263769-22-8

Basic information

• Product Name: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester
• Synonyms: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester
• CAS NO: 263769-22-8
• Molecular Formula: C₁₄H₁₈ClNO₂
• Molecular Weight: 267.75122
• Mol File: 263769-22-8.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 343.5 °C at 760 mmHg
• Flash Point: 161.5 °C
• Appearance: /
• Density: 1.157g/cm³
• Vapor Pressure: 7.01E-05mmHg at 25°C
• Refractive Index: 1.531
• PKA: 7.69±0.20(Predicted)
• CAS DataBase Reference: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester(263769-22-8)
• EPA Substance Registry System: (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester(263769-22-8)

Safety Data

• Hazardous Substances Data: 263769-22-8(Hazardous Substances Data)

Usage

Description

(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester is a complex organic compound with a specific stereochemistry and functional groups. It is characterized by its molecular structure, which includes a piperidine ring with a methyl ester group and a chlorophenyl moiety. (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester is primarily used as a research chemical, offering potential applications in various fields due to its unique properties.

Uses

Used in Pharmaceutical Research:
(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester is used as a research chemical for the development of new pharmaceuticals. Its unique structure and functional groups make it a valuable starting point for the synthesis of novel drug candidates, particularly in the areas of central nervous system disorders and other therapeutic applications.
Used in Chemical Synthesis:
In the field of chemical synthesis, (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester serves as an intermediate or building block for the creation of more complex molecules. Its specific stereochemistry and functional groups can be exploited to produce a variety of compounds with potential applications in various industries.
Used in Material Science:
(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester may also find applications in material science, where its unique properties could be utilized to develop new materials with specific characteristics. These materials could have potential uses in various industries, such as electronics, coatings, or adhesives.
Used in Analytical Chemistry:
As a research chemical, (3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester can be employed in analytical chemistry for the development of new methods and techniques. Its unique properties may be useful in the separation, detection, or quantification of other compounds, contributing to the advancement of analytical methodologies.

InChI:InChI=1/C14H18ClNO2/c1-16-8-7-12(13(9-16)14(17)18-2)10-3-5-11(15)6-4-10/h3-6,12-13H,7-9H2,1-2H3/t12-,13+/m1/s1

Synthetic route

(-)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3β-carboxylate (214335-16-7) → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
With sodium methylate In methanol epimerization; Heating;	100%
With sodium methylate In methanol for 24h; Heating;	86%
With sodium methylate In methanol at 60℃; for 6h;

arecoline (63-75-2) + (4-chlorphenyl)magnesium bromide (873-77-8) → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Stage #1: arecoline; (4-chlorphenyl)magnesium bromide In diethyl ether at -10℃; Addition; Stage #2: With O,O'-dibenzoyl-L-tartaric acid Racemate resolution; Further stages.;

arecoline (63-75-2) → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 56 percent / diethyl ether / 0.5 h / -10 °C 3: 86 percent / NaOMe / methanol / 24 h / Heating View Scheme
Multi-step reaction with 3 steps 1: tert-butyl methyl ether; diethyl ether / 3 h / -20 - -5 °C / Inert atmosphere 2: O,O'-dibenzoyl-L-tartaric acid / methanol / 0.5 h / 60 - 65 °C 3: sodium methylate / methanol / 6 h / 60 °C View Scheme

(4-chlorphenyl)magnesium bromide (873-77-8) + (+-)-2-hydroxy-1-phenyl-propan-1-one → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 56 percent / diethyl ether / 0.5 h / -10 °C 3: 86 percent / NaOMe / methanol / 24 h / Heating View Scheme

(±)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3β-carboxylate → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Multi-step reaction with 2 steps 2: 86 percent / NaOMe / methanol / 24 h / Heating View Scheme
Multi-step reaction with 2 steps 1: O,O'-dibenzoyl-L-tartaric acid / methanol / 0.5 h / 60 - 65 °C 2: sodium methylate / methanol / 6 h / 60 °C View Scheme

methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium diisopropyl amide / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2: O,O'-dibenzoyl-L-tartaric acid / methanol / 0.5 h / 60 - 65 °C 3: sodium methylate / methanol / 6 h / 60 °C View Scheme

(4-chlorphenyl)magnesium bromide (873-77-8) → (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: tert-butyl methyl ether; diethyl ether / 3 h / -20 - -5 °C / Inert atmosphere 2: O,O'-dibenzoyl-L-tartaric acid / methanol / 0.5 h / 60 - 65 °C 3: sodium methylate / methanol / 6 h / 60 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine (263769-24-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃;	92%
With lithium aluminium tetrahydride In tetrahydrofuran	92%
Stage #1: (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With water; ammonium chloride In tetrahydrofuran	92%
With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Ambient temperature;	84%
With lithium aluminium tetrahydride In tetrahydrofuran

acetamide oxime (118493-85-9, 117771-39-8, 1141922-26-0) + (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (3R,4S)-4-(4-Chloro-phenyl)-1-methyl-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidine

Conditions	Yield
With molecular sieve; sodium hydride In tetrahydrofuran Heating;	74%

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (3R,4S)-4-(4-chlorophenyl)piperidine-3-carboxylic acid methyl ester

Conditions	Yield
Stage #1: (+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate With carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In dichloromethane for 1.5h; Heating; Stage #2: In methanol for 1h; Heating; Further stages.;	67%

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylic Acid (263769-44-4)

Conditions	Yield
With hydrogenchloride Hydrolysis; Heating;
With hydrogenchloride Heating;
With hydrogenchloride Hydrolysis; Heating;

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → 2-[(3R,4S)-4-(4-Chloro-phenyl)-piperidin-3-ylmethylsulfanyl]-ethanol (896710-05-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 4: 80 percent / 1-chloroethyl chloroformate; proton sponge / CH2Cl2 5: 56 percent / LiAlH4 / tetrahydrofuran View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → 2-[(3R,4S)-4-(4-Chloro-phenyl)-piperidin-3-ylmethylsulfanyl]-1-piperidin-1-yl-ethanone (896710-06-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 4: 80 percent / 1-chloroethyl chloroformate; proton sponge / CH2Cl2 5: methanol View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-(3R,4S)-4-(4-chlorophenyl)-3-(iodomethyl)-1-methylpiperidine (807342-01-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole View Scheme
Multi-step reaction with 2 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]acetic acid methyl ester (807342-02-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 View Scheme
Multi-step reaction with 3 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C View Scheme
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol (807342-04-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 4: 56 percent / LiAlH4 / tetrahydrofuran View Scheme
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-[[(3R,4S)-4-(4-chlorophenyl)piperidin-3-yl]methylsulfanyl]acetic acid methyl ester (807342-26-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 4: 80 percent / 1-chloroethyl chloroformate; proton sponge / CH2Cl2 View Scheme
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 80 percent / 1,8-bis(dimethylamino)naphthalene; α-chloroethyl chloroformate / CH2Cl2 / 2.5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 2.5 h / Heating / reflux View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone (807342-17-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran 2: 86 percent / Ph3P; I2; imidazole 3: 88 percent / Cs2CO3 4: methanol View Scheme
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 92 percent / methanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: methanol / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-(3R,4S)-4-(4-chlorophenyl)-3-[(2-methoxyethylsulfanyl)methyl]-1-methylpiperidine (807342-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2.1: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3.1: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4.1: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C 5.1: NaH / tetrahydrofuran / 0.17 h / 0 °C 5.2: 65 percent / tetra-n-butylammonium iodide / tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3.1: caesium carbonate / acetonitrile / 20 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 5.1: sodium hydride / tetrahydrofuran / 0 °C 5.2: 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]ethanol

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C 5: 69 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 5: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-N-methylacetamide (807342-14-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 72 percent / methanol / 24 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: methanol / 24 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-(3R,4S)-4-(4-chlorophenyl)-3-[(2-methoxyethylsulfinyl)methyl]-1-methylpiperidine

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2.1: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3.1: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4.1: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C 5.1: NaH / tetrahydrofuran / 0.17 h / 0 °C 5.2: 65 percent / tetra-n-butylammonium iodide / tetrahydrofuran / 20 °C 6.1: 61 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3.1: caesium carbonate / acetonitrile / 20 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 5.1: sodium hydride / tetrahydrofuran / 0 °C 5.2: 20 °C 6.1: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)piperidin-3-yl]methylsulfanyl]acetamide (807342-27-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 90 percent / NH3(gas) / 2-methyl-propan-2-ol / 72 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 2.5 h / Heating / reflux 5: ammonia / tert-butyl alcohol / 72 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]acetamide (807342-12-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 95 percent / NH3 (gas) / 2-methyl-propan-2-ol / 72 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: ammonia / tert-butyl alcohol / 72 h / 20 °C / Sealed tube View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-N,N-dimethylacetamide (807342-15-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 91 percent / methanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: methanol / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]acetic acid methyl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 80 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-N-hydroxyacetamide (807342-13-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 76 percent / hydroxylamine hydrochloride; KOH / methanol / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: potassium hydroxide; hydroxylamine hydrochloride / methanol / 2 h / 5 - 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)piperidin-3-yl]methanesulfinyl]acetamide

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 90 percent / NH3(gas) / 2-methyl-propan-2-ol / 72 h / 20 °C 5: 73 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 2.5 h / Heating / reflux 5: ammonia / tert-butyl alcohol / 72 h / 20 °C 6: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-acetic acid 2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethyl ester (807342-08-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C 5: 70 percent / 4-(dimethylamino)pyridine; pyridine / 2 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 5: pyridine / dmap / 2 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]acetamide (807342-18-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 95 percent / NH3 (gas) / 2-methyl-propan-2-ol / 72 h / 20 °C 5: 69 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: ammonia / tert-butyl alcohol / 72 h / 20 °C / Sealed tube 5: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]-N-methylacetamide

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 72 percent / methanol / 24 h / 20 °C 5: 80 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: methanol / 24 h / 20 °C 5: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-(3R,4S)-[[4-(4-chlorophenyl)-1-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)methylsulfanyl]methyl]piperidine (807342-24-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2.1: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3.1: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4.1: NaH / tetrahydrofuran / 2.5 h / Heating 4.2: 79 percent / 4A molecular sieves / tetrahydrofuran / 16 h / Heating View Scheme
Multi-step reaction with 4 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3.1: caesium carbonate / acetonitrile / 20 °C 4.1: sodium hydride / tetrahydrofuran / 2.5 h / Heating / reflux 4.2: 16 h / Heating / reflux; Molecular sieve View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-acetic acid 2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]ethyl ester

Conditions	Yield
Multi-step reaction with 6 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 82 percent / LiAlH4 / tetrahydrofuran / 20 °C 5: 70 percent / 4-(dimethylamino)pyridine; pyridine / 2 h / 20 °C 6: 82 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 5: pyridine / dmap / 2 h / 20 °C 6: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

(+)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate (263769-22-8) → (+)-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methanesulfinyl]-N,N-dimethylacetamide

Conditions	Yield
Multi-step reaction with 5 steps 1: 92 percent / LiAlH4 / tetrahydrofuran / 20 °C 2: 86 percent / PPh3; I2; imidazole / CH2Cl2 / 2.5 h / Heating 3: 88 percent / Cs2CO3 / acetonitrile / 20 °C 4: 91 percent / methanol / 20 °C 5: 87 percent / aq. H2O2; CH3COOH / 2.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / Heating / reflux 3: caesium carbonate / acetonitrile / 20 °C 4: methanol / 20 °C 5: dihydrogen peroxide / water; acetic acid / 2.5 h / 20 °C View Scheme

Upstream product

• 873-77-8 (4-chlorphenyl)magnesium bromide 
• 205805-13-6 methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate 
• 205805-13-6 (±)-methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3β-carboxylate 
• 63-75-2 arecoline 
• 214335-16-7 (-)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3β-carboxylate 

Downstream Products

• 263769-24-0 (+)-4β-(4-Chlorophenyl)-3α-(hydroxymethyl)-1-methylpiperidine 
• 851705-32-3 (3R,4S)-[4-(4-chlorophenyl)-1-methyl-piperidin-3-ylmethylsulfanyl]-acetic acid 
• 717110-11-7 (3R,4S)-4-(4-Chloro-phenyl)-1-methyl-piperidine-3-carbonyl chloride 

Relevant articles and documents

Process development toward the pilot scale synthesis of the piperidine-based cocaine analogue and potent dopamine and norepinephrine reuptake inhibitor CTDP 31,446

(+)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate hydrochloride (CTDP 31,446) is known as a dopamine reuptake inhibitor. This cocaine analogue lacking the tropane skeleton is being considered for potential treatment of cocaine addiction. Herein we report the development of a scalable process for the preparation of this compound. This study was mainly aimed at improving the process throughput, eliminating chromatographic purifications for the separation of (±)-6-cis isomer from (±)-6-trans isomer, and developing a robust crystallization for isolation of pure (±)-6-cis in a single crop with a good mass recovery. The process development work also highlights an efficient recycle of (±)-6-trans via a kinetic epimerization followed by crystallization of the resulting (±)-6-cis isomer. The resolution of (±)-6-cis and the crystallization of the final HCl salt were optimized and implemented to afford CTDP-31,446 with high purity and good mass recovery.

Analogs of cocaine

The invention provides a compound of formula (I): STR1wherein R 1, R 2, R 3, and Y have any of the meanings defined in the specification; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson''s disease or depression comprising administering a compound of formula I, to a mammal in need of such treatment.

Synthesis and biological evaluation of 1-azabicyclo-[3.2.1]octanes: New dopamine transporter inhibitors

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