GB2431643A - Synthesis of aryl-octanoyl amide compounds - Google Patents
Synthesis of aryl-octanoyl amide compounds Download PDFInfo
- Publication number
- GB2431643A GB2431643A GB0521726A GB0521726A GB2431643A GB 2431643 A GB2431643 A GB 2431643A GB 0521726 A GB0521726 A GB 0521726A GB 0521726 A GB0521726 A GB 0521726A GB 2431643 A GB2431643 A GB 2431643A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- c16a1ky1
- methyl
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000015572 biosynthetic process Effects 0.000 title abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- -1 tartrate ester Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 8
- 239000011975 tartaric acid Substances 0.000 claims abstract description 8
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims 2
- LIXFRRDDPFCVOY-UHFFFAOYSA-N N-(3-amino-2,2-dimethyl-3-oxopropyl)-8-methylnonanamide Chemical compound CC(C)CCCCCCC(=O)NCC(C)(C)C(N)=O LIXFRRDDPFCVOY-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 abstract description 7
- 125000005843 halogen group Chemical group 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229960004601 aliskiren Drugs 0.000 abstract description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 2
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 abstract 1
- 229940095064 tartrate Drugs 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 150000001540 azides Chemical class 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000012038 nucleophile Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 150000002596 lactones Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000007142 ring opening reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229960001367 tartaric acid Drugs 0.000 description 6
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 229910001507 metal halide Inorganic materials 0.000 description 4
- 150000005309 metal halides Chemical class 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 229960001270 d- tartaric acid Drugs 0.000 description 3
- 238000011873 diastereoselective alkylation Methods 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical class CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 150000002009 diols Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical group COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- 101100181929 Caenorhabditis elegans lin-3 gene Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical class CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- PDXRQENMIVHKPI-UHFFFAOYSA-N cyclohexane-1,1-diol Chemical compound OC1(O)CCCCC1 PDXRQENMIVHKPI-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- IIXOVPGRABFCAI-UHFFFAOYSA-N cyclohexylmethanediol Chemical compound OC(O)C1CCCCC1 IIXOVPGRABFCAI-UHFFFAOYSA-N 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001421 myristyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000000913 palmityl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for the preparation of certain 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds of formula (A): <EMI ID=1.1 HE=30 WI=69 LX=715 LY=772 TI=CF> <PC>wherein R1 is halogen, haloalkyl, alkoxy-alkoxy, alkoxyalkyl; R2 is halogen, alkyl or alkoxy; R3 and R4 are branched C1-4alkyl; and R5 is H2N-C(O)-C1-6alkyl or substituents; or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid or a tartrate ester and following the reaction sequence set out in Scheme 1. Preferred compounds of formula (A) are aliskiren and salts thereof, particularly (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate. Intermediates prepared as part of this synthesis are also claimed.
Description
<p>Case PC/4-34584P1 Methods for the Preparation of Orcianic Compounds The
present invention provides methods for preparing certain 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-aminO-8-aryI-oCtanOYl amide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediates useful in the manufacture of the same.</p>
<p>More specifically, the 2(S) ,4(S) ,5(S) 7(S)-2,7dialkyl-4-hydroxy-5-amino-8-arYl-OCtaflOYl amide derivatives to which the methods of the present invention applies are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g. those disclosed in U.S. Patent No. 5,559,111.</p>
<p>Surprisingly, it has now been found that 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hYdrOXY-5-amiflO- 8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using tartaric acid as the starting material.</p>
<p>In particular, the present invention provides a method for the preparation of a compound of the formula (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-Ci6alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14a1ky1 or C1..4alkoxy; R3 and R4 are independently branched C36a1ky1; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C16aIkyl, C16aminoalkyl, C16alkylamino-C16alkYl, C16dialkylamino-Ci6alkYl, C1aIkanoylamino-C16aIkyl, HO(O)C-C1..6alkyl, C16alkyl-O-(O)C-Ci6alkYl, H2N-C(O)-C1alkyI, C1alkyI-HN-C(O)-C16alkyI or (C16alkyl)2N-C(O)-Ci6alkYl or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid and following reaction steps as outlined in Scheme 1.</p>
<p>Case PC/4-34584P1 Scheme 1: A method for preparing a compound of formula (A) starting from tartaric acid.</p>
<p>R R R R' R R' OH o ><o o><o HOJLOH RO4OR [1:3) HO)J\OH (la-c) ([Ia-c) (lila-c) (lVa-c) a: 2R, 3R; L-tartaric acid I1 d b: 2S, 3S; D-tartaric acid c: meso-tartaric acid o (A) R4 (X) (Va-d) a: 2S,4R,5R,7S b: 2S,4S,5S,7S C: 2S,4R,5S,7S d: 2S,4S,5R,7S Reaction conditions: a) e.g. (i) thionyichioride, R"OH, e.g. methanol; (ii) e.g. 2,2-dimethoxypropane, p-TsOH, MeOH (R and R' are methyl) [1,2,3]; b) e.g. NaBH4, MeOH [3] or LAH, THF [2]; C) e.g. (i) methansulfonyl chloride (MsCI), NEt3 (XOMs) [2]; (ii) LiCI, 50 C [3]; d) e.g. Iithiumdisopropylamide, isovalerianic acid esters (Z=0R6 in which R6 is methyl; R3 and R4 are i-propyl), THF.</p>
<p>[1] A.K. Gosh et.al Synthesis 2001, 1281; [2] E.A. Mash et.al Organic Synthesis Coil Vol VIII, p155- 161; [3] B.M. Kim et.aI Org. Letters 3(2001)2349-2351; [4] EP 0678503 A. Compounds of formula (Va-d), wherein R3 and R4 are as defined for formula (A); R and R' are independently hydrogen, C16alkyI or C610aryl; or R and R' combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; and Z is OR6 in which R6 is C120a1ky1, C312cycloalkyl, C312cycloalkyI-C16aIkyl, C610ary1 or C10aryl-C16alky1; or Z represents -NR7R8 in which R7 and R8 are independently C120a1kyl, C312cycloalkyl, C312cycloalkyI-C16a1ky1, C610ary1 or C610aryI-C1alkyI; are key intermediates in the methods of the present invention. Compounds of formula (Va-d) may be converted to compounds of formula (X) wherein R1, R2, R3 and R4 are as defined herein above by three different routes, Routes A, B and C, as outlined in Schemes 2, 3 and 4, respectively.</p>
<p>Subsequently, compounds of formula (A), or pharmaceutically acceptable salts thereof, may Case PC/4-34584P1 be obtained from compounds of formula (X) according to methods well known in the art, e.g using methods disclosed in U.S. Patent No. 5,559,111.</p>
<p>It should be understood that the stereo-configuration at carbons 2 and 7 in compounds of formula (Va-d) is the result of an asymmetric induction in the course of the diastereoselective alkylation reaction of compounds of formula (lVa-c) with a carboxylic acid derivative, e.g isovalerianic acid derivatives, which may also carry a suitable chiral ester or amide group Z like the Evans or Seebach auxilliary groups. Such diastereoselective alkylation reactions of a carboxylic acid derivative, in particular isovalerianic acid derivatives, have been reported with several I,4-dihalo alkyl compounds (e.g in EP 0678503 A).</p>
<p>Because of the possibilities for matched and mismatched reactant pairs in the transition states of the diastereoselective alkylation reaction it is understood that, if a chiral Z-auxilliary group in the carboxylic acid derivative is used, its respective stereochemistry essentially must fit with that of the tartaric acid derived compounds of formula (lVa-c), in such a combination that the desired (S)-configuration at carbons 2 and 7 in the resulting compounds of formula (Va-d) is obtained.</p>
<p>Scheme 2: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route A. a R4 b HO (Va-d) (VIa-d) (VIIa-d) aI R4 (VIIi a-d) e Case PC/4-34584P1 ::ii0R4::1R4 (X) (IXa-d) Reaction conditions: a) e.g. (I) NaOH; (ii) H2SO4ltoluene; 50 C; b) e.g. diisobutylaluminium hydride, THF; c) e.g. T1CI4 or Aid3 or other Lewis acid, (Xlc); d) e.g. (I) compound (Xlc), THF; (ii) hydrogenation; e) MsCl, NEt3 (R90 is methanesulfonate).</p>
<p>As illustrated in Scheme 2, compounds of formula (Va-d) wherein Z, R, R', R3 and R4 have meanings as defined herein above, may first be converted to compounds of (lXa-d) wherein R1, R2, R3 and R4 have meanings as defined herein above, and OR9 represents a leaving group such as halide, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate.</p>
<p>it should be noted that the stereochemistry at carbons 4 and 5 is maintained in compounds of formula (lXa-d) as inherited from the tartaric acid used as the starting material: (lXa): 2S,4R,5R,7S from L-tartaric acid; (lXb): 2S,4S,5S,7S from D-tartaric acid; (lXc): 2S,4R,5S,7S from meso-tartaric acid; (lXd): 2S,4S,5R,7S from meso- tartaric acid; Compounds of formula (lXa-d) may then be converted to compounds of formula (X) wherein R1, R2, R3 and R4 have meanings as defined herein above, and the transformation requires specific chemistry for each stereoisomer of formula (lXa-d). For example, a compound of formula (lXd) may be treated directly with a suitable nitrogen nucleophile, e.g a metal azide, such as NaN3, KN3 or LiN3, to give the required (2S,4S,5S,7S) configuration of a compound of formula (X). A compound of formula (lXb) may be treated with a metal halide, e.g lithium chloride, to give the 5-halo intermediate with (2S,4S,5R,7S) configuration, which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, gives the desired compound of formula (X). Alternatively, a compound of formula (lXb) may be subjected to alkaline treatment, e.g. with sodium hydroxide, which induces inversion of the 5S- stereocenter via lactone ring opening followed by intramolecular formation of an (4S,5R)-epoxide, which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, Case PC/4-34584P1 affords an (2S,4S,5S,7S) 5-azido-4-hydroxy intermediate, which will readily cyclize upon acidic treatment to give the desired (2S,4S,5S,7S) compound of formula (X). Similarly, a compound of formula (IXa) may be subjected to alkaline treatment, e.g with sodium hydroxide, that induces inversion of the 5R-stereocenter via lactone ring opening and intramolecular formation of an (4R,5S)-epoxide, which upon treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the configuration is inverted to give the (2S,4S,5S,7S) configurated hydroxy lactone of formula (VIlib) which may be converted to a compound of formula (lXb) and further transformed to compound (X) as described above. Alternatively, (IXa) may be treated with a metal halide, e.g lithium chloride, to give the 5S-halo intermediate, which upon alkaline treatment, e.g. with sodium hydroxide, generates an (2S,4S,5R,7S)-epoxide which may be treated with a suitable nitrogen nucleophile, e.g. a metal azide, to give an (2S,4S,5S,75) 5-azido-4-hydroxy intermediate, which will readily cyclize on acidic treatment to give a compound of formula (X). A compound of (lXc) may be subjected to alkaline treatment, e.g. with sodium hydroxide, that induces the inversion of the 5S-stereocenter via lactone ring opening and intramolecular formation of an (4R,5R)-epoxide, which upon treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the stereoconfiguration is inverted to give a (2S,4S,5R,7S) configurated hydroxy lactone of formula (VIlId) which is further transformed to a compound of formula (X) as described above.</p>
<p>Similarly, compounds of formula (Va-d) wherein Z, R, R', R3 and R4 have meanings as defined herein above, may be converted to compound of formula (lXa-d) wherein R1, R2, R3, R4 and OR9 have meanings as defined herein above, following the reaction sequence as outlined in Scheme 3, Route B. Compounds of formula (tXa-d) may then be transformed to a compound of formula (X) as described herein above for Route A. Case PC/4-34584P1 Scheme 3: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route B. R' a (Va-d) (XlIa-d) b,c 4? 0 R9O2R4 (lXa-d) Reaction conditions: a) a compound (XIc) (Scheme 2), THF; b) e.g. (I) hydrogenation; (ii) sulfuric acid; and C) e.g. MsCI, NEt3.</p>
<p>Finally, Scheme 4 illustrates Route C according to which the functionalization and stereochemistry at carbon 4 and 5 takes place before the aromatic fragment, characteristic to compounds of formulae (X) and (A), is introduce by addition of a compound of formula (Xlc). The key step in Route C is the selective monolactonization of compounds of formula (Va-c) wherein Z, R, R', R3 and R4 have meanings as defined herein above, to give compounds of formula (Xllla-d) which are subsequently converted to compounds of formula (XIVa-d) wherein Z, R3, R4 and OR9 have meanings as defined herein above. For Route C, the type of protecting group of the vicinal diol motive may be used advantageously, e.g. R is hydrogen and R' is aryl, to cleave that protecting moiety in a sequential way so that a half protected diol transient results. The further conversion compounds of formula (XIVa-d) to a compound of the formula (X) encompasses the introduction of the aromatic fragment according to methods known in the art, e.g. as described in EP 0678503 Al.</p>
<p>Case PC/4-34584P1 Scheme 4: Conversion of a compound of formula (Va-d) to a compound of formula (X), Route C. a, b H2 "R4 c (Va-d) (XIIIa-d) (XIVa-d) (X) (XV) Reaction conditions: a) e.g. NaOH; b) e.g. H2S04/toluene, 50 C; c) e.g. MsCI, NEt3.</p>
<p>Analogously as described herein above, the stereochemistry at carbon 4 and 5 is maintained in compounds of formula (XlVa-d) as inherited from the tartaric acid used as the starting material: (XIVa): 2S,4R,5R,7S from L-tartaric acid; (XlVb): 2S,4S,5S,7S from D-tartaric acid; (XlVc): 2S,4R,5S,7S from meso-tartaric acid; (XlVd): 2S,4S,5R,7S from meso-tartaric acid; Compounds of formula (XIVa-d) may then be converted to compounds of formula (XV) wherein Z, R3 and R4 have meanings as defined herein above, and the transformation requires specific chemistry for each stereoisomer of formula (XIVa-d). For example, a compound of formula (XIVd) may be treated directly with a suitable nitrogen nucleophile, e.g a metal azide, such as NaN3, KN3 or L1N3, to give the required (2S,4S,5S,7S) configuration of a compound of formula (XV). A compound of formula (XIVb) may be treated with a metal halide, e.g lithium chloride, to give the 5-halo intermediate with (2S,4S,5R,7S) configuration, Case PC/4-34584P1 which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, gives the desired compound of formula (XV). Alternatively, a compound of formula (XlVb) may be subjected to alkaline treatment, e.g. with sodium hydroxide, which induces inversion of the 5S-stereocenter via lactone ring opening followed by intramolecular formation of an (4S,5R)-epoxide, which upon substitution with a suitable nitrogen nucleophile, e.g. a metal azide, affords an (2S,4S,5S,7S) 5-azido-4-hydroxy intermediate, which will readily cyclize upon acidic treatment to give the desired (2S,4S,5S,7S) compound of formula (XV).</p>
<p>Similarly, a compound of formula (XIVa) may be subjected to alkaline treatment, e.g with sodium hydroxide, that induces inversion of the 5R-stereocenter via lactone ring opening and intramolecular formation of an (4R,5S)-epoxide, which upon treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the configuration is inverted to give the (2S,4S,5S,7S) configurated hydroxy lactone of formula (Xlllb) which may be converted to a compound of formula (XIVb) and further transformed to compound (XV) as described above. Alternatively, (XlVa) may be treated with a metal halide, e.g lithium chloride, to give the 5S-halo intermediate, which upon alkaline treatment, e.g. with sodium hydroxide, generates an (2S,4S,5R,7S)-epoxide which may be treated with a suitable nitrogen nucleophile, e.g. a metal azide, to give an (2S,4S,5S,7S) 5-azido-4-hydroxy intermediate, which will readily cyclize on acidic treatment to give a compound of formula (XV). A compound of (XlVc) may be subjected to alkaline treatment, e.g. with sodium hydroxide, that induces the inversion of the 5S-stereocenter via lactone ring opening and intramolecular formation of an (4R,5R)-epoxide, which upon treatment with an acid, preferably sulfuric acid, leads to the relactonization at carbon 4 in such a way, that the stereoconfiguration is inverted to give a (2S,4S,5R,7S) configurated hydroxy lactone of formula (Xllld) which is further transformed to a compound of formula (XV) as described above.</p>
<p>Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims, It should be understood, however, that the description, appended claims, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.</p>
<p>Case PC/4-34584P1 Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.</p>
<p>As an alkyl, R, R', R1 and R2 may be linear or branched and preferably comprise I to 6 C atoms, especially I or 4 C atoms. Examples are methyl, ethyl, n-and i-propyl, n-, i-and t-butyl, pentyl and hexyl.</p>
<p>As a halogenalkyl, R1 may be linear or branched and preferably comprise I to 4 C atoms, especially I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chioroethyl and 2,2,2-trifluoroethyl.</p>
<p>As an alkoxy, R1 and R2 may be linear or branched and preferably comprise I to 4 C atoms.</p>
<p>Examples are methoxy, ethoxy, n-and i-propyloxy, n-, i-and t-butyloxy, pentyloxy and hexyloxy.</p>
<p>As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises I to 4 C atoms. Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl 2ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.</p>
<p>As a C16alkoxy-C1..6alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5- ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.</p>
<p>In a preferred embodiment, R1 is methoxy-or ethoxy-C14alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula (A), wherein R1 is 3-methoxypropyloxy and R2 is methoxy.</p>
<p>Case PC/4-34584P1 As a branched alkyl, R3 and R4 preferably comprise 3 to 6 C atoms. Examples are i-propyl, i-and t-butyl, and branched isomers of pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula (A) are in each case i-propyl.</p>
<p>As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.</p>
<p>As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise I to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, I-and t-butyl are preferred.</p>
<p>As a C16hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3-or 4-hydroxybutyl, hydroxypentyl and hydroxyhexyl.</p>
<p>As a C16alkoxy-C16a1ky1, R5 may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.</p>
<p>As a C16alkanoyloxy-C16alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.</p>
<p>As a C16aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms.</p>
<p>Some examples are 2-aminoethyl, 2-or 3-am inopropyl and 2-, 3-or 4-aminobutyl.</p>
<p>As C16alkylamino-C16alkyl and C16dialkylamino-C16a1ky1, R5 may be linear or branched.</p>
<p>The alkylamino group preferably comprises C14a1ky1 groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.</p>
<p>Case PC/4-34584P1 As a HO(Q)C-C16alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.</p>
<p>As a C16a1ky1-O-(O)C-C16a1ky1, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl.</p>
<p>As a H2N-C(O)-C16a1ky1, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-I,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.</p>
<p>As a C16a1ky1-HN-C(O)-C16alkyl or (C16alkyl)2N-C(O)-C16a1ky1, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.</p>
<p>As an alkyl, R6, R7 and R8 may be linear or branched and comprise preferably I to 12 C atoms, I to 8 C atoms being especially preferred. R6 is particularly preferred as a linear C14alkyl. Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl.</p>
<p>Especially preferred are methyl and ethyl.</p>
<p>As a cycloalkyl, R6, R7 and R8 may preferably comprise 3 to 8 ring-carbon atoms, 5 or 6 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclododecyl.</p>
<p>As a cycloalkyl-alkyl, R6, R7 and R8 may comprise preferably 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1 to 4 C atoms in the alkyl group, 1 or 2 C atoms being especially preferred. Some examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopentylethyl, and cyclohexylmethyl or 2-cyclohexylethyl.</p>
<p>Case PC/4-34584P1 -12 -As an aryl, R, R', R6, R7 and R8 is preferably phenyl or naphthyl.</p>
<p>As an aralkyl, R6, R7 and R5 is preferably benzyl or phenyl ethyl.</p>
<p>Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::EoN NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.</p>
<p>Further preferred are the methods of the present invention, wherein a compound of formula (B) is (2S,4S, 5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.</p>
<p>As indicated herein above, compounds of the present invention can be converted into acid addition salts. The acid addition salts may be formed with mineral acids, organic carboxylic acids or organic sulfonic acids, e.g hydrochloric acid, fumaric acid and methanesulfonic acid, respectively.</p>
<p>In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.</p>
<p>The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.</p>
<p>The present invention further includes any variant of the above processes, in which an inter-mediate product obtainable at any stage thereof, e.g. a compound of formula (Va-d), is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.</p>
<p>Case PC/4-34584P1 -13-Compounds of the invention and intermediates can also be converted into each other according to methods generally known perse.</p>
<p>When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxyl, thiol etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.</p>
<p>Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistt', Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).</p>
<p>The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.</p>
<p>Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n-or i-propanol, n-, i-or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene Case PC/434584P1 -14 -glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).</p>
<p>The processes described herein above are preferably conducted under inert atmosphere, more preferably under nitrogen atmosphere.</p>
<p>Compounds of the present invention may be isolated using conventional methods known in the art, e.g extraction, crystallization and filtration, and combinations thereof.</p>
Claims (4)
- <p>Case PC/4-34584P1 -15-What is claimed is: 1. A method for preparing acompound of the formula :::EoNR5 (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1kyl; R2 is halogen, C1..4alkyl or C14alkoxy; R3 and R4 are independently branched C6alkyl; and R5 is cycloalkyl, C16alky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C1alkanoyloxy-C1alkyI, Ci6aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16a1kyl, C16alkanoylamino-C16alkyl, HO(O)C-C16a1ky1, C16alky1-O-(O)C-C16a1ky1, H2N-C(O)-C16aIkyl, C1aIkyl-HN-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C16a1ky1; or a pharmaceutically acceptable salt thereof; which method comprises starting from tartaric acid and following reaction steps as outlined in Scheme 1.</p><p>2. A method according to claim 1, wherein a compound of formula (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
- 2.</p><p>3. A method according to claim 2, wherein a compound of formula (A) has the formula ::EoNNH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.</p><p>4. A method according to claim 3, wherein a compound of formula (B) is (2S,4S,5S, 7S)-S-amino-4-hydroxy-2-isopropyl-7-[4-methoxy3(3methoxypropoxy)benzyl] 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.</p><p>5. Method according to claim 1, wherein a compound of formula (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
- 3.</p><p>Case PC/4-34584P1 -16 - 6. A method according to claim 5, wherein a compound of formula (A) has the formula :H2Eo NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.</p><p>7. A method according to claim 6, wherein a compound of formula (B) is (2S,4S, 5S, 7S)-5-amino-4-hyd roxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl] -8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.</p><p>8. Method according to claim 1, wherein a compound of formula (Va-d) is converted to a compound of formula (X) following reaction steps as outlined in Scheme
- 4.</p><p>9. A method according to claim 8, wherein a compound of formula (A) has the formula NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.</p><p>10. A method according to claim 9, wherein a compound of formula (B) is (2S,4S, 5S, 7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -benzyl]- 8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.</p><p>11. A compound of the formula R' (Va-d) Case PC/4-34584P1 wherein R and R' are independently hydrogen, C16alkyl, C610ary1; or R and R' combined together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclic ring; Z is OR6 in which R6 is C120 alkyl, C312cycloalkyl, C312cycloalkyl-C1aIkyl, C610ary1 or C610ary1-C16alkyl; or Z represents -NR7R8 in which R7 and R8 are independently C120 alkyl, C3..12cycloalkyl, C312cycloalkyl-C16a1ky1, C6.10aryl or C610ary1-C16alkyl; and R3 and R4 are independently branched C1..4alkyl; and R6 is C120 alkyl, C312cycloalkyl, C12cycloalkyI-C16a1ky1, C610ary1 or C610ary1-C16alkyl.</p>
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Cited By (4)
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EP2062874A1 (en) | 2007-11-20 | 2009-05-27 | KRKA, tovarna zdravil, d.d., Novo mesto | Process and intermediates for the preparation of aliskiren |
EP2189442A1 (en) | 2008-11-20 | 2010-05-26 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process and intermediates for the preparation of aliskiren |
US8203005B2 (en) | 2009-10-29 | 2012-06-19 | Carbo Design Llc | Manufacturing process for enantiomerically pure 8-aryloctanoic acids as Aliskiren |
US8703976B2 (en) | 2011-10-02 | 2014-04-22 | Milan Soukup | Manufacturing process for 8-aryloctanoic acids such as Aliskiren |
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US5606078A (en) * | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
US5659065A (en) * | 1994-04-18 | 1997-08-19 | Novartis Corporation | Alpha-aminoalkanoic acids and reduction products |
WO2002008172A1 (en) * | 2000-07-25 | 2002-01-31 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
EP1215201A2 (en) * | 2000-12-14 | 2002-06-19 | Speedel Pharma AG | Process for the preparation of aryloctanoyl amides |
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US5606078A (en) * | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
US5659065A (en) * | 1994-04-18 | 1997-08-19 | Novartis Corporation | Alpha-aminoalkanoic acids and reduction products |
WO2002008172A1 (en) * | 2000-07-25 | 2002-01-31 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
EP1215201A2 (en) * | 2000-12-14 | 2002-06-19 | Speedel Pharma AG | Process for the preparation of aryloctanoyl amides |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2062874A1 (en) | 2007-11-20 | 2009-05-27 | KRKA, tovarna zdravil, d.d., Novo mesto | Process and intermediates for the preparation of aliskiren |
EP2189442A1 (en) | 2008-11-20 | 2010-05-26 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process and intermediates for the preparation of aliskiren |
US8203005B2 (en) | 2009-10-29 | 2012-06-19 | Carbo Design Llc | Manufacturing process for enantiomerically pure 8-aryloctanoic acids as Aliskiren |
US8703976B2 (en) | 2011-10-02 | 2014-04-22 | Milan Soukup | Manufacturing process for 8-aryloctanoic acids such as Aliskiren |
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