324763-39-5

Basic information

• Product Name: Benzene, 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)-
• Synonyms: Benzene, 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)-;4-[(2R)-2-(Chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene;Aliskiren inter-1;(R)-4-(2-(ChloroMethyl)-3-Methylbutyl)-1-Methoxy-2-(3-Methoxypropoxy)benzene;-1-methoxy-2-(3-methoxypropoxy);-4-(2-(Chloromethyl)
• CAS NO: 324763-39-5
• Molecular Formula: C₁₇H₂₇ClO₃
• Molecular Weight: 314.85
• Product Categories: Drug Intermediates;Aliskiren intermediates;aliskiren
• Mol File: 324763-39-5.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 398 ºC
• Flash Point: 122 ºC
• Appearance: /
• Density: 1.034
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.491
• Storage Temp.: 2-8°C
• CAS DataBase Reference: Benzene, 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)-(CAS DataBase Reference)
• NIST Chemistry Reference: Benzene, 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)-(324763-39-5)
• EPA Substance Registry System: Benzene, 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)-(324763-39-5)

Safety Data

• Hazardous Substances Data: 324763-39-5(Hazardous Substances Data)

Usage

Uses

4-[(2R)-2-(Chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene is an intermediate in the preparation of orally active renin inhibitor Aliskiren (A536000).

InChI:InChI=1/C17H27ClO3/c1-13(2)15(12-18)10-14-6-7-16(20-4)17(11-14)21-9-5-8-19-3/h6-7,11,13,15H,5,8-10,12H2,1-4H3/t15-/m0/s1

Synthetic route

(R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol (172900-70-8) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
With tetrachloromethane; TOP at 20℃; for 16h; trioctylphosphine was added at 10 °ree;C;	82%
With pyridine; thionyl chloride	70%
With N,N-dimethyl-formamide; trichlorophosphate In toluene at 80℃;

2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutanol (943349-14-2) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
With thionyl chloride; N,N-dimethyl-formamide In toluene at 90℃; for 2h; Product distribution / selectivity;	64%

4-methoxy-3-(3-methoxypropoxy)benzaldehyde (172900-75-3) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 82 percent 2.1: H2 / Pd/C / ethyl acetate / 20 °C 3.1: (COCl)2 / dimethylformamide / 20 °C 4.1: NaOH / toluene / 20 °C 5.1: LDA; LiCl / tetrahydrofuran / 0 °C 5.2: tetrahydrofuran / 20 °C / Heating 6.1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 7.1: POCl3; DMF / toluene / 80 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 30 °C 1.2: pH 2 2.1: phosphorus tribromide / dichloromethane / 2.17 h / 0 - 5 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 3.2: -70 - 5 °C 4.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 5.2: 5.75 h / 0 - 30 °C 6.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 1.2: -30 - -25 °C 1.3: -30 - 5 °C 2.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 3.2: 11 h / 60 - 65 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme

3-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-propionic acid → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: (COCl)2 / dimethylformamide / 20 °C 2.1: NaOH / toluene / 20 °C 3.1: LDA; LiCl / tetrahydrofuran / 0 °C 3.2: tetrahydrofuran / 20 °C / Heating 4.1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 5.1: POCl3; DMF / toluene / 80 °C View Scheme

3-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-propionyl chloride → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: NaOH / toluene / 20 °C 2.1: LDA; LiCl / tetrahydrofuran / 0 °C 2.2: tetrahydrofuran / 20 °C / Heating 3.1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 4.1: POCl3; DMF / toluene / 80 °C View Scheme

(E)-3-[4-Methoxy-3-(3-methoxy-propoxy)-phenyl]-acrylic acid (324763-36-2) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: H2 / Pd/C / ethyl acetate / 20 °C 2.1: (COCl)2 / dimethylformamide / 20 °C 3.1: NaOH / toluene / 20 °C 4.1: LDA; LiCl / tetrahydrofuran / 0 °C 4.2: tetrahydrofuran / 20 °C / Heating 5.1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 6.1: POCl3; DMF / toluene / 80 °C View Scheme

(R)-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-(1-methylethyl)propanoic acid (172900-71-9) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / NaBH4; I2 / 96 h / 20 °C 2: 70 percent / SOCl2; pyridine View Scheme
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 1.2: 5.75 h / 0 - 30 °C 2.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 2: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 1.2: 0 °C / Large scale 2.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-3-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-N-methyl-propionamide (324763-37-3) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: LDA; LiCl / tetrahydrofuran / 0 °C 1.2: tetrahydrofuran / 20 °C / Heating 2.1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 3.1: POCl3; DMF / toluene / 80 °C View Scheme

N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3,N-dimethyl-butyramide (324763-38-4) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 66 percent / BH3*NH3; n-BuLi / tetrahydrofuran / 20 °C 2: POCl3; DMF / toluene / 80 °C View Scheme

3-methylbutyric acid (503-74-2) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2.2: -70 - 5 °C 3.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 4.2: 5.75 h / 0 - 30 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2.2: -70 - 5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 3.2: 11 h / 60 - 65 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2.2: -30 - -25 °C 2.3: -30 - 5 °C 3.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 4.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 4.2: 11 h / 60 - 65 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2.2: -30 - -25 °C 2.3: -30 - 5 °C 3.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 4.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 5.2: 5.75 h / 0 - 30 °C 6.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme

4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)-benzene (172900-73-1) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 1.2: -70 - 5 °C 2.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 5.75 h / 0 - 30 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 1.2: -70 - 5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 2.2: 11 h / 60 - 65 °C 3.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -10 °C / Inert atmosphere; Large scale 1.2: 20 h / 0 °C / Large scale 2.1: dihydrogen peroxide / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Large scale 2.2: Large scale 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 3.2: 0 °C / Large scale 4.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

[4-methoxy-3-(3-methoxypropoxy)-phenyl]methanol (172900-74-2) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: phosphorus tribromide / dichloromethane / 2.17 h / 0 - 5 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2.2: -70 - 5 °C 3.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 4.2: 5.75 h / 0 - 30 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: phosphorus tribromide / dichloromethane / 2.17 h / 0 - 5 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2.2: -70 - 5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 3.2: 11 h / 60 - 65 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: thionyl chloride / dichloromethane / 2 h / 0 °C 2.1: sodium iodide / tetrahydrofuran / 16 h / 25 - 30 °C 3.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 1 h / Cooling with ice; Inert atmosphere 3.2: 16 h / -30 - -5 °C 4.1: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 5.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 1.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride / dichloromethane / 3 h / 0 - 5 °C 2.1: sodium iodide / tetrahydrofuran / 16 h / 25 - 30 °C 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 3.2: 1 h / -45 - -20 °C 4.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 5.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 6.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 5 steps 1.1: phosphorus tribromide / dichloromethane / 0 - 5 °C / Inert atmosphere; Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -10 °C / Inert atmosphere; Large scale 2.2: 20 h / 0 °C / Large scale 3.1: dihydrogen peroxide / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Large scale 3.2: Large scale 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 4.2: 0 °C / Large scale 5.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

(4'R)-3-methyl-1-(2'-oxo-4'-phenyloxazolidin-3'-yl)butan-1-one → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 1.2: -70 - 5 °C 2.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 5.75 h / 0 - 30 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 1.2: -70 - 5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 2.2: 11 h / 60 - 65 °C 3.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 1.2: -30 - -25 °C 1.3: -30 - 5 °C 2.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 3.2: 11 h / 60 - 65 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 1.2: -30 - -25 °C 1.3: -30 - 5 °C 2.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 3.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 4.2: 5.75 h / 0 - 30 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme

(R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one (1350705-31-5) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 2.2: 5.75 h / 0 - 30 °C 3.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 1.2: 11 h / 60 - 65 °C 2.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Large scale 1.2: Large scale 2.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 2.2: 0 °C / Large scale 3.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

(4R)-3-(2S)-(2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one (1350705-32-6) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 2.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 5.75 h / 0 - 30 °C 4.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 2.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 2.2: 11 h / 60 - 65 °C 3.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C View Scheme

C12H17IO3 (1381757-32-9) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 1 h / Cooling with ice; Inert atmosphere 1.2: 16 h / -30 - -5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 3.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 1.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 1.2: 1 h / -45 - -20 °C 2.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 3.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 4.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme

(2S)-N-<3'-methylbutanoyl>bornane-10,2-sultam → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 1 h / Cooling with ice; Inert atmosphere 1.2: 16 h / -30 - -5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 3.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 1.5 h / 89 - 95 °C View Scheme

isopentanoyl chloride (108-12-3) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dmap; triethylamine / toluene / 0 - 25 °C 2.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 1 h / Cooling with ice; Inert atmosphere 2.2: 16 h / -30 - -5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 4.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 1.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydride / toluene / 4 h / 20 - 25 °C 1.2: 1.5 h / 15 - 30 °C 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 2.2: 1 h / -45 - -20 °C 3.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 4.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 5.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 15 - 30 °C / Inert atmosphere; Large scale 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -10 °C / Inert atmosphere; Large scale 2.2: 20 h / 0 °C / Large scale 3.1: dihydrogen peroxide / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Large scale 3.2: Large scale 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 4.2: 0 °C / Large scale 5.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

4-chloromethyl-1-methoxy-2-(3-methoxypropoxy)-benzene (1179062-77-1) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium iodide / tetrahydrofuran / 16 h / 25 - 30 °C 2.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 1 h / Cooling with ice; Inert atmosphere 2.2: 16 h / -30 - -5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 4.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 1.5 h / 89 - 95 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium iodide / tetrahydrofuran / 16 h / 25 - 30 °C 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 2.2: 1 h / -45 - -20 °C 3.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 4.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 5.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme

(R)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (145589-03-3) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 1.2: 1 h / -45 - -20 °C 2.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 3.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 4.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme

(4R)-3-{(2R)-2-{[4-methoxy-3-(methoxypropoxy)phenyl]methyl-3-methyl}-1-oxobutyl}-4-(phenylmethyl)oxazolidin-2-one (172900-72-0) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 2: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 3: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme

isovanillin (621-59-0) → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: potassium carbonate / toluene; dimethyl sulfoxide / 16 h / 25 - 90 °C 2.1: sodium tetrahydroborate / toluene; methanol / 3 h / 0 - 5 °C 3.1: thionyl chloride / dichloromethane / 3 h / 0 - 5 °C 4.1: sodium iodide / tetrahydrofuran / 16 h / 25 - 30 °C 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / -78 - -45 °C / Inert atmosphere 5.2: 1 h / -45 - -20 °C 6.1: dihydrogen peroxide; lithium hydrochloride monohydrate; water / tetrahydrofuran / 0 - 25 °C 7.1: sulfuric acid; sodium tetrahydroborate / tetrahydrofuran / 0 - 20 °C 8.1: thionyl chloride / toluene; N,N-dimethyl acetamide / 2.5 h / 89 - 95 °C View Scheme

C14H17NO3 → (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -10 °C / Inert atmosphere; Large scale 1.2: 20 h / 0 °C / Large scale 2.1: dihydrogen peroxide / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere; Large scale 2.2: Large scale 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere; Large scale 3.2: 0 °C / Large scale 4.1: thionyl chloride; sodium hydroxide / toluene; N,N-dimethyl-formamide / 0.5 h / 90 °C / Inert atmosphere; Large scale View Scheme

C10H18ClNO + ethylene dibromide (106-93-4) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → C27H45NO4

Conditions

Yield

Stage #1: ethylene dibromide With magnesium In tetrahydrofuran at 60℃; Mg was added over a period of 2 min; Stage #2: ethylene dibromide; (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane In tetrahydrofuran for 0.5h; Adding at 62-64 °ree;C; Heating / reflux; Stage #3: C10H18ClNO; 1-methyl-pyrrolidin-2-one; iron-(III)-acetylacetonate In tetrahydrofuran at 0 - 10℃; for 0.25h; Adding at -5-0 °ree;C;

81%

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (R)-­4-(2-(iodomethyl)­-3-­methylbutyl)-­1-­methoxy-2­-(3-­methoxypropoxy)benzene (900811-38-3)

Conditions	Yield
With sodium iodide In acetone at 20 - 56℃; for 240h;	80.5%

(2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide (324519-68-8) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide (325154-26-5)

Conditions	Yield
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; ethylene dibromide In 2-methyltetrahydrofuran at 60 - 65℃; Stage #2: (2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide; iron(III)-acetylacetonate In 2-methyltetrahydrofuran; 1-methyl-pyrrolidin-2-one at 10℃; for 0.25h; Product distribution / selectivity;	80%
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; ethylene dibromide In tetrahydrofuran at 63 - 68℃; for 4.16667h; Inert atmosphere; Stage #2: (2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide; iron(III)-acetylacetonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 5℃; for 1h;
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With iodine; methylmagnesium chloride; magnesium; 1-Bromo-2-chloroethane In tetrahydrofuran at 60℃; Reflux; Stage #2: (2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide With 1-methyl-pyrrolidin-2-one; iron(III)-acetylacetonate In tetrahydrofuran at 0 - 30℃; for 2h;	120 g
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With methylmagnesium chloride; magnesium; ethylene dibromide In tetrahydrofuran at 60 - 65℃; Inert atmosphere; Industrial scale; Stage #2: (2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide With iron(III)-acetylacetonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 5℃; Concentration; Reagent/catalyst; Temperature; Time; Kumada Cross-Coupling; Inert atmosphere; Industrial scale;
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; ethylene dibromide In tetrahydrofuran at 65℃; Inert atmosphere; Stage #2: (2S,4E)-5-chloro-2-isopropyl-N,N-dimethylpent-4-enamide With 1-Methylpyrrolidine; iron(III)-acetylacetonate In tetrahydrofuran at -5 - 20℃;	6.5 g

(2S,3S,5R,7S,9S)-9-Isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-aza-spiro[4.4]nonane-7-carbaldehyde (324763-44-2) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-{(1R,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (324763-45-3) + (3S,5S)-dihydro-5-{(1S,3S)-1-hydroxy-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-3-(1-methylethyl)furan-2(3H)-one (325740-67-8)

Conditions	Yield
Multistep reaction;	A 51% B n/a

diethyl malonate (105-53-3) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → C24H38O7 (1322077-28-0)

Conditions	Yield
With sodium ethanolate; sodium iodide In ethanol	37%

(S)-tetrahydro-5-oxo-2-furancarbonyl chloride (54848-33-8) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (S)-5-{(S)-3-[4-Methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentanoyl}-dihydro-furan-2-one (325740-63-4)

Conditions	Yield
With magnesium; ethylene dibromide In tetrahydrofuran at 20℃;

tetrahydro-4-isopropyl-5-oxofuran-2-carbonyl chloride (325740-60-1) + (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-3-Isopropyl-5-{(S)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentanoyl}-dihydro-furan-2-one (325740-64-5)

Conditions	Yield
With magnesium; ethylene dibromide In tetrahydrofuran at 20℃;
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; iodine In tetrahydrofuran; 1,2-dibromomethane for 5h; Inert atmosphere; Heating; Reflux; Stage #2: tetrahydro-4-isopropyl-5-oxofuran-2-carbonyl chloride In tetrahydrofuran at 22℃; for 0.5h; Cooling with ice/water bath; Stage #3: With water In tetrahydrofuran Cooling with ice;

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) + C25H32N2O3 (437656-17-2, 361460-37-9) → N-Benzyl-N-{(1S,3S)-1-((2S,3S,5S,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-aza-spiro[4.4]non-7-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-hydroxylamine (361460-39-1) + N-Benzyl-N-{(1R,3S)-1-((2S,3S,5S,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-aza-spiro[4.4]non-7-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-hydroxylamine (361460-38-0)

Conditions	Yield
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; ethylene dibromide In tetrahydrofuran at 45℃; for 1h; Stage #2: C25H32N2O3 In tetrahydrofuran at -40℃; for 15h;
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; ethylene dibromide In tetrahydrofuran at 45℃; for 1h; Stage #2: C25H32N2O3 With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at -10℃; for 15h;
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With magnesium; iodine; ethylene dibromide In tetrahydrofuran at 75℃; for 2.25h; Stage #2: C25H32N2O3 In tetrahydrofuran at -10℃; for 15h;	A n/a B n/a
Stage #1: (R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane With cerium(III) chloride Stage #2: C25H32N2O3	A n/a B n/a

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (S)-5-{(1S,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-dihydro-furan-2-one (325740-66-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: K-Selectride / tetrahydrofuran / -78 - 0 °C View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (S)-5-{(1R,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-dihydro-furan-2-one (325740-65-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: K-Selectride / tetrahydrofuran / -78 - 0 °C View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-{(1R,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (324763-45-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-dihydro-5-{(1S,3S)-1-hydroxy-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-3-(1-methylethyl)furan-2(3H)-one (325740-67-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-((1S,3S)-1-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one (325740-70-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 4: 85 percent / NaN3; 15-crown-6; DMPU View Scheme
Multi-step reaction with 5 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 1.2: 12.5 h / 0 - 5 °C 2.1: water; lithium hydroxide / tetrahydrofuran; methanol / 26 h / 65 - 70 °C 2.2: 0.5 h / 0 - 5 °C 3.1: hydrogenchloride / 1,1-dichloroethane; water / 0 - 5 °C / pH 2.5 3.2: 14.25 h / 0 - 30 °C 4.1: N-Bromosuccinimide; phosphoric acid / water; tetrahydrofuran / 1.25 h / 0 - 5 °C 5.1: sodium azide / ethylene glycol / 20 h / 80 - 85 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C 1.3: 0.75 h / 0 - 5 °C 2.1: sodium azide / ethylene glycol / 20 h / 80 - 85 °C View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-{(1S,3S)-1-azido-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-dihydro-3-(1-methylethyl)furan-2(3H)-one (324763-46-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 4: 85 percent / NaN3; 15-crown-6; DMPU View Scheme
Multi-step reaction with 3 steps 1: 51 percent 2: DMAP / CH2Cl2 / 20 °C 3: NaN3; NMP / 60 °C View Scheme
Multi-step reaction with 3 steps 1.1: magnesium; ethylene dibromide / 2-methyltetrahydrofuran / 60 - 65 °C 1.2: 0.25 h / 10 °C 2.1: N-Bromosuccinimide; phosphoric acid / water; tetrahydrofuran / 5 °C 3.1: sodium azide; Aliquat 336 / water / 48 h / 75 - 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 65 °C / Inert atmosphere 1.2: -5 - 20 °C 2.1: N-Bromosuccinimide; phosphoric acid / tetrahydrofuran; water / 2 h / 0 - 10 °C / Inert atmosphere 3.1: sodium azide / 2,2'-[1,2-ethanediylbis(oxy)]bisethanol / 72 h / 90 °C / Inert atmosphere View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-{(S)-1-[(Z)-Hydroxyimino]-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one

Conditions	Yield
Multi-step reaction with 3 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: 89 percent / NaHCO3 3: 74 percent / H2 / Pd/C / methanol View Scheme
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: 81 percent / NH2OH*HCl; NaHCO3 / methanol / 20 °C View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → Methanesulfonic acid (1R,3S)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-1-((S)-5-oxo-tetrahydro-furan-2-yl)-pentyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: K-Selectride / tetrahydrofuran / -78 - 0 °C 3: NEt3 / CH2Cl2 View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → Methanesulfonic acid (1S,3S)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-1-((S)-5-oxo-tetrahydro-furan-2-yl)-pentyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: K-Selectride / tetrahydrofuran / -78 - 0 °C 3: NEt3 / CH2Cl2 View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → Methanesulfonic acid (1R,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester (325740-68-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → Methanesulfonic acid (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester (325740-69-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (3S,5S)-5-{(S)-1-[(Z)-Benzyloxyimino]-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (325740-72-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: 89 percent / NaHCO3 View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → 4-Bromo-benzenesulfonic acid (1R,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester (387353-75-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent 2: DMAP / CH2Cl2 / 20 °C View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (2S,4S,5R,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-2-isopropylnonanamide (325154-32-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 4: 85 percent / NaN3; 15-crown-6; DMPU 5: 59 percent / 2-OH-pyridine; NEt3 6: H2; aq. HCl / Pd/C / methanol View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide (173334-57-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 4: 85 percent / NaN3; 15-crown-6; DMPU 5: 59 percent / 2-OH-pyridine; NEt3 6: H2; aq. HCl / Pd/C / methanol View Scheme
Multi-step reaction with 13 steps 1.1: sodium ethanolate; sodium iodide / ethanol 2.1: potassium acetate / water; dimethyl sulfoxide 3.1: sodium hydroxide 4.1: thionyl chloride 5.1: pyridine / 12 h / 40 °C 6.1: dicyclohexyl(trifluoromethylsulfonyloxy)borane; triethylamine / -78 - 0 °C 7.1: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0.25 h 7.2: Acidic aq. solution 8.1: water; lithium hydroxide / 1,4-dioxane / 120 h / 40 °C 9.1: diphenyl phosphoryl azide; triethylamine / toluene / 0.33 h / 20 °C 10.1: diphenyl phosphoryl azide; triethylamine / toluene / 1 h / 65 °C 11.1: 1.5 h / 65 °C 12.1: 2-hydroxypyridin / tert-butyl methyl ether / 65 °C 13.1: 10% palladium on activated charcoal; hydrogen View Scheme
Multi-step reaction with 7 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 1.2: 12.5 h / 0 - 5 °C 2.1: water; lithium hydroxide / tetrahydrofuran; methanol / 26 h / 65 - 70 °C 2.2: 0.5 h / 0 - 5 °C 3.1: hydrogenchloride / 1,1-dichloroethane; water / 0 - 5 °C / pH 2.5 3.2: 14.25 h / 0 - 30 °C 4.1: N-Bromosuccinimide; phosphoric acid / water; tetrahydrofuran / 1.25 h / 0 - 5 °C 5.1: sodium azide / ethylene glycol / 20 h / 80 - 85 °C 6.1: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C 7.1: hydrogen; ethanolamine / palladium 10% on activated carbon / isopropyl alcohol / 3 h View Scheme

(R)-2-[4-methoxy-3-(3-methoxypropoxyl)]phenylmethyl-3-methyl-1-chlorobutane (324763-39-5) → (2S,4S,5R,7S)-5-Azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide (325154-31-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: Mg; BrCH2CH2Br / tetrahydrofuran / 20 °C 2: H2 / [Ru2Cl4((S)-BINAP)]NEt3 / methanol / 40 h / 40 °C / 37503 Torr 3: NEt3 / CH2Cl2 4: 85 percent / NaN3; 15-crown-6; DMPU 5: 59 percent / 2-OH-pyridine; NEt3 View Scheme

Upstream product

• 621-59-0 isovanillin 
• 172900-72-0 (4R)-3-{(2R)-2-{[4-methoxy-3-(methoxypropoxy)phenyl]methyl-3-methyl}-1-oxobutyl}-4-(phenylmethyl)oxazolidin-2-one 
• 145589-03-3 (R)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one 
• 324763-36-2 (E)-3-[4-Methoxy-3-(3-methoxy-propoxy)-phenyl]-acrylic acid 
• 172900-75-3 4-methoxy-3-(3-methoxypropoxy)benzaldehyde 
• 172900-70-8 (R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanol 
• 1179062-77-1 4-chloromethyl-1-methoxy-2-(3-methoxypropoxy)-benzene 
• 108-12-3 isopentanoyl chloride 
• 1381757-32-9 C₁₂H₁₇IO₃ 
• 943349-14-2 2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutanol 
• 1350705-32-6 (4R)-3-(2S)-(2-(hydroxy(4-methoxy-3-(3-methoxypropoxy)phenyl)methyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one 
• 1350705-31-5 (R)-3-((R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoyl)-4-phenyloxazolidin-2-one 
• 172900-74-2 [4-methoxy-3-(3-methoxypropoxy)-phenyl]methanol 
• 172900-73-1 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)-benzene 

Downstream Products

• 325740-66-7 (S)-5-{(1S,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-dihydro-furan-2-one 
• 325740-65-6 (S)-5-{(1R,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-dihydro-furan-2-one 
• 324763-45-3 (3S,5S)-5-{(1R,3S)-1-Hydroxy-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one 
• 325740-67-8 (3S,5S)-dihydro-5-{(1S,3S)-1-hydroxy-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-3-(1-methylethyl)furan-2(3H)-one 
• 325740-70-3 (3S,5S)-5-((1S,3S)-1-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one 
• 324763-46-4 (3S,5S)-5-{(1S,3S)-1-azido-3-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-dihydro-3-(1-methylethyl)furan-2(3H)-one 
• 325740-68-9 Methanesulfonic acid (1R,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester 
• 325740-69-0 Methanesulfonic acid (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester 
• 325740-72-5 (3S,5S)-5-{(S)-1-[(Z)-Benzyloxyimino]-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one 
• 387353-75-5 4-Bromo-benzenesulfonic acid (1R,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl ester 
• 325154-32-3 (2S,4S,5R,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-2-isopropylnonanamide 
• 173334-57-1 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide 
• 325154-31-2 (2S,4S,5R,7S)-5-Azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide 
• 324763-47-5 (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(methoxypropoxy)benzyl)-8-methylnonanamide 

Relevant articles and documents

A aliskiren or its salt separation and analysis method

The invention relates to a separation analysis method using polysaccharide derivative-bonded and coated silica as a stationary phase and an organic solvent as a mobile phase for separation analysis of aliskiren and isomers thereof, effective separation of the aliskiren and isomers thereof can be realized, and the separation analysis method has the important meaning to the product quality control.

NOVEL PROCESS FOR THE PREPARATION OF RENIN INHIBITORS

The present invention relates to an improved process for the preparation of compound of Formula-II, which is an intermediate in the preparation of Aliskiren and further conversion of compound of Formula-II into Aliskiren or its pharmaceutically acceptable salts. Formula-II wherein Ri and R2 are independently of one another H, Ci-C6 alkyl, C- C6 halogenalkyl, C]-C6 alkoxy, Ci-C6 alkoxy-Ci-C6 alkyl, or Ci-C6 alkoxy-Ci- C6 alkyloxy and X is halogen selected from fluoro, chloro, bromo and iodo

Method for Producing an Alpha-Chiral Chloromethyl Compound in a Pure Form

The present invention relates to a process for preparing a specific α-chiral chloromethyl compound in pure or enriched form by distillative removal of the compound mentioned from substance mixtures which comprise this compound and higher-boiling impurities. The α-chiral chloromethyl compound in question is present in crystalline form at room temperature and is a central intermediate for the preparation of a class of medicaments.