyzed to give 3a with a 73 percent yield.
The detailed steps of a subsequent synthetic route starting from 14 to 3, are illustrated below:
17b, [a] 0-168β (c = 1.02) i-18b, R = H, [a] 0 -52 ° (c = 0.86) p. f. 157-158 ° C * - * 19b. R = Me, [a] or .32 ° (c = 0.71)
2b, [a] D-80 ° (c = 0 * 99) 3a, [a] 0 -17.1 ° (c = 1.47) p. f 33-84ß C
a) i, PhCH2C (0) Cl, toluene, -78 ° C, 1 hour; ii, 2N HCl, -78 ° C to room temperature; 67 percent; b) CSA MeOH, room temperature, 1 hour, 89 percent; c) 2- (trimethylsilyloxy) furan, BF3.Et20; CH2C12, -78 ° C, 2 hours, treo: erythro = 5: 1, 78 percent;
d) 5 percent Pd-C, H2 (1 atm), benzene, room temperature, 30 minutes, 90 percent; e) i, (TMS) 2NLi, MeJ, THF, -78 ° C, 40 minutes; ii, saturated NaHCOj, 57 percent; f) BuNHAlMe2, CH2C12, room temperature, 2 hours, 52 percent; g) (Boc) 20, 20 percent Pd (0H) 2; H2; 4.2 Kg / cm?), EtOH / EtOAc (2: 3), room temperature, 72 hours, 46 percent.
This route is generally analogous to Scheme 2, starting with the cyclized imine 14 and protecting the imino nitrogen with a carboxybenzyl group .. rather than with a carboxybutyl group, to give 77 percent (from 13) of 15b as a mixture of anomers and rotamers. Subsequently, the steps are very similar, giving 89 percent of 16b, 78 percent of 17b, with an isomeric ratio of thre: erythro of 5: 1. Pure erythro 17b crystallizes as a mixture of rotamers. The crystalline 17b is analyzed by X-rays. The continuation gives 90 percent of the lßb, 56 percent of the 19b, 52 percent of the 2b, which is converted directly into the 3a, with a yield of 46 percent. EXAMPLES (S) - (Benzyloxy-methoxy) -phenylacetic acid methyl ester 5: To the solution of 6.5 grams (39.9 millimoles) of (S) -methyl in 90 milliliters of anhydrous tetrahydrofuran, 12.0 milliliters (69 millimoles) were successively added. ) of i-Pr2EtN, 8.2 milliliters (59.5 millimoles) of benzylchloromethyl ether, and 1.46 grams (3.95 millimoles) of Bu4N-i-. Then the reaction was stirred at room temperature overnight. 4.0 milliliters (23.0 millimoles) of i-Pr2EtN, and 2.7 milliliters (19.65 millimoles) of benzylchloromethyl ether were added. The reaction was stirred at room temperature for 40 hours, and 2.0 milliliters (11.5 millimoles) of i-Pr2EtN and 1.35 milliliters (9.8 millimoles) of the alkylating agent were added, and they were stirred at room temperature for another 44 hours. Methanol (1.5 milliliters) was added to consume the excess alkylating agent. After 30 minutes, the reaction was divided between 150 milliliters of water and 250 milliliters of EtOAc. The organic layer was washed with 0.5 N HCl, pH 7 phosphate buffer, then with brine, dried over MgSO 4, and concentrated. Purification of the residue by column chromatography (silica gel, 15 percent EtOAc / hexanes), gave 9.25 grams (83 percent) of ester 5 as a colorless syrup. [] D + 119 ° (c 1.24, CHCl 3); IR (thin film) 1730, 1445, 1260, 1200, 1160, 1040 cm "1; XH NMR (CDCI3, 300 MHz) d 7.50-7.27 (m, 10H, ArH), 5.25 (s, ÍH, PhCHO), 4.92 and 4.84 (AB quartet, 2H, J = 7Hz, OCH20), 4.69 and 4.59 (AB quartet, 2H, J = 12Hz, 0CH2Ph), 3.7 (s, 3H, OCH3), 13C (CDCI3, 75 MHz) d 171.1, 137.3, 135.9, 128.7, 128.6, 128.3, 127.8, 127.7, 127.3, 93.2, 70.0, 52.2, exact mass calculated for Cl7Hl904287.12833a, found 287.130.
(2E, 4R) -4- (Benzyloxy-methoxy) -4-phenyl-but-2-enoic acid 6-methyl ester: To a cooled solution (-78 ° C) of 8.5 grams (29.7 mmol) of the 5-ester in 100 milliliters of anhydrous toluene, was added a cold solution (-78 ° C) of DIBAL-H (33 milliliters, 1M in toluene, 33 mmol) in anhydrous toluene (20 milliliters) by means of a drip tube for a period of time. 30 minutes. The reaction was stirred at -78 ° C for another 3 hours. Methanol was added dropwise (3.6 milliliters, 89 mmol), and the resulting solution was stirred at -78 ° C for 30 minutes. The cooling bath was removed, and the reaction was allowed to warm to room temperature. Methyltriphenylphosphoranylidene acetate (15.0 grams, 44.8 mmol) was added to the reaction mixture, and stirred for 20 minutes. The aluminum complex was filtered and the solvent was evaporated. Ether was added, and insoluble PPh30 and excess reagent were filtered. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, 12 percent EtOAc / hexanes), to give 0.7 grams (6 percent for the two steps) of the cis ester. and 8.5 grams (75 percent for the two steps) of the trans 6 ester as a colorless syrup; [aJ0 + 85 ° (c 1.55, CHCl3); IR (thin film) 1710, 1645, 1440, 1290, 1260, 1010 cm "1;
lH NMR (CDClj, 300 MHz) d 7.39-7.27 (m, 10H, ArH), 7.0 (dd, IH, J = 5Hz, 16Hz, CHCH =), 6.13 (dd, IH, J = 2Hz, = CHC02Me), 4.81 and 4.74 (AB quartet, 2H, J = 7Hz, OCH20), 4.64 and 4.56 (AB quartet, 2H, J = 12Hz, OCH2Ph), 3.74 (s, 3H, OCH3); 13C (CDCl3, 75 MHz) or 166.6, 147.1, 138.4, 138.3, 128.6, 128.3, 128.2, 127.9, 127.7, 127.3, 120.4, 91.9, 76.3, 69.7, 51.5; exact mass calculated for C1 () H210 (313.143984, found 313.1433.
Acid methyl ester (3R, 4R) -4- (benzyloxy-methoxy) -3-methyl-4-phenyl-butyric acid (7): methyl (116.6 mL, 1.4 M in ether, 163.2 mmol) lithium was added to the suspension at -78 ° C of 15.54 grams (81.6 millimoles) of Cul in 400 milliliters of anhydrous tetrahydrofuran. The mixture was heated to 0 ° C, maintained at that temperature for 10 minutes, and then cooled again to -78 ° C. This mixture was treated with TMS-C1 (31 milliliters, 244.8 millimoles) followed by an ester solution. unsaturated 6 (8.49 grams, 27.2 mmol) in anhydrous tetrahydrofuran (40 milliliters). The reaction was stirred at -78 ° C for 2 hours, and then quenched with 15 milliliters of 1:15 percent NH soluciónjOH aqueous solution and saturated aqueous NH ^Cl solution. The cooling bath was removed, and the reaction was allowed to warm to room temperature. Then NH.lH at 10 percent aqueous (50 milliliters) and ether (300 milliliters) were added, and the resulting mixture was stirred until a homogeneous organic phase and a dark blue aqueous phase were obtained. The two layers were separated, the organic phase was washed with water, brine, dried over MgS0, and concentrated to give an inseparable mixture of 7 as a diastereomeric mixture of 94: 6, and the deconjugated product (5 percent by XH NMR). 1 H NMR (CDC 13, 300 MHz) d 7.39-7.23 (m, 10 H, Ar H), 4.68 and 4.46 (AB quartet, 2 H, J = 12 Hz, OCH 20), 4.67 and 4.58 (AB quartet, 2 H, J = 7 Hz , OCH2Ph), 4.42 (d, IH, J = 8Hz, PhCHO), 3.67 (s, 3H, OCH3), 2.73 (dd, IH, J = 5Hz, 15Hz, one of CH2C02CH3), 2.42 (m, IH, CHCH3 ), 2.24 (dd, ÍH, J = 9Hz, 15Hz, one of CH2C02CH3), 0.83 (d, 3H, J = 7Hz, CHCH3); mass spectrum m / e (M + 4 H).
(4R, 5R) -4-methyl-5-phenyl-dihydro-furan-2-one 8: To the cooled solution (-23 ° C) of the unpurified ester 7 of the previous reaction (8.55 grams, theoretical yield of 26.1 millimoles) in 260 milliliters of anhydrous CH2C12, 10.3 milliliters (78.3 millimoles) of TMS-Br were added, and the solution was allowed to gradually warm to room temperature overnight. The reaction was diluted with more CH2C12 (100 milliliters), washed with saturated aqueous NaHCO3 (2 x 50 milliliters), water, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, 24 percent EtOAc / hexanes), to give 3.45 grams (72 percent for the two steps) of 8 as a crystalline solid, m.p. 53-54 ° C; [a] 365 -4o (c 0.88, CHC13); IR (CHC13) 1780, 1280, 1150, 1005 cm "1; [H (CDCl3, 300 MHz); or 7.44-7.27 (m, 5H, ArH);
4. 95 (d, ÍH, J = 8Hz, PhCHO), 2.81 (dd, ÍH, = 7Hz, 17Hz, one of
CH2CO), 2.49 (m, 1H, CHCH3); 2.3 (dd, ÍH, J = 10Hz, 17Hz, one of
CH2CO), 1.21 (d, 3H, J6Hz, CHCH3) 13C (CDCl3, 75 MHz) d 176.0,
137. 8, 128.6, 125.8, 88.0, 39.7, 37.1, 16.3; exact mass calculated for C ^ H ^ Q., 177.091555, found 177.0909.
Acid methyl ester (3R, 4R) -4-hidraxi-3-methyl-4-phenyl-butyric 9: To the cooled solution (0 ° C) of 2.43 grams (13.8 mmol) of the lactone 8 in methanol (40 milliliters ), 41 milliliters of 0.5N aqueous NaOH was added. The reaction was warmed to room temperature, and stirred for 2 hours. The methanol was removed in vacuo, and the residue was diluted to 140 milliliters with water. The reaction mixture was cooled and the pH was adjusted to 4 using 1 N aqueous HCl. Solid NaCl was added, and the mixture was allowed to warm to room temperature. It was extracted with EtOAc (200 milliliters x 3). The combined organic layer was washed with brine, dried over gSOq, and concentrated. The residue was dissolved in EtOAc, and methyl with diazomethane in ether. Evaporation of the solvent provided 2.82 grams (98 percent) of the hydroxyl ester 9, which was used in the next step without further purification, IR (thin film) 3600-3260, 1740, 1725, 1460, 1170. 1020 cm "1; [H NMR (CDCl 3, 300 MHz) d 7.37-7.27 (m, 5H, ArH), 4.43 (d, 1H, J = 7Hz, PhCHOH), 3.66 (s, 3H, OCH3), 2.63 (dd, ÍH, J = 5Hz, 15Hz, one of CH2C02CH3), 2.38 (br, s, ÍH, OH), 2.36 (m, 1H, CHCH3), 2.26 (dd, ÍH, J = 8Hz, 15Hz, one of CH2C02CH3), 0.85 (d , 3H, J = 7Hz, CHCH3), mass spectrum m / e 209 (M * + H).
(3R, 4R) -4-Azido-3-methyl-4-phenylbutyral 10: methyl ester: Triphenyl silicate (5.33 grams, 20.3 mmol) was added to the 2.82 gram solution (13.56 mmol) of hydroxy ester 9 in 70 milliliters of anhydrous tetrahydrofuran, and cooled to 0 ° C. DEAD was added dropwise, followed by the dropwise addition of (PhO) P (0) N3. The reaction was allowed to warm gradually to room temperature overnight. The tetrahydrofuran was removed, and the residue was purified by column chromatography (silica gel, 12 percent EtOAc / hexanes), to give 2.8 grams (89 percent) of the azido ester 10 as a diastereomeric mixture of 96: 4 , [a] 0-164 ° (c, 1.27, CHCl3); IR (thin film) 2100, 1740, 1450, 1250, 1165 cm "1; 1 H NMR (CDCl3, 300 MHz) d 7.42-7.26 (m, 5H, ArH), 4.48 (d,
1H, J = 6Hz, PhCHN3), 3.65 (s, 3H, OCH3), 2.37 (m, 2H, CHCH3, one of CH2C02CH3), 2.09 (dd, ÍH, J = 10Hz, 17Hz, one of CH2C02CH3), 0.99 ( d, 3H, J = 6Hz, CHCH3); 13C (CDC13, 75 MHz) d 172.6, 137.9, 128.5, 128.1, 127.1, 10.2, 51.4, 37.9. 36.0, 15.6; exact mass calculated for C12H16N30223 .124252, found 234.125.
(4R, 5S) -4-methyl-5-phenyl-pyrrolidin-2-one 11: To the solution of 2.5 grams (10.73 mmol) of the azido ester 10 in methanol (55 milliliters) at room temperature was added. successively 14 milliliters (80.48 millimoles) of i-Pr2EtN and 5.39 milliliters (53.65 millimoles) of 1-propanedithiol, and stirred for 48 hours. The methanol was removed in vacuo, and the residue was diluted with EtOAc. It was washed with 0.5 N aqueous NaOH (80 milliliters x 2), water, brine, dried over MgSO, and concentrated, The residue was purified by column chromatography (silica gel, 25 percent EtOAc / hexanes initial epte, and then 20 percent acetone / CHClj), to give 1.62 grams (86 percent) of lactam 11 as a colorless solid, mp 105-106 ° C; [a] Q-27 ° (c, 1.055, CHCl3); IR (CHCl3) 3460, 1710, 1450, 1340 cm "1; H NMR (CDCl 3, 300 MHz) d 7.4-7.17 (m, 5H, ArH), 6.12 (br, s, ÍH, NH), 4.79 (d, ÍH, J = 8Hz, PhCHN), 2.86 (m, ÍH, CHCH3), 2.53 (dd, 1H, J = 8Hz, 17Hz, one of CH2C0), 2.13 (dd, ÍH, J = 8Hz, 17Hz, one of CHjCO ), 0.66 (d, 3H, J = 7Hz, CHCH3); l3C NMR (CDCI3, 75 MHz) d 178.1, 138.6, 128.4, 127.7, 126.5, 61.5, 37.6, 34.2, 16.2, exact mass calculated for C ^ H ^ NO 175.09972, found 175.10029.
(2S, 3R) -3-Methyl-5-oxo-2-pheny1-pyrrolidine-1-carboxylic tertiary butyl acid 12: To a solution of 1.37 grams (7.83 mmoles) of lactam 11 in anhydrous CH-Clj (32 milliliters) ), the solution of 3.76 grams (17.2 millimoles) of tertiary dibutyl dicarbonate in CH2C1 (5 milliliters), 3.4 milliliters (19.58 millimoles) of i-Pr2EtN, and 96 milligrams (0.78 millimoles) of DMAP was successively added, and stirred at room temperature for 24 hours. The colorless ipicialmepte reaction mixture became dark brown at the end of the reaction. The solvent was removed in vacuo, and the residue was purified by column chromatography (silica gel, 30 percent EtOAc / hexanes), to give 2.12 grams (99 percent) of compound 12 as a colorless solid, m.p. 74-75 ° C; [a] D ~ 4.6 ° (c 0.835, CHClj); IR (CHClj) 1780, 1740, 1720, 1460, 1340, 1150 cm "1; [H NMR (CDCI3, 300 MHz) d 7.38-7.10 (m, 5H.ArH), 5.10 (d, H, J = 8Hz PhCHN ), 2.75 (m, ÍH, CHCH3), 2.58 (dd, ÍH, J = 8Hz, 17Hz, one of CH2C0), 2.37 (dd, ÍH, J = 12Hz, 17Hz, one of CH2C0), 1.27 (s, 9H , C (CH3) 3), 0.69 (d, 3H, J = 7Hz, CHCH3), 13C CDCI3, 75 MHz), d 174.3, 149.3, 137.0, 128.3, 127.6, 126.2, 82.5, 65.5, 38.8, 30.8, 27.5 , 15.7, exact mass calculated for C12H21N03275.15213, found 275.15349.
Tertiary butyl ester of (2S, 3R, 5R, 5S) -5-hydroxy-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acid 15a: To a cooled solution (-78 ° C) of 1.1 grams (4 mmol) ) of compound 12 in 10 milliliters of anhydrous toluene, DIBAL-H (4.4 milliliters, 1M in toluene, 4.4 mmol) was added dropwise, and stirred for 4 hours. Methanol (1.5 milliliters) was added, and the reaction mixture was stirred at -78 ° C for 30 minutes. The reaction mixture was warmed to room temperature, and 50 milliliters of ether and one drop of water were added. The aluminum complex was filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, 20 percent EtOAc / hexanes), to give 800 milligrams (72 percent) of the 15a as a mixture of nanoters and rotamers, and 240 milligrams of the starting material. l NMR (CDCl3, 300 MHz) d 7.33-7.2 (m, 16H, 4 x ArH), 7.02 (m, 4H, 4 x ArH), 5.94, 5.82 and 5.83-5.56 (m, 4H, 4 x CHOH), 4.89, 4.82, 4.74 (3 xd, 4H, J = 8Hz, PhCHN), 4.47, 3.74 3.52, and 3.21 (4 x br, s, 4H, 4 x OH, 2.98-2.86, and 2.56-2.40 (2 xm, 4H , 4 x CHCH3), 2.33-1.64 (m, 8Hz, 4 x CH2CH0H), 1.2 and 1.18 (2 xs, 36H, 4 x C (CH3) 3), 0.64 and 0.63 (2 xd, 12H J = 7Hz, 4 x CHr-CHj); mass spectrum m / e 260 (M + - OH).
Tertiary butyl ester of (2S, 3R, 5R, 5S) -5-methoxy-3-methyl-2-phenyl-pyrrolidine-l-carboxylic acid To the solution of 745 milligrams (2.69 mmol) of hemiaminal 15a, in 20 milliliters of methanol, 31 milligrams (0.133 millimoles) of CSA were added, and stirred at room temperature for 1 hour. Et3N (10 drops) was added, and the methanol was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 20 percent EtOAc / hexanes), to give 780 milligrams (100 percent) of 16a as an anomeric and rotamer mixture of four isomers, 1 H NMR (CDCl 3, 300 MHz) d 7.33-7.21 (m, 12H, 4 x ArH), 7.02 and 7.0 (2 xd, J = 8Hz 4 x Arh), 5.42 and 5.20 2 xd, 2H, J = 5Hz, 2 x CHOCH3), 5.26 ( br, s, 2H, 2 x CHOCH, 4.92 (br s, 2H, 2 x PhCHN), 4.88 and 4.78 (2 xd, 2H.J = 8Hz, 2 x PhCHN), 3.54, 3.48 and 3.43 (3 xs, 12H , 4 x OCH3), 2.93-1.63 (, 12H, 4 x CHCH3 and 4 x CH2CHOHCH3), 1.44 and 1.08 (2 xs, 36H, 4 x C (CH3) 3), 0.67, 0.59 and 0.57 (3 xd, 12H , J = 7Hz, 4 x CHCH3), mass spectrum m / e 290 (M + - H).
Tertiary butyl ester of (2S, 2'S, 3R, 5S) -3-methyl-5-oxo- (5'-oxo-2 ', 5'-dihydrofuran-2-yl) -2-phenyl-pyrrolidin-1-acid carboxylic 17a: To a cooled solution (-78 ° C) of 740 milligrams (2.54 millimoles) of 16a in 26 milliliters of anhydrous CH2C12, 0.64 milliliters (3.81 millimoles) of 2- (trimethylsiloxy) -furan and 0.19 milliliters were successively added. (1.52 millimoles) of BFj.EtjO, and the solution was stirred for 1 hour. The reaction mixture was quenched with 10 milliliters of 2N aqueous HCl, and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO, and concentrated to give 860 milligrams (98 percent) of 6: 1 (by H NMR) of threo: erythro isomers. The pure threo isomer 17a was obtained, as a mixture of rotamers, by fractional crystallization from 30 percent EtOAc / hexanes, m.p. 150-151 ° C; [a] 0-188 ° (c 1.115, CHClj): IR (CHClj) 1755, 1685, 1450, 1370, 1165, 1085 cm "1; [H NMR (CDCI3, 300 MHz) d 7.68 and 7.58 (2 x dd , 2H, J = 2Hz, 2 x 0CHCH =), 7.31-7.17 (m, 6H, 2 x ArH), 7.0 and 6.97 (2 xd, 4H, J = 7Hz, 2 x ArH), 6.24 and 6.08 (2 x dd, J = 2Hz, 6Hz, 2 x CH-CHCO), 5.55 (dt, ÍH, J = 2Hz, 4Hz, CHO), 5.40 (dt, ÍH, J = 2Hz, 3Hz, CHO), 4.88 and 4.71 (2 xd, 2H, J * = 8Hz, 2 x PhCHN), 4.66 (dt, ÍH, J = 3Hz, 4Hz, CHN), 4.62 (m, ÍH, CHN), 2.77 and 2.35 (2 xm, 2H, CHCH3), 2.05-1.83 (m, 2H, CH2CHN), 1.76 (dd, ÍH, J = 8Hz, 13Hz, one of CH2CHN), 1.60 (dd, ÍH, J = 7Hz, 13Hz, one of CH2CHN), 1.44 and 1.02 (2 xs, 18H, 2 x C (CH3) 3), 0.55 and 0.53 (2 xd, 6H, J = 7Hz, 2 x CHCH3); 13C (CDC13, 75 MHz) d 173.1, 154.8, 154.7, 141.2, 127.8, 126.7 , 126.3, 120.3, 84.7, 79.7, 66.7, 58.0, 36.1, 32.5, 27.5, 15.3, exact mass calculated for C ^ H- ^ NOQ 344.18619, found
344. 1867,
Tertiary butyl ester of (2S, 2 * S, 3R, 5'S) -3-methyl-5- (5'-oxo-tetrahydrofuran-2'-1) -2-pheny1-pyrrolidine-1-carboxylic acid ester: 250 milligrams solution (0.73 millimoles) of the 17th in 3 milliliters of EtOAc, 30 milligrams of 10 percent Pd / C were added, and the mixture was stirred under an atmosphere of Hj for 1 hour. The catalyst was filtered through a pad of celite, and the solvent was evaporated to give 230 milligrams (93 percent) of the 18a as a mixture of two rotamers, m.p. 123-125 ° C; [a] 0-49.6 ° (1.015, CHC13); IR (CHCl3) 1760, 1675, 1400, 1350, 1150 cm "1; 1" H PMN (CDClj, 300 MHz), d 7.31 and 7.21 (m, 6H, 2 x ArH), 7.0 (d, 4H, J = 8Hz, 2 x ArH), 4.80 (dt, 2H, J = 3Hz 7Hz, 2 x CHO), 4.91 and 4.76 (2 xd, 2H, J = 8Hz, 2 x PhCHN), 4.53 (dd, ÍH, J = 3Hz , 7Hz, CHN), 4.41 (t, ÍH, J = 7Hz, CHN), 2.86 (mHH, CHCHj), 2.68-2.22 (m, 4H, CH2, CH2CO), 1.96-1.90 (m, 2H, CH2CHN) , 2.86-1.79 (m, 7H, CHCH3, CHjCHjCO, CH2CHN), 1.42 and 1.05 (2 xs, 18H, 2 x C (CH3) 3), 0.58 and 0.56 (2 xd, 6H, J = 7Hz, 2 x CHCH3 ); 13 C (CDCl 3, 75 MHz) d 177.0, 155.3, 141.5, 127.7, 126.5, 126.2, 82.4, 79.4, 67.0, 58.7, 35.9, 33.4, 28.3, 27.5, 24.6, 15.4; exact mass calculated for C ^ H ^ 0 ,. 346.20184, found 346.20230.
Tertiary butyl ester of (2S, 2, S, 3R, 4'R, 5S) -3-methyl-5- (4'-methyl-5 '-oxo-tetrahydrofuran-2-yl) -2-phenyl-pyrrolidine -1-carboxylic acid 19a: To a cooled solution (-78 ° C) of (TMS) 2NLi (0.27 milliliters, 1M in tetrahydrofuran, 0.27 millimoles), the solution of 18a (85 milligrams, 0.25 millimoles) in 1 milliliter was added. of anhydrous tetrahydrofuran for a period of 3 minutes by cannula, and the solution was stirred for 40 minutes. Mel (0.16 milliliters, 2.5 mmol) was added and the solution was stirred at -78 ° C for 90 minutes, after which the reaction mixture was warmed to -50 ° C and stirred for another hour. The reaction mixture was quenched with a solution of
AcOH (0.15 milliliters) in 0.4 milliliters of anhydrous tetrahydrofuran, and allowed to warm to room temperature, then diluted with EtOAc, washed with water, brine, dried over MgSOj. , and concentrated. Purification of the residue by column chromatography (silica gel, 25 percent EtOAc / hexanes), provided 14 milligrams (15 percent) of the dimethylated lactone, and 59 milligrams (67 percent) of the monomethylated product 19a as a mixture of rotamers, mp 143-144 ° C; [a] 0-31.7 ° (c 0.85, CHClj); IR (CHCl3) 1750, 1680, 1440, 1355, 1150, 1000 cm "1; 1 H NMR (CDCl 3, 300 MHz) d 7.31-7.18 (m, 6H, 2 x ArH), 7.0 and 6.98 (2 xd, 4H, J = 7Hz, 2 x ArH), 4.91 and 4.73 (2 xd, 2H, J = 8Hz, 1 x PhCHN), 4.65 (dt, ÍH, J = 4Hz, 7Hz, CHO), 4.59 (dt, ÍH, J = * • 4Hz, 8Hz, CHO), 4.5 (dd, ÍH, J = 4Hz, 8Hz, CHN), 4.32 (t, ÍH, J = 8Hz, CHN), 2.94-2.62 (m, 5H, 2 x CHCH3CO, one of OCHCH2CHCH3), 2.62-2.29 (m, ÍH, one of 0CHCH2), 2.03-1.81 (m, 5H, 3 x one of CH2CHN, 2 x one of 0CHCH2), 1.70 (dd, ÍH, J = 6Hz, 13Hz, one of CH2N), 1.31 and 1.27 (2 xd, 6H, J = 7Hz, CHCH3CO), 1.39 and 1.03 (2 xs, 18H, 2 x C (CH3) 3), 0.54 and 0.57 (2 xd, 6H, J = 7Hz, 2 x CHCH3); 13C (CDCI3, 75 MHz) d 180.2, 155.6, 141.7, 128.0, 127.8, 126.6, 126.4, 80.8, 79.6, 67.2, 59.3, 35.9, 35.1, 34.2, 33.7, 33.3, 32.7, 28.0 , 27.6, 16.0, 15.5, exact mass calculated for 360.2175, found 360.2159.
Tertiary butyl ester of acid (1 * S, 2S, 3R, 3'R, 5S) -5- (3'-butylcarbamoyl-1'-hydroxy-butyl) -3-methyl-2-phenyl-pyrrolidin-1- carboxylic acid 2a: To the solution of 56 milligrams (0.156 millimoles) of 19a in 0.9 milliliters of anhydrous CH2C12, BuNHAlMe2 (0.28 milliliters, 0.67M in CH2C12, 0.23 millimoles) was added, and it was stirred at room temperature for 7 hours. The reaction mixture was cooled to 0 ° C, quenched with 2 milliliters of IN aqueous HCl, then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. column chromatography (silica gel, 10 percent acetone / CHClj), provided 51 milligrams (76 percent) of amide 2a as a syrup. [a) 0-79.9 ° (c, 1015 CHClj); IR (CHClj) 3480, 3500-3300, 1665, 1465, 1415, 1155 cm "1; 1 H NMR (CDCl 3, 300 MHz) d 7.30-7.19 (m, 3H, ArH), 6.98 (d, 2H, J = 7Hz , ArH), 6.0 (br, t, ÍH, J = 5Hz, NH), 4.78 (d, ÍH, J = 6Hz, OH), 4.71 (d, ÍH, J = 8Hz, PhCHN), 4.12 (t, ÍH , J = 8Hz, CHN), 3.50 (m, ÍH, CHOH), 3.35-3.15 (m, 2H, CHjNH), 2.74-2.49 (m, 2H, CHCH3), CHCH3CO), 1.94-1.70 (m, 3H) , 1.54-1.21 (m, 5H), 1.17 (d, 3H, J = 7Hz, CHCH3CO), 1.06 (s, 9H, C (CH3) 3), 0.93 (t, 3H, J = 7Hz, CH2CH3), 0.55 (d, 3H, J = 7Hz, CHCH3); 13C NMR (CDCI3, 75 MHz) d 176.1, 158.0, 141.0, 127.8, 126.6, 80.3, 74.5, 63.4, 40.9, 38.9, 37.1, 32.9, 31.7, 27.7, 20.0 , 18.5, 15.0, 13.7, mass spectrum m / e 433 (M * + H).
Butyl amide of (2R, S, 5S, 7R) -5- [[1, 1-dimethylethoxy) carbonyl-lamino] -4-hydroxy-2,7-dimetyl 1-8-phenyl-1-octanoic acid 3a: 40 milligrams solution (0.93 millimoles) of amide 2a in 1 milliliter of 40 percent EtOH / EtOAc, added 10 milligrams of "Pearlmen" catalyst (20 percent Pd (0H) 2 / c), and the The suspension was stirred under a pressure of 3.9 kg / cm2 H2 for 2 days. The catalyst was filtered and the solvent was evaporated. Purification of the residue using PTLC (10 percent acetopa / CHClj) yielded 4 milligrams of starting material and 29 milligrams (73 percent) of 3, p.f. 83-84 ° C; [a] Q-17.1 ° (c, 1.47 CHC13), IR (CHClj); 3460, 3400-3300, 1710, 1660, 1500, 1370, 1170 cm "1; * H NMR (CDClj, 300 MHz) d 7.29-7.15 (m, 5H, ArH), 5.82 (br s, CH2NH), 4.75 ( d, ÍH, J = 8Hz, NHBoc), 3.72-3.61 (m, 2H, CHOH, CHNHBoc), 3.33-3.17 (m, 2H, CH2N), 2.86 (dd, ÍH, J = 5Hz, one of PhCH2), 2.55 (m, ÍH, CHCH3CO), 2.26 (dd, ÍH, J = 9Hz, 13Hz, one of PhCH2), 1.80 (m, ÍH, CHCH3), 1.68 (t, 2H, J = 6Hz), 1.55-1.23 ( m, 6H), 1.47 (s, 9H, C (CH3) 3), 1.20 (d, 3H, J = 7Hz, CHCH3CO), 0.93 (t, 3H, J = 7Hz CH2CH3), 0.87 (d, 3H, J = 7Hz, CHCH3); 13C (CDCI3, 75 MHz) d 176.8, 156.4, 141.1, 129.1, 127.9, 125.6, 79.1, 70.1, 52.1, 42.6, 40.0, 39.1, 38.4, 37.6, 31.9, 31.6, 28.3, 19.9, 19.8, 17.0, 13.6, mass spectrum m / e 435 (M + + H).
Aldehyde (3R, 4S) -4-azido-3-methyl-4-phenyl-butyl 13: To a cooled solution (-78 ° C) of 820 grams (3.52 millimoles) of compound 10 in 35 milliliters of anhydrous toluene. DIBAL-H (3.9 milliliters, 1M in toluene, 3.9 mmol) was added by drip via cannula for a period of 15 minutes, and was stirred for another 45 minutes. Methanol (0.43 milliliters, 10.6 millimoles) was added, and the reaction mixture was stirred at -78 ° C for 20 minutes. The reaction mixture was allowed to warm to room temperature, and ether and a drop of water were added. The aluminum complex was filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, 1 percent Et3N, 14 percent EtOAc, 85 percent hexanes), to give 550 milligrams (77 percent) of 13, [] D-205 ° C (c, 1.33, CHCl3); IR (thin film) 2100, 1730, 1450, 1245 cm "1; XH NMR (CDC13, 300 MHz) 9.6 9.66 (s, HH, CHO), 7.4-7.26 (m, 5H, ArH), 4.46 (d, HH) , J = 7Hz, PhCHN3), 2.48 (m, 2H, CHCH3, one of CH2CH0), 2.22 (dd, ÍH, J = 9Hz, 18Hz, one of CH2CHO), 1.02 (d, 3H, J = 7Hz, CHCH3); 13C (CDCl3, 75 MHz) < 5 200.9, 137.7, 128.7, 128.3, 128.2, 70.4, 47.4, 33.9, 16.1; mass spectrum m / e 103 (M +).
(2S, 3R) -3-methyl-2-phenyl-4-dihydro-2H-pyrrole 1: Triphenyl phosphine (750 milligrams, 2.86 millimole) was added to the solution of 527 milligrams (2.6 millimole) of the aldehyde of azido 13, in 36 milliliters of anhydrous toluene, and stirred for 16 hours when the reaction was judged to be complete by examination. The above was used in the next step.
Benzyl ester of (2S, 3R, 5R, 5S) -5-hydroxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid 15b: To the above solution of the imine in toluene at -78 ° C, it is added benzyl chloroformate (0.37 milliliters, 2.6 mmol), and stirred for 1 hour. The reaction was quenched by the addition of 2N aqueous HCl, and allowed to warm to room temperature. The reaction mixture was diluted with EtOAc, washed with unsaturated brine, and brine, dried over MgSO4. , and concentrated. The residue was purified by column chromatography (silica gel, 1 percent EtjN, 29 percent EtOAc, 70 percent hexanes), to give 541 milligrams (67 percent for the two steps) of hemiaminal 15a as a anomeric and rotameric mixture, H NMR (CDC13, 300 MHz) d 7.4-7.16 (m, 18H, 2 x ArH), 7.37-7.02 (m, 18H, 2 x ArH), 6.9-6.87 (m, 2H, 2 x ArH), 6.80 (d, 2H, J = 7Hz, 2 x ArH), 5.86 and 5.77 (2 xd, 2H, J = 6Hz, 5Hz, 2 x CHOH), 5.68 (t, 2H, J = 7Hz, 2 x CHOH), 5.21 and 5.12; 5.08 and 4.98 (2 x AB quartet, 4H, J = 13Hz, 2 x C02CH2Ph), 5.22 and 5.11; 5.07 and 4.93 (2 x AB quartet, 4 H, J = 13 Hz, 2 x C02CH2Ph), 4.98 and 4.96 (2 xd, 2H, J = 9Hz, 2 x PhCHN), 4.95 and 4.88 (2 xd, 2H, J = 8Hz , PhCHN), 4.38, 4.0, 3.52 and 3.26 (4 x br, s, 4H, 4 x OH), 2.96 and 2.51 (2 xm, 4H, CHCH3), 2.30, 1.73 and 1.99-1.75 (3 xm, 8H, 4 x CH2CH0H), 0.65, 0.64 and 0.63 (3 xd, 12H, J = 7Hz, U x CHCHj); mass spectrum (m / e) 310 (M * - H).
Benzyl ester of (2S, 3R, 5R, 5S) -5-methaxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid 16b: To the solution of 540 milligrams (1.74 millimoles) of hemiaminal 15b, in 9 milliliters of methanol, 18 milligrams (0.078 millimoles) of CSA were added, and stirred at room temperature for 1 hour. Et3N (10 drops) was added, and the methanol was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 20 percent EtOAc / hexanes), to give 502 milligrams (89 percent) of 16b as a mixture of anomers and rotamers, [H NMR (CDClj, 300 MHz) d 7.37-6.98 (m, 36H, 4 x ArH), 6.82 and 6.6 (2 xd, 4H, J = 7Hz, 4 x ArH), 5.46 and 5.30 (2 xd, 2H, J = 5Hz, CH0CH3), 5.34 ( br, s, 2H, 2 x CHOCH3), 5.18 and 5.08; 5.02 and 4.82 (2 x AB quartet, 8H, J = 13Hz, 4 x C02CH2Ph), 4.96 and 4.91 (2 xd, 4H, J = 7Hz, 4 x PhCHN), 3.56 (br, s, 3H, OCH3), 3.52 , 3.50 and 3.53 (3 xs, 9H, 3 x OCHj), 2.99-1.66 (m, 12H, 4 x CHCH3, 4 x CH2CHOCH3), 0.68 and 0.61 (2 xd, 12H, J = 7Hz, 4 x CHCH3); mass spectrum m / e 324 (M + -H).
Benzylic acid ester (2S, 2'S, 3R, 5S) -3-methyl-5-oxo-5'-oxo-2 ', 5'-dihydrofuran-2-yl) -2-phenyl-pyrrolidine-l-carboxylic acid 17b : To a cooled solution (-78 ° C) of 500 milligrams
(1.54 millimoles) of 16b in 15 milliliters of anhydrous CH2C12, 0.38 milliliters (2.31 millimoles) of 2- (trimethylsiloxy) -franus and 0.11 milliliters (0.92 millimoles) of BFj.EtjO were successively added, and the solution was stirred for 2 hours. The reaction mixture was quenched with 5 milliliters of 2N aqueous HCl, and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSOq, and concentrated to give 452 milligrams (78 percent) of 5: 1 (by H NMR) of threo: erythro isomers. The pure threo isomer 17b was obtained as a mixture of rotamers by fractional crystallization from EtOAc / hexanes, m.p. 157-158 ° C; [α] D-168 ° (c 1.02, CHClj); IR (thin film) 1750, 1690, 1390, 1330, 1010 cm "1; [H NMR (CDCI3, 300 MHz), d 7.67 (dd, 2H, J = 2Hz, 6Hz, 2 x 0CHCH =), 7.41-6.94 (m, 16H, 2 x ArH), 6.6 (d, 4H, J = 7Hz, 2 x ArH), 6.08 (dd, 2H, J = 2Hz, 2 x CH = CHC0), 5.48 (dt, 2H, J = 2Hz, 5Hz, 2 x CHO), 5.16 and 5.07, 4.89 and 4.75 (2 x AB quartet, 4H, J = 13Hz, 2 x C02CH2Ph), 4.93 and 4.84 (2 xd, 2H, J = 8Hz, 2 x PhCHN) , 4.71 (dd, 2H, J = 2Hz, 5Hz, 2 x CHN), 2.74 and 2.45 (2 xm, 2H, 2 x CHCH3), 1.92-1.61 (m, 4H, 2 x CH2CHN), 0.55 and 0.53 (2 xd, 6H, J = 7Hz, 2 x CHCH3); 13C (CDC12, 75 MHz) d 173.0, 154.4, 140.3, 135.7, 128.6, 128.3, 128.2, 128.0, 127.5, 127.2, 127.1, 127.0, 126.1, 120.8, 66.9 , 66.4, 58.6, 36.3, 32.2, 15.2, exact mass calculated for C ^ H- ^ NOg 378.170534, found 378.1681.
Benzyl ester of (2S, 2'S, 3R, 4S) -3-methyl-5- (5'-oxo-tetrahydrofuran-2'-yl) -2-phenyl-pyrrolidin-1-carboxylic acid lßb: To the solution of 210 milligrams (0.56 millimoles) of 17b in 4 milliliters of benzene, 20 milligrams of 5 percent Pt / C were added, and the mixture was stirred under an atmosphere of H2 for 1 hour. The catalyst was filtered through a pad of celite, and the solvent was evaporated to give 190 milligrams (90 percent) of a rotary mixture of 18b as a syrup, [oc] D-52 ° (0.86, CHCl3); IR (thin film) 1780, 1700, 1400, 1340, 1160 cm "1; [H NMR (CDCI3, 300 MHz) or 7.33-6.96 (m, 16H, 2 x ArH), 6.66 (d, 4H, J = 7Hz , 2 x ArH), 5.1 (AB quartet, 2H, J = 12Hz, C02ClH2Ph), 4.97 (d, ÍH, J = 8Hz, PhCHN), 4.90-4.68 (m, 5H, 2 x OCH, PhCHN, C02CH2Ph), 4.58 (m, ÍH, CHN), 4.48 (t, ÍH, J = 7Hz, CHN), 2.88-1.83 (m, 14H =, 0.58 and 0.57 (2 xd, 6H, J = 7Hz, CHCH3); 13C NMR ( CDCI3, 75 MHz) d 176.9, 156.0, 140.6, 135.8, 128.2, 128.0, 127.4, 127.3, 126.9, 126.2, 81.8, 66.9, 66.6, 59.3, 36.3, 32.9, 28.5, 24.7, 15.5, exact mass calculated for C ^ H ^ NO, 380.186184, found 380.1822.
Benzyl ester of the acid (2S, 2'S, 3R, 4'R, 5S) -3-methyl-5- (4'-eti1-5'-oxo-tetrahydrofuran-2'-yl) -2-pheny1rololidin- 1-carboxylic 19b: To a cooled solution (-78 ° C) of (TMS) 2NLi (0.24 milliliters, 1M in hexanes, 0.24 millimoles) in 0.24 milliliters of anhydrous tetrahydrofuran, Mel (0.14 milliliters, 2.19 millimoles) was added, followed by the solution of 18b (79 milligrams, 0.21 millimoles) in 1 milliliter of anhydrous tetrahydrofuran, and the solution was stirred for 40 minutes. The reaction mixture was quenched with a saturated aqueous solution of NaHCO, and allowed to warm to room temperature, then diluted with EtOAc, washed with water, brine, dried over MgSO 4, and concentrated. Purification of the residue by column chromatography (silica gel, 35 percent EtOAc / hexanes), provided 46 milligrams (56 percent) of the monomethylated product 19b as a mixture of rotamers, [JD-32 ° (c, 1.43, CHCl3); IR (thin film) 1755, 1675, 1440, 1390, 1225 cm "1; lH NMR (CDCI3, 300 MHz), d 7.39-6.95 (m, 16H, 2 x ArH), 6.65 (d, 4H, J = 7Hz , 2 x ArH), 5.07 and 4.82 (2 x AB quartet, 4H, J = 12Hz, 2 x C02CH2Ph), 4.97 and 4.87 (2 xd, 2H, J = 8Hz,, 2 x PhCHN), 4.71 and 4.62 (2 xm, 2H, 2 x CHO), 4.53 (dd, 1H, J = 5Hz, CHN), 4.4 (t, ÍH, J = 7Hz, CHN), 2.9-1.7 (m, 12H), 1.27 and 1.18 (2 xd , 6H J x CHCH3CO), 0.57 and 0.55 (2 xd, 6H, J = 7Hz, 2 x CHCH3), 13C NMR (CDCI3, 75 MHz) d 179.9, 156.1, 140.6, 135.8, 128.2, 128.0, 127.4, 126.8, 126.1, 80.0, 66.9, 66.6, 59.8, 36.1, 33.6, 33.5, 33.1, 15.9, 15.4, exact mass calculated for C25H28N04 394.201834, found 394.20260.
Benzyl ester of acid (1 'S, 2S, 3R, 3"R, 5S) -5- (3" -butylcarbamoyl) -1' -hydraxy-butyl) -3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid 2b: To the solution of 45 milligrams (0.11 millimoles) of 19b in 0.5 milliliters of anhydrous CH2C12, BuNHAlMe2 (0.33 milliliters, 0.67M in CH2C12, 0.22 millimoles) was added, and it was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C, and quenched with 2 milliliters of 1 N aqueous HCl, then diluted with EtOAc, washed with brine, dried over Na 2 SO 5, and concentrated. Purification of the residue by PTLC (10 percent acetone / CHCl3) yielded 22 milligrams (52 percent) of the amide 2b as a syrup, [a] -80.0 ° (c 0.99, CHC13); IR (thin film) 3500-3300, 1710, 1670, 1550, 1410, 1340 cm "1; H NMR (CDC1--, 300 MHz), d 7.4-6.96 (m, 8H, ArH), 6.63 (d, 2H , J = 7Hz, ArH), 5.9 (br, s, ÍH, NH), 4.85 (d, ÍH, J = 7Hz, PhCHN), 4.89 (AB quartet, 2H, J = 13Hz, C02CH2Ph), 4.63 (br, s, ÍH, OH), 4.17 (dt, 1H, J = 2Hz, 9Hz, CHN), 3.56 (dt, ÍH, J = 2Hz, 9Hz, CHOH), 3.36-3.17 (m, 2H, CH2NH), 2.75- 2.51 (m, 2H, CHCH3, CHCH3C0), 1.96-1.72 (m, 3H), 1.55-1.23 (m, 5H), 1.19 (d, 3H, J = 7Hz, CHCH3C0), 0.93 (t, 3H, J = 7Hz, CH ^ Hj), 0.57 (d, 3H, J = 7Hz, CHCHj), 13C (CDCI3, 75 MHz) or 176.0, 158.3, 140.2, 135.8, 128.1, 128.0, 127.4, 127.0, 126.9, 126.3, 74.3, 67.2, 66.2, 64.0, 40.6, 38.9, 37.1, 20.0, 18.4, 14.9, 13.6, exact mass calculated for C ^ H- ^ Oq 467.290983, found 467.2925.
Butyl amide of (2R, 4S, 5S, 7R) -5- [[1,1-di-ethylethoxy) carbonyl-amino] - -hydroxy-2,7-dimet i-8-pheny1-octanoic acid 3a: To the mixture of milligrams (0.023 millimoles) of amide 2b, and 28 milligrams (0.129 millimoles) of tertiary dibutyl dicarbopate in 0.5 milliliters of 40 milliliters of 40 percent MeOH / EtOAc, was added 15 milligrams of "Pearlman" catalyst (20 percent Pd / (0H) 2 / C), and the suspension was stirred under a pressure of 4.2 Kg / cm of H for 3 days. The catalyst was filtered and the solvent was evaporated. Purification of the residue using PTLC (10 percent acetone / CHCl3) gave 6.4 milligrams (46 percent) of the 3a identical to the sample obtained from the hydrogenolysis of amide 2a.
As will be appreciated by those skilled in the art, these details and preferred described processes may be subject to substantial variation, modification, change, alternation, or substitution, without affecting or modifying the function of the embodiments described. Although the embodiments of the invention have been described above, it is not limited thereto, and it will be appreciated to be seen by persons skilled in the art, that numerous modifications and variations form part of the present invention as long as they do not depart from the spirit, nature , and scope of the claimed and described invention.
Claims (9)
1. A process of preparing a first compound having the formula I: where n is from 0 to 3 inclusive, A are either both hydrogen atoms, or together are a single carbon-nitrogen bond, R. is hydrogen, or hydrocarbylcarboxy, where the identity of the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms, R2 and R- * are independently alkyl of 1 to 4 carbon atoms, Rf1 is alkyl of 1 to 6 carbon atoms, or a substituent of aliphatic character such as, for example, butyl. 2-morpholinoethyl, or 2-carbamoyl-2-methylpropyl. R5 is selected from aromatic, substituted aromatic, and heteroaromatic, substituted or unsubstituted cycloalkyls. cycloalkenes having from 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives such as 3-methoxypropyloxy, alkyl derivatives of primary and secondary amides, which comprises a step selected from the group consisting of; (a) hydrogenolysis of a second compound of the above formula, wherein both A together form a single carbon-nitrogen bond, and Rj is alkylcarboxy, wherein the alkyl has from 1 to 6 carbon atoms, in the presence of Pd (0H) 2 / C; (b) hydrogenolysis of a third compound of the above formula, wherein both A together form a single carbon-nitrogen bond, and R ^ is aralkylcarboxy, wherein the aralkyl has from 7 to 10 carbon atoms, in the presence of Pd (0H) 2 / C, and dialkyl dicarbonate, wherein both alkyl groups of the dicarbonate are identical and have from 1 to 6 carbon atoms; (c) treatment of a fourth compound that has the structure: where n is 0 3 inclusive. R, is hydrocarbylcarboxy wherein the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms. R and R- are independently alkyl of 1 to 4 carbon atoms, with RlNHAlMe2 wherein R ,, is alkyl of 1 to 6 carbon atoms.
2. The process of claim 1, wherein n is zero, in both formulas.
3. The process of claim 2. which comprises the step of hydrogenating the second compound.
4. The process of claim 1, which comprises the step of hydrogenating the third compound.
5. The process of claim 1, which comprises the step of treating the fourth compound.
6. The process of claim 5, wherein R is alkylcarboxy, the alkyl group having 1 to 6 carbon atoms. The process of claim 5, wherein Rj is aralkylcarboxy, the aralkyl having 7 to 10 carbon atoms. 8. A compound of the formula that has the structure: where it is 0 3 inclusive, R is hydrocarbylcarboxy, wherein the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms, Rn and R- ^ they are independently alkyl of 1 to 4 carbon atoms, and Rr. is selected from aromatic, substituted aromatic, and heteroaromatic groups, substituted or unsubstituted cycloalkyls, cycloalkenes having from 3 to 8 carbon Stomoe, with substitutes selected from alkyl, alkoxy of 3 to 10 carbon atoms, alkoxy derivatives , alkoxy of 3 to 10 carbon atoms such as 3-methoxypropyloxy, primary and secondary amides and alkyl derivatives, or a salt thereof. 9. A compound according to claim 8, having the formula: 10, A compoteto according to claim 8, having the formula: SUMMARY Reniña inhibitors are prepared prototypes that have the general structure: where n is 0 to 3 inclusive, A are either. both hydrogen atoms, or, are together a single carbon-nitrogen bond, R \ is hydrogen, or hydrocarbylcarboxy, wherein the identity of the hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms, or aralkyl of 7 to 10 carbon atoms. R2 and R3 are independently alkyl of 1 to 4 carbon atoms, R "is alkyl of 1 to 6 carbon atoms, or a substituent of aliphatic character such as, for example. butyl, 2-morpholinoethyl, or 2-carbamoyl-2-methylpropyl, R ^ is selected from aromatics, substituted aromatics, and heteroaromatics, cycloalkyl substituted or unsubstituted. cycloalkenes having from 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives such as 3-methoxypropyloxy, alkyl derivatives of primary and secondary amides, by a synthesis novel multi-step These compounds are valuable intermediates for the manufacture of pharmaceutical products such as renin inhibitors and HIV protease inhibitors. * * * * *
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