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{{drugbox
{{Drugbox
| IUPAC_name = 3-(2-chlorothioxanthen-9-ylidene)-N, N-dimethyl-propan-1-amine
| Watchedfields = changed
| image = Chlorprothixene.png
| verifiedrevid = 460033773
| IUPAC_name = ''(Z)''-3-(2-chlorothioxanthen-9-ylidene)-''N'',''N''-dimethyl-propan-1-amine
| image = Chlorprothixene structure.png
| width = 200
| image2 = Chlorprothixene3Dan.gif
| width2 = 180
 
<!--Clinical data-->
| tradename = 
| Drugs.com = {{drugs.com|CONS|chlorprothixene}}
| pregnancy_category = 
| legal_status = [[Legend drug]] (US), ℞
| routes_of_administration = Oral, IM
 
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = Hepatic
| elimination_half-life = 8–12 hours
| excretion = Feces, urine
 
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113-59-7
| CAS_number = 113-59-7
| ATC_prefix = N05
| ATC_prefix = N05
| ATC_suffix = AF03
| ATC_suffix = AF03
| ATC_supplemental =
| PubChem = 667467
| PubChem = 2729
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = APRD00718
| DrugBank = DB01239
| C = 18 | H = 18 | Cl = 1 | N = 1 | S = 1
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 580849
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9S7OD60EWP
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00790
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 50931
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 908
 
<!--Chemical data-->
| C=18 | H=18 | Cl=1 | N=1 | S=1  
| molecular_weight = 315.861 g/mol
| molecular_weight = 315.861 g/mol
| bioavailability = incomplete
| smiles = Clc2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN(C)C
| protein_bound =
| InChI = 1/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7-
| metabolism = hepatic
| InChIKey = WSPOMRSOLSGNFJ-AUWJEWJLBL
| elimination_half-life = 8 to 12 hours
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category = ?
| StdInChI = 1S/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7-
| legal_status = Rx-Only
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| routes_of_administration = oral (tablets, syrup, concentrate), intramuscular (seldom)
| StdInChIKey = WSPOMRSOLSGNFJ-AUWJEWJLSA-N
| excretion = feces and urine }}
}}
'''Chlorprothixene''' is a [[typical antipsychotic]] drug of the [[thioxanthene]] class. It has a low [[antipsychotic]] potency (half to 2/3 of [[chlorpromazine]]). Its principal indications are the treatment of [[psychotic disorder]]s (e.g. [[schizophrenia]]) and of acute [[mania]] occurring as part of [[bipolar disorder]]s.  
__Notoc__
{{SI}}
{{CMG}}
==Overview==
 
'''Chlorprothixene''' ('''Cloxan''', '''Taractan''', '''Truxal''') is a [[typical antipsychotic]] [[drug]] of the [[thioxanthene]] class and was the first of the series to be synthesized.<ref name="isbn0-674-03958-0">{{cite book | author = Healy, David | title = The antidepressant era | publisher = Harvard University Press | location = Cambridge | year = 1997 | page = 182 | isbn = 0-674-03958-0 | oclc = | doi = | url = http://books.google.com/books?id=6lpHd_P4VOsC&lpg=RA2-PA182&dq=chlorprothixene%20antidepressant&as_brr=3&pg=RA2-PA182#v=onepage&q=chlorprothixene%20antidepressant&f=false}}</ref> It was introduced in 1959 by [[Lundbeck]].<ref name="isbn0-471-89980-1">{{cite book | author = Sneader, Walter | title = Drug discovery: a history | publisher = Wiley | location = New York | year = 2005 | page = 410 | isbn = 0-471-89980-1 | oclc = | doi = | url = http://books.google.com/books?id=Cb6BOkj9fK4C&lpg=PA410&dq=chlorprothixene%20introduced%201958&pg=PA410#v=onepage&q=chlorprothixene%20introduced%201958&f=false}}</ref>
 
Chlorprothixene is not approved for use in the United States.
 
== Pharmacology ==
 
Chlorprothixene exerts strong [[receptor antagonist|antagonism]] at the following [[receptor (biochemistry)|receptor]]s:
 
* [[5-HT2 receptor|5-HT<sub>2</sub>]]: antipsychotic effects, anxiolysis, weight gain
* [[D1 receptor|D<sub>1</sub>]], [[D2 receptor|D<sub>2</sub>]], [[D3 receptor|D<sub>3</sub>]]: antipsychotic effects, sedation, extrapyramidal side effects, prolactin increase, depression, apathy/anhedonia, weight gain
* [[H1 receptor|H<sub>1</sub>]]: sedation, weight gain
* [[Muscarinic acetylcholine receptor|mACh]]: anticholinergic effects, inhibition of extrapyramidal side effects
* [[Alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic]]: hypotension, tachycardia
 
Chlorprothixene does also act as [[FIASMA]] (functional inhibitor of [[Sphingomyelin phosphodiesterase|acid sphingomyelinase]]).<ref name="pmid18504571">{{cite journal |author=Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P|title=Identification of novel functional inhibitors of acid sphingomyelinase|journal=PLoS ONE|volume=6|issue=8|pages=e23852|year=2011|doi=10.1371/journal.pone.0023852|pmid=21909365|pmc=3166082}}</ref>


The drug was introduced 1959 to the market on a global scale and is hence a first generation antipsychotic with 45+ years of clinical experience. It is still today of clinical and also some research interest.
== Indications ==


==Mechanisms of action==
Chlorprothixene's principal indications are the treatment of [[psychotic disorder]]s (e.g. [[schizophrenia]]) and of acute [[mania]] occurring as part of [[bipolar disorder]]s.
Chlorprothixene exerts strong blocking effects at the following postsynaptic receptors:
* 5-HT2 : anxiolysis, antipsychotic effects
* D1, D2, D3 : antipsychotic effects
* H1 : sedation, weight gain
* muscarinic : anticholinergic side effects, extrapyramidal side effects attenuated
* Alpha1 : hypotension, tachycardia


==Uses==
Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of [[selective serotonin reuptake inhibitor]]s for [[clinical depression|depression]] and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.
Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of [[selective serotonin reuptake inhibitor]]s for [[clinical depression|depression]] and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.  


An intrinsic [[antidepressant]] effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) [[analgesic]] effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has [[antiemetic]] effects.
An intrinsic [[antidepressant]] effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) [[analgesic]] effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has [[antiemetic]] effects.


==Side effects==
== Side effects ==
Chlorprothixene has a strong sedative activity with a high incidence of [[anticholinergic]] side effects. The types of side effects encountered (dry mouth, massive [[hypotension]] and [[tachycardia]], [[hyperhidrosis]], substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.


Chlorprothixene is structurally related to chlorpromazine, with which it shares in principal all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle [[glaucoma]], severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.
Chlorprothixene has a strong sedative activity with a high incidence of [[anticholinergic]] side effects. The types of side effects encountered (dry mouth, massive [[hypotension]] and [[tachycardia]], [[hyperhidrosis]], substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.


Early and late [[extrapyramidal system|extrapyramidal side effects]] may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).
Chlorprothixene is structurally related to [[chlorpromazine]], with which it shares, in principle, all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle [[glaucoma]], severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.


==Dosage==
Early and late [[Extrapyramidal symptoms|extrapyramidal side effects]] may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).
In any case, the initial doses of chlorprothixene should be as low as possible (e.g. 30 mg at bedtime, 15 mg morning dose) and be increased gradually. Patients receiving 90 mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800 mg daily which can usually not be given due to side effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly.  


On the right table are some guidelines given for daily dosages as follows (dependent on the clinical situation). Some reflect extended clinical experience from decades of usage.  
===Overdosage===
Overdose symptoms can be confusion, hypotension, and tachycardia, and several fatalities have been reported with concentrations in postmortem blood ranging from 0.1 to 7.0 mg/L compared to non-toxic levels in postmortem blood which can extend to 0.4 mg/kg. <ref name="Skov 2015 41-44">{{cite journal | author = Skov L, Johansen SS, Linnet K | title = Postmortem Femoral Blood Reference Concentrations of Aripiprazole, Chlorprothixene, and Quetiapine | journal = Journal of Analytical Toxicology | volume = 39 | issue = 1 | pages = 41–44 | date = Jan 2015  | doi = 10.1093/jat/bku121 }}</ref>


{| border="1" cellpadding="3" cellspacing="0" width="250px" align="right" style="border-collapse: collapse; margin: 0 0 0 0.5em"
== Dosage ==
|-
| bgcolor="#ffffff" align="center" colspan="2" |
|-
| bgcolor="#eeeeee" | schizophrenia
| bgcolor="#ddeeff" | 100 mg to 200 mg
|-
| bgcolor="#eeeeee" | exogenic psychosis (e.g. drug psychosis)
| bgcolor="#ddeeff" | 100 mg to 200 mg
|-
| bgcolor="#eeeeee" | acute mania
| bgcolor="#ddeeff" | 45 mg to 150 mg
|-
| bgcolor="#eeeeee" | agitated depressions
| bgcolor="#ddeeff" | 45 mg to 150 mg
|-
| bgcolor="#eeeeee" | alcohol- and drug-withdrawal
| bgcolor="#ddeeff" | 50 mg to 150 mg
|-
| bgcolor="#eeeeee" | non-psychotic agitation and anxiety
| bgcolor="#ddeeff" | 30 mg to 150 mg
|-
| bgcolor="#eeeeee" | acute reactive state to stress/trauma
| bgcolor="#ddeeff" | 30 mg to 100 mg
|-
| bgcolor="#eeeeee" | [[psychoneurosis|psychoneurotic]] states
| bgcolor="#ddeeff" | 30 mg to 100 mg
|-
| bgcolor="#eeeeee" | insomnia
| bgcolor="#ddeeff" | 15 mg to 100 mg
|-
| bgcolor="#eeeeee" | cotreatment of severe chronic pain
| bgcolor="#ddeeff" | 30 mg daily initial, increasing to 60 or 90 mg (max. 120 mg)
|-
|}


If chlorprothixene is to be withdrawn, it should not be stopped abruptly, but the dose should be decreased steadily.
The initial doses of chlorprothixene should always be as low as possible (e.g. 30&nbsp;mg at bedtime, 15&nbsp;mg morning dose) and be increased gradually. Patients receiving 90&nbsp;mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800&nbsp;mg daily which can usually not be given due to side effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly. If chlorprothixene is to be withdrawn, it should not be stopped abruptly, but the dose should be decreased steadily.


==Additional remarks==
== Interactions ==
Chlorprothixene may be particularly useful in the clinical setting, when the patient is under strict control. [[Blood pressure]] (at least daily), [[Electrocardiogram|EKG]] and standard laboratory (blood cell counts, liver and kidney tests) should be monitored/assessed in close intervals during therapy as good clinical practice dictates.


==Important interactions==
Chlorprothixene may increase the plasma-level of concomitantly given [[lithium]]. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.
Chlorprothixene may increase the plasma-level of concomitantly given [[lithium]]. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.


If chlorprothixene is given concomitantly with [[opioid]]s, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.
If chlorprothixene is given concomitantly with [[opioid]]s, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.


Avoid the concomitant use of chlorprothixene and [[tramadol]] (Ultram®). Massive seizures may be encountered with this combination.
Avoid the concomitant use of chlorprothixene and [[tramadol]] (Ultram). Seizures may be encountered with this combination.


Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with [[benzodiazepine]]s or [[barbiturate]]s. Choose particular low doses of these drugs.
Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with [[benzodiazepine]]s or [[barbiturate]]s. Choose particular low doses of these drugs.


Exert particular caution in combining chlorprothixene with other anticholinergic drugs ([[tricyclic antidepressant]]s and [[antiparkinsonian]] agents): Particularly the elderly may develop delirium, high fever, severe [[obstipation]], even [[ileus]] and glaucoma.
Exert particular caution in combining chlorprothixene with other anticholinergic drugs ([[tricyclic antidepressant]]s and [[antiparkinsonian]] agents): Particularly the elderly may develop delirium, high fever, severe [[obstipation]], even [[ileus]] and glaucoma .
 
==Synthesis==
Chlorprothixene (2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene) is made starting from
[[2-Chlorothioxanthone]]. 2-Chlorothioxantone, in turn, is prepared from 2-mercaptobenzoic acid ('''1'''), the reaction of which with 1-bromo-4-chlorobenzene ('''2''') forms 2-(4-chlorophenylthio)benzoic acid '''5''', which upon reaction with [[phosphorus pentachloride]] transforms into acid chloride ('''6'''), and further undergoes intramolecular cyclization with the use of [[aluminum chloride]] to give 2-chlorthioxantone ('''6''').<ref>H. Spiegelberg, K. Doeben, {{Cite patent|DE|1044103}} (1957).</ref>
 
An alternative way of making 2-chlorthioxantone ('''7''') is by making 2-(4-chlorophenylthio)benzoic acid ('''5''') by reacting 2-iodobenzoic acid ('''3''') with 4-chlorothiophenol ('''4''').<ref>E.L. Engelhardt, J.M. Sprague, {{US Patent|2951082}} (1960).</ref>
[[File:2-Chlorothioxantone synthesis.svg|thumb|center|700px|2-Chlorothioxantone synthesis: {{Cite patent|DE|1044103}} {{US patent|2951082}}]]
 
The resulting 2-chlorothioxantone is reacted as a [[carbonyl]] component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohols '''8''', and '''9'''.


==Trade names==
[[File:Chlorprothixene synth.png|400px|center|thumb|Chlorprothixene synthesis:{{US Patent|3116291}} {{Cite patent|DE|1168446}} {{Cite patent|DE|1418517}}]]
Chlorprothixene is marketed under the brand names Taractan® and Truxal®.
Dehydration of the tertiary ('''8''') is accomplished by [[acylation]] of the tertiary hydroxyl group using [[acetyl chloride]] and the subsequent [[pyrolysis]] of the formed acetate, which leads to the desired chlorprothixene. In the second case, dehydration of the tertiary alcohol ('''9''') is accomplished by chlorination of the tertiary alcohol group by [[thionyl chloride]], forming the diene 2-chloro-9-(3-propen-1-iliden)thioxanthene ('''10'''), the addition to which of [[dimethylamine]] at high temperature forms the desired chlorprothixene ('''11''').


==See also==
== See also ==
* [[Typical antipsychotic]]
* [[Typical antipsychotic]]
* [[Thioxanthene]]
* [[Thioxanthene]]
*[[Chlorpromazine]]
== References ==
{{Reflist|2}}
{{Refimprove|date=February 2010}}


==References==
* [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=151364&namedisopt=&ncount=38#Synonyms PubChem Substance Summary: Chlorprothixene] National Center for Biotechnology Information.
* ''Psychopharmakotherapie in Klinik und Praxis'' (German), Schattauer Verlag, 1998. ISBN 3-7945-1842-X
* [http://norge.lundbeck.com/Norway/ForProfessionals/OurProducts/Truxal_bro_trykklar.pdf Truxal Prescribing Information] (PDF) Lundbeck Norge.
{{Antipsychotics}}
{{Antipsychotics}}
{{Adrenergics}}
{{Cholinergics}}
{{Dopaminergics}}
{{Histaminergics}}
{{Serotonergics}}
{{Tricyclics}}


<!--[[es:Clorprotixeno]]-->
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[[Category:Thioxanthene antipsychotics]]
[[Category:Typical antipsychotics]]
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Revision as of 17:53, 9 April 2015

Chlorprothixene
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administration		Oral, IM
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MetabolismHepatic
Elimination half-life8–12 hours
ExcretionFeces, urine
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E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC18H18ClNS
Molar mass315.861 g/mol
3D model (JSmol)
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Chlorprothixene (Cloxan, Taractan, Truxal) is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized.[1] It was introduced in 1959 by Lundbeck.[2]

Chlorprothixene is not approved for use in the United States.

Pharmacology

Chlorprothixene exerts strong antagonism at the following receptors:

  • 5-HT2: antipsychotic effects, anxiolysis, weight gain
  • D1, D2, D3: antipsychotic effects, sedation, extrapyramidal side effects, prolactin increase, depression, apathy/anhedonia, weight gain
  • H1: sedation, weight gain
  • mACh: anticholinergic effects, inhibition of extrapyramidal side effects
  • α1-adrenergic: hypotension, tachycardia

Chlorprothixene does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[3]

Indications

Chlorprothixene's principal indications are the treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occurring as part of bipolar disorders.

Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of selective serotonin reuptake inhibitors for depression and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.

An intrinsic antidepressant effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) analgesic effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has antiemetic effects.

Side effects

Chlorprothixene has a strong sedative activity with a high incidence of anticholinergic side effects. The types of side effects encountered (dry mouth, massive hypotension and tachycardia, hyperhidrosis, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.

Chlorprothixene is structurally related to chlorpromazine, with which it shares, in principle, all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle glaucoma, severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.

Early and late extrapyramidal side effects may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).

Overdosage

Overdose symptoms can be confusion, hypotension, and tachycardia, and several fatalities have been reported with concentrations in postmortem blood ranging from 0.1 to 7.0 mg/L compared to non-toxic levels in postmortem blood which can extend to 0.4 mg/kg. [4]

Dosage

The initial doses of chlorprothixene should always be as low as possible (e.g. 30 mg at bedtime, 15 mg morning dose) and be increased gradually. Patients receiving 90 mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800 mg daily which can usually not be given due to side effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly. If chlorprothixene is to be withdrawn, it should not be stopped abruptly, but the dose should be decreased steadily.

Interactions

Chlorprothixene may increase the plasma-level of concomitantly given lithium. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.

If chlorprothixene is given concomitantly with opioids, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.

Avoid the concomitant use of chlorprothixene and tramadol (Ultram). Seizures may be encountered with this combination.

Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with benzodiazepines or barbiturates. Choose particular low doses of these drugs.

Exert particular caution in combining chlorprothixene with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma .

Synthesis

Chlorprothixene (2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene) is made starting from 2-Chlorothioxanthone. 2-Chlorothioxantone, in turn, is prepared from 2-mercaptobenzoic acid (1), the reaction of which with 1-bromo-4-chlorobenzene (2) forms 2-(4-chlorophenylthio)benzoic acid 5, which upon reaction with phosphorus pentachloride transforms into acid chloride (6), and further undergoes intramolecular cyclization with the use of aluminum chloride to give 2-chlorthioxantone (6).[5]

An alternative way of making 2-chlorthioxantone (7) is by making 2-(4-chlorophenylthio)benzoic acid (5) by reacting 2-iodobenzoic acid (3) with 4-chlorothiophenol (4).[6]

File:2-Chlorothioxantone synthesis.svg
2-Chlorothioxantone synthesis: DE 1044103  U.S. Patent 2,951,082

The resulting 2-chlorothioxantone is reacted as a carbonyl component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohols 8, and 9.

Chlorprothixene synthesis:Template:US Patent DE 1168446  DE 1418517 

Dehydration of the tertiary (8) is accomplished by acylation of the tertiary hydroxyl group using acetyl chloride and the subsequent pyrolysis of the formed acetate, which leads to the desired chlorprothixene. In the second case, dehydration of the tertiary alcohol (9) is accomplished by chlorination of the tertiary alcohol group by thionyl chloride, forming the diene 2-chloro-9-(3-propen-1-iliden)thioxanthene (10), the addition to which of dimethylamine at high temperature forms the desired chlorprothixene (11).

See also

References

  1. ↑ Healy, David (1997). The antidepressant era. Cambridge: Harvard University Press. p. 182. ISBN 0-674-03958-0.
  2. ↑ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1.
  3. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE. 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365.
  4. ↑ Skov L, Johansen SS, Linnet K (Jan 2015). "Postmortem Femoral Blood Reference Concentrations of Aripiprazole, Chlorprothixene, and Quetiapine". Journal of Analytical Toxicology. 39 (1): 41–44. doi:10.1093/jat/bku121.
  5. ↑ H. Spiegelberg, K. Doeben, DE 1044103  (1957).
  6. ↑ E.L. Engelhardt, J.M. Sprague, Template:US Patent (1960).

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