170985-85-0

Basic information

• Product Name: 2-[(1S,2S)-1-Ethyl-2-(phenylmethoxy)propyl]hydrazinecarboxaldehyde
• Synonyms: [S-(R*,R*)]-2-[1-Ethyl-2-(phenylMethoxy)propyl]hydrazinecarboxaldehyde;N'-((2S,3S)-2-(Benzyloxy)pentan-3-yl)forMohydrazide;Posaconazole Impurity 15 Oxalate;Formic acid N'-(2(S)-benzyloxy-1(S)-ethyl-propyl)-hydrazide;N'-((2S,3S);pentan-3-yl);N-[[(2S,3S)-2-phenylmethoxypentan-3-yl]amino]formamide;2-[(1S,2S)-1-Ethyl-2-(phenylmethoxy)propyl]hydrazinecarboxaldehyde
• CAS NO: 170985-85-0
• Molecular Formula: C₁₃H₂₀N₂O₂
• Molecular Weight: 236.31
• EINECS: 1308068-626-2
• Product Categories: Chiral Reagents;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics
• Mol File: 170985-85-0.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 338.531 °C at 760 mmHg
• Flash Point: 158.538 °C
• Appearance: /
• Density: 1.041
• Storage Temp.: 2-8°C(protect from light)
• PKA: 13.30±0.23(Predicted)
• CAS DataBase Reference: 2-[(1S,2S)-1-Ethyl-2-(phenylmethoxy)propyl]hydrazinecarboxaldehyde(CAS DataBase Reference)
• NIST Chemistry Reference: 2-[(1S,2S)-1-Ethyl-2-(phenylmethoxy)propyl]hydrazinecarboxaldehyde(170985-85-0)
• EPA Substance Registry System: 2-[(1S,2S)-1-Ethyl-2-(phenylmethoxy)propyl]hydrazinecarboxaldehyde(170985-85-0)

Safety Data

• Hazardous Substances Data: 170985-85-0(Hazardous Substances Data)

Usage

Uses

Posaconazole intermediate. Antifungal agent.

Synthetic route

ethyl bromide (74-96-4) + (S)-N'-(2-(benzyloxy)propylidene) formohydrazide (170985-84-9) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Stage #1: ethyl bromide With iodine; magnesium In tert-butyl methyl ether at 40 - 55℃; for 2h; Inert atmosphere; Stage #2: (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide With N,O-bis-(trimethylsilyl)-acetamide In tert-butyl methyl ether at 5 - 30℃; for 9h; Temperature; Inert atmosphere;	66%
Stage #1: ethyl bromide With iodine; magnesium In tert-butyl methyl ether at 40 - 53℃; for 2h; Inert atmosphere; Stage #2: (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide With N,O-bis-(trimethylsilyl)-acetamide In tert-butyl methyl ether at 5 - 30℃; for 9h; Temperature; Inert atmosphere;	60%
Stage #1: ethyl bromide With iodine; magnesium In tert-butyl methyl ether at 40 - 55℃; for 2h; Inert atmosphere; Stage #2: (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide With N,O-bis-(trimethylsilyl)-acetamide In tert-butyl methyl ether at 0 - 30℃; Inert atmosphere;	48 g
Stage #1: ethyl bromide With iodine; magnesium In tert-butyl methyl ether at 40 - 55℃; Inert atmosphere; Stage #2: (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide With N,O-bis-(trimethylsilyl)-acetamide In tert-butyl methyl ether at 25 - 30℃; for 1.75h; Inert atmosphere;

ethylmagnesium bromide (925-90-6) + (S)-2-(Benzyloxy)-N-(Formylamino)-Propanimine → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) + N'-((2S,3R)-2-(benzyloxy)pent-3-yl)formylhydrazine

Conditions	Yield
Stage #1: (S)-2-(Benzyloxy)-N-(Formylamino)-Propanimine With N,N-bis(trimethylsilyl)acetamide In diethyl ether at 20℃; for 0.75h; Stage #2: ethylmagnesium bromide In diethyl ether at 20℃; Grignard addition;	A 62.3% B n/a

(S)-2-(benzyloxy)propanal (81445-44-5) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 80 percent / methanol 2.1: bis(trimethylsilyl) acetamide / diethyl ether / 0.75 h / 20 °C 2.2: 62.3 percent / diethyl ether / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: toluene; methanol / 4 h / 0 - 30 °C 2.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 2.2: 0 - 30 °C / Inert atmosphere View Scheme

(S)-2-(benzyloxy)-1-(pyrrolidin-1-yl)propan-1-one (122151-32-0) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 94 percent / Red-Al / toluene / 5 h 2.1: 80 percent / methanol 3.1: bis(trimethylsilyl) acetamide / diethyl ether / 0.75 h / 20 °C 3.2: 62.3 percent / diethyl ether / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: magnesium / tetrahydrofuran / 1 h / 60 - 65 °C / Inert atmosphere; Large scale 1.2: 1 h / 0 - 5 °C / Inert atmosphere; Large scale 2.1: sodium tetrahydroborate; lithium bromide; zinc dibromide / tetrahydrofuran / 0 - 5 °C / Inert atmosphere; Large scale 3.1: dmap / dichloromethane / 0.17 h / 0 - 20 °C / Large scale 3.2: 13 h / 30 - 35 °C / Large scale 4.1: hydrazine hydrate / ethanol / 13 h / 25 - 70 °C / Large scale 4.2: 1 h / 20 °C / Large scale 5.1: methanol / 4 h / 50 - 55 °C / Large scale View Scheme

methyl (S)-2-(benzyloxy)propanoate (77287-11-7) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: diisobutylaluminium hydride / toluene / 3 h / -75 - -70 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: toluene; methanol / 4 h / 0 - 30 °C 3.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 3.2: 0 - 30 °C / Inert atmosphere View Scheme

(S)-1-phenylethanamine (S)-2-(benzyloxy)propanoic acid → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 2 h / 0 - 10 °C 2.1: diisobutylaluminium hydride / toluene / 3 h / -75 - -70 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: toluene; methanol / 4 h / 0 - 30 °C 4.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 4.2: 0 - 30 °C / Inert atmosphere View Scheme

2-benzyloxypropionic acid methyl ester (53346-03-5) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: water; sodium hydroxide / 5 h / 0 - 30 °C 2.1: toluene / 6 h / 25 - 30 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 2 h / 0 - 10 °C 4.1: diisobutylaluminium hydride / toluene / 3 h / -75 - -70 °C / Inert atmosphere 4.2: Inert atmosphere 5.1: toluene; methanol / 4 h / 0 - 30 °C 6.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 6.2: 0 - 30 °C / Inert atmosphere View Scheme

benzyl chloride (100-44-7) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: potassium tert-butylate / N,N-dimethyl-formamide / 5 h / -20 - -10 °C 2.1: water; sodium hydroxide / 5 h / 0 - 30 °C 3.1: toluene / 6 h / 25 - 30 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 2 h / 0 - 10 °C 5.1: diisobutylaluminium hydride / toluene / 3 h / -75 - -70 °C / Inert atmosphere 5.2: Inert atmosphere 6.1: toluene; methanol / 4 h / 0 - 30 °C 7.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 7.2: 0 - 30 °C / Inert atmosphere View Scheme

2-(benzyloxy)propanoic acid (33106-32-0, 74431-49-5, 100836-85-9, 6625-78-1) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: toluene / 6 h / 25 - 30 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 2 h / 0 - 10 °C 3.1: diisobutylaluminium hydride / toluene / 3 h / -75 - -70 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: toluene; methanol / 4 h / 0 - 30 °C 5.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 5.2: 0 - 30 °C / Inert atmosphere View Scheme

2-[2S-1-ethyl-2-benzyloxypropylidene]hydrazinecarbaldehyde → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
With sodium tetrahydroborate In isopropyl alcohol at 0 - 15℃; for 3h;	9.1 g

(S)-2-(benzyloxy)propanoic acid (33106-32-0) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 2 h / 150 °C 2.1: sodium / ethanol / 0.5 h / 0 °C / Inert atmosphere 2.2: 1 h / Inert atmosphere; Reflux 3.1: toluene; methanol / 3 h / 0 - 30 °C 4.1: iodine; magnesium / tert-butyl methyl ether / 2 h / 40 - 53 °C / Inert atmosphere 4.2: 9 h / 5 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: phosphorus trichloride / toluene / 7 h / Reflux 2.1: hydrogen; 10 percent palladium on barium sulphate / toluene / 750.08 Torr / Reflux 3.1: methanol / 3 h / 0 - 30 °C 4.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 4.2: 9 h / 5 - 30 °C / Inert atmosphere View Scheme

(S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium / ethanol / 0.5 h / 0 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere; Reflux 2.1: toluene; methanol / 3 h / 0 - 30 °C 3.1: iodine; magnesium / tert-butyl methyl ether / 2 h / 40 - 53 °C / Inert atmosphere 3.2: 9 h / 5 - 30 °C / Inert atmosphere View Scheme

(S)-2-benzyloxy-3-pentanone (132489-33-9) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; lithium bromide; zinc dibromide / tetrahydrofuran / 0 - 5 °C / Inert atmosphere; Large scale 2.1: dmap / dichloromethane / 0.17 h / 0 - 20 °C / Large scale 2.2: 13 h / 30 - 35 °C / Large scale 3.1: hydrazine hydrate / ethanol / 13 h / 25 - 70 °C / Large scale 3.2: 1 h / 20 °C / Large scale 4.1: methanol / 4 h / 50 - 55 °C / Large scale View Scheme

(2S)-2-(benzyloxy)pentan-3-ol → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap / dichloromethane / 0.17 h / 0 - 20 °C / Large scale 1.2: 13 h / 30 - 35 °C / Large scale 2.1: hydrazine hydrate / ethanol / 13 h / 25 - 70 °C / Large scale 2.2: 1 h / 20 °C / Large scale 3.1: methanol / 4 h / 50 - 55 °C / Large scale View Scheme

(2S)-2-(benzyloxy)-1-ethylpropyl-4-chlorobenzene sulfonate → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrazine hydrate / ethanol / 13 h / 25 - 70 °C / Large scale 1.2: 1 h / 20 °C / Large scale 2.1: methanol / 4 h / 50 - 55 °C / Large scale View Scheme

C12H20N2O*C18H14O8 + formic acid ethyl ester (109-94-4) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
In methanol at 50 - 55℃; for 4h; Large scale;

(S)-2-(benzyloxy)-1-morpholinopropan-1-one → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: magnesium / tetrahydrofuran / 1 h / 60 - 65 °C / Inert atmosphere; Large scale 1.2: 1 h / 0 - 5 °C / Large scale 2.1: sodium tetrahydroborate; lithium bromide; zinc dibromide / tetrahydrofuran / 0 - 5 °C / Inert atmosphere; Large scale 3.1: dmap / dichloromethane / 0.17 h / 0 - 20 °C / Large scale 3.2: 13 h / 30 - 35 °C / Large scale 4.1: hydrazine hydrate / ethanol / 13 h / 25 - 70 °C / Large scale 4.2: 1 h / 20 °C / Large scale 5.1: methanol / 4 h / 50 - 55 °C / Large scale View Scheme

(2S)-2-Benzyloxypropanoic acid chloride (90192-47-5) → N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen; 10 percent palladium on barium sulphate / toluene / 750.08 Torr / Reflux 2.1: methanol / 3 h / 0 - 30 °C 3.1: magnesium; iodine / tert-butyl methyl ether / 2 h / 40 - 55 °C / Inert atmosphere 3.2: 9 h / 5 - 30 °C / Inert atmosphere View Scheme

N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) + [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]-carbamic acid phenyl ester → 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-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one (170985-86-1)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene	85%

4-(4-(4-(4-aminophenyl)piperazin-1-yl)phenyl)carbamic acid phenyl ester + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 2-((2S,3S)-2-(benzyloxy)-3-pentyl)-4-(4-(4-(4-aminophenyl)piperazin-1-yl)phenyl)-2,4-dihydro-1,2,4-triazole-3(4H)-one

Conditions	Yield
With triethylamine In 1,4-dioxane at 80 - 120℃; for 24h; Inert atmosphere;	82%

C23H23N3O2 + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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 (184177-83-1)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 30 - 110℃; Temperature; Reagent/catalyst; Solvent; Inert atmosphere;	75.2%

phenyl N-(4-(4-(4-hydroxyphenyl)-1-piperazinyl)phenyl)carbamate (184177-81-9) + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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 (184177-83-1)

Conditions	Yield
With triethylamine In 1,4-dioxane at 90 - 100℃; for 24h;	70%
With triethylamine In 1,4-dioxane at 90 - 95℃; Large scale;	0.89 kg
With triethylamine In 1,4-dioxane at 90 - 100℃; for 24h;
With triethylamine In acetonitrile at 65℃; for 30h;

C21H27N3O3 + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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 (184177-83-1)

Conditions	Yield
With triethylamine In 1,4-dioxane at 85℃; for 35h; Inert atmosphere;	61%

C35H40F2N6O4 + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one (170985-86-1)

Conditions	Yield
With triethylamine In 1,4-dioxane at 90℃; for 30h; Inert atmosphere;	55%

phenyl (5-iodopyridin-2-yl)carbamate + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(5-iodopyridin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Conditions	Yield
With potassium carbonate In 1,4-dioxane at 0 - 90℃; for 16h; Inert atmosphere;	45%

C24H25N3O3 + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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 (184177-83-1)

Conditions	Yield
With triethylamine In 1,2-dimethoxyethane Solvent; Inert atmosphere; Reflux;	22.5%

acetic acid 4-[4-(4-phenoxycarbonylamino-phenyl)-piperazin-1-yl]-phenyl ester (1197458-94-8) + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → C32H37N5O4

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide; toluene at 80 - 100℃; for 24 - 30h; Product distribution / selectivity;

N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one (170985-86-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / 1,4-dioxane / 24 h / 90 - 100 °C 2.1: sodium hydroxide / water; dimethyl sulfoxide / 0.75 h / 25 - 30 °C 2.2: 5 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 30 h / 65 °C 2: sodium hydroxide / dimethyl sulfoxide; water / 20 - 50 °C View Scheme

N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → posaconazote (171228-49-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / 1,4-dioxane / 24 h / 90 - 100 °C 2.1: sodium hydroxide / water; dimethyl sulfoxide / 0.75 h / 25 - 30 °C 2.2: 5 h / 25 - 30 °C 3.1: palladium 10% on activated carbon; hydrogen; hydrogenchloride / water; methanol / 5 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale 3.1: hydrogenchloride; palladium 10% on activated carbon; hydrogen / water; methanol / 50 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale 3.1: hydrogenchloride; palladium 10% on activated carbon; hydrogen / water; methanol / 50 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / 1,4-dioxane / 90 - 95 °C / Large scale 2.1: sodium hydroxide / water; dimethyl sulfoxide / 1 h / 20 °C / Large scale 2.2: Large scale 3.1: hydrogenchloride; palladium 10% on activated carbon; hydrogen / water; methanol / 50 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 30 h / 65 °C 2: sodium hydroxide / dimethyl sulfoxide; water / 20 - 50 °C 3: hydrogenchloride / water / 40 - 50 °C View Scheme

phenyl chloroformate (1885-14-9) + 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (74853-08-0) + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 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 (184177-83-1)

Conditions	Yield
Stage #1: phenyl chloroformate; 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine In N,N-dimethyl-formamide; toluene at -10 - 20℃; for 4h; Stage #2: N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide With triethylamine In N,N-dimethyl-formamide; toluene at 100 - 110℃; Temperature; Solvent;

phenyl (5-bromo-3-fluoropyridin-2-yl)carbamate + N’-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide (170985-85-0) → 2-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(5-bromo-3-fluoropyridin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Conditions	Yield
In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; Sealed tube;	600 mg

Upstream product

• 90192-47-5 (2S)-2-Benzyloxypropanoic acid chloride 
• 183871-36-5 C₁₂H₂₀N₂O*C₁₈H₁₄O₈ 
• 109-94-4 formic acid ethyl ester 
• 132489-33-9 (S)-2-benzyloxy-3-pentanone 
• 33106-32-0 (S)-2-(benzyloxy)propanoic acid 
• 74-96-4 ethyl bromide 
• 170985-84-9 (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide 
• 33106-32-0 2-(benzyloxy)propanoic acid 
• 100-44-7 benzyl chloride 
• 53346-03-5 2-benzyloxypropionic acid methyl ester 
• 77287-11-7 methyl (S)-2-(benzyloxy)propanoate 
• 122151-32-0 (S)-2-(benzyloxy)-1-(pyrrolidin-1-yl)propan-1-one 
• 81445-44-5 (S)-2-(benzyloxy)propanal 
• 925-90-6 ethylmagnesium bromide 

Downstream Products

• 170985-86-1 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-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one 
• 171228-49-2 posaconazote 
• 184177-83-1 2-[(1S,2S)-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]-3H-1,2,4-triazol-3-one 

Relevant articles and documents

Stereoselective Grignard additions to N-formyl hydrazone: A concise synthesis of NoxafilR side chain and a synthesis of Noxafil R

Addition of ethyl Grignard reagent to the formyl hydrazone 11 via in situ silylation provided the corresponding formyl hydrazine with excellent diastereoselectivity in favor of the desired S,S-diastereoisomer 6. Treatment of 6 with the phenyl carbamate 13 efficiently provided the O-benzyl protected Noxafil, which was deprotected to provide NoxafilR.

Method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine

A method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine comprises the following steps: reacting (S)-2-benzyloxypropionic acid with an acylation reagent to obtain (S)-2-benzyloxy propionyl chloride; adding a palladium barium sulfate catalyst into o-xylene and reacting in hydrogen atmosphere for 15-30 min; adding (S)-2-benzyloxy propionyl chloride hydrogen atmosphere forreflux reaction until hydrogen is not absorbed; after the reaction is finished, the catalyst is filtered and the o-xylene is removed to obtain (S)-2-benzyloxypropionaldehyde; reacting the (S)-2-benzyloxypropionaldehyde with formylhydrazine, removing the solvent after finishing the reaction, and post-treating to obtain (S)-N'-(2 benzyloxypropyl) formylhydrazine; reacting the (S)-N'-(2 benzyloxypropyl) formylhydrazine with a Grignard reagent, and post-treating to obtain N'-((2s,3s)- 2-(benzyloxy) pentyl-3-base] formylhydrazine. According to the invention, an acylating reagent which is low in price and safer and more environment-friendly in reaction and a palladium barium sulfate catalyst which can be recycled for a plurality of times are used as reaction raw materials, so that the reaction process more conforms to the principle of atom economy, and the reaction is milder.

Method for synthesizing N'-[(2S,3S)-2-(benzyloxy) penta-3-yl]formhydrazide

The invention discloses a method for synthesizing N'-[(2S,3S)-2-(benzyloxy) penta-3-yl]formhydrazide, comprising the following steps: letting (S)-2-benzyloxy propionic acid react with ethene diamine to obtain (S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole; adding metallic sodium into (S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole under the protection of nitrogen, stirring and reacting and processing to obtain (S)-2-benzyloxy propionaldehyde; letting (S)-2-benzyloxy propionaldehyde react with formhydrazide and carrying out post-treatment to obtain (S)-N'-(2-benzyloxy propylidene)formhydrazide; letting (S)-N'-(2-benzyloxy propylidene)formhydrazide react with a Grignard reagent and carrying out post-treatment after the reaction so as to obtain the product N'-[(2S,3S)-2-(benzyloxy)penta-3-yl]formhydrazide. The method of the invention has the following advantages: no expensive and unsafe organo-aluminum compound is used; preparation cost is low; post-treatments are simple; and operation is simple.