Reaktion #10853

Reaktionsgleichung

N-CBZ-isonipecotic acid Benzyl chloroformate

isonipecotic acid

sodium bicarbonate

→

N-CBZ-isonipecotic acid

Ausbeute 86.0%

Lösungsmittel

toluene

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   Extraktionthe mixture was extracted with ether (3×50 ml)
2. 2
   Sonstigeto precipitate
3. 3
   SonstigeThe product was partitioned into ethyl acetate (3×50 mL)
4. 4
   Waschenthe combined organic layers were washed with brine
5. 5
   Trocknendried over magnesium sulfate
6. 6
   Einengenconcentrated in vacuo

Vorschrift

N-CBZ-isonipecotic acid Benzyl chloroformate (16.4 mL, 115 mmol) in toluene (50 mL) was added dropwise to a stirred solution of 12.9 g (100 mmol) of isonipecotic acid (Aldrich) and 21.0 g (250 mmol) of sodium bicarbonate in 200 mL of water. After 14 h, the mixture was extracted with ether (3×50 ml) and the ether layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2, causing the product to precipitate. The product was partitioned into ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 22.6 g (86%) of N-CBZ-isonipecotic acid as a viscous oil. Step B: N-CBZ-4-(BOC-amino)-piperidine A solution of N-CBZ-isonipecotic acid (10.3 g, 38.9 mmol) in tert-butyl alcohol (100 mL) and DCM (100 mL) was treated with diphenylphosphoryl azide (11.8 g, 42.8 mmol), TEA (5.97 mL, 42.8 mmol), and the resulting mixture was heated at reflux for 3 days. The solution was concentrated in vacuo and the residue was partitioned between ether and water. The organic layer was washed successively with 10% aq citric acid, sat. sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to an oil. This residue was purified by silica gel flash chromatography (gradient elution, 7:3 to 1:1 hexane-ether) to afford 3.2 g (25%) of the title compound as a colorless crystalline solid: TLC Rf 0.21 (1:1 hexane/ethyl ether). Step C: 4-(BOC-amino)-piperidine N-CBZ-4-(BOC-amino)-piperidine (3.0 g, 9.0 mmol) was dissolved in ethanol (100 mL) and transferred into a Parr shaker bottle. After adding 10% palladium on carbon (0.5 g), the mixture was shaken under an atmosphere of hydrogen at 50 psi for 0.75 h on a Parr apparatus. The catalyst was removed by filtration through a pad of Celite. The filter cake was washed with ethanol and the combined filtrate and washings were concentrated in vacuo to yield 1.8 g (100%) of crude 4-(BOC-amino)-piperidine as a pale yellow oil. This product was used immediately in the next step without further purification. Step D: [4-(BOC-amino)-piperidine]-(COO-resin) Hydroxymethyl resin (4.0 g of 0.45 mmol/g, 1.8 mmol) was rinsed several times with toluene. A solution of 20% phosgene in toluene (50 mL) was added to the hydroxymethyl resin (2×30 min) to generate the chloroformate intermediate. After rinsing the resin several times with toluene and dioxane, a solution of 4-(BOC-amino)-piperidine (Step C, 1.8 g, 9.0 mmol) in dioxane was added, and the resulting mixture was agitated for 3 h. The resin was rinsed with dioxane, DCM, and dried in vacuo, to provide 4.4 g of the title compound. Step E: BOC-(N-Me-DβNal)-[4-(4-amino-piperidine)]-(COO-resin) An aliquot (0.82 g, ˜0.33 mmol) of the resin from Step D was treated with TFA deblock, neutralized, washed, and coupled with 3 eq of BOC-(N-Me-DβNal) (from Example 4, Step B), 3 eq of BOP, 3 eq of HOBt and 4.5 eq of NMM in DMA/DCM for 1 h, after which a negative ninhydrin test was observed. Step F: FMOC-DβNal-(N-Me-DβNal)-[4-(4-amino-piperidine)]-(COO-resin) The above sample of BOC-(N-Me-DβNal)-[4-(4-amino-piperidine)]-(COO-resin) was deblocked with TFA, neutralized, washed, and coupled with 4 eq of FMOC-D-β-naphthylalanine, 4 eq of BOP-Cl, and 6 eq of DIPEA in DCM overnight, after which a negative ninhydrin test was observed. Step G: (inip)-DβNal-(N-Me-DβNal)-N-(4-piperidinyl) amide, TFA salt The above sample of FMOC-DβNal-(N-Me-DβNal)-[4-(4-amino-piperidine)]-(COO-resin) was deblocked with 20% piperidine/DMA, washed, and coupled with 3 eq of N-BOC-isonipecotic acid (from Example 1, Method B, Step E), 3 eq of BOP, 3 eq of HOBt, and 4.5 eq of NMM in DMA/DCM for 1 h, after which a negative ninhydrin test was observed. The peptide was deblocked with TFA, washed, and dried in vacuo to give (inip)-DβNal-(N-Me-DβNal)-[4-(4-amino-piperidine)]-(COO-resin). This peptide was cleaved from the resin with HF and lyophilized as per the general procedure to provide 88 mg of a crude solid. This solid was purified by reverse phase HPLC (15-20μ, 300 Å, Vydac C-18, 1×50 cm, gradient: 23-38% acetonitrile (0.1% TFA) in water (0.1% TFA) in 60 min at 9 mL/min, rt=43 min) to give 39 mg of the title compound as a colorless powder after lyophilization. MS (electrospray, M+H) 619.4.

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