GS9857 synthesis

9synthesis methods

Product Name:GS9857
CAS Number:1535212-07-7
Molecular formula:C40H52F4N6O9S
Molecular Weight:868.93

Voxilaprevir is not in stock, may be available through custom synthesis. For cost-effective reason, minimum 1 gram order is requested. The product will be characterized by NMR, HPLC and MS analysis. Purity (HPLC) is usually >98%. CoA, QC data, MSDS will be provided when product is successfully made. The estimated lead time is 2-3 months. Please send email to sales@medkoo.com to inquire quote. Synthetic Description Reference: Cagulada, Amy; Chan, Johann; Chan, Lina; Colby, Denise A.; Karki, Kapil Kumar; Kato, Darryl; Keaton, Katie Ann; Kondapally, Sudha; Levins, Chris; Littke, Adam; Martinez, Ruben; Pcion, Dominika; Reynolds, Troy; Ross, Bruce; Sangi, Michael; Schrier, Adam J.; Seng, Pamela; Siegel, Dustin; Shapiro, Nathan; Tang, Donald; Taylor, James G.; Tripp, Jonathan; Waltman, Andrew W.; Yu, Lawrence. Synthesis of an antiviral N-(3-ethyl)prolyl-1-aminocyclopropanecarboxylic acid peptide and new routes to its difluoromethylaminocyclopropanecarboxylic acid intermediate. Assignee Gilead Sciences, Inc., USA. US 20150175626. (2015). Synthetic Description Reference: Bringley, Dustin; Chan, Johann; Fung, Peter; Keaton, Katie; Lapina, Olga; Morrison, Henry; Pcion, Dominika. Crystalline forms of an antiviral N-(3-ethyl)prolyl-1-aminocyclopropanecarboxylic acid peptide. Assignee Gilead Sciences, Inc., USA. US 20150175625. (2015). Synthetic Description Reference: Bjornson, Kyla; Canales, Eda; Cottell, Jeromy J.; Karki, Kapil Kumar; Katana, Ashley Anne; Kato, Darryl; Kobayashi, Tetsuya; Link, John O.; Martinez, Ruben; Phillips, Barton W.; Pyun, Hyung-Jung; Sangi, Michael; Schrier, Adam James; Siegel, Dustin; Taylor, James G.; Tran, Chinh Viet; Trejo Martin, Teresa Alejandra; Vivian, Randall W.; Yang, Zheng-Yu; Zablocki, Jeff; Zipfel, Sheila. Preparation of N-(3-alkyl- and 3-carbocyclyl)prolyl-1-aminocyclopropanecarboxylic acid peptides as inhibitors of hepatitis C virus. Assignee Gilead Sciences, Inc., USA. WO 2014008285. 2014).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

Reference: Cagulada, Amy; Chan, Johann; Chan, Lina; Colby, Denise A.; Karki, Kapil Kumar; Kato, Darryl; Keaton, Katie Ann; Kondapally, Sudha; Levins, Chris; Littke, Adam; Martinez, Ruben; Pcion, Dominika; Reynolds, Troy; Ross, Bruce; Sangi, Michael; Schrier, Adam J.; Seng, Pamela; Siegel, Dustin; Shapiro, Nathan; Tang, Donald; Taylor, James G.; Tripp, Jonathan; Waltman, Andrew W.; Yu, Lawrence. Synthesis of an antiviral N-(3-ethyl)prolyl-1-aminocyclopropanecarboxylic acid peptide and new routes to its difluoromethylaminocyclopropanecarboxylic acid intermediate. Assignee Gilead Sciences, Inc., USA. US 20150175626. (2015).

(33R,34S,35S,91R,92R,5S,E)-5-(tert-butyl)-34-ethyl-14,14-difluoro-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxylic acid

1535212-06-6
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1360828-80-3 Synthesis

(1R,2R)-1-amino-2-(difluoromethyl)-N-(1-methylcyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride

1360828-80-3
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1535212-07-7
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Yield:1535212-07-7 95 mg

Reaction Conditions:

with dmap;N-ethyl-N,N-diisopropylamine;HATU in N,N-dimethyl-formamide at 20; for 0.666667 h;

Steps:

17.7 Step 7. Preparation of Example 17:

Step 7. Preparation of Example 17: A mixture of carboxylic acid 17-6 (153 mg, 0.247 mmol), Intermediate AlO (90 mg, 0.297 mmol), HATU (113 mg, 0.297mmol), DMAP (45 mg, 0.37 mmol) and DIPEA (0.215 mL, 1 .24 mmol) in DMF (1 .5 mL) was stirred at rt for 40 minutes. The mixture was diluted with 2 N aqueous HCI (2 mL) and extracted with dichioromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product mixture was purified by silica gel chromatography (EtOAc in hexanes: 30% - 95%) to give Example 17 (95 mg). Analytic HPLC RetTime: 8.79 mi LCMS-ESI(m/z): [M+H]calcd for C40H53F4N609S: 869.3; found: 869.2. 1H NMR (400 MHz,ODd3) 6 9.948 (br s, 1 H), 7.99 (d, J = 9.2 Hz, 1 H), 7.29 (dd, J = 8.8, 2.4 Hz, 1 H),7.09 (d, J = 2.8 Hz, 1 H), 6.57 (br s, 1 H), 5.97 (td, JH-F = 52 Hz, J = 6.8 Hz, 1 H),5.92 (d, J = 3.6 Hz, 1 H), 5.322 (d, J = 9.6 Hz, 1 H), 4.42 (ap d, J = 7.2 Hz, 1 H),4.40 (ap s, 1 H), 4.34 (ap d, J = 10 Hz, 1 H), 4.08 (dd, J = 12.0, 3.6 Hz, 1 H), 3.99-3.94 (m, 1H), 3.96 (5, 3H), 3.67 (m, 1H), 2.52 (m, 2H), 2.06 (m, 1H), 1.93 (m,2H), 1 .77 (m, 2H), 1 .63 (m, 3H), 1 .50 (5, 3H), 1 .56 - 1 .42 (m, 4H), 1 .25 (m, 1 H),1.19 (t, J = 7.2 Hz, 3H), 1.09 (5, 9H), 1.10-0.93 (m, 2H), 0.85 (m, 2H), 0.69 (m,1 H), 0.49 (m, 1 H).

References:

WO2014/8285,2014,A1 Location in patent:Page/Page column 211; 212

tert-butyl (33R,34S,35S,91R,92R,5S,E)-5-(tert-butyl)-34-ethyl-14,14-difluoro-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphan-12-ene-35-carboxylate

1535212-03-3
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1535212-07-7
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References

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1535212-07-7
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References

L-Valine, 3-Methyl-N-[[[(1R,2R)-2-(4-penten-1-yl)cyclopropyl]oxy]carbonyl]-

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1535212-07-7
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L-Valine, 3-methyl-N-[[[(1R,2R)-2-(4-oxobutyl)cyclopropyl]oxy]carbonyl]-

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1535212-07-7
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References