Trifluoroacetic acid → N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-hydroxy-2-(4-methoxyphenyl)ethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine

HRID 254023Notes

Reaction equation

HRID 254023 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.C(OC([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]([C:55]([O:57]C(C)(C)C)=[O:56])[NH2:54])=O)(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:54][C@@H:53]([C:55]([OH:57])=[O:56])[CH2:52][CH2:51][CH2:50][CH2:49][NH2:48])=[O:36])=[O:32])=[CH:38][CH:39]=2)=[CH:6][CH:7]=1

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 4311764Sodium borohydrideHCID 56777341H-D-Lys(boc)-otbu hcl2×HCID 66842806N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine

Product 1

HCID 66842777N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-hydroxy-2-(4-methoxyphenyl)ethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysineYield 91%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

A mixture of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.0177 g, 0.032 mmol tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (0.0141 g, 0.042 mmol), N-methylmorpholin (0.0106 ml, 0.096 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.013 g, 0.042 mmol) was added and the mixture was stirred for 2 h. Additional tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (0.004 g, 0.012 mmol) was added and after 0.5 h. TBTU (0.008 g, 0.025 mmol) was added and the mixture was stirred for additional 10 minutes. Trifluoroacetic acid (0.65 ml) was added and after 3 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using a gradient of 5-100% MeCN in 0.15% 1M ammonium acetate buffer as eluent. After removing the solvents under reduced pressure, the intermediate (M/z 681.4) was dissolved in methanol (3 ml). NaBH4 (0.008 g, 0.211 mmol) was added and when the reaction was complete a few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.020 g (91%) of the title product was obtained. NMR (500 MHz, CD3COOD) 1.41-1.52 (m, 2H), 1.58-1.78 (m, 3H), 1.90-2.02 (m 1H), 2.86-3.08 (m, 4H), 3.76 (s, 1.5H), 3.77 (s, 1.5), 3.90-4.06 (m, 3H), 4.48 (dd, 1H), 4.60-4.62 (m, 2H), 4.73-4.78 (m, 1H), 4.83-4.89 (m, 1H), 6.80-6.84 (m, 2H), 6.98-7.08 (m, 4H), 7.21-7.31 (m, 4H), 7.31-7.36 (m, 2H), 8.20 (d, NH), 8.54 (t, NH).

Workup

  1. stirringthe mixture was stirred for 2 h
  2. stirringthe mixture was stirred for additional 10 minutes
  3. customwas removed under reduced pressure
  4. customThe residue was purified by preparative HPLC on a Kromasil C8-column
  5. customAfter removing the solvents under reduced pressure
  6. dissolutionthe intermediate (M/z 681.4) was dissolved in methanol (3 ml)
  7. additionwas added
  8. customThe solvent was removed under reduced pressure
  9. customthe residue was purified by preparative HPLC on a Kromasil C8-column
  10. customAfter freeze-drying

Sources & evidence

ORD record
ord-795f9c05026344fc99cf47f0d0a08927
Source dataset
uspto-grants-2011_01
Patent number
US07871998B2

Reaction notes

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