132-22-9

Basic information

• Product Name: Chloropheniramine-d4
• Synonyms: Chloropheniramine-D4
• CAS NO: 132-22-9
• Molecular Formula: C16H15D4ClN2
• Molecular Weight: 274.82
• EINECS: 205-054-0
• Mol File: 132-22-9.mol
• Article Data: 8

Chemical Properties

• Melting Point: 25°C
• Boiling Point: bp1.0 142°
• Flash Point: 183°C
• Appearance: /
• Density: 1.0895 (rough estimate)
• Refractive Index: 1.5749 (estimate)
• PKA: 9.33±0.28(Predicted)
• Water Solubility: 5.496g/L(37.5 oC)
• CAS DataBase Reference: Chloropheniramine-d4(CAS DataBase Reference)
• NIST Chemistry Reference: Chloropheniramine-d4(132-22-9)
• EPA Substance Registry System: Chloropheniramine-d4(132-22-9)

Safety Data

• Hazardous Substances Data: 132-22-9(Hazardous Substances Data)

Usage

Chemical Properties

BP

Uses

Chlorpheniramine is a drug in the class of first-generation antihistamines, used to help alleviate symptoms of allergic reactions potentiated by histamine release. Though it is included in many multisymptom over-the-counter cold relief medications, the Food and Drug Administration (FDA) issued a safety alert in March 2011 detailing some risks associated with these medications. The safety alert also indicated that increased enforcement of FDA laws governing the marketing of these drugs would occur, as many of the products had not been approved in their current formulations for safety, effectiveness, and quality. Chlorpheniramine is commonly used in small-animal veterinary medicine for its antihistaminic/antipruritic effects, especially for the treatment of pruritus in cats, and occasionally as a mild sedative.

Environmental Fate

Toxicity of antihistamines is usually related to their anticholinergic effects and may include loss of appetite, nausea, vomiting, diarrhea or constipation, and other GI effects, as well as dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors. Acetylcholine is competitively blocked at muscarinic receptors, resulting in symptoms of anticholinergic poisoning. Concurrent use of alcohol, tricyclic antidepressants, monoamine oxidase inhibitors, or other central nervous system (CNS) depressants along with antihistamines may exaggerate and extend the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. Products that were marketed prior to the FDA safety alert but not approved by the FDA included multisymptom cold medications comprised of drug combinations of chlorpheniramine with decongestants, antitussives, and analgesics. Risks associated with the use of these products included improper use in children and infants, potentially risky combination of ingredients, and patients receiving too much or too little medication because of problems with the way some ‘extendedrelease’ products were made. Newborn and premature infants are even more prone to anticholinergic side effects and an increased susceptibility toward convulsions; thus, this drug is not recommended at all in this age group. Geriatric patients are also more prone to anticholinergic effects, and a paradoxical reaction characterized by hyperexcitability may occur in some children taking antihistamines. Overdosage may also produce central excitation resulting in convulsions.

InChI:InChI=1/C16H19ClN2/c1-19(2)11-9-16(14-4-3-10-18-12-14)13-5-7-15(17)8-6-13/h3-8,10,12,16H,9,11H2,1-2H3

Synthetic route

3-(p-chlorophenyl)-3-(2-pyridyl)propanal (55486-47-0) + dimethyl amine (124-40-3) → Chlorpheniramine (132-22-9)

Conditions	Yield
With hydrogen; platinum(IV) oxide In toluene at 120℃; under 38000 Torr; for 12h; catalytic reductive amination;	100%

chloropheniramine nitrile (65676-21-3) → Chlorpheniramine (132-22-9)

Conditions	Yield
With potassium hydroxide at 160℃; for 4h;	95%

3-(4-chlorophenyl)-3-pyridin-2-yl-propan-1-ol (73486-85-8) + dimethyl amine (124-40-3) → Chlorpheniramine (132-22-9)

Conditions	Yield
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; bis[2-(diphenylphosphino)phenyl] ether In toluene at 20℃; Inert atmosphere; Reflux;	81%

2-(4-chloro-phenyl)-4-dimethylamino-butyronitrile (73775-50-5) + acetylene (74-86-2) → Chlorpheniramine (132-22-9)

Conditions	Yield
(η5-cyclopentadienyl)-η4-cycloocta-1,5-dienecobalt(I) In toluene at 140℃; under 10640 Torr; for 36h;	75%

1-(4-chlorophenyl-1-(2-pyridyl))ehylene (160911-84-2) + C12H12N2O4 → Chlorpheniramine (132-22-9)

Conditions	Yield
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; 0.8C12H6N2O4(2-)*HO(1-)*Al(3+)*0.4CF3O3S(1-)*0.1Ir(3+)*0.2C11H8N(1-)*0.1Cl(1-) In acetonitrile at 20℃; for 6h; Inert atmosphere; Irradiation;	36%

2-bromo-pyridine (109-04-6) + p-chlorobenzyl cyanide (140-53-4) → Chlorpheniramine (132-22-9)

Conditions	Yield
With sodium amide; benzene anschl. mit <2-Chlor-aethyl>-dimethyl-amin und anschl. Erhitzen mit wss. H2SO4;
With sodium amide; benzene anschl. mit <2-Chlor-aethyl>-dimethyl-amin und anschl. Erhitzen mit NaOH in Butan-1-ol;

2-(4-chlorobenzyl)pyridine (4350-41-8) + 2-(dimethylamino)ethyl chloride (107-99-3) → Chlorpheniramine (132-22-9)

Conditions	Yield
With potassium amide
With sodium amide
Stage #1: 2-(4-chlorobenzyl)pyridine With sodium amide In tetrahydrofuran at 20 - 25℃; for 1h; Stage #2: 2-(dimethylamino)ethyl chloride In tetrahydrofuran; toluene at 30 - 45℃; for 2h;

1-(4-chlorophenyl)-3-dimethylamino-1-propanone (2138-38-7) → Chlorpheniramine (132-22-9)

Conditions	Yield
With 2-pyridyllithium; diethyl ether

1t-(4-chloro-phenyl)-3-dimethylamino-1c-[2]pyridyl-propene (88848-63-9) → Chlorpheniramine (132-22-9)

Conditions	Yield
With palladium on activated charcoal; acetic acid Hydrogenation;

(+-)-2-<4-chloro-phenyl>-4-dimethylamino-2-<2>pyridyl-butyric acid dimethylamide → Chlorpheniramine (132-22-9)

Conditions	Yield
With sulfuric acid; water

(+-)-2-<4-chloro-phenyl>-4-dimethylamino-2-<2>pyridyl-butyronitrile → Chlorpheniramine (132-22-9)

Conditions	Yield
With sulfuric acid; water

(+-)-3-<4-chloro-phenyl>-3-<2>pyridyl-propionaldehyde diethylacetal → Chlorpheniramine (132-22-9)

Conditions	Yield
With formic acid; water; N,N-dimethyl-formamide

2-bromo-pyridine (109-04-6) + (+-)-2-<4-chloro-phenyl>-4-dimethylamino-butyronitrile → Chlorpheniramine (132-22-9)

Conditions	Yield
With sodium amide; toluene anschl. mit wss. H2SO4;

2-(4-chlorobenzyl)pyridine (4350-41-8) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium diisopropylamide; HMPT / 2 h / 0 °C 1.2: 80 percent / HMPT / 3 h / -78 - 20 °C 2.1: 100 percent / 5 percent aq. HCl / methanol / 24 h / 20 °C 3.1: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

1-(4-chlorophenyl-1-(2-pyridyl))ehylene (160911-84-2) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 30 percent / Na / 6 h / 20 °C 2: aq. potassium tert-butoxide / diethyl ether / 25 °C 3: 70 percent / tetrabutylammonium periodate / dioxane / 20 h / Heating 4: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

3-(p-chlorophenyl)-4,4-diethoxybutanenitrile (233760-10-6) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / (η5-cyclopentadienyl)<(1,5-η)-cyclooctadienyl>cobalt / toluene / 72 h / 120 °C / 9500 Torr 2: 100 percent / 5 percent aq. HCl / methanol / 24 h / 20 °C 3: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

2-(4-chloro-phenyl)-3-[1,3]dioxolan-2-yl-propionaldehyde oxime → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrabutylammonium hydrogen sulfate; carbon disulfide; 15 percent aq. NaOH / benzene / 0.5 h / 20 °C 2: 85 percent / (η5-cyclopentadienyl)<(1,5-η)-cyclooctadienyl>cobalt / toluene / 72 h / 120 °C / 9500 Torr 3: 100 percent / 5 percent aq. HCl / methanol / 24 h / 20 °C 4: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

2-[1-(4-chloro-phenyl)-2-[1,3]dioxolan-2-yl-ethyl]-pyridine (233760-12-8) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / 5 percent aq. HCl / methanol / 24 h / 20 °C 2: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

4-(4-chloro-phenyl)-2-hydroxy-4-pyridin-2-yl-butyric acid → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / tetrabutylammonium periodate / dioxane / 20 h / Heating 2: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

N,N-dimethyl-4-(p-chlorophenyl)-4-(2-pyridyl)-2-hydroxybutanamide (233760-14-0) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: aq. potassium tert-butoxide / diethyl ether / 25 °C 2: 70 percent / tetrabutylammonium periodate / dioxane / 20 h / Heating 3: 100 percent / H2 / PtO2 / toluene / 12 h / 120 °C / 38000 Torr View Scheme

p-Chloro-N,N-dimethylcinnamylamine (42817-51-6) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2 / HRh(CO)(PPh3)3 / benzene / 24 h / 80 °C / 76000 Torr 2: NH2OH 3: 92 percent / CS2, n-Bu4N(1+)*HSO4(1-), 15percent aq. NaOH / CH2Cl2 / 0.5 h / Ambient temperature 4: 75 percent / (η5-cyclopentadienyl)<(1,5-η)-cyclopentadienyl>cobalt / toluene / 36 h / 140 °C / 10640 Torr View Scheme

2-(4-Chloro-phenyl)-4-dimethylamino-butyraldehyde (158696-49-2) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: NH2OH 2: 92 percent / CS2, n-Bu4N(1+)*HSO4(1-), 15percent aq. NaOH / CH2Cl2 / 0.5 h / Ambient temperature 3: 75 percent / (η5-cyclopentadienyl)<(1,5-η)-cyclopentadienyl>cobalt / toluene / 36 h / 140 °C / 10640 Torr View Scheme

2-(4-Chloro-phenyl)-4-dimethylamino-butyraldehyde oxime (158696-52-7) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / CS2, n-Bu4N(1+)*HSO4(1-), 15percent aq. NaOH / CH2Cl2 / 0.5 h / Ambient temperature 2: 75 percent / (η5-cyclopentadienyl)<(1,5-η)-cyclopentadienyl>cobalt / toluene / 36 h / 140 °C / 10640 Torr View Scheme

pyridine (110-86-1) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine hydrochloride; copper (II)-chloride 2: NaNH2 View Scheme

4-chlorobenzyl bromide (622-95-7) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine hydrochloride; copper (II)-chloride 2: NaNH2 View Scheme

p-chlorobenzyl cyanide (140-53-4) → Chlorpheniramine (132-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: cobaltocene / 4 h / 150 - 170 °C / Autoclave 2.1: sodium amide / tetrahydrofuran / 1 h / 20 - 25 °C 2.2: 2 h / 30 - 45 °C View Scheme

2-(2-methylphenyl)pyridine (10273-89-9) + Chlorpheniramine (132-22-9) → C28H29N3

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 50℃; for 72h; Inert atmosphere;	81%

ethyl-2-thiourea (625-53-6) + Chlorpheniramine (132-22-9) → 3-(4-ethylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (1378243-75-4)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	78%

1-(methyl)-thiourea (598-52-7) + Chlorpheniramine (132-22-9) → 3-(4-methylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (1378243-73-2)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	75%

Chlorpheniramine (132-22-9) → Chlorpheniramine-N-oxide

Conditions	Yield
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane at -10℃; for 2h;	72.37%

thiourea (17356-08-0) + Chlorpheniramine (132-22-9) → 3-(4-thiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (1377320-76-7)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	67.7%

Chlorpheniramine (132-22-9) + monophenylthiourea (103-85-5) → 3-(4-phenylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (1378243-72-1)

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	67%

ethyl 2-cyanoacetate (105-56-6) + Chlorpheniramine (132-22-9) → C18H21N3

Conditions	Yield
Stage #1: ethyl 2-cyanoacetate; Chlorpheniramine With N-(2-methylnaphthalen-1-yl)-N’-(pyridin-2-ylmethyl)oxalamide; copper(I) bromide; sodium t-butanolate In isopropyl alcohol at 105℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With water In isopropyl alcohol at 105℃; for 12h; Schlenk technique; Inert atmosphere; Cooling;	66%

ethylenethiourea (1483-58-5) + Chlorpheniramine (132-22-9) → 3-(4-allylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine

Conditions	Yield
In isopropyl alcohol for 4h; Reflux;	65%

indole (120-72-9) + Chlorpheniramine (132-22-9) → (±)-3-(4-(1H-indol-3-yl)phenyl)-N,N-dimethyl-3-(pyridin-2-yl)propan-1-amine

Conditions	Yield
With Cy-DHTP*HBF4; palladium diacetate; lithium tert-butoxide In toluene at 20 - 110℃; for 49h; Inert atmosphere; Sealed tube;	53%

Chlorpheniramine (132-22-9) → chlorpheniramine-d4

Conditions	Yield
With deuterosulfonic acid In water-d2 at 120℃; for 6h;	50%

trifluoromethylsulfonic anhydride (358-23-6) + triphenylphosphine (603-35-0) + Chlorpheniramine (132-22-9) → (2-(1-(4-chlorophenyl)-3-(dimethylamino)propyl)pyridin-4-yl)triphenylphosphonium trifluoromethanesulfonate

Conditions	Yield
Stage #1: trifluoromethylsulfonic anhydride; Chlorpheniramine at -78℃; Inert atmosphere; Stage #2: triphenylphosphine Inert atmosphere; Cooling; Stage #3: Alkaline conditions; Inert atmosphere; regioselective reaction;	40%
at -78 - 20℃; Alkaline conditions;	40%

Chlorpheniramine (132-22-9) → 2-(4-chlorobenzoyl)pyridine (6318-51-0) + C16H17ClN2O (1449714-76-4)

Conditions	Yield
With copper(l) iodide; oxygen; acetic acid In dimethyl sulfoxide at 120℃; for 16h;	A 13% B 26%

Chlorpheniramine (132-22-9) + 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester (21085-72-3) → ((2R,3R,4S,5S,6S)-6-Carboxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-[3-(4-chloro-phenyl)-3-pyridin-2-yl-propyl]-dimethyl-ammonium; chloride (145823-27-4)

Conditions	Yield
With XAD-2 ion-exchange resin; sodium hydrogencarbonate In chloroform; water for 96h; Ambient temperature;	15%

Chlorpheniramine (132-22-9) → L-chlorpheniramine (32188-09-3)

Conditions	Yield
With C18H18O6

Chlorpheniramine (132-22-9) → (S)-chlorpheniramine

Conditions	Yield
Stage #1: Chlorpheniramine With sec.-butyllithium; (-)-sparteine In diethyl ether at -78℃; for 2h; Stage #2: With deuteromethanol at -78℃;

Upstream product

• 65676-21-3 chloropheniramine nitrile 
• 160911-84-2 1-(4-chlorophenyl-1-(2-pyridyl))ehylene 
• 140-53-4 p-chlorobenzyl cyanide 
• 73486-85-8 3-(4-chlorophenyl)-3-pyridin-2-yl-propan-1-ol 
• 124-40-3 dimethyl amine 
• 622-95-7 4-chlorobenzyl bromide 
• 110-86-1 pyridine 
• 158696-52-7 2-(4-Chloro-phenyl)-4-dimethylamino-butyraldehyde oxime 
• 158696-49-2 2-(4-Chloro-phenyl)-4-dimethylamino-butyraldehyde 
• 42817-51-6 p-Chloro-N,N-dimethylcinnamylamine 
• 233760-14-0 N,N-dimethyl-4-(p-chlorophenyl)-4-(2-pyridyl)-2-hydroxybutanamide 
• 233760-12-8 2-[1-(4-chloro-phenyl)-2-[1,3]dioxolan-2-yl-ethyl]-pyridine 
• 233760-10-6 3-(p-chlorophenyl)-4,4-diethoxybutanenitrile 
• 4350-41-8 2-(4-chlorobenzyl)pyridine 

Downstream Products

• 1108610-85-0 C₈Cl₂N₂O₂*C₁₆H₁₉ClN₂ 
• 113-92-8 chlorphenamine maleate 
• 120244-82-8 Chlorpheniramine-N-oxide 
• 6318-51-0 2-(4-chlorobenzoyl)pyridine 
• 1449714-76-4 C₁₆H₁₇ClN₂O 
• 1378243-72-1 3-(4-phenylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine 
• 1377320-76-7 3-(4-thiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine 
• 1378243-73-2 3-(4-methylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine 
• 1378243-75-4 3-(4-ethylthiocarbamidophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine 
• 25523-97-1 dexchlorpheniramine 
• 32188-09-3 L-chlorpheniramine 
• 145823-27-4 ((2R,3R,4S,5S,6S)-6-Carboxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-[3-(4-chloro-phenyl)-3-pyridin-2-yl-propyl]-dimethyl-ammonium; chloride 

Relevant articles and documents

Mass fragmentographic determination of d and l chlorpheniramine with aid of the stable isotope technique

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Novel synthetic method for chlorpheniramine maleate

The invention belongs to the field of medicinal chemistry, and specifically relates to a synthetic method for chlorphenamine maleate. The method provided by the invention comprises the following steps in sequence: (1) allowing p-cyanobenzylchloride to react with acetylene under the catalysis of a catalyst namely cobaltocene so as to generate p-chlorobenzyl pyridine; and (2) allowing p-chlorobenzyl pyridine to react with N,N-dimethyl chloroethane under the catalysis of sodium amide so as to generate chlorpheniramine, and subjecting chlorpheniramine and maleic acid to a neutralization reaction so as to generate chlorpheniramine maleate.

New synthetic route to N,N-disubstituted 3-aryl-3-pyridylpropylamines: Pheniramines from 3-aryl-3-(2-pyridyl)propanals

3-Aryl-3-(2-pyridyl)propanals 3, useful precursors compound for the H1 antihistaminic agents Pheniramines 1 were prepared following three different reaction pathways: the first one involves the rhodium catalyzed regiospecific hydroformylation of cinnamaldehyde acetals 4; the second one was carried out through the hydro-hydroxyacetamidation reaction on 1-aryl-1-(2-pyridyl)ethenes 2 followed by oxidative cleavage of the intermediate α-hydroxybutanamides 10; the third one was accomplished through alkylation of 2-benzylpyridines 12 with 2-bromomethyl-1,3-dioxolane 13 using LDA as deprotonating agent. The last preparative route showed to be the most convenient giving Pheniramine 1 up to 80 percent overall yield.