4-Methylmorpholine → N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycylglycine

HRID 1176071Notes

Reaction equation

HRID 1176071 reaction equation
[Si]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([OH:39])=O)=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.Cl.[NH2:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([O:58]C)=[O:57])=[O:53].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C(Cl)Cl>[F:48][C:45]1[CH:44]=[CH:43][C:42]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([OH:58])=[O:57])=[O:53])=[O:39])=[CH:40][CH:41]=2)=[CH:47][CH:46]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 590018TBDMS etherHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 13029724Methyl 2-(2-aminoacetamido)acetate hydrochlorideHCID 68774413{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid

Product 1

HCID 68773488N-({4-[(2R,3R)-3-{[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycylglycine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (19.4 mg, 0.027 mmol) (9.7 mg, 0.014 mmol) was dissolved in DCM (1 ml, dry). Methyl glycylglycinate hydrochloride (3.1 mg, 0.017 mmol) followed by N-methylmorpholine (4 μl, 0.041 mmol) were added. TBTU (5.8 mg, 0.018 mmol) was added and the reaction mixture was stirred for 2 hours. LC-MS confirmed the formation of the methylester and TBDMS-ether of the title compound, M/z: 839.58 (M−1). The solvent was removed under reduced pressure. The residue was dissolved in MeCN (1 ml). Triethyamine (40 μl, 0.287 mmol), water (10 μl) and LiCl (23.6 mg, 0.55 mmol) were added and the reaction mixture was stirred over the weekend. LC-MS showed complete hydrolysis giving the TBDMS-ether of the title compound, M/z: 827.32 (M+1) and 825.56 (M−1). The solvent was removed under reduced pressure. The crude was dissolved in acetic acid (1 ml) and water (100 μl) and LiCl (27 mg, 0.64 mmol) were added. The reaction mixture was stirred for 6 hours and 30 minutes. Additional LiCl (30 mg, 0.71 mmol) and water (40 μl) were added and the reaction mixture was stirred overnight. The acetic acid was co-evaporated with toluene and the residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 60% MeCN in a 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give a the title compound. 2.91-2.96 (m, 2H), 2.98 (s, 3H), 3.38 (d 2H), 3.74 (d, 2H), 4.01 (s, 2H), 4.33 (d, 1H), 4.55 (s, 2H), 4.72 (t, 1H), 5.10 (d, 1H), 7.01 (d, 2H), 7.11 (t, 2H), 7.21 (d, 2H), 7.32-7.42 (m, 6H), 7.47 (b, 1H), 8.37 (t, 1H). M/z: 713.33 (M+1) and 711.45 (M−1).

Workup

  1. additionwere added

Sources & evidence

ORD record
ord-46b0d749c0ee410986d80d5bd35c88cb
Source dataset
uspto-grants-2010_11
Patent number
US07842684B2

Reaction notes

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