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Onions contain a powerful cancer fighting compound — ClinicalNews.Org

October 27, 2016 12:57 am / Leave a comment

https://youtube.com/watch?v=GKv2q5cBEhE%3Fversion%3D3%26rel%3D1%26fs%3D1%26autohide%3D2%26showsearch%3D0%26showinfo%3D1%26iv_load_policy%3D1%26hd%3D1%26wmode%3Dtransparent

Onions contain a powerful cancer fighting compound Onions contain a powerful cancer fighting compound We review the study” Anti-cancer effects found in natural compound derived from onions ” This study was done in regard to Ovarian Cancer, but should have potential in a variety of cancers. * Tsuboki, J. et al. Onionin A inhibits ovarian […]

via Onions contain a powerful cancer fighting compound — ClinicalNews.Org

BMS-442608

October 26, 2016 10:59 am / Leave a comment

BMS-442608

8-Azaspiro(4.5)decane-7,9-dione, 6-hydroxy-8-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-, (6R)-

(6R)-6-Hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

(R)-6-Hydroxybuspirone, UNII-93881477KV, CAS 477930-30-6,

Molecular Formula, C21-H31-N5-O3, Molecular Weight, 401.5079

BMS-442608 is a 5-HT1A partial agonist. BMS-442608 is the R-enantiomer. (R)-Enantiomer showed higher affinity and selectivity for the 5HT1A receptor compared to the (S)-enantiomer. (S)-Enantiomer has advantage of being cleared more slowly from blood compared to the (R)-enantiomer.

PAPER

Enantioselective α-Hydroxylation of 2-Arylacetic Acid Derivatives and Buspirone Catalyzed by Engineered Cytochrome P450 BM-3

Marco Landwehr ,^† Lisa Hochrein ,^† Christopher R. Otey ,^† Alex Kasrayan ,^‡ Jan-E. Bäckvall ,^‡ and Frances H. Arnold *^†

Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, Pasadena, California 91125-4100, U.S.A., and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE−106 91 Stockholm, Sweden.

J. Am. Chem. Soc., 2006, 128 (18), pp 6058–6059

DOI: 10.1021/ja061261x

http://pubs.acs.org/doi/abs/10.1021/ja061261x

Here we report that an engineered microbial cytochrome P450 BM-3 (CYP102A subfamily) efficiently catalyzes the α-hydroxylation of phenylacetic acid esters. This P450 BM-3 variant also produces the authentic human metabolite of buspirone, R-6-hydroxybuspirone, with 99.5% ee.

PATENT

US 20020193380

http://www.google.st/patents/US20020193380

PATENT

WO 2003009851

https://google.com/patents/WO2003009851A1?cl=en

PAPER

Tetrahedron: Asymmetry (2005), 16(16), 2711-2716.

Tetrahedron: Asymmetry

Volume 16, Issue 16, 22 August 2005, Pages 2711–2716

Preparation of (R)- and (S)-6-hydroxybuspirone by enzymatic resolution or hydroxylation

Department of Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, One Squibb Drive, New Brunswick, NJ 08903, USA

http://www.sciencedirect.com/science/article/pii/S0957416605005549

http://dx.doi.org/10.1016/j.tetasy.2005.07.020

Abstract

6-Hydroxybuspirone is an active metabolite of the antianxiety drug buspirone. The (R)- and (S)-enantiomers of 6-hydroxybuspirone were prepared using an enzymatic resolution process. l-Amino acid acylase from Aspergillus melleus (Amano Acylase 30000) was used to hydrolyze racemic 6-acetoxybuspirone to (S)-6-hydroxybuspirone in 95% ee after 45% conversion. The remaining (R)-6-acetoxybuspirone with 88% ee was converted to (R)-6-hydroxybuspirone by acid hydrolysis. The ee of both enantiomers could be improved to 99% by crystallization as a metastable polymorph. (S)-6-Hydroxybuspirone was also obtained in 88% ee and 14.5% yield by hydroxylation of buspirone using Streptomyces antibioticus ATCC 14890.

Graphical abstract


(S)-6-Hydroxybuspirone C₂₁H₃₁N₅O₃ Ee = 99.6% (c 1, 1 M HCl) Source of chirality: enzymatic resolution Absolute configuration: 6S

PAPER

Tetrahedron: Asymmetry (2005), 16(16), 2778-2783

http://dx.doi.org/10.1016/j.tetasy.2005.07.015

Abstract

The enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 1 to either of the corresponding (R)- or (S)-6-hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-diones 2 and 3 is described.

Graphical abstract

PAPER

Enzyme and Microbial Technology (2006), 39(7), 1441-1450.

http://dx.doi.org/10.1016/j.enzmictec.2006.03.033

Abstract

The enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione (1) to either of the corresponding (S)- and (R)-6-hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-diones (2 and 3, respectively) is described. The NADP⁺-dependent (R)-reductase (RHBR) which catalyzes the reduction of 6-ketobuspirone (1) to (R)-6-hydroxybuspirone (3) was purified to homogeneity from cell extracts of Hansenula polymorpha SC 13845. The subunit molecular weight of the enzyme is 35,000 kDa based on sodium dodecyl sulfate gel electrophoresis and the molecular weight of the enzyme is 37,000 kDa as estimated by gel filtration chromatography. (R)-reductase from H. polymorpha was cloned and expressed in Escherichia coli. To regenerate the cofactor NADPH required for reduction we have cloned and expressed the glucose-6-phosphate dehydrogenase gene from Saccharomyces cerevisiae in E. coli. The NAD⁺-dependent (S)-reductase (SHBR) which catalyzes the reduction of 6-ketobuspirone (1) to (S)-6-hydroxybuspirone (2) was purified to homogeneity from cell extracts of Pseudomonas putida SC 16269. The subunit molecular weight of the enzyme is 25,000 kDa based on sodium dodecyl sulfate gel electrophoresis. The (S)-reductase from P. putida was cloned and expressed in E. coli. To regenerate the cofactor NADH required for reduction we have cloned and expressed the formate dehydrogenase gene from Pichia pastoris in E. coli. RecombinantE. coli expressing (S)-reductase and (R)-reductase catalyzed the reduction of 1 to (S)-6-hyroxybuspirone (2) and (R)-6-hyroxybuspirone (3), respectively, in >98% yield and >99.9% e.e.

PATENT

https://www.google.com/patents/US6686361

Inventors	Joseph P. Yevich, Robert F. Mayol, Jianqing Li,Frank Yocca
Original Assignee	Bristol-Myers Squibb Company

The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.

Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR® from Bristol-Myers Squibb Company.

Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or

as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.

Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991, Psychopharmacology, 105:513-520).

Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.

Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.

It can be seen that it is desirable to find a medicament with buspirone’s advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.

Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drug—drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.

R-6-hydroxy-buspirone may be prepared utilizing methods of synthesis and enantiomeric separation known to one skilled in the art. One method of preparation (Scheme 1) utilizes buspirone as a starting material to produce racemic 6-hydroxy-buspirone that is separated into the two enantiomers by chiral chromatographic techniques.

An improved one-step synthesis of racemic 6-hydroxy-buspirone is set forth in Scheme 2. Again, enantiomeric separation provides R-6-hydroxy-buspirone.

EXAMPLE 1 Preparation of 6-Hydroxy-buspirone

A. Di-4-nitrobenzyl Peroxydicarbonate (V)

Di-4-nitrobenzyl peroxydicarbonate was prepared using a modification of the literature procedure¹. Thus, to an ice-cold solution of 4-nitrobenzyl chloroformate (10.11 g, 4.7 mmol) in acetone (20 mL) was added dropwide over 30 min an ice-cold mixture of 30% H₂O₂(2.7 mL, 24 mmol) and 2.35 N NaOH (20 mL, 47 mmol). The mixture was vigorously stirred for 15 min and then it was filtered and the filter-cake was washed with water and then with hexane. The resulting damp solid was taken up in dichloromethane, the solution was dried (Na₂SO₄) and then it was diluted with an equal volume of hexane. Concentration of this solution at 20° C. on a rotary evaptor gave a crystalline precipitate which was filtered, washed with hexane and dried in vacuo to give compound III (6.82 g, 74%) as pale yellow microcrystals, mp 104° C. (dec).

¹F. Strain, et al., J. Am. Chem. Soc., 1950, 72, 1254

Di-4-nitrobenzyl peroxydicarbonate was found to be a relatively stable material which decomposed as its melting point with slow gas evolution. In comparison, dibenzyl peroxydicarbonate²decomposed with a sudden vigorous expulsion of material from the melting point capillary.

²Cf. M. P. Gove, J. C. Vedaras, J. Org. Chem., 1986, 51, 3700

B. 6-(4-Nitrobenzyl peroxydicarbonatyl)-8-[4-[4-(2-pyrimidinyl)-piperazinyl]-butyl]-8-azaspiro[4.5]-7,9-dione (III)

To a solution of 8-[4-[4-(2-pyrimidinyl)-piperazinyl]-butyl]-8-azaspiro[4.5]-7,9-dione (buspirone: 10 g, 26 mmole) in dry THF (250 mL) was added LiN (Me₃Si)₂(28.5 mL of a 1 M THF solution) at 78° C. and stirred for 3 h and then a solution of di-4-nitrobenzyl peroxydicarbonate (11.2 g) in dry THF (150 mL) was added dropwide over 1 h. Stirring was continued at −78° C. for 1 h.

The cooling bath was removed and the reaction solution was poured into a mixture of H₂O and EtOAc. The organic phase was separated and washed with H₂O and then brine. The organic base was dried and then evaporated to a viscous oil. Flash chromatography of this oil, eluting the silica column with MeCN-EtOAc (1:2) gave crude product which was washed with acetone, to remove unreacted buspirone, leaving 6.23 g of a white solid (46%) product (III).

C. 6-Hydroxy-8-[4-[4-(2-pyrimidinyl)-piperazinyl]-butyl]-8-azaspiro[4.5]-7,9-dione (I; 6-Hydroxy-buspirone)

A mixture of III (4.0 g; 6.9 mmole) and 10% Pd/C (about 1 g) in MeOH (100 mL) was hydrogenated in a Parr shaker at 40-45 psi for 1 h. The hydrogenation mixture was filtered through a Celite pad which was then washed with EtOAc. The filtrate was evaporated to a gum which was purified by flash chromatography through a silica gel column eluting with EtOAc to give 0.41 g of an off-white solid (I).

Anal. Calcd. for C₂₁H₃₁N₅O₃: C, 62.82; H, 7.78; N, 17.44. Found: C, 62.84; H, 7.81; N, 17.33.

EXAMPLE 2 Enantiomeric Separation

Preparative Chiral HPLC Purification Procedure for 6-hydroxy-buspirone

1.1 g 6-Hydroxy-buspirone is dissolved in 55 mL HPLC grade methanol (20 mg/mL). Repetitive 0.5 mL injections of the solution are made on a Chirobiotic-Vancomycin Chiral HPLC column, 22.1 mm×250 mm, 10 um particle size (Advanced Separation Technologies, Inc., Whippany, N.J.) equilibrated with a mobile phase of MeOH/acetic acid/triethylamine, 100/0.2/0.1, v/v/v, at a flow rate of 20 mL/minute. The UV trace is monitored at 236 nm. Each enantiomer (RTs˜10.9 and ˜13.4 minutes, respectively) is collected in ˜1000 mL of mobile phase and condensed separately under reduced pressure at 40° C. ˜2 mL of clear solution resulting from the evaporation of methanol is diluted with 5 mL of H₂O. The pH of these solutions is adjusted from 5 to ˜8 with NH₄OH, upon which a white precipitate is observed. The precipitates are centrifuged, and the aqueous layers extracted three times with equal volumes of methylene chloride. The methylene chloride layers are evaporated and any remaining solid is re-chromatographed. The centrifuged precipitates are washed three times with H₂O to remove any residual salts and air dried at room temperature.

The basic form of R-6-hydroxy-buspirone can be converted to the hydrochloride salt by treatment of an ethanol solution of R-6-hydroxy-buspirone with ethanolic HCl.

EXAMPLE 3 One-Step Synthesis of 6-Hydroxy-buspirone (I)

Buspirone (19.3 g, 50 mmole) was dissolved in dry THF (400 mL) and the resulting solution was cooled to −78° C. A solution of KN(SiMe₃)₂in toluene (100 mL, 1 M) was added slowly. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, prepared according to literature method: F. A. Davis, et al., Org. Synth., 1988, 66, 203) (17.0 g, 65 mmole) in dry THF (150 mL, precooled to −78° C.) was added quickly via a cannular. After stirred for 30 mins at −78° C., the reaction was quenched with 1 N HCl solution (500 mL). It was extracted with EtOAc (3×500 mL). The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid residue which was subjected to column chromatography using CH₂Cl₂/MeOH/NH₄OH (200:10:1) as the eluent to give pure 6-hydroxy-buspirone (I, 7.2 g) and a mixture of buspirone and 6-hydroxy-buspirone (I). The mixture was purified by above column chromatography to afford another 3.3 g of pure 6-hydroxy-buspirone (I).

¹H NMR (CDCl₃) δ8.30 (d, J=4.7 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.20 (s, 1H), 3.83-3.72 (m, 5H), 3.55 (s, 1H), 2.80 (d, J=17.5 Hz, 1H), 2.55-2.40 (m, 7H), 2.09-2.03 (m, 1H), 1.76-1.54 (m, 10 H), 1.41-1.36 (m, 1H), 1.23-1.20 (m, 1H).

EXAMPLE 4 5-HT1A Receptor Binding Assay

Membranes are prepared for binding using the human 5-HT1 A receptor expressed in HEK293 cells. Cells are collected and ruptured using a dounce homogenizer. The cells are spun at 18000×g for 10 minutes and the pellet is resuspended in assay buffer, frozen in liquid nitrogen and kept at −80° C. until the day of the assay.

A total of 30 ug protein is used per well. The assay is carried out in 96-deep-well plates. The assay buffer is 50 mM HEPES containing 2.5 mM MgCl₂and 2 mM EGTA. The membrane preparation is incubated at 25° C. for 60 minutes with 0.1 nM to 1000 nM test compound and 1 nM 3H-8-OH-DPAT. 10 mM serotonin serves as blocking agent to determine non-specific binding. The reaction is terminated by the addition of 1 ml of ice cold 50 mM HEPES buffer and rapid filtration through a Brandel Cell Harvester using Whatman GF/B filters. The filter pads are counted in an LKB Trilux liquid scintillation counter. IC₅₀values are determined using non-linear regression by Excel-fit.

EXAMPLE 5 Rat Pup Isolation-Induced Ultrasonic Vocalization Test

Harlan Sprague-Dawley rat pups (male and female) were housed in polycarbonate cages with the dam until 9-11 days old. Thirty minutes before testing, pups were removed from the dam, placed into a new cage with a small amount of home bedding and brought into the lab and placed under a light to maintain body temperature at 37° C. Pups were then weighed, sexed, marked and returned to the litter group until behavioral assessment. Testing took place in a Plexiglas recording chamber that contained a metal plate maintained at (18-20° C.) with a 5×5 cm grid drawn on the plate. A microphone was suspended 10 cm above the plate to record ultrasonic vocalizations. Ultrasonic calls were recorded using the Noldus UltraVox system providing online analysis of the frequency and duration of calls. The number of grid cells entered by the pup was also collected by visual scoring. Pups that failed to emit at least 60 calls during a 5 minute pretest session were excluded from pharmacological assessment. Immediately following the collection of the baseline measures, pups were injected with vehicle or drug subcutaneously at the nape of the neck and returned to its littermates. Thirty minutes later, pups were retested on each of the dependent measures (vocalization and grid cell crossings) to assess drug effects. Unless otherwise specified, each pup was used only once. Baseline differences and percent change from baseline for the frequency of ultrasonic vocalizations and grid cell crossings were analyzed using a one-way ANOVA. Bonferroni/Dunn post hoc comparisons were performed to assess the acute drug effects with vehicle control. Log-probit analysis was used to estimate the dose (milligrams per kilogram) of each agonist predicted to inhibit isolation-induced ultrasonic vocalizations by 50% (ID₅₀). All comparison were made with an experimental type I error rate (α) set at 0.05.

Doses for each drug were administered in an irregular order across several litters. R-6-hydroxy-buspirone and racemic 6-hydroxy-buspirone were dissolved in physiological saline (0.9% NaCl; vehicle). All injections were administered subcutaneously in a volume of 10 ml/kg. Doses of the drug refer to weight of the salt.

Clip

http://onlinelibrary.wiley.com/doi/10.1002/bdd.566/abstract?systemMessage=Due+to+essential+maintenance+the+subscribe%2Frenew+pages+will+be+unavailable+on+Wednesday+26+October+between+02%3A00+-+08%3A00+BST%2F+09%3A00+%E2%80%93+15%3A00++SGT%2F+21%3A00-+03%3A00+EDT.+Apologies+for+the+inconvenience.

Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans

DOI: 10.1002/bdd.566

The objective of this study was to assess the pharmacokinetics of 6-hydroxybuspirone (6OHB) when given orally via three forms: racemate (BMS-528215), S-enantiomer (BMS-442606) and R-enantiomer (BMS-442608), versus following the administration of buspirone. A double-blind, randomized, four-period, four-treatment, crossover study balanced for residual effects in healthy subjects was conducted (n=20). Subjects received single 10 mg doses of each compound in a randomized fashion with pharmacokinetics determined over a 24 h period. There was a 4-day washout between each dosing period. All three forms of 6OHB (racemate, S-enantiomer and R-enantiomer) were well tolerated. There was nterconversion between enantiomers. The dominant enantiomer was the S-enantiomer no matter which form of 6OHB was administered. All three forms of 6OHB produced approximately 2- to 3-fold greater exposure to total 6OHB than did buspirone. All three forms produced equal exposure to 1-(2-pyrimidinyl)-piperazine (1-PP) which was approximately 30% less than the 1-PP exposure derived from buspirone administration. All three forms of 6OHB produced approximately 3-fold higher 6OHB:1-PP ratios and approximately 2.5-fold higher total 6OHB exposures than did buspirone administration. All compounds were well tolerated. There seemed to be no advantage of one of the enantiomers of 6OHB over the racemate. Therefore, the racemate was chosen for further clinical development. Copyright © 2007 John Wiley & Sons, Ltd.

Cited Patent	Filing date	Publication date	Applicant	Title
US6150365	Jun 6, 2000	Nov 21, 2000	Bristol-Myers Squibb Company	Anxiety method

Reference
1		Mayol, et al., “Pharmacokinetics and Disposition of 14C-Buspirone HCI After Intravenous and Oral Dosing in Man,” Clin. Pharmacol. Ther., 37, p. 210, 1985.
2	*	Robichaud et al. in Annual Reports in Medicinal Chemistry, vol. 35,pp. 11-20 (2000).*
3		Winslow, et al., “Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists,” Psychopharmacology, 105, pp. 513-520, 1991.

Citing Patent	Filing date	Publication date	Applicant	Title
US20090023744 *	Jun 17, 2008	Jan 22, 2009	The General Hospital Corporation	Combination therapy for depression
WO2015197079A1	Jun 25, 2015	Dec 30, 2015	Contera Pharma Aps	Use of buspirone metabolites

REFERENCES

1: Dockens RC, Tran AQ, Zeng J, Croop R. Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans. Biopharm Drug Dispos. 2007 Oct;28(7):393-402. PubMed PMID: 17668416.

///////////////BMS-442608, BMS 442608, (R)-6-Hydroxybuspirone, UNII-93881477KV, CAS 477930-30-6

c1cnc(nc1)N2CCN(CC2)CCCCN3C(=O)CC4(CCCC4)[C@H](C3=O)O

BMS-442606
477930-31-7

2D chemical structure of 477930-31-7 MW: 401.5079

S FORM

https://www.google.com/patents/US6821976

Cetilistat, セチリスタット

October 26, 2016 10:57 am / Leave a comment

ChemSpider 2D Image | Cetilistat | C25H39NO3

Cetilistat, セチリスタット

Molecular FormulaC₂₅H₃₉NO₃
Average mass401.582 Da

CAS 282526-98-1

2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one

282526-98-1 [RN]

2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one

2-hexadecyl-oxy-6-methyl-4H-3,1-benzoxazin-4-one

4H-3,1-Benzoxazin-4-one, 2-(hexadecyloxy)-6-methyl

[282526-98-1]

2-(Hexadecycloxy)-6-methyl-4H-3,1-benzoxazin-4-one

ATL-962; ATL962;ATL 962

Trade Name：Oblean^®

MOA：Pancreatic lipase inhibitor

Indication：Obesity

Status：Approved, 2013-09-20 JAPAN, Japan PMDA.

Company：Norgine (Originator) , Takeda

UPDATE 09.07.2021 INDIA CDSCO For the treatment of Obseity (limited to
patients with both type 2 diabetes mellitus
and dyslipidaemia, and with a BMI ≥ 25
kg/m2 inspite of dietary treatment and /or
excersise therapy)…………Cetilistat bulk and Cetilistat 120 mg tablets

Cetilistat was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on September 20, 2013. It was developed by Norgine and Takeda, then marketed as Oblean^® by Takeda in Japan.

Cetilistat is a pancreatic lipase inhibitor, and it acts in the same way as the older drug orlistat (Xenical) by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. It is usually used for the treatment of obesity (limited to patients with both type 2 diabetes mellitus and dyslipidemia, and with a BMI≥25 kg/m² in spite of dietary treatment and/or exercise therapy).

Oblean^® is available as tablet for oral use, containing 120 mg of free Cetilistat. The recommended dose is 120 mg three times a day immediately after each meal.

Cetilistat is a drug designed to treat obesity. It acts in the same way as the older drug orlistat (Xenical) by inhibitingpancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.^[1]

In human trials, cetilistat was shown to produce similar weight loss to orlistat, but also produced similar side effects such as oily, loose stools, fecal incontinence, frequent bowel movements, and flatulence.^[2]^[3] It is likely that the same precautions would apply in that absorption of fat-soluble vitamins and other fat-soluble nutrients may be inhibited, requiring vitamin supplements to be used to avoid deficiencies.

Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contribute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon and disappointing. Drug therapy is considered for individuals with a body mass index greater than 30 kg/m² or ranging from 25 to 30 kg/m² if they have comorbid conditions. Antiobesity agents can be helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceutical tools are of limited effectiveness considering the magnitude of the problem. At the present, only two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss.

Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis.

Image result for Cetilistat

Cetilistat has completed Phase 1 and 2 trials in the West and is currently in Phase 3 trials in Japan where it is partnered with Takeda.^[4] Norgina BV has now acquired the full global rights to cetilistat from Alizyme after the latter went into administration.^[5]

A published phase 2 trial found cetilistat significantly reduced weight with and was better tolerated than orlistat.^[6

Image result for Cetilistat

CLIP

Cetilistat (Oblean®)
Cetilistat is a selective pancreatic lipase inhibitor which was approved in Japan in September 2013
for the treatment of obesity. The drug was discovered by Alizyme PLC and later co-developed with
Takeda. Cetilistat demonstrated a lower incidence of adverse gastrointestinal events during a 12 week clinical trial, and the degree of weight loss associated with cetilistat is comparable to that of other approved antiobesity therapies.30 The most likely process-scale preparation of cetilistat is described below in Scheme. 4.31
Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the
corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5-
methylbenzoic acid (23) in pyridine. Subsequent slow addition of methyl chloroformate at room
temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from
hexadecanol.31

REF FOR ABOVE ONLY

30 Kopelman, P.; Groot, G. d. H.; Rissanen, A.; Rossner, S.; Toubro, S.; Palmer, R.; Hallam, R.;
Bryson, A.; Hickling, R. I. Obesity 2010, 18, 108.
31. Hodson, H. F.; Downham, R.; Mitchell, T. J.; Carr, B. J.; Dunk, C. R.; Palmer, R. M. J. US
Patent 20030027821A1, 2003.

SYNTHESIS

Route 1

WO2000040569

AND

http://www.google.co.in/patents/US6624161

WO0040569A1 / US6656934B2.2. WO0040247A1 / US6624161B2.

Route 2

http://www.google.co.in/patents/US7396952

Carbamic ester derivatives of the general formula (1) and especially (2-carboxy-4-methylphenyl)carbamic esters of the general formula (1′)

are suitable intermediates for active pharmaceutical ingredients.

Thus, for example, hexadecyl (2-carboxy-4-methylphenyl)carbamate as compound of the formula (1′) with R═C₁₆H₃₃is disclosed as an intermediate in the preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3)

from the originally published version of WO-A 00/40569.

2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3) is described therein as potential active ingredient for the treatment of obesity and type II diabetes.

In this originally published version of WO-A 00/40569, two synthetic routes 1 and 2 are described for preparing 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), each of which starts from the 5-methyl-substituted anthranilic acid (4).

In the two-stage synthetic route 1, the 5-methyl-substituted anthranilic acid (4) is reacted with hexadecyl chloroformate (5) and subsequently with methyl chloroformate to give 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), although the overall yield obtained is only 31%.

The one-stage synthetic route 2 with an excess of pyridine affords 2-hexadecyl-oxy-6-methyl-4H-3,1-benzoxazin-4-one (3) in an even lower yield of 15%.

The starting compound which is required for both the synthetic routes 1 and 2, the 5-methyl-substituted anthranilic acid (4), is not easily obtainable, however.

It is prepared by the method described in J. Org. Chem. 1952, 17, 141. This starts from p-toluidine, which is reacted with chloral hydrate and hydroxylamine hydrochloride. The resulting oxime is cyclized with acid catalysis, and subsequently the ring is cleaved again by oxidation under basic conditions.

The disadvantages of this synthesis are the low yields and the fact that only very low concentrations can be used. For this reason, this synthetic route is unattractive for an industrial reaction.

Further alternative routes known in principle for obtaining anthranilic acids are as follows:

J. Org. Chem. 1978, 43, 220 and Chem. Ber. 1909, 42, 430 disclose initial nitration of 3-cyanotoluene, then reduction of the nitro group and subsequent hydrolysis of the nitrile to the carboxylic acid.

A disadvantage of this synthesis is that the nitration of 3-cyanotoluene does not proceed selectively and therefore a further purification step is necessary. This requires additional effort and reduces the yield.

The synthesis which is described in J. Chem. Soc. Perkin I, 1973, 2940 and which starts from 3-toluic acid with subsequent nitration and reduction of the nitro group also has the same disadvantage.

The synthesis which is disclosed in Monatsh. Chem. 1920, 41, 155 and starts from 2,4-dimethyl-1-nitrobenzene is likewise unsuitable because oxidation of the methyl group next to the nitro group does not proceed selectively and therefore an elaborate separation of isomers is necessary.

EP-A 0 034 292 discloses a process for preparing optionally substituted anthranilic acids which includes a transition metal-catalysed carbonylation reaction with carbon monoxide to give an anthranilic acid derivative. This carbonylation reaction takes place in an aqueous reaction medium containing a trialkylamine and a catalyst formed from palladium and a tertiary phosphine. The anthranilic acid derivatives can be obtained by eliminating the protective group. The precursors employed for the carbonylation are obtained starting from optionally substituted anilines as shown in principle in the reaction scheme below:

EP-A 0 034 292 describes this reaction sequence of acetylation (a), halogenation (b), carbonylation (c) and subsequent elimination of the acetyl group (d) as affording the optionally substituted anthranilic acids in good yields (>80%). However, the introduction of the acetyl group is a disadvantage. This is necessary because the free anilines give only poor yields in transition metal-catalysed carbonylation reactions because of pronounced complexation [J. Org. Chem. 1981, 46, 4614-4617].

WO-A 97/28118 discloses a comparable process.

Because of the diverse difficulties, described above, associated with the known processes for preparing optionally substituted anthranilic acids and the yields, which are only unsatisfactory and thus limiting for the overall process, of the subsequent synthetic routes 1 and 2, the object of the present invention was to provide an improved process for preparing carbamic ester derivatives of the general formula (1).

US7396952B2.

EXAMPLES Example 1 Synthesis of hexadecyl 4-methylphenylcarbamate

91 g (375 mmol) of 1-hexadecanol were added to a solution of 50 g (375 mmol) of p-tolyl isocyanate in 50 ml of toluene, and the resulting solution was heated under reflux for 8 h. After cooling to room temperature and stirring at this temperature for 12 h, the precipitated solid was filtered off. The colourless solid was washed twice with 10 ml of toluene each time and then dried in vacuo. 80 g (213 mmol, 57%) of the desired carbamate were obtained in the form of a colourless solid with a melting point of 75° C. The melting point agreed with literature data (75-76° C., Microchem J. 1962, 6, 179).

¹H-NMR (CDCl₃, 400 MHz): δ=0.88 ppm (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 26 H), 1.66 (sext, J=6.9 Hz, 2H), 2.30 (s, 3H), 4.14 (t, J=6.9 Hz, 2H), 6.53 (br, 1 H), 7.10 (d, J=7.8 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H). Elemental Analysis Showed: Calculated: C 76.8%, H 11.0%, N 3.7% Found: C 76.9%, H 11.2%, N 3.7%.

Example 2 Synthesis of hexadecyl (2-bromo-4-methylphenyl)carbamate

19 g (119 mmol) of bromine were added dropwise to a solution of 45 g (119 mmol) of the carbamate in 225 ml (235 g) of glacial acetic acid at room temperature over the course of 1 h, and then the resulting solution was stirred at room temperature for 1 h. After addition of a further 25 ml (26 g, 437 mmol) of glacial acetic acid, the reaction mixture was stirred at 40° C. for 5 h and then cooled to room temperature. The precipitated solid was filtered off and washed with 20 ml of glacial acetic acid. Drying in vacuo resulted in 40 g (88 mmol, 74%) of the desired bromo compound in the form of a colourless solid with a melting point of 57° C.

¹H-NMR (CDCl₃, 400 MHz): δ=0.93 ppm (t, J=6.6 Hz, 3H), 1.25-1.43 (m, 26 H), 1.73 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.21 (t, J=6.7 Hz, 2H), 7.04 (br, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 8.02 (d, J=8.3 Hz, 1H). ¹³C-NMR (CDCl₃, 100 MHz): δ=14.2 ppm, 20.4, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2C), 29.7 (2C), 29.8 (4C), 32.0, 65.7, 112.5, 120.3, 129.0, 132.5, 133.5, 134.1, 153.5. Elemental Analysis Showed: Calculated: C 63.4%, H 8.9%, N 3.1% Found: C 63.6%, H 8.9%, N 3.1%.

Example 3 Synthesis of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid

217.5 g (478.5 mmol) of hexadecyl (2-bromo-4-methylphenyl)carbamate, 0.5 g (0.7 mmol) of bis(triphenylphosphine)palladium dichloride and 2.5 g (9.3 mmol) of triphenylphosphine were introduced into an autoclave. The autoclave was closed, flushed with nitrogen and an oxygen-free solution of 78.1 g (565.3 mmol) of potassium carbonate in 400 ml of water is added. The autoclave is evacuated and then 2 bar of carbon monoxide are injected and heated to 115° C. The pressure is subsequently adjusted to 8 bar. After CO uptake ceases, the mixture is cooled to RT and 200 ml of toluene are added. The pH is adjusted to 2 with 2M aqueous HCl solution, and the organic phase is separated off. The aqueous phase is extracted anew with 100 ml of toluene, the organic phase is separated off, and the two toluene extracts are combined. Removal of the solvent in vacuo results in 154.9 g (369.2 mmol, 77%) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid in the form of a pale yellow-coloured solid.

¹H-NMR (CDCl₃, 400 MHz): δ=0.88 ppm (t, J=6.7 Hz, 3H), 1.24-1.40 (m, 26 H), 1.70 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.17 (t, J=6.8 Hz, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 8.35 (d, J=8.6 Hz, 1H). Signal of the NH proton not identifiable.¹³C-NMR (CDCl₃, 100 MHz): δ=14.1 ppm, 20.5, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2 C), 29.7 (6 C), 32.0, 65.5, 113.6, 119.0, 131.1, 131.8, 136.3, 140.1, 153.9, 172.5.

Example 4 Synthesis of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one

4.0 g (10.0 mmol) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid are introduced into 20 ml of pyridine at 0° C. under a nitrogen atmosphere, and 4.93 g (45.4 mmol) of ethyl chloroformate are added dropwise to the resulting solution at 0° C. over the course of 20 min. After the reaction mixture has been stirred at 0° C. for 1 h and at room temperature for 2 h it is added to 30 ml of ice-water. The solid is filtered off and dried in vacuo. 3.3 g (8.2 mmol, 82%) of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one are obtained in the form of a pale yellow coloured solid with a melting point of 67° C. (literature: 72-73° C., WO 00/40569).

¹H-NMR (CDCl₃, 400 MHz): δ=0.86 ppm (t, J=6.6 Hz, 3H), 1.24-1.42 (m, 26 H), 1.75-1.82 (m, 2H), 2.40 (s, 3H), 4.41 (t, J=6.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.2, 1.9 Hz, 1H), 7.90 (d, J=0.9 Hz, 1H).

The ¹H-NMR data agree with the literature data from WO-A 00/40569.

Route 3

CN103936687B

CN103936687A.

Patent

https://www.google.com/patents/CN104341370A?cl=en

cetirizine orlistat (2-methyl-6-firing sixteen -4H-3, 1- benzo ah winded -4- Korea, cetilistat) is a long-acting Alizyme developed and potent specific gastrointestinal lipase inhibitor, with the active serine site of the gastric and intestinal lumen gastric lipase and lipase membrane forms a covalent bond to inactivate the enzyme, and to reduce calorie intake, weight control therapeutic effect. The biggest advantage of the drug is not acting on the nervous system, does not affect other activity in the gastrointestinal tract, it is more secure than existing similar drugs orlistat. Its structural formula is as follows:

West Division for the benefit of his synthesis and intermediates have been described in U.S. Patent US2007232825 and US2003027821, domestic literature orlistat no cetirizine synthesis of relevant reports.

U.S. Patent US2007232825 2-amino-5-methyl-benzoic acid starting material, direct and vilify chloroformate cetyl alcohol vinegar into the ring, get cetirizine orlistat. The reaction byproducts and more difficult W purification needs over baby gel column, resulting in a low yield, suitable for mass industrialization. Directions are as follows:

Patent US2003027821 W toluene different acid vinegar as raw material to produce amino acid vinegar intermediate chloroformate, cetyl alcohol and vinegar reaction, after the desert generation essays glycosylation chloroformate caprolactone ring closure to give cetirizine orlistat. This method requires a great deal of glacial acetic acid, the presence of H waste discharge more harsh reaction conditions, equipment requirements, is not conducive to industrial production and other defects.

The present invention is a W under the technical program realization:

Figure CN104341370AD00091

The following combination of embodiments of the present invention will be further described below.

(Sixteen essays firing oxygen-amino) -5- Preparation of 2-methyl benzoate desert vinegar; [0041] Example 1

4. 9g H phosgene will be added to 50 blood dichloromethane firing, the temperature was lowered to OC, a solution of 2-amino-5 Desert benzoic acid methyl ester (5g) and H hexylamine (13.8 blood) dichloro A firing (20 blood) solution, the addition was complete OC to maintain 15min, warmed to room temperature the reaction mix of football.

[0042] The 5. 26g cetyl alcohol was added to the reaction solution at room temperature the reaction of. After completion of the reaction, filtered and the filtrate was concentrated in vacuo spin dry, dry methanol residue fight starched coating, filtration, the filter cake is dried to constant weight. To give a white solid powder 9. Ig, namely 2- (sixteen essays firing oxygen-ylamino) -5-benzoic acid methyl ester desert; Yield; 85%.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid methyl ester prepared; [0043] Example 2

Under nitrogen blanket IOg 2- (sixteen grilled oxygen essays) -5- desert benzoic acid methyl ester was dissolved in 1,4-dioxane (50mL) and water Qiao blood), and Ilg anhydrous carbonate Bell, 1.44g methacrylic acid test, 0. 731g Pd (dppf) 2Cl2, the mixture at 105C for 3 hours. Completion of the reaction, cool down, filtered and the filtrate spin dry, the residue of anhydrous methanol wash coating, the filter cake dried to give a gray solid 6. 5g, is 2- (xvi grilled oxygen essays) -5-methyl benzoic acid methyl ester in 75% yield.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid; [0044] Example 3

The 7g 2- (sixteen grilled oxygen essays) -5-methyl-benzoic acid methyl ester was added to 35mL tetraammine clever furans and 7mL water mixture, adding ammonia oxidation in 20. Ig, 6 (TC reaction of the reaction is completed, the reaction mixture was concentrated, the residue was added 70mL of ice water, 6M hydrochloric suppression of 7, the filter cake was dried to constant weight to give a gray solid 6. 2g, namely 2- (sixteen firing oxygen-ylamino essays ) -5-methyl-benzoic acid, yield 92%.

Preparation of 2-methyl-6-firing sixteen -4H-3, 1- benzo Lai ah winded -4- (cetirizine Division him); 4 [0045] Example

The 66g 2- (XVI essays firing oxo-ylamino) -5-methylbenzoic acid in 330mL of information coincidence floating in an ice bath, was slowly added dropwise 45mL chloroformate caprolactone, after the addition was complete, naturally rise to room temperature The reaction of. After completion of the reaction, the reaction solution was poured into 700mL ice water, filtered, and the filter cake was dried to constant weight to give a gray solid 56g, that is, sixteen firing-6-methyl-2- -4H-3, 1- benzo Lai ah winded -4- (cetirizine orlistat), a yield of 85%. Mass spectrum shown in Figure 2, ESI-MS〇b / z): 402 [M + Tin +; X- ray diffraction as shown in (3 consistent with the data reported in FIG patent US2012101090), analyzed as shown in Table 1, Figure 1 FIG. 2 W and W Table 1 confirm that the product was obtained as cetirizine orlistat.

[0046] Table 1

CLIP

CJPH

2015, Vol. 46

Issue (09): 946-947 DOI: 10.16522/j.cnki.cjph.2015.09.003

Synthesis of Cetilistat

1. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050; 2. Beijing Union Pharmaceutical Factory, Beijing 102600

Cetilistat was synthesized from 2-amino-5-methylbenzoic acid and cetyl chloroformate via acylation to give 2-[[(hexadecyloxy)carbonyl]amino]-5-methylbenzoic acid, which was subjected to intramolecular dehydrationcyclization in the presence of POCl3 with an overall yield of 90％ and purity over 99％. This one-pot method was simple and suitable for large-scale application.

CLIP

http://amogsobgy.com/downloads/AkumentisChechwt/CurrOpinInvestigDrugs.pdf

CLICK ON IMAGE

Cetilistat, a new lipase inhibitor for the treatment of obesity – AMOGS

amogsobgy.com/downloads/AkumentisChechwt/CurrOpinInvestigDrugs.pdf

by R Padwal – ‎Cited by 26 – ‎Related articles

clinical trials, and the above-mentioned lipase inhibitor cetilistat, which is the focus of this review.Synthesis and SAR. Cetilistat (2-hexadecyloxy-6-methyl-4H-3 …

PATENT

SEE

http://www.google.co.in/patents/WO1999016758A1?cl=en

CLIP

Taken from Ayurajan

https://ayurajan.blogspot.in/2016_01_01_archive.html

Cetilistat | Inhibitor of Gastrointestinal Lipases | Inhibitor of Pancreatic Lipases | Anti-Obesity Drug

Cetilistat [2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one] is a novel highly lipophilic benzoxazinone that inhibits gastrointestinal (GI) and pancreatic lipases, and is chemically distinct from Orlistat [1].

Cetilistat: 2D and 3D Structure

Pancreatic lipase is the enzyme that breaks down triglycerides in the intestine. Inhibition of this enzyme ensures that triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.

In Phase I clinical trials in healthy volunteers, Cetilistat increased faecal fat excretion and was well tolerated. Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that Cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

The NDA submission is based on the results of three Phase 3 clinical trials in obese patients with type 2 diabetes and dyslipidemia: a 52-week placebo-controlled, double-blind study to evaluate the efficacy and safety, and two open-label studies to evaluate safety, 24-week and 52-week respectively. The results of the 52-week placebo-controlled, double-blind study demonstrate that Cetilistat 120mg three times daily is superior to placebo in the primary endpoint, with a mean reduction in body weight from baseline of -2.776% with Cetilistat versus -1.103% with placebo (p=0.0020). Greater reduction in HbA1c and low-density lipoprotein cholesterol were also observed in patients treated with Cetilistat, compared to placebo. In all these three studies, Cetilistat showed a good safety profile and was well tolerated.

Cetilistat was approved in Japan in September 2013 for the treatment of obesity. Cetilistat (Tradename: Oblean) is approved for a dosage of 120 mg three times a day for the treatment of obesity with complications.

The drug was discovered by UK based Alizyme PLC and in 2003 Takeda acquired the rights for development and commercialisation for Japan. Norgine acquired all rights to the product from Alizyme in October 2009 [3].

Cetilistat Synthesis

US20030027821A1: It appears to be the industrial process. The yields are in the range of 30-35%.

Identification:

1H NMR (Estimated) for Cetilistat

Experimental: 1H-NMR δH (400 MHz, CDCl₃) 0.87 (3H, t, J 6.8, CH₂CH₃), 1.24-1.45 (26H, m, 13×CH₂), 1.75-1.83 (2H, m, OCH₂CH₂), 2.41 (3H, s, ArCH₃), 4.41 (2H, t, J 6.7, OCH₂), 7.3 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); M Pt. 72-73° C.

Sideeffects: The most frequently experienced adverse events were those involving the gastrointestinal (GI) tract. The proportion of patients and the total number of GI adverse events reported in each of the active treatment groups were higher compared to the placebo group. However, GI adverse events were predominantly mild to moderate in intensity, with no evidence of a dose relationship.

The most frequently reported GI-related adverse events included increased defecation, soft stools, abdominal pain, flatulence and fatty/oily stool, which were all reported more frequently in the treatment arms compared to the placebo arm.

Faecal incontinence, flatus with discharge, oily evacuation and oily spotting occurred in only 1.8-2.8% of subjects in the active treatment arms and was not dose-related. Adverse events generally occurred on only one occasion and resolved rapidly.

Serum vitamin D, vitamin E and β-carotene levels were decreased significantly in the Cetilistat treatment arms. Generally, these reductions in vitamin levels did not take the levels outside the normal range and none required the use of vitamin supplements.

References FOR ABOVE ONLY

Kopelman, P.; et. al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond) 2007, 31(3), 494-499.
Hodson, H.; et. al. 2-Oxy-benzoxazinone derivatives for the treatment of obesity.US20030027821A1
Cetilistat Approval (here).

CN1359378A *	Jan 6, 2000	Jul 17, 2002	阿利茨默治疗学有限公司	2-oxy-benzoxazine derivatives for the treatment of obesity
CN1785967A *	Dec 12, 2005	Jun 14, 2006	兰爱克谢斯德国有限责任公司	Process for the preparation of carbamic acid derivatives
CN103936687A *	Mar 24, 2014	Jul 23, 2014	重庆东得医药科技有限公司	Method for preparing cetilistat
WO2013166037A1 *	Apr 30, 2013	Nov 7, 2013	The Trustees Of Columbia University In The City Of New York	Non-retinoid antagonists for treatment of eye disorders

PATENT

Cited Patent	Filing date	Publication date	Applicant	Title
US20030013707	6 Jul 2001	16 Jan 2003	Hodson Harold Francis	2-amino-benzoxazinone derivatives for the treatment of obesity
EP0034292A2	31 Jan 1981	26 Aug 1981	F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft	Process for the preparation of anthranilic acid derivatives
WO1997028118A1	30 Jan 1997	7 Aug 1997	Hoechst Celanese Corporation	Process for preparing anthranilic acids

Reference
1		Chem. Ber. 1909, 42, 430.
2		J. Chem. Soc. Perkin I, 1973, 2940; Peter H. Gore et al. Friedel-Crafts Reactions, Part XXV.<SUP>1 </SUP>Acetylation and Benzoylation of Iodobenzene and of o-, m-, and p- Iodotoluenes.
3		J. Org. Chem. 1952, 17, 141 B. R. Baker et al.; “An Antimalarial Alkaloid From Hydrangea, XIV, Synthesis of 5- ,6-,7-, and 8-Monosubstituted Derivatives“.
4		J. Org. Chem. 1978, vol. 43, No. 2, 220 T.H. Fisher et al.; “Kinetic Study of the N-Bromosuccin-imide Bromination of Some 4-Substituted 3-Cyanotoluenes“.
5		J. Org. Chem. 1981, 46, 4614-4617 Donald Valentine, Jr. et al; “Practical, Catalytic Synthesis of Anthranilic Acids“.
6		Monatsch. Chem. 1920, 41, 155.
7		Thomas G. Back et al.: “Conjugate Additions of o-Iodoanilines and Methyl Anthranilates to Acetylenic Sulfones. A New Route to Quinolones Including First Syntheses of Two Alkaloids from the Medical Herb Ruta chalepensis” Journal of Organic Chemistry., Bd. 68, 2003, Seiten 2223-2233, XP002371555 USAmerican Chemical Society, Easton. Seite 2227, Spalte 1, Reaktionsschema 4 und Spalte 2, Zeile 8-Zeile 9; Seite 2231, Spalte 2, Zeile 43-Zeile 54.
8	*	Yadav et al., New Journal of Chemistry (2000), 24(8), 571-573.

Citing Patent	Filing date	Publication date	Applicant	Title
US8883780	22 Apr 2010	11 Nov 2014	Norgine B.V.	Crystal of a benzoxazinone compound

References

Yamada Y, Kato T, Ogino H, Ashina S, Kato K (2008). “Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats”. Hormone and Metabolic Research. 40 (8): 539–43. doi:10.1055/s-2008-1076699. PMID 18500680.
Kopelman, P; Bryson, A; Hickling, R; Rissanen, A; Rossner, S; Toubro, S; Valensi, P (2007). “Cetilistat (ATL-962), a novel lipase inhibitor: A 12-week randomized, placebo-controlled study of weight reduction in obese patients”. International journal of obesity (2005). 31 (3): 494–9. doi:10.1038/sj.ijo.0803446. PMID 16953261.
Padwal, R (2008). “Cetilistat, a new lipase inhibitor for the treatment of obesity”. Current opinion in investigational drugs (London, England : 2000). 9 (4): 414–21. PMID 18393108.
http://www.alizyme.com/alizyme/products/cetilistat/ Archived January 7, 2009, at the Wayback Machine.
Norgine acquires cetilistat
“Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).”. Obesity. 18: 108–15. Jan 2010. doi:10.1038/oby.2009.155. PMID 19461584.
Japan PMDA.

セチリスタット
Cetilistat

C₂₅H₃₉NO₃ : 401.58
[282526-98-1]

Cetilistat
Systematic (IUPAC) name

2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one
Identifiers
CAS Number	282526-98-1
ATC code	none
PubChem	CID 9952916
ChemSpider	8128526
UNII	LC5G1JUA39
KEGG	D09208
ChEMBL	CHEMBL2103825
Chemical data
Formula	C₂₅H₃₉NO₃
Molar mass	401.582 g/mol
SMILES CCCCCCCCCCCCCCCCOc2oc(=O)c1cc(C)ccc1n2

///////////////Cetilistat, ATL-962, ATL962, ATL 962, 2013-09-20, JAPAN, APPROVED, Japan PMDA, 282526-98-1, セチリスタット

SEE

Annual Reports in Medicinal Chemistry

https://books.google.co.in/books?isbn=0128003723

2014 – ‎Science

… versus vehicle-treated mice.34Noteworthy in the multistep synthesis of canagliflozin is …CETILISTAT (ANTIOBESITY)43–52 Class: Pancreatic lipase inhibitor …

BMS-852927

October 24, 2016 11:16 am / 1 Comment on BMS-852927

BMS-852927

CAS 256918-39-4

609.51 MW

C₂₉ H₂₈ Cl₂ F₂ N₂ O₄ S MF

2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

1H-Imidazole-4-methanol, 2-[1-(2,6-dichlorophenyl)-1-methylethyl]-1-[3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)[1,1′-biphenyl]-4-yl]-α,α-dimethyl-

Treat metabolic syndrome

Brett Busch, Ph.D.

https://www.linkedin.com/in/brettbbusch

Exelixis

Brett B. Busch, William C. Stevens, Jr., Ellen K. Kick, Haiying Zhang, Venkataiah Bollu,Richard Martin, Raju Mohan
Applicant	Exelixis, Inc.

Brett B. Busch, William C. Stevens, JR., Ellen K. Kick, Haiying Zhang, Venkataiah Bollu,Richard Martin, Raju Mohan
	Bristol-Myers Squibb Company, Exelixis Patent Company Llc

Originator Exelixis
Developer Bristol-Myers Squibb
Class Antihyperlipidaemics; Small molecules
Mechanism of Action Liver X receptor modulators

Discontinued Atherosclerosis; Hypercholesterolaemia

Most Recent Events

04 Jun 2014 BMS 852927 is still in phase I trials for atherosclerosis and in preclinical development for hypecholesterolaemia in USA
02 Aug 2013 Bristol-Myers Squibb terminates the planned phase I trial for Hypercholesterolaemia in Germany, Canada and Switzerland (NCT01651273)
06 Jul 2012 Bristol-Myers Squibb plans a phase I trial for Hypercholesterolaemia in Germany, Canada and Switzerland (NCT01651273)

1H-NMR (DMSO-d6, 400 MHz) δ 7.94 (m, 2H), 7.63 (dd, 1H, J = 11.29, 1.51 Hz), 7.34 (d, 1H, J = 9.54
Hz), 7.14 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 5.58 (t, 1H, J = 5.27 Hz), 4.96 (d, 2H, J = 4.27 Hz), 4.70
(s, 1H), 3.46 (s, 3H), 1.96 (s, 6H), 1.45 (s, 6H); MS m/e 609.16 (M+H+);

13CNMR (DMSO-d6, 400MHz) 161.42 (d, J=249.49 Hz), 156.85 (d, J=250.25 Hz), 153.18, 148.39, 141.69 (d, J=3.05 Hz), 139.45 (dd, J=9.16, 1.53 Hz), 139.32 (dd, J=8.39, 1.53 Hz), 138.58, 134.68, 131.39, 129.96, 128.40,
127.12 (d, J=17.55 Hz), 125.72 (d, J=12.97 Hz), 123.15 (d, J=2.29 Hz), 122.49 (d, J=3.05 Hz), 119.04
(d, J=25.18 Hz), 116.30, 114.52 (d, J=22.13 Hz), 68.11, 51.97 (d, J=5.34 Hz ), 45.53, 44.78, 44.29,
31.01, 30.53.

19F-NMR (JEOL 500 MHz, CDCl3) -113.55, -116.73.

HPLC (XBridge 5μ C18 4.6x50mm, 4 mL/min, Solvent A: 10 % MeOH/water with 0.2 % H3PO4, Solvent B: 90 % MeOH/water with0.2 % H3PO4, gradient with 0-100 % B over 4 minutes): 2.56 minutes, Purity, 99.7%.

HRMS (m/z,Obs.): 609.12065 [M+H]+; (Calc.): 609.11877. Formula: C29H29Cl2F2N2O4S. Anal. Calcd. for
C29H28N2O4SCl2F2•0.10 C2H6O•0.10 C4H5O2: C, 57.05; H, 4.75; Cl, 11.42; F, 6.10; N, 4.50; S, 5.15.
Found: C, 57.14; H, 4.54; Cl, 11.57; F, 5.94; N, 4.36; S, 5.07. The residual solvents, ethyl acetate (1.39
weight %), ethanol (0.74 weight %), dichloromethane (0.05 weight %), and heptane (< 0.05 weight %)
were identified in the sample by GC/MS and the retention times were matched with the reference standards.

Image result for BMS-852927

Liver X receptors (LXRs) belong to a family of nuclear hormone receptors that are endogenously activated by cholesterol and its oxidized derivatives to mediate transcription of genes involved in maintaining glucose, cholesterol, and fatty acid metabolism. LXRa is found predominantly in the liver, with low levels found in kidney, intestine, spleen, and adrenal tissue. LXRp is ubiquitous in mammals and was found in nearly all tissues examined. Given the intricate link between lipid metabolism and cancer cell growth, the ubiquitous expression of LXRp in some types of cancer is unlikely to be coincidental, allowing cancer cells to synthesize lipids and lipoprotein particles to sustain their growth. At the same time, however, such stable basal expression levels make LXRp an ideal therapeutic target.

Examples of LXR agonists reported in the literature

PATENT

WO 2010138598

PATENT

WO 2012135082

PATENT

WO 2014028461

PATENT

WO 2016100619

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016100619&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

https://www.google.com/patents/US8618154?cl=enIt

Figure US08618154-20131231-C00002

Example 9 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

Example 9a Preparation of 2-(2,6-dichlorophenyl)-2-methylpropanenitrile

To a 1 M solution of potassium tert-butoxide (403 mL, 403 mmol) at −66° C. (acetone/dry ice) was slowly added 2-(2,6-dichlorophenyl)acetonitrile (25.0 g, 134 mmol) in anhydrous THF (150 mL). The mixture was stirred at −66° C. for 20 minutes. Then, iodomethane (33.6 mL, 538 mmol) was added drop-wise over 25 minutes at −66° C. At this stage, it was exothermic and a large amount of light yellow precipitate was observed. The suspension was stirred at −60° C. for 30 minutes. The reaction mixture was quenched with 200 mL ice water, and extracted with ether (3×150 mL). The organics were combined, washed with 150 mL brine, dried over Na₂SO₄, and concentrated on a rotary evaporator. The crude product (30 g, yellow oil) was purified by column chromatography (ISCO, 330 g silica, 20% EtOAc in hexanes) to afford 2-(2,6-dichlorophenyl)-2-methylpropanenitrile (28.2 g, 132 mmol, 98% yield) as a light yellowish oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.35 (d, 2H, J=8.03 Hz), 7.16 (t, 1H, J=8.0 Hz), 2.09 (s, 6H); ¹³C-NMR (CDCl₃, 126 MHz) δ134.6, 133.8, 131.4, 129.0, 124.1, 38.6, 29.2; MS m/e 214.10 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 3.16 minutes.

Example 9b Preparation of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide

2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N₂. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na₂SO₄, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). ¹H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); ¹³C-NMR (DMSO-d₆, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.32 minutes.

Example 9c Preparation of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate

To a mixture of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (48.0 g, 119 mmol), K₂CO₃(41.0 g, 297 mmol) in toluene (180 mL) and THF (180 mL) at 55° C. was added slowly a solution of ethyl 3-bromo-2-oxopropanoate (23.3 mL, 166 mmol) in 24 mL of THF over 50 minutes. The reaction mixture was kept at 55° C. for 1.5 hours. A white slurry was observed. The reaction mixture was cooled to 5° C. HCl (0.5N, 450 mL) was added drop-wise (end point pH=9˜10). After addition, the suspension was cooled to 0° C. The solid was collected by filtration, washed with water (2×50 mL), and then dried in a vacuum oven at 60° C. overnight. Ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (59 g, 114 mmol, 96% yield) was obtained as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.11 (m, 3H), 6.96 (m, 2H), 6.72 (t, 1H, J=8.28 Hz), 4.35 (m, 2H), 4.25 (d, 1H, J=10.5 Hz), 3.80 (d, 1H, J=10.8 Hz), 1.98 (s, 3H), 1.93 (s, 3H), 1.38 (t, 3H, J=7.03 Hz); ¹³C-NMR (CDCl₃, 126 MHz) δ 173.0, 171.5, 159.8, 157.8, 137.3, 135.7, 132.1, 131.1, 128.1, 127.4, 125.6, 122.2, 120.1, 93.5, 62.5, 45.5, 30.2, 14.0; MS m/e 517.05 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.74 minutes.

Example 9d Preparation of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole,4-carboxylate

To a mixture of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (38 g, 73 mmol) in EdOH (200 mL) was added TFA (25.0 g, 220 mmol). The mixture was stbsequently heated tn 95° C. HPLC analysis after 2.5 hours showed <1% of alcohol intermediate remaining The mixture was diluted with 300 mL of CH₂Cl₂and cooled to approximately 5° C. with an ice bath. The mixture was neutralized with 1N NaOH (120 mL) and the organic layer was separated. The aqueous layer was dxtracted with CH₂Cl₂(2×100 mL). The combined organic layers were concentrated on a rotary evaporator to give crude material. Recrystallization in EtOH (5 mL/1 g) provided 32 g of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophdnyl)propan-2-yl)-1H-imidazole-4-carboxylate as `n off-white solhd (86% yield). ¹H-NMR (DMSO-d_{6, 400 MHz) δ 7.92 (s, 1H), 7.16 (d, 1H, J=8.0 Hz), 7.22 (m, 3H), 7.11 (m, 1H), 7.04 (t, 1H, J=12.0 Hz), 4.25 (q, 2H, J=8.0 Hz), 1.94 (s, 6H(, 1.27 (t, 3H, J=8.0 Hz); MS m/e 502.68 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 3.87 minutes.}

Example 9e Prepar`tion of 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol

To a mixture of methylmagnesium bromide (60.0 mL, 180 mmol, 3M in ether) in 120 ml, of THF cooled with an ice/salt bath (−15 to −17° C.) was added slowly a solution of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole-4-carboxylate (30 g, 60 mmol) in 65 mL of CH₂Cl₂and 87 mL of THF over 45 minutes. The internal temperature was carefully kept below 0° C. A further 2×20 mL of CH₂Cl₂was used to wash forward the residual material. The reaction mixture temperature was maintained below 0° C. for 1 hour with stirring. Then the reaction mixture was diluted with 100 mL of CH₂Cl₂, and saturated NH₄Cl was added slowly. The resulting mixture was extracted with CH₂Cl₂(2×80 mL). Organics were combined, washed with brine, dried with Na₂SO₄, and concentrated on a rotary evaporator to afford 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (28.5 g, 58.6 mmol, 98% yield) as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.13 (dd, 1H, J=9.03, 2.01 Hz), 7.09 (s, 1H), 7.07 (s, 1H), 6.93 (m, 2H), 6.75 (t, 1H, J=8.16 Hz), 6.55 (s, 1H), 3.18 (s, 1H), 2.00 (s, 6H), 1.58 (s, 6H); ¹³C-NMR (CDCl₃, 126 MHz) δ 158.1, 156.1, 154.5, 147.8, 139.3, 135.7, 131.3, 130.3, 127.8, 126.9, 122.7, 119.8, 115.1, 68.7, 44.8, 31.1, 29.9; MS m/e 485.05 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.78 minutes.

Example 9 Preparation of 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol

To a 1 L 3-necked round bottom flask under nitrogen was added 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (12.0 g, 24.7 mmol), [2-fluoro-6-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (9.78 g, 29.6 mmol), K₂CO₃(10.2 g, 74 mmol), DME (120 mL) and water (12 mL). The mixture was heated to 60° C., and then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex (4.06 g, 4.94 mmol) was added under nitrogen. The reaction mixture was heated to 80° C. for 30 minutes. The resulting darkly colored mixture was cooled with an ice bath, and partitioned in 200 mL of CH₂Cl₂and 200 mL of water. The organic layers were combined and dried with Na₂SO₄. After concentration, the crude product was purified by flash chromatography (ISCO, 330 g silica, 0% to 100% EtOAc in hexanes) to afford 12.79 g of crude product (85% yield) as a light yellow solid.

Recrystallization was carried out by dissolving 9.5 g of crude product in acetone (80 mL) at 65° C. The resulting solution was cooled slowly to 25° C. over 5 hours, and then cooled to 0° C. for an additional 30 minutes. Crystals began to form at 45° C. The solid was collected by filtration and rinsed with cold acetone. After drying in an oven at 45° C. under vacuum for 14 hours, 4.9 g of pure product was obtained. To recover additional crystalline product, the mother liquid was concentrated to approximately 10 mL and passed through a silica pad. EtOAc (100 mL) was used to elute the compound. The filtrate was concentrated under vacuum to give a crude solid. The crude solid was recrystallized in acetone following the procedure above to afford an additional 2.5 g of product. The combined recovery for the two crops after recrystallization was a 78% yield. ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.94 (m, 2H), 7.63 (dd, 1H, J=11.29, 1.51 Hz), 7.34 (d, 1H, J=9.54 Hz), 7.14 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 5.58 (t, 2H, J=5.27 Hz), 4.96 (d, 2H, J=4.27 Hz), 4.70 (s, 1H), 3.46 (s, 3H), 1.96 (s, 6H), 1.45 (s, 6H); MS m/e 609.16 (M+H⁺); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H₃PO₄, Solvent B: 90% MeOH/water with 0.2% H₃PO₄, gradient with 0-100% B over 4 minutes): 2.56 minutes.

Alternatively, Example 9 was prepared as follows:

To a 1 L 3-necked round bottom flask under nitrogen was added methyltetrahydrofuran (“MeTHF”, 6.9 kg), 2-(1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (1.994 kg, 4.1 moles) and (2-fluoro-6-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.38 kg, 4.19 moles). The mixture was agitated at 23° C. for 15 min until all the solids dissolved. At the conclusion of this period, (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.022 kg, 0.041 moles) and Pd(OAc)₂(0.01 kg, 0.045 moles) were added as a slurry via a subsurface line. Upon completion of addition, the mixture was rinsed with additional MeTHF (1.65 kg). The resulting mixture was evacuated to less than 80 Torr and backfilled with nitrogen. This process was repeated two more times. After completion of the degassing sequence, the reaction mixture was agitated for at least 15 min and a clear, golden color was observed. In a separate reaction vessel, a solution of potassium hydroxide (0.352 kg) in water (10.00 kg) was prepared and degassed by sparging the solution with nitrogen gas for at least 15 min prior to use. The KOH solution (10.35 kg) was transferred into the reactor by vacuum. The reaction temperature exhibited a known exotherm from 20° C. to 29° C. Upon completion of addition, the resulting biphasic mixture was degassed by a series of pressure swings. The mixture was warmed to between 45-50° C. where it was stirred for at least 2 h. After this time, the reaction mixture was analyzed by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 23° C. and the stirring was stopped. The mixture was allowed to separate for 30 min and the lower spent KOH stream was removed. The product rich organic was passed through a column of thiourea functionalized silica gel (0.782 kg) (Silicycle) at ˜0.1 kg per min to remove the palladium. The product rich organic phase was washed with a 5% NaHCO₃solution (5 vol) and the phases separated. The organic phase was washed with water (5 vol) and the organic and aqueous phases separated.

The product rich organic phase was polish filtered into a clean reaction vessel and then concentrated to ˜8 volumes (˜16 L) under vacuum (80 Torr, Tjacket=60° C.). Once at the prescribed volume, the reaction mixture was allowed to cool to 25° C. Once at the prescribed temperature the reaction mixture was seeded with 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (0.5%, 0.008 kg). The resulting slurry was stirred at 25° C. for about 18 h. At the conclusion of this period, the reaction mixture was concentrated to ˜8 L under vacuum (150 Torr, Tjacket=60° C.). Once at the prescribed volume, the reaction mixture was heated to 50° C. and isopropyl acetate (IPAc, 13.90 kg) was added to the reactor during a 90 min period. Upon completion of addition, the reaction mixture was cooled to 25° C. during a 3 h period. Once at the prescribed temperature the reaction mixture was stirred at room temperature for about 16 h. At the conclusion of this period, the reaction mixture was filtered, deliquored, and washed with additional IPAc (10.4 kg). The filter cake was dried via suction on the filter under a stream of dry nitrogen to yield a white solid. The white solid was transferred to a dryer and dried at 50° C. under full vacuum to afford 2.03 kg of product (81% yield, 99.40 AP, 98 wt %).

PAPER

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitroproperties, excellent pharmacokinetic parameters, and a favorable lipid profile.

Discovery of Highly Potent Liver X Receptor β Agonists

Ellen K. Kick ^*†§, Brett B. Busch^‡§, Richard Martin^‡, William C. Stevens^‡, Venkataiah Bollu^‡, Yinong Xie^‡, Brant C. Boren^‡, Michael C. Nyman^‡, Max H. Nanao^‡, Lam Nguyen^‡, Artur Plonowski^‡, Ira G. Schulman^‡, Grace Yan^‡,Huiping Zhang †, Xiaoping Hou †, Meriah N. Valente †, Rangaraj Narayanan #, Kamelia Behnia #, A. David Rodrigues #, Barry Brock #, James Smalley #, Glenn H. Cantor #, John Lupisella ∥, Paul Sleph ∥, Denise Grimm ∥,Jacek Ostrowski ∥, Ruth R. Wexler †, Todd Kirchgessner ∥, and Raju Mohan^‡

^†Department of Discovery Chemistry, ^∥Department of Cardiovascular Biology, ^#Pharmaceutical Candidate Optimization, Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States

^‡ Exelixis Inc., 210 East Grand Avenue, South San Francisco, California 94080, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00234

Publication Date (Web): October 23, 2016

*Tel: 609 466-5053. E-mail: ellen.kick@bms.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00234

WO2007002563A1	Jun 26, 2006	Jan 4, 2007	Exelixis, Inc.	Imidazole based lxr modulators
WO2008073825A1	Dec 7, 2007	Jun 19, 2008	Exelixis, Inc.	Lxr and fxr modulators

Citing Patent	Filing date	Publication date	Applicant	Title
US8901106	Mar 26, 2012	Dec 2, 2014	Bristol-Myers Squibb Company	Imidazole prodrug LXR modulators
US20140163081 *	Nov 21, 2013	Jun 12, 2014	Exelixis Patent Company Llc	Lxr modulators
US20150299136 *	May 4, 2015	Oct 22, 2015	Bristol-Myers Squibb Company	Lxr modulators

///////////Discovery, Highly Potent, Liver X Receptor β Agonists, ABCA1, ABCG1, Liver X receptor, LXRα, LXRβ, α-1-acid glycoprotein, BMS-852927, BMS 852927

CS(=O)(=O)c1cc(cc(F)c1CO)c2cc(F)c(cc2)n3cc(nc3C(C)(C)c4c(Cl)cccc4Cl)C(C)(C)O

ANDA Submissions – Prior Approval Supplements Under GDUFA, FDA Guidance document

October 23, 2016 1:56 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

ANDA Submissions – Prior Approval Supplements Under GDUFA, FDA Guidance document, oct 2016, Generics

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WAY-315193

October 15, 2016 11:40 am / Leave a comment

7-fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one

str0

7-f luoro-1 -[(1 S,2R)-1 -(3-fluorophenyl)-2-hydroxy-3- (methylamino)propyl]-3,3- dimethyl-1 ,3-dihydro-2H-indol-2-one hydrochloride

WAY-315193

7-fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methyl amino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
Molecular Formula:	C₂₀H₂₂F₂N₂O₂
Molecular Weight:	360.397686 g/mol

7-Fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimethylindolin-2-one Hydrochloride

Callain Younghee Kim, Paige Erin Mahaney,Eugene John Trybulski, Puwen Zhang,Eugene Anthony Terefenko, Casey Cameron Mccomas, Michael Anthony Marella, Richard Dale Coghlan, Gavin David Heffernan,Stephen Todd Cohn, An Thien Vu, Joseph Peter Sabatucci, Fei Ye,
Applicant	Wyeth

Drugs that possess norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition, have been used for multiple indications including major depressive disorder, attention deficit hyperactivity disorder, stress urinary incontinence, vasomotor symptoms, and pain disorders such as diabetic neuropathy and fibromyalgia.1 In the search for new candidates with improvements in both potency and selectivity, one of the lead compounds in the 1-(3-amino- 2-hydroxy-1-phenylpropyl)indolin-2-one series, WAY-315193 (1), was identified.2

Vasomotor symptoms (VMS), referred to as hot flushes and night sweats, are the most common symptoms associated with menopause, occurring in 60% to 80% of all women following ‘ natural or surgically-induced menopause. VMS are likely to be an adaptive response of the central nervous system (CNS) to declining sex steroids. To date, the most effective therapies for VMS are hormone-based treatments, including estrogens and/or some progestins. Hormonal treatments are very effective at alleviating VMS, but they are not appropriate for all women. It is well recognized that VMS are caused by fluctuations of sex steroid levels and can be disruptive and disabling in both males and females. A hot flush can last up to thirty minutes and vary in their frequency from several times a week to multiple occurrences per day. The patient experiences a hot flash as a sudden feeling of heat that spreads quickly from the face to the chest and back and then over the rest of the body. It is usually accompanied by outbreaks of profuse sweating. It may sometimes occur several times an hour, and it often occurs at night. Hot flushes and outbreaks of sweats occurring during the night can cause sleep deprivation. Psychological and emotional symptoms observed, such as nervousness, fatigue, irritability, insomnia, depression, memory loss, headache, anxiety, nervousness or inability to concentrate are considered to be caused by the sleep deprivation following hot flush and night sweats (Kramer et al., In: Murphy et al., 3^rd Int’l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment- Proceedings, Paris, France: SCI: 3-7 (1992)).

Hot flushes may be even more severe in women treated for breast cancer for several reasons: 1) many survivors of breast cancer are given tamoxifen, the most prevalent side effect of which is hot flush, 2) many women treated for breast cancer undergo premature menopause from chemotherapy, 3) women with a history of breast cancer have generally been denied estrogen therapy because of concerns about potential recurrence of breast cancer (Loprinzi, et al., Lancet, 2000, 356(9247): 2059-2063).

Men also experience hot flushes following steroid hormone (androgen) withdrawal. This is true in cases of age-associated androgen decline (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35) as well as in extreme cases of hormone deprivation associated with treatments for prostate cancer (Berendsen, et al., European Journal of Pharmacology, 2001, 419(1): 47-54. As many as one-third of these patients will experience persistent and frequent symptoms severe enough to cause significant discomfort and inconvenience.

The precise mechanism of these symptoms is unknown but generally is thought to represent disturbances to normal homeostatic mechanisms controlling thermoregulation and vasomotor activity (Kronenberg et al., “Thermoregulatory Physiology of Menopausal Hot Flashes: A Review,” Can. J. Physiol. Pharmacol., 1987, 65:1312-1324).

The fact that estrogen treatment (e.g. estrogen replacement therapy) relieves the symptoms establishes the link between these symptoms and an estrogen deficiency. For example, the menopausal stage of life is associated with a wide range of other acute symptoms as described above and these symptoms are generally estrogen responsive.

It has been suggested that estrogens may stimulate the activity of both the norepinephrine (NE) and/or serotonin (5-HT) systems (J. Pharmacology & Experimental Therapeutics, 1986, 236(3) 646-652). It is hypothesized that estrogens modulate NE and 5-HT levels providing homeostasis in the thermoregulatory center of the hypothalamus. The descending pathways from the hypothalamus via brainstem/spinal cord and the adrenals to the skin are involved in maintaining normal skin temperature. The action of NE and 5-HT reuptake inhibitors is known to impinge on both the CNS and peripheral nervous system (PNS). The pathophysiology of VMS is mediated by both central and peripheral mechanisms and, therefore, the interplay between the CNS and PNS may account for the efficacy of dual acting SRI/NRIs in the treatment of thermoregulatory dysfunction. In fact, the physiological aspects and the CNS/PNS involvement in VMS may account for the lower doses proposed to treat VMS (Loprinzi, et al., Lancet, 2000, 356:2059-2063; Stearns et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat the behavioral aspects of depression. The interplay of the CNS/PNS in the pathophysiology of VMS and the presented data within this document were used to support the claims that the norepinephrine system could be targeted to treat VMS.

Although VMS are most commonly treated by hormone therapy (orally, transdermally, or via an implant), some patients cannot tolerate estrogen treatment (Berendsen, Maturitas, 2000, 36(3): 155-164, Fink et al., Nature, 1996, 383(6598): 306). In addition, hormone replacement therapy is usually not recommended for women or men with or at risk for hormonally sensitive cancers (e.g. breast or prostate cancer). Thus, non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs] and clonidine) are being evaluated clinically. WO9944601 discloses a method for decreasing hot flushes in a human female by administering fluoxetine. Other options have been studied for the treatment of hot flashes, including steroids, alpha- adrenergic agonists, and beta-blockers, with varying degree of success (Waldinger et al., Maturitas, 2000, 36(3): 165-168).

It has been reported that α₂-adrenergic receptors play a role in thermoregulatory dysfunctions (Freedman etal., Fertility & Sterility, 2000, 74(1): 20- 3). These receptors are located both pre- and post-synaptically and mediate an inhibitory role in the central and peripheral nervous system. There are four distinct subtypes of the adrenergic_α2 receptors, i.e., are ₂A, O₂B, 0.2c and α₂D (Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther., 1995, 68: 175). It has been reported that a non-select ₂-adrenoceptor antagonist, yohimbine, induces a flush and an ₂-adrenergic receptor agonist, clonidine, alleviates the yohimbine effect (Katovich, et al., Proceedings of the Society for Experimental Biology & Medicine, 1990, 193(2): 129-35, Freedman et al., Fertility & Sterility, 2000, 74(1): 20-3). Clonidine has been used to treat hot flush. However, using such treatment is associated with a number of undesired side effects caused by high doses necessary to abate hot flash described herein and known in the related arts.

Patent

https://www.google.com/patents/WO2005097744A1?cl=en

invention relates to phenylaminopropanol derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

EXAMPLE 101 : 7-f luoro-1 -[(1 S,2R)-1 -(3-fluorophenyl)-2-hydroxy-3- (methylamino)propyl]-3,3- dimethyl-1 ,3-dihydro-2H-indol-2-one hydrochloride

[0538] Step 1 : A mixture of 7-fluoro-3, 3-dimethyl-1 ,3-dihydro-2H-indol-2-one (EXAMPLE 99, step 5, 1.0 g; 5.58 mmol) and sodium tert-butoxide (1.0 g, 11.16 mmol) in dry dichloromethane (15 mL) was stirred at room temperature under nitrogen for 20 minutes. Titanium isopropoxide (2.0 mL, 6.70 mmol) was added to a solution of [(2R,3R)-3-(3-fluorophenyl)oxiran-2-yl]methanol (EXAMPLE 47, step 3, 844 mg, 5.02 mmol) in dry dichloromethane (6 mL) and stirred for 20 minutes at room temperature. The epoxide complex was added drop-wise to the mixture of tert- butoxide and allowed to stir for 4 days. The reaction mixture was poured into a 2N aqueous solution of hydrochloric acid and diluted with ethyl acetate. The layers were separated, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.0 g of crude product. The crude product was purified via Isco chromatography (RediSep, silica, gradient of 0% to 100% ethyl acetate in hexane) to yield 600 mg (31 %) of (2S,3S)-7-Fluoro-1 -[1 -(3-fluoro-phenyl)-2,3-dihydroxy-propyl]-3,3-dimethyl- 1 ,3-dihydro-indol-2-one as an oil. MS (ESI) m/z 348 ([M+Hf).

[0539] Step 2: In an analogous manner to EXAMPLE 1 , step 2 (2S, 3S)-toluene- 4-sulfonic acid 3-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1 -yl)-3-(3-fluoro- phenyl)-2-hydroxy-propyl ester was prepared from (2S,3S)-7-fluoro-1-[1-(3-fluoro- phenyl)-2,3-dihydroxy-propyl]-3,3-dimethyl-1 ,3-dihydro-indol-2-one. MS (ESI) m/z 502 ([M+Hf).

¹⁰ A. Kende, Synth. Comm. 1 : 12 (1982) [0540] Step 3: In an analogous manner to EXAMPLE 5 7-fluoro-1-[(1S,2R)-1-(3- fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3- dimethyl-1 ,3-dihydro-2H-indol- 2-one hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid 3-(7-fluoro- 3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-3-(3-fluoro-phenyl)-2-hydroxy-propyl ester. MS (ESI) m/z 360 ([M+Hf), HRMS: calcd for C20H22F2N2O2 + H⁺, 361.17221; found (ESI, [M+Hf), 361.1719.

PATENT

https://www.google.com/patents/WO2008024492A2?cl=en

Scheme A

cat.

Scheme B

Acetylbromidθ

EtOH

Scheme C (cat.)

1. TSCI₁ TEA₁ CH₃CN A_{+ B} dlbutyltln oxide cat. 1. 33 wt% CH₃NH₂In EtOH. MeOH

1.35 equiv. 2. NaOH aq., toluene 2. 5N HCI in IPA, toluene

HCI salt

Example 1 :

Preparation of (1 R3/?)-3-(3-fluoropheπv0-2-(hvdroxymethv0oxirane

[0117] A thoroughly dried 5-L jacketed reactor was equipped with a mechanical stirrer, a 500-mL addition funnel, a temperature probe and a nitrogen inlet. The reactor was charged with D-(-)-DIPT (13.0 g 46 mmol), 4-A 5-μm molecular sieves (90 g) and dichloromethane (4.00 L) and then it was purged with nitrogen. The contents of the reactor were cooled to -15°C. Titanium isopropoxide (12.19 g, 43 mmol) was added rapidly to the reaction mixture via the addition funnel and the reaction mixture was further cooled to -20⁰C. A solution of allylic alcohol (127 g, 0.854 mol) in CH₂CI₂ (380 mL) was added to the reaction mixture via the addition funnel at a rate to keep the temperature in the reactor below -20⁰C. The resulting mixture was allowed to stir at -20⁰C for 10 minutes. A solution of TBHP in CH₂CI₂ (4.5 M, 380 mL, 1.71 mol) was added to the reaction mixture via the addition funnel at a rate to maintain the temperature below -20⁰C and above -25°C (addition rate 7 ml/min). The reaction mixture was stirred at -20⁰C for 4 hours. Reaction progress was monitored by HPLC: an aliquot was drawn out of the reactor and diluted with MeCN-water. The reaction was deemed complete when the amount of the starting olefin fell below 1 %.

[0118] The reaction mixture was transferred from the reactor into a 6-L flask containing a solution of FeSCU x 7H₂O (356 g, 1.28 mol), citric acid monohydrate (93 g, 0.39 mol) and de-ionized water (to the total volume of 1.0 L) chilled in an ice bath to 0⁰C. The rate of transfer was adjusted to maintain the temperature of the mixture below 10⁰C. The flask with the resulting mixture was equipped with a mechanical stirrer and the mixture was stirred for 25 minutes.

[0119] The organic layer was separated and filtered through a pad of Celite. The aqueous phase was extracted with MTBE (2 x 300 mL). Combined organic solutions were cooled to 0⁰C in an ice bath. A 30% solution of NaOH (100 mL) in brine (prepared by dissolving 5 g of NaCI in a solution of NaOH (30.0 g) in 90 mL of water) was cooled in an ice bath to 0⁰C and then added to the combined organic phases. The resulting mixture was stirred rapidly for 2 hours at 0⁰C. Water (400 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with MTBE (2 x 250 mL). The combined organic layers were dried with Na₂SO4 (300 g), the drying agent was filtered off through a paper filter and the filtrate was evaporated on rotary evaporator. The oily residue was mixed with 700 mL of toluene and the solvent was removed on a rotary evaporator. The residue after evaporation: Weight 125.9 g.

HPLC purity (area% 215 nm): 94%, impurities: toluene (3.1 %), starting olefin (1.0%), 3 unknown impurities (< 0.7% each).

¹H NMR (CDCI₃). Impurities: toluene (1.7 weight%), DIPT (1.1 weight%), t-BuOH (0.4 weight%).

Example 2: Preparation of 7-fluoro-1-r(1 S,2SM-(3-fiuorophenv[)-2,3-dihvdroxypropyπ-3.3- dimethylindolin-2-one

[0120] 7-Fluoro-3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one (60 g, 335 mmol) was mixed under nitrogen with anhydrous dimethylformamide (DMF) (10.8 ml_). To the resulting viscous solution, cooled to 5-7°C, was added via syringe a solution of LiHMDS in THF (1 M in THF, 140 ml, 140 mmol) at a rate to keep the reaction mixture temperature below 7-1O⁰C (addition of the first 60 ml was very exothermic, later the rate of addition could be increased). The resulting purple-red clear solution was allowed to warm up to 10⁰C.

[0121] In a separate flask, [(2/?,3fl)-3-(3-fluorophenyl)oxiran-2-yl]methanol (59.1 g, 352 mmol, 1.05eq.) was dissolved in 600 ml_ of anhydrous THF, the flask was purged with nitrogen and the solution was cooled to 5-7°C. Titanium isopropoxide (104 ml, 100 g, 584 mmol) was added to the epoxide solution dropwise via syringe maintaining the temperature in the 7-12°C range. The resulting bright-yellow solution was stirred for 40 minutes, allowing it to warm up to room temperature.

[0122] The contents of the second flask, the epoxy-titanium solution, were transferred to the solution of the indolinone salt via cannula maintaining the temperature of the mixture below 15°C. The resulting mixture was stirred at room temperature. The reaction progress was monitored by HPLC: after 20 hours, about 17 area% of indolinone was left, while no epoxide was detectable. Additional amount of the epoxide-titanium isopropoxide complex was prepared from epoxide (9.85 g, 58.4 mmol) and titanium isopropoxide (17.3 ml, 16.6 g, 58.4 mmol) in THF (100 mL) as described above and added slowly to the reaction mixture. The mixture was kept at room temperature for 20 hours longer, at which point HPLC analysis showed 4 area% of the unreacted indolinone and no detectable amount of the epoxide.

[0123] The reaction mixture was transferred into 1.80 L of cold (0⁰C) 2 M aqueous HCI solution (Exotherm. The rate of addition was adjusted to keep the temperature below 15°C). The resulting clear solution was extracted with MTBE (3 x 800 ml), the combined organic phase were washed with brine (800 ml), dried over magnesium sulfate and filtered through a pad of magnesol. The filtrate was evaporated, diluted with toluene (600 ml), and evaporated again to remove maximum amount of solvents. The residue (133 g) contained a sufficiently pure product to be used in the next step without further purification.

HPLC purity (area% at 215 nm): 95%, impurities: indolinone (3.5%).

¹H NMR (CDCI₃). Impurities: residual solvents (DMF, toluene, MTBE).

Example 3:

Preparation of 7-fluoro-1 -f(SH3-f luorophenylUf S)-oxiran-2-yl)methv0-3.3- dimethylindolin-2-one

[0124] A 2-L round bottom flask, equipped with a mechanical stirrer, a 100-mL addition funnel, a temperature probe and a nitrogen inlet, was charged with a solution of 7-fluoro-1 -[(1 S,2S)-1 -(3-fluorophenyl)-2,3-dihydroxypropyl]-3,3- dimethylindolin-2-one (50.0 g, 144 mmol) in CH₂CI₂ (500 mL), triethylamine (62 mL, 0.433 mol), solid dibutyltin oxide (716 mg, 2.9 mmol) and DMAP (1.74 g, 14.4 mmol). Tosyl chloride (28.23 g, 148 mmol) was dissolved in CH₂CI₂ (60 mL) and the solution was added slowly to the reaction mixture (addition rate 5.6 mL/min). Temperature range 20⁰C to 23°C. The reaction flask was cooled in an ice water bath during the addition to keep the temperature below 25°C. After the addition was finished, the bath was removed and the reaction mixture was stirred at room temperature. The reaction progress was monitored by HPLC.

[0125] After about one hour, the amount of the diol fell below 10%. A solution of NaOH, prepared by diluting 72 mL of 10 M aqueous NaOH with 360 mL of deionized water, was added rapidly to the reaction mixture. Solid Bu₄N⁺ CP hydrate (2.05 g, 7.2 mmol) was added and the reaction mixture was stirred rapidly at room temperature. The progress of the epoxide closure was monitored by HPLC. After 2 hour, all fosylate was consumed.

[0126] The layers were separated. The aqueous layer was extracted with 100 mL of CH₂CI₂. Combined organic solutions were washed with 100 mL portions of 0.5 M aqueous HCI until pH of the washes fell below 5, then with 50 mL of 0.5 M aqueous NaOH, then it was dried with Na₂SO_-I. The solution was gravity-filtered through a pad of Silica gel (150 g, thickness of the pad 5 cm) prepared in a glass filter funnel. The drying agent and the pad were washed with dichloromethane. The washing continued until no more epoxide was detectable in the eluent (by HPLC). The filtrate was evaporated to dryness on rotary evaporator (room temp. bath).

[0127] The residue after evaporation: weight 42.6 g. HPLC purity 82%, impurities: bis-tosylate (12%), diol (2.5%), indolinone (2.4%). The crude intermediate was used in the next step without further purification.

Example 4:

Preparation of 7-fluoro-1-iY1 S.2fl)-1-(3-fluorophenyl)-2-hvdroxy-3-(methyl amino)propyπ-3,3-dimethylindolin-2-one hydrochloride

[0128] The residue from the previous step (42.6 g) was dissolved in ethanol (160 mL) and the solution was placed into a 1-L round bottom flask equipped with a mechanical stirrer and a temperature probe. Aqueous methylamine (40 weight%, 240 mL, 2.74 mol) was added to the solution and the resulting suspension was stirred at room temperature. The reaction was monitored by HPLC. After 15 hours, the amount of the epoxide fell below 1%. Ethanol was removed on rotary evaporator (bath temperature 27°C). The residue was mixed with MTBE (250 mL) and water (100 mL). The layers were separated. The aqueous layer was extracted with 50 mL of MTBE. Combined organic solutions were washed with 100 mL of water. Small amount of brine was added to speed up the phase separation. The resulting organic solution was extracted with aqueous HCI (200 m L of 2 M solution, then 50 mL of 1 M solution). Combined acidic extracts were washed with 50 mL of MTBE.

[0129] MTBE (200 mL) was added to the aqueous solution. Aqueous NaOH (10 M solution^ 50 mL, 500 mmol) was added to the bi-phasic mixture. The mixture was shaken and the layers were separated. The aqueous layer was extracted with MTBE (100 mL). Combined organic solutions were dried with Na₂SO₄ (75 g). The drying agent was filtered off and the filtrate was evaporated in vacuum. [0130] The residue (38.0 g) was mixed with 70 ml_ of ethanol and the solvent was removed on rotary evaporator. The residue was re-dissolved in 100 ml_ of ethanol. With magnetic stirring, 2 M HCI in Et₂O (57 mL, 114 mmol) was added to the solution. The acidity of the solution was checked by placing a drop of the solution on a wet pH paper to ensure the solution is strongly acidic. The resulting solution was seeded with crystals of 7-fluoro-1-[(1 S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methyl amino) propyl]-3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one hydrochloride salt which caused slow crystallization of the salt in about 30 minutes. The slurry was stirred at room temperature for 1 hour.

[0131] The reaction flask was placed into a 0°C bath (equipped with thermostat) and the slurry was stirred magnetically for 21 hours. The cold slurry was filtered through a paper filter. The solid was washed with a 1 :1 mixture of EtOH-Et₂O (70 mL) and then was dried on the filter in a stream of air for 2 hours.

[0132] Weight of the crystals 29.7 g (54% from theoretical yield calculated from the diol).

HPLC purity (area% at 215 nm): 98.2%, impurities (relative retention time): 1.05

(0.46%), 0.98 (0.42%), 1.07 (0.15%), 2.05 (0.14%).

Enantiomeric purity 99.4% ee. m.p. 209.5-211.2⁰C.

[a)? = -,10.7°.

¹H NMR (D₂O, 400 MHz), δ: 7.45-7.30 (m, 3H), 7.16-6.97 (m, 4H), 5.53-5.30 (2H₁ broad m), 3.35-3.24 (2H, broad m), 2.82 (s, 3H), 1.41 (s, 3H), 1.27 (broad s, 3H).

Impurities: ethanol (0.3 weight%).

ES⁺ MS, m/z 361 (MH⁺).

Anal, calc’d for C₂₀H₂₃CIF₂N₂O₂ (396.9): C, 60.53; H, 5.84; N, 7.06. Found: C, 60.43;

H, 5.69; N, 6.84.

Sn content: 3 ppm.

Example 5:

Preparation of 7-fluoro-3. 3-dimethyl-oxindole via selective C-methylation of 7- fluoro-oxindole [0133] To a stirred slurry of potassium tert-butoxide (185 g, 1.65 mol) in tθtrahydrofuran (1350 mL) was added 7-fluoro-oxindole (50 g, 0.33 mol) and copper (I) bromide-dimethyl sulfide complex (7 g, 0.033 mol). Methyl iodide (150 g, 1.06 mol.) was added to the mixture at 5-10⁰C. The reaction mixture was stirred at 20- 25°C for 1 hour. 10% NH₄CI (1000 mL) was added to the reaction mixture. The two layers were separated. The organic layer was concentrated via vacuum distillation at 25-40⁰C to reach a volume of 250 mL. The aqueous layer is extracted with tert- butyl methyl ether (2 x 500 mL). The concentrated organic layer and tert-butyl methyl ether extraction layers were combined and washed with 15% NaCI (250 mL). The organic solution was filtered through silica gel (100 g). Heptane (1250 mL) was added to the filtrate. The mixture was concentrated under atmosphere at 60-95⁰C to reach a volume of 700 mL. The concentrate was cooled to 0-5⁰C from 85-95°C over 2 hours to crystallize. Solid was filtered, washed with heptane (100 mL), and oven- dried to give 41 g (69.4%) of a beige solid 7-fluoro-3, 3-dimethyl-oxindole, 92% w/w purity by HPLC.

Example 6:

Preparation of 3-(3-fluoro-phenyl)-prop-2-en-1-ol

[0134] A 5-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with MeOH (1.40 L) and 3-fluorocinnamic acid (0.20 kg, 1.20 mol). To the slurry charged p-TSA (0.023 kg, 0.120 mol) at 20⁰C to 25°C. The suspension was refluxed at 65°C to 68°C for 3-5 hours. The mixture was concentrated via atmospheric distillation to reach a volume of 700 mL. Methanol was then chased off by adding toluene (1.8 L) and was further concentrated to a solution (about 1.5 L). The reaction mixture then washed successively with 5% aqueous NaHCU3 (1.5) and water (1.5 L). The organic mixture was concentrate via atmospheric distillation to a minimum volume of 500 mL. HPLC analysis indicates that the solution strength 53.5% KF 0.17%, 98.8% area HPLC purity of the product. [0135] A 3-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with diisobutylaluminum hydride 25% w/w in Toluene (1.56 kg, 1 ,85 L₁2.75 mol). The solution was cooled to -25°C. To the reactor was then added using FMI pump a solution of 3-(3-Fluoro-phenyl)-acrylic acid methyl ester (0.41 kg, 0.40 L, 1.20 mol) in toluene while maintaining the internal temperature between -15°C to -8°C. The reaction mixture was stirred at -15 to -8°C for 60 minutes. The reaction mixture was then quenched in a 5-L reactor into a solution of concentrated HCI (0.40 L, 0.48 kg; 4.87 mol) in water (0.75 kg) maintaining internal temperature at 40⁰C to 45°C. The biphasic mixture was separated. The lower aqueous layer was washed with Toluene (0.34 kg, 0.40 L). The combined organic phase was successively washed with a 5% aqueous solution of sodium bicarbonate (0.7 L) and 10% brine (0.7 L). The*organic solution was concentrated via atmospheric distillation to reach a volume of 500 mL. HPLC analysis indicates that the solution strength is 53%, 169 g (93% Y), Al: 9 ppm, KF: 0.04%, 99% area HPLC purity of the allylic alcohol.

Example 7:

Preparation of r3-(3-fluoro-phenyl)-oxiranyπ-methanol

[0136] A 3-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with toluene (200 mL) and pre-activated molecular sieves powder (4A, 70 g). The resultant slurry was cooled to — 35°C. To the reactor was then added a solution of D-(-)-diisopropyl tartrate (21.6 g, 92.0 mmol) in toluene (25 mL), followed by addition of titanium (IV) isopropoxide (18.7 g, 65.7 mmol). The temperature of the reaction mixture was maintained between -30⁰C to -40⁰C during the addition. To the reactor was then charged with a solution of 3-(3-fluoro-phenyl)- prop-2-en-1-ol (100 g, 657 mmol) in toluene (490 mL) while maintaining the temperature of the reaction mixture between -30⁰C to -40⁰C. The reaction mixture was stirred at -35°C for 30 minutes. To the reactor was then added a solution of 5.5 M tert-butyl hydroperoxide in decane (240 mL, 1310 mmol) while maintaining the temperature of the reaction mixture between -30⁰C to -40⁰C. The reaction mixture was stirred at -35°C for 6 hours, followed by 8 hours at -20⁰C. The reaction mixture was warmed to room temperature and filtered through a thin layer of celite. The filter cake was washed with toluene (2 x 100 ml_). The combined filtrate and washes were cooled to 0⁰C and a solution of 30% sodium hydroxide saturated with sodium chloride (100 mL) was then added. The reaction mixture is stirred at 0°C for 2 hours. To the reaction mixture was then added a solution of sodium metabisulfite (69 g) and citric acid (50 g) in water (600 mL). The biphasic mixture was stirred at room temperature for 1 hour and the phases were separated. The organic phase was successively washed with a 5% sodium bicarbonate (500 mL) and 10% brine (500 mL). The organic solution was then concentrated under vacuum to reach a volume of 500 mL. HPLC analysis indicates that the solution contains 90.3 g (81.7%) of the epoxy alcohol product.

Example 8:

Preparation of r3-(3-fluoro-pheny[)-oxiranyll-methanol

[0137] A 1-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet is charged with toluene (140 mL) and pre-activated molecular sieves powder (4A, 14 g). The resultant slurry was cooled to -35°C. To the reactor is then added a solution of D-(-)-diisopropyl tartrate (4.31 g, 18.4 mmol) in toluene (20 mL), followed by addition of titanium (IV) isopropoxide (3.74, 13.1 mmol). The temperature of the reaction mixture was maintained between -30⁰C to -40⁰C during the addition. To the reactor is then charged with a solution of 3-(3-fluoro-phenyl)- prop-2-en-1 -ol (20 g, 131 mmol) in toluene (80 mL) while maintaining the temperature of the reaction mixture between — 30⁰C to — 40⁰C. The reaction mixture is stirred at -35°C for 30 minutes. To the reactor is then added a solution of cumene hydroperoxide (88% purity, 45.5 g, 263 mmol) while maintaining the temperature of the reaction mixture between -30⁰C to -40⁰C. The reaction mixture is stirred at – 35°C for 16 hours. A solution of 30% sodium hydroxide saturated with sodium chloride (20 mL) is charged while maintaining temperature of the reaction mixture below -20⁰C. To the reaction mixture is then added a solution of sodium metabisulfite (13.7 g) in water (60 mL) while maintaining the reaction mixture temperature below 25°C. The biphasic mixture is stirred at room temperature for 1 hour. To the reaction mixture is added Celite (70 g) and the mixture is filtered. The filter cake is washed with toluene (2 x 50 mL). The filtrate is successively washed with 5% sodium bicarbonate (100 mL) and 10% brine (100 mL). The organic solution is then concentrated under vacuum to reach a volume of 100 mL.

Example 9:

Preparation of r3-(3-fluoro-phenyl)-oxiranvn-methanol

[0138] A 5-L jacketed reactor equipped with a mechanical stirrer, addition funnel, temperature probe, and nitrogen inlet. All equipment must be rigorously dry. The reactor was charged with D-(-)-DIPT (10.0 mL, 11.0 g, 46 mmol), 4-A, 5-um molecular sieves (49.3 g), dichloromethane (3 L). The flask was purged with nitrogen. The contents of the flask were cooled to 0⁰C. Titanium isopropoxide (9.34 g, 9.73 mL was added rapidly to the flask via an addition funnel. The reaction mixture was cooled to -20⁰C. A solution of allylic alcohol (100 g, 0.657 mol) in CH₂CI₂ (300 mL) was added to the reaction mixture via an addition funnel while keeping the temperature below -20⁰C.

[0139] The reaction mixture was stirred at -20⁰C for 10 minutes. A solution of TBHP in CH₂CI₂ (188 mL, 5.7 M) was added to the reaction mixture via an addition funnel while maintaining the temperature between -20⁰C to -25°C. The reaction mixture was stirred at -20⁰C for 4 hours. Reaction progress was monitored by HPLC. A solution prepared from FeSO₄ x 6H₂O (217 g, 0.79 mol), citric acid monohydrate (72 g, 0.39 mol) and de-ionized water to the total volume of 660 mL, was chilled in an ice bath to 0⁰C.

[0140] The reaction mixture was quenched into the chilled solution of FeSO₄ and citric acid in water. The mixture was stirred for 30-60 minutes. The organic layer was checked for the presence of organic peroxides. The layers were separated. The aqueous phase was extracted with MTBE (2 x 200 mL). Combined organic solutions were cooled to 0⁰C in an ice bath. [0141] A 30% solution of NaOH (60 ml_) in brine (prepared by dissolving 5 g of NaCI in a solution of NaOH (30.0 g) in 90 mL of water) was cooled in an ice bath to 0⁰C and then added to the combined organic phases. The resulting mixture was stirred rapidly for 1-2 hours at 0⁰C. Water (300 mL) was added to the mixture. The two layers were separated. The aqueous layer was extracted with MTBE (2 x 250 mL). The combined organic layers were evaporated on. rotary evaporator. HPLC analysis indicates that the solution contains 90.5 g (81.5%) of the epoxy alcohol product with chiral purity 95.6/4.4 and chemical purity 96.5 area %.

Example 10:

Preparation of 7-fluoro-1- f(1S, 2S)-1-(3-fluorophenv0-2,3-dihvdroxypropyl1-3,3- dimethvM . 3- dihvdro-2H-indol-2-one

[0142] To a suspension of 7-fluoro-3, 3-dimethyl-oxindole (35 g, 0.195 mol) in N, N dimethylformamide (36 g, 0.49 mol) and toluene (200 mL) was added (1 M / toluene) lithium bis (trimethylsilyl) amide (585 mL, 0.585 mol). To the resulting mixture was added a solution of (20% / toluene) [3-(3-fluoro-phenyl)-oxiranyl]-methanol (210 g, 0.253 mol) and titanium (IV) isopropoxϊde (72g, 0.253 mol) in toluene (300 mL) at 5- 10⁰C. The reaction mixture was stirred for 3-4 hours at 40-45°C. To the reaction mixture was added 37% HCI (460 g, 2.34 mol) and water (500 mL) at 20-25⁰C to give a bi-phasic mixture. The organic layer was separated. The aqueous layer was extracted with toluene (1000 mL). The combined organic layers were washed with 1N NaOH (200 g), and then with 10% NaCI (200 g). The organic layer was concentrated via atmospheric distillation at 100-110⁰C to a volume of (1800 mL). The concentrated solution was filtered through silica gel (150 g). The silica gel plug was rinsed with ethyl acetate (850 mL). The filtrate was concentrated via atmospheric distillation at 80-110⁰C to reach a volume of (250 mL). The concentrate was cooled to 0-5⁰C from 100-1 10⁰C over 4 hours to crystallize. Solid was filtered, washed with heptane (150 mL), and oven-dried to give 50.6 g (74.7%) of a beige solid, 97.4% w/w purity by HPLC.

Example 11 : Preparation of 7-fluoro-1-rf1S.2R)-1-(3-ftuorophenyl)-2-hvdroxy-3-fmethyl amino) propyl1-3.3-dirnethyl-1.3-dihvdro-2H-indol-2-one:

[0143] To the solution of the diol (52 g, 0.144 mol) in MeCN (500 mL) was added Bu₂SnO (0.39 g, 1.44 mmol) and TsCI (28.8 g, 0.151 mol). To the resulting solution was added Et₃N (29 g, 0.288 mol) dropwise at 0-5⁰C. The reaction was stirred for 1 hour at 0-5⁰C until the tosylation was complete by HPLC. To the reaction containing the mono-tosylate was added a solution of NaOH (58 g, 0.72 mol) in water (400 mL) at 0⁰C. At the end of the epoxide formation, toluene (800 mL) and NaCI (25 g) in water (150 mL) were added to form a bi-phasic reaction mixture. The two layers were separated. The organic layer was washed with 37% w/w HCI (56 g) in water (256 mL) followed by NaCI (50 g) in water (300 mL). The organic layer was diluted with toluene (700 mL) and concentrated to a volume of about 900 mL. The resulting concentrated solution was filtered through a silica gel (200 g) plug. The silica gel plug was eluted with toluene (1.5 L). The combined filtrate was concentrated under vacuum to about 300 mL. Methylamine in EtOH (33 weight %, 245 mL, 2.0 mol) and Ca(OTf)₂ (15 g, 43 mmol) were added to the toluene solution. The reaction mixture was stirred at 20-25⁰C for 12 hours then concentrated via vacuum distillation to about 200 mL. MTBE (500 mL) and water (500 mL) were added. The two layers were separated. 37% w/w HCI (160 g,) in water (340 g) was added to the organic layer. Stirred and the two layers were separated. The aqueous organic layer was washed with MTBE (500 mL). To the acidic aqueous layer was charged MTBE (500 mL) then the mixture was cooled to 0-5⁰C and basified with NaOH (50% w/w, 150 g, 100 mL). Reaction mixture was stirred for 20 minutes then the two layers were separated. The organic layer was washed with 15% NaCI (170 mL) then concentrated to about 250 mL via atmospheric distillation. To the MTBE concentrate was added EtOH (2B) (150 mL) followed by HCI (5.7 N in EtOH, 45 mL, 0.26 mol). The mixture was stirred at 20 to 25°C for a minimum of 2 hours and then cooled to 0 to 5°C over 1 hour. The suspension was filtered and washed with MTBE (50 mL) to give 26 g (45%) of an off-white solid.

Example 12:

Preparation of (2EKH3,5-difluorophenvQprop-2-en-1-ol [0144] A 5-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with MeOH (1.40 L), 3, 5-difluorocinnamic acid (0.20 kg, 1.09 mol) and p-TSA (0.0207 kg, 0.109 mol) at 20⁰C to 25°C. The suspension was refluxed at 65°C to 68°C for 4-6 hours. The mixture was concentrated via atmospheric distillation to reach a volume of about 700 mL. Methanol was then chased off by adding toluene (1.8 L) and was further concentrated to a solution (about 1.5 L). The reaction was cooled to 50⁰C to 55°C then washed successively with 5% aqueous NaHCO₃ (1.5 L) and water (1.5 L). The organic mixture was concentrated via atmospheric distillation to a minimum volume of about 1.5 L. KF 0.17%.

[0145] A 3-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with diisobutylaluminum hydride 25% w/w in toluene (1.42 kg, 1.68 L, 2.31 mol). The solution was cooled to -25°C. To the reactor was then added using FMI pump a solution of 3-(3, 5-difluoro-phenyl)-acrylic acid methyl ester (1.4 L, 1.09 mol) in toluene while maintaining the internal temperature between -15°C to -8°C. The reaction mixture was stirred at that temperature for 60 minutes then quenched into a 5-L reactor with a solution of concentrated HCI (0.40 L, 0.48 kg; 4.87 mol) in water (0.70 kg) while maintaining the internal temperature at 40⁰C to 45°C. The biphasic mixture was separated. The lower aqueous layer was washed with toluene (0.34 kg, 0.40 L). The combined organic phase was successively washed with a 5% aqueous solution of sodium bicarbonate (0.70 L) and 10% brine (0.70 L). The organic solution was concentrated via atmospheric distillation to reach a volume of 0.386 Kg, about 500 mL. HPLC analysis indicates that the solution contains 170 g, 91% yield of (2E)-3-(3,5-difluorophenyl)prop-2-en-1-ol. Al: 1 ppm, KF: 0.12%, 99.8% area HPLC purity.

Example 13:

Preparation of r(2ff,3/?)-3-(3.5-difluorophenyl)oxiran-2-vH-methanol [0146] A 3-L reactor equipped with a mechanical stirrer, thermocouple, and nitrogen inlet was charged with toluene (100 mL) and pre-activated molecular sieves powder (4A, 70 g). The resultant slurry was cooled to -35°C. To the reactor was then added a solution of D-(-)-diisopropyl tartrate (19.3 g, 0.082 mol) in toluene (25 mL), followed by addition of titanium (IV) isopropoxide (16.7 g, 0.059 mol). The temperature of the reaction mixture was maintained between -30⁰C to -40⁰C during the addition. To the reactor was then added a solution of 3-(3,5-difluoro-phenyl)- prop-2-en-1-ol (100 g, 0.588 mol) in toluene (250 mL) while maintaining the temperature of the reaction mixture between -30⁰C to -40⁰C. The reaction mixture was stirred at -35°C for 30 min. To the reactor was then added a solution of 5.5 M tert-butyl hydroperoxide in decane (173 g, 1.18 mol) while maintaining the temperature of the reaction mixture between -30⁰C to -40⁰C. The reaction mixture was stirred at -35°C for 6 hours, followed by 8 hours at -25°C. The reaction mixture was warmed to room temperature and filtered through a thin bed of celite (25 g). The filter cake was washed with toluene (2 x 200 mL). The combined filtrate and washes were cooled to 0⁰C and a solution of 30% sodium hydroxide saturated with sodium chloride (100 mL) was then added. The reaction mixture is stirred at 0⁰C for 3 h. To the reaction mixture was then added a solution of sodium metabisulfite (61.5 g) and citric acid (44.5 g) in water (600 mL). The biphasic mixture was stirred at room temperature for 1 hour and the phases were separated. The organic phase was successively washed with a 5% sodium bicarbonate (500 mL) and 10% brine (500 mL). The organic solution was then concentrated under vacuum to reach a volume of about 400 mL. A small portion of the concentrate was taken out for seed generation at 25-30⁰C. To the suspension was then charged 3 volume parts of heptane (300-400 mL). The mixture was cooled to 5-10⁰C then filtered to give 71.3 g, 65% yield of [(2R,3R)-3-(3,5-difluorophenyl)oxiran-2-yl]-methanol as an off-white solid with chiral purity 94 %ee, mp: 48-50°C.

Example 14:

Preparation of 1-r(7S,2S>-1-(3,5-difluorophenyl)-2,3-dihvdroxypropyH-7-fluoro- 3,3-dimethyl-1,3-dihvdro-2H-indol-2-one [0147] To a suspension of dimethyl oxidole (68 g of 74 % strength crude, 280 mmol) in DMF (51 g, 700 mmol.) and toluene (200 rriL), a toluene solution of (Me₃Si)₂NLi (840 ml_, 1 M, 840 mmol) was added dropwise while keeping the mixture below 10⁰C to give a dark solution. A solution of epoxy alcohol (76 g of 85% strength, 350 mmol) and Ti(OiPr)₄ (103 g, 360 mmol) in toluene (400 ml_) was added to the above dark solution at below 10⁰C. The reaction mixture was stirred for 20 hours at 20⁰C before cooling to 0⁰C. A solution of HCI (660 g, 37% in water) in water (750 g) was added at below 20⁰C to give a bi-phasic mixture. The two layers were separated. The organic layer was washed with NaOH (400 ml_, 0.7 N in water, 280 mmol), and brine (230 g). The organic layer was filtered through a silica gel (150 g) plug. The silica gel plug was rinsed with. EtOAc (1100 ml_). The filtrate was concentrated in vacuo at 50°C to a volume of 240 ml_. This concentrate was diluted with CH₃CN (300 ml_) to give 1-[(1S,2S)-1-(3,5-difluorophenyl)-2,3-dihydroxypropyl]- 7-fluoro-3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one as a CH₃CN solution, 431 g of a 20.8% strength solution, yield: 88%.

Example 15:

Preparation of 1-r(7S..g/?)-1-(3,5-d.fluorophenvπ-2-hvdroxy-3-(methylamϊno) propyπ-7-fluoro-3,3-dimethyl-1,3-dihvdro-2H-indol-2-one

[0148] To the solution of 1-[( 7S,2S)-1 -(3,5-difluorophenyl)-2,3-dihydroxypropyl]-7- fluoro-3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one in acetonitrile (394 g of 20.8% strength solution, 224 mmol) at 20⁰C, tosyl chloride (56g, 269 mmol) and Bu₂SnO (1.4 g 5.6 mmol) were added. The reaction mixture was cooled to 5°C, and then Et₃N (45 g, 448 mmol) was added dropwise. The reaction mixture was stirred for about 1 hour at 20⁰C until tosylation is complete.

[0149] A solution of NaOH (90 g of 50% w/w solution in water, 1120 mmol) in water (492 g) was added at 5°C. The reaction mixture was stirred for 1 hour. Toluene (1312 ml_) was added to the reaction mixture to give a bi-phasic mixture. The organic layer was separated and washed with HCI (44 g of 37% solution in water, 448 mmol) in water (32OmL) then with brine (400 mL). The organic layer was then concentrated to a volume of (400 mL) under vacuum keeping the temperature below 50⁰C. The concentrate was diluted with toluene (1120 mL). The resulting solution was filtered through a silica gel (320 g) plug. The silica gel plug was eluted with toluene (2400 ml_). The filtrate was concentrated to a volume of 400 ml_ in vacuo keeping the temperature below 50⁰C.

[0150] Methanol (1200 mL) was charged to the mixture then concentrated down to about 400 mL in vacuo while keeping temperature below 50⁰C. To the concentrate was added methanol (1600 mL) and methylamine (252 g of 33 wt % solution in ethanol, 2688 mmol.). The reaction mixture was stirred for 20 hours at 40⁰C until the aminolysis is complete. The mixture was concentrated down to about 400 mL in vacuo. Toluene (960 mL) was added to the concentrate. The mixture was concentrated in vacuo down to about 400 mL.

[0151] HCI (40 g of 5N solution in isopropanol, 224 mmol.) in IPA was added to the mixture. Stirred at 20⁰C for 2 hours. The resulting slurry was filtered then dissolved in acetone (1230 mL) at 40⁰C. Heptane (1640 mL) was added. The resulting solution was concentrated at 70⁰C to a volume of (1230 mL). The resulting slurry was filtered and dried for 18 hours at 55°C to give 46.5 g, 50% overall yield of 1- [(1 S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3- dimethyl-1 ,3-dihydro-2H-indol-2-one as a white solid.

Example 16:

Preparation of 7-fluoro-1-fπSH3-fluorophenvθr(2S)-oxiran-2-vπmethyl}-3.3- dimethyl-1.3-dihvdro-2H-indol-2-one

[0152] Diethyl-azodicarboxylate (100 g, 572 mmol) was added dropwise to a solution of 1-[(1S, 2S)-1-(3,5-difluorophenyl)-2,3-dihydroxypropyl]-7-fluoro-3,3- dimethyl-1 ,3-dihydro-2H-indol-2-one (90 g, 260 mmol) and Ph₃P (129g, 520 mmol) in toluene (1042 mL) at 25⁰C. The mixture was stirred for 1 hour at 80⁰C. Ph₃P (7 g, 26 mmol) was added to the mixture at 80⁰C. The mixture was stirred for 8 hours at 😯⁰C. Diethyl-azodicarboxylate (9 g, 52 mmol) was added to the mixture at 80⁰C. The mixture was stirred for about 2 hours at 80⁰C until the reaction is complete. Heptane (3120 mL) was added to the reaction mixture at 80⁰C. The mixture was cooled to 10⁰C and then filtered through a silica gel (720 g) plug. The filtrate was discarded. The silica gel plug was rinsed with a solution of ethyl acetate (1100 mL) in heptane (3300 mL). The filtrate was concentrated to dryness at 50⁰C to give 56 g, 80% purity, 52% yield of 7-fluoro-1-{(1 S)-(3-fluorophenyl)[(2S)-oxiran-2-yl]methyl}- 3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one.

Example 17:

Preparation of 7-fluoro-1-rf1S.2R)-1-f3-fluorophenvπ-2-hydroxy-3-(methyl amino) propyll-3,3-dimethyl-1 ,3-dihydro-2H-indol-2-one:

[0153] In a flask with 7-fluoro-1-[(1 S,2S)-1-(3-fluorophenyl)-2,3-dihydroxypropyl]- 3,3-dimethylindolin-2-one (10 g, 0.0288 mol) and para-toluenesulfonic acid (pTSA) (0.0438 g, 0.023 mol) in THF (50 mL), trimethyl orthoacetate (4.15 g, 4.3 mL, 0.0346 moles) was added dropwise. The amber color solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to oil then THF (50 mL) was added. Cooled to 0⁰C to 5°C then acetyl bromide (8.50 g, 0.0692 mol) was added. The resulting mixture was stirred at room temperature for 3 to 4 hours then concentrated to oil and charged with THF (25 mL) and EtOH 2B (25 mL) followed by K₂CO₃ -325 (39.8 g, 0.288 mol). The mixture was stirred at room temperature then the mixture was concentrated in vacuo to oil. MTBE (100 mL) and H₂O (170 mL) were added to dissolve the oil. The two layers were separated. The aqueous layer was extracted with MTBE (2 x 100 mL). The combined organic layer was concentrated to oil then 33% solution of methylamine in ethanol (15 eq.) was added and stirred at room temperature. At the completion of the reaction, the mixture was concentrated to oil. MTBE 100 mL) and H₂O (100 mL) were added. The two layers were separated. The organic layer was extracted with 37% concentrated HCI (30.7g) in H₂O (65 g). The lower aqueous layer was extracted with MTBE (100 mL) then cooled to 0-5⁰C. MTBE (100 mL) and a solution of 50% NaOH (30 g) in H₂O (30 g) were added to the aqueous layer. The mixture was stirred for 20 minutes at room temperature and the layers were separated. The aqueous layer was back extracted with MTBE (50 mL). The combined organic layer was washed with a 15% NaCI (23 mL) solution. The organic layer was concentrated to give as oil (8.4 g, about 90% by LC/MS, 60% yield). [0154] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges specific embodiments therein are intended to be included.

Paper

Organic Process Research & Development 2009, 13, 880–887

Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter:
Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol
and Process Implications
Asaf Alimardanov,* Alexander Gontcharov, Antonia Nikitenko, Anita W. Chan, Zhixian Ding, Mousumi Ghosh,
Mahmut Levent, Panolil Raveendranath,† Jianxin Ren, Maotang Zhou, Paige E. Mahaney,‡ Casey C. McComas,‡
Joseph Ashcroft, and John R. Potoski
Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A., and Wyeth Research, 500 Arcola Road,
CollegeVille, PennsylVania 19426, U.S.A.

TREATMENT OF GYNECOLOGICAL DISORDERS
WAY-315193 (Wyeth Pharmaceuticals)

Development of a scalable synthesis of WAY-315193 is described.
Use of LiHMDS as a base and Ti(O-i-Pr)4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylationmethylamination.
The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.

The synthetic route used initially for preparation of 1 is shown in Scheme 1. The key step of the synthesis was the
Sharpless epoxidation of fluorocinnamic alcohol 3 which selectively introduced both relative and absolute configurations at the C-2 and C-3 positions. At the early stages of the project, allylic alcohol 3 was prepared in two steps from commercially available fluorocinnamic acid 2 by treatment with MeI in the presence of Cs2CO3 in acetone, followed by DIBAL reduction at -78 °C. The epoxide 4 was opened with the sodium salt of dimethylfluoroindolinone in DMF to afford the diol. The diol 6 was further elaborated into the final aminoalcohol hydrochloride 1 in 30-34% yield via tosylation with p-toluenesulfonyl chloride (TsCl) in pyridine, isolation of the intermediate monotosylate, treatment with MeNH2, and conversion to HCl salt. Dimethylfluoroindolinone was prepared by reduction and bis-methylation of 7-fluoroisatin by a process developed earlier as described in a prior publication.3

white solid (58% yield). Mp 209-212 °C.
[R]D25°)+10.7°.

1H NMR (D2O, 400 MHz) δ: 7.40-7.25 (m,3H), 7.16-6.97 (m, 4H), 5.47-5.25 (2H, broad m), 3.27-3.20
(2H, broad m), 2.76 (s, 3H), 1.37 (s, 3H), 1.24 (broad s, 3H).
ES+ MS, m/z 361 (MH+). Anal. Calc’d for C20H23ClF2N2O2:C, 60.53; H, 5.84; N, 7.06. Found: C, 60.43; H, 5.69; N, 6.84.
Sn content: <1 ppm. Enantiomeric purity: 99.1% ee. Chiral SFCanalysis conditions: column: Chiralcel OF 250 mm × 4.6 mm;mobile phase: 30% ethanol, 0.4% diethylamine in CO2; detection wavelength: 254 nm; 2 mL/min, 40 °C.

* Corresponding author. E-mail: alimara@wyeth.com.
† Deceased.
‡ Wyeth Research, Collegeville, PA.
(1) (a) For a review on norepinephrine reuptake inhibitors, see: Babu,R. P. K.; Maiti, S. N. Heterocycles 2006, 69, 539. (b) Krell, H. V.;Leuchter, A. F.; Cook, I. A.; Abrams, M. Psychosomatics 2005, 46,379. (c) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown,M. T.; Wong, E. H. W. CNS Drug ReV. 2004, 10, 23. (d) McCormack,
P. L.; Keating, G. M. Drugs 2004, 64, 2567.
(2) Kim, C. Y.; Mahaney, P. E.; Trybulski, E. J.; Zhang, P.; Terefenko,E. A.; McComas, C. C.; Marella, M. A.; Coghlan, R. D.; Heffernan,G. D.; Cohn, S. T.; Vu, A. T.; Sabatucci, J. P.; Ye, F. Phenylaminopropanol
Derivatives and Methods of Their Use. U.S. Patent 7,517,899,2009.

(3) Wu, Y.; Wilk, B. K.; Ding, Z.; Shi, X.; Wu, C. C.; RaveendranathP.; Durutlic, H. Process for the Synthesis of Progesterone ReceptorModulators. U.S. Patent Publ. Appl. US 2007/027327, 2007.
(4) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) For a recent example of large-scale asymmetric epoxidation, see: Henegar,
K. E.; Cebula, M. Org. Process Res. DeV. 2007, 11, 354.

(5) (a) For indolinone deprotonation for epoxide opening, see: Proudfoot,J. R.; Regan, J. R.; Thomson, D. S.; Kuzmich, D.; Lee, T. W.;Hammach, A.; Ralph, M. S.; Zindell, R.; Bekkali, Y. Preparation ofPropanol and Propylamine Derivatives and Their Use as Glucocorticoid Ligands. WO 2004/063163, 2004. (b) Gillman, K.; Bocchino, D. M.
Preparation of Monosaccharides Prodrugs of Fluorooxindoles Useful in Treatment of Disorders Which are Responsive to the Opening of Potassium Channels. U.S. Patent Publ. Appl. US 2004/0152646, 2004.
(c) For amide deprotonation for epoxide opening, see: Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787. (d) Chan, W. N.; Evans, J. M.; Hadley, M. S.; Herdon, H. J.; Jerman, J. C.; Morgan,H. K. A.; Stean, T. O.; Thompson, M.; Upton, N.; Vong, A. K. J. Med.Chem. 1996, 39, 4537.
(6) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(7) (a) Smith, J. G. Synthesis 1984, 629. (b) Parker, R. E.; Isaacs, N. S.Chem. ReV. 1959, 59, 737.

Patent ID	Date	Patent Title
US7595338	2009-09-29	Process for preparing 3, 3-disubstituted oxindoles and thio-oxindoles
US2009099164	2009-04-16	Phenylaminopropanol Derivatives and Methods of Their Use
US7517899	2009-04-14	Phenylaminopropanol derivatives and methods of their use
US2009093469	2009-04-09	Phenylaminopropanol Derivatives and Methods of Their Use
US2008146645	2008-06-19	Process for Preparing Indolinone Phenylaminopropanol Derivatives

Citing Patent	Filing date	Publication date	Applicant	Title
WO2006118955A2 *	Apr 27, 2006	Nov 9, 2006	Wyeth	Process for preparing 3,3-disubstituted oxindoles and thio-oxindoles
WO2006118955A3 *	Apr 27, 2006	Jan 11, 2007	Bogdan Kazimierz Wilk	Process for preparing 3,3-disubstituted oxindoles and thio-oxindoles
WO2007041023A1 *	Sep 27, 2006	Apr 12, 2007	Wyeth	1- (1h- indol- 1-yl) -3- (methylamino) -1- phenylpropan-2-ol derivatives and related compounds as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (vms)
WO2008024492A2 *	Aug 22, 2007	Feb 28, 2008	Wyeth	Indolinone phenylaminopropanol derivatives and process for the preparation thereof
WO2008024492A3 *	Aug 22, 2007	May 15, 2008	Wyeth Corp	Indolinone phenylaminopropanol derivatives and process for the preparation thereof
US9403807	Dec 2, 2014	Aug 2, 2016	Merck Sharp & Dohme Corp.	Mineralocorticoid receptor antagonists

WO2005097744A1 *	Mar 29, 2005	Oct 20, 2005	Wyeth	1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine (ne) and the serotonine (5-ht) activity and the monoamine reuptake for the treatment of vasomotor symptoms (vms)
WO2005097761A1 *	Mar 29, 2005	Oct 20, 2005	Wyeth	Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (vms)
WO2007041023A1 *	Sep 27, 2006	Apr 12, 2007	Wyeth	1- (1h- indol- 1-yl) -3- (methylamino) -1- phenylpropan-2-ol derivatives and related compounds as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (vms)
US20070072897 *	Sep 27, 2006	Mar 29, 2007	Wyeth	Phenylaminopropanol derivatives and methods of their use

//////////WAY-315193

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How does a company demonstrate the implementation of PQS in accordance with ICH?

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ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” into practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented? Please read more about the GMP Questions and Answers.

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ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” in practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented?

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What are the GMP Responsibilities of the Marketing Authorisation Holders?

October 15, 2016 7:22 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The European Medicines Agency (EMA) has published a concept paper to summarise the GMP responsibilities of the Marketing Authorisation Holders (MAH).

http://www.gmp-compliance.org/enews_05618_What-are-the-GMP-Responsibilities-of-the-Marketing-Authorisation-Holders_15367,15360,15355,15618,Z-QAMPP_n.html

The GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) has published a concept paper to summarise the GMP responsibilities of the Marketing Authorisation Holders (MAH). It is not intended to introduce any new responsibilities on MAHs but to document existing requirements in a better way.

The current EU GMP-Guidelines define in several chapters and annexes GMP tasks and responsibilities of the MAH. However, there seems to be a lack of clarity and understanding as to what these responsibilities actually are in their totality, and what they mean for MAHs at a practical level. All these tasks and responsibilities have now been summarised in this concept paper:

Chapter 1: responsibility to evaluate the results of the PQR review
Chapter 7: responsibility to put contracts in place
Chapter 8: responsibilities…

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Ranitidine

October 15, 2016 7:09 am / 1 Comment on Ranitidine

Ranitidine

Ranitidine, sold under the trade name Zantac among others, is a medication that decreases stomach acid production.^[1] It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome.^[1] There is also tentative evidence of benefit for hives.^[2] It can be taken by mouth, by injection into a muscle, or into a vein.^[1]

Common side effects include headaches and pain or burning if given by injection. Serious side effects may include liver problems, a slow heart rate, pneumonia, and the potential of masking stomach cancer.^[1] It is also linked to an increased risk ofClostridium difficile colitis.^[3] It is generally safe in pregnancy. Ranitidine is an H₂ histamine receptor antagonist that works by blocking histamine and thus decreasing the amount of acid released by cells of the stomach.^[1]

Ranitidine was discovered in 1976 at Glaxo Pharmaceuticals, now a part of GlaxoSmithKline.^[4]^[5] It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.^[6] It is available as a generic medication.^[1] The wholesale price in the developing world is about 0.01 to 0.05 USD per pill.^[7] In the United States it is about 0.05 USD per dose.^[1]

Image result for SYNTHESIS ranitidine.

Laboratory Synthesis Of Ranitidine

Synthesis Of Ranitidine

—————————————————————————————

Ranitidine Synthetic procedure/method of synthesis

The reaction of 5-dimethylaminomethyl-2-furanylmethanol (I) with 2-mercaptoethylamine (II) by means of aqueous HCl gives 2-[[(5-dimethylamino-methyl-2-furanyl)methylthio]ethaneamine (III), which is then condensed with N-methyl-1-methylthio-2-nitrotheneamine (IV) by heating at 120 C. Compound (IV) is obtained by reaction of 1,1-bis(methylthio)-2-nitroethene (V) with methylamine in refluxing ethanol

Ranitidine reference

Serradell, M.N.; Blancafort, P.; Casta馿r, J.; Hillier, K.; Ranitidine. Drugs Fut 1979, 4, 9, 663
Price, B.J. et al. (Allen and Hanburys, Ltd.); US 4128658.
Price, B.J.; Bradshaw, J.; Clitherow, J.W. (Allen & Hansburys Ltd.); Aminoalkyl furan derivatives.. DE 2734070; FR 2360587; US 4128658 ,DE 2734070; FR 2360587; US 4128658.

PAPER

Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

Mark Mascal*^a and Saikat Dutta^a

*Corresponding authors

^aDepartment of Chemistry, University of California Davis, 1 Shields Avenue, Davis, US
E-mail: mascal@chem.ucdavis.edu
Fax: 530-752-8995
Tel: 530-754-5373

Green Chem., 2011,13, 3101-3102

DOI: 10.1039/C1GC15537G

http://pubs.rsc.org/en/content/articlelanding/2011/gc/c1gc15537g#!divAbstract

http://www.rsc.org/suppdata/gc/c1/c1gc15537g/c1gc15537g.pdf

The biomass-derived platform chemical 5-(chloromethyl)furfural is converted into the blockbuster antiulcer drug ranitidine (Zantac) in four steps with an overall 68% isolated yield.

Graphical abstract: Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

Image result for A new method for the synthesis of ranitidine.

PROCESS

Image result for A new method for the synthesis of ranitidine.

2. Experimental Procedures

5-[[(2-Acetamidoethyl)thio]methyl]furfural 14

Sodium hydride (95%) (103 mg, 4.08 mmol) was added to a solution of Nacetylcysteamine (0.4051 g, 3.40 mmol) in dry THF (20 mL) under argon. The resulting suspension was stirred at RT for 30 min and a solution of CMF 12 (0.4912 g, 3.40 mmol) in dry THF (10 mL) was added dropwise over a 10 min period. The resulting light yellow solution was allowed to stir overnight at RT. The solvent was evaporated and saturated brine (50 mL) was added. The mixture was extracted with CH2Cl2 (2 × 50 mL) and the organic layers were combined and washed with saturated brine (100 mL). The organic layer was dried over Na2SO4. Charcoal (100 mg) was added and the mixture was stirred for 20 min and filtered. The solvent was evaporated to give 14 as a yellow liquid (0.7042 g, 91 %). 1H NMR (CDCl3, 300 MHz) 9.58 (1H, s), 7.21 (1H, d, J = 3.6 Hz), 6.48 (1H, s, br), 5.95 (1H, d, J = 3.6 Hz), 3.79 (2H, s), 3.45 (2H, q, J = 6.3 Hz), 2.72 (2H, t, J = 6.6 Hz), 2.00 (3H, s); 13C NMR (CDCl3, 75 MHz) 23.1, 27.8, 31.7, 38.4, 110.7, 121.9, 152.2, 158.9, 170.7, 177.4; IR (neat) 3298, 3101, 1663, 1548, 1512, 1287, 1022, 772 cm-1; HRMS (ESI): calculated for C10H14O3NS: [M+H]+ 228.0694: found 228.0690.

5-[[(2-Acetamidoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine 15

Me2NH (1.0 mL) was added to a solution of 14 (0.2105 g, 0.926 mmol) in dry methanol (20 mL) and the mixture was stirred at RT for 1 h. The resulting red solution was cooled to 0 °C and NaBH4 (98 %) (55 mg, 1.42 mmol) was added over a 5 min period. The mixture was allowed to come to RT and stirred for 30 min. The solvent was evaporated while keeping the bath temperature below 45 °C. The residue was dissolved in CH2Cl(50 mL) and filtered to remove inorganic impurities. The solvent was evaporated to give 15 (0.2145 g, 90 %) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) 6.42 (1H, s, br), 6.09 (1H, s), 3.67 (2H, s), 3.37 (2H, s), 3.26 (2H, q, J = 6.0 Hz), 2.62 (2H, t, J = 6.4 Hz) 2.21 (6H, s), 1.93 (3H, s); 13C NMR (CDCl3, 75 MHz) 23.5, 28.4, 31.9, 38.7, 45.4, 56.2, 108.4, 109.9, 151.4, 152.1, 170.5; IR (neat) 3273, 2944, 1656, 1545, 1291, 1019, 729 cm- 1 ; HRMS (ESI): calculated for C12H21O2N2S: [M+H]+ 257.1322: found 257.1323.

5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine 5

A solution of 15 (0.2473 g, 0.965 mmol) in freshly prepared 2N aq NaOH (10 mL) was heated at reflux for 2 h. The mixture was cooled to RT and extracted with CH2Cl2 (3×30 mL). The organic layers were combined and washed with saturated brine, dried over Na2SO4, and evaporated to give 5 (0.1934 g, 94 %) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) 6.02 (2H, s), 3.61 (2H, s), 3.33 (2H, s), 2.74 (2H, t, J = 6.3 Hz), 2.52 (2H, t, J = 6.6 Hz), 2.16 (6H, s); 13C NMR (CDCl3, 75 MHz) 28.2, 35.9, 40.9, 45.1, 55.9, 108.1, 109.5, 151.4, 152.1; IR (neat) 3359 cm-1, 2947, 2769, 1559, 1459, 1015, 797 cm-1; HRMS (ESI): calculated for C10H19ON2S: [M+H]+ 215.1212: found 215.1218.

N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’-methyl-2-nitro- 1-Ethenediamine (Ranitidine) 1 The experimental procedure is modified from existing literature:2 A solution of 5 (0.1501 g, 0.700 mmol ) in distilled water (10 mL) was added dropwise over a period of 10 min to a suspension of 1-methylthio-1-methylamino-2-nitroethylene 7 (0.1041 g, 0.703 mmol) in distilled water (5 mL) with stirring. The resulting light yellow solution was placed in an oil bath at 55 °C and the mixture was stirred at that temperature overnight. Saturated brine (30 mL) was added and the mixture was extracted with CHCl3 (3×20 mL). The combined organic layer was dried over Na2SO4. Evaporation of the solvent gave 1 as a pale yellow oil (0.1935 g, 88 %). 1H NMR (CDCl3, 300 MHz, 56 oC) 10.23-10.15 (1H, br, NH), 6.57 (1H, s), 6.13 (2H, d, 6.0 Hz), 5.04 (1H, br, NH), 3.73 (2H, s), 3.41 (4H, s), 2.92 (2H, s), 2.76 (2H, t, 6.0 Hz), 2.24 (6H, s); 13C NMR (CDCl3, 75 MHz, 56 °C) 28.2, 30.6, 40.7, 44.6, 55.6, 97.9, 108.1, 109.1, 150.4, 152.1, 156.6; IR (neat) 3209, 2944, 2815, 2776, 1620, 1574, 1384, 1230, 1019, 761 cm-1; HRMS (ESI): calculated for C13H23O3N4S: [M+H]+ 315.1491: found 315.1497.

SEE NMR AT http://www.rsc.org/suppdata/gc/c1/c1gc15537g/c1gc15537g.pdf

Zantac (ranitidine) 300-mg tablet

PATENT

Image result for A new method for the synthesis of ranitidine.

Patent EP0796256B1 – Process for preparing ranitidine – Google Patents

Google

Figure 00060001

HPLC

Image result for A new method for the synthesis of ranitidine.

An Improved HPLC Method for the Determination of Ranitidine …

Separation Science

An Improved HPLC Method for the Determination of Ranitidine Suitable for All Dosage Forms

PATENT

Patent WO2012082665A1 – Preparation of aminomethyl furans and …

Google

Figure imgf000004_0001

CLIP

http://faculty.weber.edu/ewalker/Medicinal_Chemistry/topics/Antihistam_local_anesth/antihista.htm

CLIP

Image result for SYNTHESIS ranitidine.

The paper was found in Green Chemistry,“Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural” by Mark Mescal et al, Green Chemistry, 2011,13, 3101-3102, DOI: 10.1039/c1gc15537g. Once again, I am beating the press before they print so I supplied the Digital Object Identifier. I am sure the sales for Ranitidine are quite large; who doesn’t get heartburn at one time or another. I think it is very fortunate the author shows you can use a starting material that can be derived from just about any source of cellulose. I find it interesting how renewable feedstocks can be utilized in industry and become part of important commodities, such as plastics, pharmaceuticals, etc. This paper refers to another discussing where the starting material was derived from. Starting material can be sugars, cellulose or raw cellulosic biomass and the reaction can produce yields of 80-90 %. M.Mascal and E. B. Nikitin, Angew. Chem., Int. Ed., 2008, 47, 7924; furans On with the show, though. The original synthetic route was provided in the paper and I will provide it to you.

originalsynranit

Furfural 1 was reduced to give the furfuryl alcohol 2. The furfuryl alcohol is methylaminated to give 3, which is reacted with cysteamine in concentrated HCl to give 4. This is condensed with 1-methylthio-1-methylamino-2-nitroethylene to give the final product. The patent literature has the yield < 50 % for the aminomethylation and subsequent reaction with cysteamine, but recently, these steps have been reported to have higher conversions.

newsynranit

This new synthesis, apart from using a renewable feedstock as a starting material, has synthetic steps with an average yield of 91 %, and requires no chromatography. Note that N-acetylcysteamine was used as opposed to cysteamine in the first step, in high yield. A reductive amination with methylamine gives 8 again in high yield. Treatment with KOH provides the free amine 9 and the final step is the condensation with the nitroethylene used in the previous synthesis

https://developingtheprocess.wordpress.com/2014/06/22/got-heartburn-here-is-a-synthesis-to-satisfy-that-appetite-for-good-chemistry/

Paper

Critical influence of 5-hydroxymethylfurfural aging and decomposition on the utility of biomass conversion in organic synthesis
Angewandte Chemie, International Edition (2016), 55, (29), 8338-8342

http://onlinelibrary.wiley.com/doi/10.1002/anie.201602883/abstract

http://onlinelibrary.wiley.com/store/10.1002/anie.201602883/asset/supinfo/anie201602883-sup-0001-misc_information.pdf?v=1&s=5b3f04dbb73a9be9c1d9c5350763b4e292d64f27

5-HMF. 1H NMR (400 MHz, DMSO-d6) δ = 9.54 (s, 1H, C(O)H), 7.49 (d, J = 3.5 Hz, 1H, CHfuran), 6.60 (d, J = 3.5 Hz, 1H, CH-furan), 5.57 (t, J = 5.9 Hz, 1H, OH), 4.51 (d, J = 5.9 Hz, 2H, CH2OH). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 177.9 (C(O)H), 162.2, 151.7 (C-furan), 124.4, 109.7 (CH-furan), 55.9 (CH2OH). Anal. calcd. For C6H6O3 (126.11): C 57.14, H 4.80; found: C 57.08, H 4.79.

Abstract

Spectral studies revealed the presence of a specific arrangement of 5-hydroxymethylfurfural (5-HMF) molecules in solution as a result of a hydrogen–bonding network, and this arrangement readily facilitates the aging of 5-HMF. Deterioration of the quality of this platform chemical limits its practical applications, especially in synthesis/pharma areas. The model drug Ranitidine (Zantac®) was synthesized with only 15 % yield starting from 5-HMF which was isolated and stored as an oil after a biomass conversion process. In contrast, a much higher yield of 65 % was obtained by using 5-HMF isolated in crystalline state from an optimized biomass conversion process. The molecular mechanisms responsible for 5-HMF decomposition in solution were established by NMR and ESI-MS studies. A highly selective synthesis of a 5-HMF derivative from glucose was achieved using a protecting group at O(6) position.

PAPER

Phytochemical screening and investigation of antiulcer activity of Tridax procumbens
International Journal of Pharmacy and Technology (2015), 6, (4), 7679-7690

Lavanya Asula* , A. Sony John, Deepthi Kotturi, P. Srividyalaxmi, R. Soni and Y. Mamatha Kalyani Department of Pharmacy, Jawaharlal Nehru Technological University, Holy Mary Institute of Technology and Science College of Pharmacy Hyderabad, India. Email: lavanya.asula@gmail.com

PATENT

CN 104258704

Waste gas treatment and methyl mercaptan recovery process in production process of cimetidine and ranitidine

cimetidine and ranitidine terms widely used in the treatment of stomach is bound to promote the continuous mass production of APIs, however, the raw material in the manufacturing process of the drug inevitably produce methyl mercaptan, dimethyl sulfide, a methylamine, carbon disulfide and nitromethane workshop emissions. Because of methyl mercaptan, dimethyl sulfide into the atmosphere having foul odor. Resulting in the production shop around smelling, and even affect the normal life of residents of several kilometers around. So some manufacturers use incineration method expects to dispose of the waste gas combustion, which reduces air pollution to some extent. But using incineration method has two drawbacks: one gas methyl mercaptan, dimethyl sulfide gas combustion higher value produce a few meters of flames burning heat generated while it is easy to burn incinerator, security posed by the chemical production big risk; on the other hand by a combustion method can not solve the odor problem, air pollution is still grim, because incomplete combustion, odor difficult to eliminate people’s sense of smell is particularly sensitive to the perception of mercaptans, while burning a large amount of sulfur dioxide in the same air pollution. There’s manufacturers to adopt authoritarian incinerator burning after the first use of chlorine dioxide generator eliminate odor, although this method has a certain smell to eliminate the effect of improving, but requires authoritarian equipment, increasing the cost of gas treatment and discharge sulfur dioxide into the air is still there.

PATENT

CN 102408398

https://www.google.com/patents/CN102408398A?cl=en

Title: Ranitidine

CAS Registry Number: 66357-35-5

CAS Name: N-[2-[[[-5-[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N¢-methyl-2-nitro-1,1-ethenediamine

Molecular Formula: C13H22N4O3S

Molecular Weight: 314.40

Percent Composition: C 49.66%, H 7.05%, N 17.82%, O 15.27%, S 10.20%

Literature References: Histamine H2-receptor antagonist which inhibits gastric acid secretion. Prepn: B. J. Price et al., FR2384765; eidem, US 4128658 (both 1978 to Allen & Hanburys). HPLC determn in plasma: P. F. Carey, L. E. Martin, J. Liq. Chromatogr. 1979, 1291. Pharmacological studies: J. Bradshaw et al., Br. J. Pharmacol. 66, 464 (1979); M. J. Daly et al., Gut 21,408 (1980). Efficacy in treatment of duodenal ulcers: A. Berstad et al., Scand. J. Gastroenterol. 15, 637 (1980); R. P. Walt et al.,Gut 22, 49 (1981). Review of pharmacology and therapeutic use: R. N. Brogden et al., Drugs 24, 267-303 (1982). Comprehensive description: M. Hohnjec et al., Anal. Profiles Drug Subs. 15, 533-561 (1986).

Properties: Solid, mp 69-70°.

Melting point: mp 69-70°

Derivative Type: Hydrochloride

CAS Registry Number: 66357-59-3

Manufacturers’ Codes: AH-19065

Trademarks: Azantac (GSK); Melfax (Apotex); Noctone (GEA); Raniben (Firma); Ranidil (Menarini); Raniplex (Fournier); Sostril (Cascan); Taural (Roemmers); Terposen (Vir); Trigger (Polifarma); Ulcex (Guidotti); Ultidine (GSK); Zantac (GSK); Zantic (GSK)

Molecular Formula: C13H22N4O3S.HCl

Molecular Weight: 350.86

Percent Composition: C 44.50%, H 6.61%, N 15.97%, O 13.68%, S 9.14%, Cl 10.10%

Properties: Off-white solid, mp 133-134°. Freely sol in acetic acid and water, sol in methanol, sparingly sol in ethanol. Practically insol in chloroform.

Melting point: mp 133-134°

Derivative Type: Bismuth citrate

CAS Registry Number: 128345-62-0

Additional Names: Ranitidine bismutrex

Manufacturers’ Codes: GR-122311X

Trademarks: Pylorid (GSK); Tritec (GSK)

Molecular Formula: C13H22N4O3S.C6H5BiO7

Molecular Weight: 712.48

Percent Composition: C 32.03%, H 3.82%, N 7.86%, O 22.46%, S 4.50%, Bi 29.33%

Literature References: Pharmacology and activity vs Helicobacter sp: R. Stables et al., Aliment. Pharmacol. Ther. 7, 237 (1993).

Therap-Cat: Antiulcerative.

Keywords: Antiulcerative; Histamine H2-Receptor Antagonist.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Ranitidine”. The American Society of Health-System Pharmacists. Retrieved Dec 1, 2015.
Jump up^ Fedorowicz, Z; van Zuuren, EJ; Hu, N (14 March 2012). “Histamine H2-receptor antagonists for urticaria.”. The Cochrane database of systematic reviews. 3: CD008596.doi:10.1002/14651858.CD008596.pub2. PMID 22419335.
Jump up^ Tleyjeh, IM; Abdulhak, AB; Riaz, M; Garbati, MA; Al-Tannir, M; Alasmari, FA; Alghamdi, M; Khan, AR; Erwin, PJ; Sutton, AJ; Baddour, LM (2013). “The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.”. PLOS ONE. 8 (3): e56498. doi:10.1371/journal.pone.0056498.PMC 3587620. PMID 23469173.
Jump up^ Fischer, Janos (2010). Analogue-based Drug Discovery II. John Wiley & Sons. p. 4.ISBN 9783527632121.
Jump up^ Hara, Takuji (2003). Innovation in the pharmaceutical industry the process of drug discovery and development. Cheltenham, U.K.: Edward Elgar. p. 94.ISBN 9781843765660.
Jump up^ “WHO Model List of EssentialMedicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

Ranitidine
Systematic (IUPAC) name


N-(2-[(5-[(dimethylamino)methyl]furan-2-yl)methylthio]ethyl)-N’-methyl-2-nitroethene-1,1-diamine
Clinical data
Pronunciation	/rəˈnɪtᵻdiːn/
Trade names	Zantac, others
AHFS/Drugs.com	Monograph
MedlinePlus	a601106
License data	US FDA: Ranitidine
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Routes of administration	Oral, IV
Legal status
Legal status	AU: S2 (Pharmacy only) UK: General sales list (GSL, OTC) US: OTC/RX
Pharmacokinetic data
Bioavailability	39 to 88%
Protein binding	15%
Metabolism	Hepatic: FMOs, including FMO3; other enzymes
Biological half-life	2–3 hours
Excretion	30–70% Renal
Identifiers
CAS Number	66357-35-5
ATC code	A02BA02 (WHO) A02BA07 (WHO) (ranitidine bismuth citrate)
PubChem	CID 3001055
IUPHAR/BPS	1234
DrugBank	DB00863
ChemSpider	4863
UNII	884KT10YB7
KEGG	D00422
ChEBI	CHEBI:8776
ChEMBL	CHEMBL1790041
Synonyms	Dimethyl [(5-{[(2-{[1-(methylamino)- 2-nitroethenyl]amino}ethyl)sulfanyl] methyl}furan-2-yl)methyl]amine
Chemical data
Formula	C₁₃H₂₂N₄O₃S
Molar mass	314.4 g/mol

//////////

CB-618

October 15, 2016 7:07 am / Leave a comment

CB-618, CB-238618

CAS 1463520-70-8

C₈ H₁₀ N₄ O₆ S, 290.25

Sulfuric acid, mono[(1R,2S,5R)-2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester

(25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester

SODIUM SALT

sodium salt of (2S,5R)-sulfuric acid mono-(2-[1,3,4]oxadiazol-2-yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl)ester

CAS 1628207-16-8

C₈ H₁₀ N₄ O₆ S . Na

Sulfuric acid, mono[(1R,2S,5R)-2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester, sodium salt (1:1)

PATENTS

WO2013149121

US 20140275001

US 20150094472

WO 2016081452

Infection, multidrug resistant bacteria (MDR) in phase 1 at Merck
CB-618 is in phase I clinical trails by Cubist for the treatment of resistant bacterial infections, including carbapenem-resistant Enterobacteriaceae and Klebsiella pneumonia carbapenemases infection.

CB-618 is a beta-Lactamase inhibitor in phase I clinical trials at Merck & Co. for the treatment of multidrug resistant bacterial infections, including those caused by carbapenem-resistant Enterobacteriaceae and Klebsiella pneumoniae carbapenemases.

The product was originally developed at Cubist. In 2015, Merck & Co. acquired the company

Originator Cubist Pharmaceuticals
Class Antibacterials
Mechanism of Action Beta lactamase inhibitors

Highest Development Phases

Phase I Gram-negative infections

Most Recent Events

01 Apr 2015 Cubist Pharmaceuticals completes a phase-I clinical trial in Gram-negative infections in USA (IV) (NCT02341599)
21 Jan 2015 Cubist Pharmaceuticals has been acquired by Merck & Co
14 Jan 2015 Phase-I clinical trials in Gram-negative infections in USA (IV)

Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivates the antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that are not effectively inhibited by the current clinical BLIs (e.g. KPC, class C and class D β-lactamases) and that could be used in combination with β-lactam antibiotics to treat infections caused by β-lactam resistant bacteria.

PATENT

WO2013149121

Yu Gui Gu, Yong He, Ning Yin, Dylan C. ALEXANDER, Jason B. CROSS, Chester A. Metcalf, Robert Busch
Applicant	Cubist Pharmaceuticals, Inc.

Example 3: Synthesis of (2S,5R)-2-(l ,3,4-oxadiazol-2-yl)-7-oxo-l ,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 701 )

Step 1: Ι,Γ-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0 °C solution of (2S,5R)- 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and exatracted with EtOAc (3x). The combined organic layer was washed with saturated sodium chloride (2x), dried over Na₂S0₄, and concentrated to afford crude (25,5 ?)- 6-(benzyloxy)-N-formyl-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (-11 g), which was directly used in the next step. ESI-MS (Ef , m/z): 319.1 [M+H]⁺.

Step 2: To a -10 °C solution of (25′,5«)-6-(benzyloxy)-N-formyl-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carbohydrazide (11 g) in dry DCM (200 mL) was added pyridine (28 mL), followed by dropwise addition of (CF₃S0₂)₂0 (28 mL). The reaction mixture was allowed to warm to rt and was stirred for 3 hrs. The reaction mixture was then cooled to -10 °C and quenched with sat. NaHCC>3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was dried over Na₂S0₄, concentrated and purified by silica gel column chromatography (gradient elution 1 :3 to 2: 1 EtOAc/hexanes) to give (25,5/?)-6-(benzyloxy)-2-(l,3,4-oxadiazol-2-yl)-l ,6- diazabicyclo[3.2.1]octan-7 -one (4.6 g, 86% for two steps) as a slightly yellow solid. ESI-MS (EI⁺, m/z): 301.0 [M+H]⁺.

Step 3: To a solution of (25,5/?)-6-(benzyloxy)-2-(l,3,4-oxadiazol-2-yl)-l ,6- diazabicyclo[3.2.1]octan-7-one (4.6 g, 15.3 mmol) in THF (150 mL) was added 10% Pd/C (1 g). The mixture was stirred under H₂ atmosphere at rt for 3 hrs. The reaction mixture was then filtered and concentrated to afford (25,5/?)-6-hydroxy-2-(l,3,4-oxadiazol-2-yl)-l,6- diazabicyclo[3.2.1]octan-7-one (2.9 g, 91 %), which was used directly in the next step. ESI- MS (EI⁺, m/z): 211.1 [M+H]⁺. Step 4: To a solution of (25,5fl)-6-hydroxy-2-(l,3,4-oxadiazol-2-yl)-l,6- diazabicyclo[3.2.1]octan-7-one (2.9 g, 13.8 mmol) in dry pyridine (60 mL) was added SC>3- Py (11.0 g, 69.0 mmol). The reaction mixture was stirred at rt for 8 hrs and then concentrated under vacuum. The residue was re-dissolved in aqueous NaH₂PC>4 (1.5 M, 100 mL) then tetrabutylammonium hydrogensulphate (5.88 g, 17.3 mmol) was added. The mixture was stirred at rt for 20 minutes, then was extracted with EtOAc (4x). The combined organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (gradient elution 10:1 to 2:1 DCM/acetone) to afford tetrabutylammonium (25,5/?)-2-(l ,3,4-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl sulfate (4.1 g, 97%) as a white solid. ESI-MS (EL, m/z): 289.0 [M-H]\ ^lH NMR (400 MHz, CDC1₃): δ 8.48 (s, 1H), 4.75 (d, / = 6.5 Hz, 1H), 4.40 (br s, 1H), 3.34-3.26 (m, 9H), 2.82 (d, / = 12.0 Hz, 1H), 2.37-2.25 (m, 3H), 2.06-1.98 (m, 1H), 1.71-1.65 (m, 8H), 1.49-1.42 (m, 8H), 1.01 (t, / = 7.5 Hz, 12H).

Step 5: Resin Exchange: Tetrabutylammonium (25, 5R)-2-(l, 3, 4-oxadiazol-2-yl)-7-oxo-l, 6-diaza-bicyclo[3.2.1]octan-6-yl sulfate (4.1 g, 7.72 mmol) was dissolved in a minimum amount of HPLC grade water (~ 40 mL) and passed through a column of 80 g of DOWEX 50WX 8 Na⁺ resin (the resin was prewased with >4 L of HPLC grade water) and eluted with HPLC grade water to afford sodium (25,5fl)-2-(l,3,4-oxadiazol-2-yl)-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl sulfate (2.2 g, 91 %) as a white solid after lyophilization. ESI- MS (EI⁺, m/z): 291.2 [M+H]⁺. ^lH NMR (300 MHz, D₂0) δ 8.92 (s, 1H), 4.84 (d, J = 6.1 Hz, 1H), 4.20 (br s, 1H), 3.25-3.16 (m, 1H), 2.92 (d, / = 12.3 Hz, 1H), 2.41-2.26 (m, 1H), 2.26- 2.11 (m, 2H), 2.04-1.89 (m, 1H).

PATENT

WO-2016157057

Wockhardt Ltd

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016157057&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

A compound of Formula (I), chemically known as sodium salt of 2S, 5R) mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diazabicyclo[3.2.1 ]oct-6-yl)ester has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/US2013/034562. The compound of Formula (I) is also generically disclosed in PCT International Patent Application No. PCT/IB2012/054296. The present invention discloses a process for preparation of a compound of Formula (I).

Formula (I)

Scheme 1.

(VI) Compound of Formula (I)

Example 1

Sodium salt of (25, 5R) sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester

Step I: Synthesis of (25,5R)-2-(iV’-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (III):

To a turbid solution of sodium salt of (2<S’,5i?)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1 ] octane-2-carboxylic acid (II, 20 g, 0.067 mol) (prepared according to process disclosed in PCT/IB2013/059264) in dimethylformamide (200 ml) was added EDC hydrochloride (19.44 g, 0.10 mol) followed by formyl hydrazide (4.02 g, 0.067 mol) and N-hydroxybenzotriazole (9 g, 0.67 mol) at about 25°C under stirring. Diisopropylethylamine (35.62 ml, 0.20 mol) was added to the reaction mixture and stirred at 25°C temperature for 18 hours. The reaction mixture was evaporated under vacuum to provide a residue. The residue was dissolved in ethyl acetate (500 ml) and washed with water (500 ml ^χ 2), followed by saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude intermediate, which was purified by silica gel column chromatography to provide 11 g of the titled compound as solid in 52% yield.

Analysis:

Mass: 319.1 (M+l); for Molecular Formula of C15H18N4O4 and Molecular Weight of 318.34;

H¹ NMR (DMSO-d6): δ 9.93 (s, 1H), 9.87 (s, 1H), 8.01 (s, 1H), 7.36-7.46 (m, 5H), 4.91-4.97 (dd, 2H), 3.83-3.84 (br s, 1H), 3.70 (s, 1H), 3.15-3.18 (br s, 1H), 2.90-2.95 (m, 1H), 1.99-2.03(m, 1H), 1.86(br s, 1H), 1.73-1.75 (m, 1H), 1.66 (m, 1H).

Step II: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (IV):

To a clear solution of (2<S’,5i?)-2-(N’-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l ,6-diaza-bicyclo[3.2.1 ] octane (III, 11 g, 0.0345 mol) in chloroform (120 ml) was added diisopropylethylamine (18.31 ml, 0.1035 mol) and p-tolylsulfonylchloride (9.83 g, 0.0517 mol). The solution was stirred at 60°C for 15 hours. Reaction mixture was cooled to room temperature and water (100 ml) was added. Organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude residue, which was purified by silica gel column chromatography to provide 7 g of the titled compound as a solid in 68% yield.

Analysis:

Mass: 301.3 (M+l); for Molecular Formula of Ci₅Hi₆N₄0₃ and Molecular Weight of 300.32;

H¹ NMR (CDC1₃): δ 8.45 (s, 1H), 7.25-7.44 (m, 5H), 5.07-5.10 (dd, 1H), 4.92-4.95 (dd, 1H), 4.76-4.78 (br s, 1H), 3.37 (br s, 1H), 2.93-.95 (br s, 1H), 2.75-2.77 (m, 1H), 2.32-2.33 (m, 2H), 2.13-2.16 (m, 1H), 1.93-2.01 (m, 1H).

Step III: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (V):

To a clear solution of (2<S’,5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1 ] octane (IV, 7.0 g, 0.0233 mmol) in methanol (70 ml) was added 10% palladium on carbon (2.5 g). The suspension was stirred under atmospheric hydrogen pressure at a temperature 25° C for 2 hrs. The catalyst was filtered over a celite bed and the bed was washed with methanol (30 ml). The filtrate was concentrated under vacuum to provide an oily residue. The residue was triturated with cyclohexane (100 ml) to effect solid formation. The suspension was filtered under suction and the wet cake was washed with additional cyclohexane (50 ml). The soild was dried under vacuum to provide 4.5 g of the titled compound as a whitish solid in 92% yield, which was used for the next reaction immediately.

Analysis:

Mass: 211.2 (M+l); for Molecular Formula of C₈Hi₀N₄O₃ and Molecular Weight of 210.19; 1H NMR (DMSO-d6): δ 9.88 (br s, 1H), 9.29 (s, 1H), 4.65 (d, 1H ), 4.64 (br s, 1H), 2.94-2.97 (br d, 1H), 2.63-2.66 (d, 1H), 1.89-2.09 (m,3H), 1.82-1.86 (m, 1H).

Step IV: Synthesis of tetrabutylammonium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI):

To a clear solution of (2<S’,5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l ,6-diaza-bicyclo[3.2.1 ] octane (V, 4.5 g, 0.0214 mol) in dichloromethane (50 ml) was added triethylamine (9 ml, 0.642 mol), followed by the addition of sulfur trioxide pyridine complex (6.83 g, 0.428 mol). The resulting reaction mixture was stirred for 2 hours. Tetrabutylammonium hydrogen sulfate (7.26 g,

0.0214 mol) was added to the reaction mixture and it was stirred for 1.5 hours. A solution of aqueous 0.5 N KH₂PO₄ (100 ml) was added to the reaction mixture. Layers were separated and the aqueous layer was washed with dichloromethane (125 ml). Combined organic layer was dried over Na2S04, and was evaporated under vacuum to yield crude foam, which was purified on silica gel column chromatography to give 7 g of the titled compound as white foam in 98% yield.

Analysis:

Mass: 289.1 (M-l); for Molecular Formula
and Molecular Weight of 517.26;

¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 4.69 (d, 1H), 4.06 (br s, 1H ), 3.14-3.18 (m, 8H), 2.94-2.97 (br d, 1H), 2.67-2.70 (d, 1H), 1.98-2.05 (m,lH), 2.85-2.92 (m, 1H), 1.53-1.60 (m, 8H), 1.27-1.36 (m, 8H), 0.91-0.95 (m, 12H).

Step V: Sodium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (I):

The compound sodium salt of (2S, 5i?)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester of Formula (I) was prepared by loading tetrabutylammonium salt of sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI, 7 g) on a column packed with Amberlite IR 120 Na form of resin, and by eluting the column with methanol water mixture (9: 1). Fractions containing compound were collected and solvent was evaporated under vacuum below 40°C, to provide formula- 1 compound in 4 gm (62%) quantity as a white solid.

Analysis:

Mass: 289.3 (M-l) as free acid; for Molecular Formula
and Molecular Weight 290.26;

H¹ NMR (DMSO-d6): δ 9.29 (s, 1H), 4.70(d, 1H), 4.061 (d, 1H), 2.95 (d, 1H), 2.69 (d, 1H), 2.19 (m, 1H), 2.07 (m, 2H), 1.90 (m, 1H);

Purity as determined by HPLC: 89 86%;

WO2010056827A1 *	Nov 12, 2009	May 20, 2010	Protez Pharmaceuticals, Inc.	Beta-lactamase inhibitors
WO2010118361A1 *	Apr 9, 2010	Oct 14, 2010	Sopharmia, Inc.	Beta lactamase inhibitors
US20110294777 *	Jan 15, 2009	Dec 1, 2011	Merck Sharp & Dohme Corp.	Beta-lactamase inhibitors

Reference
1	*	CROMPTON, I. E. ET AL.: “Beta-Lactamase inhibitors: The inhibition of serine beta-lactamases by specific boronic acids“, BIOCHEM. J., vol. 251, 1988, pages 453 – 459, XP055170895
2	*	See also references of EP2831075A4

//////////CB-618, phase 1

O=S(=O)(O)ON3[C@H]1C[N@]([C@@H](CC1)c2nnco2)C3=O

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Enantioselective α-Hydroxylation of 2-Arylacetic Acid Derivatives and Buspirone Catalyzed by Engineered Cytochrome P450 BM-3

Preparation of (R)- and (S)-6-hydroxybuspirone by enzymatic resolution or hydroxylation

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Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans

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are suitable intermediates for active pharmaceutical ingredients.

from the originally published version of WO-A 00/40569.

2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3) is described therein as potential active ingredient for the treatment of obesity and type II diabetes.

In this originally published version of WO-A 00/40569, two synthetic routes 1 and 2 are described for preparing 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), each of which starts from the 5-methyl-substituted anthranilic acid (4).

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Ranitidine

Laboratory Synthesis Of Ranitidine

Synthesis of ranitidine (Zantac) from cellulose-derived 5-(chloromethyl)furfural

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