Macrocyclic HCV NS3 inhibits tripeptide synthesis
A compound, closed-loop metathesis technology, applied in the direction of cyclic peptides, peptides, drug combinations, etc., can solve the problems of difficult to achieve virological cure, and achieve the effect of high total yield and high efficiency
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Embodiment 1
[0448] Example 1. (1aR, 5S, 8S, 9S, 10R, 22aR)-5-tert-butyl-N-[(1R, 2R)-2-(difluoromethyl)-1-{[(1-methyl Cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4 ,5,6,9,10,18,19,20,21,22,22a-Tetrahydro-8H-7,10-methyl bridge-cyclopropane[18,19][1,10,3,6 Synthesis of ]dioxadiazaaryl ninecyclo[11,12-b]quinoxaline-8-carboxamide (I) via route I
[0449] Compounds of Formula I are synthesized via Route I as follows:
[0450]
[0451] Synthesis of intermediates for compounds of formula I
[0452] A. Synthesis of (2S,3S,4R)-3-ethyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester tosylate (II)
[0453]
[0454] The order of reduction of the double bond and ketone is reversed to form new intermediates, B (R = tert-butyl) and C (R = tert-butyl). The tert-butyl ester was used in the preparation of D in US Publication No. 2014-0017198; however, it was directly converted to the methyl ester tosylate without chromatography and crystallize...
Embodiment 2
[0753] Example 2. (1aR, 5S, 8S, 9S, 10R, 22aR)-5-tert-butyl-N-[(1R, 2R)-2-(difluoromethyl)-1-{[(1-methyl Cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4 ,5,6,9,10,18,19,20,21,22,22a-Tetrahydro-8H-7,10-methylcyclopropane[18,19][1,10,3,6] Synthesis of Dioxadiazaaryl Nonadecacyclo[11,12-b]quinoxaline-8-carboxamide (I) via Route II
[0754]
[0755] a. Hydrolysis, ring-closing metathesis and hydrogenation:
[0756]
[0757] Route II differs from Route I of Example 1 in the order of assembly. Compounds of formula VIII are first hydrolyzed to provide compounds of formula XVIII followed by ring-closing metathesis to provide compounds of formula XIX which upon hydrogenation yield compounds of formula XI. The reaction conditions for hydrolysis, ring-closing metathesis, and hydrogenation are similar to those disclosed in Pathway I. Compounds of formula XI were converted to compounds of formula I as described in Example 1 above. ...
Embodiment 3
[0758] Example 3. (1aR, 5S, 8S, 9S, 10R, 22aR)-5-tert-butyl-N-[(1R, 2R)-2-(difluoromethyl)-1-{[(1-methyl Cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4 ,5,6,9,10,18,19,20,21,22,22a-Tetrahydro-8H-7,10-methylcyclopropane[18,19][1,10,3,6] Synthesis of Dioxadiazaaryl Nonadecacyclo[11,12-b]quinoxaline-8-carboxamide (I) via Route III
[0759] Compounds of formula I are synthesized via route III as follows:
[0760]
[0761] Synthesis of A.XV
[0762]
[0763] Compound XIV (R=CH 3 ) (180 mg, 0.35 mmol, 1 equiv) and XIII (180 mg, 0.67 mmol, 1.9 equiv) were dissolved in 15 volumes of degassed toluene (2.7 mL). The system was inertized under nitrogen and loaded with Zhan 1B catalyst (53 mg, 0.073 mmol, 0.20 equiv.). The mixture was warmed to about 95°C and stirred for about 45 minutes. The reaction was cooled to about 20 °C and purified by silica gel chromatography to provide intermediate XV (R=CH 3 ). LCMS(M+1):749m / z. 1 ...
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