Two asymmetric syntheses of AMG 221, an inhibitor of 11β- hydroxysteroid dehydrogenase type 1

Journal of Organic Chemistry

Volumn 74, Issue 10, 2009, Pages 3833-3842

  Caille, Seb ^a   Cui, Sheng ^a   Hwang, Tsang Lin ^a   Wang, Xiang ^a   Faul, Margaret M ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ASYMMETRIC SYNTHESIS; CHEMICAL EQUATIONS; HYDROXYACIDS; HYDROXYSTEROID DEHYDROGENASE; INVERSION OF CONFIGURATION; STARTING MATERIALS; STEP SEQUENCES; TRIMETHYLSILYL;

AMINES; DEHYDROGENATION; ENZYMES; THIOUREAS; UREA;

SYNTHESIS (CHEMICAL);

11BETA HYDROXYSTEROID DEHYDROGENASE 1; 2 AMINOTHIAZOLONE DERIVATIVE; 2 HYDROXYACID; AMG 221; AMINE; CYANOHYDRIN; ENZYME INHIBITOR; THIAZOLE DERIVATIVE; THIOUREA; TRIMETHYLSILYLCYANOHYDRIN; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; ASYMMETRIC SYNTHESIS; CHEMICAL STRUCTURE; CHIRALITY; CYCLIZATION; DRUG SYNTHESIS; STEREOCHEMISTRY;

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ALCOHOLS; CHLORIDES; CYCLIZATION; ENZYME INHIBITORS; SOLVENTS; STEREOISOMERISM; SUBSTRATE SPECIFICITY; THIAZOLES;

EID: 65949101862     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo900287b     Document Type: Article

References (54)

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24. A baseline separated chiral GC assay was developed for 14. No such assay was available for 4. It was assumed that no important change in % ee occurred going from 14 to 4. This assumption was proven correct after synthesis of 2 from 4. The reported yield of 14 (40-42%) includes 4-6% of 4 (if 4 is excluded the isolated yield of 14 is 34-38%) generated in the KOH step and separated by chromatography. One plausible reason for the low isolated yield of 14 is the difficulty in extracting this species from water (high water solubility, see the Experimental Section, ref 38).
25. The aliquots were treated with KOH to generate 14 and allow for quantitative achiral and chiral analyses (GC). The assay yields of 14 were typically 10-20% higher than the corresponding isolated yields.
26. Mixtures of 2 and its diastereomer (having the opposite absolute configuration at C-5 on the 2-aminothiazolone ring, compound 16) of >85/15 DR could be upgraded to >99.5/0.5 DR through a single recrystallization of a mixture of the corresponding salts (made with a simple achiral acid). The complete details associated with this upgrade will be included in a separate paper, which is currently in preparation. Alternatively, the same two compounds could be separated by chiral chromatography.
27. The absolute configuration of amine 6 was ascertained using single-crystal X-ray analysis of the phthalamic acid salt presented below, prepared from 6 and a phthalamic acid derivative of known absolute configuration (R). 2 was synthesized from 6 and the absolute configuration of 2 at C-5 was thus determined by single-crystal X-ray analysis of 2. For this last analysis, although the angles refine to 90°, the data show that the crystal is truly monoclinic, with the R(int) for the orthorhombic system of 0.47 and that of the other two monoclinic systems 0.509 and 0.519, respectively, with the correct monoclinic setting value of 0.020. (Chemical Equation Presented)
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47. Complex ent-11 was synthesized utilizing an identical procedure and the opposite enantiomer of the chiral Salen ligand.
48. We have encountered difficulties with regard to the completion of the subsequent mesylation reaction when the residue did not remain under high vacuum (∼1 mmHg) for the described amount of time (12 h). If any problem is encountered with completion of the mesylation, the cyanohydrin intermediate can be distilled (20 mmHg, 110°C). We have utilized this alternative procedure and it resolved any issues observed with completion of the mesylation reaction.
49. A fourth extraction with IPAC still yielded ∼4% of 14. This finding supports the hypothesis that the low isolated yield in this step is in part due to the water solubility of 14.
50. 1H NMR integration ratios obtained from a mixture of 4 and 15. The chromatographic separation of 4 and acid 15 is very challenging.
51. 3, DMF.
52. This lot of ent-7 was of 77% ee. The difference in % ee relative with the previous lot (87% ee) arose in the formation of ent-12.
53. The retention times of 2 and 16 were slightly shifted in this trace relative to other data. The identity of the peaks was confirmed employing a 50/50 mixture of 2/16.
54. Racemic 7 was prepared according to the procedure described in the following report: Mori, K.; Ebata, T.; Takechi, S. Tetrahedron 1984, 40, 1761-1766.