메뉴 건너뛰기




Volumn 15, Issue 1, 2011, Pages 64-72

Kilogram synthesis of a second-generation LFA-1/ICAM inhibitor

Author keywords

[No Author keywords available]

Indexed keywords

DEPROTECTION; HIGH QUALITY; HYDANTOINS; PROCESS DEVELOPMENT; SYNTHESIS FEATURES;

EID: 79251503933     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100225g     Document Type: Article
Times cited : (11)

References (29)
  • 1
    • 79251515252 scopus 로고    scopus 로고
    • For a discussion on the inhibition of LFA-1/ICAM-1as an approach to treating autoimmune diseases see
    • For a discussion on the inhibition of LFA-1/ICAM-1as an approach to treating autoimmune diseases see
  • 3
    • 79251471524 scopus 로고    scopus 로고
    • For a discussion of therapeutic options for treatment of psoriasis, see
    • For a discussion of therapeutic options for treatment of psoriasis, see
  • 6
    • 79251531411 scopus 로고    scopus 로고
    • For other small-molecule LFA-1/ICAM-1 antagonists as potential drugs please see
    • For other small-molecule LFA-1/ICAM-1 antagonists as potential drugs please see
  • 14
    • 79251490446 scopus 로고    scopus 로고
    • Due to the higher level of reactivity of isopropanol relative to that of tert -butanol, the isopropyl impurity 6 is enriched to a higher level than the level of isopropanol observed in the tert -butanol.
    • Due to the higher level of reactivity of isopropanol relative to that of tert -butanol, the isopropyl impurity 6 is enriched to a higher level than the level of isopropanol observed in the tert -butanol.
  • 16
    • 79251500422 scopus 로고    scopus 로고
    • note
    • Identification of alternative reagents for the tert -butyl ester formation was desired to avoid the use of the very odiferous thionyl chloride. Ideally, an alternative procedure would also obviate the need to source ultra-pure tert -butanol which was free of isopropanol.
  • 18
    • 79251503050 scopus 로고    scopus 로고
    • note
    • To the best of our knowledge, this mechanism has not been studied in detail. Our hypothesis regarding the induction period is that at the beginning of the reaction the majority of the DMAP is not initially available to enter the catalytic cycle as it forms a salt with the nicotinic acid.
  • 19
    • 79251489849 scopus 로고    scopus 로고
    • note
    • 2O was utilized on scale-up with a molar feed rate of 0.163 mol/min. Since the gas evolution was addition controlled, the maximum potential offgassing rate was ∼7.4 L/min.
  • 21
    • 79251489552 scopus 로고    scopus 로고
    • Throughout this publication mL/g refers to mL of solvent to grams of input material.
    • Throughout this publication mL/g refers to mL of solvent to grams of input material.
  • 22
    • 79251487265 scopus 로고    scopus 로고
    • The same impurity was also observed during the Discovery development work (see ref. 6).
    • The same impurity was also observed during the Discovery development work (see ref. 6).
  • 23
    • 79251469497 scopus 로고    scopus 로고
    • note
    • 7 in the presence of 2 equiv of DBU. After 2 h, NMR and HPLC indicated ∼15% formation of the undesired diastereomer 10. This amount increased to ∼30% after 4 h of heating.
  • 24
    • 79251475339 scopus 로고    scopus 로고
    • 2O was evidenced by absence of the tert -butyl carboxylate of 4a which could be observed if 4b was charged to the mixture immediately.
    • 2O was evidenced by absence of the tert -butyl carboxylate of 4a which could be observed if 4b was charged to the mixture immediately.
  • 25
    • 79251513370 scopus 로고    scopus 로고
    • Yields reported are corrected yields, and the HPLC area percent purity reported is the combined HPLC area percent purity for the spirocyclic hydantoin 5a and p -TSA.
    • Yields reported are corrected yields, and the HPLC area percent purity reported is the combined HPLC area percent purity for the spirocyclic hydantoin 5a and p -TSA.
  • 26
    • 79251481235 scopus 로고    scopus 로고
    • A D90 < 60 -m was desired.
    • A D90 < 60 -m was desired.
  • 27
    • 79251488547 scopus 로고    scopus 로고
    • For a review on the Ritter reaction see
    • For a review on the Ritter reaction see
  • 29
    • 79251487595 scopus 로고    scopus 로고
    • note
    • The high loss of 1 to mother liquor may have been due to the uncontrolled crystallization, the new morphology or the higher than previously observed level of impurities. It is notable that pXRD indicated 1 had the correct polymorphic form with little to no amorphous content.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.