Name: 171228-49-2|4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-Triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one|98%
Brand: Ambeed
SKU: A133379
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1
[ 69171-62-6 ]
[ 171228-49-2 ]
4-(<i>tert</i>-butyl-dimethyl-silanyloxy)-butyric acid 2-{4-[4-(4-{4-[5-(2,4-difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1-methyl-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2001,vol. 42,p. 7141 - 7143

2
[ 10385-30-5 ]
[ 171228-49-2 ]
[ 221615-79-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	To a stirred mixture of 1.0g of 4-benzyloxybutyroic acid from Step (B) 0.507 mmol, 3.62 g of the compound of formula IV (prepared in accordance with the procedure of Example 32 of WO 96/38443, published 5 December 1996) and 0.82 g of the base, 4-(N,N-dimethylamino)pyridine ("DMAP") in 50 mL of methylene chloride, 1.26g of dicyclohexylcarbodimide ("DCC") were added and the resulting reaction mixture was stirred at room temperature until the reaction was determined to be complete (4 hrs) by thin layer chromatography ("TLC"). The reaction mixture was partitioned between 5% aqueous citric acid and EtOAc. The organic phase was separated, washed with water and dried over MgSO4. The organic solvent was removed and the so-formed residue was purified on a silica gel chromatography column using EtOAc as the eluent to provide 2.8 g of the benzyl ether VIII. The H1 NMR was consistent with the structure of VIII. FABMS (Found :[MH]+, 877.4182 C48H55N8O6F2 requires 877.4213); [alpha]D24 = (-) 56.5 (c, 1.01; CHCl3); 1H nmr : deltaH (CDCl3), 8.12 (s,1), 7.80 (s,1), 7.58 (d,1), 7.24-7.43 (m, 8), 6.75 -7.01 (m, 8), 5.18 -5.27 (m,1), 4.64 (A of AB, 1), 4.52 (B of AB, 1), 4.44 (s, 2), 4.16-4.24 (m,1), 4.09 -4.14 (m, 1), 3.76 -3.81 (m, 1), 3.68-3.74 (m, 1), 3.59 -3.65 (m, 1), 3.41-3.46 (m, 2), 3.30 -3.36 (m, 4), 3.18-3.24 (m,4), 2.51-2.66 (m,2), 2.34-2.40 (m, 2), 2.05 -2.12 (m, 1), 1.74-1.99 (m, 4), 1.29 (d, 3), and 0.89 (t, 3).

Reference： [1]Tetrahedron Letters,2001,vol. 42,p. 7141 - 7143
[2]Patent: EP1027349,2005,B1 .Location in patent: Page 11

3
[ 170985-86-1 ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; water; at 25 - 63℃;	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±2C. The reaction mixture was slowly heated to 63+2 C and stirred at 63±2C for 2 to 3h. Reaction mass was cooled to 25±2C 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±5C, 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±2C 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±5C 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
93.6%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In methanol; water; at 50℃; under 750.075 Torr; for 2h;Sealed tube; Large scale;	In the above 100L enameled reactor, 60 L of methanol was added, 4 kg of the compound represented by Formula II, 4 L of hydrochloric acid at a concentration of 36.5 wt% 320 g of a 10% palladium on carbon catalyst (50% water) Sealed reactor, Turn on the stirrer (stirring speed 350 rpm). First with nitrogen replacement kettle air 3 times, And then replaced with hydrogen 3 times, The hydrogen pressure was maintained at 0.1 MPa (gauge) Heated to 50 C, HPLC monitoring reaction, 2h reaction ends. Cooling, Replaced with nitrogen 3 times, Filtration gave 10% palladium on carbon catalyst. The filtrate was poured into another 200L enameled reactor, Add ice, Cooling to 0-5 , A 2 mol / L NaOH solution was added dropwise to the filtrate, Adjust the pH to 11, There is a lot of solid precipitation, After stirring for 2 h, Centrifugal, And washed with water filter cake 3 times, The solid was dried in a 55 C blast oven, To obtain 3.32 kg of product, Figure 1 shows the NMR spectrum of the product, Figure 2 shows the nuclear magnetic spectrum of the product, With reference to Figures 1 and 2, The product is exactly what is required for posaconazole, The yield of the product was calculated to be 93.6% HPLC purity was 99.754%.
84.2%	With hydrogenchloride; In water; at 60 - 65℃;	Concentrated hydrochloric acid (40 ml) was added to a 100 ml three-necked flask, and compound II (8.0 g, 10.1 mmol) was added thereto, stirred and dissolved at 60 to 65 C for 2 to 4 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (120 ml) and washed twice with ethyl acetate (50 ml x 2) to remove impurities. The remaining aqueous phase was added to ethyl acetate (50 ml) and then adjusted to pH 5 by the addition of 20% aqueous ammonia, and the organic phase was separated by collection. The organic phase was washed with sodium chloride solution and concentrated. The concentrate was dissolved in ethanol (240ml), and then the medicinal activated charcoal (0.15g) was added. After refluxing and stirring for 2 ~ 3h, the filtrate was filtered while the filtrate was added with water (16ml). The filter cake was crystallized from ethanol / water = 15: 1 (116 ml) (15 ml / g). After filtration, the cake was vacuum dried (55-60C) to give 5.96 g of a white solid, yield 84.2% and HPLC purity 99.8%.

77.42%	With ammonium formate; palladium(II) hydroxide; In isopropyl alcohol; at 70 - 75℃;	5 g of the compound of formula I is added to 80 ml of isopropanol and 1 g of palladium hydroxide is added.4.8 g of ammonium formate (12 eq), 70-75 C reaction until the starting reaction is complete,The purity of posaconazole in the reaction solution was determined by HPLC to be 96.8%. The reaction solution was filtered under hot water at 40-50 C, and the filtrate was concentrated to dryness. The obtained solid was dissolved in ethyl acetate. The organic phase was washed with brine and concentrated to give a crude product of 4.0 g, yield 90.23%, HPLC purity 98.63 %. The obtained crude product was heated to a clear solution with a mixture of 32 ml of methanol and 8 ml of acetone, and then slowly cooled to room temperature, and filtered to obtain 3.83 g of posaconazole in a yield of 77.42%.The purity by HPLC was 99.68%. Its nuclear magnetic data is basically the same as in the first embodiment.
75%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In methanol; water; at 50℃; for 5h;	Example-16 Preparation of Posaconazole (Formula-1) 5N hydrochloric acid (72 ml) and 10% Pd-C(10 g) were added to a solution of 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3R)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one compound of formula-21 (42 g) in methanol (420 ml). The reaction mixture was hydrogenated for 5 hours under a hydrogen gas pressure of 4-5 kg/cm2 at 50. After completion of reaction, the catalyst was filtered off and washed with methanol. pH of the filtrate was adjusted to ?7.0 using 4N sodium hydroxide. Water was added to the reaction mixture and stirred for 2 hours at 25-35 C. Filtered the separated solid and washed with water. The obtained solid was dissolved in acetone (320 ml) and stirred at reflux temperature for 30 minutes. Filtered the undissolved product and added water to the filtrate and stirred the reaction mixture for 4 hours at 25-35 C. Filtered the separated solid and washed with water. Further the solid was recrystallized from isopropyl alcohol to get the title compound. Purity by HPLC: 99.85%; Yield: 75.0%: Chiral purity by HPLC: 99.82%.
56.4%	With hydrogen bromide; for 4h;Large scale;	6.00 kg of compound (II) and 41.37 kg of mass concentration of 40%Hydrobromic acid(The mass concentration referred to as the mass of hydrogen bromide as a percentage of the total mass of hydrobromide) was added to a 100 L glass reactor,Stirring, heating to 50 ~ 60 , reaction 4 ± 0.5 hours. TLC monitoring reaction, after the reaction is completed. Cooled to 15 to 25 C, 32.27 kg of ethyl acetate was added,Stirring for 0.5 to 1 hour, suction filtration.The filter cake was washed twice with 21.51 kg of ethyl acetate. The filter cake was dissolved in 47.8 kg of dichloromethane,A mass concentration of 10% aqueous sodium hydroxide solution (sodium hydroxide 3.00 kg dissolved in pure water 27.00 kg, said mass concentration means that the mass of sodium hydroxide is the percentage of the total mass of the aqueous sodium hydroxide solution) to pH = 10 ~ 11 (sodium hydroxide aqueous solution to the amount of pH).The layers were allowed to stand, the lower organic phase was collected and the reactor was purged with purified water.The organic phase was added to the reaction vessel and 29.98 kg of purified water was added. Stirring for 10 to 20 minutes, standing and stratifying, collecting the organic phase,The organic phase repeats the above water wash step once. The organic phase was transferred to a 20 L rotary vial, and at a vacuum of -0.08 to -0.1 MPa,Control temperature 40 ~ 50 under reduced pressure to solvent-free distillation, a white solid.The resulting white solid was transferred to a reaction kettle, and 11.69 kg of acetone and 2.36 kg of methanol were added. Temperature rise.0.29 kg of activated carbon was added, and the mixture was stirred for 2 ± 0.5 hours. Filtration by hot, the filtrate transferred to the reactor, heated to 50 ~ 60 , adding purified water 3.00kg, natural cooling to 15 ~ 25 .Stir for 2 to 3 hours. Centrifuge the filter to the solvent-free effluent, filter cake with a mixed solvent (acetone 2.36kg methanol 0.46kg) washing, centrifugal filtration to solvent-free effluent. Will be centrifuged to get the whole batch of wet goods in the vacuum -0.08 ~ -0.1MPa, the control temperature of 40 ~ 50 vacuum drying 6 to 10 hours.A white solid of 3.00 kg was obtained. HPLC purity 99.92%, maximum single product 0.06%, chiral HPLC did not detect isomers, yield: 56.4%.
12.9%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 25 - 30℃; under 1500.15 Torr; for 5h;Large scale;	Add 192 kg of absolute ethanol, 1 kg of palladium on carbon (10%) to a 500 L hydrogenator. 19.2kg POC, the replacement system N2 is replaced five times, H2 is replaced five times, The pressure of the control system H2 is not higher than 0.2 MPa. After incubating for 5 hours at 25~30 C, the monitoring was carried out until the raw materials were ?0.1%. After replacing the system with N2 for five times, the material is pressed out to filter out palladium carbon. The filtrate is controlled to a temperature of T ? 40 C and concentrated under reduced pressure to about 30 L. After adding 40 kg of n-heptane and stirring and crystallization for 3 hours, the temperature was lowered to 0 to 10 C at a rate of 10 C / h, and the filter cake was rinsed with pre-cooled 5 kg of n-heptane. Drain and transfer to the drying room for 40h at 40~45C. Received 15.2 kg of posaconazole.The HPLC purity was 99.8%, the diastereomer content was 0.01%, and the total yield was 12.9%.
		Benzyl ether of posaconazole (12.5g) was taken in 5N hydrochloric acid (25ml) in methanol (125ml), and was hydrogenated for 4-5 hours under a hydrogen gas pressure of 4 kg/cm2 at 50 C in the presence of palladium on carbon (10%, 1.2g). After completion of hydrogenation (monitored by TLC), the catalyst was filtered off and washed with methanol (25ml). The combined filtrate was concentrated to obtain a residue. Residue was dissolved in tert. butanol (250ml) and pH of the reaction mixture was adjusted to 6-7 with 4N sodium hydroxide solution to give 1Og of crude title compound having purity of 93.5% by HPLC.Purification: Crude posaconazole obtained above was taken in methanol (100ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (20ml) and dried at 50 C to obtain 7g of the title compound having purity of 99.5% by HPLC
		EXAMPLE 3PREPARATION OF POSACONAZOLE OF FORMULA (I); In a clean, dry Pari shaker bottle 5 gm of benzyl posaconazole, 50 ml of methanol were charged and 3.1 ml of methane sulfonic acid and 0.5 gm of 10% Pd/C were added at about room temperature. 5 kg/cm2 of hydrogen gas pressure was applied and stirred for about 4 hours at about room temperature. After completion of the reaction, the pressure was released and the reaction solution was filtered and the catalyst was washed with 1 5 ml of methanol. The methanol solution was concentrated completely under vacuum. Then 15 ml of isopropyl alcohol and 25 ml of water were added to the residue and stirred for about 15 minutes and cooled to about 5C. The pH of the solution was adjusted to 7.5 using 4N NaOH solution and stirred for about 1 hour at about 5C. The solid obtained was filtered and washed with 30 ml of water. The wet material was dried in a vacuum oven at about 50 C for about 12 hours to yield 4.3 gm of the title compound.Purity by HPLC: 95%
41 g	With hydrogenchloride; In water; at 25 - 63℃; for 11h;	Example-21: Preparation of 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4- difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yI)phenyl)-1-((2S,3S)-2-hydroxypentan -3-yI)-1H-1,2,4-triazol-5(411)-one (Posaconazole)4-(4-(4-(4-(((3R,5R)-5-(( I H-i ,2,4-triazol- 1 -yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methoxy)phenyl)piperazin- 1 -yl)phenyl)- 1 -((2S,3 S)-2-(benzyloxy) pentan-3-yl)- 1 Hl,2,4-triazol-5 (4H)-one (50 gms) was added to hydrochloric acid (150 ml) at 25-30C. Heated the reaction mixture to 60-63C and stirred for 11 hours at the same temperature. A mixture of water (500 ml), methanol (400 ml) and acetone (200 ml) was added to the reaction mixture at 25- 30C. Cooled the reaction mixture to 10-15C. Adjusted the pH of the reaction mixture to 7.0using aqueous sodium hydroxide solution below 15C. Raised the temperature of the reaction mixture to 25-30C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with water. To the obtained wet compound, acetone (500 ml) was added at 25-30C. Heated the reaction mixture to 55-60C and stirred for 30 minutes at the same temperature. Carbon (5.0 gins) was added to the reaction mixture at 55-60C and stirred for 30 minutes at thesame temperature. Filtered the reaction mixture through hy-flow bed and washed with hot acetone. Distilled off the solvent from the filtrate under reduced pressure. Acetone (500 ml) was added to the obtained compound at 25-30C. Heated the reaction mixture to 55-60C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30C. Water was slowly added to the reaction mixture at 25-30C and stirred for 2 hours at the same temperature.Filtered the precipitated solid, washed with water and dried to get the title compound.26 Yield: 41 gms.
9.4 g		10 g of compound of formula B, 100 mL methanol and 10 g refined hydrochloric acid were added to a reaction flask at room temperature, and stirred for 1 h. Then, 1 g of 5% Pd/C was added thereto. Then, hydrogen was introduced thereto. The mixture was warmed up to 40 C., and stirred and reacted for 10-16 h. After the reaction was completed, the mixture was filtered under suction. The resultant solid was washed with 10 mL methanol. The filtrate was warmed up to 45 C. And an alkaline solution prepared from 2.7 g sodium hydroxide and 17 g water was dropwise added thereto to adjust the pH of the solution to 7-8. Then, the mixture was warmed up to 60-65 C. And 60 mL purified water was slowly dropwise added thereto. After that, the mixture was cooled to 45 C., crystallized while keeping the temperature for 1 h, further cooled to 15-20 C., crystallized while keeping the temperature for 1 h, and filtered under suction. The resultant solid was first drip washed with 5 mL of 50% aqueous methanol solution, and then drip washed with 4×50 mL purified water. The solid was collected, placed in a ventilated oven at 50-55 C. and dried for 16 h to obtain 9.4 g of product.
0.68 kg	With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In methanol; water; at 50℃;Large scale;	4-(4-(4-(4-(((3R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)- tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-l-yl)phenyl)-2-((2S,3S)-2- (benzyloxy)pentan-3-yl)-2H-l,2,4-triazol-3(4H)-one (1 kg) was added to the flask along with Methanol (7 lit), followed by the addition of 10% Pd / C (0.24 kg) and Hydrochloric acid (1.78 lit) at room temperature. Hydrogen gas (5 kg) was applied and temperature was raised to 50C. The resultant material was cooled to room temperature, filtered through the Hyflow bed and washed with Methanol (1 lit). The resultant filtration mass was cooled to 0-5C and pH was adjusted to 7.0-7.5 with 16% Sodium hydroxide solution, maintained for 2 hrs and filtered the solid and washed with Methanol.The resultant material was added to the Flask along with Methanol (10 lit) and heated to 60-65C and maintained for 1 hr. Activated Carbon was added, stirred for 30 min and filtered through Hyflow bed and washed with methanol (1 lit). The resultant mass was cooled to room temperature and maintained for 1-2 hrs, filtered the solid and washed with Methanol (1 lit) to get the title compound.Yield: 0.68Kg; HPLC: 99.4%.

Reference： [1]Patent: WO2017/51342,2017,A1 .Location in patent: Page/Page column 19; 20
[2]Patent: CN106366076,2017,A .Location in patent: Paragraph 0020; 0044; 0045; 0049; 0050; 0054; 0055
[3]Tetrahedron Letters,2004,vol. 45,p. 8249 - 8251
[4]Patent: CN105622591,2016,A .Location in patent: Paragraph 0021
[5]Patent: CN109970725,2019,A .Location in patent: Paragraph 0045-0099
[6]Patent: US2014/343285,2014,A1 .Location in patent: Paragraph 0344
[7]Patent: CN106749207,2017,A .Location in patent: Paragraph 0038; 0039; 0040
[8]Patent: CN109796446,2019,A .Location in patent: Paragraph 0043; 0069; 0070; 0071; 0097
[9]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363
[10]Patent: WO2009/141837,2009,A2 .Location in patent: Page/Page column 23
[11]Patent: WO2011/158248,2011,A2 .Location in patent: Page/Page column 30-31
[12]Patent: WO2015/59716,2015,A2 .Location in patent: Page/Page column 26; 27
[13]RSC Advances,2016,vol. 6,p. 58088 - 58098
[14]Patent: US2019/71408,2019,A1 .Location in patent: Paragraph 0250
[15]Patent: WO2019/77627,2019,A1 .Location in patent: Page/Page column 14; 35; 36

4
[ 185961-30-2 ]
[ 171228-49-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 186 - 190

5
[ 171228-61-8 ]
[ 171228-49-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 186 - 190

6
[ 170985-80-5 ]
[ 171228-49-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 186 - 190

7
4-[4-(4-{4-[(3R,5R)-5-(2,4-Difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 186 - 190

8
[ 106-41-2 ]
concentrated aqueous KOH-solution [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

9
2-((1S,2S)-2-Benzyloxy-1-ethyl-propyl)-4-(4-bromo-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

10
[ 454479-36-8 ]
[ 171228-49-2 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

11
[ 454479-39-1 ]
[ 171228-49-2 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

12
((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-chlorobenzenesulfonate [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

13
[ 927-58-2 ]
[ 171228-49-2 ]
[ 221615-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; at 20℃;	Example 1 To a stirred mixture of 10 g (14 mmol) of the compound of formula IV (prepared in accordance with the procedure of Example 32 of WO 96/38443, published 5 December 1996) and 2.27 g, (1.3 eq) of the base, 4-(N,N-dimethylamino)pyridine ("DMAP") in 200 mL of methylene chloride, 4-bromobutyryl chloride (1.3 eq, 18.6 mmol, 3.44g) was added dropwise and the resulting reaction mixture was stirred at room temperature until the reaction was determined to be complete by thin layer chromatography ("TLC"). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate("EtOAc"). The organic phase was separated, washed with water and dried over MgSO4. The organic solvent was removed and the so-formed residue was purified on a silica gel chromatography column using EtOAc as the eluent to provide 8.58 g of the bromide VI as a white solid

Reference： [1]Patent: EP1027349,2005,B1 .Location in patent: Page 8-9

14
[ 221615-76-5 ]
[ 171228-49-2 ]

Reference： [1]Patent: EP1027349,2005,B1 .Location in patent: Page 3

15
(-)-4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-[1,2,4]triazol-1-ylmethyl)tetrahydrofuran-3-yl]-methoxy]-phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-2-[(1S,2S)-1-ethyl-2-hydroxylpropyl]-[1,2,4]triazol-3-one; mixture of [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol; at 20 - 63℃;Heating / reflux;	Two grams (2 g) of crude the starting material prepared in accordance with Example 1 was dissolved in refluxing isopropyl alcohol (20 mL). To the solution was added water (20 ml) while maintaining a reflux temperature. The solution was allowed to cool slowly to about 63 C. when crystalization occurred. The resulting mixture was agitated for 10 mins at this temperature, then cooled slowly to room temperature and further agitated for 1 hour. The solids that formed were collected by filtration . The product was then dried in a draft oven (45 C., 24 hours) to yield a white solid.
	In dichloromethane;	Approximately 1 g of crude starting material prepared as described in Example 1 was dissolved in hot 5 ml methylene chloride and was allowed to dry slowly in a fume hood. A form II material was obtained together with some amorphous form.
	In acetonitrile; at 0 - 50℃;Heating / reflux;	Five grams (5 g)of the crude starting material prepared in accordance with Example 1 was dissolved in refluxing acetonitrile (100 mL). The solution was allowed to cool slowly to about 50 C. when crystallization occurred. The resulting mixture was agitated for 30 mins at this temperature, then cooled slowly to 0 C. and further agitated for 30 mins. The solids that formed were collected by filtration and washed with chilled acetonitrile (25 mL). The product was then dried in an oven (40 C., 29 psi vacuum, 12 hours) to yield 3.9 g of white crystals.

	In water; acetone; at 20℃;Heating / reflux;	Approximately 1 g of crude starting material prepared as described in Example 1 was dissolved in refluxing acetone (10 mL). Water (3 mL) was added to this mixture while maintaining a reflux temperature. The resulting yellow solution was allowed to cool without agitation to room temperature. The solids that formed were collected by filtration and washed with acetone-water (1:1, about 5 ml). The product was then dried in an oven (45 C., 29 psi vacuum, 24 hours) to yield 0.63 g of white crystals.
	In methanol; at 20℃;	Approximately 2 g g of crude starting material prepared as described in Example 1 was dissolved in hot 10 ml methanol. The resulting solution was allowed to cool without agitation to room temperature in a fume hood. The solids that formed were collected by filtration and dried in the fume hood.

Reference： [1]Patent: US6713481,2004,B1 .Location in patent: Page/Page column 13
[2]Patent: US6713481,2004,B1 .Location in patent: Page/Page column 14
[3]Patent: US6713481,2004,B1 .Location in patent: Page/Page column 13
[4]Patent: US6713481,2004,B1 .Location in patent: Page/Page column 13; 14
[5]Patent: US6713481,2004,B1 .Location in patent: Page/Page column 14

16
[ 4480-83-5 ]
[ 171228-49-2 ]
[ 1038994-53-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; In dichloromethane; for 2h;	Compound 1 (5.0 g, 7.135 mmol), 4-(dimethylamino)pyridinen (DMAP) (3.49 g, 28.5 mmol), diglycolic anhydride (1.66 g, 14.3 mmol) were dissolved in 200 mL anhydrous methylene chloride and stirred for 2 hours. The solution was then washed by 4×100 mL 0.1 N HCl and dried by MgSO4. The solution was filtered, evaporated, and dried over P2O5 under vacuum overnight to give pure compound 2 (5.61 g, 6.87 mmol, 96%). 13C NMR (67.8 MHz, CDCl3) delta 10.23, 17.11, 22.07, 37.33, 38.65, 48.73, 50.69, 53.34, 55.88, 60.18, 68.03, 68.18, 68.75, 70.53, 71.96, 83.76 (JCF=4 Hz), 104.46 (JCF=26 Hz), 111.18 (JCF=20 Hz), 115.03, 116.51, 118.66, 123.53, 125.11 (JCF=12 Hz), 125.39, 128.44 (JCF=7 Hz), 134.64, 144.32, 144.81, 150.21, 150.32, 153.03, 153.32, 158.78 (JCF=244 Hz, JCF=12 Hz), 162.59 (JCF=248 Hz, JCF=12 Hz), 169.07, 171.42.

Reference： [1]Patent: US2008/171013,2008,A1 .Location in patent: Page/Page column title page; 10; figure 1

Yield	Reaction Conditions	Operation in experiment
	In methanol; water; at 20℃; for 144h;Product distribution / selectivity;	EXAMPLE 1; 250 mg of posaconazole in amorphous form were suspended in a solution consisting of 5 ml of water and 1.25 ml of methanol. The mixture was stirred at ambient temperature for 6 days. The white suspension was filtered and the product was dried in vacuum overnight to yield 240 mg of a white crystalline solid. The product was analyzed by DSC, FT-IR using an attenuated total reflectance cell as herein described and XRPD and found to be a novel form of posaconazole denominated as form IV. The melting point of the product of Example 1 was 170.1 +/- 0.5 C.
	In dichloromethane; at 25 - 30℃;Purification / work up;	EXAMPLE 8PREPARATION OF CRYSTALLINE POSACONAZOLE POLYMORPHIC FORM V1 0 gm of posaconazole was charged in 100.0 ml dichloromethane at about 25C to about 30C and stirred for dissolution for about 15-20 minutes. The solution was filtered and was transferred in to a conical flask. An empty clean and dry 1 .0 liter Buchi flask was fixed to rotavapour and vacuum was applied and heated to about 70C to about 75C under rotation. At the temperature of about 70C to about 75C and vacuum of not less than 650 mmHg, dichloromethane solution was sucked out with a pipe attached to the rotavapour knob into Buchi flask portion-wise at 10 ml/ min. After completion of suction of solution, the crystallized material was dried for about another 120 minutes at same conditions.Unloaded material was subjected to drying in vacuum oven for about 12 hrs at about 40C to about 45C.Yield: 9.2 gm
	In water; acetone; at 5℃;Reflux;Purification / work up;	Example 1; Preparation of the Crystalline Form II-S of <strong>[171228-49-2]Posaconazole</strong>; 28.8 g of <strong>[171228-49-2]Posaconazole</strong> in the form of crystalline form I prepared by the method of example 3 described in U.S. Pat. Nos. 6,958,337 and 300 ml acetone were heated under reflux in a round bottom flask provided with a reflux condenser. 90 ml water were added through the condenser and a clear solution was obtained. The hot solution was filtered and cooled down from 45 C. to 20 C. within 45 min. Crystallization started and the mixture was put in a refrigerator at 5 C. without agitation over night. The precipitated crystals were collected by filtration and then dried in a vacuum oven to yield 24.9 g of the a crystalline form of posaconazole in form of white needlesThe product was analyzed by DSC, FT-IR using an attenuated total reflectance cell as herein described and XRPD and found to be a novel form of posaconazole denominated as form II-S.Crystalline form II-S obtained according to example 1 has an X-ray powder diffraction spectrum as shown in FIG. 1. Characteristic XRPD angles, d-spacings and relative intensities are shown in Table 1.Crystalline form II-S of posaconazole obtained above has an attenuated total reflectance IR spectrum with absorption bands at 3650, 3392, 2968, 1688, 1510, 1227, 1036, 946, 820 and 680 cm-1 (+/-2 cm-1; FIG. 2).The obtained crystalline form II-S was subjected to differential thermal analysis. As can be seen in FIG. 3 (lower curve), crystalline form II-S shows a significant dehydration endotherm between 25 C. and 112 C. with peaks at 96 C. and 111 C. followed by a exothermic peak at 120.2 C. and melting at 171.4 C. with a Tonset of 169 C. (10 C./minute, open pan).At ambient conditions form II-S contains approximately 1 mol water (monohydrate). The moisture sorption isotherm of crystalline form II-S shows a distinct step over 0.5 mol water uptake/loss between 0 and 10% relative humidity. The maximum water content peaks at 5.2% at 90% relative humidity, which corresponds to a water mol ratio of 2.0 (FIG. 4).

18
(1S)-(2S)-2-(1-ethyl-2-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-phenyl}-2,4-dihydro-[1,2,4]triazol-3-one hydrochloride [ No CAS ]
((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-chlorobenzenesulfonate [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (lS)-(2S)-2-(l-ethyl-2-hydroxy-. propyl)-4- {4- [4-(4-hydroxy-phenyl)-piperazin- 1 -yl] -phenyl} -2,4-dihydro- [ 1 ,2,4]triazol-3 -one obtained above in dimethylsulfoxide (140ml), a solution of sodium hydroxide (5.15g) in water was added at ambient temperature and stirred for 15 minutes. The reaction mixture was cooled to 10 0C and (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazole-l-yl)methyl]-tetrahyro-3- furanmethanol-4-chlorobenzenesulphonate (30.0 g) was added. The temperature of the reaction mass was raised to 35-40 C with stirring for 10-12 hours. To the resulting solution, water was added dropwise and further stirred for 60 minutes. The resulting mixture was filtered to obtain 36.4 g of the crude title compound as a white solid having purity of 97.0% by HPLC. The crude posaconazole was taken in methanol (360ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (50ml) and dried to obtain 32g of the title compound having purity of 99.5% by HPLC.

Reference： [1]Patent: WO2009/141837,2009,A2 .Location in patent: Page/Page column 22

19
[ 51336-94-8 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

20
[ 74853-08-0 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1
[3]Patent: US2014/343285,2014,A1
[4]Patent: CN106632284,2017,A
[5]Patent: CN106632284,2017,A
[6]Patent: CN106632284,2017,A
[7]Patent: CN106632284,2017,A
[8]Patent: CN106749207,2017,A

21
[ 165115-73-1 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

22
[ 192448-07-0 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

23
[ 1350560-52-9 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

24
[(R)-5-(2,4-Difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-yl]-methanol [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

25
C₁₄H₁₅F₂N₃O₂*(x)ClH [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1

26
C₁₄H₁₅F₂N₃O₂*(x)ClH [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1

27
[ 149809-43-8 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1
[3]Patent: WO2015/59716,2015,A2
[4]Patent: CN108239077,2018,A

28
[ 156570-10-4 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

29
C₁₂H₁₉N₃O₂ [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1

30
[ 1350560-57-4 ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide; In water; isopropyl alcohol; for 3h;Reflux;	20.0 g (22.97 mmol) of compound (IVb) as a 1/1/1 crystallisate with DCM and imidazole as obtained from Reference Example 1.4 were dissolved in a mixture of isopropanol (104 ml) and H2O (104 ml). Next, solid NaOH (0.9 g, 1.0 equivalent) was added and the mixture was refluxed for a period of 3 h. The solution was cooled to 70 C. and diluted with isopropylacetate (450 ml). Subsequently, the mixture was cooled to 15 C. and treated with aqueous HCl (124 ml, 15.7%). The layers were separated, and the aqueous layer was mixed with DCM (320 ml). The pH value of the mixture was adjusted to 1.0 by addition of 20% aqueous NaOH (122 ml). The aqueous layer was discarded, and the organic layer was washed with 0.1 M HCl (200 ml) followed by 5% aqueous NaHCO3 (200 ml). The organic solvent was removed via distillation to give a solid residue. This was then taken up in a mixture of acetone (461 ml) and water (115 ml). The solution was diluted with water (39 ml), cooled to 15 C. and seeded with seed crystals obtained according to the method of Reference Example 2. The mixture was allowed to stir for 60 min at 15 C. Thereafter, the resulting suspension was further cooled to 10 C. and stirring was continued for a period of 30 min. Then, water (400 ml) was added dropwise over a period of 49 min. The suspension was left to stir for a period of 120 min at 10 C. The solid was filtered off, and the filter cake was washed twice with cold acetone/water: 1/2 (2×45 ml). The wet product was dried under reduced pressure at 40 C. for a period of 16 h to give 14.5 g (20.4 mmol, purity 99.7 area % as determined by HPLC analysis according to the HPLC method of Reference Example 1.4, 90% yield) of posaconazole in a crystalline form.
		Example 5: Synthesis of the compound of formula (Vb)50.0 g of the compound of formula (IVb) as obtained according to Example 4 above (1 eq, 57.39 mmol) were dissolved in 1600 mL isopropylacetate. To the suspension ,18.66 g imidazole (5.8 eq in total with the imidazole contained in the starting material,332.8 mmol) and 20.83 g BSA (1.78 eq, 102.4 mmol, 25.0 mL) were added and the mixture was stirred for 45 min until a clear solution occurred.Afterwards 4.30 g of TMSI solution in DCM containing 2.56 g TMSI (0.22 eq,12.78 mmol) were added, and the reaction mixture was heated to reflux (89 C) and stirred at that temperature for 19 hours until complete conversion of the compound of formula (IVb) was observed.The reaction mixture was added dropwise at a temperature between 50- 60 C to 500 mL 10 % HC1. The aqueous phase was separated, and 750 mL DCM were added. Afterwards the pH of the mixture was adjusted to 1.02 by the addition of about 225 mL of 20 % NaOH solution. The organic phase was separated and washed with 500 mL 0.1 M HC1 followed by a washing with 330 mL 5 % sodium bicarbonate solution. Afterwards the organic solvent was removed under reduced pressure (40 C, 600 - 20 mbar) leading to 50.71 g of compound of formula (Vb) as a white solid.The solid was dissolved in acetone and afterwards 325 mL water were added. To the solution lOg charcoal (Ceca Eno) were added and the mixture was stirred for 30 min. Afterwards the charcoal was removed via filtration, the filter cake was washed with 300 mL of an acetone/water (5/1) mixture leading to a slightly yellow solution. The solution was warmed to 27 C and 1000 mL water were added.Subsequently 40 mg seeding crystals (obtained according to above-described process followed by purification by chromatography) were added and the mixture was stirred for 60 min leading to white slurry. Additional 500 mL water were added and the mixture was stirred at 30 C for 30 min, cooled to 15 C and stirred at that temperature for 120 min. Afterwards the white solid was separated via filtration (G3, d = 12 cm) and the filter cake was washed with 375 mL of an acetone/water (1/2) mixture. The isolated solid was dried under vacuum (< 45mbar) at 40 C for 16 hours leading to 32.57 g of the compound of formula (Vb) (46.48 mmol, 81.0 %, contents 98.9 %).At least 99% of the molecules of the compound of formula (Vb) were obtained as isomer of formula (Vd)

Reference： [1]Patent: US2014/303184,2014,A1 .Location in patent: Paragraph 0490
[2]Patent: WO2011/144653,2011,A1 .Location in patent: Page/Page column 74-76

31
[ 159276-62-7 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2011/144653,2011,A1
[2]Patent: US2014/303184,2014,A1

32
[ 83948-53-2 ]
[ 171228-49-2 ]
[ 1370642-06-0 ]

Yield	Reaction Conditions	Operation in experiment
78%		Preparation of the Boc- rotected <strong>[171228-49-2]Posaconazole</strong>-linker Amine 2:[000124] To a solution of posaconazole (1, 200 mg, 0.29 mmol) in THF (10 mL) was added under stirring NaH (19 mg, 0.80 mmol) in 4-5 portions at rt. After completion of the addition, the reaction mixture was stirred at the same temperature for 30 min and l-boc-3- bromopropylamine (82 mg, 0.34 mmol) was added to it in one portion and stirring continued overnight. After completion of the reaction (TLC: 30% methanol in chloroform) it was diluted with water (5 mL) and extracted with CHC13 (3x10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgS04 andevaporated. The crude product was purified by preparative TLC (5% methanol in chloroform) to yield 2 (193 mg, 78 %) as a colorless oil. ES+ MS m/z 858 [M + H]+; HPLC-MS >99.0% (AUC).

Reference： [1]Patent: WO2012/47762,2012,A2 .Location in patent: Page/Page column 44

33
[ 171228-49-2 ]
[ 1370642-04-8 ]

Reference： [1]Patent: WO2012/47762,2012,A2

34
[ 171228-49-2 ]
[ 200346-83-4 ]

Reference： [1]Organic Process Research and Development,2001,vol. 5,p. 622 - 629

35
[ 171228-49-2 ]
C₄₁H₄₉F₂N₈O₉P*2C₈H₁₉NO₄ [ No CAS ]

Reference： [1]Organic Process Research and Development,2001,vol. 5,p. 622 - 629

36
[ 157547-59-6 ]
[ 171228-49-2 ]
[ 221615-78-7 ]

Reference： [1]Organic Process Research and Development,2001,vol. 5,p. 622 - 629

37
[ 1350466-82-8 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/303184,2014,A1

38
[ 1350538-60-1 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/303184,2014,A1

39
[ 170985-85-0 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1
[4]Patent: WO2019/77627,2019,A1

40
[ 184177-83-1 ]
[ 149809-43-8 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1

41
(R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2

42
C₁₆H₁₈F₂O₃ [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1

43
(R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1

44
(R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2

45
(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2

46
[ 165115-70-8 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2

47
[ 182210-71-5 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2
[3]Patent: WO2019/77627,2019,A1
[4]Patent: WO2019/77627,2019,A1

48
[ 160709-02-4 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2
[3]Patent: CN106632284,2017,A
[4]Patent: CN106632284,2017,A
[5]Patent: CN106632284,2017,A
[6]Patent: CN106632284,2017,A
[7]Patent: US2019/71408,2019,A1
[8]Patent: WO2019/77627,2019,A1
[9]Patent: WO2019/77627,2019,A1

49
[ 110931-77-6 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: WO2015/59716,2015,A2

50
[ 184177-81-9 ]
[ 171228-49-2 ]

Reference： [1]Patent: US2014/343285,2014,A1
[2]Patent: CN106749207,2017,A

51
(3R,5R)-2-(2,4-difluorophenyl)-tetrahydro-2-(iodomethyl)-4-((trityloxy)methyl)furan [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2015/59716,2015,A2
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1

52
1-(((2R,4R)-2-(2,4-difluorophenyl)-tetrahydro-4-((trityloxy)methyl)furan-2-yl)methyl)-1H-1,2,4-triazole [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2015/59716,2015,A2
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1

53
(R)-3((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2015/59716,2015,A2

54
[ 16179-41-2 ]
[ 124482-92-4 ]
[ 171228-49-2 ]
C₅₂H₆₈F₂N₉O₈P [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A .Location in patent: Paragraph 0087

55
[ 17863-69-3 ]
[ 124482-92-4 ]
[ 171228-49-2 ]
C₆₃H₈₈F₂N₉O₁₀P [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A .Location in patent: Paragraph 0089

56
[ 57-88-5 ]
[ 104495-49-0 ]
[ 171228-49-2 ]
C₆₆H₉₁F₂N₈O₆P [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A .Location in patent: Paragraph 0090

57
[ 104495-49-0 ]
[ 204652-39-1 ]
[ 171228-49-2 ]
C₇₂H₉₉F₂N₈O₁₀P [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A .Location in patent: Paragraph 0091

58
[ 67-48-1 ]
[ 124482-92-4 ]
[ 171228-49-2 ]
C₄₅H₅₈F₂N₁₀O₆P⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A .Location in patent: Paragraph 0086

59
[ 171228-49-2 ]
C₄₂H₅₅F₂N₉O₇P⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A

60
[ 171228-49-2 ]
C₄₂H₅₄F₂N₉O₇P [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A

61
[ 171228-49-2 ]
C₄₅H₅₈F₂N₁₀O₇P⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]Patent: CN106432338,2017,A

62
[ 64-18-6 ]
[ 171228-49-2 ]
C₃₈H₄₂F₂N₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.7 g	With acetic anhydride; at 20℃; for 5h;	10 g of posaconazole was added to a 250 ml three-necked flask,Adding 20 ml of anhydrous formic acid and 10 ml of acetic anhydride,The mixture was stirred at room temperature for 5 hours,The end point of the reaction was monitored by HPLC (less than 0.1% of paclitaxel remaining)After completion of the reaction,To the reaction solution was added 150 ml of purified water,Stir for 30 minutes,Filter,The filter cake was washed with 150 ml of purified water,The resulting wet product was blasted at 50 to 60 C under normal pressure for 12 hours to obtain 9.7 g of formylated posaconazole.

Reference： [1]Patent: CN106317032,2017,A .Location in patent: Paragraph 0014

63
[ 108-24-7 ]
[ 171228-49-2 ]
C₃₉H₄₄F₂N₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.5 g	With sulfuric acid; at 20℃; for 5h;	10 g of posaconazole was added to a 250 ml three-necked flask,Add 20ml acetic anhydride and 0.5ml concentrated sulfuric acid,The mixture was stirred at room temperature for 5 hours,The end point of the reaction was monitored by HPLC (less than 0.1% of paclitaxel remaining)After completion of the reaction,To the reaction solution was added 150 ml of purified water,Stir for 30 minutes,Filter,The filter cake was washed with 150 ml of purified water,The obtained wet product was blast-dried at 50 to 60 C for 12 hours under normal pressure,Get itAcetylated propalconazole 9.5 g.

Reference： [1]Patent: CN106317032,2017,A .Location in patent: Paragraph 0015; 0016

64
C₃₈H₄₂F₂N₈O₅ [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	With triethylamine; In methanol; at 60 - 70℃; for 1h;	The compound of formula II (7.23 g) obtained in Example 1 and methanol (70 mL) were added to a 250 mL three-necked flask and stirred at 60-70 C. Mix and dissolve, add triethylamine (1.21g), continue stirring for 1 h, cool to room temperature, suction filtration, filter cake with 50% aqueous methanol solution (10 mL), and dry at 50 C under vacuum to obtain posaconazole (I) 6 .93 g, yield 95.8%, purity by HPLC was 99.94%.
8.8 g	With methanol; sodium methylate; at 20℃; for 12h;	10 g of formylated posaconazole was added to a 250 ml three-necked flask,100 ml of methanol and 1 ml of sodium methoxide were added,Room temperature reaction for 12 hours,The end point of the reaction was monitored by HPLC (less than 0.01% of the posaconazole residue)After completion of the reaction,Filter,The filter cake was washed with 15 ml of methanol,The obtained wet product was blown dry at 50 to 60 C for 6 hours under normal pressure,Get itPosaconazolePure 8.8g,HPLC content of 99.8%.

Reference： [1]Patent: CN108239077,2018,A .Location in patent: Paragraph 0036; 0038; 0039; 0040
[2]Patent: CN106317032,2017,A .Location in patent: Paragraph 0020

65
C₃₉H₄₄F₂N₈O₅ [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
8.5 g	With ethanol; sodium hydroxide; at 20℃; for 12h;	In a 250 ml three-necked flask, 10 g of acetylated posaconazole was added,Add 75% ethanol 100ml and 1g sodium hydroxide,Room temperature reaction for 12 hours,The end point of the reaction was monitored by HPLC (less than 0.01% of the posaconazole residue)After completion of the reaction,Filter,The filter cake was washed with 15 ml of ethanol,The resulting wet product was air-dried at atmospheric pressure for 50 hours at 60-60 C for 6 hours,Get itPosaconazolePure product 8.5g,HPLC content of 99.8%.

Reference： [1]Patent: CN106317032,2017,A .Location in patent: Paragraph 0021; 0022

66
C₂₀H₁₉F₂N₃O₄S [ No CAS ]
C₂₉H₄₃N₅O₃Si [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

67
C₂₃H₂₂N₄O₅ [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A
[2]Patent: CN106632284,2017,A

68
C₁₅H₁₇F₂N₃O₄S [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

69
C₃₇H₃₅F₂N₇O₆ [ No CAS ]
C₁₂H₂₈N₂O₂Si [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

70
C₄₃H₅₆F₂N₈O₄Si [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrabutyl ammonium fluoride; water; In tetrahydrofuran;	7 g of the compound 7b was dissolved in 50 mL of tetrahydrofuran, and thereto was added 2.5 g of tetrabutylammonium fluoride and5 mL of water. After completion of the reaction, 20 mL of water and 20 mL of dichloromethane were added to the reaction mixture, stirred, allowed to stand, and the organic phase was passed throughDried, concentrated after crystallization of the target product 4.8g, the yield of 80%.

Reference： [1]Patent: CN106632284,2017,A .Location in patent: Paragraph 0060; 0071; 0072; 0082; 0083

71
C₂₃H₂₂ClN₃O₃ [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A
[2]Patent: CN106632284,2017,A

72
C₁₅H₁₄F₅N₃O₄S [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

73
C₁₅H₁₄F₅N₃O₄S [ No CAS ]
C₂₉H₄₃N₅O₃Si [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

74
C₃₇H₃₅ClF₂N₆O₄ [ No CAS ]
C₁₂H₂₈N₂O₂Si [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: CN106632284,2017,A

75
C₄₃H₅₆F₂N₈O₄Si [ No CAS ]
[ 171228-49-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With water; pyridine hydrogenfluoride; In tetrahydrofuran;	7 g of compound 7c was dissolved in 50 mL of tetrahydrofuran, and thereto was added 2.5 g of pyridine hydrofluoride and5 mL of water. After completion of the reaction, 20 mL of water and 20 mL of dichloromethane were added to the reaction mixture, stirred, allowed to stand, and the organic phase was passed throughDried, concentrated after crystallization of the target product 4.5g, the yield of 75%.

Reference： [1]Patent: CN106632284,2017,A .Location in patent: Paragraph 0100; 0106; 0107

76
[ 171228-49-2 ]
C₃₇H₄₂F₂N₈O₆ [ No CAS ]
C₃₇H₄₂F₂N₈O₅ [ No CAS ]
C₃₇H₄₂F₂N₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.1%; 8.5%; 9.8%	With hydrogenchloride; dihydrogen peroxide; In ethanol; water; at 15 - 30℃; for 24h;pH 1 - 2;	posaconazole (1.5 g) was suspended in water (20.0 mL), ethanol (10.0 mL) was added, adjusted to pH using concentrated hydrochloric acid To 1 to 2, 30% hydrogen peroxide (2.0 mL) was added, stirred at 15 to 30 C for 24 hours, and adjusted with 25% sodium hydroxide solution pH to 8 ~ 9, will precipitate a small amount of solid filter, take the filtrate, with dichloromethane (15.0mL each) extraction twice, combined two The methyl chloride layer was washed with 20% sodium sulfite solution (10.0 g) and the resulting organic phase was concentrated and purified by preparative liquid phase purification. 0.19 g (21.1%) of impurities I solid; 0.13 g (8.5%) of impurities II solid; 0.15 g (9.8%) of impurity III solid.

Reference： [1]Patent: CN106674211,2017,A .Location in patent: Paragraph 0048; 0049

77
[ 150994-82-4 ]
[ 171228-49-2 ]
4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate 4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-1-(4-(1-((2S,3S)-2-hydroxypentan-3-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-ium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetonitrile; at 50℃; for 6h;	To a solution of 4-((l,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid 6 (4.20 g, 0.009 mol) in acetonitrile (100 mL) was added 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-l-yl)phenyl)- 2-((2S,3S)-2-hydroxypentan-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one 13 (6.63 g, 0.009 mol) at ambient temperature. The resulting reaction mixture was heated up to 50C for next 6h followed by the evaporation of solvent under reduced pressure to get the desired product 14, FORMULA I as off-white hygroscopic solid. Yield: 10.83 g, quant.

Reference： [1]Patent: WO2018/96497,2018,A1 .Location in patent: Paragraph 00112-00113

78
(2E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid [ No CAS ]
[ 171228-49-2 ]
(2E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate 4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-1-(4-(1-((2S,3S)-2-hydroxypentan-3-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-ium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetonitrile; at 50℃; for 3h;	To a solution of (E)-4-((l,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid 6 (100 mg, 0.18 mmol) in acetonitrile (5 inL) was added 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-l-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one 9 (126 mg, 0.18 mmol) at ambient temperature. The resulting reaction mixture was heated up to 50C for next 3h followed by the evaporation of solvent under reduced pressure to get the desired product 10 as off-white solid (M.P. 78.6C), yield: 225 mg, quant.

Reference： [1]Patent: WO2018/96497,2018,A1 .Location in patent: Paragraph 00128-00129

79
[ 184177-83-1 ]
[ 171228-49-2 ]

Reference： [1]Patent: CN108239077,2018,A
[2]Patent: WO2019/77627,2019,A1
[3]Patent: CN109796446,2019,A

80
[ 171228-49-2 ]
C₃₇H₄₁ClF₂N₈O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.35%	With thionyl chloride; In toluene; at 80℃;	To 250ml three-necked flask posaconazole (10g,14.27 mmol), a (100ml), thionyl chloride (17g, 142. 7mmoia0eq.), Stirring, was raised to 80C the reaction.After completion of the reaction was monitored by TLC, the solvent was evaporated under reduced pressure to give a red-brown solid was concentrated; 450ml of dichloromethane was added and dissolved with stirring, the pH was adjusted to 7-8 with saturated sodium carbonate solution, liquid separation, the organic phase was concentrated under reduced pressure and the solvent was evaporated to giveColumn chromatography, eluent petroleum ether-ethyl acetate (volume ratio 5:1) to give 1. 378 product as a white solid, yield 13. 35%, purity 97. 6%.

Reference： [1]Patent: CN109053708,2018,A .Location in patent: Paragraph 0036-0051; 0055; 0057; 0059; 0061

81
[ 110-15-6 ]
[ 171228-49-2 ]
C₄₁H₄₆F₂N₈O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With trimethylsilyl trifluoromethanesulfonate; In 1,4-dioxane; at 25℃;	Add 1,4-dioxane 20 mL to a 100 mL single-mouth bottle.<strong>[171228-49-2]Posaconazole</strong> 2.5g (3.56mmol),Succinic acid 0.42 g (3.56 mmol),Trimethylsilyl triflate 0.79 g (3.56 mmol),The reaction was stirred at 25 ± 5 C overnight.TLC monitors the reaction completely,The reaction was dropwise added with 3.5 mL of a 1M aqueous solution of sodium hydrogen carbonate.Concentrated to dryness, dissolved in 30 mL of dichloromethane.Filtered, the filtrate was washed with water 3×30 mL, and the dichloromethane phase was collected.Dry over anhydrous sodium sulfate,Filtration and concentration of white solid 2.7 g yield 94.7%,The purity is 96.8%.

Reference： [1]Patent: CN108976218,2018,A .Location in patent: Paragraph 0020-0042

82
[ 132489-33-9 ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1
[4]Patent: CN109796446,2019,A
[5]Patent: CN109796446,2019,A

83
(2S)-2-(benzyloxy)pentan-3-ol [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1
[4]Patent: CN109796446,2019,A
[5]Patent: CN109796446,2019,A

84
(2S)-2-(benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1

85
C₁₂H₂₀N₂O*C₁₈H₁₄O₈ [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1
[2]Patent: WO2019/77627,2019,A1
[3]Patent: WO2019/77627,2019,A1

86
[ 184177-83-1 ]
((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-chlorobenzenesulfonate [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1

87
[ 184177-83-1 ]
[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-yl]methyl-4-nitrobenzene sulfonate [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1

88
(4S)-3-[(5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one [ No CAS ]
[ 171228-49-2 ]

Reference： [1]Patent: WO2019/77627,2019,A1
[2]Patent: WO2019/77627,2019,A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	171228-49-2	MDL No. :
Formula :	C₃₇H₄₂F₂N₈O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RAGOYPUPXAKGKH-XAKZXMRKSA-N
M.W :	700.78	Pubchem ID :	468595
Synonyms :	SCH 56592;POS;Schering 56592;Noxafil	Chemical Name :	4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-Triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one

Signal Word:	Warning	Class:	N/A
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Hazard Statements:	H361-H413	Packing Group:	N/A
GHS Pictogram:

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[ CAS No. 171228-49-2 ] {[proInfo.proName]}

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[ CAS No. 171228-49-2 ] {[proInfo.proName]}

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[ 171228-49-2 ] Synthesis Path-Downstream 1~88

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