Synthesis of a histamine H(3) receptor antagonist-manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup.
We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. dpippel@its.jnj.com
Daniel J
DJ
Pippel
Lana K
LK
Young
Michael A
MA
Letavic
Kiev S
KS
Ly
Bita
B
Naderi
Aki
A
Soyode-Johnson
Emily M
EM
Stocking
Nicholas I
NI
Carruthers
Neelakandha S
NS
Mani
D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D001894:Borohydrides / Q000737:chemistry*; D002845:Chromatography / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D006909:Hydroxyproline / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D012964:Sodium / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013696:Temperature
C550998:1-(2-(4-cyclobutyl-(1,4)diazepane-1-carbonyl)-4-(3-fluorophenoxy)pyrrolidin-1-yl)ethanone; D001381:Azepines; D001894:Borohydrides; D054828:Histamine H3 Antagonists; D011759:Pyrrolidines; D012997:Solvents; D012964:Sodium; D006909:Hydroxyproline