HCID 86145184, compound → HCID 55299788, compound

HRID 709101Notes

Reaction equation

HRID 709101 reaction equation
[CH3:1][CH:2]([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:3]([O:5]N1C(=O)CCC1=O)=[O:4].CC(CC#CCC)C(Cl)=O.OC[C@H](NC(=O)C(C)CC#CCC)C1C=CC=CC=1>>[CH3:1][CH:2]([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:3]([OH:5])=[O:4]

Participants

4

Reactant 3

HCID 86145184HCID 86145184, compoundHCID 90025567HCID 90025567, compoundHCID 118160452HCID 118160452, compound

Product 1

HCID 55299788HCID 55299788, compound

Procedure

(S)-(+)-Dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared by following the sequence of reaction steps described in Scheme 7a, 7f and Scheme 8, Step A. The intermediate 2-methylhept-4-ynoic acid was prepared according to a method described in WO 2011/003058 A1. (S)-(+)-Diethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared according to the method described in the Journal of Medicinal Chemistry, 1986, 29(3), 313-315, except that 2,5-dioxopyrrolidin-1-yl 2-methylhept-4-ynoate (N-hydroxysuccinimide 2-methylhept-4-ynoate) was prepared as an activated acyl species (activated ester) instead of 2-methylhept-4-ynoyl chloride to make the intermediate diastereomeric pair N—((R)-2-hydroxy-1-phenylethyl)-2-methylhept-4-ynamide. The diastereomers were separated by silica gel chromatography and the desired diastereomer was manipulated as described to afford the title intermediate as a clear oil. The absolute stereochemistry of the title intermediate was proven by determination of its specific rotation. [α]Tλ=α/cl, [α]21.9D=+0.574/(0.025 g/1 mL×0.5)=+45.83° (c=1, CHCl3). Literature reported specific rotation from Liebigs Annalen der Chemie, 1989, 11, 1081-1083; [α]20D=+37.7° (c=1, CHCl3); chiral analytical HPLC (stationary phase: Chiralcel OJ-H normal phase 250×4.6 mm; mobile phase: 85:15 hexane/1-propanol; flow rate: 1 mL/min) retention time 6.4 min, 100% purity; TLC Rf 0.32 (solvent system: 4:1 v/v ethyl acetate-hexane); 1H-NMR (CDCl3) δ 3.76-3.80 (m, 6H), 3.11-3.29 (m, 2H), 2.86-2.95 (m, 1H), 2.36-2.44 (m, 1H), 2.26-2.33 (m, 1H), 2.09-2.16 (m, 2H), 1.16-1.20 (m, 3H), 1.06-1.11 (m, 3H); MS (ESI+) m/z 247 (M+1).

Workup

  1. custom(S)-(+)-Dimethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared
  2. customthe sequence of reaction steps
  3. custom(S)-(+)-Diethyl(3-methyl-2-oxooct-5-yn-1-yl)phosphonate was prepared
  4. customThe diastereomers were separated by silica gel chromatography

Sources & evidence

ORD record
ord-4b350e30386d4df9a9f1fa07540193c0
Source dataset
uspto-grants-2015_11
Patent number
US09180116B2

Reaction notes

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