[ CAS No. 184177-83-1 ] {[proInfo.proName]}

Name: 184177-83-1|1-((2S,3S)-2-(Benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one|98%
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Quality Control of [ 184177-83-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 184177-83-1 ]

Product Details of [ 184177-83-1 ]

CAS No. :	184177-83-1	MDL No. :	MFCD11977288
Formula :	C₃₀H₃₅N₅O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QLRPRKJUMRQTOV-IADCTJSHSA-N
M.W :	513.63	Pubchem ID :	46223297
Synonyms :

Calculated chemistry of [ 184177-83-1 ]

Physicochemical Properties

Num. heavy atoms :	38
Num. arom. heavy atoms :	23
Fraction Csp3 :	0.33
Num. rotatable bonds :	9
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	157.21
TPSA :	75.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.38
Log Po/w (XLOGP3) :	5.23
Log Po/w (WLOGP) :	3.71
Log Po/w (MLOGP) :	3.6
Log Po/w (SILICOS-IT) :	3.1
Consensus Log Po/w :	4.0

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-6.17
Solubility :	0.000345 mg/ml ; 0.000000671 mol/l
Class :	Poorly soluble
Log S (Ali) :	-6.57
Solubility :	0.000138 mg/ml ; 0.00000027 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-7.11
Solubility :	0.0000403 mg/ml ; 0.0000000785 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.77

Safety of [ 184177-83-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 184177-83-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 184177-83-1 ]
Downstream synthetic route of [ 184177-83-1 ]

[ 184177-83-1 ] Synthesis Path-Upstream 1~11

1
[ 184177-81-9 ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
77.4%	Stage #1: With N-ethyl-N,N-diisopropylamine In 1,4-dioxaneLarge scale Stage #2: at 80℃; Large scale	Will be 4.36kgN '- ((2S, 3S) -2-benzyloxy) pentyl-3-formylhydrazide oxalate(VI)And 45.36 kgDioxane into the 100L glass reactor,Stir, add 3.45kgN, N-diisopropylethylamine. Stirring for 1 to 1.5 hours,Add another 5.47kgPhenyl (4- (4- (4-hydroxy) -1-piperazinyl) phenyl) carbamate(V).After the addition is complete, the temperature is raised to 80 ± 5 ° C for 24 to 30 hours. TLC monitoring.After the reaction is completed, the system is cooled to 15 ~ 25 ,57.79 kg of dichloromethane and 21.81 kg of pure water were added and stirred for 10 to 20 minutes.Collect the lower organic phase and discard the aqueous phase.The organic phase was transferred to a 100 L glass reactor, and 21.81 kg of purified water was added to the autoclave,Stirring for 10 to 20 minutes, standing and stratifying, collecting the lower organic phase and discarding the aqueous phase. The organic phase was transferred to a 100 L glass reactor. Saturated aqueous sodium chloride solution (6.54 kg of sodium chloride was dissolved in purified water 21.81 kg) was added and stirred for 10 to 20 minutes. The layers were allowed to stand and the organic phase was collected and the aqueous phase was discarded.The organic phase was transferred to a 20 L rotary vial, and at a vacuum of -0.08 to -0.1 MPa,Control the temperature of 30 ~ 40 , concentrated to remove the dichloromethane, to the solvent-free distillation. A brown solid was obtained.The solid was transferred to a 100 L glass autoclave, 32.27 kg of methyl t-butyl ether was added, and the mixture was heated to 50 to 60 ° C for 0.5 to 1 hour, cooled to 20 ± 5, and stirred for 2 to 3 hours. Centrifuge the filter to the basicSolvent-free, filter cake with 12.91kg methyl tert-butyl ether leaching, centrifugal rejection to the basic solvent-free effluent. Will be all wet goodsAt a vacuum of -0.08 to -0.1 MPa,Control temperature 40 ~ 50 Drying under reduced pressure 6 to 10 hours. A gray solid5.31kg, that is2 - ((2S, 3S) -2- (benzyl) -3-pentyl) -4- (4- (4-(4-hydroxy) -1-piperazine) phenyl)-2,4-dihydro-3-dihydro-1,2,4-triazol-3-one (III), HPLC purity: 98.8percent, yield: 77.4percent

Reference： [1] Patent: CN106749207, 2017, A, . Location in patent: Paragraph 0032; 0033; 0034

2
[ 184177-81-9 ]
[ 170985-85-0 ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In 1,4-dioxane at 90 - 100℃; for 24 h;	mixture of N′-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-17 (45.5 g) obtained in example-13, dioxane (500 ml) added phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate compound of formula-19 (50 g) was heated to 90-100° C. Triethylamine (26 g) was added to the reaction mixture at 90-100° C. over a period of 1 hour and stirred for 24 hours at 90-100° C. After completion of the reaction, the reaction mixture was cooled to 25-30° C. and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2percent sodium hydroxide solution followed by water, and then with 5percent hydrochloric acid solution followed by water and 5percent NaHCO₃solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30° C. The reaction mixture was stirred for 6 hours at 25-30° C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 28 g; Purity by HPLC: 97.67percent; Impurity-A: 0.37percentb) Purification of Compound of Formula-20 The obtained compound of formula-20 (30 g) was dissolved in methanol (960 ml) by heating at 60-65° C. The reaction mixture was cooled to 25-30° C. and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the pure compound of formula-20. Yield: 70percent; Purity by HPLC: 99.15percent; Impurity-A: 0.09percent

Reference： [1] Patent: US2014/343285, 2014, A1, . Location in patent: Paragraph 0340; 0341; 0342

3
[ 170985-85-0 ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With triethylamine In 1,4-dioxane at 85℃; for 35 h; Inert atmosphere	5 g of compound 2a and 3.8 g of compound 6a were added to dioxane, and the temperature was raised to 85 ° C under argon protection1.5 g of triethylamine was added and the reflux was continued for about 35 hours after completion of the dropwise addition. The solvent was evaporated under reduced pressure and extracted with dichloromethane. The residue was recrystallized from methanol and filtered to give a pale yellow solid in 61percent yield and 95.6percent HPLC purity.

Reference： [1] Patent: CN106632284, 2017, A, . Location in patent: Paragraph 0049; 0052; 0053

4
[ 1885-14-9 ]
[ 74853-08-0 ]
[ 170985-85-0 ]
[ 184177-83-1 ]

Reference： [1] Patent: CN105461644, 2016, A, . Location in patent: Paragraph 0072-0078

5
[ 170985-85-0 ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
22.5%	With triethylamine In 1,2-dimethoxyethaneInert atmosphere; Reflux	Under nitrogen protection, 5.4 g (0.013 mol) of the compound II was added to 100 ml of ethylene glycol dimethyl ether,5.5 g (0.023 mol) of compound IV, 2.6 g (0.026 mol) of triethylamine were added inone portion under stirring, and the mixture waswarmed to reflux. the reaction trap 24 - 48h,after completion of hot filtration, the filtrate was cooled to 0-5 deg.] C 3-5h crystallization, filtration, and dried to give 1.6g blowing 40-50 deg.] C as a white solid, yieldrate: 22.5percent,

Reference： [1] Patent: CN107619396, 2018, A, . Location in patent: Paragraph 0016; 0018

6
[ 74853-08-0 ]
[ 184177-83-1 ]

Reference： [1] Patent: US2014/343285, 2014, A1,
[2] Patent: CN106632284, 2017, A,
[3] Patent: CN106749207, 2017, A,

7
[ 77287-11-7 ]
[ 184177-83-1 ]

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

8
[ 53346-03-5 ]
[ 184177-83-1 ]

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

9
[ 100-44-7 ]
[ 184177-83-1 ]

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

10
[ 33106-32-0 ]
[ 184177-83-1 ]

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

11
[ 81445-44-5 ]
[ 184177-83-1 ]

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

[ 184177-83-1 ] Synthesis Path-Downstream 1~49

1
C₃₂H₃₇N₅O₄ [ No CAS ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of 2-(2(S)-benzyloxy-l(S)-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yI]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one: To a stirred mixture of acetic acid 4- [4-(4-amino-phenyl)-piperazin-l-yl] -phenyl ester (43g), triethylamine (28g) in toluene (860ml) and N,iV-dimethylformamide (86ml), phenyl chloroformate (26g) was added at 0 C-10 0C. The resulting mixture was warmed to ambient temperature and stirred for 5-6 hours. To the resulting mixture 2-[3-(2S, 3S)-2-(benzyloxy)pentyl]formic acid hydrazide (43 g) was added and further stirred for 24-30 hours at 80 0C-IOO C. After completion of reaction (monitored by TLC), solvent was distilled and residue was dissolved in methanol (430ml). The solution was cooled to 0 0C-IO 0C. The pH of the cooled solution was adjusted to 8-9 with aqueous sodium hydroxide (10%w/v) and further stirred for 30 minutes. The pH of the resulting mixture was again adjusted to 6-7 with hydrochloric acid (IN) and the product was extracted with dichloromethane (2x400ml). The organic layer was separated and subsequently washed with saturated solution of sodium bicarbonate (400ml) and brine (400ml). The organic layer was treated with activated , charcoal, solvent was distilled off and the title compound was crystallized in methyl tert-butyl ether to obtain 64.Og of the title compound having purity of 97.0% by HPLC.

Reference： [1]Patent: WO2009/141837,2009,A2 .Location in patent: Page/Page column 18

2
[ 184177-83-1 ]
(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 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; at 50℃; under 2942.29 Torr; for 2 - 3h;Product distribution / selectivity;	2-(2(S)-Benzyloxy-l-ethyl-propyl)- 4- {4-[4-(4-hydroxy-phenyl)-piperazin- 1 -yl] -phenyl} -2,4-dihydro- [ 1 ,2,4]triazol-3-one (3 Og) was taken in 5N hydrochloric acid (60 ml) in methanol (300ml), and was hydrogenated for 2-3 hours under a hydrogen pressure of 4 kg/cm2 at 50 C in the presence of palladium on carbon (10%, 3g). After completion of reaction (monitored by TLC), the catalyst was filtered off and catalyst was washed with methanol (60 ml). The combined filtrate was concentrated and the resulting mass was dissolved in ethyl acetate (600ml) and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 26g of the title compound having purity of 98.0% by HPLC.

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

3
[ 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 ]
[ 170985-86-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (lS)-(2S)-2-(2-benzyloxy-l-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazole-3-one (1Og) in dimethylsulfoxide (100ml), a solution of sodium hydroxide (1.3g) in water (5ml) was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4- triazole-1-yl) methyl] -tetrahyro-3 -furanmethanol-4-chlorobenzene sulphonate (10.0 g) was added, raising the temperature to 35-45 C and stirred at the same temperature for 10-12 hours. To the resulting solution water was added and stirred for 60 minutes. The resulting mixture was filtered to obtain 12.5g of the title compound having purity of 97.0% by HPLC.
1.28 kg		2-[(l S2S)-l-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-l- piperozinyl] phenyl]-3H-l,2,4-triazol-3-one (1 kg) was added to the flask along with Dimethylsulfoxide (8 lit) at room temperature and stirred for 15 min. Solution of Sodium hydroxide (0.15 kg) in Water (0.3 lit) was added at same temperature and maintained for 1 hr. ((3S,5R)-5-((lH-l,2,4-triazol-l-yl) methyl)-5-(2,4- difluorophenyl)-tetrahydrofuran-3-yl)methyl-4-chlorobenzene sulfonate (1.2 kg) was added and maintained for 4-5 hrs. Water (10 lit) was added to the reaction mixture and stirred for 15 min. Ethyl acetate (7.5 lit) was added and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was extracted with Ethyl acetate (3 lit). Aqueous layer and Ethyl acetate layer were separated and total aqueous layer was washed with Water (5 lit) and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was washed with brine solution and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was dried with Sodium sulfate and distilled under vacuum at below 50C. The resultant crude was treated with Isopropyl alcohol (10 lit) and heated to 75-80C, maintained for material dissolved and charged with activated Carbon (0.05 kg) and maintained for 1 hr. The material was filtered through the Hyflow bed and washed with Isopropyl alcohol (1 lit). The resultant mass was cooled to room temperature, maintained for 2 hrs, filtered the solid and washed with Isopropyl alcohol (1 lit).Yield: 1.28Kg; HPLC: 98%

Reference： [1]Patent: WO2009/141837,2009,A2 .Location in patent: Page/Page column 23
[2]Patent: WO2019/77627,2019,A1 .Location in patent: Page/Page column 14; 34

4
[ 184177-83-1 ]
[ 149809-43-8 ]
[ 170985-86-1 ]

Yield	Reaction Conditions	Operation in experiment
98%		Example-15 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one (Formula-21) Added 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-20 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) and water (7 ml) at 25-30 C. and stirred for 45 minutes at 25-30 C. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-10 (31.5 g) was added to the above reaction mixture at 25-30 C. and stirred 5 hours at 25-30 C. After completion of the reaction, water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50 C. Filtered the solid, washed with water and dried to get the title compound. Yield: 98%; Purity by HPLC: 95.1%
96%		Example -3: Preparation of 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)-l- ((2S,3S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one of the structural formula (III) of crystalline Form B-3 l-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenyl)- lH-l,2,4-triazol-5(4H)-one (4.0 Kg, 1.0 eq.) of the structural formula (II) was dissolved in Dimethyl sulfoxide (6.0 vol.) at 25±2C under nitrogen and cooled to 15-20 C. 25% aqueous sodium hydroxide solution (1.3 eq.) was added to the reaction mixture and was stirred for 10 minutes. ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4- difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate of the structural formula (I) (4.02 Kg) was added to the reaction mixture and continued to stir for lh at 15- 20 C. Reaction temperature was raised to 28±2C and stirred for 45-50 h. Ethyl acetate (5.0 vol.) was added to the reaction mass and cooled to 15-20 C followed by addition of water (5.0 vol.), reaction mass was slowly warmed to 25±2C and stirred. Layers were separated; organic layer was collected. Aqueous layer was again extracted with Ethyl acetate (3 vol.). Combined organic layers were washed with water (3 vol.) and organic layer was concentrated partially to contain 5.0 Vol. of Ethyl acetate. Cooled the partially concentrated solution to 25±2C and was added n-Heptane (5.0 vol.), stirred at 28±2C for 30 min and further diluted with n- Heptane (2.0 vol.) heated to 42±2C, stirred for 30 min and then slowly cooled to 28±2C and continue to stir at 28±2C for 2h. The above mixture was cooled to 0-5 C and stirred for lh. Solid was filtered; washed with Heptane (5 vol.). Dried under VTD at 60+5 C to yield 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol- 1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin- 1 - yl)phenyl)-l-((2S,3S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one of the structural formula (III) of crystalline Form B-3 with 96% yield. Characteristic Physico-Chemical Data of Crystalline Form B-3 of the Compound of Structural Formula III Physical appearance: Off-white to white solid X-ray Powder Diffraction Pattern: See Figure 3 and Table 3 DSC: See Figure 4 IR: See Figure 5
95.6%		100 mL three-neck flask was added 2-[(1S,2S)-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (formula III) (6.08 g) and DMSO (30 mL) were dissolved with stirring. A 25% aqueous solution of sodium hydroxide (1.7 mL) was added and the mixture was stirred for 15 min. Add (5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-yl)methyltetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate (formula IV) (6.12 g), the mixture is stirred at 40-50 C for 12-18 h. The reaction mixture was poured into water (60 mL) with vigorous stirring, stirring vigorously for 30 min, suction filtration, the filter cake was washed with water (30 mL), and dried under vacuum at 50 C to obtain 8.83 g of the compound of formula (V), yield 95.6 %.

73.4%		The 35.01 kg dimethyl sulfoxide, the mass concentration is 50% aqueous sodium hydroxide solution (sodium hydroxide 1.24 kg dissolved in pure water 1.24 kg, the mass concentration of the refer to sodium hydroxide of the quality of the sodium hydroxide solution the percentage of the total mass of the), adding 50L glass in the reactor, stirring solution cleaning, then adding 5.31 kg compound (III), stirring 20 - 30 minutes, adding 4.60 kg (3S, 5R) - toluene -4 - sulfonic acid 5 - (2, 4 - difluorophenyl) -5 - (1H - 1, 2, 4 - triazole -1 - yl) methyl tetrahydrofuran -3 - yl methyl ester (IV). After the completion of the feeding, temperature control 25 ± 5 C reaction 8 - 12 hours. TLC monitoring reaction, after the reaction. Control the temperature 20 - 30 C, the reaction with the sampler to 53.05 kg purification of water 100L glass reactor (rotational speed 200 - 300 rpm, dropping time 0.5 - 1.0 hours), continuously stirred for 0.5 - 1 hour. Centrifugal then adding to the basic solvent-free outflow; cake purified water 10.61 kg rear plate the basic solvent-free centrifugal to flow out. The centrifugal solid all input 50L glass in the reactor, adding 23.79 kg ethyl acetate, stirring until the solid completely dissolved. Layered, collecting the upper organic phase. Add silica gel 1.06 kg, heating to 50 - 60 C stirring 0.5 - 1 hour, cooled to 15 - 25 C, filtering. The filtrate batch transfer to 20L in the rotary evaporating bottle, at the vacuum degree of - 0.08 - - 0.1 mpa lower, control temperature 50 ± 10 C, concentrated to remove the ethyl acetate, to the solvent-free steam. To obtain brown oily matter. The oil of transfer to the 50L glass in the reactor, adding ethyl acetate 23.79 kg, heating to 50 ± 5 C, adds by drops positively hexane 36.71 kg (the dropping time 0.5 - 1.0 hours). Lowering the temperature to 20 ± 5 C stirring 2 - 3 hours, centrifugal to the solvent-free outflow, filter cake using mixed solvent (ethyl acetate 4.76 kg hexane 7.34 kg) leaching, centrifugal then adding to the solvent-free outflow. The centrifugal throughout the batch of wet product at the vacuum degree of - 0.08 - - 0.1 mpa lower, control temperature 40 - 50 C decompression drying 6 - 10 hours. A gray solid 6.00 kg compound (II). HPLC purity: 96.1%, yield: 73.4%.
		EXAMPLE 2PREPARATION OF BENZYL POSACONAZOLE OF FORMULA (Ila); In a clean, dry round bottomed flask 23 ml of dimethylsulfoxide and 4.74 gm of compound of formula (III) were charged at room temperature and stirred for about 15 minutes. Previously prepared NaOH solution (0.53 gm of NaOH dissolved in 3.74 ml of water) was added into the flask at about room temperature and stirred for about 30 minutes. 5 gm of compound of formula (IVa) was added to the reaction solution and stirred at about 35C to about 40C for about 12 hours. After completion of the reaction, the reaction solution was cooled to about 0C and 50 ml of water was added dropwise and stirred for about 30 minutes. The formed precipitate was filtered and washed with 80 ml of water. The solid was dried in air oven at about 45C to about 50C to yield 6.6 gm of the title compound. Purity by HPLC: 92%
69.29 g	With sodium hydroxide; In water; dimethyl sulfoxide; at 25 - 43℃; for 10h;	Example-20: Preparation of 4-(4-(4-(4-(((3R,5R)-5-((1H-i,2,4-triazol-1-yi)methyl)-5-(2,4- difluorophenyl)tetrahydrofuran-3-yI)methoxy)phenyl)piperazin-1-yI)phenyl)-1-((2S,3S)-2-(benzyloxy)pentan-3-yI)-1H-1,2,4-triazol-5(4H)-oneSodium hydroxide solution [prepared by dissolving sodium hydroxide (7.8 gins) in water (10 ml)] was added to dimethyl sulfoxide (175 ml) at 25-30C. ((3S,5R)-5-((1H-1,2,4-triazol-1- yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzene sulfonate (48.12 gms) and then followed by 1 -((2S,3 S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin- 1 -yl)phenyl)- 1 H-i ,2,4-triazol-5(4H)-one (50.Ogms) was added to the reaction mixtureat 25-30C. Heated the reaction mixture to 38-43C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30C and slowly added to water at the same the same temperature. Cooled the reaction mixture to 10-15C and adjusted the pH of the reaction mixture to 7.0 using hydrochloric acid solution at the same temperature. Raised the temperature5 of the reaction mixture to 25-30C and stirred for 3 hours at the same temperature. Filtered the precipitated silid and washed with purified water. To the obtained wet compound, isopropanol (500 ml) was added at 25-30C. Heated the reaction mixture to 65-70C to get clear solution. Cooled the reaction mixture to 25-30C and stirred for 4 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound.10 Yield: 69.29 gins.
13.2 g		10 g of compound of formula A and 76 mL DMSO were added into a reaction flask at room temperature, and stirred until clarification. An alkaline solution previously prepared from 1.4 g sodium hydroxide and 6 g water was further added thereto. The mixture was stirred for 1 h. Then, 10 g of compound of formula IX was added thereto. The mixture was warmed up to 38 C. and reacted for 16 h. After the reaction was completed, the mixture was warmed up to 45 C. 6 mL water was added thereto. The mixture was stirred for 30-60 min. 154 mL water was further added thereto. The mixture was stirred for 1 h, and filtered under suction. The resultant solid was drip washed with 4×50 mL purified water to obtain a wet product. (0249) The wet product and 60 mL of 90% aqueous ethanol solution were added to a reaction flask, warmed up to 65 C., and stirred. After clarification, 1.5 g active carbon was added thereto. The mixture was stirred for 15 min, filter-pressed while hot, and washed with 15 mL of 90% aqueous ethanol solution. Then, the filtrate was warmed up to 65 C., stirred, cooled to 40-45 C. after clarification, crystallized while keeping the temperature for 1 h, further cooled to 0-5 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 ethanol 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 13.2 g of product.
1.3 kg		2-[(l S2S)-l-Ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-l- piperozinyl] phenyl]-3H-l,2,4-triazol-3-one (1 kg) was added to the Flask along with Dimethylsulfoxide (8 lit) at room temperature and stirred for 15 min. Solution of Sodium hydroxide (0.15 kg) in Water (0.3 lit) was added at same temperature and maintained for 1 hr. ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4- difluorophenyl)-tetrahydrofuran-3-yl)methyl-4-methylbenzene sulfonate (1.2 kg) was added and maintained for 4-5 hrs. Water (10 lit) was added to the reaction mixture and stirred for 15 min. Ethyl acetate (7.5 lit) was added and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and aqueous layer was extracted with Ethyl acetate (3 lit). Aqueous layer and Ethyl acetate layer were separated and total aqueous layer was washed with Water (5 lit) and stirred for 15 min. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was washed with brine solution. Aqueous layer and Ethyl acetate layer were separated and Ethyl acetate layer was dried over Sodium sulfate and distilled under vacuum at below 50C. The resultant crude was treated with Isopropyl alcohol (10 lit) and heated to 75-80C, maintained for material dissolved and treated with activated Carbon (0.05 kg) and maintained for 1 hr. The material was filtered through the Hyflow bed and washed with Isopropyl alcohol (1 lit). The resultant mass was cooled to room temperature, maintained for 2 hrs, filtered the solid and washed with Isopropyl alcohol (1 lit). Yield: 1.3Kg; HPLC: 98.6%.
19.2 kg		In a dry 300 L reactor, 70 kg of tetrahydrofuran was added under vacuum. The mixture was stirred, and after nitrogen replacement, the temperature was lowered to -10 C, and then 0.6 kg of sodium hydride was added in portions under nitrogen protection, and after stirring for 0.5 h, Continue to control the temperature T ? -10 C to add 12 kg of POB/24 kg of tetrahydrofuran solution to the system, After the dropwise addition, the mixture was stirred for 1 hour. Add 10 kg of POA/20 kg of tetrahydrofuran solution to the system. The reaction was carried out at a temperature of -10 to 0 C, and the monitoring until the POA disappeared. The temperature was controlled by T ? -10 C, and 1 kg of methanol was added dropwise. After stirring for 0.5 h, the reaction was quenched by adding 1 kg of water. Temperature control T ? 40 C under reduced pressure to concentrate about 70 L of tetrahydrofuran, Add 200 kg of dichloromethane and wash with 50 kg * 3 tap water. Wash with 50 kg of saturated brine, and dry the organic phase with 10 kg of anhydrous sodium sulfate. Filtration, temperature control T ? 40 C, concentrated under reduced pressure to no fraction, 60 kg of ethyl acetate was added while hot, and the temperature was raised to 70 C for 1 h. Then, the temperature is lowered to 0 to 10 C at a rate of 10 C / h, and suction filtration is performed. The filter cake was rinsed with pre-cooled 5 kg of ethyl acetate and drained. Transfer to the drying room at 40 ~ 45 C under reduced pressure for 40h, Received 19.2 kg of POC.

Reference： [1]Patent: US2014/343285,2014,A1 .Location in patent: Paragraph 0343
[2]Patent: WO2017/51342,2017,A1 .Location in patent: Page/Page column 15; 16
[3]Patent: CN108239077,2018,A .Location in patent: Paragraph 0015; 0027; 0032; 0034
[4]Patent: CN106749207,2017,A .Location in patent: Paragraph 0035; 0036; 0037
[5]Patent: WO2011/158248,2011,A2 .Location in patent: Page/Page column 29
[6]Patent: WO2015/59716,2015,A2 .Location in patent: Page/Page column 25; 26
[7]Patent: US2019/71408,2019,A1 .Location in patent: Paragraph 0248-0249
[8]Patent: WO2019/77627,2019,A1 .Location in patent: Page/Page column 14; 33; 34
[9]Patent: CN109796446,2019,A .Location in patent: Paragraph 0043; 0067; 0068; 0095; 0096

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[ 170985-85-0 ]
[ 184177-83-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In 1,4-dioxane; at 90 - 100℃; for 24h;	mixture of N?-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-17 (45.5 g) obtained in example-13, dioxane (500 ml) added <strong>[184177-81-9]phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate</strong> compound of formula-19 (50 g) was heated to 90-100 C. Triethylamine (26 g) was added to the reaction mixture at 90-100 C. over a period of 1 hour and stirred for 24 hours at 90-100 C. After completion of the reaction, the reaction mixture was cooled to 25-30 C. and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2% sodium hydroxide solution followed by water, and then with 5% hydrochloric acid solution followed by water and 5% NaHCO3 solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30 C. The reaction mixture was stirred for 6 hours at 25-30 C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 28 g; Purity by HPLC: 97.67%; Impurity-A: 0.37%b) Purification of Compound of Formula-20 The obtained compound of formula-20 (30 g) was dissolved in methanol (960 ml) by heating at 60-65 C. The reaction mixture was cooled to 25-30 C. and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the pure compound of formula-20. Yield: 70%; Purity by HPLC: 99.15%; Impurity-A: 0.09%
0.89 kg	With triethylamine; In 1,4-dioxane; at 90 - 95℃;Large scale;	N'-[(l S,2S)-2-(Benzyloxy)-l-ethylpropyl]formic hydrazide (1 kg) and 1,4- Dioxane (5 lit) were added to the flask at room temperature along with Phenyl 4- (4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate (1.4 kg). The reaction mass was heated to 90-95C and Triethylamine (0.89 lit) was slowly added and stirred for 1 hr and maintained for 12-18 hrs. TLC was checked for intermediate and cooled to Room temperature and Dichloromethane (20 lit) was charged and filter through the Hyflow bed and washed with Dichloromethane (5 lit). Water (4 lit) was added and stirred for 10 min. Aqueous layer and Organic layer were separated and organic layer was washed with brine solution. Organic layer was separated and dried with Sodium sulphate and distilled completely under vacuum at below 50C and co- distilled with Toluene (1 lit) and Isopropyl alcohol (1 lit). Isopropyl alcohol (2.5 lit) was added to the crude and maintained at 65-70C for 1 hr, then cooled to Room temperature, stirred for 30 min and cooled to 10-15C, and then filtered and washed with Isopropyl alcohol (0.5 lit).Out Put: 0.89 kg; HPLC: 97%.
	With triethylamine; In 1,4-dioxane; at 90 - 100℃; for 24h;	A mixture of compounds 4 (18.0 g, 0.046 mol), 5 (16.38 g, 0.069 mol), and dioxane (180 mL) was heated to 90-100 C. Triethylamine (9.36 g, 0.092 mol) was added to the reaction mixture and then stirred for 24 h at 90-100 C. After the completion of the reaction, the reaction mixture was cooled to 25-30 C and dichloromethane (25 mL) was added to the reaction mixture. Compound 1 was obtained by filtration and concentration under vacuo and stirred in isopropyl alcohol (27 mL) at 25-30 C for 6 h. Pure compound 1 was got by recrystallization with methanol. 1H NMR (DMSO-d6, 400 MHz): delta 0.793 (t, 3H, CH3), 1.242 (d, 3H, CH3), 1.765 (q, 2H, CH2), 3.122 (t, 4H, piperazine-CH2), 3.327 (t, 4H, piperazine-CH2), 3.745 (m, 1H, N-CH), 3.990 (m, 1H, O-CH), 4.275-4.544 (d, 2H, Ar-CH2), 6.691 (d, 2H, Ar-H), 6.869 (d, 2H, Ar-H), 7.119 (d, 2H, Ar-H), 7.172 (q, 2H, Ar-H), 7.232 (m, 3H, Ar-H), 7.476 (d, 2H, Ar-H), 8.323 (s, 1H, N2C-H), 8.787 (s, 1H, Ar-OH). HRMS (ESI+): m/z: calcd for C30H35N5O3: 536.2638 [M+Na+]; found: 536.2619. IR (KBr, lambda, cm-1): 3468.1 (s), 1678.2 (s), 1605.1 (m), 1485.07 (s), 1231.9 (s), 1115.4 (s).

Reference： [1]Patent: US2014/343285,2014,A1 .Location in patent: Paragraph 0340; 0341; 0342
[2]Patent: WO2019/77627,2019,A1 .Location in patent: Page/Page column 12; 22; 23
[3]Journal of Structural Chemistry,2019,vol. 60,p. 1173 - 1179

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