Diisopropylcarbodiimide → (-)-3-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin-7-yl)phenyl)propanamide

HRID 1525856Notes

Reaction equation

HRID 1525856 reaction equation
[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)[CH2:16][C:17](O)=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.C([N:40]=C=NC(C)C)(C)C.[Br-].[NH4+].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:35]=[C:34]6[C:29]([CH:30]=[CH:31][CH:32]=[N:33]6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)[CH2:16][C:17]([NH2:40])=[O:18])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 12734DiisopropylcarbodiimideHCID 25514Ammonium Bromide2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 712707553-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin-7-yl)phenyl)propanoic acid

Product 1

HCID 71270904(-)-3-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin-7-yl)phenyl)propanamide

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalyst3×HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 3-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin-7-yl)phenyl)propanoic acid (0.152 mmol) in dichloromethane (1 mL) was treated with 4-(dimethylamino)pyridine (8.19 μmol), N,N′-diisopropylcarbodiimide (0.183 mmol), and ammonium bromide (0.229 mmol). The reaction mixture was sealed and was allowed to stir at room temperature overnight. Minimal conversion of starting material occurred, so additional 4-(dimethylamino)pyridine (8.19 μmol) was added and the reaction was stirred 3 hours at room temperature, at which point the mixture was diluted with acetonitrile (1 mL), and the reaction vessel was sealed and was stirred at 40° C. overnight. Minor conversion had occurred, so N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.183 mmol), 4-(dimethylamino)pyridine (0.457 mmol) and an additional portion of ammonium bromide (0.229 mmol) were added. The reaction mixture was sealed and allowed to stir at room temperature overnight. At this point the reaction was concentrated to dryness under a nitrogen stream. The crude material was purified by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA). The fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v ammonium hydroxide solution. This was concentrated to a minimal volume in vacuo and was then extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, filtered and concentration in vacuo to afford the racemate of the title compound. Resolution of the racemate using chiral HPLC (Chiralpak AS-H, 9:1 acetonitrile:methanol) followed by concentration in vacuo and lyophilization from water with 5% acetonitrile yielded the title compound as a white solid in >99% ee (23% yield). MS(ES)+ m/e 485.4 [M+H]+. αD=−20 deg (c=0.01, 9:1 acetonitrile:methanol).

Workup

  1. customThe reaction mixture was sealed
  2. stirringthe reaction was stirred 3 hours at room temperature, at which point the mixture
  3. customthe reaction vessel was sealed
  4. stirringwas stirred at 40° C. overnight
  5. customThe reaction mixture was sealed
  6. stirringto stir at room temperature overnight
  7. concentrationAt this point the reaction was concentrated to dryness under a nitrogen stream
  8. customThe crude material was purified by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA)
  9. additionThe fractions containing the desired product
  10. concentrationThis was concentrated to a minimal volume in vacuo
  11. extractionwas then extracted with dichloromethane three times
  12. dry with materialThe combined organic layer was dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentration in vacuo

Sources & evidence

ORD record
ord-5f8092d8b4454fcd921b0094c7097518
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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