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Amitriptyline

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Amitriptyline Basic information

Product Name:
Amitriptyline
Synonyms:
  • 5-(3-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,d)cycloheptatriene
  • 5-(3-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,d)cycloheptene
  • 5-(3-dimethylaminopropylidene)-10,11-dihyro-5h-dibenzo(a,d)cycloheptene
  • 5-(3'-Dimethylaminopropylidene)-dibenzo-(a,d)(1,4)-cycloheptadiene
  • 5-(3-Dimethylpropylidene)dibenzo(a,d)(1,4)cycloheptadiene
  • 5-(gamma-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,d)cycloheptene
  • 5-(gamma-Dimethylaminopropylidene)-5H-dibenzo(a,d)-10,11-dihydrocycloheptene
  • 5-(gamma-Dimethylaminopropylidene)-5H-Dibenzo[a,d][1,4]cycloheptadiene
CAS:
50-48-6
MF:
C20H23N
MW:
277.4
EINECS:
200-041-6
Mol File:
50-48-6.mol
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Amitriptyline Chemical Properties

Melting point:
196-197°C
Boiling point:
410.26°C (rough estimate)
Density 
0.9415 (rough estimate)
refractive index 
1.7500 (estimate)
pka
9.4(at 25℃)
Water Solubility 
9.7 mg/mL
CAS DataBase Reference
50-48-6(CAS DataBase Reference)
NIST Chemistry Reference
Amitriptyline(50-48-6)
EPA Substance Registry System
Amitriptyline (50-48-6)
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Safety Information

HazardClass 
IRRITANT
Hazardous Substances Data
50-48-6(Hazardous Substances Data)
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Amitriptyline Usage And Synthesis

Originator

Elavil HCl Merck Sharp and,Dohme,US,1961

Uses

Antidepressant.

Uses

Amitriptyline is used for anxious-depressive conditions. It is easier to tolerate than imipramine.

Definition

ChEBI: An organic tricyclic compound that is 10,11-dihydro-5H-dibenzo[a,d][7]annulene substituted by a 3-(dimethylamino)propylidene group at position 5.

Manufacturing Process

Phthalic anhydride is reacted with phenylacetic acid to form 3- benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d]cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(γ- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene.
Then, as described in US Patent 3,205,264, a solution of 5-(γ- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene (42 grams; 0.153 mol) in 105 ml of ethanol is hydrogenated over Raney nickel (1.5 grams) at 65°C under an initial hydrogen pressure of 450 lb. After 1 mol of hydrogen is absorbed (3.5 hours), the reaction mixture is filtered to remove the catalyst and is acidified with 80 ml of 2.5 N hydrochloric acid (0.2 mol). The acidic solution is concentrated to dryness under vacuum and is flushed three times with 100 ml of benzene to remove residual water. The solid residue then is dried under vacuum at 40°C to yield 44.9 grams (94% of theory) of the product, MP 187-189.5°C, equivalent weight 307, ultraviolet absorption A% 2380432. Recrystallization from isopropyl alcohol and ether affords the product in high purity.
In practice it is usually used as hydrochloride.

brand name

Elavil (AstraZeneca); Endep (Roche);Ami-anelun;Amilent;Amilit-ifi;Aminiurin;Amitimid;Amitriptol;Amyline;Amyzol;Annolytin;Apo-amitriptylline;Apo-pram;Deprelio;Deprestal;Diapatal;Elatrolet;Elavil plus;Emitrip;Enovil;Entrafon-210;Entrafon-2-10;Entrafon-2-25;Entrafon-a;Entrafon-forte;Etarfon;Etrafon-a;Etrafon-forte;Laroxal;Larozyl;Levate;Limbatarail;Limbatral;Limbitryl;Limitrol;Longopax;Loxaryl;Mareline;Meravil;Muaban d;Mutaban a/d/f;Nobrital;Novotriptyn;Novotryptin;Novo-tryptin;Parks-plus;Pms levazine;Prouvil;Saratem;Sarotena;Sedans;Sylvemid;Tensorelax;Teperin;Trepiline;Trepulin;Triptizol;Triptonal;Triptpane;Trivial-4-10.

Therapeutic Function

Antidepressant

World Health Organization (WHO)

Amitriptyline, a tricyclic antidepressant was introduced in 1961 for the management of endogenous depression and is listed in the 8th WHO Model List of Essential Drugs. Much of the adverse effects are caused by its antimuscarinic actions. These include dry mouth, cardiac arrhythmias, central nervous system disturbances, blood disorders and risk of suicide. The risk of suicide and dangers related to overdosage led the Norwegian Medicines Control Authority to put the higher strength formulation under prescribing restriction in 1992. The risk of death following overdosage is apparently higher for products containing tricyclic compounds as compared with nontricyclic products.

Biological Functions

Amitriptyline is a tertiary amine dibenzocycloheptadiene TCA with a propylidene side chain extending from the central carbocyclic ring. The diarylpropylideneamine moiety for amitriptyline makes it sensitive to photo-oxidation; therefore, its hydrochloride solutions should be protected from light to avoid ketone formation and precipitation.

Pharmacokinetics

Amitriptyline is rapidly absorbed from the GI tract and from parenteral sites.Amitriptyline and its active metabolite, nortriptyline, are distributed into breast milk. Amitriptyline is primarily (65%) metabolized by N-demethylation by CYP2D6 to nortriptyline and hydroxylation to its E-10-hydroxy metabolite. Nortriptyline is pharmacologically active as a secondary amine TCA. Amitriptyline shows approximately equal affinity for 5-HT and NE transporters.

Synthesis

Amitriptyline, 5-(3-dimethylaminopropyliden)-10,11-dihydrodibenzocycloheptene (7.1.4), differs from imipramine in that the nitrogen atom in the central part of the tricyclic system is replaced by a carbon, which is bound to a side chain by a double bond. Amitriptyline (7.1.4) is synthesized by interaction of 10,11-dihydro-N,N-dimethyl- 5H-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropylmagnesium bromide and the subsequent dehydration of the resulting tertiary alcohol (7.1.3) using hydrochloric acid [6–11].

An alternative way of synthesis of amitriptyline is by interaction of 10,11-dihydro-N,Ndimethyl-5H-dibenzo[a,d]-cyclohepten-5-one with cyclopropylmagnesium bromide, giving 10,11-dihydro-N,N-dimethyl-5H-dibenzo[a,d]-cyclohepten-5-cyclopropyl-5-ol (7.1.5). Reacting this with hydrogen bromide in acetic acid results in an opening of the cyclopropyl ring, which forms 5-(3-bromopropyliden)-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene (7.1.6). Alkylating this with dimethylamine gives amitriptyline (7.1.4) [12,13].

Amitriptyline Preparation Products And Raw materials

Preparation Products

AmitriptylineSupplier

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