Serotonin → Desvenlafaxine

HRID 1496807Notes

Reaction equation

HRID 1496807 reaction equation
[CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].OC1C=C2C(NC=C2CCN)=CC=1.C1C([C@@H](O)CN)=CC(O)=C(O)C=1>>[CH3:3][N:2]([CH3:1])[CH2:4][CH:5]([C:14]1([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1

Participants

4

Reactant 3

HCID 5202Serotonin2×HCID 5656Venlafaxine3×HCID 439260Norepinephrine2×

Product 1

HCID 125017Desvenlafaxine

Procedure

It is reported that venlafaxine of formula (II), 1-[2-dimethylamino-1-(4-methoxylphenyl)ethyl]cyclohexanol, is a reuptake inhibitor of 5-hydroxytryptamine (5-HT) and norepinephrine (NA), and is widely used for inhibiting reuptake of 5-hydroxytryptamine (5-HT) and norepinephrine (NA) and treating or adjuvantly treating central nervous system diseases such as depression. Venlafaxine is metabolized in liver to form a strongly active metabolite of formula (III), 1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, a weakly active metabolite of formula (IV), 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol, and a metabolite of formula (V), 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, in which the metabolite (III) and venlafaxine have the same therapeutic effects (see U.S. Pat. No. 4535186A, US20040176468A1, US20040147601A1, US20030191347A1). Moreover, the direct uptake of the metabolite (III) for treating central nervous system diseases, especially, depression, has the advantages of using a single active compound, facilitates the adjustment of dosage and therapeutic effects, alleviates side-effects, and reduces the risk of interaction with other drugs (see U.S. Pat. No. 6673838B2). However, because of the presence of more hydroxyl groups, the metabolite (III) has increased hydrophilicity, thus decreasing absorption rate via oral or transdermal routes of administration and possibly increasing pre-system side effects of unabsorbed drugs. In order to overcome the above defects of the metabolite (III), a series of derivatives represented by formula (VI) were synthesized. These compounds of formula (VI), which are prodrugs of the metabolite (III), were shown to have metabolized in vivo to produce the metabolite (III), thereby exhibiting therapeutic effects (see Chinese Patent No. CN1955159A, CN1706813A). Chinese Patent No. CN1955159A discloses a compound of formula (I), 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, and a method for preparing the same. The compound of formula (I), as described in CN1955159A, is a white crystalline solid with a melting point of 203.2° C.-206.5° C.

Workup

  1. additiontreating
  2. additionadjuvantly treating central nervous system diseases such as depression

Sources & evidence

ORD record
ord-06b6f73015f64c70bc941a15ea2784c4
Source dataset
uspto-grants-2015_12
Patent number
US09199912B2

Reaction notes

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