Triethylamine → tert-butyl [(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

HRID 530694Notes

Reaction equation

HRID 530694 reaction equation
Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH:31]1([CH2:34][O:35][C:36]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])[CH2:39][NH:38][CH2:37]2)[CH2:33][CH2:32]1.[C:47]([O:51][C:52]([NH:54][C@H:55]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=1)[C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[CH:31]1([CH2:34][O:35][C:36]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])[CH2:37][N:38]([C:56](=[O:57])[C@H:55]([NH:54][C:52](=[O:53])[O:51][C:47]([CH3:48])([CH3:49])[CH3:50])[CH2:59][C:60]3[CH:61]=[CH:62][C:63]([O:66][CH3:67])=[CH:64][CH:65]=3)[CH2:39]2)[CH2:32][CH2:33]1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7017908Boc-O-methyl-D-tyrosineHCID 711523703-Cyclopropylmethoxy-3-o-tolylazetidine hydrochloride

Product 1

HCID 86729200tert-butyl [(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamateYield 41.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 21899848Ethylacetate heptaneSolvent

Procedure

1.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.2 mmol), 1.4 g of N-hydroxybenzotriazole (10.2 mmol), 3.8 ml of triethylamine (27.2 mmol) and then 2.2 g (8.7 mmol) of 3-cyclopropylmethoxy-3-o-tolylazetidine hydrochloride dissolved in 35 ml of N,N-dimethylformamide are successively added to a solution of 2.7 g (9.2 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propanoic acid in 55 ml of N,N-dimethylformamide. The reaction medium is stirred at room temperature for 38 hours. A 1/1 heptane/ethyl acetate mixture is added and the reaction medium is washed with aqueous 1N sodium hydroxide solution. The organic phase is then washed with aqueous 1N hydrochloric acid solution, dried over sodium sulfate, filtered and concentrated under vacuum. 2.7 g of crude residue are obtained and are purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 95/5 to 60/40. 1.8 g (41%) of tert-butyl [(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a white solid.

Workup

  1. washthe reaction medium is washed with aqueous 1N sodium hydroxide solution
  2. washThe organic phase is then washed with aqueous 1N hydrochloric acid solution
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. custom2.7 g of crude residue are obtained
  7. customare purified by chromatography on silica gel
  8. washeluted with a heptane/ethyl acetate mixture
  9. temperaturethe polarity being increased from 95/5 to 60/40

Sources & evidence

ORD record
ord-42e3484d30c846f7a9a2b5360cf1dca4
Source dataset
uspto-grants-2016_05
Patent number
US09353083B2

Reaction notes

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