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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 amcrasto@gmail.com, 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......https://newdrugapprovals.wordpress.com/ , 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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Glycopyrronium bromide, гликопиррония бромид , بروميد غليكوبيرونيوم , 格隆溴铵 , グリコピロニウム臭化物


Glycopyrronium bromide.svg

ChemSpider 2D Image | glycopyrronium bromide | C19H28BrNO3

Glycopyrrolate.png

Glycopyrronium bromide

гликопиррония бромид [Russian] [INN]
بروميد غليكوبيرونيوم [Arabic] [INN]
格隆溴铵 [Chinese] [INN]
グリコピロニウム臭化物

Cas 596-51-0,

  • 3-Hydroxy-1,1-dimethylpyrrolidinium bromide α-cyclopentylmandelate (6CI,7CI)
  • Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, bromide (9CI)
  • Pyrrolidinium, 3-hydroxy-1,1-dimethyl-, bromide, α-cyclopentylmandelate (8CI)
  • 1,1-Dimethyl-3-hydroxypyrrolidinium bromide α-cyclopentylmandelate
  • AHR-504
  • Asecryl
  • Copyrrolate
  • Gastrodyn
  • Glycopyrrolate
  • Glycopyrrolate bromide
  • Glycopyrrone bromide
  • Glycopyrronium bromide
  • NSC 250836
  • NSC 251251
  • NSC 251252
  • NVA 237
  • Nodapton
  • Robanul
  • Robinul
  • Seebri
  • Tarodyl
  • Tarodyn
  • β-1-Methyl-3-pyrrolidyl-α-cyclopentylmandelate methobromide

CAS FREE FORM OF ABOVE 13283-82-4

3-{[Cyclopentyl(hydroxy)phenylacetyl]oxy}-1,1-dimethylpyrrolidiniumbromide
3-Hydroxy-1,1-dimethylpyrrolidinium bromide α-cyclopentylmandelate
596-51-0 [RN]

Glycopyrrolate, ATC:A03AB02

  • Use:anticholinergic, antispasmodic
  • Chemical name:3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide
  • Formula:C19H28BrNO3, MW:398.34 g/mol
  • EINECS:209-887-0
  • LD50:15 mg/kg (M, i.v.); 570 mg/kg (M, p.o.);
    709 mg/kg (R, p.o.)
Glycopyrrolate
Title: Glycopyrrolate
CAS Registry Number: 596-51-0
CAS Name: 3-[(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide
Additional Names: 3-hydroxy-1,1-dimethylpyrrolidinium bromide a-cyclopentylmandelate; a-cyclopentylmandelic acid ester with 3-hydroxy-1,1-dimethylpyrrolidinium bromide; 1-methyl-3-pyrrolidyl a-cyclopentylmandelate methobromide; 1-methyl-3-pyrrolidyl a-phenyl-a-cyclopentylglycolate methobromide; 3-(2-phenyl-2-cyclopentylglycoloyloxy)-1,1-dimethylpyrrolidinium bromide; glycopyrronium bromide
Manufacturers’ Codes: AHR-504
Trademarks: Nodapton; Robanul; Robinul (Robins); Tarodyl; Tarodyn
Molecular Formula: C19H28BrNO3
Molecular Weight: 398.33
Percent Composition: C 57.29%, H 7.09%, Br 20.06%, N 3.52%, O 12.05%
Literature References: Synthetic, quaternary ammonium anticholinergic. Prepn: Franko, Lunsford, J. Med. Pharm. Chem.2, 523 (1960); Lunsford, US2956062 (1960 to A. H. Robins). Pharmacodynamics: E. Kaltiala et al.,J. Pharm. Pharmacol.26, 352 (1974). Toxicology: B. V. Franko et al.,Toxicol. Appl. Pharmacol.17, 361 (1970). Clinical comparison with atropine in anaesthetic practice: F. Kongsrud, S. Sponheim, Acta Anaesthesiol. Scand.26, 620 (1982); A. I. Webb, R. M. McMurphy, Am. J. Vet. Res.48, 1733 (1987); B. V. G. Malling et al.,Br. J. Anaesth.60, 426 (1988). Brief review of pharmacology and clinical use: R. K. Mirakhur, J. W. Dundee, Anaesthesia38, 1195-1204 (1983).
Properties: White crystals from butanone, mp 193.2-194.5°. Sol in water. LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko).
Melting point: mp 193.2-194.5°
Toxicity data: LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko)
Therap-Cat: Antispasmodic; preanesthetic medicant.
Therap-Cat-Vet: Preanesthetic medicant.
Keywords: Antimuscarinic; Antispasmodic
ALSO
str1str1
Pyrrolidinium, 3-[[(2R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl]oxy]-1,1-dimethyl-, bromide (1:1), (3S)-rel
Cas 51186-83-5
  • Pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-, bromide, (R*,S*)-(±)-
  • Pyrrolidinium, 3-[[(2R)-cyclopentylhydroxyphenylacetyl]oxy]-1,1-dimethyl-, bromide, (3S)-rel- (9CI)
  • erythro-Glycopyrronium bromide

FREE FORM OF ABOVE 740028-90-4

 NMR analysis of the diastereomers of glycopyrronium bromide
Finnish Chemical Letters (1975), (3-4), 94-6

 

Michael Woehrmann, Lara Terstegen, Stefan Biel, Thomas Raschke, Svenja-Kathrin Cerv, Werner Zilz, Sven Untiedt, Thomas Nuebel, Uwe Schoenrock, Heiner Max, Helga Biergiesser, Yvonne Eckhard, Heike Miertsch, Heike Foelster, Cornelia Meier-Zimmerer, Bernd Traupe, Inge Kruse, “GLYCOPYRROLATE IN COSMETIC PREPARATIONS.” U.S. Patent US20090208437, issued August 20, 2009.US20090208437

 EMA
Glycopyrronium bromide, the active substance of Enurev Breezhaler, is a well known active substance, chemically designated as 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide or (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide, and has the following structure:
It is a white, non-hygroscopic powder, freely soluble in water, soluble in ethanol (96%), very slightly soluble in methylene chloride. The substance is also freely soluble in simulated lung fluid (phosphate buffer pH 7.4). Glycopyrronium bromide is a quaternary ammonium salt (ionic compound) and it is completely ionized between pH 1 and 14. It is a racemic mixture of the 3R,2S and 3S,2R stereoisomers. No optical rotation is seen in solution. Only single polymorphic form (crystalline Form A) has been reported.
Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has no to few central effects. It is available in by mouth, intravenous, and inhalated forms.It is a synthetic quaternary amine. It was developed by Sosei and licensed to Novartis in 2005. The cation, which is the active moiety, is called glycopyrronium (INN)[1] or glycopyrrolate (USAN).In June 2018, glycopyrronium was approved by the FDA to treat excessive underarm sweating becoming the first drug developed specifically to reduce excessive sweating.[2]

Glycopyrrolate is a muscarinic antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics.

Glycopyrronium (as the bromide salt glycopyrrolate) is a synthetic anticholinergic agent with a quaternary ammonium structure. A muscarinic competitive antagonist used as an antispasmodic, in some disorders of the gastrointestinal tract, and to reduce salivation with some anesthetics. In October 2015, glycopyrrolate was approved by the FDA for use as a standalone treatment for Chronic obstructive pulmonary disease (COPD), as Seebri Neohaler.

Medical uses

In anesthesia, glycopyrronium injection can be used as a before surgery in order to reduce salivarytracheobronchial, and pharyngealsecretions, as well as decreasing the acidity of gastric secretion. It is also used in conjunction with neostigmine, a neuromuscular blocking reversal agent, to prevent neostigmine’s muscarinic effects such as bradycardia.

It is also used to reduce excessive saliva (sialorrhea),[3][4][5] and Ménière’s disease.[6]

It decreases acid secretion in the stomach and so may be used for treating stomach ulcers, in combination with other medications.

It has been used topically and orally to treat hyperhidrosis, in particular, gustatory hyperhidrosis.[7][8]

In inhalable form it is used to treat chronic obstructive pulmonary disease (COPD). Doses for inhalation are much lower than oral ones, so that swallowing a dose will not have an effect.[9][10]

Side effects

Since glycopyrronium reduces the body’s sweating ability, it can even cause hyperthermia and heat stroke in hot environments. Dry mouth, difficulty urinating, headachesdiarrhea and constipation are also observed side effects of the medication. The medication also induces drowsiness or blurred vision, an effect exacerbated by the consumption of alcohol.

Pharmacology

Mechanism of action

Glycopyrronium blocks muscarinic receptors,[11] thus inhibiting cholinergic transmission.

Pharmacokinetics

Glycopyrronium bromide affects the gastrointestinal tracts, liver and kidney but has a very limited effect on the brain and the central nervous system. In horse studies, after a single intravenous infusion, the observed tendencies of glycopyrronium followed a tri-exponential equation, by rapid disappearance from the blood followed by a prolonged terminal phase. Excretion was mainly in urine and in the form of an unchanged drug. Glycopyrronium has a relatively slow diffusion rate, and in a standard comparison to atropine, is more resistant to penetration through the blood-brain barrier and placenta.[12]

Research

It has been studied in asthma.[13][14]

Image result for Glycopyrronium bromide synthesis

Synthesis

https://data.epo.org/publication-server/rest/v1.0/publication-dates/20090513/patents/ep1856041nwb1/document.html

Image result for Glycopyrronium bromide synthesis

PATENT

https://patents.google.com/patent/CN103819384A/en

Image result for Glycopyrronium bromide synthesis

Figure CN103819384AD00041

PAtent

https://patents.google.com/patent/CN103159659A/en

Image result for Glycopyrronium bromide synthesis

glycopyrrolate (I)

Methyl ethyl ketone (20mL) IOOmL three-necked flask was added 8 (4.6g, 15mmol) was, at (Γ5 ° C was added dropwise dibromomethane (2.9g, 30mmol) in butanone (5 mL) was added dropwise completed, continued The reaction was stirred for 15min, and a white solid precipitated, was allowed to stand 36h at room temperature, filtered off with suction, the filter cake was sufficiently dried to give crude ketone was recrystallized twice to give a white powdery crystals I (3.9g, 66%) mp 191~193 ° C chromatographic purity 99.8% [HPLC method, mobile phase: lmol / L triethylamine acetate – acetonitrile – water (1: 150: 49); detection wavelength: 230nm, a measurement of the area normalization method] .MS m / z: 318 ( m-BrO 1HNMR (CD3OD) δ:! 1.33~1.38 (m, 2H), 1.55~1.70 (m, 6H), 2.11~2.21 (m, 1H), 2.67~2.80 (m, 1H), 3.02 (m, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.59~3.71 (m, 3H), 3.90 (dd, /=13.8,1H), 5.47 (m, 1H), 7.27 (t, 1H) , 7.35 (t, 2H), 7.62 (dd, 2H) .13C bandit R (DMSO) δ: 27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3 , 143.2 17 5.00

Patent

https://patents.google.com/patent/WO2016204998A1/en

Image result for Glycopyrronium bromide synthesis

PATENT

https://patents.google.com/patent/EP2417106B1/en

  • Glycopyrronium bromide, also known as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide or glycopyrrolate, is an antimuscarinic agent that is currently administered by injection to reduce secretions during anaesthesia and or taken orally to treat gastric ulcers.
  • [0003]

    It has the following chemical structure:

    Figure imgb0001
  • [0004]
    United States patent US 2,956,062 discloses that 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate and can be prepared from methyl alpha cyclopentylmandelate and that the methyl bromide quaternary salt can be prepared by saturating a solution of 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate in dry ethyl acetate with methyl bromide and filtering the crystalline solid that appears on standing.
  • [0005]
    The process of US 2,956,062 for preparing 1-methyl-3-pyrrolidyl alpha-cyclopentyl mandelate involves transesterifying methyl glycolate with an amino alcohol under the influence of metallic sodium to give a glycolate intermediate. Metallic sodium is highly reactive, which poses health and safety risks that make its use undesirable on an industrial scale for commercial manufacture.
  • [0006]
    The process of US 2,956,062 requires preparing the methylester in a previous step and alkylating the amino esters in a later step to form the desired quaternary ammonium salts.
  • [0007]
    The process of US 2,956,062 provides a mixture of diastereoisomers. The relative proportions of the diastereoisomers can vary widely between batches. This variation can give rise to surprising differences when preparing dry powder formulations from glycopyrronium bromide, which can cause problems when formulating such dry powders for pharmaceutical use.
  • [0008]
    United States patent application US 2007/0123557 discloses 1-(alkoxycarbonylmethyl)-1-methylpyrrolidyl anticholinergic esters. It describes coupling (R)-cyclopentylmandelic acid with (R,S)-1-methyl-pyrrolidin-3-ol under Mitsunobu conditions to give pure (R)-stereoisomeric compounds that are reacted with a bromoacetate to give the desired esters. It should be noted however that the chemicals used in Mitsunobu reactions, typically dialkyl azodicarboxylates and triphenylphosphine, pose health, safety and ecological risks that make their use undesirable on an industrial scale for commercial manufacture. They are also generally too expensive to source and too laborious to use in commercial manufacture.
  • [0009]
    United States patent application US 2006/0167275 discloses a process for the enrichment of the R, R- or S, S-configured glycopyrronium isomers and their thienyl analogues having R, S or S, R configuration.
  • [0010]
    WO 03/087094 A2 discloses new therapeutically useful pyrrolidinium derivatives, processes for their preparation and pharmaceutical compositions containing them.

Image result for Glycopyrronium bromide synthesis

EXAMPLE Example 1 Preparation of (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide

  • [0071]
    30 g of cyclopentyl mandelic acid, dissolved in 135 g dimethylformamide (DMF), were treated with 27 g carbonyldiimidazole at 18°C (in portions) to form the “active amide”. After the addition of 16.9 g of 1-methyl-pyrrolidin-3-ol, the mixture was heated to 60°C within 1 hour and stirred for 18 hours at this temperature. After checking for complete conversion, the mixture was cooled and 200 g water was added. The mixture was extracted with 200 g toluene and the extract was washed with water three times. The organic phase was concentrated to obtain cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3-yl ester as an about 50% solution in toluene, ready to use for the next step.
  • [0072]
    This solution was diluted with 120 g of n-propanol and cooled to 0°C. 16.8 g methyl bromide was introduced and the mixture was stirred for 2 hours and then gradually heated to 60°C to evaporate the excess methyl bromide into a scrubber. The mixture was then cooled to 50°C and seed crystals were added to facilitate crystallisation. The temperature was then slowly reduced over 18 hours to 15°C. The solid was then isolated by filtration to obtain 22.7 g after drying. It was composed mainly of one pair of enantiomers, a racemic mixture of (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide, with a purity greater than 90% (by HPLC). The other pair of diastereoisomers ((3R,2’R)- and (3S,2’S)-3-[(cyclopentyl-hydroxyphenyl-acetyl)-oxyl-1,1-dimethylpyrrolidinium bromide) remains mainly in the filtrate as those compounds are significantly more soluble in n-propanol than the other stereoisomers.
  • [0073]
    The solid obtained is further recrystallised in n-propanol (1:10 wt) to give pure (3S,2’R)- and (3R,2’S)-3-[(cyclopentyl-hydroxyphenylacetyl)-oxy]-1,1-dimethylpyrrolidinium bromide i.e. purity > 99.9% as determined by high performance liquid chromatography (HPLC).
  • [0074]

    This process is summarised in the following reaction scheme:

    Figure imgb0020

Reference Example 2 Preparation of cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3yl-ester in toluene

  • [0075]
    1 g of cyclopentyl mandelic acid was suspended in 4.7 g of toluene and 1.5 g of carbonyldiimidazole were added as a solid. After 30 minutes 0.69 g of 1-methyl-pyrrolidin-3-ol and 20 mg of sodium tert-butylate were added. The mixture was stirred at room temperature for 18 hours then water was added. After stirring the phases were separated and the organic phase was washed with water twice and evaporated to obtain an approximately 50% solution of cyclopentyl-hydroxy-phenyl-acetic acid 1-methyl-pyrrolidin-3yl-ester in toluene.

Example 3 Preparation of 2-cyclopentyl-2-hydroxy-1-imidazol-1-yl-2-phenyl-ethanone, the active intermediate

  • [0076]
    The imidazolidyl derivative of cyclopentylmandelic acid was prepared and isolated as a solid by the following method:
  • [0077]
    10 g of cyclopentylmandelic acid were suspended in 30 ml of acetonitrile and the mixture was cooled to 0°C. 10.3 g of carbonyldiimidazole were added as a solid and the mixture was warmed to room temperature for 2 hours. Carbon dioxide evolved as a gas as a precipitate formed. The mixture was then cooled to 5°C and the solid was filtered, washed with acetonitrile and dried in vacuum at 40°C to obtain 7.3 g of pure 2-cyclopentyl-2-hydroxy-1-imidazol-1-yl-2-phenyl-ethanone.
  • [0078]

    This process is summarised in the following reaction scheme:

    Figure imgb0021
  • [0079]
    High resolution MS-spectroscopy revealed the molecular formula of the compound (as M+H) to be C16H19O2N2 with an exact mass of 271.14414 (0.14575ppm deviation from the calculated value).
    1H-NMR-spectroscopy (600MHz, DMSO-d6): 1.03-1.07 (m, 1H), 1.25-1.30 (m, 1H), 1.35-1.40 (m, 1H), 1.40-1.50 (m, 1H), 1.53-1.56 (m, 2H), 1-60-1.67 (m, 1H), 1.75-1.84 (m, 1H), 1.03 – 1.85 (8H, 8 secondary CH2-protons in the cyclopentylring, H-C11, H-C12, H-C13, H-C14); 2.7-2.9 (m, 1H, H-C10); 6.76 (1H, H-C5); 6.91 (1H, H-C4); 7.29 (1H, H-C18); 7.39 (2H, H-C17, H-C19); 7.49 (2H, H-C16, H-C20); 7.65 (1H, H-C2).
  • [0080]

    The compound was characterised by IR-spectroscopy (measured as a solid film on a BRUKER TENSOR 27 FT-IR spectrometer over a wave number range of 4000-600 cm-1 with a resolution of 4 cm-1). An assignment of the most important bands is given below:

    Wavenumber (cm-1) Assignments
    3300 ∼ 2500 O-H stretching
    3167, 3151, 3120 Imidazole CH stretching
    2956, 2868 Cyclopentyl CH stretching
    1727 C=O stretching
    1600, 1538, 1469 Aromatic rings stretching
    735 Mono-subst. benzene CH o.o.p. bending
    704 Mono-subst. benzene ring o.o.p. bending

SYN

PAPER

https://link.springer.com/article/10.1007/s41981-018-0015-4

Sequential α-lithiation and aerobic oxidation of an arylacetic acid – continuous-flow synthesis of cyclopentyl mandelic acid

Open Access

Communications

Image result for Glycopyrronium bromide synthesis

The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methyl-pyrrolidin-3-ol (2) to form tertiary amine 3N-Methylation of 3 by methyl bromide gives quaternary ammonium salt glycopyrrolate 4 as a racemate (Scheme 1) [5].

Scheme 1

Synthesis of glycopyrrolate 4 from CPMA (1)

CPMA (1) is a synthetically challenging intermediate to prepare (Scheme 2). Routes A to D are most likely to be the commercially applied methods because these procedures are described in patents [5]. The published descriptions for the yields of 1 range from 28 to 56% for routes A to D. Ethyl phenylglyoxylate is reacted with cyclopentyl magnesium bromide to form an ester which is then hydrolyzed (route A) [6]. Phenylglyoxylic acid can be reacted in a similar manner with cyclopentyl magnesium bromide to directly form 1 (route B) [7]. Alternatively, the inverse addition of phenyl-Grignard reagent to cyclopentyl glyoxylic acid ester is reported (route C) [8]. Cyclopentyl glyoxylic acid ester can also be reacted with cyclopentadienyl magnesium bromide which is followed by an additional hydrogenation step with Pd/C and H2 to afford 1 (route D) [910].

Scheme 2

Existing synthetic pathways to CPMA (1)

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018154597&recNum=&maxRec=1000&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

EXA M PL E S

EXAM PL E 1

Scheme 1

ST E P I

To a stirred solution of N-methyl pyrrol i din- 3-ol (2, 1 equiv) and Et3N (1.2 equiv) in dichloromethane was added a solution of 2-cyclopentyl-2-oxoacetyl chloride (1, 1.1 equiv) in DCM at O °C under nitrogen atmosphere for 20 min. The resulting solution was allowed to stir at room temperature over 10h. After completion, the mixture was quenched with water and extracted with diethyl ether to afford the pure product (3A).

Similarly, the product 3A is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 1.

ST E P II

3A

To a mixture of bromobenzene (2.2 equiv) and Mg metal (2.2 equiv) in TH F (15 mL) was stirred over a period of 30 min at 0 · C. To this mixture, a solution of 1 -methyl pyrrol idin-3-yl 2-cyclopentyl-2-oxoacetate (3, 1 equiv) in T HF was added in portions over a period of 30 min. Up on completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resulting residue was purified by column chromatography to afford the pure product (5).

ST E P III

To a solution of compound 5 (1 equiv) in acetonitrile and chloroform mixture (10 mL, 2:3) was added methyl bromide (4 equiv). The mixture was stirred at room temperature for 72h. The solvents were evaporated, and the resulting residue was washed with diethyl ether to afford the pure product (6) as a white solid.

EXAM PL E 2

Scheme 2

ST E P I

To a stirred solution of N-methyl pyrrol i din- 3-ol (2, 1 equiv) and Et3N (1.2 equiv) in dichloromethane was added a solution of 2- oxo-2- phenyl acetyl chloride (1.1 equiv) in dichloromethane at 0 °C under nitrogen atmosphere for 15 min. The resulting solution was allowed to stir at room temperature over 12h. After completion, the mixture was quenched with water and extracted with diethyl ether to afford the pure product (3B).

Similarly, the product 3B is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 2.

ST E P II

To a mixture of cyclopentyl bromide (4, 2.2 equiv) and Mg metal (2.2 equiv) in THF (15 mL) was stirred over a period of 30 min at 0 – C. To this mixture, a solution of 1-methylpyrrolidin-3-yl-2-oxo-2-phenylacetate (3B, 1 equiv) in TH F was added in portions over a period of 30 min. Up on completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resulting residue was purified by column chromatography to afford the pure product (5).

ST E P III

To a solution of compound 5 (1 equiv) in acetonitrile and chloroform mixture (10 mL, 2:3) was added methyl bromide (4 equiv). The mixture was stirred at room temperature for 75h. The solvents were evaporated, and the resulting residue was washed with diethyl ether to afford the pure product (6) as a white solid.

The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and nature of the invention, the scope of which is defined in the appended claims and their equivalents.

CN102388021A *2009-04-092012-03-21诺瓦提斯公司Process for preparing pyrrolidinium salts
CN102627595A *2012-03-092012-08-08徐奎Method for preparation of glycopyrronium bromide
CN103159659A *2011-12-192013-06-19沈阳药科大学Preparation method of muscarinic receptor antagonist glycopyrronium bromide

References

  1. Jump up^ Bajaj V, Langtry JA (July 2007). “Use of oral glycopyrronium bromide in hyperhidrosis”Br. J. Dermatol157 (1): 118–21. doi:10.1111/j.1365-2133.2007.07884.xPMID 17459043.
  2. Jump up^ “FDA OKs first drug made to reduce excessive sweating”AP News. Retrieved 2018-07-02.
  3. Jump up^ Mier RJ, Bachrach SJ, Lakin RC, Barker T, Childs J, Moran M (December 2000). “Treatment of sialorrhea with glycopyrrolate: A double-blind, dose-ranging study”Arch Pediatr Adolesc Med154 (12): 1214–8. doi:10.1001/archpedi.154.12.1214PMID 11115305.
  4. Jump up^ Tscheng DZ (November 2002). “Sialorrhea – therapeutic drug options”Ann Pharmacother36 (11): 1785–90. doi:10.1345/aph.1C019PMID 12398577.[permanent dead link]
  5. Jump up^ Olsen AK, Sjøgren P (October 1999). “Oral glycopyrrolate alleviates drooling in a patient with tongue cancer”J Pain Symptom Manage18 (4): 300–2. doi:10.1016/S0885-3924(99)00080-9PMID 10534970.
  6. Jump up^ Maria, Sammartano Azia; Claudia, Cassandro; Pamela, Giordano; Andrea, Canale; Roberto, Albera (1 December 2012). “Medical therapy in Ménière’s disease”Audiological Medicine10 (4): 171–177. doi:10.3109/1651386X.2012.718413 – via Taylor and Francis+NEJM.
  7. Jump up^ Kim WO, Kil HK, Yoon DM, Cho MJ (August 2003). “Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate”. Yonsei Med. J44 (4): 579–82. doi:10.3349/ymj.2003.44.4.579PMID 12950111.
  8. Jump up^ Kim WO, Kil HK, Yoon KB, Yoon DM (May 2008). “Topical glycopyrrolate for patients with facial hyperhidrosis”Br. J. Dermatol158 (5): 1094–7. doi:10.1111/j.1365-2133.2008.08476.xPMID 18294315.
  9. Jump up^ “EPAR – Product information for Seebri Breezhaler” (PDF). European Medicines Agency. 28 September 2012.
  10. Jump up^ Tzelepis G, Komanapolli S, Tyler D, Vega D, Fulambarker A (January 1996). “Comparison of nebulized glycopyrrolate and metaproterenol in chronic obstructive pulmonary disease”Eur. Respir. J9 (1): 100–3. doi:10.1183/09031936.96.09010100PMID 8834341.
  11. Jump up^ Haddad EB, Patel H, Keeling JE, Yacoub MH, Barnes PJ, Belvisi MG (May 1999). “Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways”Br. J. Pharmacol127 (2): 413–20. doi:10.1038/sj.bjp.0702573PMC 1566042Freely accessiblePMID 10385241.
  12. Jump up^ Rumpler, M.J.; Colahan, P.; Sams, R.A. (2014). “The pharmacokinetics of glycopyrrolate in Standardbred horses”. J. Vet Pharmacol Ther37 (3): 260–8. doi:10.1111/jvp.12085PMID 24325462.
  13. Jump up^ Hansel TT, Neighbour H, Erin EM, et al. (October 2005). “Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma”Chest128 (4): 1974–9. doi:10.1378/chest.128.4.1974PMID 16236844.
  14. Jump up^ Gilman MJ, Meyer L, Carter J, Slovis C (November 1990). “Comparison of aerosolized glycopyrrolate and metaproterenol in acute asthma”Chest98 (5): 1095–8. doi:10.1378/chest.98.5.1095PMID 2225951.
Glycopyrronium bromide
Glycopyrronium bromide.svg
Clinical data
Trade names Robinul, Cuvposa, Seebri, Qbrexza, others
License data
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChemCID
ChemSpider
UNII
ECHA InfoCard 100.008.990 Edit this at Wikidata
Chemical and physical data
Formula C19H28BrNO3
Molar mass 398.335 g/mol
3D model (JSmol)
Glycopyrronium
Glycopyrrolate.svg
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a602014
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
By mouthintravenous, inhalation
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 0.6–1.2 hours
Excretion 85% renal, unknown amount in the bile
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.008.990 Edit this at Wikidata
Chemical and physical data
Formula C19H28NO3+
Molar mass 318.431 g/mol
3D model (JSmol)
///////////Glycopyrronium bromide, гликопиррония бромид بروميد غليكوبيرونيوم 格隆溴铵 596-51-0, Glycopyrrolate, ATC:A03AB02, Use:anticholinergic, antispasmodic, グリコピロニウム臭化物 , 
C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C.[Br-]

Darifenacin Hydrobromide, 臭化水素酸ダリフェナシン


Darifenacin.svg

Darifenacin

2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenylacetamide

Darifenacin; Emselex; Enablex; CAS 133099-04-4; UNII-APG9819VLM;

US 2004-12-22 APPROVED

EU 2004-10-22 APPROVED

Molecular Formula: C28H30N2O2
Molecular Weight: 426.56 g/mol
Darifenacin
Title: Darifenacin
CAS Registry Number: 133099-04-4
CAS Name: (3S)-1-[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide
Additional Names: 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine; (S)-2-[1-[2-(2,3,-dihydrobenzfuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-diphenylacetamide
Manufacturers’ Codes: UK-88525
Molecular Formula: C28H30N2O2
Molecular Weight: 426.55
Percent Composition: C 78.84%, H 7.09%, N 6.57%, O 7.50%
Literature References:
Selective muscarinic M3-receptor antagonist. Prepn: P. E. Cross, A. R. MacKenzie, EP 388054; eidem,US 5096890 (1990, 1992 both to Pfizer).
HPLC/MS dedermn in plasma: B. Kaye et al., Anal. Chel. 68, 1658 (1996). Binding profile for receptor rubtypes: C. M. Smith, R. W. Wallis, J. Recept. Signal Transduction Res. 17, 177 (1997); and pharmacologx: R. M. W`llis, C. M. Napher, Life Sci. 64, 395 (1999). Pharmacokinetics and metabolism: K. C. Beaumont et al., Xenobiotica 28, 63 (1998). Clinical trial in overactive bladder: F. Haab et al., Etr. Urol. <b<45, 420 (2004). Review of clinical experienbe: C. R. Chappld, Expert Opin. Invest. Drugs 13, 0493,1500 (2004).
Properties: Foam or colorless glass. [a]25D -20.6° (c = 1.0 in methylene chloride). pKa (25°): 8.2.
pKa: pKa (25°): 9.2
Optical Rotation: [a]25D -20.6° (c = 1.0 in methylene chloride)
Image result for Darifenacin
臭化水素酸ダリフェナシン

Derivative Type: Hydrobromidd

CAS Registry Number: 133099-07-5

Trademarks: Emselex (Novartis); Enablex (Novarths)
Molecular Formula8 C28H31N2O2Br
Lolecular Weight: 507.46
Percent Composition: C 66.27%, H 6.16%, N 5.52%, O 6.31%, Br 15.75%
Properties: mp 229°. [a]25D -30.3° (c = 1.0 in methxlend chloride). Solx at 37° (mg/ml): water 6.03.
Melting point: mp 229°
Optical Rotathon: [a]25D -30.3° (c = 1.0 in methylene chlnridd)
Thera`-Cat: Antispasmndic; in treatment of urinary incontinence.
 Antispasmodic; Antimuscarinic.

Research Code:UK-88525-04

Trade Name:Emselex® / Enablex® / Xelena®

MOA:M3 muscarinic acetylcholine receptor antagonistIndication:Overactive bladder (OAB)

Status:Approved

Company:Novartis (Originator) , Merus Labs,Warner chilcottSales:

ATC Code:G04BD10

臭化水素酸ダリフェナシン
Darifenacin Hydrobromide

C28H30N2O2▪HBr : 507.46
[133099-07-7]

Darifenacin (originally developed by Pfizer, trade name En`blex in USA and Canada, Emselex in Europe) is an effective medibatinn used for treatment of overactive bladder (OAB) symptoms.

Darifenacin.pngDarifenacin

OAB is a common condition symptomized by urinary urgency, with or without urge in continence, usually with frequency and nocturia that notably affects the lives of millions of people. Human bladder tissue contains M2 (80%) and M3 (20%) muscarinic receptors, and the latter act as the primary mediator of detrusor contraction in response to cholinergic activation.

So muscarinic receptor antagonists are the current treatment of choice for OAB. As different subtypes of muscarinic receptors are widely distributed in the human body to play key physiological roles, a very selective M3 receptor antagonist is in high demand in the market for OAB medication. Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA) that has been shown to have high affinity and selectivity (59-fold higher) for the M3 receptor, with low selectivity for the other muscarinic receptor subtypes. Its hydrobromide salt  is the active ingredient of pharmaceutical formulations. The efficacy, tolerability and safety of darifenacin in the treatment of OAB are well established.

Darifenacin (trade name Enablex in US and Canada, Emselex in Europe) is a medication used to treat urinary incontinence. It was discovered by scientists at the Pfizer research site in Sandwich, UK under the identifier UK-88,525 and used to be marketed by Novartis. In 2010 the US rights were sold to Warner Chilcott for 400 million US$.

Mechanism of action

Darifenacin works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. It thereby decreases the urgency to urinate. It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.

It should not be used in people with urinary retention. Anticholinergic agents, such as darifenacin, may also produce constipation and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as darifenacin are used in a hot environment.[1]

Clinical uses

Darifenacin is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency in adults.

clip

http://nopr.niscair.res.in/bitstream/123456789/18844/1/IJCb%2052B(6)%20824-828.pdf

The substance was first described in EP 388 054. The method of its preparation in accordance with this document is shown in the following scheme.

Scheme 1

Figure imgf000002_0001

DARIFENACIN

Figure imgf000002_0002

wherein the substituents R and X can be

Figure imgf000003_0001

A particular preferable embodiment is shown in Scheme 2, wherein substance VII is alkylated with 5-(2-bromoethyl)-2,3-dihydrobenzofuran (VIII) in the presence of potash by reflux in acetonitrile. Crude darifenacin (IX) is purified using column chromatography and crystallized from diisopropylether

Scheme 2

Figure imgf000003_0002

Scheme 2: Synthesis of darifenacin by N-alkylation of pyrrolidine VII with 5-(2-bromoethyi)-

2,3-dihydrobenzofuran (VIII)

Darifenacin hydrobromide is prepared by precipitation of purified darifenacin base dissolved in acetone by addition of concentrated aqueous HBr.

However, in repeated reproduction these procedures did not provide a product of an adequate quality in a reasonable industrially applicable yield. It has been found out that a portion of the resulting darifenacin undergoes subsequent alkylation to the second stage, producing the twice substituted substance X. In the course of the reaction undesired reactions of 5-(2-biOmoethyl)-2,3-dihydrobenzofuran VIII also occur, namely hydrolysis producing a hydroxy derivative (XI) and elimination producing a vinyl derivative (XII). All these reactions reduce the yield of the desired substance and complicate the preparation of high-quality API.

By reproduction of the above mentioned procedure a substance was obtained with the following contents of constituents in accordance with HPLC [%] : VII 2.8 VIII 14.2 1X 57.2 X 7.8 XI 1.2 XII 8.0.

Figure imgf000004_0001

A purification procedure for darifenacin was published in WO03080599A1.

Darifenacin in t-amyl alcohol is heated with Amberlite (22 h), the solid fraction is filtered off, the solvent is evaporated from the filtrate and the residue is dissolved in toluene; a solvate of darifenacin with toluene is separated by cooling. This solvate can be directly used for the preparation of darifenacin hydrobromide (the solvate is dissolved in 2-butanol, concentrated HBr is added and the darifenacin salt is separated by cooling).

Another method of purification of darifenacin, described in the same document, is conversion of the darifenacin/toluene solvate to darifenacin hydrate (the solvate is dissolved in acetonitrile and water is added under gradual separation of darifenacin hydrate (Scheme 3)), which can be used for the preparation of salts or can be directly incorporated into pharmaceutical forms. The hydrate can be optionally converted to the hydrogen bromide in a similar way as the solvate.

Figure imgf000005_0001

(IX.W)

Scheme 3: Methods of purification of crude darifenacin and its conversion to hydrobromide

During reproduction of the purification procedure it was possible to separate a portion of substance X in the solid phase form after dissolution of crude darifenacin in toluene. However, the attempt to obtain the desired toluene solvate of darifenacin from the toluene solution was not successful during the reproduction. This means that this method does not lead to the pure substance.

WO2007076159 (TEVA) describes preparation of darifenacin from dihydrobenzofuran ethylchloride and carbamoyl(diphenylmethyl)pyrrolidine tartrate in the aqueous phase using K2CO3 as the base. After cooling of the reaction mixture n-butanol is added, the aqueous and organic phases are separated, acetanhydride is added and a reaction with concentrated hydrobromic acid (48%) is performed.

This method enables preparation of the substance with a satisfactory yield, ca. 77%; however, the reaction in the aqueous phase takes place in the melt, which is very thick, which causes techno logical problems, e.g. difficult stirring, sticking of the mixture on the walls of the reaction vessel, etc. During a reproduction of this procedure it was found that acetanhydride caused partial decomposition of the product and formation of further impurities. The crude product prepared this way cannot be converted to hydrobromide without further purification. N-butanol mentioned in the procedure is partly miscible with water, which also has a negative impact on the process yield. Contents of constituents (HPLC [%]) in the crude product within the reproduction of the procedure in accordance with WO2007076159 (TEVA):

Reaction with dihydrobenzofuran ethylchloride: VII 1.9 VIII 6.1 1X 82.0 X 6.3 XI not found XII not found

Reaction with dihydrobenzofuran ethylbromide: VII 2.8 VIII 0.5 1X 77.5 X 9.5 XI 2.0 XII 2.4

The above mentioned analysis of the described procedures and attempts to reproduce them have revealed that compound X is the major problem. During the application it was never possible to obtain the product that would contain less than 5% of this impurity. The substance is similar to the desired product in its character, it has similar solubility in most solvents and moreover it also changes to hydrogen bromide or other salts. For this reason it is very difficult to separate this substance by normal crystallization of the base or one of the salts of darifenacin.

While toluene has proved suitable for this function in the above-described procedures (WO03080599A1), after the separation of a portion of substance X it was not possible to obtain the desired toluene solvate of darifenacin. The procedure appears to be hardly usable without further modification and it does not lead to the desired pure product.

Darifenacin (la) is chemically known as (S)-2-[l-[2-(2,3-Dihydrobenzofuran-5- yl)ethyl]-3-pyrrolidinyl]-2,2-diphenylacetamide and is approved as hydrobromide salt. Darifenacin is a potent muscarinic M3 receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder, gastrointestinal smooth muscle, saliva production, and iris sphincter function. Darifenacin has greater affinity for the M receptor than for the other known muscarinic receptors. Darifenacin hydrobromide is commercially available under the brand name Enablex® in the US. It has been approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

US 5,096,890 disclosed Darifenacin and its pharmaceutically acceptable salts. US ‘890 discloses several processes for preparing Darifenacin. According to the process disclosed in US ‘890, Darifenacin (la) may be prepared by condensing 5-(2-bromoethyl)-2,3-dihydrobenzofuran (II) with 3-(S)-(-)-(l – carbamoyl-l , l -diphenylmethyl)pyrrolidine (III) in the presence of K2C03 in acetonitrile.

The process is as shown in Scheme-I below:

1. Anhydrous K2C03

Figure imgf000003_0001

US ‘890 also discloses a variant process for the preparation of Darifenacin (la) by condensing 5-(2-bromoethyl)-2,3-benzofuran (IV) with 3-(S)-(-)-(l -carbamoyl- 1 , 1- diphenylmethyl)pyrrolidine (III) in the presence of K2C03 in acetonitrile to produce (S)-2-[l-[2-(2,3-benzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-diphenylacetamide (V), which is further hydrogenated in the presence of Pd/C in acetic acid to produce Darifenacin crude, followed by purification using column chromatography.

The rocess is as shown in Scheme-II below:

Figure imgf000003_0002

Darifenacin

(la)

US ‘890 also discloses an another variant process for the preparation of Darifenacin hydrobromide (I) by condensing 5-chloroacetyl-2,3-dihydrobenzofuran (VI) with 3- (S)-(-)-(l-carbamoyl-l ,l-diphenylmethyl)pyrrolidine (III) in the presence of K2CO3 in an industrial methylated spirit to produce (S)-2-[l-[2-(2,3-benzofuran-5-yl)-2- oxoethyl]-3-pyrrolidinyl]-2,2-diphenylacetamide hydrochloride (VII), which is further hydrogenated in the presence of Pd/C in acetic acid to produce Darifenacin crude, followed by purification using column chromatography to produce pure Darifenacin (la), which is converted to Darifenacin hydrobromide (I) using aqueous hydrobromic acid in acetone.

The rocess is as shown in Scheme-Ill below:

Figure imgf000004_0001

The disadvantage with the above processes is the use of column chromatography in the purification of Darifenacin (la). Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.

US 6,930,188 discloses a process for the preparation of Darifenacin hydrobromide (I), by condensing 2-(2,3-dihydrobenzofuran-5-yl)acetic acid (VIII) with (S)-2,2- diphenyl-2-(3-pyrrolidinyl)acetonitrile hydrobromide (IX) in the presence of carbonyldiimidazole in ethyl acetate to produce (S)-3-(cyanodiphenylmethyl)-l-[2- (2,3-dihydrobenzofuran-5-yl)acetyl]pyri lidine (X), which is further reduced in the presence of sodium borohydride and boron trifluoride tetrahydrofuran complex to produce (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2- diphenyl acetonitrile (XI), followed by treating with HBr to produce (S)-2-{ l-[2- (2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenyl acetonitrile hydrobromide (XIa). Compound (XIa) is treated with potassium hydroxide at 50 to 60°C to produce Darifenacin (la), followed by treating with ion-exchange resin to produce Darifenacin toluene solvate (lb), which is further converted to Darifenacin hydrobromide (I) using 48% hydrobromic acid in 2-butanone.

The rocess is as shown in Scheme-IV below:

Figure imgf000005_0001

Darifenacin HBr

(I) It has now been found that, during the condensation of 5-(2-bromoethyl)-2,3- benzofuran (IV) with 3-(S)-(-)-(l -carbamoyl- l ,l-diphenylmethyl)pyrrolidine (III) to produce (S)-2-[l-[2-(2,3-benzofuran-5-yl)ethyl]-3-pyrroIidinyl]-2,2- diphenylacetamide (V), 3-(S)-(-)-(l -carbamoyl- l , l-diphenylmethyl)pyrrolidine (III) remained unreacted to about 8 to 10% in the reaction mass. It is difficult to separate the compound (III) through crystallization from Darifenacin hydrobromide (I), which typically require two to three crystallizations to achieve desired Darifenacin hydrobromide (I) purity. The second and third crystallization adds time to the manufacturing process and thus negatively impacts product throughput. Additionally, a second and third crystallization reduces yield as some Darifenacin hydrobromide (I) remains uncrystallized and is not recovered from the liquid phase.

Hence, there is a need to develop a purification process, which removes the unreacted intermediate compound 3-(S)-(-)-(l-carbamoyl-l ,l – diphenylmethyl)pyrrolidine (III) from the reaction mass, which in turn provides Darifenacin hydrobromide of high purity with improved yield.

Further, it has been found that Darifenacin produced by the condensation of 5-(2- bromoethyl)-2,3-dihydrobenzofuran (II) with 3-(S)-(-)-( 1 -carbamoyl- 1 ,1 – diphenylmethyOp rrolidine (III) contains dimmer impurity (XII).

Formula (XII)

Figure imgf000006_0001

Hence, there is a need to develop process, which reduces the unwanted Darifenacin dimer (XII), which is influenced by controlling the quantity of compound (XIII).

Figure imgf000007_0001

Formula (XIII)

PROCESS

(a) Dunn, P. J.; Matthews, J. G.; Newbury, T. J.; O’Connor, G.US 6,930,188 B2, 2005.

(b) Narayan, K; Reddy, J. M.; Rao, G.; Chary, S.; Islam, A.; SivakumaranWO 2011/D70419 A1, 2011.

(c) Evansa, P.; Thomas, J.; Davies, R. H.US 2003/0199494 A1, 2003.

(d) Bhanu, M. N.; Naik, S.; Bodkhe, A.; Soni, A.US 2011/0144354 A1, 2011.

(e) Merli, V.; Canavesi, A.; Baverio, P.US 7,442,806 B2, 2008.

(f) Merli, V.; Canavesi, A.; Baverio, P.US 2009/0156831 A1, 2009.

(G)  WO2009125426A2.

(H) Ludmica, H.; Josef, J.WO 2009/094957 A1, 2009.

PATENT

https://www.google.com/patents/WO2011070419A1?cl=en

Image result for Darifenacin

EXAMPLE – 1

Stage-1:

PREPARATION OF 5-(2-TOSYLOXYETHYL)-2,3-

DIHYDROBENZOFURAN

2-(2,3-Dihydrobenzofuran-5yl)ethanol (65 g, 0.39 mol) was dissolved in dichloromethane (650 ml) at 20-25°C under nitrogen atmosphere. The solution was cooled to 0-5°C and p-toluenesulfonyl chloride (79.27 g, 0.41 mol) was added in one lot. Triethylamine (60.04 g, 0.59 mol) was added slowly at 0-10°C, stirred for ~ 15 h at 20-25°C and the reaction was monitored by HPLC. Water was added and stirred for 10 min at 20-25°C. Layers were separated and the aqueous layer was extracted with dichloromethane (130 ml). The organic layer was combined and washed with water (2 x 130 ml) at 20-25°C at pH 12 – 12.5. Finally the organic layer was washed with saturated brine solution (130ml) and concentrated to complete dryness under reduced pressure at 35-45°C. The product was crystallized from ethyl acetate and n- hexanes mixture.

Yield: 96.5 g

Chromatographic purity (By HPLC): 97.85%

Stage-2:

PREPARATION OF DARIFENACIN HYDROBROMIDE

3-(S)-(-)-(l -Carbamoyl- l , l -diphenylmethyl)pyrrolidine L-(+)-tartrate (10 g, 0.02 mol), anhydrous potassium carbonate (22.50 g, 0.16 mol) and 5-(2-tosyloxyethyl)- 2,3-dihydrobenzofuran (7 g, 0.02 mol) were suspended in anhydrous acetonitrile ( 100 ml) under nitrogen atmosphere at 25 ± 2°C. The reaction suspension was heated to 70 ± 2 °C and stirred for 4 h. Reaction progress was monitored by HPLC. The reaction mass was cooled to 30 + 2°C, the salts were filtered and washed with acetonitrile (10 ml). The filtrate was concentrated under reduced pressure at 50 ± 2 °C. The residue was dissolved in dichloromethane (50 ml), water (50 ml) was added and the pH was adjusted to 2 ± 0.1 with 24% w/w aqueous hydrobromic acid at 25- 30°C. The layers were separated and the aqueous layer was extracted with aqueous dichloromethane (20 ml). Water (50 ml) was added to the combined dichloromethane layer and pH was adjusted to 9 ± 0.1 with 25% w/w aqueous potassium carbonate solution at 25 ± 2°C. The layers were separated and concentrated under reduced pressure at 35-40°C. The residue was dissolved in acetone (50 ml), cooled to 5-10°C and the pH was adjusted to acidic with 48% w/w aqueous hydrobromic acid at 5-10°C. The residue was stirred for 2 h at 20-25°C, cooled to 0-5°C and stirred for 1 h at 0-5°C. The product was filtered, washed with chilled acetone (10 ml) and dried at 50-55°C.

Yield: 9.4 g

Chromatographic purity (By HPLC): 98.2%.

5 -(2-Tosy loxyethy l)-2, 3 -dihydrobenzofuran : Nil

Darifenacin dimer impurity: 0.96%.

EXAMPLE – 2

Stage-1 :

PREPARATION OF 5-(2-BROMOETHYL)-2,3-DIHYDROBENZOFURAN

2- (2,3-Dihydrobenzofuran-5-yl)ethanol (10 g, 0.06 mol) was dissolved in acetonitrile (60 ml) at 25 ± 2°C under nitrogen atmosphere and triphenylphosphine dibromide (27.02 g, 0.06 mol) was added in one lot at 25 ± 2°C. The reaction mass was heated to 76-78°C and stirred for 2 h. Reaction progress was monitored by TLC [Ethyl acetate: n-Hexanes; 2:8 v/v], Acetonitrile was completely distilled off under reduced pressure at 76-78°C. The residue was cooled and the product was extracted with n-hexanes (4 x 30 ml) at 25 ± 2°C. The solution was filtered and diluted with ethyl acetate (50 ml) and washed with 5% w/w aqueous sodium bicarbonate solution (2 x 50 ml) at 25 ± 2°C. The organic layer was concentrated under reduced pressure at 40-50°C.

Yield: 7 g

Stage-2

PREPARATION OF DARIFENACIN HYDROBROMIDE

3- (S)-(-)-(l -Carbamoyl- l ,l-diphenylmethyl)pyrrolidine L-(+)-tartrate (5 g, 0.01 mol), anhydrous potassium carbonate (1 1.25 g, 0.08 mol) and 5-(2-bromoethyl)-2,3- dihydrobenzofuran (2.5 g, 0.01 mol) were suspended in anhydrous acetonitrile (50 ml) under nitrogen atmosphere at 25 ± 2°C. The reaction suspension was heated to 70 ± 2 °C and stirred for 4 h. Reaction progress was monitored by HPLC. The reaction mass was cooled to 30 ± 2°C, salts were filtered and washed with acetonitrile (5 ml). The filtrate was concentrated under reduced pressure at 50 ± 2 0 C. The residue was dissolved in dichloromethane (25 ml), water (25 ml) was added and the pH was adjusted to 2 ± 0.1 with 24% w/w aqueous hydrobromic acid at 25- 30°C. The layers were separated and the aqueous layer was extracted with dichloromethane (10 ml). Water (25 ml) was added to the combined dichloromethane layer and pH was adjusted to 9 ± 0.1 with 25% w/w aqueous potassium carbonate solution at 25 ± 2°C. The layers were separated and the organic layer was concentrated under reduced pressure at 35-40°C. The residue was dissolved in acetone (25 ml), cooled to 5-10°C and the pH was adjusted to acidic with 48% w/w aqueous hydrobromic acid at 5-10°C. The residue was stirred for 2 h at 20-25°C, cooled to Q-5°C and stirred for 1 h at 0-5°C. The product was filtered, washed with chilled acetone (5 ml) and dried at 50-55°C.

Yield: 4.5 g

Chromatographic purity (By HPLC): 99.24%

5-(2-bromoethyl)-2,3-dihydiObenzofuran: Nil

Darifenacin dimer impurity: 0.39%.

EXAMPLE – 3

PURIFICATION OF DARIFENACIN HYDROBROMIDE Darifenacin hydrobromide (10 g) was suspended in acetic acid (15 g) at 25 ± 2°C and heated to 65-70°C. Activated carbon (0.25 g) was added and stin-ed for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with hot acetic acid (5 g). Water (200 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20-25 °C and stin-ed for 1 h and further cooled to 0-5 °C and stirred for 1 h. The solid was filtered and washed with cold water (10 ml). The product was dried at 50-55°C.

Yield: 7.6 g

Chromatographic purity (By HPLC): 99.52%

5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil 5-(2-Tosyloxyethyl)-253-dihydrobenzofuran: Nil

Darifenacin dimer impurity: 0.20%.

EXAMPLE – 4

PURIFICATION OF DARIFENACIN HYDROBROMIDE

Darifenacin hydrobromide (15 g) was suspended in a mixture of acetic acid (25 g) and water (25 ml) at 25 ± 2°C and heated to 65-70°C. Activated carbon (0.75 g) was added and stirred for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with a mixture of acetic acid and DM water (10 g). Water (120 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20- 25°C and stirred for 1 h and further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with cold water (30 ml). The product was dried at 50-55°C. Yield: 1 1.9 g

Chromatographic purity (By HPLC): 99.71 %

5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil

5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: Nil

Darifenacin dimer impurity: 0.20%. EXAMPLE – 5

PURIFICATION OF DARIFENACIN HYDROBROMIDE

Darifenacin hydrobromide (9 g) was suspended in acetone (45 ml) at 25 ± 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55-60°C. The resulting solution was cooled to 20-25°C and stin-ed for 30 + 5 min, which is further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.

Yield: 8.8 g

Chromatographic purity (By HPLC): 99.87%

5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil

5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: Nil

Darifenacin dimer impurity: 0.08%. EXAMPLE – 6

PURIFICATION OF DARIFENACIN HYDROBROMIDE

Darifenacin hydrobromide (9 g) was suspended in a mixture of acetone (45 ml) and DM water (1.77 ml) at 25 ± 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55- 60°C. The resulting solution was cooled to 20-25°C and stirred for 30 + 5 min, which was further cooled to 0-5°C and stirred for 1 h. The product was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.

Yield: 8.4 g

Chromatographic purity (By HPLC): 99.88%

EXAMPLE – 7

PURIFICATION OF DARIFENACIN HYDROBROMIDE

Darifenacin hydrobromide (10 g) was suspended in a mixture of acetone (50 ml) and DM water (3.95 ml) at 25 ± 2°C, heated to 55-58°C and stirred for 30 ± 5 min. The resulting solution was cooled to 20-25°C and stirred for 30 ± 5 min, which was further cooled to 0-5 °C and stirred for 1 hour. The product was filtered and washed with chilled acetone (10ml, 0-5°C). The product was dried at 50-55°C.

Yield: 8.30g

Chromatographic Purity (By HPLC): 99.83 %

Darifenacin dimmer: 0.10%

EXAMPLE – 8

PURIFICATION OF DARIFENACIN HYDROBROMIDE

Darifenacin hydrobromide (10 g) was suspended in a mixture of acetone (50 ml) and DM water (7.9 ml) at 25 ± 2°C, heated to 55-60°C and stirred for 30 + 5 min. The resulting solution was cooled to 20-25°C and stirred for 30 ± 5 min, which was further cooled to 0-5°C and stirred for 1 hour. The product was filtered and washed with chilled acetone (10 ml, 0-5°C). The product was dried at 50-55°C.

Yield: 6.70g

Chromatographic Purity (By HPLC): 99.94 %

Darifenacin dimmer: Nil.

Paper

A New Solvent System (Cyclopentyl Methyl Ether–Water) in Process Development of Darifenacin HBr

API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune-411057, India
Org. Process Res. Dev., 2012, 16 (10), pp 1591–1597
DOI: 10.1021/op300119s
*Fax: +91-20-39821445. E-mail: chinmoy.pramanik@emcure.co.in.
Abstract Image

Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA), and its hydrobromide salt (1) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide (1).

1H NMR (DMSO-d6, 400 MHz, δ ppm): 9.8 (bs, 0.7H), 9.3 (bs, 0.3 H), 7.4–7.3 (m, 10 H), 7.1–7.0 (m, 1H), 7.0–6.7 (m, 2H), 6.7 (m, 1H), 4.5 (m, 2H), 4.0–3.9 (m, 1.3 H), 3.8–3.7 (m, 0.7 H), 3.4–3.3 (m, 2H), 3.1 (m, 2H), 2.9 (m, 1.3 H), 2.8–2.7 (m, 2H), 2.6 (m, 0.7H), 2.4–2.3 (m, 0.7H), 2.2 (m, 1.3H), 1.6 (m, 0.7 H), 1.5 (m, 0.3 H).

13C NMR (DMSO-d6, 100 MHz, δ ppm): 174.4, 174.2, 158.5, 141.2, 140.7, 140.6, 129.7, 129.4, 129.5, 128.3, 128.0, 127.9, 127.5, 127.2, 127.1, 125.4, 125.2, 108.7, 70.8, 62.4, 62.1, 56.1, 55.2, 55.1, 54.7, 53.0, 52.2, 40.0, 40.8, 30.3, 30.1, 29.0, 26.9, 25.6.

Calcd for C28H30N2O2·HBr, (M+)/z: 425.56; found (M + H)/z 427.2, (M + Na)/z 449.3.

Anal. Calcd for C28H31BrN2O2: C, 66.27; H, 6.16; N, 5.52. Found: C, 66.36; H, 6.07; N, 5.68.

PATENT

https://www.google.com/patents/WO2009094957A1?cl=en

Scheme 4:

Figure imgf000008_0001

Example 1

Figure imgf000010_0001

Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium phosphate (9.43 g; 0.041 mol in 20 ml of water) at the laboratory temperature. A toluene solution (20 ml) of intermediate VIII (2.41 g; 0.011 mol) is added to the mixture and the mixture is heated up in an oil bath T=90 0C while being stirred for 3.5 h. After cooling the toluene layer is separated and the aqueous layer is extracted with toluene. The combined toluene extracts are shaken with water and the solvent is distilled off at a reduced pressure. The evaporation residue is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacin hydrobromide is filtered off and dried.

Yield: 85% of theory.

Example 2

Figure imgf000010_0002

Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium carbonate (6.1 g; 0.044 mol in 20 ml of water) at the laboratory temperature. A toluene solution (20 ml) of intermediate VIII (2.41 g; 0.011 mol) is added to the mixture and the mixture is heated in an oil bath T=90 °C while being stirred for 3.5 h. After cooling the toluene layer is separated and the aqueous layer is extracted with toluene. The combined toluene extracts are shaken with water and the solvent is distilled off at a reduced pressure. The evaporation residue is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacine hydrobromide is filtered off and dried.

Yield: 86% of theory.

Example 3

Figure imgf000011_0001

Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium phosphate (9.43 g; 0.041 mol in 20 ml of water) at the laboratory temperature. A solution of intermediate VIII (2.41 g; 0.011 mol) in cyclohexane (20 ml) is added to the mixture and the mixture is heated in an oil bath T=90 0C while being stirred for 3.5 h. The layers are separated while hot. The cyclohexane solution is cooled to the laboratory temperature under intensive stirring. This way the darifenacin base is separated. The product is filtered off and dried. The base is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacin hydrobromide is filtered off and dried.

Yield: 85% of theory.

clip

Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MSn

Graphical abstract: Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MSn

References

External links

Citing Patent Filing date Publication date Applicant Title
WO2011070419A1 * Dec 3, 2010 Jun 16, 2011 Aurobindo Pharma Limited An improved process for the preparation of darifenacin hydrobromide
Cited Patent Filing date Publication date Applicant Title
WO2003080599A1 Mar 17, 2003 Oct 2, 2003 Novartis International Pharmaceutical Ltd. Stable hydrate of a muscarinic receptor antagonist
WO2007076157A2 * Dec 27, 2006 Jul 5, 2007 Teva Pharmaceuticals Industries Ltd. Processes for preparing darifenacin hydrobromide
WO2007076158A2 * Dec 27, 2006 Jul 5, 2007 Teva Pharmaceutical Industries Ltd. Processes for preparing darifenacin hydrobromide
WO2007076159A2 Dec 27, 2006 Jul 5, 2007 Teva Pharmaceutical Industries Ltd. Pure darifenacin hydrobromide substantially free of oxidized darifenacin and salts thereof and processes for the preparation thereof
EP0388054A1 Mar 2, 1990 Sep 19, 1990 Pfizer Limited Pyrrolidine derivatives
WO2009094957A1 * Jan 14, 2009 Aug 6, 2009 Zentiva, K.S. A method for the preparation of darifenacin hydrogen bromide
US5096890 Mar 13, 1990 Mar 17, 1992 Pfizer Inc. Pyrrolidine derivatives
US6930188 Mar 25, 2003 Aug 16, 2005 Novartis International Pharmaceutical, Ltd. Stable hydrate of a muscarinic receptor antagonist
Darifenacin
Darifenacin.svg
Darifenacin-hydrobromide-from-xtal-2009-CM-3D-balls.png
Clinical data
Trade names Enablex
AHFS/Drugs.com Monograph
MedlinePlus a605039
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code G04BD10 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 15 to 19% (dose-dependent)
Protein binding 98%
Metabolism Hepatic (CYP2D6– and CYP3A4-mediated)
Biological half-life 13 to 19 hours
Excretion Renal (60%) and biliary (40%)
Identifiers
CAS Number 133099-04-4 Yes
PubChem (CID) 444031
IUPHAR/BPS 321
DrugBank DB00496 Yes
ChemSpider 392054 Yes
UNII APG9819VLM Yes
KEGG D01699 
ChEBI CHEBI:391960 Yes
ChEMBL CHEMBL1346 Yes
ECHA InfoCard 100.118.382
Chemical and physical data
Formula C28H30N2O2
Molar mass 426.55 g/mol
3D model (Jmol) Interactive image

/////////Darifenacin, 臭化水素酸ダリフェナシン ,  Antispasmodic, Antimuscarinic, UK-88525-04, Emselex® ,  Enablex® ,  Xelena®, 

C1CN(CC1C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N)CCC4=CC5=C(C=C4)OCC5

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