119193-19-0

Basic information

• Product Name: (+)-(3R,4R)-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE
• Synonyms: (+)-(3R,4R)-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE;(+)-(3R,4R)-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine ,98%;(3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol;3-(3,4-diMethylpiperidin-4-yl)phenol;(+)-(3R,4R)-DiMethyl-4-(3-hydroxyphenyl)piperidine;(3R-cis)-3-(3,4-diMethyl-4- piperidinyl)phenol;3-[(3R,4R)-3,4-DiMethyl-4-piperidinyl]phenol;3-((3R,4R)-3,4-diMethylpiperidin-4-yl)phenol
• CAS NO: 119193-19-0
• Molecular Formula: C₁₃H₁₉NO
• Molecular Weight: 205.3
• EINECS: 1592732-453-0
• Product Categories: Building Blocks/Intermediates
• Mol File: 119193-19-0.mol
• Article Data: 7

Chemical Properties

• Melting Point: 174-175 °C
• Boiling Point: 335.464 °C at 760 mmHg
• Flash Point: 115.716 °C
• Appearance: white like or light brown crystalline powder
• Density: 1.009 g/cm³
• Vapor Pressure: 6.14E-05mmHg at 25°C
• Refractive Index: 1.521
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• PKA: 9.85±0.10(Predicted)
• CAS DataBase Reference: (+)-(3R,4R)-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE(CAS DataBase Reference)
• NIST Chemistry Reference: (+)-(3R,4R)-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE(119193-19-0)
• EPA Substance Registry System: (+)-(3R,4R)-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE(119193-19-0)

Safety Data

• Hazard Codes: Xi
• Hazardous Substances Data: 119193-19-0(Hazardous Substances Data)

Usage

Uses

(3R,4R)-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine is an intermediate in the preparation of Alvimopan (A575800).

InChI:InChI=1/C13H19NO/c1-10-9-14-7-6-13(10,2)11-4-3-5-12(15)8-11/h3-5,8,10,14-15H,6-7,9H2,1-2H3/t10-,13-/m0/s1

Synthetic route

(3R,4R)-3,4-dimethyl-4-<3-(1-methylethoxy)phenyl>piperidinecarboxylic acid phenyl ester (145678-86-0) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
With hydrogen bromide In acetic acid Reflux;	88%
With sodium hydroxide; hydrogen bromide; acetic acid 1.) reflux, 19 h, 2.) MeOH, pH 10.3-10.5, 25 deg C, 1.5 h; Yield given. Multistep reaction;

(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine (149655-33-4) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
With hydrogen bromide In acetic acid for 18h; Heating; Yield given;
With hydrogen bromide; acetic acid Heating;

C9H16NO3SBr (951240-63-4) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: triethylamine; 4-(dimethylamino)pyridine / CH2Cl2 / 2.5 h / 0 - 20 °C 2.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 3.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 4.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 5.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 6.1: n-butyllithium / tetrahydrofuran / -15 °C 6.2: tetrahydrofuran / -50 °C 7.1: sodium borohydride / methanol 8.1: phenyl chloroformate / toluene 9.1: hydrogen bromide; acetic acid / Heating View Scheme

C13H25NO6SBrP (951240-64-5) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 2.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 3.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 4.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 5.1: n-butyllithium / tetrahydrofuran / -15 °C 5.2: tetrahydrofuran / -50 °C 6.1: sodium borohydride / methanol 7.1: phenyl chloroformate / toluene 8.1: hydrogen bromide; acetic acid / Heating View Scheme

C10H18NO2SBr (951240-65-6) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 2.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 3.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 4.1: n-butyllithium / tetrahydrofuran / -15 °C 4.2: tetrahydrofuran / -50 °C 5.1: sodium borohydride / methanol 6.1: phenyl chloroformate / toluene 7.1: hydrogen bromide; acetic acid / Heating View Scheme

C17H25O3SN (951240-66-7) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 2.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 3.1: n-butyllithium / tetrahydrofuran / -15 °C 3.2: tetrahydrofuran / -50 °C 4.1: sodium borohydride / methanol 5.1: phenyl chloroformate / toluene 6.1: hydrogen bromide; acetic acid / Heating View Scheme

C13H17ON (951240-71-4) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 2.1: n-butyllithium / tetrahydrofuran / -15 °C 2.2: tetrahydrofuran / -50 °C 3.1: sodium borohydride / methanol 4.1: phenyl chloroformate / toluene 5.1: hydrogen bromide; acetic acid / Heating View Scheme

C14H19ON (220503-22-0) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / -15 °C 1.2: tetrahydrofuran / -50 °C 2.1: sodium borohydride / methanol 3.1: phenyl chloroformate / toluene 4.1: hydrogen bromide; acetic acid / Heating View Scheme

C15H21ON → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium borohydride / methanol 2: phenyl chloroformate / toluene 3: hydrogen bromide; acetic acid / Heating View Scheme

C9H15NO4S → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 13 steps 1.1: 1.68 g / triethylsilane; BF3*OEt2 / CH2Cl2 / 3 h / 0 °C 2.1: bromine / CH2Cl2 / 0.5 h / 0 °C 3.1: 0.73 g / triethylamine / CH2Cl2 / 0.5 h / 0 °C 4.1: (R)-1-Me-3,3-Ph-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-N,N-diethylaniline complex / tetrahydrofuran / 16 h / 0 - 20 °C 5.1: triethylamine; 4-(dimethylamino)pyridine / CH2Cl2 / 2.5 h / 0 - 20 °C 6.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 7.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 8.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 9.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 10.1: n-butyllithium / tetrahydrofuran / -15 °C 10.2: tetrahydrofuran / -50 °C 11.1: sodium borohydride / methanol 12.1: phenyl chloroformate / toluene 13.1: hydrogen bromide; acetic acid / Heating View Scheme

C9H15NO3S (951240-61-2) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 12 steps 1.1: bromine / CH2Cl2 / 0.5 h / 0 °C 2.1: 0.73 g / triethylamine / CH2Cl2 / 0.5 h / 0 °C 3.1: (R)-1-Me-3,3-Ph-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-N,N-diethylaniline complex / tetrahydrofuran / 16 h / 0 - 20 °C 4.1: triethylamine; 4-(dimethylamino)pyridine / CH2Cl2 / 2.5 h / 0 - 20 °C 5.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 6.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 7.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 8.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 9.1: n-butyllithium / tetrahydrofuran / -15 °C 9.2: tetrahydrofuran / -50 °C 10.1: sodium borohydride / methanol 11.1: phenyl chloroformate / toluene 12.1: hydrogen bromide; acetic acid / Heating View Scheme

C9H15NO3SBr2 → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 11 steps 1.1: 0.73 g / triethylamine / CH2Cl2 / 0.5 h / 0 °C 2.1: (R)-1-Me-3,3-Ph-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-N,N-diethylaniline complex / tetrahydrofuran / 16 h / 0 - 20 °C 3.1: triethylamine; 4-(dimethylamino)pyridine / CH2Cl2 / 2.5 h / 0 - 20 °C 4.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 5.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 6.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 7.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 8.1: n-butyllithium / tetrahydrofuran / -15 °C 8.2: tetrahydrofuran / -50 °C 9.1: sodium borohydride / methanol 10.1: phenyl chloroformate / toluene 11.1: hydrogen bromide; acetic acid / Heating View Scheme

C9H14NO3SBr (951240-62-3) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: (R)-1-Me-3,3-Ph-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-N,N-diethylaniline complex / tetrahydrofuran / 16 h / 0 - 20 °C 2.1: triethylamine; 4-(dimethylamino)pyridine / CH2Cl2 / 2.5 h / 0 - 20 °C 3.1: CuBr*SMe2 / tetrahydrofuran; diethyl ether / -40 - -35 °C 4.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 5.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 6.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 7.1: n-butyllithium / tetrahydrofuran / -15 °C 7.2: tetrahydrofuran / -50 °C 8.1: sodium borohydride / methanol 9.1: phenyl chloroformate / toluene 10.1: hydrogen bromide; acetic acid / Heating View Scheme

3-methoxyphenylboronic acid (10365-98-7) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium carbonate / Pd(Ph3P)4 / ethanol; toluene; H2O / 0.75 h / 80 °C 2.1: anisole; triflic acid / CH2Cl2 / 0.5 h / 0 °C 3.1: sodium cyanoborohydride / acetonitrile; H2O / 0.5 h 4.1: n-butyllithium / tetrahydrofuran / -15 °C 4.2: tetrahydrofuran / -50 °C 5.1: sodium borohydride / methanol 6.1: phenyl chloroformate / toluene 7.1: hydrogen bromide; acetic acid / Heating View Scheme

(+)-1,3(R),4(R)-Trimethyl-4-(3-methoxyphenyl)piperidine (132697-07-5) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: phenyl chloroformate / toluene 2: hydrogen bromide; acetic acid / Heating View Scheme
Multi-step reaction with 2 steps 1: 1) Proton sponge, vinyl chloroformate, 2) HCl gas / 1) 1,2-dichloroethane, reflux, 5 h, 2) EtOH, reflux, 3 h 2: aq. HBr / acetic acid / 18 h / Heating View Scheme

(3R,5R)-1,3,4-trimethyl-4-<3-(1-methylethoxy)phenyl>piperidine (143919-34-0) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / toluene / 2 h / Heating 2: 1.) 48percent HBr, glacial AcOH, 2.) aq. NaOH / 1.) reflux, 19 h, 2.) MeOH, pH 10.3-10.5, 25 deg C, 1.5 h View Scheme
Multi-step reaction with 3 steps 1.1: ethanol / 25 - 35 °C 2.1: HO- 2.2: 2 h / Reflux 3.1: hydrogen bromide / acetic acid / Reflux View Scheme

(3RS,4SR)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-<3-(1-methylethoxy)phenyl>pyridine → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaBH4 / methanol / 3 h / 25 °C 2: 97 percent / toluene / 2 h / Heating 3: 1.) 48percent HBr, glacial AcOH, 2.) aq. NaOH / 1.) reflux, 19 h, 2.) MeOH, pH 10.3-10.5, 25 deg C, 1.5 h View Scheme

C20H23NO3 → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Stage #1: C20H23NO3 With hydrogen bromide; acetic acid for 18h; Heating / reflux; Stage #2: With sodium hydroxide; water at 10 - 30℃; for 1h; pH=1.7;	n/a
Stage #1: C20H23NO3 With hydrogen bromide; acetic acid In water at 10 - 60℃; for 18h; Heating / reflux; Stage #2: With sodium hydroxide In water at 10 - 30℃; for 1h; pH=< 1.7;
Stage #1: C20H23NO3 With hydrogen bromide; acetic acid In water at 50 - 60℃; for 18h; Heating / reflux; Stage #2: With sodium hydroxide In water at 10 - 60℃; for 1h; pH=< 1.7;

(R)-1,2,3,4-tetrahydro-1,3-dimethyl-4-<3-(1-methylethoxy)phenyl>pyridine (143919-32-8) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 2.1: sodium tetrahydroborate / methanol / 25 - 35 °C 3.1: ethanol / 25 - 35 °C 4.1: HO- 4.2: 2 h / Reflux 5.1: hydrogen bromide / acetic acid / Reflux View Scheme

(3R,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-<3-(1-methylethoxy)phenyl>pyridine → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / methanol / 25 - 35 °C 2.1: ethanol / 25 - 35 °C 3.1: HO- 3.2: 2 h / Reflux 4.1: hydrogen bromide / acetic acid / Reflux View Scheme

C17H27NO*C20H18O8 (1184775-81-2, 145415-19-6) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: HO- 1.2: 2 h / Reflux 2.1: hydrogen bromide / acetic acid / Reflux View Scheme

3-(isopropyloxy)phenylbromide (131738-73-3) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: n-butyllithium / tetrahydrofuran / -65 °C 2.1: ethyl acetate / 25 - 35 °C 3.1: (2S,3S)-di-4-toluoyltartaric acid / ethanol / 20 h / 25 - 35 °C / Resolution of racemate 4.1: decalin / 190 - 195 °C 5.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 6.1: sodium tetrahydroborate / methanol / 25 - 35 °C 7.1: ethanol / 25 - 35 °C 8.1: HO- 8.2: 2 h / Reflux 9.1: hydrogen bromide / acetic acid / Reflux View Scheme

1,3-dimethyl-4-piperidinone (4629-80-5) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: n-butyllithium / tetrahydrofuran / -65 °C 2.1: ethyl acetate / 25 - 35 °C 3.1: (2S,3S)-di-4-toluoyltartaric acid / ethanol / 20 h / 25 - 35 °C / Resolution of racemate 4.1: decalin / 190 - 195 °C 5.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 6.1: sodium tetrahydroborate / methanol / 25 - 35 °C 7.1: ethanol / 25 - 35 °C 8.1: HO- 8.2: 2 h / Reflux 9.1: hydrogen bromide / acetic acid / Reflux View Scheme

1,3-dimethyl-4-[3-(propan-2-yloxy)phenyl]-4-piperidinol (145340-44-9) → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: ethyl acetate / 25 - 35 °C 2.1: (2S,3S)-di-4-toluoyltartaric acid / ethanol / 20 h / 25 - 35 °C / Resolution of racemate 3.1: decalin / 190 - 195 °C 4.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 5.1: sodium tetrahydroborate / methanol / 25 - 35 °C 6.1: ethanol / 25 - 35 °C 7.1: HO- 7.2: 2 h / Reflux 8.1: hydrogen bromide / acetic acid / Reflux View Scheme

cis-(-)-carbonic acid ethyl 1,3-dimethyl-4-[3-(l-methylethoxy)phenyl]-4-piperidinyl ester → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: (2S,3S)-di-4-toluoyltartaric acid / ethanol / 20 h / 25 - 35 °C / Resolution of racemate 2.1: decalin / 190 - 195 °C 3.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 4.1: sodium tetrahydroborate / methanol / 25 - 35 °C 5.1: ethanol / 25 - 35 °C 6.1: HO- 6.2: 2 h / Reflux 7.1: hydrogen bromide / acetic acid / Reflux View Scheme

C19H29NO4 → 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: decalin / 190 - 195 °C 2.1: n-butyllithium / tetrahydrofuran / 3 h / -60 - -55 °C 3.1: sodium tetrahydroborate / methanol / 25 - 35 °C 4.1: ethanol / 25 - 35 °C 5.1: HO- 5.2: 2 h / Reflux 6.1: hydrogen bromide / acetic acid / Reflux View Scheme

di-tert-butyl dicarbonate (24424-99-5) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-tert-butyloxycarbonylpiperidine (205999-74-2)

Conditions	Yield
With triethylamine In tetrahydrofuran at 25℃;	100%
With triethylamine In tetrahydrofuran at 20℃; for 2h;	100%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 19h;	100%
With triethylamine In tetrahydrofuran for 2h;

trifluoromethylsulfonic anhydride (358-23-6) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-[(3R,4R)-3,4-dimethyl-1-(trifluoromethane)sulfonylpiperidin-4-yl]phenyl trifluoromethanesulfonate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃;	100%
With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃;	100%

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + acrylic acid methyl ester (292638-85-8) → methyl (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinepropanoate (170098-39-2)

Conditions	Yield
In tetrahydrofuran at 40 - 45℃; for 4h;	98%
In tetrahydrofuran at 45℃; for 4h;	96%
In tetrahydrofuran at 40 - 45℃; for 18.5 - 19.5h;
Stage #1: 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol; acrylic acid methyl ester In tetrahydrofuran at 40 - 45℃; for 18.5 - 19.5h; Stage #2: With hyflo supercel

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + 3-oxocyclohex-1-en-1-yl 4-methylbenzenesulfonate (77708-66-8) → 1-(3'-oxo-1'-cyclohexenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine (205999-78-6)

Conditions	Yield
With triethylamine In tetrahydrofuran for 8h; Heating;	90%

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + 3-oxocyclopent-1-en-1-yl 4-methylbenzenesulfonate (205999-79-7) → 1-(3'-oxo-1'-cyclopentenyl)-(3R,4R)-dimethyl-(3-hydroxyphenyl)piperidine (205999-80-0)

Conditions	Yield
With triethylamine In tetrahydrofuran for 8h; Heating;	90%

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + 3-cyclohexyl-3-hydroxypropyl (4-bromobenzene)sulfonate → (+)-1-(3(S)-3-hydroxy-3-cyclohexylpropyl)-3(R),4(R)-dimethyl-4-(3-hydroxyphenyl)piperidine (119193-09-8)

Conditions	Yield
With sodium hydrogencarbonate In 1,2-dimethoxyethane for 8h; Heating;	82%

ethyl N-[(2S)-2-benzyl-3-{[(4-bromophenyl)sulfonyl]oxy}propanoyl]glycinate (1352995-69-7) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → ethyl N-{(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl}glycinate

Conditions	Yield
With sodium hydrogencarbonate In 1,2-dimethoxyethane at 25 - 85℃; Reflux;	80%

phenylacetaldehyde (122-78-1) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-((3R,4R)-3,4-Dimethyl-1-phenethyl-piperidin-4-yl)-phenol (654647-95-7)

Conditions	Yield
With pyridine; borane In ethanol at 25℃;	71%

2-Benzylacrylic acid ethyl ester (20593-63-9) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → C25H33NO3*ClH

Conditions	Yield
Stage #1: 2-Benzylacrylic acid ethyl ester; 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol In toluene for 4h; Reflux; Stage #2: With hydrogenchloride In ethanol; toluene at 20℃; pH=1;	34.7%

methyl 2-benzylacrylate (3070-71-1) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → (2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl)-3-phenylpropanoic acid methyl ester hydrochloride

Conditions	Yield
Stage #1: methyl 2-benzylacrylate; 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol In toluene for 4h; Reflux; Stage #2: With hydrogenchloride In methanol; toluene at 20℃; pH=1;	29.6%

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + 2-benzylacrylic acid butyl ester → (2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl)-3-phenylpropanoic acid butyl ester hydrochloride

Conditions	Yield
Stage #1: 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol; 2-benzylacrylic acid butyl ester In toluene for 4h; Reflux; Stage #2: With hydrogenchloride In butan-1-ol at 20℃; pH=1;	24%

3-(2-thienyl)-propanoic acid chloride (5834-04-8) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 1-[(3R,4R)-4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-3-thiophen-2-yl-propan-1-one

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 90℃; for 2h;
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In N,N-dimethyl-formamide for 1h; Ambient temperature;

5-methylhexanoyl chloride (5699-78-5) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 1-[(3R,4R)-4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-5-methyl-hexan-1-one

Conditions	Yield
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In N,N-dimethyl-formamide for 1h; Ambient temperature;

N-(2-benzoylethyl)-N,N,N-trimethylammonium iodide (5724-15-2) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → (+)-1-(1-phenyl-1-oxoprop-3-yl)-3(R),4(R)-dimethyl-4-(3-hydroxyphenyl)piperidine

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide for 4h; Ambient temperature;

(-)-(1S)-1-(tert-Butyldimethylsiloxy)-1-cyclohexyl-3-hydroxypropane (132621-42-2) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-{(3R,4R)-1-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-3-cyclohexyl-propyl]-3,4-dimethyl-piperidin-4-yl}-phenol

Conditions	Yield
With sodium hydrogencarbonate; methanesulfonyl chloride; triethylamine 1) CH2Cl2, 0 deg C, 30 min, 2) DMF, reflux, 1 h; Multistep reaction;

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + Hexanoyl chloride (142-61-0) → 1-[(3R,4R)-4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-hexan-1-one

Conditions	Yield
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In N,N-dimethyl-formamide for 1h; Ambient temperature;

3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) + N,N,N-trimethyl-3-cyclohexyl-3-oxopropanaminium iodide → 1-Cyclohexyl-3-[(3R,4R)-4-(3-hydroxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-propan-1-one

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;

2-Benzylacrylic acid ethyl ester (20593-63-9) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 4-(3-hydroxyphenyl)-3(R),4(R)-dimethyl-2'(SR)-(phenylmethyl)-1-piperidinepropanoic acid ethyl ester

Conditions	Yield
In methanol for 240h; Ambient temperature;	8.0 g

Benzofuran-2-carboxylic acid (496-41-3) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-((3R,4R)-1-Benzofuran-2-ylmethyl-3,4-dimethyl-piperidin-4-yl)-phenol

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

benzo[b]thiophene-2-carboxylic acid (6314-28-9) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-((3R,4R)-1-Benzo[b]thiophen-2-ylmethyl-3,4-dimethyl-piperidin-4-yl)-phenol

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

(E)-3-phenylacrylic acid (140-10-3) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → RTI-5989-1

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

cis-cinnamic acid (140-10-3, 621-82-9, 102-94-3) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-[(3R,4R)-3,4-Dimethyl-1-((Z)-3-phenyl-allyl)-piperidin-4-yl]-phenol

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

(E)-3-(2-methylphenyl)acrylic acid (939-57-1, 2373-76-4, 41397-71-1) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → RTI 5989-25

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

trans-2-chlorocinnamic acid (704-96-1) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → RTI-5989-23

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

(1S*,2R*)-2-phenylcyclopropane-1-carboxylic acid (939-89-9, 939-90-2, 3471-10-1, 5685-38-1, 23020-15-7, 23020-18-0, 42916-14-3, 48126-51-8, 67528-68-1, 111956-00-4, 111956-01-5) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-[(3R,4R)-3,4-Dimethyl-1-((1R,2S)-2-phenyl-cyclopropylmethyl)-piperidin-4-yl]-phenol

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

trans-2-phenylcyclopropane-1-carboxylic acid (939-90-2) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → 3-[(3R,4R)-3,4-Dimethyl-1-((1S,2S)-2-phenyl-cyclopropylmethyl)-piperidin-4-yl]-phenol

Conditions	Yield
With sodium dihydro-bis-(2-methoxyethoxy)aluminate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine 1.) THF, RT, 1 h, 2.) THF, toluene, RT, 1 h; Yield given. Multistep reaction;

BOC-glycine (4530-20-5) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → {2-[(3R,4R)-4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester

Conditions	Yield
With TEA; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In tetrahydrofuran for 1h; Ambient temperature;

t-Boc-L-valine (13734-41-3) + 3-[(3R,4R)-3,4-dimethylpiperidin-4-yl]phenol (119193-19-0) → {(S)-1-[(3R,4R)-4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidine-1-carbonyl]-2-methyl-propyl}-carbamic acid tert-butyl ester

Conditions	Yield
With TEA; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In tetrahydrofuran for 1h; Ambient temperature;

Upstream product

• 149541-62-8 C₁₉H₂₉NO₄ 
• 149541-62-8 cis-(-)-carbonic acid ethyl 1,3-dimethyl-4-[3-(l-methylethoxy)phenyl]-4-piperidinyl ester 
• 145340-44-9 1,3-dimethyl-4-[3-(propan-2-yloxy)phenyl]-4-piperidinol 
• 4629-80-5 1,3-dimethyl-4-piperidinone 
• 131738-73-3 3-(isopropyloxy)phenylbromide 
• 1184775-81-2 C₁₇H₂₇NO*C₂₀H₁₈O₈ 
• 143919-32-8 (R)-1,2,3,4-tetrahydro-1,3-dimethyl-4-<3-(1-methylethoxy)phenyl>pyridine 
• 143919-34-0 (3R,5R)-1,3,4-trimethyl-4-<3-(1-methylethoxy)phenyl>piperidine 
• 132697-07-5 (+)-1,3(R),4(R)-Trimethyl-4-(3-methoxyphenyl)piperidine 
• 10365-98-7 3-methoxyphenylboronic acid 
• 951240-62-3 C₉H₁₄NO₃SBr 
• 951240-61-2 C₉H₁₅NO₃S 
• 220503-22-0 C₁₄H₁₉ON 
• 951240-71-4 C₁₃H₁₇ON 

Downstream Products

• 654647-95-7 3-((3R,4R)-3,4-Dimethyl-1-phenethyl-piperidin-4-yl)-phenol 
• 156130-44-8 2‐((R)‐2‐benzyl‐3‐((3R,4R)‐4‐(3‐hydroxyphenyl)‐3,4‐dimethylpiperidin‐1‐yl)propanamido)acetic acid 
• 205999-77-5 3-[(3R,4R)-4-(3-Benzyloxy-phenyl)-3,4-dimethyl-piperidin-1-yl]-1-phenyl-cyclohexanol 
• 205999-75-3 1-tert-butoxycarbonyl-(3R,4R)-dimethyl-4-(3-benzyloxyphenyl)piperidine 
• 205999-81-1 (+)-(3R,4R)-4-(3-(benzyloxy)phenyl)-3,4-dimethylpiperidine 

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