28289-54-5

Basic information

• Product Name: 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROXPYRIDINE
• Synonyms: MPTP;1,2,3,6-tetrahydro-1-methyl-4-phenyl-pyridin;1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine;1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)ochloride;1-METHYL-4-PHENYL-PIPERIDINE-3-EN;1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDRO-PYRIDINE;1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROXPYRIDINE;1-METHYL-4-PHENYL-1,2,3,6-TETRA-*HYDROPY RIDINE FREE
• CAS NO: 28289-54-5
• Molecular Formula: C₁₂H₁₅N
• Molecular Weight: 173.25
• EINECS: 248-939-7
• Product Categories: Heterocyclic Compounds;Neurochemicals
• Mol File: 28289-54-5.mol
• Article Data: 8

Chemical Properties

• Melting Point: aprox. 36°C
• Boiling Point: 128-132 °C12 mm Hg(lit.)
• Flash Point: 105.8°C
• Appearance: /
• Density: 1.001g/cm³
• Vapor Pressure: 0.0136mmHg at 25°C
• Refractive Index: 1.553
• Storage Temp.: -20°C Freezer
• PKA: 8.66±0.40(Predicted)
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 13,6319
• CAS DataBase Reference: 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROXPYRIDINE(CAS DataBase Reference)
• NIST Chemistry Reference: 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROXPYRIDINE(28289-54-5)
• EPA Substance Registry System: 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROXPYRIDINE(28289-54-5)

Safety Data

• Hazard Codes: T
• Statements: 25-39/23/24/25
• Safety Statements: 45
• RIDADR: UN 2811 6.1/PG 2
• WGK Germany: 3
• RTECS: UT8358900
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 28289-54-5(Hazardous Substances Data)

Usage

Chemical Properties

Light Yellow Solid

Uses

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a dopaminergic neurotoxin that reportedly causes a severe and irreversible Parkinsonian condition in humans and monkeys.

Definition

ChEBI: A tetrahydropyridine that is 1,2,3,6-tetrahydropyridine substituted by a methyl group at position 1 and a phenyl group at position 4.

Metabolic pathway

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a rat pheochromocytoma cell line is oxidized to give the N-methyl-4-phenylpyridinium ion.

InChI:InChI=1/C12H15N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-7H,8-10H2,1H3

Synthetic route

CH3(BH3)(C6H5)C5H7N → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
In ethanol Heating;	97%

1-methyl-4-phenyl-2(1H)-pyridone (67970-80-3) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
With lithium aluminium tetrahydride; titanium(III) chloride In tetrahydrofuran at 0℃;	97%

4-phenyl-N-methylpyridinium iodide (36913-39-0) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + CH3(BH3)(C6H5)C5H7N

Conditions	Yield
With sodium tetrahydroborate In methanol	A 92% B 0.5%

sodium tetrahydroborate (16940-66-2) + 4-phenyl-N-methylpyridinium iodide (36913-39-0) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + CH3(BH3)(C6H5)C5H7N

Conditions	Yield
In methanol to a soln. of pyridinium iodide in methanol cooling in an ice bath NaBH4 was added with stirring, mixt. stirred for 15 min at 0°C and 30min at room temp.;	A 92% B 0.5%
In water to a soln. of pyridinium iodide in water (cooled in an ice bath) NaBH4 was added with stirring, mixt. stirred for 15 min at 0°C and 30 min at room temp.; extn. with ether, extract dried over Na2SO4 and evapd. to dryness; chromy. on silica gel column with CH2Cl2; elem. anal.;	A 60% B 22%

4-phenyl-N-methylpyridinium iodide (36913-39-0) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
With tetrahydroxydiboron; potassium tert-butylate; water In methanol at 60℃; for 8h; Reagent/catalyst; Solvent; Inert atmosphere;	91%
With sodium tetrahydroborate In methanol
Multi-step reaction with 2 steps 1: 0.5 percent / sodium borohydride / methanol 2: 97 percent / ethanol / Heating View Scheme

1-methyl-4-phenyl-piperidin-4-ol (4972-68-3) + acetonitrile (75-05-8) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + N-(1-methyl-4-phenyl-[4]piperidyl)-acetamide (201055-91-6)

Conditions	Yield
With sulfuric acid at 20℃; for 24h;	A n/a B 86%

1-methyl-4-phenyl-piperidin-4-ol (4972-68-3) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + N-(1-methyl-4-phenyl-[4]piperidyl)-acetamide (201055-91-6)

Conditions	Yield
With sulfuric acid In acetonitrile at 20℃; for 24h;	A n/a B 86%

1-methyl-4-phenyl-piperidin-4-ol (4972-68-3) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
With sulfuric acid; sodium cyanide In acetic acid for 6h;	64%
With hydrogenchloride
With hydrogen bromide; acetic acid
With hydrogenchloride for 4h; Heating; Yield given;

sodium tetrahydroborate (16940-66-2) + 1-methyl-3-phenyl-1-pyridinium iodide (60684-91-5) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + CH3(BH3)(C6H5)C5H7N

Conditions	Yield
In water to a soln. of pyridinium iodide in water (cooled in an ice bath) NaBH4 was added with stirring, mixt. stirred for 15 min at 0°C and 30 min at room temp.; extd. with ether, extract dried over Na2SO4 and evapd. to dryness; chromy. on silica gel column with CH2Cl2; elem. anal.;	A 60% B 22%

3,6-dimethyl-6-phenyl-1,3-oxazinane (19798-88-0) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + 1-methyl-4-phenyl-piperidin-4-ol (4972-68-3)

Conditions	Yield
With hydrogenchloride

1-methyl-4-phenyl-piperidin-4-ol (4972-68-3) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + 4-amino-1-methyl-4-phenylpiperidine (100316-65-2)

Conditions	Yield
With potassium hydroxide; sodium cyanide 1.) acetic acid / H2SO4; 2.) ethanol, reflux, 3 h; Yield given. Multistep reaction. Yields of byproduct given;

1-methyl-4-phenyl-2(1H)-pyridone (67970-80-3) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + 1-methyl-4-phenyl-3,6-dihydro-2-pyridone-3,3-d2

Conditions	Yield
With lithium aluminium tetrahydride; deuteromethanol 1.) THF, 0 deg C, 2 h, 2.) -78 deg C; Multistep reaction;

sulfuric acid (7664-93-9) + 4-methanesulfonyl-1-methyl-4-phenyl-piperidine + water (7732-18-5) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

methylamine hydrochloride (593-51-1) + isopropenyl alcohol → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
With formaldehyd; sulfuric acid

tetrachloromethane (56-23-5) + thionyl chloride (7719-09-7) + (1-methyl-4-phenyl-[4]piperidyl)-phenyl ketone oxime → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + benzonitrile (100-47-0)

1-Methyl-4-piperidone (1445-73-4) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 2: 10percent HCl / 4 h / Heating View Scheme
Multi-step reaction with 2 steps 1: benzene 2: acetic acid; aqueous hydrobromic acid View Scheme
Multi-step reaction with 2 steps 1: diethyl ether 2: acetic acid; aqueous hydrobromic acid View Scheme
Multi-step reaction with 2 steps 1: benzene 2: concentrated aqueous hydrochloric acid View Scheme
Multi-step reaction with 2 steps 1: diethyl ether 2: concentrated aqueous hydrochloric acid View Scheme

phenyllithium (591-51-5) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 2: 10percent HCl / 4 h / Heating View Scheme
Multi-step reaction with 2 steps 1: diethyl ether 2: acetic acid; aqueous hydrobromic acid View Scheme
Multi-step reaction with 2 steps 1: diethyl ether 2: concentrated aqueous hydrochloric acid View Scheme

phenylmagnesium bromide → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: benzene 2: acetic acid; aqueous hydrobromic acid View Scheme
Multi-step reaction with 2 steps 1: benzene 2: concentrated aqueous hydrochloric acid View Scheme

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine oxalate → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
With potassium carbonate

p-phenylpyridine (939-23-1) → 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetone / 12 h / 90 °C / Inert atmosphere 2: water; tetrahydroxydiboron; potassium tert-butylate / methanol / 8 h / 60 °C / Inert atmosphere View Scheme

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide (95969-40-7)

Conditions	Yield
With dihydrogen peroxide In ethanol at 50℃; for 8h;	94%
With dihydrogen peroxide; palladium on activated charcoal In ethanol; dichloromethane a) 60 deg C, 20 h, b) 60 deg C, 3 h;	46%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 3,4-dihydroxy-1-methyl-2-oxo-4-phenylpiperidine

Conditions	Yield
With potassium permanganate In water; acetonitrile at 20 - 30℃; for 1.5h;	76%
Multi-step reaction with 2 steps 1: 65 percent / potassium permanganate / acetonitrile; H2O / 20 °C 2: 76 percent / potassium permanganate / H2O; acetonitrile / 2 h / 30 °C View Scheme

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + α-bromoacetophenone (70-11-1) → 1-methyl-1-(2-oxo-2-phenylethyl)-4-phenyl-1,2,3,6-tetrahydropyridinium bromide (1100765-97-6)

Conditions	Yield
In benzene at 20℃; for 72h;	75%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + Diethyl 2-bromomalonate (685-87-0) → 1-di(ethoxycarbonyl)methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium bromide (1226911-45-0)

Conditions	Yield
In tetrahydrofuran for 3h; Reflux; Inert atmosphere;	70%
In tetrahydrofuran for 3h; Reflux; Inert atmosphere;

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridin-2-one (94515-22-7)

Conditions	Yield
With potassium permanganate In water; acetonitrile at 20℃;	65%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + chloroacetic acid ethyl ester (105-39-5) → 1-ethoxycarbonylmethyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium chloride

Conditions	Yield
In benzene at 20℃; for 72h;	62%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + diiodomethane (75-11-6) → 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane (868557-58-8)

Conditions	Yield
With diethylzinc In dichloromethane; toluene at 20℃; for 18h; Simmons-Smith reaction;	57%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 1-(N-formyl-N-methyl)amino-3-phenylpropan-2-one (207395-42-4)

Conditions	Yield
With potassium permanganate In acetonitrile at 50℃; for 1h;	53%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → p-phenylpyridine (939-23-1)

Conditions	Yield
With manganese(IV) oxide In toluene for 3h; Heating;	45%
With manganese(IV) oxide In toluene for 3h; Heating;	45%
With aluminum oxide; palladium/alumina; nitrobenzene at 130℃;
Multi-step reaction with 2 steps 1: 22 percent / aq. NaOH; MnO2 / benzene / 1.5 h / 20 - 40 °C 2: 10 percent / aq. KMnO4 / acetonitrile / 1.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 36.5 percent / aq. MnO2 / benzene / 2 h / 20 °C 2: 10 percent / aq. KMnO4 / acetonitrile / 1.5 h / 20 °C View Scheme

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + nitromethane (75-52-5) → 1,2,5,6-tetrahydro-1-methyl-2-nitromethylene-4-phenylpyridine

Conditions	Yield
With potassium permanganate In chloroform for 2.5h; Ambient temperature;	40%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + malononitrile (109-77-3) → 3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (86219-77-4)

Conditions	Yield
With manganese(IV) oxide In benzene at 20℃; for 2h;	36.5%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + 4-nitro-aniline (100-01-6) → 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridin-2-one (94515-22-7) + 1-methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine

Conditions	Yield
With potassium permanganate In acetonitrile at 20℃; for 2h;	A 2% B 33%

formaldehyd (50-00-0) + 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 2-methyl-5-phenyl-6-oxa-2-azabicyclo[3.2.1]octan-4-one

Conditions	Yield
With manganese(IV) oxide; sulfuric acid for 7h; Prins reaction; Heating;	31%
With manganese(IV) oxide; sulfuric acid for 7h; Heating;	31%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + acetone (67-64-1) → (E)-2-acetylmethylene-1,2,5,6-tetrahydro-1-methyl-4-phenylpyridine + (Z)-2-acetylmethylene-1,2,5,6-tetrahydro-1-methyl-4-phenylpyridine

Conditions	Yield
With potassium permanganate for 1.16667h; Ambient temperature;	A 30% B 12%

formaldehyd (50-00-0) + 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (86219-77-4)

Conditions	Yield
With manganese(IV) oxide; sodium hydroxide In benzene at 20 - 40℃; for 1.5h;	22%
With sulfuric acid Prins reaction;

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + aniline yellow (60-09-3) → 1-methyl-4-phenyl-2-[4-(phenylazo)phenyl]-1,2,5,6-tetrahydropyridine

Conditions	Yield
With potassium permanganate In acetonitrile at 20℃; for 2h;	20%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 3-(N-methylamino)propiophenone (27152-62-1)

Conditions	Yield
With potassium permanganate In acetonitrile at 20 - 60℃; for 26h;	20%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + 4-bromo-aniline (106-40-1) → 2-(4-bromophenylimino)-1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine

Conditions	Yield
With potassium permanganate In acetonitrile at 20℃; for 2h;	17%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) + acetophenone (98-86-2) → 2-benzoylmethylene-1,2,5,6-tetrahydro-1-methyl-4-phenylpyridine

Conditions	Yield
With potassium permanganate for 1.16667h; Ambient temperature;	7%

2-Acetylthiophene (88-15-3) + 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 2-[1-Methyl-4-phenyl-5,6-dihydro-1H-pyridin-(2E)-ylidene]-1-thiophen-2-yl-ethanone

Conditions	Yield
With potassium permanganate for 1.16667h; Ambient temperature;	6%

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) → 1-methyl-4-phenyl-piperidin-4-ol (4972-68-3)

Conditions	Yield
With hydrogen bromide; acetic acid Erwaermen des Reaktionsprodukts in Wasser;

Upstream product

• 4972-68-3 1-methyl-4-phenyl-piperidin-4-ol 
• 36913-39-0 4-phenyl-N-methylpyridinium iodide 
• 75-05-8 acetonitrile 
• 939-23-1 p-phenylpyridine 
• 16940-66-2 sodium tetrahydroborate 
• 60684-91-5 iodure de 1-methyl-3-phenylpyridinium 
• 591-51-5 phenyllithium 
• 1445-73-4 1-Methyl-4-piperidone 
• 56-23-5 tetrachloromethane 
• 7719-09-7 thionyl chloride 
• 593-51-1 methylamine hydrochloride 
• 7664-93-9 sulfuric acid 
• 7732-18-5 water 
• 67970-80-3 1-methyl-4-phenyl-2(1H)-pyridone 

Downstream Products

• 10338-69-9 1,2,3,6-tetrahydro-4-phenylpyridine 
• 86219-77-4 3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine 
• 27152-62-1 3-(N-methylamino)propiophenone 
• 1226911-45-0 1-di(ethoxycarbonyl)methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium bromide 
• 74904-13-5 2-Methyl-5-phenyl-2-aza-bicyclo[3.3.1]non-3-ene 
• 74904-16-8 2-Methyl-4a-phenyl-2,3,4,4a,5,6,7,8-octahydro-isoquinoline 
• 50790-97-1 2-methyl-4a-phenyl-trans-decahydroisoquinoline 
• 744220-55-1 2-methyl-5-phenyl-2-azabicyclo[3.3.1]nonane 
• 101355-59-3 1-methyl-4-phenyl-4-propyl-piperidine 
• 50790-97-1 cis-2-methyl-4a-phenyldecahydroisoquinoline 
• 774-52-7 1-methyl-4-phenylpiperidine 
• 868557-58-8 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane 
• 207395-42-4 1-(N-formyl-N-methyl)amino-3-phenylpropan-2-one 

Relevant articles and documents

Reaction of benzophenone triplet with aliphatic amines. What a potent neurotoxin can tell us about the reaction mechanism

A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP (1)] and two of it's derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (2) and (±)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (3) were performed. Literature precedent and calculations reported herein suggest that the barrier to ring opening for aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) will be low. The LFP results reported herein demonstrate that pathways for the reaction of 3BP with 1, 2, and 3 are very similar. In each instance, disappearance of 3BP is accompanied solely by appearance of bands corresponding to the diphenylhydroxylmethyl radical and neutral radical derived from MPTP and it's two derivatives 2 and 3. These results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway.

Synthesis of substituted 4-acetylamino-4-phenylpiperidines from the corresponding 4-piperidols under ritter reaction conditions

The reaction of substituted 4-phenyl-4-piperidols with acetonitrile under Ritter reaction conditions leads to formation of mixtures of the corresponding 4-acetylamino-4-phenylpiperidines and 1,2,5,6-tetrahydropyridines, from which we isolated the target amides by fractional crystallization. 1997 Plenum Publishing Corporation.

POTENTIAL NEUROLEPTICS OF THE ORTHOPRAMIDE SERIES; SYNTHESIS OF N-SUBSTITUTED 5-(AMINOSULFONYL)-2-METHOXYBENZAMIDES

The mixed anhydride of 5-(aminosulfonyl)-2-methoxybenzoic acid (VII) and monoethyl carbonate reacted with benzylamine, 1-methylpiperazine, and 1-benzylpiperazine to give the 5-(aminosulfonyl)-2-methoxybenzamides II, IV, and V.Heating the ethyl ester X with 4-amino-1-methylpiperidine resulted in the amide III.Reaction of 5-(chlorosulfonyl)-2-methoxybenzoyl chloride (XI) with 1-benzylpiperazine afforded 5-(4-benzylpiperazinosulfonyl)-2-methoxybenzoic acid 4-benzylpiperazide (VI).Compounds II-VI are analogues of the antidopaminergic and antiemetic agent sulpiride (I) but only the benzylpiperazides V and VI showed indications of psychotropic activity of the neuroleptic type.