Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 16, 1998, Pages 2247-2252

  Sakaki, Junichi ^a   Murata, Toshiki ^a   Yuumoto, Yoko ^a   Nakamura, Ikushi ^a   Hayakawa, Kenji ^a  

^a NOVARTIS PHARMA K K   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ENDOTHELIN RECEPTOR ANTAGONIST; N BUTANESULFONYL[N (3,5 DIMETHYLBENZOYL) N METHYL 3 [4 (5 ISOXAZOLYL)PHENYL]ALANYL]VALINEAMIDE; UNCLASSIFIED DRUG;

ARTICLE; CHIRALITY; COUPLING FACTOR; CRYSTALLIZATION; DRUG POTENCY; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NONHUMAN; STEREOCHEMISTRY; X RAY ANALYSIS;

ANIMALS; BIPHENYL COMPOUNDS; CRYSTALLOGRAPHY, X-RAY; DIPEPTIDES; INDICATORS AND REAGENTS; KINETICS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; OPTICAL ROTATION; RECEPTOR, ENDOTHELIN A; RECEPTOR, ENDOTHELIN B; RECEPTORS, ENDOTHELIN; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032544171     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00388-6     Document Type: Article

References (16)

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6. 3. Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, Th.; Pitterna, Th.; Iwasaki, G.; Okada, T.; Yamamura, T.; Hayakawa, K. Bioorg. Med. Chem. Lett accepted.
7. B receptors expressed in CHO (Chinese hamster ovary) cells. For a detailed description of the binding assay: Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. WO97/11960.
8. 3. A total of 4719 independent intensities were measured of which 1011 were classified as observed with I>3σ(I). The structure was solved by direct methods (Program SHELXS86). The structure was refined using full matrix least squares calculations with isotropic displacement parameters for S and anisotropic ones for all the other non-hydrogen atoms (Program CRYSTALS). The positions of the hydrogen atoms were calculated and not refined. The final R-factor for 157 variables was 0.086. The authors will deposit the atomic coordinates with the Cambridge Crystallographic Data Centre. They can be obtained on request from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EW, UK.
9. 6. When the same coupling reaction was carried out using the Boc protected fragment (13) with the right hand fragment (2), the isomerization of the asymmetric center was surpressed to give the mixtures in 1:1-3:2 ratio. formula presented
10. 7.1-Menthol was also applied to the isomer separation as the chiral auxiliary. Although separation of the diastereoisomers (14) by HPLC was easier than 5, removal of the chiral secondary alcohol by hydrolysis was unsuccessful. Drastic conditions resulted in degradation of the isoxazol ring (15).
11. 8. Chiral amines such as (D)-(+)-phenylethylamine, (-)-brucine, cinchonidine, or quinine were also tried to use for the chiral resolution of the acid (1) without success
12. 3).
13. 10. Grieco, P. A.; Bahsas, A. J. Org. Chem. 1987, 52, 5746.
14. 11. When acylation of 8 with 3,5-dimethylbenzoyl chloride was performed prior to methylation, the chiral center was racemized to some extent by the base (NaH) used for methylation.
15. 3).
16. 13. Chiralpak AD (Daicel): hexane : EtOH : TFA=SS : 15 : 0.5 (1.0 ml/min). 11 [(L,D)-isomer], 33.1 min; 4 [(L,L)-isomer], 41.6 min; 3 [(D,L)-isomer], 64.7 min; 12 [(D,D)-isomer], 127.0 min.