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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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  • Molecular FormulaC28H27ClF5NO
  • Average mass523.965 Da
CAS Registry Number: 26864-56-2
CAS Name: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
Additional Names: 1-[4,4-bis(p-fluorophenyl)butyl]-4-(4-chloro-a,a,a-trifluoro-m-tolyl)-4-piperidinol; 1-(4,4-bis(4-fluorophenyl)butyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine
Manufacturers’ Codes: R-16341
MCN-JR-16,341 / R 16,341
Trademarks: Semap (Janssen)
Molecular Formula: C28H27ClF5NO
Molecular Weight: 523.97
Percent Composition: C 64.18%, H 5.19%, Cl 6.77%, F 18.13%, N 2.67%, O 3.05%
Literature References: Prepn: H. K. F. Hermans, C. J. E. Niemegeers, DE 2040231eidem, US 3575990 (both 1971 to Janssen); Sindelár et al., Collect. Czech. Chem. Commun. 38, 3879 (1973). Pharmacology and toxicology: Janssen et al., Eur. J. Pharmacol.11, 139 (1970). Crystal structure: Koch, Acta Crystallogr. 29B, 1538 (1973).
Properties: White, microcrystals, mp 105-107°. Slightly sol in water, dil HCl (<0.5 mg/ml). LD50 orally in mice (day 7): 86.8 mg/kg (Janssen).
Melting point: mp 105-107°
Toxicity data: LD50 orally in mice (day 7): 86.8 mg/kg (Janssen)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic.
Penfluridol (SemapMicefalLongoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic.[1] It was discovered at Janssen Pharmaceutica in 1968.[2] Related to other diphenylbutylpiperidine antipsychotics, pimozide and fluspirilene, penfluridol has an extremely long elimination half-life and its effects last for many days after single oral dose. Its antipsychotic potency, in terms of dose needed to produce comparable effects, is similar to both haloperidol and pimozide. It is only slightly sedative, but often causes extrapyramidal side-effects, such as akathisiadyskinesiae and pseudo-Parkinsonism. Penfluridol is indicated for antipsychotic treatment of chronic schizophrenia and similar psychotic disorders, it is, however, like most typical antipsychotics, being increasingly replaced by the atypical antipsychotics. Due to its extremely long-lasting effects, it is often prescribed to be taken orally as tablets only once a week (q 7 days). The once-weekly dose is usually 10–60 mg. A 2006 systematic review examined the use of penfluridol for people with schizophrenia:
Penfluridol compared to typical antipsychotics (oral) for schizophrenia[3]
Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The effectiveness and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for people with long-term schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.[3]


    • ATC:N05AG03
  • Use:neuroleptic
  • Chemical name:1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
  • Formula:C28H27ClF5NO
  • MW:523.97 g/mol
  • CAS-RN:26864-56-2
  • EINECS:248-074-5
  • LD50:87 mg/kg (M, p.o.);
    160 mg/kg (R, p.o.)



Late stage functionalization of secondary amines via a cobalt-catalyzed electrophilic amination of organozinc reagents
Org Lett 2019, 21(2): 494

Scheme 6

Scheme 6. A New Synthesis of Penfluridol 5
str1 str2

English: DE patent 2040231

US patent 3575990


File:Penfluridol synthesis.png



    • US 3 575 990 (Janssen; 20.4.1971; appl. 3.9.1969).
    • DOS 2 040 231 (Janssen; appl. 13.8.1970; USA-prior. 3.9.1969).
  • alternative synthesis:

    • FR-appl. 2 161 007 (Janssen; appl. 23.11.1972; J-prior. 25.11.1971).


Although Penfluridol listed for many years, but its chemical preparation technology abroad little studied in the earlier literature, there are several prepared as follows:

[0013] Process (a): 1971 Document Ger.0ffen [P], 2040231, (1971) Hermans.HKF first reported Penfluridol chemical synthesis, which process is as follows:


Figure CN106187863AD00101

[0015] The process of cyclopropyl methanol (ΙΠ) by 4,4, _-difluorophenyl-one ([pi) as a starting material, the reaction of cyclopropyl magnesium bromide-bis 4- (fluorophenyl), then the reaction with thionyl chloride to give 1,1_-bis (4-fluorophenyl) -4-chloro-butene (IV), obtained by catalytic hydrogenation 1,1_-bis (4-phenyl gas) burning chlorobutanol _4_ (V), and finally with 4-chloro-3-methylphenyl gas-4-piperidinol (X VH) in methyl isobutyl ketone was refluxed for three days the reaction to produce Penfluridol (the I), Document: al, Collect Czech.Chem.Commun [J], 38 (12): 3879-3901, (1973).

[0016] In the above process, starting material and documentation of cyclopropyl magnesium bromide hardly prepared each reaction were not reported preparation yield, and therefore Document Sindelar · K · et al, Collect Czech · Chem · Commun [ J], 38 (12):. 3879-3901, (1973) that this technology is not very good.

[0017] Process (b): 1973, Sindelar.K successful research and the following other technology, which process is as follows:


Figure CN106187863AD00111

[0019] The process consists of 4,4_-bis (4-fluorophenyl) butoxy alkyl iodide as a starting material, 4,4_ ethylenedioxythiophene condensing piperidone removal of generated hydrogen iodide in N-pentanone – [4,4-bis (4-fluorophenyl) butoxy group] -4,4-dioxo-condensing vinyl piperidone, N-then obtained by acid hydrolysis [4,4-bis (4-fluorophenyl ) azetidinyl] -4-piperidone (W), the compound (W) with 4-chloro-3-trifluoromethyl phenyl magnesium bromide reacted Penfluridol (I).

[0020] This process route may seem simple, but there are more desired to prepare intermediates, the process is more complex, with low yields reported in the literature.

[0021] Process (c): as follows:


Figure CN106187863AD00121

[0023] In this process, 4-chloro – (4-fluorophenyl) butyryl-one (Shan) starts, 4-fluorophenyl magnesium bromide reacts with 4-chloro – bis (4-fluorophenyl) butanol ( IX), and then boiling the reaction hydroiodic acid to give 4-iodo-in, red phosphorus catalyst – bis (4-fluorophenyl) butoxy left foot and finally burning ^^ – ^ – methyl ^ two gas – chlorophenyl Bu ‘piperidinol prepared products San ^ top five gas profitable ⑴.

[0024] This synthesis has the characteristics of high yield, but the intermediate (IX), (X) quality is not purified, many by-products, difficult to control the quality of products, and hydroiodic acid to be used, the source of raw material is difficult, therefore, not ideal technology.

[0025] Process (d), as follows:


Figure CN106187863AD00131

[0027] The process begins by Stobber reaction with 4,4 – fluorophenyl ketone reaction product diethyl succinate and compound (XI), and then generates bis (4-fluorophenyl) methine acid or base hydrolysis after succinic acid (M), by catalytic hydrogenation to give 4,4_-bis (4-fluorophenyl) butanoic acid after, the reaction with thionyl chloride without isolating the compound (XIV) with the compound directly (XW), by reduction after obtain the final product – Penfluridol. The disadvantage of this process is that, in the above reaction step, Stobber the reaction yield is low; hydrogenation catalyst manufacturing operation more difficult and unsafe; reaction with thionyl chloride, large air pollution, and other refractory.

[0028] The various preparation techniques Penfluridol other drug earlier British Patent Brit. 1141664 and German patent Ger. Off en. 2040231 has been reported, but no other foreign patent reports. In neither country has patent coverage, and no magazine reported.

 The reaction formula is as follows:


Figure CN106187863AD00151

[0059] Step (5), the preparation of compounds of formula (XW) as shown, may be employed a method reported in the literature, or prepared using a method specifically includes the following steps:


Figure CN106187863AD00161

0124] (6) Penfluridol drug (I) were prepared:


Figure CN106187863AD00221

[0126] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a calcium chloride tube, was added 250ml of anhydrous diethyl ether, 2 · 4g (0 · 0631mol) tetrahydro lithium aluminum hydride, stirring was started, was added 20g (0 · 0372mol) amide (6), the addition was completed, 38 ° C for 6 hours.

[0127] completion of the reaction, water was added 4.2ml decomposition for 25 minutes, followed by addition of 5.4ml of 20% by weight concentration of sodium hydroxide solution decomposition for 20 minutes, 14.2ml decomposed with water for 15 minutes;

[0128] The decomposition was filtered, the filtrate (ethyl ether) and dried over anhydrous potassium carbonate. Filtered, the filter cake was washed with a little ether. The filtrate and the washings added to a distillation flask, recovery ether atmospheric distillation, vacuum drained, was added a mixed solvent l〇〇ml [chloroform: petroleum ether (60-90 ° C) = 1: 4, weight ratio, stirred and heated to reflux dissolution, filtered while hot, the filtrate was allowed to stand for crystallization at about 10 ° C, to be naturally deposited crystal after freezing -5 ° C overnight, filtered, the cake was washed with a mixed solvent, drain, ventilation pressure at 70 ° C dried to constant weight to give white crystalline product Penfluridol drug (I), mp 105-107 ° C, yield 81.5%.

[0129] Intermediate 4_ (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (XW) (referred piperidinol) Preparation:

[0130] (1) benzylamine (Beta) Preparation:


Figure CN106187863AD00222

[0132] equipped with a mechanical stirrer, a condenser, a thermometer 2000ml three reaction bottle, were added ammonium bicarbonate 240g (3.04mol), aqueous ammonia at a concentration of 20 wt %% of 15148 (17.812111〇1,

[0133] 1640ml), benzyl chloride 80g (0.632mol), reaction was stirred for 6 hours.Reaction to complete rested stratification. Aqueous layer was separated, and aqueous ammonia recovery bicarbonate atmospheric heating to 100 ° c, the water was distilled off under reduced pressure, with 50% sodium hydroxide PH12 above, extraction with benzene and dried solid sodium hydroxide. Recovery of benzene atmospheric distillation, vacuum distillation, collecting 33.4 g of the product obtained, yield 50.7%, content 99%,


Figure CN106187863AD00223

[0135] (3) N_ benzyl – bis ([beta] methoxycarbonyl-ethyl) amine (C) (referred to as diester thereof):


Figure CN106187863AD00231

[0137] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 250ml, 43g methyl acrylate (0.5111〇1) methanol 328 (401111), was added with stirring 21.48 benzylamine (0.2111〇1), The reaction was stirred for 7 hours. Completion of the reaction, recovery of excess methyl acrylate and methanol, water chestnut vacuum distillation until the internal temperature l〇〇-ll〇 ° C, to give the crude product as a yellow oil (C) 54g, yield 97%, content 94.3%.

[0138] (3) 1 – benzyl-4-piperidone (E) (referred to as the hydrolyzate) is prepared:


Figure CN106187863AD00232

[0140] In a reaction flask equipped with a 500ml three mechanical stirrer, thermometer, fractional distillation apparatus, was added 27% sodium methoxide 27g, crude diester was 33.4g (0.12mol), toluene 300ml, stirred and heated, the temperature reached 90 when ° C or more, additional 50ml toluene was reacted for 3 hours. Cooled to room temperature, and neutralized with acetic acid to PH6, standing layer. The toluene layer was separated and extracted with 150ml of 22% hydrochloric acid three times. Hydrochloric acid extracts were combined, heated with stirring for 4 hours. Recovered by distillation under reduced pressure and hydrochloric acid (about 120ml distilled dilute hydrochloric acid) was cooled to distillation l〇 ° C below, with 40% sodium hydroxide PH12 above. With 80ml ethyl acetate 3 times extracted with ethyl acetate extracts were combined, sub-net water, dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, recovering ethyl acetate atmospheric distillation, vacuum drained hydrolyzed to give (E) and the crude product 19g, yield 84%.

Figure CN106187863AD00233

[0141] (4) 1-ethoxycarbonyl-4-piperidone (F) (referred to as a carbonyl group-piperidone) Preparation:


Figure CN106187863AD00234

[0143] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, was added ethyl chloroformate 23.9g (0 · 22mo 1), benzene 100ml, stirring slowly added dropwise [The crude hydrolyzate (E ) 37 · 8g (0 · 2mo 1) + 20ml phenyl] solution dropwise, the reaction was heated with stirring for 5 hours.Water chestnut evaporated under reduced pressure and ethyl benzene chlorine, Li mechanical change stream distilled off under reduced pressure, low boiling point evaporated to give the product 268 was collected, yield 76%.

[0144] (5) 1 – ethoxycarbonyl-4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (G) (referred to as a carbonyl group-piperidinol) is:


Figure CN106187863AD00241

[0146] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a dropping funnel and a calcium chloride drying tube over anhydrous anhydrous absolute, at room temperature was added magnesium metal shoulder 2.5g (0.103mol) 20ml of anhydrous ethyl ether and slowly stirring was started.

[0147] 2-chloro-5-bromo – trifluorotoluene (referred bromide) was dissolved under 27g (0.104mol) at room temperature in 130ml anhydrous diethyl ether and stirred to obtain a uniform liquid mass (W is);

[0148] When the liquid material taken (W) 15ml was added to the above reaction, a solution of iodine 0.13g, 1,2- dibromoethane 0.2g, initiated Grignard reaction was heated until the iodine color disappeared, the reaction slowed down, slow slow dropping liquid material (W). The addition was completed, refluxing was continued for 1 hour. Completion of the reaction, cooled to room temperature, slowly added dropwise at room temperature carbonyl piperidone (F) water solution was cooled at normal [carbonyl-piperidone 13.6g (0.0795mol) + 40ml dry ether], dropwise, the reaction was heated with stirring 1.5 hour. L〇〇ml ammonium chloride solution concentration of 20% by weight was added, refluxed for 15 minutes and allowed to stand 30 minutes at room temperature stratification. Discharged aqueous layer (lower layer), the residual liquid was distilled (upper layer) at an external temperature of 55 ° C atmospheric distillation recovery ether, discharge hot, refrigerated overnight, the precipitated solid. Filtered, washed with a small amount of time, drained, and dried to give the product (G) 24.1g, yield 85.7%, mp 118-126Γ.

[0149] (6) 4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (X VH) (referred piperidinol) Preparation:


Figure CN106187863AD00242

[0151] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, were added ethanol 40ml, 158 of sodium hydroxide (0.375111〇1), carbonyl piperidinol (6) 2 (^ (0.0569111〇1 ), heated to reflux, and the reaction stirred for 3.5 hours. the reaction was completed, 50ml of water was added, the reaction was refluxed for 10 minutes, the hot reaction solution was placed in 300g of crushed ice, stirred well, and the precipitated solid, -5 ° C frozen standing for 2 hours the above.

[0152] filtered, washed with water to pH 8-9, drained, and dried to give piperidinol (XVH) 15g, yield 94%, mp 137-144 ° C, ash content <5%.

[0153] Example 2

[0154] (a) 3- (4-fluorobenzoyl) propionic acid (2) (the acid) is prepared:


Figure CN106187863AD00251

[0156] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 500ml, was added 17.1g (0.171mol) of succinic anhydride, l〇5g (1 · 09mol) fluorobenzene, stirred and dissolved. Added in one portion 60g (0 · 306mol) in dry wrong trichloride, stirring, the reaction was stirred at 100 ° C for 2 hours, at a concentration of 10% by weight hydrochloric acid 165ml exploded 30 minutes;

[0157] Other embodiments with Example 1, the product, 111.? 105-107 ° (:, this step a yield of 81.5%, 46.7% overall yield.


  1. ^ van Praag HM, Schut T, Dols L, van Schilfgaarden R., Controlled trial of penfluridol in acute psychosis, Br Med J. 1971 December 18;4(5789):710-3
  2. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, Van Nueten JM, Schaper WK., The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug, Eur J Pharmacol. 1970 July 15;11(2):139-54
  3. Jump up to:a b Soares, B; Silva de Lima, M (2006). “Penfluridol for schizophrenia”Cochrane Database of Systematic Reviews2: CD002923.pub2. doi:10.1002/14651858.CD002923.pub2.

Further reading

  • Benkert O, Hippius H.: Psychiatrische Pharmakotherapie, Springer-Verlag, 1976, 2. Auflage. ISBN3-540-07916-5
  • R Bhattacharyya, R Bhadra U Roy, S Bhattacharyya, J Pal S Sh Saha – Resurgence of Penfluridol:Merits and Demerits, Eastern Journal of Psychiatry, January-June 2015 vol 18, Issue 1 p 23 –29
Clinical data
AHFS/ International Drug Names
ATC code
CAS Number
CompTox Dashboard(EPA)
ECHA InfoCard 100.043.689Edit this at Wikidata
Chemical and physical data
Formula C28H27ClF5NO
Molar mass 523.965 g·mol−1
3D model (JSmol)

/////////Penfluridol, Antipsychotic, SemapMicefalLongoperidol, MCN-JR-16,341, R 16,341, MCN-JR-16,341 / R 16,341, 


Xanomeline (LY-246,708; Lumeron, Memcor) ксаномелин , كسانوميلين , 诺美林 ,


Xanomeline (LY-246,708LumeronMemcor)

CAS 131986-45-3

  • Molecular FormulaC14H23N3OS
  • Average mass281.417 Da
ксаномелин كسانوميلين 诺美林 
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist.
Pyridine, 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methyl-
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist. in vitro: Xanomeline had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for a number of other neurotransmitter receptors and uptake sites. In cells stably expressing genetic m1 receptors, xanomeline increased phospholipid hydrolysis in CHO, BHK and A9 L cells to 100, 72 and 55% of the nonselective agonist carbachol. In isolated tissues, xanomeline had high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.006 nM), low affinity for M2 receptors in guinea pig atria (EC50 = 3 microM), was a weak partial agonist in guinea pig ileum and was neither an agonist nor antagonist in guinea pig bladder. Xanomeline produced small increases in striatal acetylcholine levels and did not antagonize the large increases in acetylcholine produced by the nonselective muscarinic agonist oxotremorine, indicating that xanomeline did not block M2 autoreceptors. in vivo: Xanomeline increased striatal levels of dopamine metabolites, presumably by acting at M1 heteroreceptors on dopamine neurons to increase dopamine release. In contrast, xanomeline had only a relatively small effect on acetylcholine levels in brain, indicating that it is devoid of actions at muscarinic autoreceptors. The effects of xanomeline on ex vivo binding and DOPAC levels lasted for about 3 hr and were evident after oral administration. An analog of xanomeline with similar in vivo effects did not inhibit acetylcholinesterase or choline acetyltransferase and inhibited choline uptake only at concentrations much higher than those required to inhibit binding. These data indicate xanomeline is selective agonist for M1 over M2 and M3 receptors in vivo in rat.
Xanomeline (LY-246,708LumeronMemcor) is a muscarinic acetylcholine receptor agonist with reasonable selectivity for the M1 and M4 subtypes,[1][2][3][4] though it is also known to act as a M5 receptor antagonist.[5] It has been studied for the treatment of both Alzheimer’s disease and schizophrenia, particularly the cognitive and negative symptoms,[6] although gastrointestinal side effects led to a high drop-out rate in clinical trials.[7][8] Despite this, xanomeline has been shown to have reasonable efficacy for the treatment of schizophrenia symptoms, and one recent human study found robust improvements in verbal learning and short-term memoryassociated with xanomeline treatment.[9]
Image result for Xanomeline

Xanomeline oxalate

CAS No.:141064-23-5,

Molecular Weight, :371.45,

Molecular Formula, :C16H25N3O5S

5‐[4‐(hexyloxy)‐1,2,5‐thiadiazol‐3‐yl]‐1‐methyl‐1,2,3,6‐tetrahydropyridine; oxalic acid


Title: Xanomeline

CAS Registry Number: 131986-45-3

CAS Name: 3-[4-(Hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine

Molecular Formula: C14H23N3OS

Molecular Weight: 281.42

Percent Composition: C 59.75%, H 8.24%, N 14.93%, O 5.69%, S 11.39%

Literature References: Selective muscarinic M1-receptor agonist.

Prepn: P. Sauerberg, P. H. Olesen, EP384288 (1990 to Ferrosan); eidem,US5043345 (1991 to Novo Nordisk); eidemet al.,J. Med. Chem.35, 2274 (1992).

Prepn of crystalline tartrate: L. M. Osborne et al.,WO9429303 (1994 to Novo Nordisk).

Muscarinic receptor binding study: H. E. Shannon et al.,J. Pharmacol. Exp. Ther.269, 271 (1994). Pharmacology: F. P. Bymaster et al.,ibid. 282.

HPLC determn in plasma: C. L. Hamilton et al.,J. Chromatogr.613, 365 (1993).

Derivative Type: Oxalate

CAS Registry Number: 141064-23-5

Molecular Formula: C14H23N3OS.C2H2O4

Molecular Weight: 371.45

Percent Composition: C 51.74%, H 6.78%, N 11.31%, O 21.54%, S 8.63%

Properties: Crystals from acetone, mp 148°.

Melting point: mp 148°

Derivative Type: (+)-L-Hydrogen tartrate

CAS Registry Number: 152854-19-8

Additional Names: Xanomeline tartrate

Manufacturers’ Codes: LY-246708; NNC-11-0232

Trademarks: Lomeron (Lilly); Memcor (Lilly)

Molecular Formula: C14H23N3OS.C4H6O6

Molecular Weight: 431.50

Percent Composition: C 50.10%, H 6.77%, N 9.74%, O 25.95%, S 7.43%

Properties: Crystals from 2-propanol, mp 95.5°.

Melting point: mp 95.5°

Therap-Cat: Cholinergic; nootropic.

Keywords: Cholinergic; Nootropic.


Image result for Xanomeline

Image result for Xanomeline

EP 0384288; US 5260311; US 5264444; US 5328925, US 5834495; WO 9429303, EP 0687265; JP 1996507298; WO 9420495
The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.



Image result for Xanomeline nmr

Xanomeline (39) has emerged as one of the most potent unbridged arecoline derivatives. It has higher potency and efficacy for m1 and m4 than for m2, m3 and m5 receptor subtypes [73], binds to the m1receptor subtype uniquely tightly [74,75] and stimulates phosphoinositide hydrolysis in the brain. In cells containing human m1 receptors which are stably expressing amyloid precursor protein (APP), xanomeline (39) stimulates APP release with a potency 1000 greater than carbachol and reduces the secretion of Aβ by 46% [76] (cf 2.6 Central nervous system). In patients with Alzheimer’s disease, it halted cognitive decline and reduced behavioural symptoms such as hallucinations, delusions and vocal outbursts [77,78]. As might be expected there have been numerous attempts to prepare analogues with comparable potency and efficacy. Transplanting the thiadiazole ring of xanomeline to a range of bicyclic amines reduced selectivity [79,80] as did the use of pyrazine analogues (40) [81].


J Med Chem 1992,35(12),2274-83



Classics in Chemical Neuroscience: Xanomeline

 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
§ Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
ACS Chem. Neurosci.20178 (3), pp 435–443
DOI: 10.1021/acschemneuro.7b00001
Publication Date (Web): January 31, 2017
Copyright © 2017 American Chemical Society


Abstract Image

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer’s disease (AD) patients. Despite the compound’s promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound’s unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address xanomeline’s overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.



  1. Jump up^ Farde L, Suhara T, Halldin C, et al. (1996). “PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man”. Dementia (Basel, Switzerland)7 (4): 187–95. PMID 8835881.
  2. Jump up^ Jakubík J, Michal P, Machová E, Dolezal V (2008). “Importance and prospects for design of selective muscarinic agonists” (PDF). Physiological Research / Academia Scientiarum Bohemoslovaca. 57 Suppl 3: S39–47. PMID 18481916.
  3. Jump up^ Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). “Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice”European Journal of Pharmacology603 (1-3): 147–9. PMID 19111716doi:10.1016/j.ejphar.2008.12.020.
  4. Jump up^ Heinrich JN, Butera JA, Carrick T, et al. (March 2009). “Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists”European Journal of Pharmacology605 (1-3): 53–6. PMID 19168056doi:10.1016/j.ejphar.2008.12.044.
  5. Jump up^ Grant MK, El-Fakahany EE (October 2005). “Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor”The Journal of Pharmacology and Experimental Therapeutics315 (1): 313–9. PMID 16002459doi:10.1124/jpet.105.090134.
  6. Jump up^ Lieberman JA, Javitch JA, Moore H (August 2008). “Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry”The American Journal of Psychiatry165 (8): 931–6. PMID 18676593doi:10.1176/appi.ajp.2008.08050769.
  7. Jump up^ Messer WS (2002). “The utility of muscarinic agonists in the treatment of Alzheimer’s disease”. Journal of Molecular Neuroscience : MN19 (1-2): 187–93. PMID 12212779doi:10.1007/s12031-002-0031-5.
  8. Jump up^ Mirza NR, Peters D, Sparks RG (2003). “Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists”. CNS Drug Reviews9 (2): 159–86. PMID 12847557doi:10.1111/j.1527-3458.2003.tb00247.x.
  9. Jump up^ Shekhar A, Potter WZ, Lightfoot J, et al. (August 2008). “Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia”The American Journal of Psychiatry165 (8): 1033–9. PMID 18593778doi:10.1176/appi.ajp.2008.06091591.
Clinical data
ATC code
  • None
CAS Number
PubChem CID
ECHA InfoCard 100.208.938
Chemical and physical data
Formula C14H23N3OS
Molar mass 281.42 g/mol
3D model (JSmol)

///////XanomelineLY 246708, LumeronMemcor, ксаномелин كسانوميلين 诺美林 allosteric modulation, Alzheimer’s disease, antipsychotic,  muscarinic acetylcholine receptors, schizophrenia, 

Iloperidone (Fanapt)


Iloperidone (Fanapt), ILO-522, HP-873, Zomaril, 133454-47-4, antipsychotic

1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone; 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine; 4′-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3′-methoxyacetophenone

Aventis Pharma (Originator), Novartis (Licensee), Titan (Licensee)Vanda Pharmaceuticals (Licensee)

Iloperidone(Fanapt) is a monoamine directed towards acting upon and antagonizing specific neurotransmitters, particularly multiple dopamine and serotonin receptor subtypes.

Schizophrenia is a chronic, severe, and debilitating mental disorder that affects approximately 2.4 million Americans, around 1.1% of the population. The net cost of this disorder is staggering as estimates from 2002 reveal this disorder to cost $62.7 billion. A major issue with the treatment of schizophrenia is that patients show varying levels of response and tolerance to available therapies. Although the symptoms of the disease are very severe, estimates show that approximately 3 out of 4 patients discontinue medication prior to completing 18 months of treatment, many times due to the severe side effects of the approved medications.


J.T. Strupczewski, K.J. Bordeau, Y. Chiang, E.J. Glamkowski, P.G.
Conway, R. Corbett, H.B. Hartman, M.R. Szewczak, C.A. Wilmot andG.C. Helsley, J. Med. Chem., 38, 1119 (1995).

US 4355037
V. Miklos, WO Patent 031497 (2010).
J.T. Strupczewski, EP Patent 0402644 (1990)

The product is protected by the U.S. Pat. No. 5,364,866, U.S. Pat. No. RE 39198 E and EP 402644 B1.U.S. Pat. No. 5,364,866 and U.S. Pat. No. 5,663,449.EP 542136, EP 612318, EP 730452, JP 95501055, JP 97511215, US 5364866, US 5776963, WO 9309102, WO 9511680.US 4355037,EP 0542136; EP 0612318; EP 0730452; EP 0957102; EP 0959075; EP 0959076; EP 0963984; JP 1995501055; JP 1997511215; US 5364866; US 5776963; WO 9309102; WO 9511680

The first reported synthetic method for Iloperidone is described in patent EP 402644 A1.

In U.S. Patent US5776963 and patent family EP4 (^ 644, there is disclosed a method for preparing iloperidone,

The synthetic method reported(4, 5) for 1 involves two chemical steps: O-alkylation of acetovanillone (2) with 1-bromo-3-chloropropane (3) to obtain chloro derivative 4 followed byN-alkylation of piperidine intermediate 5 with 4. The reported process for 4 comprises O-alkylation of 2 with 3 in acetone in the presence of potassium carbonate for 20 h to provide 4as an oil after usual work up, which was then vacuum (0.1 mmHg) distilled to collect desired product 4 at 141–143 °C with around 85% yield (Scheme 1, Path A). Some of the drawbacks of this process are as follows: longer reaction time (around 20 h), formation of 6–7% of dimer impurity (10, Scheme 2), high-vacuum distillation to achieve the quality, which is always a cumbersome process at industrial scale, requiring special apparatus and skill set, and degradation and charring of some portion of product during high-vacuum distillation. Further, the next step comprises N-alkylation of 4 with 5 in N,N-dimethylformamide (DMF) in the presence of potassium carbonate to provide iloperidone (1) as a crude solid, which was purified by crystallization using ethanol to yield pure 1 with 58% yield (Scheme 1, Path A). Some of the lacunae observed with the above process includes the following: (a) low yields, (b) formation of carbamate impurity 13 (Scheme 2) in the range 15–20% due to the use of potassium carbonate, (c) ineffective purification by crystallization using ethanol to eliminate carbamate impurity below 0.15%, and (d) iloperidone obtained by the above synthetic process was beige in color.

Scheme 1. Reported (Path A) and Improved (Path B) Process for Preparation of 1
Scheme 2. Flow Chart Representing the Formation of Impurities
A few other improved processes reported…(Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent)subsequently for 1 follow the same reaction sequence (Scheme 1, Path A) using compounds 4 and 5 as key starting materials with different bases and solvents.(6-13) However, the reported processes do not address a control mechanism for impurities 8911, and 13 (Scheme 2) formed during the synthesis of 1. In order to eliminate these impurities, the reported processes involve employment of multiple purifications using a single solvent or mixture of solvents or purification by means of formation of the acid addition salt of 1 followed by converting back to pure 1.(6-13)

The synthetic route is as follows:

The reaction of piperidine-4-carboxylic acid (I) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (II), which is treated with SOCl2 and acetic anhydride to yield the corresponding acyl chloride (III). The Friedel-Crafts condensation of (III) with refluxing 1,3-difluorobenzene (IV) by means of AlCl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (V), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (VI). The cyclization of (VI) by means of NaH in hot THF/DMF yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (VII), which is treated with HCl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (VIII). Finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) by means of K2CO3 in hot DMF. The intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (IX) with 3-chcloropropyl bromide (X) by means of NaH or K2CO3 in DMF.

Figure CN102443000AD00032

Iloperidone, also known as FanaptFanapta, and previously known as Zomaril, is an atypical antipsychotic for the treatment ofschizophrenia.


Accordingly, 6-fluoro-3-(4-piperidyl)-1,2-benzoxazole 1 and 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone 2 were heated in presence of potassium carbonate using dimethylformamide solvent to afford 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidyl]propoxy]-3-methoxy-phenyl]ethanone also called Iloperidone

It was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009.

It’s not yet approved in India.

Hoechst Marion Roussel Inc. made initial inquiries into the drug; however, in May 1996, they discontinued research, and in June 1997 gave research rights to Titan Pharmaceuticals. Titan then handed over worldwide development, manufacturing and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals announced that the Phase III development rights have been acquired by Vanda Pharmaceuticals. The original launch date was scheduled for 2002. On November 27, 2007, Vanda Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had accepted their New Drug Application for iloperidone, confirming the application is ready for FDA review and approval. On July 28, 2008, the FDA issued a “Not Approvable” letter to Vanda Pharmaceuticals concerning the drug, stating that further trials are required before a decision can be made concerning marketed usage of iloperidone.

Chemically designated as 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, is a second generation atypical antipsychotic agent. Iloperidone, also known as Fanapt, Fanapta, and Zomaril, was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on May 6, 2009 and is indicated for the acute treatment of schizophrenia in adults. Iloperidone has been shown to act as an antagonist at all tested receptors. It was found to block the sites of noradrenalin (α2C), dopamine (D2A and D3), and serotonin (5-HT1A and 5-HT6) receptors.(2) In addition, pharmacogenomic studies identified single nucleotide polymorphisms associated with an enhanced response to iloperidone during acute treatment of schizophrenia. It is considered an “atypical” antipsychotic because it displays serotonin receptor antagonism, similar to other atypical antipsychotics. The older typical antipsychotics are primarily dopamine antagonists.(3)

Iloperidone won FDA approval for use treating schizophrenia in the United States on May 6, 2009

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone) is an atypical new-generation antipsychotic medicament belonging to the class of piperidinyl-benzisoxazole derivatives, which is used to treat schizophrenia, bipolar disorder and other psychiatric conditions. Iloperidone acts as a serotonin/dopamine receptor antagonist (5-HT2A/D2).

Iloperidone, also known as Fanapt, Fanapta, and previously known as Zomaril, is an atypical antipsychotic drug used for the treatment of schizophrenia. The chemical name of iloperidone is l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl]propoxy] -3-methoxyphenyl]ethanone.

EP 0402644 patent discloses first synthetic route of synthesis of iloperidone as shown in Scheme I, which consists of alkylation reaction between l-(4-(3-chloropropoxy-3- methoxyphenyl)ethanone of the formula (II) and 6-fluoro-3-piperidin-4-yl-l ,2 benzisoxazole hydrochloride of the formula (III) in presence of potassium carbonate in N,N dimethyl formamide. The reaction has been subsequently worked up and the compound of formula (I) is extracted from water using ethyl acetate. The compound of formula (I) is purified by crystallization using ethanol. The overall yield of compound of formula (I) is 58%.

Figure imgf000003_0001

Formula (I)

SCHEME 1 Further, we have analyzed the reported synthetic route for synthesis of iloperidone; following limitations have been observed and identified in the reported synthetic route:

a) The yield obtained using said synthetic route as reported in US RE39198 is 58%. Hence, this route of synthesis is not cost efficient at commercial scale due to low yield;

b) Use of potassium carbonate as a base in reaction leads to formation of carbon dioxide as one of the side products during the reaction, which further hinders in the manufacturing process by actively participating in manufacturing process and thereby leads to the formation o

Figure imgf000004_0001

Formula (IV)

which is in the range of 15-20%, and thereby resulting in low yield of iloperidone;

c) Purification by crystallization using ethanol as a solvent is not effective in eliminating or controlling carbamate impurity below 0.15% as per the ICH guide lines for the known impurities; and

d) Iloperidone obtained by the above synthetic process is beige in colour.

CN101768154 discloses the synthesis of iloperidone by N-alkylation reaction between l-(4-(3- chloropropoxy-3-methoxyphenyl)ethanone of the formula (II) and 6-fluoro-3-piperidin-4-yl-l,2 benzisoxazole hydrochloride of the formula (III) in inorganic alkaline solution, particularly; alkali metal carbonate solution. We have analyzed the reported synthetic route for synthesis of iloperidone and have observed and identified that the use of alkaline carbonate solution leads to the formation of carbamate impurity in the range of 1 to 1.5%.

Several patents were published after, describing essentially the same synthetic way such as US5364866 and US5663449.

The synthesis of iloperidone is described in USRE39198 (corresponding to EP 0 402 644 example 3) according to the following synthesis scheme:

Figure US20130261308A1-20131003-C00002

In agreement with said patent, the intermediate isolated, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, is reacted with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride in N,N-dimethyl formamide at 90° C. for 16 hours. When the reaction is complete, the mixture is poured into water and extracted with ethyl acetate. The crude product thus obtained is crystallised twice from ethanol to give crystallised iloperidone with a total yield of 58%.

The yield of this process is very low; moreover, the process begins with two isolated intermediates, and requires an aqueous extractive work-up step with an increase in volumes and consequent reduction in the productivity and efficiency of the process. Said process also requires a double crystallisation step to obtain a beige product. The quality levels obtained are not described in the text of the example, but a beige color does not suggest a high-quality product, as iloperidone is a white substance.

The synthesis of intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is disclosed in U.S. Pat. No. 4,366,162. Example 1 describes the preparation of said intermediate by reacting acetovanillone with 1-bromo-3-chloropropane in acetone with potassium carbonate. At the end of the reaction the resulting product is purified by distillation and obtained as an oily intermediate which is left to stand in order to obtain the solid intermediate.

The synthesis of intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is also disclosed in U.S. Pat. No. 4,810,713. Preparation 12 describes the synthesis of said intermediate from acetovanillone and 1-bromo-3-chloropropane in sodium hydroxide alkalinized water. At the end of the reaction the product obtained is extracted in toluene, the organic phases are washed with basic aqueous solutions and finally, the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone is crystallised with the aid of diisopropyl ether. The intermediate isolated is then recrystallised twice from cyclohexane and twice from petroleum ether.

An alternative process for the synthesis of iloperidone is reported in CN 102070626.

Scheme 2 shows the synthesis procedure:

Figure US20130261308A1-20131003-C00003

The decision to alkylate acetovanillone with 1-chloro-3-propanol requires an extra synthesis step (to convert the OH group to an OR leaving group) compared with the procedure reported by the combination of patents USRE39198 (EP402644) and U.S. Pat. No. 4,366,162/U.S. Pat. No. 4,810,713, making said process less efficient from the economic standpoint.

WO2011061750 discloses an alternative iloperidone synthesis process as reported in Scheme 3:

Figure US20130261308A1-20131003-C00004

Said process uses reagents such as methyl magnesium chloride to effect the Grignard reaction to convert the aldehyde group to a secondary alcohol group, which are much more complicated to manage on an industrial scale than the synthesis methods previously described. Moreover, the oxidation reaction of the next step uses reagents such as chromic acid or potassium permanganate, which have a very high environmental impact and very low industrial applicability.

WO2011055188 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. The same patent application also gives preparation examples of the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone isolated as crystalline solid by procedures similar to those known in the literature.

CN 101824030 reports an iloperidone synthesis method similar to that of CN 102070626 which involves the same problems of inefficiency due to the additional step of inserting the leaving group required for alkylation with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

CN 101781243 discloses an alternative iloperidone synthesis process as reported in Scheme 4.

Figure US20130261308A1-20131003-C00005

Said process is not advantageous compared with the preceding processes as the intermediate with the oxime group, due to the nature of this functional group, is particularly liable to degradation due to the action of numerous factors such as the presence of metals, acid pHs and basic pHs.

CN101768154 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

CN 101735208 describes a process for the synthesis of iloperidone comparable to the one reported in CN 101781243, namely through the intermediate with the functional oxime group.

IN 2007MU01980 discloses a process for the synthesis of iloperidone comparable to the one reported in USRE39198 from two isolated intermediates, 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.

WO 2010031497 describes an alternative iloperidone synthesis process as reported in Scheme 5.

Figure US20130261308A1-20131003-C00006

The considerable economic disadvantage of the process reported in WO2010031497 is based on the fact that by reversing the order of alkylation and performing that of intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride first, a greater loss of yield is generated on this intermediate which, according to the literature, is more difficult to synthesise and consequently more expensive than the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, with a globally greater economic inefficiency of the iloperidone preparation process.

CN 102212063 discloses a process for the synthesis of iloperidone with the same arrangement of the synthesis steps as patent application WO 2010031497.

WO2011154860 describes a process for the synthesis of iloperidone wherein a phase transfer catalyst is used to prepare the intermediate 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone which, as in all the other preparation examples previously described, is crystallised, isolated and dried before use in the next step with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. Scheme 6 shows the synthesis scheme of the process of WO2011154860.

Figure US20130261308A1-20131003-C00007



Figure US20100076196A1-20100325-C00003




Tetrabutyl ammonium bromide (2.40 gm) was added to a stirred solution of Potassium hydroxide (0.724 kg) in mixture of Heptane (2.0L). and water (10.0L), followed by addition of 1- [4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2, 1.0kg) and 6-fluoro-3-piperidin-4-yl-l,2- benzisoxazole hydrochloride^, 1.1 1kg) at 30°C. This reaction mass was stirred for 15 to 20 min. The temperature of the reaction mass was raised to 70°C and was maintained for 8 to 10 hours. After completion of reaction (by TLC, Mobile Phase: Toluene/ Acetone/Ethyl acetate = 6:2:2 mL), the mixture was cooled to 30°C, diluted with dichloromethane (2.5 L) and stirred for 30 minutes. The dichloromethane layer was separated. The aqueous layer was re-extracted with dichloromethane (1.0L). The combined dichloromethane layer was washed with water (1.5L) and decolorized with activated charcoal (0.05 kg). The solvent was distilled off completely to obtain the residue. The residue obtained was dissolved in isopropyl alcohol (5.0L) at reflux temperature to obtain the clear solution. The clear solution obtained was cooled to 30°C followed by 0°C and stirred for 60 min to precipitate out crystals. The colorless crystals of compound (I) obtained were filtered. The crystalline solid was dried under vacuum (650-700 mm/Hg) to obtain pure compound (I) as a crystalline solid. HPLC analysis was performed for the crystalline solid obtained. The purity of Iloperidone, impurity profile and yield are shown in table 1 below.

Table 1 : Analysis data of iloperidone i.e. purity, yield and impurity profile.

Figure imgf000023_0001


Tetrabutyl ammonium bromide (2.40 gm) was added to a stirred solution of Potassium hydroxide (0.724 kg) in mixture of Heptane (2.0L) and water (10.0L), followed by addition of 1- [4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2, 1.0kg) and 6-fluoro-3-piperidin-4-yl-l,2- benzisoxazole hydrochloride^, 1.1 1kg) at 30°C. This reaction mass was stirred for 15 to 20 min. The temperature of the reaction mass was raised to 70°C and maintained for 8 to 10 hours. After completion of reaction (by TLC, Mobile Phase: Toluene/ Acetone/Ethyl acetate = 6:2:2 mL), the mixture was cooled to 30°C, the reaction mixture was filtered to obtain wet crude iloperidone. Further, the obtained wet crude was dried at 60-65 °C under vacuum to furnish crude iloperidone (1.72 kg). The dried crude iloperidone was dissolved in isopropyl alcohol (5.0 L) at reflux temperature and decolorized with activated charcoal (0.05 kg). Obtained filtrate was cooled to 30°C followed by 0°C and stirred for 60 min to precipitate out crystals. The colorless crystals of compound (I) obtained were filtered. The crystalline solid was dried under vacuum (650-700 mm/Hg) to obtain pure compound (I) as a crystalline solid. HPLC analysis was performed for the crystalline solid obtained. The purity of Iloperidone, impurity profile and yield are shown in table 2 below.

Table 2: Analysis data of iloperidone i.e. purity, yield and impurity profile.

Figure imgf000024_0001




UPLC-MS [M+H+]=427

1H-NMR (in DMSO) (chemical shifts expressed in ppm with respect to the TMS signal): 2.06-1.78 (6H, m); 2.13 (2H, m); 2.49 (2H, t); 2.52 (2H, m); 2.97 (2H, m); 3.11 (1H, tt); 3.83 (3H, s); 4.12 (2H, t); 7.06 (1H, d); 7.22 (1H, m); 7.46 (1H, d); 7.61-7.58 (2H, m); 7.94 (1H, dd).


.Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent

Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op400335p

Abstract Image

The present work describes an improved and highly efficient process for the synthesis ofiloperidone (1), an antipsychotic agent, which is free from potential impurities. The synthesis comprises N-alkylation of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (4) with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride (5) in a mixture of water and heptane as solvent and sodium hydroxide as a base in the presence of tetrabutylammonium bromide as a phase transfer catalyst to yield iloperidone (1) with a yield of around 95% and a purity of 99.80% by HPLC. The present work also describes the optimization details performed to achieve the process attributes responsible for high yield and purity.

FT-IR (KBr, λmax, cm–1): 3031, 2949, 2779, 2746, 2822, 1669, 1614, 1585, 1510, 1462, 1448, 1415, 1380, 1313, 1262, 1221, 1177, 1150, 1123, 1077, 1034, 997, 985, 955, 884, 876, 853, 812, 781, 643, 610, 569, 475.

1H NMR (CDCl3): δ 2.03–2.10 (m, 6H), 2.12–2.18 (m, 2H), 2.55–2.56 (s, 3H), 2.58–2.60 (t, 2H), 3.02–3.09 (m, 3H), 3.91 (s, 3H), 4.10–4.19 (t, 2H), 6.91–6.93 (d, 1H), 7.01–7.06 (dd, 1H), 7.21–7.24 (dd, 1H), 7.51–7.52 (d, 1H), 7.53–7.56 (dd, 1H), 7.69–7.65 (dd, 1H).

13C NMR (CDCl3): 26.02, 26.40, 30.36, 34.34, 53.36, 54.90, 55.80, 67.16, 97.04, 97.31, 110.20, 111.02, 111.98, 112.23, 117.12, 122.36, 122.46, 123.06, 130.11, 149.00, 152.66, 160.91, 162.60, 163.53, 163.66, 165.09, 198.59.

MS (ESI, m/z): 427.2 [M + H].+

Anal. Calcd (%) for C24H27FN2O4(426.48): C, 67.54; H, 6.33; found (%): C, 67.24; H, 6.18.


HPLC analysis developed at Megafine  India using a Hypersil BDS C18 column (250 mm × 4.6 mm, particle size 5 μm); mobile phase A comprising a mixture of 5.0 mM ammonium dihydrogen orthophosphate buffer and 0.1% triethylamine; mobile phase B comprising a mixture of acetonitrile/methanol in the ratio 80:20 v/v; gradient elution: time (min)/A (v/v): B (v/v); T0.01/65:35, T8.0/65:35, T25.0/35:65, T35.0/35:65, T37.0/65:35, T45.0/65:35; flow rate 1.0 mL/min; column temperature 30 °C; wavelength 225 nm. The observed retention time of iloperidone under these chromatographic conditions is about 17.0 min.


N oxide impurity

m.p. 155-157 ºC;

FT-IR (KBr, νmax, cm-1):
3083, 2958, 2878, 1655, 1606, 1584, 1509, 1467, 1419, 1348,1273, 1223, 1182, 1143, 1121, 1032, 971, 957, 881, 857, 813,

1H NMR (300 MHz, CDCl3)

δ 1.89-1.93 (m, 2H), 2.31-2.40 (m, 2H), 2.55 (s, 3H), 2.60-2.72 (m, 2H), 3.29-3.52 (m,
2H), 3.29-3.52 (m, 2H), 3.29-3.52 (m, 2H), 3.29-3.52 (m, 1H),3.85 (s, 3H), 4.23(t, 2H, J = 6.0 Hz), 7.11 (d, 1H, J = 8.4 Hz),7.30-7.36 (m, 1H), 7.62-7.65 (m, 1H), 7.71-7.74 (dd, J = 9.3and 2.0 Hz, 1H), 8.02-8.07 (dd, J = 8.7 and 5.4 Hz, 1H);

13CNMR (75 MHz, CDCl3)

δ 22.13, 24.70, 26.35, 31.49, 55.54,63.21, 67.07, 67.82, 97.51, 110.35, 111.86, 112.67, 123.11,
123.67, 129.95, 148.63, 152.22, 160.79, 163.10, 163.69,196.40;

MS (ESI, m/z): 443 [M + H]+.

Anal. calcd. (%) forC24H27N2O5F (442.19): C, 65.15; H, 6.15; N, 6.33; found (%):C, 65.11; H, 6.09; N, 6.29.




Acetovanillon (4-hydroxy-3-methoxyacetophenone) 6 is also a first-generation fine chemical obtained as a reaction product from the oxidation−hydrolysis of lignosulfonate LS. The compound serves as substrate in synthetic processes leading to several second-generation fine chemicals, such as acetoveratron, veratric acid, and veratric acid chloride. Moreover, recently, a new compound iloperidone REF 20,21   34 [1-(3-(4-acetyl-2-methoxyphenoxy)propyl)-4-(6-fluorobenzisoxazol-3-yl)piperidine] that includes an acetovanillon 6 moiety was reported to be under development for use as an antipsychotic dopamine D2 antagonist and a 5-HT2Aantagonist.
The synthesis of iloperidone 34 is performed by means of an eight-step synthetic process. The acetovanillon 6, which constitutes an integral part of this substance, is condensed with 3-chloropropylbromide 43 in DMF in the presence of potassium carbonate or sodium hydride as base to obtain the key intermediate 44. In the last step of the process 44 is reacted with 42 to afford iloperidone 34. The intermediate 42 is synthesised by reacting piperidine-4-carboxylic acid 35 with formic acid and acetic acid anhydride to obtain 1-formylpiperidine-4-carboxylic acid 36 that upon treatment with thionyl chloride in acetic acid anhydide gives the corresponding acyl chloride 37 (1-formylpiperidine-4-carbonyl chloride). Under Friedel−Craft conditions, the acyl chloride 37 is condensed with 1,3-difluorobenzene 38 to afford 4-(2,4-difluorobenzoyl)piperidine-1-carbaldehyde 39. Treatment of this intermediate with hydroxylamine in refluxing ethanol yields the oxime 40 (4-[(2,4-difluorophenyl)hydroxyiminomethyl]piperidine-1-carbaldehyde). When the oxime 40 is exposed to basic conditions by means of sodium hydride in hot DMF and THF in the following step, a cyclisation proceeds to afford benzo[d]isoxazol 41 (4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine-1-carbaldehyde), which upon treatment with HCl in refluxing ethanol affords the key intermediate 42.


FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4′-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3′-methoxyacetophenone. Its molecular formula is C24H27FN2O4 and its molecular weight is 426.48. The structural formula is:

FANAPT® (iloperidone) Structural Formula Illustration

Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.

Title: Iloperidone
CAS Registry Number: 133454-47-4
CAS Name: 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone
Manufacturers’ Codes: HP-873; ILO-522
Trademarks: Zomaril (Novartis)
Molecular Formula: C24H27FN2O4
Molecular Weight: 426.48
Percent Composition: C 67.59%, H 6.38%, F 4.45%, N 6.57%, O 15.01%
Literature References: Combined dopamine (D2) and serotonin (5HT2) receptor antagonist. Prepn: J. T. Strupczewski et al., EP402644eidem, US 5364866 (1990, 1994 both to Hoechst-Roussel); eidem, J. Med. Chem. 38, 1119 (1995).
Pharmacology: M. R. Szewczak et al., J. Pharmacol. Exp. Ther. 274, 1404 (1995).
Clinical pharmacokinetics: S. M. Sainati et al., J. Clin. Pharmacol.35, 713 (1995).
HPLC determn in plasma: A. E. Mutlib, J. T. Strupczewski, J. Chromatogr. B 669, 237 (1995). Receptor binding study: S. Kongsamut et al., Eur. J. Pharmacol. 317, 417 (1996).
Review of pharmacology and therapeutic potential in schizophrenia: J. M. K. Hesselink, Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs 2, 71-78 (2000); K. K. Jain, Expert Opin. Invest. Drugs 9, 2935-2943 (2000).
Properties: Crystals from ethanol, mp 118-120°.
Melting point: mp 118-120°
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Benzisoxazoles; Serotonin-Dopamine Antagonist.


  1. King, D. R.; Kanavos, P. Croat. Med. J. 2002, 43, 462– 9

    [PubMed], [CAS]
  2. Kalkman, H. O.; Feuerbach, D.; Lötscher, E.; Schoeffter, P. Life Sci. 2003, 1151

     [PubMed], [CAS]
  3. Scott, L. J. CNS Drugs 2009, 23, 867

     [PubMed], [CAS]
  4. Bjork, A. K. K.; Abramo, A. L.; Kjellberg, B. E. S. US 4366162, 1982.

  5. Strupczewski, J. T.; Helsley, G. C.; Chiang, Y.; Bordeau, K. J. EP 0402644A1, 1990.

  6. Ansari, S. A.; Hirpara, H. M.; Yadav, A. K.; Gianchandani, J. P. WO2012164516, 2012.

  7. Azad, M. A. K.; Pandey, G.; Singh, K.; Prasad, M.; Arora, S. K. WO2012/090138 A1, 2012.

  8. Dwivedi, S. D.; Patel, D. J.; Shah, A. P. WO2012/063269, 2012.

  9. Athalye, S. S.; Parghi, K. D.; Ranbhan, K. J.; Sarjekar, P. B. WO2012/153341, 2012.

  10. Raman, J. V.; Rane, D.; Kevat, J.; Patil, D. WO2011/154860, 2011.

  11. Reguri, B. R.; Arunagiri, M.; Yarroju, P. C.; Kasiyappan, G. S.; Ponnapall, K. WO2011/055188, 2011.

  12. Shiwei, Z.; Feng, J. US 2012/0172699A1, 2012.

  13. Bettoni, P.; Roletto, J.; Paissoni, P. EP 2644608A1, 2013.

  14. Mathad, V. T.; Solanki, P. V.; Pandit, B. S.; Uppelli, S. B. WO2012/123963 A2, 2012.

  15. Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761–769

    [ACS Full Text ACS Full Text], [PubMed], [CAS]

    1.  20       Mucke, H. A. M.; Castañer, J. Drugs Future 200025(1), 29.

    2. (21) Steiner, G.; Bach, A.; Bialojan, S.; Greger, G.; Hege, H.-G.;.Höger, T.; Jochims, K.; Munschauer, R.; Neumann, B.; Teschendorf, H.-J.; Traut, M.; Unger, L.; Gross, G. Drugs Future 1998 23(2), 191.

    3. (22)     Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 197327, 888. [CAS]
    4. (23)     Pearl, I. A. J. Am. Chem Soc194668, 2180.[ACS Full Text ACS Full Text], [CAS]
    WO2003037337A1 * Oct 29, 2002 May 8, 2003 Markus Ahlheim Depot formulations of iloperidone and a star polymer
    WO2008027993A2 * Aug 29, 2007 Mar 6, 2008 Eurand Inc Drug delivery systems comprising solid solutions of weakly basic drugs
    CN101768154A Sep 19, 2009 Jul 7, 2010 浙江华海药业股份有限公司 New preparation method of iloperidone
    EP0402644A1 May 16, 1990 Dec 19, 1990 Hoechst-Roussel Pharmaceuticals Incorporated N-(aryloxyalkyl)heteroarylpiperidines and -heteroarylpiperazines,a process for their preparation and their use as medicaments
    EP0542136A1 * Nov 5, 1992 May 19, 1993 Hoechst-Roussel Pharmaceuticals Incorporated Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgetics
    US5364866 Oct 30, 1992 Nov 15, 1994 Hoechst-Roussel Pharmaceuticals, Inc. Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analetics
    US5663449 Jun 6, 1995 Sep 2, 1997 Hoechst Marion Roussel, Inc. Intermediate compounds in the synthesis of heteroarylpiperidines, pyrrolidines and piperazines
    USRE39198 Nov 15, 2000 Jul 18, 2006 Aventis Pharmaceuticals Inc. Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
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