ChemicalBook CAS DataBase List Posaconazole

Posaconazole synthesis

5synthesis methods

Product Name:Posaconazole
CAS Number:171228-49-2
Molecular formula:C37H42F2N8O4
Molecular Weight:700.78

Several routes to the synthesis of posaconazole have been published in the literature. The most likely route to large scale synthesis uses convergent synthesis of a key chiral THF subunit 101 and aryl piperazine amine 102 followed by introduction of the triazole subunit at the end.The readily accessible allyl alcohol 94 was brominated (PBr3) to give bromide 95 which was alkylated with sodium diethylmalonate and the resulting diester was reduced with NaBH4/LiCl, to give the key diol 97 in very good yields. After scanning many hydrolases to desymmetrize the diol via selective acylation, hydrolase SP 435 was found to be suitable. Thus reaction of the diol 97 in the presence of SP 435 with vinyl acetate in acetonitrile gave monoacetate 98 in greater than 90% yield. Iodine mediated cyclization of the monoacetate 98 with iodine in dichloromethane gave chiral iodide 99 in 86% yield. The iodide was converted to triazole (sodiumtriazole, DMF: DMPU) and immediately followed by hydrolysis of the acetate with sodium hydroxide to provide alcohol 100. Activation of the alcohol to the pchlorobenzene sulfonate 101 proceeded in 76% yield which was then coupled with commercially available amino alcohol piperazine 102 with aqueous sodium hydroxide in DMSO to give amine intermediate 103 in 96% yield. The amine was reacted with benzoyl chloride to give benzoate 104 (97%), which was subsequently converted to triazine of posaconazole.

For the preparation of chiral hydrazine 107, intermediate needed to make the triazolone, lactam 105 was reduced with Red-Al to give (S)-2-benzyloxy propanal 106 (94%) which was then reacted with formyl hydrazine to give hydrazone 107 in 81% yield. Addition of EtMgBr directly to formyl hydrozones 107 gave mixture of (S,S)stereoisomer 109 and (S,R)-diastereomer 110 in relative good diastereoselectivity (94:6) in 55% yield. However, protection of the formyl group as TBDMS ether 108 followed by treatment of the EtMgCl gave 95% yield of the (S,S)-diastereomer 109 and (S,R)-diastereomer 110 in 99:1 ratio.
For finishing off the synthesis, the formyl hydrazine 109 was coupled with the phenyl carbamate 104 in toluene at 75 - 85°C for 12 – 24 hrs. After the completion of coupling, the intermediate was heated at 100 – 110°C for 24 – 48 hrs to completely cyclize to the benzyloxy triazolone 108, which was deprotected with 5% Pd/C and formic acid at room temperature overnight and 40°C for 24 h to give posaconazole (XV) in 80% overall yield. QQ截圖20210210144042.jpg

170985-86-1 Synthesis

170985-86-1
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171228-49-2
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Yield:171228-49-2 95%

Reaction Conditions:

with hydrogenchloride;water at 25 - 63;Temperature;

Steps:

7 Example -7

Example -7: Preparation of 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro- 5(lH-l,2,4-triazol-l-ylmethyl)-3-furanyl]methoxy]phenyl]-l-piperazinyl]phenyl]-2- [(lS,2S)-l-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one of the structural formula (IV) of amorphous form. 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4- difluorophenyl)tetrahydrofuran -3-yl)methoxy)phenyl)piperazin- 1 -yl)phenyl)- 1 -((2S,3S)- 2- (benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one of the structural formula (III) (350.0 g) of crystalline form B-3 was charged to a RBF containing Concentrated Hydrochloric Acid (5.0 vol.) at 25±2°C. The reaction mixture was slowly heated to 63+2 °C and stirred at 63±2°C for 2 to 3h. Reaction mass was cooled to 25±2°C and Dichloromethane (5.0 vol. X 2 times) was charged, stirred and layers were separated. The aqueous layer was added dichloromethane (6.0 vol.) and water (5.0 vol.). The contents were cooled to 15±5°C, pH of the above mass was adjusted to 10 to 12 pH using 25% aqueous sodium hydroxide. Layers were separated. The aqueous layer was re-extracted with dichloromethane (5.0 vol. X 2 times). Combined dichloromethane layers were washed with 10 % aqueous sodium hydroxide (3.0 vol. X 2 times), followed by water (3.0 vol.). Dichloromethane layer was concentrated under vacuum at 43±2°C up to 4.0 volume stage. Acetone (4.0 vol.) was added to the reaction mass. This reaction mass was added dropwise to Cyclohexane (20.0 vol.) at 10 to 14 °C with constant stirring, the reaction mass was slowly warmed to 25 °C and continued to stir at the same temperature for 1 hour. Filtered and washed with Cyclohexane (5.0 vol.) and suck dried; dried in VTD at 60±5°C for 30 to 40 h under vacuum to yield 4-[4-[4-[4-[[ (3R,5R)-5- (2,4- difluorophenyl)tetrahydro-5(lH- 1 ,2,4-triazol- 1 -ylmethyl)-3-furanyl]methoxy]phenyl] - 1 - piperazinyl]phenyl]-2-[(lS,2S)-l-ethyl-2-hydroxy propyl] -2,4-dihydro-3H-l,2,4-triazol- 3- one of the structural formula (IV) of amorphous form with 95 % yield. Characteristic Physico-Chemical Data of Amorphous Form of the Compound of Structural Formula IV Physical appearance: Off-white to white solid X-ray Powder Diffraction Pattern: See Figure 6 DSC: See Figure 7

References:

WO2017/51342,2017,A1 Location in patent:Page/Page column 19; 20