![](/CAS/GIF/74844-91-0.gif)
N-Boc-trans-4-Hydroxy-L-proline methyl ester synthesis
- Product Name:N-Boc-trans-4-Hydroxy-L-proline methyl ester
- CAS Number:74844-91-0
- Molecular formula:C11H19NO5
- Molecular Weight:245.27
![Boc-Hyp-OH](/CAS/GIF/13726-69-7.gif)
13726-69-7
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![(TRIMETHYLSILYL)DIAZOMETHANE](/CAS/GIF/18107-18-1.gif)
18107-18-1
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![N-Boc-trans-4-Hydroxy-L-proline methyl ester](/CAS/GIF/74844-91-0.gif)
74844-91-0
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Yield:74844-91-0 100%
Reaction Conditions:
in methanol at 0; for 1 h;
Steps:
56
To a stirred solution of (2S, 4R) -4-hydroxyproline (Aldrich) (25 g, [108] mmol) in methanol (50 mL) at [0 °C] was added [TRIMETHYLSILYLDIAZOMETHENE] (24.6 g, 216 mmol). The mixture was stirred at [0 °C FOR] 1 hour. The residue obtained on removal of solvent and purification by column chromatography using 50% ethyl acetate in hexanes (27 g, 100%) was used in the next step. To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) [AT-78 °C,] DMSO (18.6 mL, 236 mmol) was added slowly over 15 minutes. After the completion of addition, the above product (2S, [4R)-N-BOC-4-HYDROXYPROLINE] methylester (26.5 g, 108 mmol) in DCM (100 mL) was added at-78 °C for 20 minutes. Triethylamine (54.6 g, 540 mmol) was added followed by stirring at room temperature for 2 hours. The reaction mixture was then washed with 10% aq [HC1] (200 mL) and the organic layer was separated and dried over sodium sulfate. The crude product obtained on removal of solvent was purified on silica gel column chromatography using 50% EtoAc in hexanes to obtain (2S, 4R) -N-Boc-4-Ketoproline methylester (20 g, [78%).] [[0477] 1H] NMR (300 MHz, [CDC13)] 8 4.80 (m, 1), 3.88 (d, [J=8.] 7,2), 3.77 (s, 3), 2.98 (m, 1), 2.58 (m, 1), 1.45 (s, [9) ;] MS (ES+): [244] [(M+1).] [[0478]] To a stirred solution of [(2S,] 4R) -N-Boc-4-Ketoproline methylester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to [0 °C] before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at [0 °C] for lh and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in [5ML] water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water [(LOOML)] and brine 100 mL), dried over [MGS04] and evaporated to dryness. T he residue obtained on removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain 4-Hydroxy-4-allylproline methylester (0.94 g, 80%). [[0479] 1H] NMR (300 MHz, [CDC13)] 8 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 [(D,] [J=4.] 8, 3), 3.50 (m, 3), 2.37 (m, 1), 2.21 (m, 1), 1.39 (d, [J=12.] 9,9) ; MS (ES+): 308 [(M+23).] [[0480]] To a stirred solution of DAST (1.06 g, 6. [58] mmol) in DCM (10 mL) [AT-78 °C,] [4-HYDROXY-4-ALLYLPROLINE] methylester (940 mg, 3.3 mmol) in dry DCM (10 mL) was added slowly. The mixture was then stirred at-78 °C for [LH,] then at-10 °C for an additional [LH.] DCM (50 mL) was added, quenched with [NH4C1] [(10%,] 150 mL) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 5% EtOAc in hexanes as eluent to obtain [4-FLUORO-4-ALLYLPROLINE] methylester (330 mg, 34%). [[0481] IH] NMR (300 MHz, [CDC113)] [&] 5.82 (m, 1), 5.12 (m, 2), 4.43 (m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1), 2.43 (m, 4), 1.37 (dd, [J=4.] 5,13. 8, [9) ;] MS (ES+): [310 (M+23).] [[0482]] To a solution of 4-fluoro-4-allylproline methylester (0. [33] g, 1.15 mmol) in MeOH (15 mL) was added 10% Pd/C (40 mg) and hydrogenated at 1 atmosphere. The catalyst was filtered through celite and washed with methanol. To the product obtained on removal of solvent (330 mg, 1.15 mmol) in THF (12 mL) was added aq lithium hydroxide monohydrate (60 mg, 1. [38] mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was taken up in ethyl acetate (50 mL), washed with 10% citric acid (100 mL) and brine (20 mL). Removal of solvent resulted in 4-fluoro-4-propylproline (310 mg, 100%). [[0483] 1H] NMR [(300] MHz, CD30D) 8 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96 (m, 3); MS (ES-): 274 (M-1). [[0484]] To a solution of 4-fluoro-4-propylproline (310 mg, 1.15 mmol) in DMF (3 mL) at [0 °C,] 7-Methyl MTL 2b [(RL] =Me, R2=Me) (272 mg, 1.15 mmol), HBTU (469 [MG, L] 1.3 mmol) and DIEA (290 mg, 2.3 mmol) was added, left stirred at room temperature for 16 hours. DMF was removed and the residue obtained was purified by 3% MeOH in DCM (40 mg, 93%). The product from the column purification was taken in DCE (6 mL), to which triethylsilane (0.16 mL), TFA (2 mL) and water (0.16 mL) was added and stirred at room temperature for 1.5 hours. Removal of solvent followed by purification on silica gel column chromatography using 10% MeOH in DCM resulted in the title compound as isomeric mixtures with lower RF fraction (160 mg, 50%). [[0485] 1H] NMR (300 MHz, CD30D) 8 5.25 (d, [J=5.] 7, [1),] 4.46 (m, 1), 4.24 (dd, [J=5.] 7,10. 2, 1), 4.08 (m, 2), 3.81 [(D,] [J=2.] 4,1), 3.52 (m, 3), 2.73 (m, 1), 2.10 (m, 4), 1.88 (m, 2), 1.50 (m, 2), 0.99 [(T,] [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (ES+): 409 [(M+L) ;)] and higher Rf fraction (40 mg, [12%). 1H] NMR (300 MHz, CD30D) [8] 5. [38 (D, J=5.] 4,1), 4.46 (m, 1), 4.24 (dd, [J=2.] 7,7. 2, 1), 4.08 (m, 2), 3.81 (d, [J=2.] 4,1), 3.64 (m, 3), 2.73 (m, 1), 2.11 (m, 4), 1.84 (m, 2), 1.47 (m, 2), 0.98 (t, [J=7.] 5,3), 0.91 (dd, [J=3.] 0,6. 9,6) ; MS (METHOD ES+): 409 [(M+1).]
References:
WO2004/16632,2004,A2 Location in patent:Page 124-126
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![N-Boc-trans-4-Hydroxy-L-proline methyl ester](/CAS/GIF/74844-91-0.gif)
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![Di-tert-butyl dicarbonate](/CAS/GIF/24424-99-5.gif)
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![N-Boc-trans-4-Hydroxy-L-proline methyl ester](/CAS/GIF/74844-91-0.gif)
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![Boc-Hyp-OH](/CAS/GIF/13726-69-7.gif)
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![Iodomethane](/CAS/GIF/74-88-4.gif)
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![N-Boc-trans-4-Hydroxy-L-proline methyl ester](/CAS/GIF/74844-91-0.gif)
74844-91-0
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![Boc-Hyp-OH](/CAS/GIF/13726-69-7.gif)
13726-69-7
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![Dimethyl sulfate](/CAS/GIF/77-78-1.gif)
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![N-Boc-trans-4-Hydroxy-L-proline methyl ester](/CAS/GIF/74844-91-0.gif)
74844-91-0
406 suppliers
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