1822-51-1

Basic information

• Product Name: 4-(Chloromethyl)pyridine hydrochloride
• Synonyms: 4-(CHLOROMETHYL)PYRIDINE HYDROCHLORIDE;4-(CHLOROMETHYL)PYRIDINIUM CHLORIDE;4-PICOLYL CHLORIDE HYDROCHLORIDE;TIMTEC-BB SBB003917;4-Picolyl chloride HCl (65% in water);4-(Chloromethyl)pyridine HCL;4-Plcolyl Chloride Hydrochloride;Pyridine, 4-(chloromethyl)-, hydrochloride
• CAS NO: 1822-51-1
• Molecular Formula: C₆H₆ClN*ClH
• Molecular Weight: 164.03
• EINECS: 217-350-7
• Product Categories: blocks;Pyridines;Halides;Heterocycles;Pyridines, Pyrimidines, Purines and Pteredines;Pyridines derivates;Heterocyclic Compounds;Pyridinium Compounds
• Mol File: 1822-51-1.mol
• Article Data: 8

Chemical Properties

• Melting Point: 166-173 °C(lit.)
• Boiling Point: 212 °C at 760 mmHg
• Flash Point: 102 °C
• Appearance: Yellow to orange/Fine Crystalline Powder
• Density: 1.156g/cm³
• Vapor Pressure: 0.257mmHg at 25°C
• Refractive Index: 1.53
• Storage Temp.: 2-8°C
• Water Solubility: 750 g/L (20 ºC)
• Sensitive: Hygroscopic
• BRN: 3689154
• CAS DataBase Reference: 4-(Chloromethyl)pyridine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(Chloromethyl)pyridine hydrochloride(1822-51-1)
• EPA Substance Registry System: 4-(Chloromethyl)pyridine hydrochloride(1822-51-1)

Safety Data

• Hazard Codes: C,Xi
• Statements: 34-4-22-36/37/38
• Safety Statements: 26-36/37/39-45-36
• RIDADR: UN 3261 8/PG 3
• WGK Germany: 3
• F: 3-10
• HazardClass: 8
• PackingGroup: III
• Hazardous Substances Data: 1822-51-1(Hazardous Substances Data)

Usage

Chemical Properties

YELLOW TO ORANGE FINE CRYSTALLINE POWDER

Uses

It finds its application as a reagent for protection of carboxyl termini of peptides as 4-picolyl esters, providing a polar 'handle' which aids in separation and purification of the peptide. The group can be introduced in the presence of a base, e.g. tetramethylguanidine, is stable to acid-catalyzed removal of Cbz protecting group and can be removed by base, Na in liquid ammonia or catalytic hydrogenolysis. It is also applied in conjunction with Amberlyst?15 resin in peptide synthesis. It is an important raw material and intermediate used in organic synthesis, pharmaceuticals and agrochemicals.

Purification Methods

Purify it by recrystallisation from EtOH or EtOH/dry Et2O. It melts between 171o and 175o, and the clear melt resolidifies on further heating at 190o and turns red to black at 280o but does not melt again. The picrate-hydrochloride (prepared in EtOH) has m 146-147o. The free base is an oil. [Mosher & Tessieri J Am Chem Soc 73 4925 1951, Beilstein 20 III/IV 2752.]

InChI:InChI=1/C6H6ClN/c7-5-6-1-3-8-4-2-6/h1-4H,5H2

Synthetic route

pyridine-4-methanol (586-95-8) → 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
With thionyl chloride In acetonitrile at 50℃; for 1h;	100%
With thionyl chloride In acetonitrile
With thionyl chloride In dichloromethane
With thionyl chloride In methanol	26.9 g

4-(phenoxymethyl)pyridine (63608-12-8) + 4-pyridinemethanol hydrochloride (62302-28-7) → 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
With thionyl chloride In benzene	76%

4-methylpyridine-1-oxide (1003-67-4) → 2-chloro-4-picoline (3678-62-4) + 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
With diisopropylamine; trichloromethyl chloroformate In dichloromethane at -40 - 20℃;

triethylamine (121-44-8) → 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
In N-methyl-acetamide

picoline (108-89-4) → 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium permanganate / water / 0.58 h / 75 - 80 °C 2: sulfuric acid 3: sodium tetrahydroborate; aluminum (III) chloride / toluene; tetrahydrofuran / 0 - 5 °C 4: thionyl chloride / methanol View Scheme

pyridine-4-carboxylic acid (55-22-1) → 4-picolylchloride hydrochloride (1822-51-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid 2: sodium tetrahydroborate; aluminum (III) chloride / toluene; tetrahydrofuran / 0 - 5 °C 3: thionyl chloride / methanol View Scheme

sodium methylate (124-41-4) + 4-picolylchloride hydrochloride (1822-51-1) → 4-(methoxymethyl)pyridine (70199-60-9)

Conditions	Yield
In methanol at 90℃; for 12h;	100%
With methanol
for 4h; Inert atmosphere; Reflux;

4-picolylchloride hydrochloride (1822-51-1) + triphenylphosphine (603-35-0) → Triphenyl-4-pyridylmethylphosphonium chloride hydrochloride (73870-25-4)

Conditions	Yield
In N,N-dimethyl-formamide at 140℃; for 20h;	100%

2,2’-dimethyl-3’-(pyridin-4-ylmethoxy)-[1,1’-biphenyl]-3-ol + 4-picolylchloride hydrochloride (1822-51-1) → 4,4’-(((2,2’-dimethyl-[1,1’-biphenyl]-3,3’-diyl)bis(oxy))bis-(methylene))dipyridine

Conditions	Yield
With caesium carbonate at 20℃;	100%

2-(2-benzyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (178980-30-8) + tetrabutylammomium bromide (1643-19-2) + 4-picolylchloride hydrochloride (1822-51-1) → 4-[2-(2-benzyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-ylmethyl]pyridine

Conditions	Yield
With sodium hydroxide In tetrahydrofuran	98%

bisphenol M (13595-25-0) + 4-picolylchloride hydrochloride (1822-51-1) → C36H36N2O2 (1020725-78-3)

Conditions	Yield
With sodium hydroxide; tetra(n-butyl)ammonium hydroxide In benzene at 80℃; for 48h;	98%

4-picolylchloride hydrochloride (1822-51-1) + potassium thioacetate (10387-40-3) → S-(pyridin-4-ylmethyl) ethanethioate (138311-91-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 0 - 50℃; for 1h; Inert atmosphere;	98%

4-picolylchloride hydrochloride (1822-51-1) + (3S)-tert-butyl 3-((1R)-2-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxybenzamido)-1-hydroxyethyl)-7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate → tert-butyl (3S)-3-[(1R)-2-[[2-ethoxy-4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoyl]amino]-1-hydroxyethyl]-7-(4-pyridylmethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 50℃;	97.01%

4-picolylchloride hydrochloride (1822-51-1) + thiourea (17356-08-0) → C7H10N3S(1+)*Cl(1-)

Conditions	Yield
In ethanol for 2h; Heating;	97%

4-picolylchloride hydrochloride (1822-51-1) → 4-(Chloromethyl)pyridine (10445-91-7)

Conditions	Yield
With sodium hydrogencarbonate In water	97%
With sodium hydroxide In diethyl ether; water
With sodium hydroxide; water In tetrahydrofuran

4-picolylchloride hydrochloride (1822-51-1) + 3,5-bis-[3,5-3,5-(dimethoxycarbonylphenoxymethyl)phenoxymethyl]phenol → C70H63NO23 (1587638-88-7)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 6h; Inert atmosphere; Schlenk technique;	97%

2,2’-dimethyl-[1,1’-biphenyl]-3,3’-diol + 4-picolylchloride hydrochloride (1822-51-1) → 2,2’-dimethyl-3’-(pyridin-4-ylmethoxy)-[1,1’-biphenyl]-3-ol

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;	97%

4-picolylchloride hydrochloride (1822-51-1) + (Z)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione → (Z)-5-(4-ethoxybenzylidene)-3-(pyridin-4-ylmethyl)thiazolidine-2,4-dione (1438409-42-7)

Conditions	Yield
Stage #1: (Z)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 4-picolylchloride hydrochloride In N,N-dimethyl-formamide at 20℃;	96.1%

5-(chloromethyl)-1,3-oxazolidin-2-one (22625-57-6) + 4-picolylchloride hydrochloride (1822-51-1) → 5-Chloromethyl-3-pyridin-4-ylmethyl-oxazolidin-2-one (251345-16-1)

Conditions	Yield
In NMP (N-methylpyrrolidone); water	96%
In NMP (N-methylpyrrolidone); water	96%

6-hydroxy-5-methoxyindan-1-one (90843-62-2) + 4-picolylchloride hydrochloride (1822-51-1) → 5-methoxy-6-(pyridin-4-ylmethoxy)indan-1-one (760995-12-8)

Conditions	Yield
With potassium carbonate In acetone Heating / reflux;	95%

indole (120-72-9) + 4-picolylchloride hydrochloride (1822-51-1) → 1-(4-pyridylmethyl)indole (82485-24-3)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide 1.) RT, 90 min, 2.) RT, 4 h;	94%
With potassium hydroxide In dimethyl sulfoxide for 4h; Ambient temperature;	92%
	83%
With potassium hydroxide In dimethyl sulfoxide

4-picolylchloride hydrochloride (1822-51-1) + (E)-N-((pyridine-3-yl)methylene)benzenamine (82299-13-6) → 3-(1-phenyl-3-pyridin-4-ylaziridin-2-yl)pyridine

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃;	94%

2-mercaptoethylamine hydrochloride (156-57-0) + 4-picolylchloride hydrochloride (1822-51-1) → 4-<(2-aminoethyl)thiomethyl>pyridine (57667-43-3)

Conditions	Yield
With sodium hydroxide In ethanol at 20℃; for 3h; Cooling with ice;	94%

C15H10N2O3S2 + 4-picolylchloride hydrochloride (1822-51-1) → C21H15N3O3S2

Conditions	Yield
With sodium hydroxide In ethanol at 0 - 20℃; for 17.5h;	94%

3-(hydroxymethy)piperidine (4606-65-9) + chloroform methanol (7285-11-2) + 4-picolylchloride hydrochloride (1822-51-1) → 3-hydroxymethyl-1-(pyridin-4-ylmethyl)piperidine

Conditions	Yield
With sodium iodide; potassium carbonate In butanone	93%

methyl 3-hydroxy-6-methylbenzoate (73505-48-3) + 4-picolylchloride hydrochloride (1822-51-1) → methyl 2-methyl-5-(pyridin-4-ylmethoxy)benzoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃;	93%

4-picolylchloride hydrochloride (1822-51-1) + triphenylphosphine (603-35-0) → triphenyl-4-pyridylmethylphosphonium chloride hydrochloride

Conditions	Yield
In acetonitrile for 3h; Reflux;	93%
In acetonitrile for 24h; Reflux;	87%

4-picolylchloride hydrochloride (1822-51-1) + methyl 2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-7-hydroxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate (212492-78-9) → methyl 2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-7-(4-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate (212498-25-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 40℃;	92%

4-picolylchloride hydrochloride (1822-51-1) + (2R,3R,4S,5R,6R)-2-(5-Azido-pentyloxymethyl)-4,5-bis-benzyloxy-6-methoxy-tetrahydro-pyran-3-ol (543697-42-3) → 4-[(2R,3R,4S,5R,6R)-2-(5-Azido-pentyloxymethyl)-4,5-bis-benzyloxy-6-methoxy-tetrahydro-pyran-3-yloxymethyl]-pyridine (543697-45-6)

Conditions	Yield
Stage #1: (2R,3R,4S,5R,6R)-2-(5-Azido-pentyloxymethyl)-4,5-bis-benzyloxy-6-methoxy-tetrahydro-pyran-3-ol With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: 4-picolylchloride hydrochloride With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 0℃;	92%

1-(2,6-dichlorophenyl)indolin-2-one (15362-40-0) + 4-picolylchloride hydrochloride (1822-51-1) → N-(2,6-dichlorophenyl)-3,3-di(4-pyridylmethyl)-2-indolinone

Conditions	Yield
With potassium fluoride on basic alumina for 0.0833333h; microwave irradiation;	92%

morpholine (110-91-8) + 4-picolylchloride hydrochloride (1822-51-1) → 4-(4-morpholinylmethyl)-pyridine (61777-51-3)

Conditions	Yield
With potassium carbonate; sodium iodide In acetonitrile at 20℃; for 12h; Inert atmosphere;	92%

4-picolylchloride hydrochloride (1822-51-1) + 4-Fluoro-3-hydroxy-benzoic acid methyl ester (214822-96-5) → methyl 4-fluoro-3-(pyridin-4-ylmethoxy)benzoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃;	92%

4-(aminomethyl)pyridine (3731-53-1) + 4-picolylchloride hydrochloride (1822-51-1) → N-(4-pyridinylmethyl)-4-pyridinemethanamine (1539-39-5)

Conditions	Yield
With potassium carbonate In ethanol; water	91%

1-phenyl-1,3-dihydro-indol-2-one (3335-98-6) + 4-picolylchloride hydrochloride (1822-51-1) → linopirdine (105431-72-9)

Conditions	Yield
With potassium fluoride on basic alumina for 0.05h; microwave irradiation;	90%

4-picolylchloride hydrochloride (1822-51-1) + 1-ethyl-1,3-dihydro-2H-indol-2-one (61-28-9) → N-ethyl-3,3-di(4-pyridylmethyl)-2-indolinone

Conditions	Yield
With potassium fluoride on basic alumina for 0.0666667h; microwave irradiation;	90%

Upstream product

• 1003-67-4 4-methylpyridine-1-oxide 
• 55-22-1 pyridine-4-carboxylic acid 
• 108-89-4 picoline 
• 63608-12-8 4-(phenoxymethyl)pyridine 
• 62302-28-7 4-pyridinemethanol hydrochloride 
• 121-44-8 triethylamine 
• 586-95-8 pyridine-4-methanol 

Downstream Products

• 105431-72-9 linopirdine 
• 353744-16-8 2-(4-nitro-phenyl)-1-pyridin-4-ylmethyl-1H-indole 
• 668262-21-3 3-[(pyridin-4-ylmethyl)thio]benzoic acid 
• 613679-13-3 (6-methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone 
• 347174-21-4 ethyl 1-cyclohexyl-2-{4-[3-(pyridin-4-ylmethoxy)phenyloxy]phenyl}-benzimidazole-5-carboxylate 
• 1190746-33-8 C₃₈H₃₃N₃O₃ 
• 1006301-45-6 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1-pyridin-4-ylmethyl-1H-pyrimidine-2,4-dione 
• 21819-91-0 picolyl N-Cbz-glycinate 
• 353744-17-9 2-(4-bromo-phenyl)-1-pyridin-4-ylmethyl-1H-indole 

Relevant articles and documents

A 4 - chloromethyl pyridine hydrochloride synthetic method

The invention belongs to the field of organic synthesis, in particular to a 4 - chloromethyl pyridine hydrochloride synthetic method, the method comprises the following steps: (1) to 4 - methyl pyridine as raw materials, takes water as a solvent, the potassium permanganate oxide it to 4 - pyridine carboxylic acid, wherein 4 - methyl pyridine with potassium permanganate in a molar ratio of 1: 2.1 - 2.3, the oxidation temperature is 75 - 80 °C, heating 35 min, the reaction is complete the reaction liquid is adjusted to be acidic, and then cooling and filtering to obtain 4 - pyridine carboxylic acid; (2) 4 - pyridine carboxylic acid with methanol under acidic conditions to produce the 4 - pyridine carboxylic acid methyl ester, wherein the 4 - pyridine carboxylic acid with methanol in a molar ratio of 1: 1.3; (3) reduction of 4 - pyridine carboxylic acid methyl ester for 4 - pyridine methanol; (4) 4 - pyridine methanol with thionyl chloride reaction to obtain the target product 4 - chloromethyl pyridine hydrochloride, 4 - pyridine methanol with thionyl chloride in a molar ratio of 1: 1.1 - 1.3.

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