PH26454A - Derivatives of bicyclic aminocarboxylic acids a process and intermediates for their preparation and use - Google Patents
Derivatives of bicyclic aminocarboxylic acids a process and intermediates for their preparation and use Download PDFInfo
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- PH26454A PH26454A PH37896A PH37896A PH26454A PH 26454 A PH26454 A PH 26454A PH 37896 A PH37896 A PH 37896A PH 37896 A PH37896 A PH 37896A PH 26454 A PH26454 A PH 26454A
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- 238000002360 preparation method Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 title description 6
- 239000000543 intermediate Substances 0.000 title description 4
- -1 of bicyclic aminocarboxylic acids Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NSMXQKNUPPXBRG-SECBINFHSA-N (R)-lisofylline Chemical compound O=C1N(CCCC[C@H](O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-SECBINFHSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- MARYDOMJDFATPK-UHFFFAOYSA-N 3-hydroxy-1h-pyridine-2-thione Chemical compound OC1=CC=CN=C1S MARYDOMJDFATPK-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 240000000491 Corchorus aestuans Species 0.000 description 1
- 235000011777 Corchorus aestuans Nutrition 0.000 description 1
- 235000010862 Corchorus capsularis Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101100506034 Fibrobacter succinogenes (strain ATCC 19169 / S85) cel-3 gene Proteins 0.000 description 1
- 101000852489 Homo sapiens Inositol 1,4,5-triphosphate receptor associated 1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100036344 Inositol 1,4,5-triphosphate receptor associated 1 Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 241001289721 Lethe Species 0.000 description 1
- 241000528415 Moana Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101150034459 Parpbp gene Proteins 0.000 description 1
- 241001195395 Pilica Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000718541 Tetragastris balsamifera Species 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940060515 aleve Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 229940000201 avapro Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QDWJUBJKEHXSMT-UHFFFAOYSA-N boranylidynenickel Chemical compound [Ni]#B QDWJUBJKEHXSMT-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- YOSHYTLCDANDAN-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2NN=NN=2)C(CCCC)=NC21CCCC2 YOSHYTLCDANDAN-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 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
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- NQLVQOSNDJXLKG-UHFFFAOYSA-N prosulfocarb Chemical compound CCCN(CCC)C(=O)SCC1=CC=CC=C1 NQLVQOSNDJXLKG-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
fuk 26494
DERIVATIVES OF BICYCLIC AMINOCARBOXYLIC ACIDS,
A PROCESS AND INTERMEDIATES FOR THEIR
FREPARATION, AND THEIR USE
Acyl derivatives of cctahydroindole-2- carboxylic acid, cctahydrocyclopenta {blpyrrole-2-carboxylic acid or decahydrocyclohepta (blpyrrole-2-carboxylic acid are disclosed, for example, in EP-A- 19 79,022, EF-A-50, 800, EP-A-84,164, EP-A- 111,873, EP-A-37,231, U8 Patent 4,350,794 or US
Patent 4,587,258. Many of these compounds exhibit a notable biclogical activity. For example, they inhibit, highly effectively, the - anglotensin-converting enzyme or are distinguished by a nootropic action.
Compounds of the formula IV rR fin 2/n_ 4
COR (1v) —- 2 — -«
INAL d pAD ORIG ee fad. 26451 in which RS denotes hydrogen or an acyl radical, and rd denotes hydrogen, an ester group or another carboxyl protecting group, play a key role in the synthesis of the acyl derivatives mentioned initially.
It is often advantageous for carbon atom C-2 in position 2 of the bicyclic ring system of these active compounds to have a certaln absolute configuration, preferably the § configuration.
Their eyntehsis therefore preferably starts from intermediates of the formula IV which already have this desired configuration at C-2.
In the preparation processes which are already known for compounds of the formula IV, =a racemate resolution wae unavoidable if compounds having a defined configuration at C-2 were desired.
It has now been found that thiohydroxamic acld derivatives, in particular N-hydroxy-2- 3 - . \ L J
UI
Jk 26454 thicpyridens derivatives, of appropriately substituted and configured aspartic scids oan be converted into orbically uniform compounds of th formula IV having 1:he desired confignration at C-2 through cyclization and subsequent removal of a 2-thloxo-2H-[ 1) pyridyl radical, withcut a racemate resclution being necessary in any of the steps in thins novel rrocess. 1a Compounds of the formnwla I _ R [fi cor’ (1) 2 “Nl oT = are important intermedlates in this rroaeag, - 4 - \ 0
NAL J pAD ORIG
Tod 26454
The invention therefore relates to compounds of the formula I in which
H=1, 2 or 3,
R denctes (Cq-Cyy)-acyl and ri denotes (Cy-Cg)-alkyl, (Cq-Cy)-cyeloalkyl, (Cq-Cyq)-aralkyl or another carboxvl protecting group, the hydrogen atoms on the Wr idgashead carbon atoms 2a and (E4n)a preferably having a 18 clig-configuration,
The carbon atom in peoeltion 2 nf the Dbloyclie ring system can have either tbe BF or the 5 configuration; the s ronfignration is preferred. 16 R ies prefevably (C-Cg)-alkanovl, (Cg-Cp)-aryl-(Cy-Cy)-alkarovl, (Cq-Cip)-arorl, (Cy-Cg)~alkoxvearhenyl or (1; -Cyyq) nralkyloxy- carbonyl, but in partlioular (Cy -Cy)-alkanoyl, guch ae acetyl or propionyl. or henzoyl or substituted benzoyl, - 5 —- ! gap ORGNAS Dy \ .
Td. #6454
In abd von W030 nn sdlpaendy coves Ub hy Ge defile. io ile mm tegie greg! a nrethane
Lyfe Soran pp ob t aegpr elon wld oh je
CLASES hig . pest he bem pe by ie [a ! nari bee doable ch Fp ree Meg 0 2a
Fre tly. Eau no be Eg pe pe for
Sie Te bPooc 0 TT ds. Bpeer,
Ade Poo Me Te nee ne The adpo. dd wend Lb ct hresrn dpe ide be coop bhony “il nl Perovic fe a) ty Ta Aik. a, fore same Too pi en 0b a be faba ber (Dy
Cyyi apa tind. eh Po ap be bona d,
In sd 1itisn. U0 0 abalone coed by the defi Cobos alee eo 0 may en an > apheone f [RE protec tine wrap whith Poe ape ob tonal in pept! io shea ds tay vod Co Swamy be, Eiye abovesan dt Gonesed 0 Ube Te ibd hoa Fara protect diner ar nye sve. Uo orp be. ha aleve ment onad Al) pred te dg cp benayl
Te furtaycemors, modi Cie? eel oa d0000 0 auch ane p-niieehans ot peomethonyT oon ay lp ba geobeanny ~
BAD ORIGINAL J
L p-chlorobenzyl and radicals such as 4-picolyl or benzoyvlmethyl, are suitable. Above and below, alkyl ig taken Lo mean gtralght-chain or branched alkyl. In a corresponding fashion, the same applies to radicals derived therefrom, such as, for example, mlkanoyl and aralkyl,
Lower alkyl preferably has up to 6 oarbon atoms. (Cg-Cqip)-aryl is, for example, phenyl or naphthyl, rhenyl is preferred. In a corresponding fashion, the same applies to radicalsderived therefrom, such as, for example, aroyl and aralkyl.
The invention furthermore relates to a process for the preparation of compounds of the formula
I, wherein a compound of the formula It
R
1
Se /) (11) 8 - 7 — 0
BAD ORIGINAL
\
fod. 20454 i in which nn. B and wn! ara mar def ined adeove, be gubiactad Co fees radioal deoavhony lat ony,
Free codlical decarborylaticne oan bs carried wat, Loar enamel, Ly warming the compound to i 43 IVC, preferably 890 130°C. in ow suitable guivont, or alternatively glilbal golvent, If approptiat In tha preconca of a froo radical
Inklintor, gut table polyants Lopes are, fn partion larv, aprotic polvento, gach as hanzsane, li} Le dua: or xylene, Sultable todtiators are,
Lor crompls, orgnulo peroxides, such as tert. bubs) pres res i doke sy and substituted ascavabonitriles.
In addition, the free radicsl decarbocylation 150 2a be carried out photolytieally or radlulytically in a sultable dipolar aprotic solvent between - 207°C and the bolling point of ‘ ther reaction mixture, preferably between 1@ and 60, Fhololvlle decarboxylation le preferred. nid Suitable dipolar aprotic solvents are, for exp le, a bhrra ench an diethyl other, . & .
J. ORIGINAL J hf. 264 5 tetrahydrofuran and dloxane.
The compounds of the formula II are prepared starting from coycloalkenyl bromides of the formala V —_ Br c in which n is 1, 2 or 3. The latter compounds are reacted with aspartic acid derivatives of the formula VI 1 - Bal
CH, (vi)
HN - ba co.R"' 2 2 - 9 — 0 p OR aM \
ut. 264.54 in which r! 1a as defined above, but prafarably denotes (Cg lg) alkyl, anah as btsrt.-butyl, and which prefzrably has the L conf guration, in the preacnee of a bass, puch ae KnCOy, in =a dipolar aprotic solvent, such an acetonitrile, between 0°¢ and the boiling point of the reaction mixture, preferably at room temperatura, to form aompounds of the formula
VII in which
Lad n and Rr! are ag defined above, [aa io
N - CH = co R’
The latter are acylated to form compounds of ~ the formula VIII /c8 2/a— CO,Bzl : (VIII) \ R CH « NN | 2
N - CH = COR" 2 \ \ ) (GINA
Lo fk. 264 54 in which n, R and rl are as defined above. The acylation is expediently carried out in a dipolar aprotic aolvent, such as acetone, in between -2@°C and thes boiling point of the b reaction mixture, preferably at room temperature, preferably in the presence of a base. Suitable acylating agente are, for example, chlorides of the formula RC1 or anhydrides of the formula RoC. gultable bases 19 are tertiary amlnes, such as friethylamine, and inorganic basee, guch as KyCO4.
Hydrolyeis of the diester VII using an alkali, preferably NaOH, in DMF at room temperature gives the compound of the formula IX
Rr con’ . Y, 2 2 mn N
CT hd (1X) = cok 2 —- 11 —- \ ,
NAL os \
Jad. 26454 in which n, R and rl are ag defined above.
The latter compound ie sotivated at -3@ to @A°C in a dipolar aprotic saclvent, euch AE tetrahydrofuran, by adding a lower alkyl b chloroformate, preferably tgobutyl chloroformale, and an bage such ag 1 - methyluworpholline, giving jute medinte componnds of the formalz J
R ba ? | cor r T 2
CO=0=CO=1ower alkyl in which rw, rod pl have the meaning above.
While mobiatoinbae ha tomperatnre, the alkali a meatal ualt preTaraply the sollun ralt, of thi chy los amier ae ide, prafeprably n-hydrogy--2H- pyridine? thicne, la how add~d, forming the - 12 - \ INAL J
AD ORIG lod, 26454 compound of the formula II.
Beeides M-hydroxy-2H-pyridine-2-thione ()
NN the following thiohydroxamic acide are also gultable, for example: i -N-CH OK OR 3 pd
OH 1 ~N 0 8 \ »
NN -0f or 5
Pra 1S
OR
_ 13 - \ 0 aap ORC
(if 264 54
The invention also relates to compounds of the formula III
Icy, ! con’ s/n N 2 oo ¢-0-R% a 0 in which n, R and rl are ag defined above, and
RZ denotes, ing. parftveular, 2-thioxo-2H- [11pyridyl or (Cy-Cgl-alkoxycarbonyl, which are intermediates in the abovementioned procese.
In addition, the invention relates to the use of compounds of the formula I in a process for 19 the preparatinn of a compound of the formula IV in which
RS denotes hydrogen or is ag defined for R, and r4 denotes hydrogen or is as defined for rl, through treatment of a compound of the formula - 14 - \ INAL J v wr od Tetasgsy Ch
I “with Raney nickel in a suitable solvent, preferably a lower alcohol, water or dioxane, 1 or 2 of the radicals R and/or R4 which do not denote hydrogen subsequently being replaced, if
Bb appropriate, by hydrogen with the sid of acide : : and/or bases and/or hydrogenolytically, and a compound of the formula IV being converted, if desired, into an ester of the formula Iv in which RY 1s as defined for R by esterification . 19 or transesterification. Bromine substituents on R = aroyl are replaced by hydrogen in this process. Lower alcohol 1s taken to neat an } aliphatic alcohol having 1 to 4 carbon atoms; : ethanol is preferred. The reaction | 1s
Ln 16 praferably carried out between -2@°C and; the =
Co . boiling point of the reaction mixture; . in - - particular between 18 and 42°C. Besides : ‘Rahey
EE x niokel, other desulfurising agents, such’ as, : oo g for, example, nickel boride, can also be used.
Soo a SER 29 The examples below serve to illustrate the , invention without representing a Limitation.’
CE FO
! : LL Cn ! ! Dens i TC » pl bee
Jat 764 5¢
Bxampl 1
B Pen: tot busted 1 ooh hae Dory 1 anpartate
A geo dat too of 300 mg (E20 mmo do id a rom ey co ohey ce Ine 07 wml ef Acetonitrile is intpodr sod ind ABR mt flank centainige 4,374 a {sr mm le of 1 Leepary Ll bev to Tage), aepart ate and coA4LT go CABLE med oT peas ium sarbopate ta AE mY of anhydre ae acaeten di bed le.
Xa The mi buy bor tiers vigoremer ly ah room temper 2 hore for 48 hours Tha F..000q ia
Fhltear:dd AT sel pinaedt o ith pboaty nf acetonl Lei le. Ther wmodvent do ovaper ated nd reduce tb presenye aed Klee nme be pari fied nver allio ge? cae luegt ns Lethe ell Shean 1:1).
Yield: vo in 20 af there of oy em lightly yeellowlseh oil,
Co Tn? es methane) cg LR: VO AnR@L TNA, IRE 1An5 ap 1h \ AL b) \G\WN \
SEE 5 iE i gE : bea
CH same aig ee - fap 26459 14 yur: 4 [opml= to 1.49 (9H, 5, OtBu); 1.24 - 2.12 (yi, nm; - (CHp)g- + NH) aE Bh 3.12" (1H, m, -CH-NH- ); 2.63 (2H, d, J=6Hs, - CHy~COOBal); “ " 3.62 ' (1H, t, J=6Hz, -CH t); 5.09 (2H, =, -CHy- vd
Ph); 5.8, (2H, m, -CH=CH-); 7.28 (5H, 8, PH). Co.
Elemental analysis (CpyHpgNO,:359): E . | .. 10 caloulated: % C 79.17 H 8.13 017.68
ERS found: XC69.008 H 7.98 O 17.88 .. 0 Co
Po CHE he en ' Mass spectrum: m/e; 38@(M* 1) 268 (M'-COOLBU).
Pe CoE i : oe (RIT. in the optical rotation value représdnts ) va ‘ CoA ou po “room temperature”). i oo
Cie SH Ch -
Coe GE Ea ta | a ES, :
EEE 16 Bxddple 2 a boy | B-Benzyl of -tert.butyl = N-acetyl-H-(2- ( | iN 0 cyglohexen-1-yl)-L-aspartate Sh bo Hi my a En
Fo 1.4: g (3.96 mmol) of the amine from Example - 1
Po are ‘dissolved in 12 ml of acetone, and 1d g bo CER aE
Ca co 20 (dpe mmol) of potassium carbonate are added.
Lo 0.48 m1 of acetyl chloride (2 equivalents). & a
EN tar Sin dL
Lo a Co
Pe CE SPO : ih Ci : Vad Pa . A Ce oo A ER or
TRE SoA Co 2 VaR J
Dn BAD, oRIG fag. 264% dissolved in 3 ml of ether is then added, and the mixture is stirred vigorously at room temperature for 2 days. The carbonate is filtered off and rinsed with plenty of acetone, and the solvent is evaporated at reduced preasure. The polatb amide is purified over a pilica gel column (eluent: diethyl ether, hexane 1:1, then 2:1).
Yield: 1.19 g (97 % of theory ) of a colorless 13 oil; [ ®T =~ 44.4% (¢ = 1, methanol) ir: @ - 1748; 1730; 1675; 1668; 1589 cm’! l4.NMR: (ppm) = 1.41 (9H, s, OtBu); 1.85 (6H, m) 16 2.96 (3H, 8, COCH4); 3.62 (2H, m, -CHy-C0OBzl); 4.19 (1H, 44, J =9Hz, Jo=3Hz, CHyp) 4.36 (1H, m, -CH-N); 6.1 (2H, s, -CHo-Fh); £.82 (2H, m, -CH=CH-):; 7.3 *bH, 8, ~Fh).
Elemental analyels (CoaHayOgh: 401) calculated: % © 68.8% H 7.78 O 19 93 found: C 68.71 H 7.85 0 19.95
Mase spectrum m/e = 491 (M' - COCHjy) - 18 - gh ORIGINA- Dy \
Jod - 26454
Example 3
Ld ~Tert.butyl N-acetyl-N-(2-cyclohexen-1- yl)-L-aspartate 1.3 g (3.24 mmol) of the amide from Example 2 are dissolved in 5 ml of DMF and hydrolysed at room temperature for 2 1/2 days using 2 ml (1.2 equivalents) of 28 sodium hydroxide golution.
The solvent is evaporated and the reeidus 18 dissolved in 2 ml of water. 1t should be 19 ensured that the pH is alkaline. This aqueous phage 18 waghed with ether in order to removve the benzyl alcohol, and then acidified to a pH of 4 using aolid elitric acid. The mixture 1s then extracted with ethyl acetate. The organic phase is washed with gaturated aqueous NaCl solution, dried over Nan80y,. filtered and evaporated on 2 rotary avaporalor. The acid thus obtaoned ig purified over a silica gel column (42 & of £104 6-204) um; eluent
CHoClp/methancl aB:2).
Yield: 910 mg (9R% of theory ) of a foam, [of RT = -108.0° (c= 1.94 methanol) — 19 —- \ NAL J \G\ - \
hd 26454
IR: ¥ = 3350; 1749: 1700 om”!
TH WHR o {pm = 1.42 (OH. eo, DtBu): 1.92 (6H, m); 2.12 (3H, 8, COgHz); 3.56 (2H. m, -CHp-): 4.16 (1H, dd, Jq=9Ha, Jeo=3Ha, -CHo) 3 4.35 (1H, m, -CH-H-); 5.51-5.86 (2H, m,--CH=CH--)
Mase spcolyum m/e: 311 (MY; z1z (MY); 212 (MP-COOtBu): 268 ut - 43) 12 Example 4
B-Benzyl & tert. butyl H-(p-bromobenzoyl)-N- (2-oyclohesen Lv) L-aspartate . cat 2.6 g (6.9 mmol) of B-benzyl -tert butyl L- scparlate are added to a suspension of 3.86 g 16 (28 mmol) of potassium carbonate in 32 ml of avetons, and the solution of 2.26 g (10.3 mmol) of p-bromobenzoyl chlovide in 10 ml of ether ie , added. The mixtnre ie then stirred vigorously at room temperature for 2 daye, the carbonate tg filtered «ff and vinsed with plenty of acetone, and the solvent ia evaporated at — 720 - \ \
BAD ORIGIN
[bt 26457 reduced preegsure. The oll which remains 16 purified over a silica gel column (eluent: diethyl ether/hexane 1:3).
Yield: 3.948 g (81 ¥ of theory); m.p.: 100- 121°C (from diethyl ether/hexane); [ o IR-T.p =-49.8° (c=1.8; methanol)
IR (Nujol): # = 1738, 1636; 1599; 1420 cm”! ’ 14 NMR (200 MHz): [ppm] = 1.45 (8H, 8, OtBu); 1.32-2.15 (6H, m, -CHp-); © 2.47 (1H, dt, Jy=3Hz; Jp=12ha; -CHp-); 3.73 (1H, m, 1H of CHy); 4.23 (2H, wm, -CH-N-
CH); 5.13 (2H, m, -CHyp-ph); 5.7 (2H, m, -CH=CH-); 7.28 (9H, m, Ar).
Elemental analysis (Cag,/H3gN0gBr: 542)
Calculated: % €C 61.99 H 5.94 N 2.569 0 14.74 found: % C 61.87 H 5.78 N 2.46 0 14.47 — 21 —- pp ORIGIA 9 (—
fod 76454
Example 5 or ~Tert. butyl N-{(p-bromobenzoyl)-N-(2- cyelohexsn-1-yl)-L-agpartate 1 g (1.8 mmol) of the amide from Example 4 is hydrolysed Ly adding 2 ml (1.1 equivalenta) of
I N egodium hydroxide solution, the mixture is stirred at room temperature for 1 day, and the dioxane is then evaporated. The aqueous phase is waghed with ether, ite pR is adiuasted to 4 1a aging solid citric acid. and the wmlxture is then extracted with athyl acetate.
The acid thus obtaluod Is purified over a silica gel column (2 g of S104 TA-208 um; eluent) CHpClg/ methanol 98:2)
Yield: 685 mg (34 % of theory) of a foam.
IRy = 3450; 1730; 1680; 1586; cm} ly wMR: [pom] ~~ 1.47 (8H, 8, tBu); 1,3 2,62 (6H, m}; 3.47 (BH, &, OtBuj; 1,3-2,62 (GH, m); ) 21 3.606 (2G, nm, “UHo- COOH; 4.22 (2°, m, CH-N-CH-) 5.84 (2H, m, ~CH-):; 7.16 (2H, Ad, J=8Hz); - 22 - i \ NAL dP ’ \ INA \
Er 7.47 (2H, d, J=BHz, Ar); 8.1 (1H, s, -COOH).
Microanalyeie was oarried out on the dicyelohexylamine galt, and similarly the melting point and optical rotation were determined for the dicyclohexylamine ealh.
Elemental analysis: (CggHyglpOgBr : 633) caloulated: % C £2.55 H 7.79 N 4.42 0 12.62 found: % C 62.32 H 7.68 N 4.25 0 12.47 fo 18:T-p = -9.1° (c=0.76; methanol) 1@ m.p.: 166-157°C [from ethyl acetate/petroleum ether].
Example 6
Tert. butyl 1-acetyl-4-(2 ~pyridyl)- mercaptoperhydroindole-2-L-carboxylate 0.28 ml i 16 (2.5 \ mmol) of N-methylmorpholine and @.36 ml : (2.5 hmol) of isobutyl chloroformate are added : whit 1s stirring to a solution of 776 mg (2.5 : mmol) of the acid from Example 3 in 13 ml of
THI tindere argon at -15°C. After an activatlon ’ time of b minutes, 464 mg (1.3 equivalents) of the | sodium galt of B-hydroxy-2H-pyridine-2- ‘ oo - 23 - : ; / / !
A | \
A oo BAD ORIGINAL 9)
A
Ji. 26454 thione are added, and the mixture is stirred for 1.5 hours at -15°C under argon while excluding light. The mixture is then diluted with 20 wl of THF and allowed to shand ah room temperature for 2 hours. The THF 1s evaporated under reduced preesure, and the reeldue is purified over silica gel (eluent: diethyl ether/hexane 2:1, 3:1, then 4:1 and, as soon as the first diastereocisomer has been removed, 19 diethyl ether must be used as the eluent.
Balance: diastereomer 1 283 mg
Mixture of diastereomers 1 and 2 160 mg By
Diastereomer 2 1561 mg
Total yield 574 mg (56 %X of theory) - 24 -
GAD ORIGINAL 9) .
Cy # oo To Ey 2, A Es b Le c Co " 00,43u 5 ha x, Ey " oo
Aes Th ay Bh ‘ t . “4. : oo : nh oo 3 iN Co LE . ~ diasteromer 1 © diasteromer 2° . (Py = 2 -pyridyl; AC: Boetyl: tBu © & 4h Cl s . i ~ tertibutyl) oo Co
Hf SE Co ~~. Bb The 180 mg of the diastereomeric mixture above oo - were separated by means of preparative’ thin- Tee lagel; chromatography (8103 mobile phase! oo diethyl ethor/hexane 1:1), a further 17 mg of diastereomer 1 and 126 mg of diastereomer. 2 bein obtained. | Co
Diastereomer 1 1
Pale yellow oil; [o¢ 18:T:p = -67.9° (0=8.61 - - 26 -
A VU aiGINAS J
Er psp OF fer, oo Co fof. 26454 res Lhaaol)
WEL vv UIs, Lome, nh nan Ree en
Pi ouMr (en mee 6 Tred
Poneto FURL 0 11 Hy SH Ch TH ey Fas
Cn Ce Wears UTE OH wm Mp 4 0h
TRE He
LE CI om Tew Sao ant cal ay ey a, (IH, =m oo by $i Maya gpa room som eT an! crooan' yore oa! = .
CN Pu) sat onto by
Diagboareom: rr 2 1h mop. dn rant Ce a dis the oe the er heexane Jl [A pie .. (1a en Bo me Lane 10) boomer 100 mio 0 Leen! 1.0L (9H, « Ciba), Soleo uy, CMa dg . 1.16-2 0% PTH, wy. 29 TH, om, H,, ob Hels ne TLB3 oI, ow, Hr 3.97 iH. om. Hy oo
Tr (iH. or, 7 Ae Wy p04 36 CHL om, Ma eR. oR RH, wm. Pyar BOF 0 om)
IR: ¥ PPA; LTS IRAG TURD ILBE em 26 gap ORGINA Dy \
a . . Lp eet . oo re ; MER ky Cd :
Hd Hh or Clad
Es hme wy ah Etiined
Li wu i ¥ ah mE ed Loa i : AT poodle
LL fat Cd
Mass speotrum: a i} m/e = 376 (M'), 320 (M' - 2 ), 276 (H' -
COOtBu), 266 (M* -8-Py) :
Example 7
B Tert.-butyl 1- (p-bromobengoyl)-4-[ (2° -pyridyl)- mercaptol-perhydroindole-2-L-carboxylate he
SE Ge i ns 3 The title compound was prepared in a fashion Lo ; . = al, Re: o
LL analogous to Example 6 starting from 608 ng gE LAE (1.3 mmol) of the acid from Example 6. + : RE i ; 19 Separation by column chromatography (8105, : ) . eluént diethyl ether/hexane 1:2, later 1:1§7%ed ¢ to“resolution of the diastereomers. Cas
SE CUR :
Rr Mn : Balance: diastereomer 1° 206 ng pA rd oo
Co (Hh Coon i " Co Eas mixture of Po : = 16 CE diastereomers 1° and 2° 136 wi: ©
CoS Ly idle
EN diastereomer 2° 126 wg: bl Baa : ‘ pris eee til \ rs Cane . ! oi, total yield 485 wg’ Co
LR Fa
Ey (88 % of theory) ii :
A ising Co
JR $ER
J ER wl CEL 3 - 21 - go
EX SE
Ga LL AmIGINA ) Lo
BE 8A © “ i
Va } a ol
FE Clg
Qt. 20054 - (Py = 2 -pyrldyl; PrBz ~ p-bromobenzoyl; tBuztert. butyl)
Diastersomer 1: m.p.: 164-165°C [from ethanol], 6 o¢ Ip ~ _179.8° (¢ = 1.99; methanol)
IR: 4 = 1740; 1640; 1600; 1580; 1560; 1450; . em! in 1g NMR (200 MHz): (peml = re 1.48 (8H, m); 1.1-2.33 HTH, m, = CHp) 16 2.48 (2H, m, Hg + Hp or (Hg))s 3.167 (1H, "m,
Hg); 4.31 (11, m, Hp)); 4.45 (1H, m, Hp): 6.86-7.68 (8H, Ar); 8.36 (1H, nm). ! Elementary analyele (CopHoglpOgBr: 517)
J 16 calculated: % C 58.01 1H 5.64 N 5.44 0 9.27 found : w ¢ 57.88 H 5.48 N 5.49 09.08
Diastersomar 27: roam; & ® Tp _ , 63.9° (c=0.8; methanol)
Lj MK (400 MHz):> [ppm] = 26 1.44 (PH, 8, -OBUS o.8 - 1.91 (6H, mm, ~
Co (pEyIgt)s
EE - 28 - oo os ore ) \
SRN ToT aes NRT Sl) ead aR SES
RR EE. a Ce RTS SHR i Ce Re 7 v 2 I ET nT CT | CL x = AR : SAE A Ba : Ro RY 5 CER ue fd Ts y Wh vo CR | TARE Tf aes
Cui | | i AP Sd Ee gp Sie en , So 2.99 (1H, dd, Jgs=0, Jgp=13Hs, Jgc=THa, Hg) ° x CL 3: Feo 2.368 (1H, dt, Jpg=Ypc=13Ha, Jpa=10Hz, Hp) o ; 2:83 (1H, m, Hg); 4.83 (1H, m, Hp): AS 4.27 (1H, m, Hg); 4.6 (1H, d, Jpa=10Ha, Hy)} - 6.90-7.68 (TH, m); 8.32 (1H, m). He
Mags spectrum: pa m/et 516, 517, 518, (M*), 461 (M* - = ) oo 317 (M* -COOtBu), 406 (M*-B-Py). : Example 8: CL
SE 18 Tert.butyl cis, exo-N-benzoyl-perhydroindole-2-...., / 2 i : i . L-garboxylate LE ! \ . SA ot
Lo . 160. mg (0. 29 mmol) of diastereomer 1; from
Extbple 7 are dissolved in 2 ml of absolute . : [REN Foo x co ethanol and reduced ovvernight at: ..rooms
CL 16 temperature using Raney niokel ((® prolabo,: box : - . ! L . ns \ i i shtink in water). The mixture is subsequently : ; cau es : [oc SL J filtered, the catalyst ie rinsed with plénty, of = ; og jE 8 | an’ ethanol/water mixture, and the solvent’ is
La 3 “ . , eV8porated on a rotary evaporator. 5 in
RRL gE
Pe 20 - yield: 120 mg of crude product. we : Can | Rr
CE TE A
: a * fa ; : ER - 29 - TI a as a he go ya >»
BE Hag
N aR : apd Po de A
A So - Ei sa A Rh .
af. 26.45%
Example 9:
Cis, exo-N- bensoyl=perhydroindole-2-L- . carboxylic acid
The crude product from Example 8 ie hydrolysed for one hour at room temperature in 2 mixture cf 0.0 ml oof a trafivorcacetic acid and #.2 ml of CHACln. Theos mlutorr= in subregquently evaporated, and Lhe olly vesldue (87 mg) is washed with poentap: 13 Example 180: i
Ethyl cis, exo N-benzoyl-perhydrolindcle-2-L- carboxylate
The arid from Example 9 is dissolved in 1.2 ml ' of DMF and neutralised using H2 mg (@.6 mmol) of RaliCO4,. A olution of @.1 ml (1.25 mmol) of ethyl DUbromide in t.2 ml of DHF is now added, and the mixture is stirred at room temperature for 24 houre. The DMF is evaporated under reduced pressure, and the residue ls taken up - 30 - \ ) srl
Se age te RE te ie SN
Eh we BE EL a - | Ja i | ’ in 1.5 ml of a 1&0 % strength aqueous citric acid solution. The title compound is extracted
With ethyl acetate and then purified by chromatography (preparative TLC, 510,; hoblle phase: diethyl ether/hexane 1:1).
Yield 57 mg (65 % of theory) of a colorless oll: [ a 1p = -41.1° (c=0.48, methanol). oo
IR: v = 1750; 1640; 1600; 1578 cm. : 10 1H NMR (400 MHz): &[ppm]-= 1.38 (3H, m, -CO-CH,~CHy); ©.86-1.94 (6H, m, - 3 (CHa) 4) ; : 3 pg 207 (1H, dt, Jgp=Ogg=13Hs, Jg,=8Hs, Hp)’ 2:23 (1H, m, Hp); 2.38 (1H, m, Hg); g 16 3.87 (Hm m, Hg); 4.24 (2H,m, -CO-CH,~CHa); 4.62 (1H, dd, Jug=6Hz, Jpp=6Ha, Hp); 7:31 (2.6H, ar); 6.87 (2.5 H, ar). Ei [numbering of the H atoms as for diastereomers 1% Ana 2°] TR
Masa spectrum: LE m/e = 391 (M*-COOEt), 186 (M*-CO-Ph). RE
Go - 31 - i ; ay: OR
Wf 264.5% -
Example 11:
Ethyl cls, endo N-benzoyl porbydvoindele-2-L- carboxylate
The procedure described above under Eyapprlaee 8- 1 is carrvisd oat urirg 1200 mg (0.22 mmol) of diastercomer 2° from Exampls 7,
Yield: 48 mg (85 % of theory) of white crystals; m.p.: 111-1129 {from diethyl ether/pentanal: 19 | « Ty Sood 0T (en AT; methancel)
IR: +» = Li; L640; 1509; 1570 om™1,
L NMR (490 MHz); of [pEmi- 1.3 (8H, t, J:-THz, CHg-); B.83 1.78 (8H, m», - (CHp-) 4): 1.87 (1H, dd, Iga, Jgg~13Hs, Jgn=6,5Hz, Hg); 2.23 (IH, dt, dpa 10x, Jpgotpe=13Kz. Hp); 2.67 (1H, mw, Ho) 2.20 (IH, m, Hp); 4.22 (2H, «q, J-7H=z, -CH. CHgz) 3 4.69 (1H, d, Jap 10Ha, Hp); 7.37 (4.5 H, m, Ar): 7.48 (2.510, m, Ar). fmamberlong of the H atoms =n for disstereomers 17 and 27] © 82 - \ ora ) ; gh®
; ol Hi boo : (of. 2645
Mass spectrum: - n/e = 391 (M*), 237 (M* -COOEt), 196 (M*-COFh). 4
Example 12: b Tert.butyl cie, exo-N-acetyl=perhydroindole-2-
L-carboxylate : A 160° ng (0.4 mmol) of diastereomer 1 from ] Example 6 are dissolved In 3 ml of ethanol and : reduced overnight while stirring at room 19 temperature using a raney nickel. The nickel 1s filtered off and rinsed with a water/ethanol mixture, and the filtrate ie evaporated in . vacuo. =
Crude yield: 130 mg “ { . Ys } 5
Example 13: a
Cis; exo-perhydroindole-2-L-carboxyllic acid hydrochloride fo
The crude product from Example 12 is refllixed - 33 - | ” = Lo mGINAL JP i» \ c
For cape hong with 4omloaf 6H hye oochlorle noid, fof too cow aperab jon a Fev the
Pryde il vob potas bre bee En f = a1).
Ramp le Ud h Eihy? el pes dee ey Prgylate hydpreoh ls ye yole : Hydvoea-o oo bt ci Poropoedd iabe a ition of
Lhe bode ooctiion Pde from emg to 14 i 1 ml of aba lite chet fot Ho panther at Y oom 17 fempey oto Gel UTE rapt bE After avapro on cf Lhe ahunne ld he vontdae remains . aE Bos Dogebe onebi boy Bole of tha avy ld neler (19 me).
Example: 10 1h Ethyl od eae Wo tp bhronibaeazsoyl) perbyhoindola 01 caploxy date
The eter Hoel schber ide from Example 14 ip dippclnot fy oa mixtapes of 3 mb of THE and 1 ml oe of CTCPo. aed, at oC, @asi ml (2.5 mmol) of \ pp OREN
RA aR . so Ch fot Zest oo $00 2 oa Ty - : CL triethylamine is added. 161 mg (8.75 mmol) of p-bromobenzoic acid, 116 mg (9.75 mmol) of ] hydroxybenzotriazole and 155 mg (2.75 nmol) of dioyolohexyloarbodiimide are then ‘ édded b successively at 0°C, and the mixture is stirred vigorously at room temperature for 24 hours.
The dicyclohexylures 1s filtere off and ‘rinsed : with THF, and the solvent is evaporated from the flltrate. . ¢ . . . o 10 The . residue ie dissolvved in 5 ml of “sthyl acetate, and the organic phase is “Washed : sudcessively with @.1 N aqueous RalHCOy .. : solution, water, @.6 N hydrochloric acid, ‘again wlth water and a saturated aqueous’: NaCl
Lo 15 solution. The organic phase is then aridd over
NagB0,. filtered and evaporated in vacuo: | The deFivative thus obtained is now purified: by Co . or means of preparative thin-layer chromatography , (6105; eluent diethyl ether/hexane 1:1). 5
Yield: 62 mg (41 % of theory) of a colorless : | 011; Co 3 : : RI
Cs ap ORIN i \ i
SE oy
Jaf. 2¢€5t
Lo 15 Tp = -30.17 (208.85 ethanol).
IR: = 1745; 1635; 1585; 14002 amb ly NMR (200 MHz): 4 Leem] ~ 1.3 (3H, m, CHyz); B.a3-1,95 (81, wm, (CHa) a7)
H 2.17 (in, JUIN Hgts oT a1, at, Jpe=Tpa=6Ha,
Jpg=1€Hz, Hy 2.71 (WM, m, Hots 4.6 (IH. m, Hg); 4.27 (ZH, m, Cid, Chg bs 4.067 01, om, Heds ‘ 7.32 (2H, 4, J.9Hz); 1.6 Cal, od, Js0Ha). 19 { numbe t Ing gpootnme mow = an@ (Hh, eT (MY COOEt). 196 (MY 10AT)
Exampla L6
Ethyl cis, ondo-N- (bromobhenzoyl)- perhydroindole-2 -L carboxylate
Starting from 120 meg (@.32 mmol) of diastereomer 2 from Example €, 55 mg (45 % of theory) of the title compound are obtained, in the form of an oil, analogously to Example 12- 16.
R.T. — 0 — . . & 1 D~ 54.47 (ec=1.1; ethanol).
IRV © 1745; 1635; 1095; 1495; om L. - 38 - d) \_ ore
Bho fof. 2645
IONMR (oon Hits); oI ppml 1.32 (an, tL, JdoT7Hs, CHn) @.63-1.8 (8H, m, - (CHoY g )s 1.93 (IN, dd, Jp 130s, Jos 6 6H, Hels 5h ConT (at, Tp pe PES Jp Ma, Hits 2.6 woe (in, add (CR 1EHa. ‘BH, 10. blz,
TRe=BHz Hg) 4.7 (24H, a, J THz, 0 Ala CHa) : 1 Ih 4 68 (1H. a, FT Oa, Ue 7.38 10H, da, I 9a)
TORS (Wd, ToD) {numbering of the 0 atoms ae fur disagleraomers 1 ara 21} ot
Hage apeaectoan tn mon moana (qty eT ont Cont), ‘tH CoAr).
Example 17:
Tart.butyl cig, oxo-H beusoyl parhydroindoele-2-
L-carboxylate
The title compound tg obtained starting from diasterecmer i from Example 7 through
Lreatment itls Raney nickel in cthanol.
Soar [A ) \ 0 ore eh
Vat. 2644
Purification is effected by means if preparative thin-layer chromatography (8300; mobile phage diethyl ethar/hexane 1:1). m.p.: 114- 115°C [from ethanol]; 6 0 oq 1% Tp = -44.2° (620.9; methanol). -
IR: vv = 1749; 1640; 16900: 1429 emt 14 NMR (200MHz): o [ppm] = 1.88 (9H, m, OtBu); ©.96-1,96 (BH, m, ~(CHp~
Yq); 2.18 (2H, m, Hp, Hg); 2.43 (1H, m, He) 3.73 (1H, m, Hg); 4.7 (1H, m, Hadi 7.7 (8H, wm, Ar). [numbering of the H atoms as for diastereomers 1" and 2°] 156 Mags spectrum: m/e = 329 (M'), 229 (M*-cootBu), 224 (Mi-co-
Ph).
Example 18:
Tert.butyl cis, endo-N-benzoyl-perhydroindole- 2-L-carboxylate - 38 - - d
A ach \ anf .
fat 2¢as¢
The title compound ie obtained etarting from the diastereomer 2" from example 7 to treatment wlth Raney nickel in ethanol.
Purification ise effected by means of preparative thin-layer chromatograhy (5105; mobile phase diethyl ether/hexane 1:1). m.p.: 111-112°C [from ethanol]; [ 17 Tp= -96.6° (c = 1.05; methanol).
IR: + = 174); 1648; 1698; 1420 om™ 1. lH MR (400 MHz): , (oem) = 1.5 (8H, &, OtBu); @.82-1.7 (8H, m, -(CHg) 4: 1.84 (1H, dd, Jga=@, Jgp=13Hz, Jgg=6.5Hz, Hg); 2.31 (1H, dt, Jpa=1@0Hz, Jpg-Jpeo=13Hs, Hp); 2.67 (1H, wm, Hg); 3.86 (1H, m, Hp); 4.56 (1H, d, J=1PHz, Hp); 7.42 (5H, m, Ar). [numbaring of the H atome as for diastereomers 17 and 27]
Elemental analysis (CgynH,7NOg): calculated: % C 72.91 H 8.26 0 14.57 found: ¥ C 72.83 H 8.38 0 14.81 - 39 - » \ aon ’ os0 0
Claims (1)
1. A preooess for the preparation of a compound of the formula r> ~ Loop \L - CO x (1v) _— 2 in which pd A-nctesg hydrvogen or (Cq-Cyq) acyl, RY danotes hydrogen, (Cy-Cg)-alkyl, n denotes 1, 2 or 3 which vcomprlires tresting a compound of the formala - 49 - 0 \ AV d act gro ©
Fat-20p54 14 RB /% fo l Ngo a’ 1 / 2 8
Ps . in which Th . R denotes (Cy-C,4)alkanoyl, benzoyl or \ bromo substituted benzoyl rl denotes (C;-Cg)-alkyl, n denotes 1,2 or 3, oo with Raney nickel in a suitable solvvent; subsequently, when in the resulting compound Rd and/or r4 do not denote hydrogen, reacting 1t with an acid or base and/or hydrogenolytically to obtain R3 and/or RY? as hydrogen; and if ' desired, converting a compound of formula 1IVV into an egter by esterification or transesterification.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863641451 DE3641451A1 (en) | 1986-12-04 | 1986-12-04 | DERIVATIVES OF BICYCLIC AMINOCARBONIC ACIDS, METHODS AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION AND USE THEREOF |
| PH36151A PH26415A (en) | 1986-12-04 | 1987-12-02 | Derivatives of bicyclic aminocarboxylic acids and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26454A true PH26454A (en) | 1992-07-27 |
Family
ID=25850015
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH37896A PH26454A (en) | 1986-12-04 | 1988-12-07 | Derivatives of bicyclic aminocarboxylic acids a process and intermediates for their preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| PH (1) | PH26454A (en) |
-
1988
- 1988-12-07 PH PH37896A patent/PH26454A/en unknown
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