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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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FDA approves drug to treat Duchenne muscular dystrophy


FDA approves drug to treat Duchenne muscular dystrophy

Feb. 9, 2017

The U.S. Food and Drug Administration today approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system.

Read more.

New FDA Logo Blue

New Website goflow.at online! from C. Oliver Kappe, University of Graz


New Website goflow.at online!

C. Oliver Kappe

Professor at University of Graz

Institute of Chemistry

Univ.-Prof. Mag. Dr.rer.nat.

+43 316 380-5352
+43 (0) 316 380 – 9840

Research in the Kappe lab focuses on flow chemistry, microreactor technology, process intensification and the continuous generation of active pharmaceutical ingredients (APIs). Check out our new webiste at: goflow.at

Recent Hot Papers from the Kappe Lab


Web of Science Highly Cited and Hot Article

Continuous Flow Technology – A Tool for the Manufacturing of Active Pharmaceutical Ingredients
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015 , 54, 6688-6729.
DOI: 10.1002/anie.201409318

Chemistry – A European Journal Hot Paper
Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals – A Fast and Scalable Protocol for Trifluoromethylation
J. L. Monteiro, P. F. Carneiro, P. Elsner, D. Roberge, P. G. M. Wuts, K. Kurjan, B. Gutmann, C. O. Kappe,
Chem. Eur. J. 2017 , 23, in press.
DOI: 10.1002/chem.201604579

Journal of Organic Chemistry Featured Article
A Lab-Scale Membrane Reactor for the Generation of Anhydrous Diazomethane
D. Dallinger, V. D. Pinho, B. Gutmann, C. O. Kappe, J. Org. Chem. 2016 , 81, 5814-5823.
DOI: 10.1021/acs.joc.6b01190

Active Pharmaceutical Ingredients (APIs) in Flow

Continuous flow processes form the basis of the petrochemical and bulk chemicals industry where strong competition, stringent environmental and safety regulations, and low profit margins drive the need for highly performing, cost effective, safe and atom efficient chemical operations. In contrast to the commodity chemical industry, however, the fine chemical industry primarily relies on its existing infrastructure of multipurpose batch or semi-batch reactors. Fine chemicals, such as drug substances and active pharmaceutical ingredients (APIs), are generally considerably more complex than commodity chemicals and usually require numerous, widely diverse reaction steps for their synthesis (typically 6 to 10 synthetic steps), and multiple rounds of quenching, separation and purification. These requirements, together with the comparatively low production volumes and often short life time of many of these materials, make versatile and reconfigurable multipurpose batch reactors the technology of choice for their preparation. However, the advantages of continuous flow processing are increasingly being appreciated also by the pharmaceutical industry and, thus, a growing number of scientists, from research chemists in academia to process chemists and chemical engineers in pharmaceutical companies, are now starting to employ continuous flow technologies on a more routine basis. Together with our industrial partners, the Kappe laboratories are involved in numerous flow API synthesis projects.

apis


Key Publications

Review: Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6729. DOI: 10.1002/anie.201409318 (Web of Science “Highly Cited Paper”).

Towards the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow N-Demethylation Strategies. B. Gutmann, P. Elsner, D. P. Cox, U. Weigl, D. M. Roberge, C. O. Kappe, ACS Sust. Chem. Eng. 2016, 4, in press. DOI: 10.1021/acssuschemeng.6b01371

Batch and Continuous Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines – A Concise Synthesis of Noroxymorphone
B. Gutmann, U. Weigl, D. P. Cox, C. O. Kappe, Chem. Eur. J. 2016, 22, 10393–10398. DOI:10.1002/chem.201601902 (selected as ”Hot Paper” by the Editors).

Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O2 under Intensified Continuous Flow Conditions
B. Pieber, D. P. Cox, C. O. Kappe, Org. Process Res. Develop. 2016, 20, 376−385. DOI: 10.1021/acs.oprd.5b00370

Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles: Toward the Continuous Production of Daclatasvir
P. F. Carneiro, B. Gutmann, R. O. M. A. de  Souza, C. O. Kappe, ACS Sust. Chem. Eng. 2015, 3, 3445−3453. DOI: 10.1021/acssuschemeng.5b01191

Continuous Flow Reduction of Artemisinic Acid Utilizing Multi-Injection Strategies – Closing the Gap Towards a Fully Continuous Synthesis of Antimalarial Drugs
B. Pieber, T. Glasnov, C. O. Kappe, Chem. Eur. J. 2015, 21, 4368-4376. DOI: 10.1002/chem.201406439 (selected as “Hot Paper“ by the Editors, covered by Chemical & Engineering News).

Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions
B. Gutmann, P. Elsner, A. O’Kearney-McMullan, W. Goundry, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2015, 19, 1062-1067. DOI: 10.1021/acs.oprd.5b00217

Continuous Flow Synthesis of alpha-Haloketones – Essential Building Blocks of Antiretroviral Agents
V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555-1562. DOI: 10.1021/jo402849z (selected as “Featured Article” by the Editors).

Combined Batch and Continuous Flow Procedure to the Chemo-Enzymatic Synthesis of Biaryl Moiety of Odanacatib.
R. de Oliveira Lopes, A. S. de Miranda, B. Reichart, T. Glasnov, C. O. Kappe, R. C. Simon, W. Kroutil, L. S. M. Miranda, I. C. R.Leal, R. O. M. A. de Souza, J. Mol. Catal. B. 2014, 104, 101-107. DOI: 10.1016/j.molcatb.2014.03.017

On the Fischer Indole Synthesis of 7-Ethyltryptophol- Mechanistic and Process Intensification Studies under Continuous Flow Conditions.
B. Gutmann, M. Gottsponer, P. Elsner, D. Cantillo, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2013, 17, 294-302. DOI: 10.1021/op300363s

A Three Step Continuous Flow Synthesis of the Biaryl Unit of the HIV Protease Inhibitor Atazanavir.
L. Dalla-Vechia, B. Reichart, T. N. Glasnov, L. S. M. Miranda, C. O. Kappe, R. O. M. A. de Souza, Org. Biomol. Chem. 2013, 11, 6806-6813. DOI: 10.1039/c3ob41464g

A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones.
M. Viviano, T. N. Glasnov, B. Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Develop. 2011, 15, 858-870. DOI: 10.1021/op2001047

Image result for C. Oliver Kappe

DR SANJAY BAJAJ,,,,,,,,,,,,,,,,,,,DR ANTHONY CRASTO…………PROF OLIVER KAPPE FLOW CHEM CONFERENCE , MUMBAI, 22 JAN 2015……SELECTBIO

////////////New Website,  goflow.at,  online,  C. Oliver Kappe, University of Graz, flow chemistry

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


Darifenacin.svg

Darifenacin

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

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

US 2004-12-22 APPROVED

EU 2004-10-22 APPROVED

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

Derivative Type: Hydrobromidd

CAS Registry Number: 133099-07-5

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

Research Code:UK-88525-04

Trade Name:Emselex® / Enablex® / Xelena®

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

Status:Approved

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

ATC Code:G04BD10

臭化水素酸ダリフェナシン
Darifenacin Hydrobromide

C28H30N2O2▪HBr : 507.46
[133099-07-7]

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

Darifenacin.pngDarifenacin

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

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

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

Mechanism of action

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

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

Clinical uses

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

clip

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

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

Scheme 1

Figure imgf000002_0001

DARIFENACIN

Figure imgf000002_0002

wherein the substituents R and X can be

Figure imgf000003_0001

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

Scheme 2

Figure imgf000003_0002

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

2,3-dihydrobenzofuran (VIII)

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

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

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

Figure imgf000004_0001

A purification procedure for darifenacin was published in WO03080599A1.

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

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

Figure imgf000005_0001

(IX.W)

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

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

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

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

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

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

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

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

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

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

The process is as shown in Scheme-I below:

1. Anhydrous K2C03

Figure imgf000003_0001

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

The rocess is as shown in Scheme-II below:

Figure imgf000003_0002

Darifenacin

(la)

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

The rocess is as shown in Scheme-Ill below:

Figure imgf000004_0001

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

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

The rocess is as shown in Scheme-IV below:

Figure imgf000005_0001

Darifenacin HBr

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

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

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

Formula (XII)

Figure imgf000006_0001

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

Figure imgf000007_0001

Formula (XIII)

PROCESS

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

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

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

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

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

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

(G)  WO2009125426A2.

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

PATENT

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

Image result for Darifenacin

EXAMPLE – 1

Stage-1:

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

DIHYDROBENZOFURAN

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

Yield: 96.5 g

Chromatographic purity (By HPLC): 97.85%

Stage-2:

PREPARATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 9.4 g

Chromatographic purity (By HPLC): 98.2%.

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

Darifenacin dimer impurity: 0.96%.

EXAMPLE – 2

Stage-1 :

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

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

Yield: 7 g

Stage-2

PREPARATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 4.5 g

Chromatographic purity (By HPLC): 99.24%

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

Darifenacin dimer impurity: 0.39%.

EXAMPLE – 3

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

Yield: 7.6 g

Chromatographic purity (By HPLC): 99.52%

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

Darifenacin dimer impurity: 0.20%.

EXAMPLE – 4

PURIFICATION OF DARIFENACIN HYDROBROMIDE

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

Chromatographic purity (By HPLC): 99.71 %

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

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

Darifenacin dimer impurity: 0.20%. EXAMPLE – 5

PURIFICATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 8.8 g

Chromatographic purity (By HPLC): 99.87%

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

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

Darifenacin dimer impurity: 0.08%. EXAMPLE – 6

PURIFICATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 8.4 g

Chromatographic purity (By HPLC): 99.88%

EXAMPLE – 7

PURIFICATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 8.30g

Chromatographic Purity (By HPLC): 99.83 %

Darifenacin dimmer: 0.10%

EXAMPLE – 8

PURIFICATION OF DARIFENACIN HYDROBROMIDE

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

Yield: 6.70g

Chromatographic Purity (By HPLC): 99.94 %

Darifenacin dimmer: Nil.

Paper

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

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

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

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

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

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

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

PATENT

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

Scheme 4:

Figure imgf000008_0001

Example 1

Figure imgf000010_0001

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

Yield: 85% of theory.

Example 2

Figure imgf000010_0002

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

Yield: 86% of theory.

Example 3

Figure imgf000011_0001

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

Yield: 85% of theory.

clip

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

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

References

External links

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

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

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

MK 0633, SETILEUTON


SETILEUTON.pngstr1

Figure

MK 0633, SETILEUTON

(-)-enantiomer

910656-27-8 CAS free form

MW 463.3817, C22 H17 F4 N3 O4  FREE FORM

Tosylate cas 1137737-87-1

2H-1-Benzopyran-2-one, 4-(4-fluorophenyl)-7-[[[5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]amino]methyl]-

4-(4-Fluorophenyl)-7-[[[5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl]amino]methyl]-2H-1-benzopyran-2-one

Image result for Merck Frosst Canada Ltd.

WO2006099735A1

Inventors Thiadiazole substituted coumarin derivatives and their use as leukotriene biosynthesis inhibitor
WO 2006099735 A1Marc Blouin, Erich L. Grimm, Yves Gareau, Marc Gagnon, Helene Juteau, Sebastien Laliberte, Bruce Mackay, Richard Friesen
Applicant Merck Frosst Canada Ltd.

Image result for Merck Frosst Canada Ltd.

MK-0633 had been in early clinical development for several indications, including the treatment of chronic obstructive pulmonary disease (COPD), asthma and atherosclerosis

Leukotriene metabolism plays a central role in inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and atherosclerosis. In particular, the activation of the enzyme 5-lipoxygenase (5-LO) and its associated protein, 5-LO activating protein (FLAP), initiates a cascade that transforms arachidonic acid into inflammatory leukotrienes

Inhibition of leukotriene biosynthesis has been an active area of pharmaceutical research for many years. The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. Leukotrienes are potent contractile and inflammatory mediators deπved by enzymatic oxygenation of arachidonic acid by 5-hρoxygenase. One class of leukotriene biosynthesis inhibitors are those known to act through inhibition of 5 -lipoxygenase (5-LO).
The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4 and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenases on arachidonic acid to produce the epoxide known as Leukotriene A4 (LT A4), which is converted to the other leukotπenes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotπenes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotπenes in living systems and their contπbution to various diseases states are also discussed in the book by Rokach.
In general, 5 -LO inhibitors have been sought for the treatment of allergic rhinitis, asthma and inflammatory conditions including arthπtis. One example of a 5-LO inhibitor is the marketed drug zileuton (ZYLOFT®) which is indicated for the treatment of asthma. More recently, it has been reported that 5-LO may be an important contributor to the atherogenic process; see Mehrabian, M. et al., Circulation Research, 2002 JuI 26, 91(2): 120-126.
Despite significant therapeutic advances in the treatment and prevention of conditions affected by 5-LO inhibition, further treatment options are needed. The instant invention addresses that need by providing novel 5-LO inhibitors which are useful for inhibiting leukotriene biosynthesis.

Image result for mk 0633

Synthesis of coumarin intermediate in MK-0633. Reagents and conditions: a) 2.7 M H2SO4 (1 mL/1 mmol), 1.1 equiv. NaNO2, –5 °C, 15 min, 1.5 equiv. KI (1 M H2SO4, 1 mL/0.5 mmol), 0–70 °C, 20 min; b) 1.5 equiv. CuCN, DMF, 110 °C, 24 h, 72 % (over two steps); c) 0.05 equiv. H2SO4, MeOH, 60 °C, 12 h, 81 %; d) 2.5 equiv. 2 M AlMe3, 1.5 equiv. NH(OMe)Me·HCl, THF, room temp., 24 h, 86 %; e) 4.0 equiv. C6H4FMgBr, THF, 0 °C to room temp., 3 h, 74 %; f) toluene, reflux, 24 h, 83 %.

Study of the Chemoselectivity of Grignard Reagent Addition to Substrates Containing Both Nitrile and Weinreb Amide Funct…

Article · Aug 2013 · European Journal of Organic Chemistry
Paper
Synthesis of 4-arylcoumarins via palladium-catalyzed arylation/cyclization of ortho-hydroxylcinnamates with diaryliodonium salts
Tetrahedron Letters (2015), 56, (24), 3809-3812

An efficient method for the palladium-catalyzed arylation/cyclization of ortho-hydroxylcinnamate ester derivatives with diaryliodonium salts is described. A range of 4-arylcoumarins are obtained in good to excellent yield. Furthermore, the route can be applied to the synthesis of versatile building block of 5-lipoxygenase inhibitor.

Image for unlabelled figure

PATENT

WO 2006099735

EXAMPLE 7
(+) and (-)-4-(4-Fluorophenyl)-7-[(|5-[l-hvdroxy-l-(tnfluoromethyl)propyn-K3,4-oxadiazol-2-vUammo)methyl1-2H-chromen-2-one
Step 1: Ethyl 2-hvdroxy-2-(trifluoromethyl)butanoate

To a -78 0C solution of ethyl tπfluoropyruvate (129 0 g 758 mmol) in ether was added dropwise withm 90 mm a solution of EtMgBr 3.0 M m ether (252 mL). The solution was brought over one Ih to ca. -10 0C and poured over 2L of saturated NH4Cl. The layers were separated and the aqueous phase extracted with ether (3 X 500 mL) The organic phases were combined, dried over MgSO4 and the solvent removed. Distillation at 50-65 0C (30 mm Hg) gave the title compound. 1H NMR (400 MHz, acetone- d6): δ 5.4 (s, IH), 4.35 (q, 2H), 2.07 (m, IH), 1.83 (m, IH), 1.3 (t, 3H) and 0.93 (t, 3H).
Step 2: 2-Hvdroxy-2-(tπfluoromethyl)butanohvdrazide

The ethyl ester of step 1 (50.04 g, 250 mmol) and hydrazine hydrate (25.03 g, 50 mmol) were heated at 80 0C for 18 h. The excess hydrazine was removed under vacuum and the crude product was filtered through a pad of silica gel with EtOAc-Hexane (ca. 3L) to furnish the title compound. 1H NMR (400 MHz, acetone-d6): δ 9.7 (s, IH), 6.10 (s, IH), 2.25 (m, IH), 1.85 (m, IH) and 0.95 t, (3H). Step 3: 2-(5-Ammo-l ,3,4-oxadiazol-2-yl)-l , 1 , l-tπfluorobutan-2-ol

To hydrazide (34.07 g, 183 mmol) of step 2 m 275 mL of water was added KHCO3 (18.33 g, 183 mmol) followed by BrCN (19.39 g, 183 mmol) portionwise. After 3h, the solid was filtered, washed with cold water and dπed to afford the title compound. Additional compound could be recovered from the aqueous phase by extraction (ether-hexane, 1:1). 1H NMR (400 MHz, acetone-d6): δ 6.54 (s, 2H), 6.01 (s, IH), 2.22 (m, IH), 2.08 (m, IH) and 0.99 (m, 3H).
Step 4: 4-(4-Fluorophenyl)-7-|Y { 5-[ 1 -hydroxy- 1 -(tnfluoromethyl)propyll -1,3,4- oxadiazol-2-yl}amino)methyl1-2H-chromen-2-one


A mixture of oxadiazole (14.41 g, 68.2 mmol) of step 3 and 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (14.1 g, 52.5 mmol) in toluene (160 mL) with 10% of PPTS was brought to reflux and let go overnight. The system was equipped with a Dean-Stark trap to collect water. The solvent was removed and the crude oil (1H NMR (400 MHz, acetone-d6): δ 9.33 (IH, s, imme)) obtained was diluted in EtOH (ca. 75 mL) at 0 0C. To this solution was added NaBH4 (1.9 g) portionwise and the reaction was quenched with a solution OfNH4Cl after 45 mm. The mixture was saturated with NaCl and extracted with EtOAc (3 X 200 mL). The organic phases were combined and dried over MgSO4.
Purification over silica gel chromatography using toluene-EtOAc (55.45) gave the title compound . 1H NMR (400 MHz, acetone-d6): δ 7.65 (m, 2H), 7.50 (m, 3H), 7.38 (m, 3H), 6.35 (s, IH), 6.06 (s, IH), 4.70 (m, 2H), 2.21 (m, IH), 2.11 (m, IH) and 0.98 (t, 3H).
Step 5: Separation on chiral HPLC column of (+) and (-) enantiomers of 4-(4-fluorophenyl)-7- [((5-ri-hvdroxy-l-(trifluoromethyl)propyl1-l,3,4-oxadiazol-2-yl}amino)methvn-2H- chromen-2-one

A solution of (±)-4-(4-fluorophenyl)-7-[({5-[l-hydroxy-l-(trifluoromethyl)propyl]-l,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one (0.5-0.6 g) in EtOΗ-Ηexane (30:70, ca. 40 mL) was injected onto a CΗIRALPAK AD® preparative (5cm x 50cm) ΗPLC column (eluting with
EtOΗ/Ηexane, 30/70 with UV detection at 280 nm). The enantiomers were separated with the faster eluting enantiomer having a retention time of – 34 mm for the (-)-enantiomer and the slower eluting enantiomer having a retention time of ~ 49 mm for the (+)-enantiomer.

PAPER

The Discovery of Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor

Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1
ACS Med. Chem. Lett., 2010, 1 (4), pp 170–174
DOI: 10.1021/ml100029k
Publication Date (Web): April 13, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. E-mail: yves_ducharme@merck.com.
Abstract Image
The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.
4-(4-fluorophenyl)-7-[({5-[(2R)-1,1,1-trifluoro-2-hydroxybutan-2-yl]- 1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one ((R)-16) and 4-(4- fluorophenyl)-7-[({5-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1,3,4-oxadiazol-2- yl}amino)methyl]-2H-chromen-2-one ((S)-16)
str1
A solution of (±)-4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4- oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one (16) (0.5-0.6 g) in EtOH-Hexane (30:70, ca. 40 mL) was injected on a CHIRALPAK AD preparative (5 cm x 50 cm) HPLC column (eluting with EtOH/Hexane, 30/70 with UV detection at 280 nm). The enantiomers were separated with the fast-eluting enantiomer having a retention time of ~ 34 min for the (-) and the slow-eluting enantiomer having a retention time of ~ 49 min for the (+)-enantiomer.
4-(4-fluorophenyl)-7-[({5-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1,3,4-oxadiazol- 2-yl}amino)methyl]-2H-chromen-2-one ((S)-16, MK-0633, setileuton):
str1
A mixture of oxadiazole (S)-35 (41.9 g, 156 mmol) and aldehyde 25 (39.2 g, 186 mmol) in toluene (2 L) with 10% of pyridinium p-toluenesulfonate was refluxed overnight. The system was equipped with a Dean-Stark apparatus to collect water. The solvent was removed and the crude oil [1 H NMR (400 MHz, acetone-d6): δ 9.33 (s, 1H, imine)] obtained was diluted in THF (600 mL) and EtOH (100 mL). To this solution was added at 0 o C NaBH4 (7.2 g) portionwise. After 1 h of stirring, aqueous ammonium acetate was added. The mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (toluene/EtOAc; 1:1) to give the title compound (39.4 g, 54%).
FREE FORM
1 H NMR (400 MHz, acetone-d6): δ 7.65 (m, 2H), 7.50 (m, 3H), 7.38 (m, 3H), 6.35 (s, 1H), 6.06 (s, 1H), 4.70 (m, 2H), 2.21 (m, 1H), 2.11 (m, 1H), 0.98 (t, 3H);
HRMS calcd for C22H17F4N3O4 [MH+]: 464.1233; found: 464.1228.
PATENT
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CLIP

J. Org. Chem. 2010, 75, 4154−4160

Synthesis of a 5-Lipoxygenase Inhibitor

 Abstract Image

Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).


Leukotriene metabolism plays a central role in inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and atherosclerosis. In particular, the activation of the enzyme 5-lipoxygenase (5-LO) and its associated protein, 5-LO activating protein (FLAP), initiates a cascade that transforms arachidonic acid into inflammatory leukotrienes. Consequently, compounds that can inhibit 5-LO have potential as new treatments for the conditions listed above. Gosselin and co-workers at Merck describe two routes towards one such compound (MK-0633) brought forward as a development candidate at Merck ( J. Org. Chem. 2010, 75, 4154−4160). The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route (shown here) featured an inexpensive diastereomeric salt resolution of a vinyl hydroxy-acid followed by a through-process hydrazide acylation/1,3,4-oxadiazole ring-closure/salt-formation sequence to afford MK-0633 as the p-toluenesulfonate salt.

A Practical Synthesis of 5-Lipoxygenase Inhibitor MK-0633

Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec, Canada H9H 3L1
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
J. Org. Chem., 2010, 75 (12), pp 4154–4160
DOI: 10.1021/jo100561u
MK-0633 tosylate salt (1) was obtained as a white solid (6.64 kg, 91.4% yield): mp 164−165 °C;
[α]20D − 0.86 (c 10.0, EtOH);
1H NMR (500 MHz, DMSO-d6) δ 8.58 (1 H, t, J = 6.2 Hz), 7.62 (2 H, dd, J = 8.3, 5.4 Hz), 7.49 (2 H, d, J = 7.8 Hz), 7.47−7.38 (4 H, m), 7.33 (1 H, d, J = 8.3 Hz), 7.13 (2 H, d, J = 7.7 Hz), 6.44 (1 H, s), 4.53 (2 H, d, J = 5.6 Hz), 2.30 (3 H, s), 2.17−2.05 (1 H, m), 2.03−1.93 (1 H, m), 0.90 (3 H, t, J = 7.37 Hz);
13C NMR (125 MHz, DMSO-d6) δ 164.1, 162.9 (d, J = 246.8 Hz), 159.6, 156.1, 153.7, 153.6, 145.5, 143.7, 137.7, 131.1 (d, J = 3.5 Hz), 130.9 (d, J = 8.7 Hz), 128.1, 126.8, 125.4, 124.5 (q, J = 286.6 Hz), 123.5, 117.4, 115.9 (d, J = 22.0 Hz), 115.4, 114.7, 73.7 (q, J = 28.6 Hz), 45.4, 26.1, 20.8, 7.0;
19F NMR (375 MHz, DMSO-d6) δ −79.7, −113.1;
HRMS calcd for C22H18F4N3O4 [M + H] 464.1228, found 464.1246.
IR (cm−1, NaCl thin film) 3324, 3010, 2977, 1735, 1716, 1618, 1510, 1428, 1215, 1178.
HPLC analysis: eclipse XDB-phenyl column 4.6 mm × 15 cm (0.1% aq H3PO4/CH3CN 65:35 to 10:90 over 50 min, 1.0 mL/min, 210 nm, 25 °C); MK-0633 (1) tR = 16.86 min. Chiral HPLC analysis: Chiralpak AD-H column 4.6 mm × 25 cm (EtOH/hexane 60:40, hold 15 min, 0.5 mL/min, 300 nm, 30 °C); (S)-enantiomer tR = 9.5 min; (R)-enantiomer tR = 11.5 min.
1 to 6 of 6
Patent ID Patent Title Submitted Date Granted Date
US2016193168 Treatment of Pulmonary Arterial Hypertension with Leukotriene Inhibitors 2015-11-30 2016-07-07
US2013251787 Treatment of Pulmonary Hypertension with Leukotriene Inhibitors 2013-03-15 2013-09-26
US7915298 Compounds and methods for leukotriene biosynthesis inhibition 2009-04-02 2011-03-29
US2009227638 Novel Pharmaceutical Compounds 2009-09-10
US7553973 Pharmaceutical compounds 2007-06-28 2009-06-30
US2009030048 Novel pharmaceutical compounds 2009-01-29
/////////////MK 0633, PHASE 2
CCC(C1=NN=C(O1)NCC2=CC3=C(C=C2)C(=CC(=O)O3)C4=CC=C(C=C4)F)(C(F)(F)F)O

AMG-3969


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AMG-3969

M.Wt: 522.46
Cas : 1361224-53-4 , MF: C21H20F6N4O3S

WO 2012027261 PRODUCT PATENT

Inventors Kate Ashton, Michael David Bartberger, Yunxin Bo, Marian C. Bryan, Michael Croghan, Christopher Harold Fotsch, Clarence Henderson Hale, Roxanne Kay Kunz, Longbin Liu, Nobuko Nishimura, Mark H. Norman, Lewis Dale Pennington, Steve Fong Poon, Markian Myroslaw Stec, Jean David Joseph St., Jr., Nuria A. Tamayo, Christopher Michael Tegley, Kevin Chao Yang
Applicant Amgen Inc.

2-[4-[(2S)-4-[(6-Amino-3-pyridinyl)sulfonyl]-2-(1-propyn-1-yl)-1-piperazinyl]phenyl]-1,1,1,3,3,3-hexafluoro-2-propanol)

(S)-2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol,

mp 113–123 °C;
[α]D20 = +75.1 (c = 2.2, MeOH).
Agents for Type 2 Diabetes,  PRECLINICAL

AMG-3969, a novel and stable small-molecule disruptor of glucokinase (GK) and glucokinase regulatory protein (GKRP) interaction by the optimization of initial screening hit and AMG-1694. AMG-3969 potently induced the dissociation of the GK-GKRP complex and promoted GK translocation both in-vitro and in-vivo. In rodent model of diabetes, AMG-3969 reduced blood glucose levels without affecting euglycemic animals. The study represents the first successful discovery of a small molecule that targets the GK-GKRP complex as a novel pathway for managing blood glucose levels with reduced hypoglycemic risk.

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 Kate Ashton

Kate Ashton

Senior Scientist at Amgen, Inc

Amgen
Thousand Oaks, United States
Dr. Kate Ashton received a Masters in Chemistry with Industrial Experience from the University of Edinburgh. She conducted her PhD thesis research on the synthesis and structure elucidation of Reidispongiolide A with Prof. Ian Paterson at the University of Cambridge, and her postdoctoral work on SOMO catalysis with Prof. David W. C. MacMillan at both Caltech and Princeton. She has been at Amgen for 6 years and has worked on indications for cancer, Alzheimer’s and diabetes.Dr Fecke works in the area of industrial early drug discovery since 1996. He is currently Group Leader in the Primary Pharmacology department at UCB Pharma (UK) and is involved in the identification and characterization of NCE and NBE drugs in molecular interaction assays for both immunological and CNS diseases. Prior to joining UCB, he worked for Novartis and Siena Biotech in the areas of transplant rejection, neurodegeneration and oncology. He obtained his PhD at the Heinrich-Heine-University Dusseldorf in Germany in 1994.

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(S)-2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol, AMG-3969

Glucokinase (GK) is a member of a family of four hexokinases that are critical in the cellular metabolism of glucose. Specifically GK, also known as hexokinase IV or hexokinase D, facilitates glucose induced insulin secretion from pancreatic β-cells as well as glucose conversion into glycogen in the liver. GK has a unique catalytic activity that enables the enzyme to be active within the physiological range of glucose (from 5mM glucose to lOmM glucose).

Genetically modified mouse models support the role of GK playing an important role in glucose homeostasis. Mice lacking both copies of the GK gene die soon after birth from severe hyperglycemia, whereas mice lacking only one copy of the GK gene present with only mild diabetes. Mice that are made to overexpress the GK gene in their livers are hypoglycemic.

Numerous human mutations in the GK gene have been identified, with the vast majority of them resulting in proteins with impaired or absent enzymatic activity. These loss-of-function mutations are thought to contribute to the hyperglycemia seen with maturity-onset diabetes of the young type II (MODY-2). A small fraction of these mutations result in a GK with increased catalytic function. These individuals present with moderate to severe hypoglycemia.

GK activity in the liver is transiently regulated by glucokinase regulatory protein (GKRP). GK catalytic activity is inhibited when GK is bound to GKRP. This interaction is antagonized by increasing concentrations of both glucose and fructose -1 -phosphate (F1P). The complex of the two proteins is localized primarily to the nuclear compartment of a cell. Post prandially as both glucose and fructose levels rise, GK released from GKRP translocates to the cytoplasm. Cytoplasmic GK is now free of the inhibitory effects of GKRP and able to kinetically respond to glucose. Evidence from the Zucker diabetic fatty rat (ZDF) indicates that their glucose intolerance may be a result of this mechanism failing to function properly.

A compound that acts directly on GKRP to disrupt its interaction with GK and hence elevate levels of cytoplasmic GK is a viable approach to modulate GK activity. Such an approach would avoid the unwanted hypoglycemic effects of over stimulation of GK catalytic activity, which has been seen in the

development of GK activators. A compound having such an effect would be useful in the treatment of diabetes and other diseases and/or conditions in which GKRP and/or GK plays a role.

CLIP

Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors
Nature 2013, 504(7480): 437

Image result for Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors.

Image result for Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors.

SYNTHESIS

Figure

aReagents and conditions: (a) 1-propynylmagnesium bromide, THF, 0 °C, 99%; (b) TFA, DCM, then NaBH(OAc)3 77%; (c) NH4OH, EtOH, 120 °C, 88%; (d) chiral SFC, 38%………..Nature 2013,504, 437440

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012027261

EXAMPLE 241 : 2-(4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROP YN- 1 – YL)- 1 -PIPERAZINYL)PHENYL)- 1,1,1 ,3 ,3 ,3 -HEXAFLUORO-2-PROPANOL

STEP 1 : 4-BENZYL 1 -TERT-BUTYL 2-0X0-1,4-PIPERAZINEDICARBOXYLATE

A 2-L Erlenmeyer flask was charged with 2-piperazinone (36.5 g, 364 mmol, Sigma- Aldrich, St. Louis, MO), sodium carbonate (116 g, 1093 mmol), 600 mL of dioxane, and 150 mL of water. To this was slowly added benzyl chloroformate (62.1 g, 364 mmol, Sigma-Aldrich, St. Louis, MO) at room temperature over 20 min. After the addition was complete, the mixture was stirred for 2 h and then diluted with water and extracted with EtOAc (2 L). The combined organic extracts were dried (MgS04), filtered, and concentrated to give a white solid. To this solid was added 500 mL of DCM, triethylamine (128 mL, 911 mmol), DMAP (4.45 g, 36.4 mmol), and di-tert-butyl dicarbonate (119 g, 546 mmol, Sigma-Aldrich, St. Louis, MO). After 1 h at room temperature, the mixture was diluted with water and the organics were separated. The organics were dried (MgS04), filtered, and concentrated to give a brown oil. To this oil was added 100 mL of DCM followed by 1 L of hexane. The resulting white solid was collected by filtration to give 4-benzyl 1-tert-butyl 2-oxo-l,4-piperazinedicarboxylate (101 g).

STEP 2: BENZYL (2-((TERT-BUTOXYCARBONYL)AMINO)ETHYL)(2-OXO-3 -PENTYN- 1 -YL)CARBAMATE

A 150-mL round-bottomed flask was charged with 4-benzyl 1-tert-butyl

2- oxo-l,4-piperazinedicarboxylate (1.41 g, 4.22 mmol) and THF (5 mL). 1-Propynylmagnesium bromide (0.5 M in THF, 20.0 mL, 10.0 mmol, Sigma-Aldrich, St. Louis, MO) was added at 0 °C slowly. The mixture was stirred at 0 °C for 2 h. Saturated aqueous NH4C1 (40 mL) was added and the aqueous phase was extracted with EtOAc (200 mL, then 2 x 100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo- 3- pentyn-l-yl)carbamate (1.55 g) as a clear oil.

STEP 3: BENZYL 3-(l-PROPYN-l-YL)-l-PIPERAZINECARBOXYLATE

A 3-L round-bottomed flask was charged with 2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-l-yl)carbamate (82.2 g, 219 mmol) and 300 mL of DCM. After cooling to -10 °C, TFA (169 mL, 2195 mmol) was added and the resulting dark solution was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (186 g, 878 mmol, Sigma-Aldrich, St. Louis, MO) was then added portion- wise over 10 min. After 2 h, the mixture was

concentrated, diluted with EtOAc (1 L), and neutralized with 5 N NaOH. The layers were separated and the organic extracts were washed with brine, dried (MgS04), filtered and concentrated. The resulting orange oil was purified via column chromatography (750 g of silica gel, 0 to 4.5 % MeOH/DCM) to give benzyl 3-(l-propyn-l-yl)-l-piperazinecarboxylate (43.7 g) as a brown foam.

STEP 4: BENZYL 3-(l-PROPYN-l-YL)-4-(4-(2,2,2-TRIFLUORO-l-HYDROXY- 1 -(TRIFLUOROMETHYL)ETHYL)PHENYL)- 1 -PIPERAZINECARBOXYLATE

A 150-mL reaction vessel was charged with benzyl 3-(prop-l-yn-l-yl)piperazine-l-carboxylate (2.88 g, 11.2 mmol), 2-(4-bromophenyl)-l, 1,1, 3,3,3-hexafluoropropan-2-ol (4.36 g, 13.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxy-[ 1 , 1 ‘-biphenyl]-2-yl)phosphine, RuPhos (0.530 g, 1.14 mmol, Sigma- Aldrich, St. Louis, MO), RuPhos Palladacycle (0.417 g, 0.572 mmol, Strem Chemical Inc, Newburyport, MA), sodium tert-butoxide (2.73 g, 28.4 mmol, Strem Chemical Inc, Newburyport, MA) and toluene (35 mL). The mixture was degassed by bubbling Ar through the solution for 10 min. The vessel was sealed and heated at 100 °C for 1.5 h. The reaction mixture was cooled to room temerature and water (100 mL) was added. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with saturated aqueous sodium chloride (150 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (100 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl 3-(l-propyn-l-yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinecarboxylate as a yellow solid.

STEP 5: 2-(4-(4-((6-CHLORO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- 1 -PIPERAZIN YL)PHENYL)- 1,1,1 ,3 ,3 ,3 -HEXAFLUORO-2-PROPANOL

A 500-mL round-bottomed flask was charged with benzyl 3-(l-propyn-l-yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinecarboxylate (3.13 g, 6.25 mmol) and TFA (40 mL).

Trifluoromethanesulfonic acid (1.25 mL, 14.1 mmol, Acros/Fisher Scientific, Waltham, MA) was added dropwise at room temperature. After 5 min, additional TfOH (0.45 mL, 5.1 mmol) was added. After an additional 10 min, solid

NaHC03 was carefully added in potions. Saturated aqueous NaHC03 (250 mL) was added slowly to bring pH to approximately 7. The aqueous phase was extracted with EtOAc (100 mL). At this time, more solid NaHC03 was added to the aqueous phase and extracted again with EtOAc (100 mL). The combined organic phases were washed with water (200 mL) and saturated aqueous sodium chloride (200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3.10 g of tan solid.

A 500-mL round-bottomed flask was charged with this material, triethylamine (5.00 mL, 35.9 mmol) and CH2CI2 (30 mL). 6-Chloropyridine-3-sulfonyl chloride (1.58 g, 7.43 mmol, Organic Process Research & Development 2009, 13, 875) was added in potions at 0 °C. The brown mixture was stirred at 0 °C for 10 min. The volume of the reaction mixture was reduced to approximately 10 mL in vacuo then the mixture was purified twice by column chromatography (100 g of silica, 0 to 50% EtOAc in hexanes) to afford 2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3-hexafluoro-2-propanol (3.46 g) as an off-white solid.

STEP 6: 2-(4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- 1 -PIPERAZIN YL)PHENYL)- 1,1,1 ,3 ,3 ,3 -HEXAFLUORO-2-PROPANOL

A 20-mL sealed tube was charged with 2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3-hexafluoro-2-propanol (0.340 g, 0.627 mmol), concentrated ammonium hydroxide (5.00 mL, 38.5 mmol) and EtOH (5 mL). The reaction mixture was heated in an Initiator (Biotage, AB, Uppsala, Sweden) at 120 °C for 1 h. The reaction mixture was further heated in a heating block at 110 °C for 5 h. The reaction mixture was concentrated and purified by column chromatography (25 g of silica, 30 to 80% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3-hexafluoro-2-propanol (0.289 g) as a mixture of two enantiomers.

1H NMR (400 MHz, CDC13) δ ppm 8.49 (br. s., 1 H), 7.80 (dd, J= 2.3, 8.8 Hz, 1 H), 7.59 (d, J= 8.8 Hz, 2 H), 6.97 (d, J= 9.0 Hz, 2 H), 6.55 (d, J= 8.8 Hz, 1 H), 5.05 (s, 2 H), 4.46 (br. s., 1 H), 3.85 – 3.72 (m, 2 H), 3.54 (br. s., 1 H), 3.50 – 3.34 (m, 2 H), 2.83 (dd, J= 3.3, 11.0 Hz, 1 H), 2.69 (dt, J= 3.4, 11.0 Hz, 1 H), 1.80 (s, 3 H). m/z (ESI, +ve ion) 523.1 (M+H)+. GK-GKRP IC50 (Binding) = 0.003 μΜ

The individual enantiomers were isolated using chiral SFC. The method used was as follows: Chiralpak® ADH column (21 x 250 mm, 5 μιη) using 35% methanol in supercritical C02 (total flow was 70 mL/min). This produced the two enantiomers with enantiomeric excesses greater than 98%.

2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(l -propyn- 1-yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol and 2-(4-((2R)-4-((6-amino-3 -pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3-hexafluoro-2-propanol.

FIRST ELUTING PEAK (PEAK #1)

1H NMR (400 MHz, CDC13) δ 8.48 (d, J= 2.3 Hz, 1 H), 7.77 (dd, J= 2.5, 8.8 Hz, 1 H), 7.57 (d, J= 8.8 Hz, 2 H), 6.95 (d, J= 9.2 Hz, 2 H), 6.52 (d, J= 8.8 Hz, 1 H), 4.94 (s, 2 H), 4.44 (br. s., 1 H), 3.82 – 3.71 (m, 2 H), 3.58 – 3.33 (m, 3 H), 2.81 (dd, J= 3.2, 11.1 Hz, 1 H), 2.67 (dt, J= 3.9, 11.0 Hz, 1 H), 1.78 (d, J = 2.2 Hz, 3 H). m/z (ESI, +ve ion) 523.2 (M+H)+. GK-GKRP IC50 (Binding) = 0.002 μΜ.

SECOND ELUTING PEAK (PEAK #2)

1H NMR (400 MHz, CDC13) δ 8.49 (d, J= 1.8 Hz, 1 H), 7.78 (dd, J= 2.3, 8.8 Hz, 1 H), 7.59 (d, J= 8.6 Hz, 2 H), 6.97 (d, J= 9.0 Hz, 2 H), 6.54 (d, J= 8.8 Hz, 1 H), 4.97 (s, 2 H), 4.46 (br. s., 1 H), 3.77 (t, J= 11.7 Hz, 2 H), 3.67 (br. s., 1 H), 3.51 – 3.33 (m, 2 H), 2.82 (dd, J= 3.3, 11.0 Hz, 1 H), 2.68 (dt, J= 3.9, 11.1 Hz, 1 H), 1.79 (d, J= 2.0 Hz, 3 H). m/z (ESI, +ve ion) 523.2 (M+H)+. GK-GKRP IC50 (Binding) = 0.342 μΜ.

Alternative procedure starting after Step 4.

STEP 5 : 2-(4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- 1 -PIPERAZIN YL)PHENYL)- 1,1,1 ,3 ,3 ,3 -HEXAFLUORO-2-PROPANOL

Alternatively, 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)-l-piperazinyl)phenyl)-l,l,l,3,3,3-hexafluoro-2-propanol was synthesized from benzyl 3-( 1 -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinecarboxylate as follows.

A 2-L round-bottomed flask was charged with benzyl 3 -(1 -propyn- 1-yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinecarboxylate (21.8 g, 43.5 mmol, step 5) and TFA (130 mL).

Trifluoromethanesulfonic acid (11.6 mL, 131 mmol, Acros/Fisher Scientific, Waltham, MA) was added slowly at rt resulting orange cloudy mixture. After stirring at rt for 10 min, the volume of the reaction mixture was reduced to half in vacuo. Solid NaHC03 was added in potions until the mixture became sludge. Saturated aqueous NaHC03(800 mL) was added slowly until the pH was about

8. The aqueous phase was extracted with EtOAc (3 x 250 mL). The combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved into DCM (200 mL) and triethylamine (31.0 mL, 222 mmol) was added. Then 6-aminopyridine-3-sulfonyl chloride (9.40 g, 48.8 mmol, published PCT patent application no. WO

2009/140309) was added in potions over 10 min period. The brown mixture was stirred at room temperature for 10 min. The reaction mixture was washed with water (300 mL) and saturated aqueous NaCl (300 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (780 g of total silica, 30 to 90% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(l-propyn-l-yl)-l-piperazinyl)phenyl)-l,l,l,3,3,3-hexafluoro-2-propanol (19.4 g) as a mixture of two enantiomers.

Paper

Nonracemic Synthesis of GK–GKRP Disruptor AMG-3969

Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
Amgen Inc. 360 Binney Street, Cambridge, Massachusetts 02142, United States
J. Org. Chem., 2014, 79 (8), pp 3684–3687

Abstract Image

A nonracemic synthesis of the glucokinase–glucokinase regulatory protein disruptor AMG-3969 (5) is reported. Key features of the synthetic approach are an asymmetric synthesis of the 2-alkynyl piperazine core via a base-promoted isomerization and a revised approach to the synthesis of the aminopyridinesulfonamide with an improved safety profile.

(S)-2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol, AMG-3969 (5)

(S)-2-(4-(4-((6-aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (5) (64.0 g, 49% yield) as white solid. The enanatiomeric excess was found to be >99.5% by chiral SFC (see Supporting Information):
1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.55 (d, J = 8.8 Hz, 1 H), 5.06 (br s, 2 H), 4.45 (br s, 1 H), 3.96 (br s, 1 H), 3.77 (t, J = 12.1 Hz, 2 H), 3.50–3.35 (m, 2 H), 2.82 (d, J = 11.0 Hz, 1 H), 2.68 (t, J = 10.9 Hz, 1 H), 1.79 (s, 3 H);
13C NMR (101 MHz, CD3OD) δ 163.8, 152.0, 150.1, 138.2, 129.0, 124.7 (q), 123.9, 121.1, 117.5, 109.3, 82.8, 78.3 (m), 75.5, 52.0, 47.2, 44.9, 3.2;
 
HRMS (ESI-TOF) m/z [M + H]+calcd for C21H21F6N4O3S 523.1239, found 523.1229;
 
mp 113–123 °C;
 
[α]D20 = +75.1 (c = 2.2, MeOH).
 

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AMG-3969 is a disruptor of the glucokinase (GK)–glucokinase regulatory protein (GKRP) protein–protein interaction. Bourbeau and co-workers at Amgen describe their efforts towards an asymmetric synthesis of this compound ( J. Org. Chem. 2014, 79, 3684). The discovery route to this compound involved seven steps (14% overall yield), had certain safety concerns and relied upon SFC separation of the API enantiomers. The new route requires five steps (26% overall yield) and delivers the API in excellent enantiomeric excess (99% ee). A key feature of the synthetic approach was an asymmetric synthesis of the 2-alkynylpiperazine core via a base-promoted isomerization. It was found that the strongly basic conditions employed for the “alkyne-walk” did not erode the previously established stereocenter. Also, safety concerns around a late-stage amination of a 2-chloropyridine intermediate in the discovery route were alleviated by starting with a Boc-protected diaminopyridine instead.
PATENT

INTERMEDIATE A: TERT-EUTYL (5-(CHLOROSULFONYL)-2-PYRIDINYL)CARBAMATE

0,N

STEP 1 : TERT-BUTY (5-NITRO-2-PYRIDINYL)CARBAMATE

A 3-L round-bottomed flask was charged with 5-nitro-2-pyridinamine (75.0 g, 539 mmol, Alfa Aesar, Ward Hill, MA) and 500 mL of DCM. To this was added triethylamine (82 g, 810 mmol), di-tert-butyl dicarbonate (129 g, 593 mmol, Sigma-Aldrich, St. Louis, MO), and N,N-dimethylpyridin-4-amine (32.9 g, 270 mmol, Sigma-Aldrich, St. Louis, MO). After stirring at rt for 18 h, the mixture was diluted with water and the solid was collected by filtration. The yellow solid was washed with MeOH to give tert-butyl (5-nitro-2-pyridinyl)carbamate (94.6 g) as a light yellow solid.

STEP 2: TERT-BUTY (5 – AMINO-2-P YRIDINYL)C ARB AM ATE

A 3-L round-bottomed flask was charged with tert-butyl (5-nitro-2-pyridinyl)carbamate (96.4 g, 403 mmol), 500 mL of MeOH, 500 mL of THF, and 100 mL of sat aq NH4Cl. Zinc (105 g, 1610 mmol, Strem Chemical Inc, Newburyport, MA) was slowly added (over 10 min) to this solution. The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was concentrated and then diluted with EtOAc and washed with water. The organic extracts were dried over MgS04, filtered, and concentrated. The resulting solid was recrystallized from MeOH to give tert-butyl(5-amino-2-pyridinyl)carbamate (38.6 g) as a light-yellow solid.

STEP 3: TERT-BUTYL (5-(CHLOROSULFONYL)-2-PYRIDINYL)CARBAMATE

A 3-L round-bottomed flask was charged with sodium nitrite (15.3 g, 221 mmol, J. T. Baker, Philipsburg, NJ), 100 mL of water and 500 mL of MeCN. After cooling to 0 °C, cone, hydrochloric acid (231 mL, 2770 mmol) was slowly added keeping the internal temperature below 10 °C. After stirring at 0 °C for 10 min, tert-butyl (5-amino-2-pyridinyl)carbamate (38.6 g, 184 mmol) was added as a suspension in MeCN (200 mL). The mixture was stirred for 30 min, then 150 mL of AcOH, copper(ii) chloride (12.4 g, 92.2 mmol, Sigma-Aldrich, St. Louis, MO), and copper(i) chloride (0.183 g, 1.85 mmol, Strem Chemical Inc,

Newburyport, MA) were added. S02 gas (Sigma-Aldrich, St. Louis, MO) was bubbled through the solution for 15 min. The mixture was stirred at 0 °C for 30 min, then about 500 mL of ice-cold water was added. The resulting precipitate was collected by filtration and dried over MgS04 to give tert-butyl (5-(chlorosulfonyl)-2-pyridinyl)carbamate (15.5 g) as a white solid.

1H NMR (400MHz, CDC13) δ ppm 8.93 (br s, 1 H), 8.63 – 8.42 (m, 1 H), 8.35 -7.94 (m, 2 H), 1.58 (s, 9 H).

INTERMEDIATE B: (3S)-l-BENZYL-3-(l-PROPYN-l-YL)PIPERAZINE

STEP 1 : (3S)-l-BENZYL-3-(2-PROPYN-l-YL)-2,5-PIPERAZINEDIONE

A 1-L round-bottoemd flask was charged with (S)-2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid (42.0 g, 197 mmol, AK Scientific, Union City, CA), ethyl 2-(benzylamino)acetate (40.0 g, 207 mmol, Sigma-Aldrich, St. Louis, MO), HATU (90 g, 240 mmol, Oakwood Products, West Columbia, SC) and 200 mL of DMF. To this was added N-ethyl-N-isopropylpropan-2-amine (51.5 ml, 296 mmol, Sigma-Aldrich, St. Louis, MO). After 15 min of stirring at rt, the mixture was diluted with water 300 mL and extracted with 1 L of 20% EtOAc in diethyl ether. The layers were separated and the organic was washed with 2 M HCl, water, sat. aq. NaHC03 and brine. The extracts were dried and concentrated to give an off-white solid. To this was added 200 mL of DCM and TFA (152 ml, 1970 mmol, Sigma-Aldrich, St. Louis, MO). After stirring at rt for 30 min, the mixture was concentrated and then azetroped with 100 mL toluene (twice). To the brown oil obtained was added ammonia (2 M in MeOH, 394 ml, 789 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was stirred at rt for 30 min. The mixture was concentrated, dissolved in EtOAc, and washed with water. The organics were dried (MgS04), filtered, and concentrated to give a white solid that was triturated with diethyl ether to give (S)-l-benzyl-3-(prop-2-yn-l-yl)piperazine-2,5-dione (37.3 g) as a white solid.

STEP 2: (3S)-l-BENZYL-3-(2-PROPYN-l-YL)PIPERAZINE

A 1-L round-bottomed flask was charged with (S)-l-benzyl-3-(prop-2-yn-l-yl)piperazine-2,5-dione (37.3 g, 154 mmol) and 150 mL of THF. To this was slowly added aluminum (III) lithium hydride (1M in THF, 539 ml, 539 mmol, Sigma-Aldrich, St. Louis, MO). After the addition was complete the mixture was heated at 80 °C for 12 h. The mixture was then cooled to 0 °C and solid sodium sulfate decahydrate was added until bubbling ceased. The mixture was filtered and the filtrate was concentrated to give (S)-l-benzyl-3-(prop-2-yn-l-yl)piperazine (18.1 g) as a yellow oil.

STEP 3: (35)-l-BENZYL-3-(l-PROPYN-l-YL)PIPERAZINE

To a solution of (35)-l-benzyl-3-(2-propyn-l-yl)piperazine (2.3 g, 11 mmol) in THF (50 mL) was added potassium t-butoxide (2.41 g, 21.5 mmol, Sigma-Aldrich, St. Louis, MO). The reaction mixture was stirred at rt for 30 min, then quenched with water (200 mL) and EtOAc (300 mL) was added. The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum to give a solid that was purified by silica gel column chromatography (0 to 10% MeOH in CH2CI2) and then recrystallized from hexanes to afford (35)- 1-benzyl-3-(l-propyn-l-yl)piperazine (2.16 g) as an off-white solid.

1H NMR (400MHz, CD3OD) δ ppm 7.42 – 7.21 (m, 5 H), 3.59 – 3.49 (m, 3 H), 2.93 (td, J= 2.9, 12.4 Hz, 1 H), 2.86 – 2.73 (m, 2 H), 2.68 (d, J= 11.3 Hz, 1 H), 2.22 – 2.04 (m, 2 H), 1.80 (d, J= 2.3 Hz, 3 H).

INTERMEDIATE C: N,N-BIS(4-METHOXYBENZYL)-5-(((35)-3-(l-PROPYN- 1 – YL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE

STEP 1 : (35)-l-((6-CHLORO-3-PYRIDINYL)SULFONYL)-3-(l-PROPYN-l-YL)PIPERAZINE

To a stirred solution of benzyl (35)-3-(l-propyn-l-yl)-l-piperazinecarboxylate (2.51 g, 9.71 mmol, Intermediate E) in TFA (20 mL) in 250-mL round-bottomed flask, trifluoromethanesulfonic acid (2.59 mL, 29.1 mmol, Alfa Aesar, Ward Hill, MA) was added slowly at rt. After stirring at room temperature for 3 min, the reaction mixture was concentrated to dryness under a vacuum. DCM (20 mL) was added to the residue followed by triethylamine (13.5 mL, 97 mmol). After the material went into solution, the mixture was cooled to 0 °C and 6-chloro-3-pyridinesulfonyl chloride (2.06 g, 9.73 mmol, Organic Process Research & Development 2009, 13, 875) was added portion-wise. After 5 min of stirring at 0 °C, water (40 mL) was added at that temperature and the layers were separated. The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (60 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum. The crude product was purified by column chromatography (100 g of silica, 30 to 90% EtOAc in hexanes) to afford (35)- 1-((6-chloro-3-pyridinyl)sulfonyl)-3-(l-propyn-l-yl)piperazine (2.61 g) as an off-white solid.

STEP 2: N,N-BIS(4-METHOXYBENZYL)-5-(((35)-3-(l-PROPYN-l-YL)-l-PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE

A mixture of (35)-l-((6-chloro-3-pyridinyl)sulfonyl)-3-(l-propyn-l-yl)piperazine (2.6 g, 8.7 mmol), N-(4-methoxybenzyl)-l-(4-methoxyphenyl)methanamine (2.40 g, 9.33 mmol, WO2007/109810A2), and DIPEA (2.4 mL, 14 mmol) in z-BuOH (8.0 mL) was heated at 132 °C using a microwave reactor for 3 h. This reaction was run three times (total starting material amount was 7.2 g). The mixtures from the three runs were combined and partitioned between EtOAc (200 mL) and aqueous NaHC03 (half saturated, 50 mL). The organic layer was washed with aqueous NaHC03 (3 x 50 mL), dried over Na2S04, filtered, and concentrated. The residue was purified (5-times total) by chromatography on silica using MeOH:DCM:EtOAc:hexane

(4:20:20:60) as eluent to give N,N-bis(4-methoxybenzyl)-5-(((3S)-3-(l-propyn-i-yl)-l-piperazinyl)sulfonyl)-2-pyridinamine (6.6 g) as a white foam.

1H NMR (400MHz ,CDC13) δ ppm 8.55 (d, J= 2.3 Hz, 1 H), 7.64 (dd, J= 2.5, 9.0 Hz, 1 H), 7.13 (d, J= 8.6 Hz, 4 H), 6.91 – 6.81 (m, 4 H), 6.47 (d, J= 9.0 Hz, 1 H), 4.75 (s, 4 H), 3.80 (s, 6 H), 3.68 – 3.61 (m, 1 H), 3.57 (d, J= 11.2 Hz, 1 H), 3.41 (d, J= 11.3 Hz, 1 H), 3.07 (td, J= 3.3, 12.1 Hz, 1 H), 2.87 (ddd, J= 2.9, 9.7, 12.2 Hz, 1 H), 2.63 – 2.47 (m, 2 H), 1.80 (d, J= 2.2 Hz, 3 H). One exchangeable proton was not observed, m/z (ESI, +ve ion) 521.2 (M+H)+.

INTERMEDIATE D: rEi?r-BUTYL(5-(((35)-3-(l-PROPYN-l-YL)-4-(4-(2-(TRIFLUOROMETHYL)-2-OXIRANYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE

step 1 step 2

STEP 1 : l-BR0M0-4-(l-(TRIFLU0R0METHYL)ETHENYL)BENZENE

To a 1-L round-bottomed flask was added methyl phenylphosphonium bromide (25.4 g, 71.1 mmol, Sigma- Aldrich, St. Louis, MO) and toluene (75 mL). The resulting mixture was stirred for 5 min then concentrated and dried under high vacuum for 30 min. To this residue was added THF (300 mL) followed by n-butyllithium (2.5 M in hexanes, 29.0 mL, 71.1 mmol, Aldrich, St. Louis, MO) dropwise via an addition funnel. After being stirred for 1 h at rt, a solution of l-(4-bromophenyl)-2,2,2-trifluoroethanone (15.0 g, 59.3 mmol, Matrix Scientific, Columbia, SC) in THF (20 mL) was added to the reaction mixture dropwise via an addition funnel. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4C1 and the mixture was concentrated. The residue was partitioned between diethyl ether (150 mL) and saturated aqueous NH4C1 (80 mL). The organic layer was washed with water and brine, dried over MgS04, filtered, and concentrated. The resulting crude product was purified by column chromatography (330 g of silica gel, 2 to 5% EtOAc in hexanes) to afford l-bromo-4-(l-(trifluoromethyl)ethenyl)benzene (14.0 g) as a brown liquid.

STEP 2: 2-(4-BROMOPHENYL)-3,3,3-TRIFLUORO-l,2-PROPANEDIOL

To a solution of l-bromo-4-(l-(trifluoromethyl)ethenyl)benzene (13.5 g, 53.8 mmol) in acetone (100 mL) and water (100 mL) was added NMO (6.90 g, 59.2 mmol, Sigma- Aldrich, St. Louis, MO) and osmium tetroxide (0.140 mL, 2.70 mmol, Sigma-Aldrich, St. Louis, MO). The resulting mixture was stirred at rt for 6 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc (100 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2 x 75 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The resulting product was purified by column chromatography (330 g of silica gel, 0 to 8% MeOH in DCM) to afford 2-(4-bromophenyl)-3,3,3-trifluoro-l,2-propanediol (14.5 g) as an off-white solid.

STEP 3: 4-(4-BROMOPHENYL)-2,2-DIMETHYL-4-(TRIFLUOROMETHYL)-1,3-DIOXOLANE

To a solution of 2-(4-bromophenyl)-3,3,3-trifluoro-l,2-propanediol (14.5 g, 51.0 mmol) in acetone (200 mL) was added 2,2-dimethoxypropane (19.0 mL, 153 mmol, Sigma-Aldrich, St. Louis, MO) and /?-toluenesulfonic acid (0.485 g, 2.54 mmol, Sigma-Aldrich, St. Louis, MO). The resulting mixture was stirred at rt for 20 h. Additional 2,2-dimethoxypropane (19.0 mL, 153 mmol, Sigma-Aldrich, St. Louis, MO) and /?-toluenesulfonic acid (0.485 g, 2.54 mmol, Sigma-Aldrich, St. Louis, MO) were added and the reaction was stirred for another 20 h. The reaction was quenched with saturated aqueous NaHC03 (10 mL). The reaction mixture was concentrated and the residue was partitioned between

EtOAc (100 mL) and saturated aqueous NaHC03 (60 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The resulting product was purified by column chromatography (330 g of silica gel, 0 to 8% EtOAc in hexanes) to afford 4-(4-bromophenyl)-2,2-dimethyl-4-(trifluoromethyl)-l,3-dioxolane (15.7 g) as a colorless liquid.

STEP 4: BENZYL (3S)-4-(4-(2,2-DIMETHYL-4-(TRIFLUOROMETHYL)-l,3-DIOXOLAN-4-YL)PHENYL)-3-(l -PROPYN- 1 -YL)- 1 -PIPERAZINECAPvBOXYLATE

To a 20-mL vial was added benzyl (3S)-3-(l -propyn- l-yl)-l-piperazinecarboxylate (1.0 g, 3.87 mmol, Intermediate E), RuPhos Palladacycle (0.250 g, 0.310 mmol, Strem Chemical, Newburyport, MA), 4-(4-bromophenyl)-2,2-dimethyl-4-(trifluoromethyl)-l,3-dioxolane (2.50 g, 7.74 mmol), dioxane (15.0 mL), and sodium t-butoxide (0.740 g, 7.74 mmol, Sigma-Aldrich, St.

Louis, MO). The reaction mixture was degassed by bubbling N2 through the solution for 5 min, then the vial was capped. The reaction mixture was heated at 80 °C for 30 min then allowed to cool to rt and partitioned between EtOAc (70 mL) and water (40 mL). The aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The crude product was purified by column chromatography (80 g of silica, 5% to 30% EtOAc in hexanes) to afford benzyl (35)-4-(4-(2,2-dimethyl-4-(trifluoromethyl)- 1 ,3-dioxolan-4-yl)phenyl)-3-(l -propyn- 1 -yl)- 1 -piperazinecarboxylate (1.6 g) as a yellow foam.

STEP 5: rEi?r-BUTYL(5-(((35)-3-(l-PROPYN-l-YL)-4-(4-(2,2,2-TRIFLUORO- 1 -HYDROXY- 1 -(HYDROXYMETH YL)ETHYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE

To a 150-mL round-bottomed flask was added benzyl (3S)-4-(4-(2,2-dimethyl-4-(trifluoromethyl)- 1 ,3 -dioxolan-4-yl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinecarboxylate (1.60 g, 3.18 mmol) and TFA (20 mL, Sigma-Aldrich, St. Louis, MO). After the substrate was completely dissolved in TFA,

trifluoromethanesulfonic acid (0.850 mL, 9.55 mmol, Alfa Aesar, Ward Hill,

MA) was added and the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was slowly poured into a 300-mL beaker which contained 100 mL ice water. The resulting mixture was stirred while NaOH pellets (11.0 g) were slowly added to adjust the pH to 7. The solution was extracted with EtOAc (2 x 70 mL) and 10% IPA in CHCI3 (2 x 40 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The resulting intermediate was redissolved in DCM (60 mL). Triethylamine (2.20 mL, 16.0 mmol, Sigma-Aldrich, St. Louis, MO) and tert-butyl (5-(chlorosulfonyl)-2-pyridinyl)carbamate (1.04 g, 3.60 mmol, Intermediate A) were added. The reaction mixture was stirred at rt for 1 h then partitioned between DCM (70 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The crude product was purified by column chromatography (120 g of silica, 10% to 40% acetone in hexanes) to afford tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4-(2,2,2-trifiuoro-l-hydroxy- 1 -(hydroxymethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinyl)carbamate (1.0 g) as a yellow foam.

STEP 6: rEi?r-BUTYL(5-(((35)-3-(l-PROPYN-l-YL)-4-(4-(2-(TRIFLUOROMETHYL)-2-OXIRANYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE

To a solution of tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4-(2,2,2-trifiuoro- 1 -hydroxy- 1 -(hydroxymethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinyl)carbamate (0.300 g, 0.513 mmol) in DCM (5 mL) was added triethylamine (0.400 mL, 2.88 mmol, Sigma-Aldrich, St. Louis, MO) and p-toluenesulfonyl chloride (0.108 g, 0.564 mmol, Sigma-Aldrich, St. Louis, MO). The resulting mixture was heated at reflux (50 °C) under N2 for 2 h. The reaction mixture was cooled to rt and partitioned between sat. NaHCOs (30 mL) and DCM (70 mL). The aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 40%> acetone in hexanes) to afford tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4-(2-(trifluoromethyl)-2-oxiranyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinyl)carbamate (0.240 g) as an off-white solid.

1H NMR (400MHz, CDC13) δ ppm 8.66 (dd, J= 0.6, 2.3 Hz, 1 H), 8.20 – 8.10 (m, 1 H), 8.04 (dd, J= 2.2, 8.9 Hz, 1 H), 7.63 (s, 1 H), 7.41 (d, J= 8.6 Hz, 2 H), 6.94 (d, J= 8.8 Hz, 2 H), 4.42 (d, J= 2.2 Hz, 1 H), 3.89 – 3.67 (m, 2 H), 3.38 (d, J = 5.3 Hz, 3 H), 2.97 – 2.83 (m, 2 H), 2.80 – 2.60 (m, 1 H), 1.78 (dd, J= 0.8, 2.0 Hz, 3 H), 1.55 (s, 9 H). m/z (ESI, +ve ion) 567.2 (M+H)+.

ALTERNATIVE ROUTE TO 2-(4-BROMOPHENYL)-3,3,3-TRIFLUORO-l,2-PROPANEDIOL (INTERMEDIATE D STEP 2):

F3

step 1

STEP 1 : 2-(4-BROMOPHENYL)-2-(TRIFLUOROMETHYL)OXIRANE

To a flame-dried, 50-mL, round-bottomed flask was added potassium t-butoxide (0.450 g, 4.01 mmol, Sigma- Aldrich, St. Louis, MO), DMSO (5.0 mL) and trimethylsulfoxonium iodide (1.00 g, 4.54 mmol, Sigma- Aldrich, St. Louis, MO). The resulting mixture was stirred at rt for 40 min. To this reaction mixture was added l-(4-bromophenyl)-2,2,2-trifluoroethanone (1.0 g, 4.0 mmol, Matrix Scientific, Columbia, SC) in DMSO (5.0 mL) dropwise via an addition funnel. The reaction mixture was stirred at rt for 30 min then quenched with water (1 mL) and partitioned between EtOAc (70 mL) and water (30 mL). The organic layer was washed with water (4 x 30 mL), dried over MgS04, filtered, and concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 20% acetone in hexanes) to afford 2-(4-bromophenyl)-2-(trifluoromethyl)oxirane (0.610 g) as a pale-yellow liquid.

STEP 2: 2-(4-BROMOPHENYL)-3,3,3-TRIFLUORO-l,2-PROPANEDIOL

To a 20-mL vial was added 2-(4-bromophenyl)-2-(trifluoromethyl)oxirane (0.200 g, 0.750 mmol), dioxane (2.0 mL), and water (3.0 mL). The resulting mixture was heated at 85 °C for 24 h. The reaction mixture was cooled to rt and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford 2-(4-bromophenyl)-3,3,3-trifluoro-l,2-propanediol (2.0 g) as a white solid.

INTERMEDIATE E: BENZYL (3S)-3-(l-PROPYN-l-YL)-l-PIPERAZINECARBOXYLATE

-Cbz

STEP 1 : 4-BENZYL 1 – TER Γ-BUT YL 2-0X0-1,4-PIPERAZINEDICARBOXYLATE

A 2-L Erlenmeyer flask was charged with 2-piperazinone (36.5 g, 364 mmol, Sigma-Aldrich, St. Louis, MO), sodium carbonate (116 g, 1090 mmol, J. T. Baker, Philipsburg, NJ), 600 mL of dioxane, and 150 mL of water. To this was slowly added benzyl chloroformate (62.1 g, 364 mmol, Sigma-Aldrich, St. Louis, MO) at rt over 20 min. After the addition was complete, the mixture was stirred for 2 h and then diluted with water and extracted with EtOAc (2 L). The combined organic extracts were dried (MgS04), filtered, and concentrated to give a white solid. To this solid was added 500 mL of DCM, triethylamine (128 mL, 911 mmol, Sigma-Aldrich, St. Louis, MO), DMAP (4.45 g, 36.4 mmol, Sigma-Aldrich, St. Louis, MO), and di-tert-butyl dicarbonate (119 g, 546 mmol, Sigma-Aldrich, St. Louis, MO). After stirring at room temperature for 1 h, the mixture was diluted with water and the organics were separated. The organics were dried (MgS04), filtered, and concentrated to give a brown oil. To this oil was added 100 mL of DCM followed by 1 L of hexane. The resulting white solid was collected by filtration to give 4-benzyl 1-tert-butyl 2-oxo-l,4-piperazinedicarboxylate (101 g).

STEP 2: BENZYL (2-((7¾’i?J,-BUTOXYCARBONYL)AMINO)ETHYL)(2-OXO-3 -PENT YN- 1 – YL)C ARB AMATE

A 150-mL round-bottomed flask was charged with 4-benzyl 1-tert-butyl 2-oxo- 1 ,4-piperazinedicarboxylate (1.41 g, 4.22 mmol) and THF (5 mL). 1-Propynylmagnesium bromide (0.5 M in THF, 20.0 mL, 10.0 mmol, Sigma-Aldrich, St. Louis, MO) was added at 0 °C slowly. The mixture was stirred at 0 °C for 2 h. Saturated aqueous NH4C1 (40 mL) was added and the aqueous phase was extracted with EtOAc (200 mL, then 2 x 100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under a vacuum. The crude product was purified by column chromatography (50 g of silica, 0 to 50% EtOAc in hexanes) to afford benzyl (2- tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-l-yl)carbamate (1.55 g) as a clear oil.

STEP 3: BENZYL 3-(l-PROPYN-l-YL)-l-PIPERAZINECARBOXYLATE

A 3-L round-bottomed flask was charged with 2-((tert-butoxycarbonyl)amino)ethyl)(2-oxo-3-pentyn-l-yl)carbamate (82.17 g, 219 mmol) and 300 mL of DCM. After cooling to -10 °C, TFA (169 mL, 2200

mmol) was added and the resulting dark solution was stirred at rt for 15 min.

Sodium triacetoxyborohydride (186 g, 878 mmol, Sigma- Aldrich, St. Louis, MO) was then added portion- wise over 10 min. After 2 h, the mixture was

concentrated, diluted with EtOAc (1 L), and neutralized with 5 N NaOH. The layers were separated and the organic extracts were washed with brine, dried (MgS04), filtered and concentrated. The resulting orange oil was purified via column chromatography (750 g of silica gel, 0 to 4.5 % MeOH/DCM) to give benzyl 3 -(l-propyn-l-yl)-l -piperazmecarboxylate (43.67 g) as a brown foam.

STEP 4: 4-BENZYL 1 – TER Γ-BUT YL 2-(l -PROP YN-l-YL)- 1,4-PIPERAZINEDICARBOXYLATE

A 20-mL vial was charged with benzyl 3-(l-propyn-l-yl)-l-piperazinecarboxylate (0.616 g, 2.38 mmol), di-tert-butyl dicarbonate (0.979 g, 4.49 mmol, Sigma-Aldrich, St. Louis, MO), DMAP (0.0287 g, 0.235 mmol, Sigma-Aldrich, St. Louis, MO), TEA (0.90 mL, 6.5 mmol) and DCM (8 mL). The mixture was stirred at rt for 30 min. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The organic phase was washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered, and concentrated under a vacuum. The crude product was purified by column chromatography (25 g of silica, 0 to 50% EtOAc in hexanes) to afford 4-benzyl 1-tert-butyl 2-(l-propyn-l-yl)-l,4-piperazinedicarboxylate (0.488 g) as a colorless oil.

STEP 5: 4-BENZYL 1 – TER Γ-BUT YL (2S)-2-( 1 -PROP YN-l-YL)- 1,4-PIPERAZINEDICARBOXYLATE

The individual enantiomers of 4-benzyl 1-tert-butyl 2-(l-propyn-l-yl)-1 ,4-piperazinedicarboxylate were isolated using chiral SFC. The method used was as follows: Chiralpak® ADH column (Daicel Inc., Fort Lee, NJ) (30 x 250 mm, 5 μιη) using 12% ethanol in supercritical C02 (total flow was 170 mL/min).

This separated the two enantiomers with enantiomeric excesses greater than 98%. The first eluting peak was subsequently identified as 4-benzyl 1-tert-butyl (2S)-2-(l-propyn-l-yl)-l,4-piperazinedicarboxylate and used in the next step.

STEP 6: BENZYL (3S)-3-(l-PROPY -l-YL)-l-PIPERAZINECAPvBOXYLATE

A 100-mL round-bottomed flask was charged with 4-benzyl 1-tert-butyl (25)-2-(l-propyn-l-yl)-l,4-piperazinedicarboxylate (0.145 g, 0.405 mmol), TFA (1.0 mL, 13 mmol) and DCM (2 mL). The mixture was stirred at rt for 40 min. The mixture was concentrated and solid NaHC03 was added followed by saturated aqueous NaHC03. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with IN NaOH (40 mL), saturated aqueous NaHC03 (40 mL), water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under a vacuum to afford benzyl (35)-3-(l-propyn-l-yl)-l-piperazinecarboxylate (0.100 g) as a pale yellow clear oil which solidified upon standing to give a pale yellow solid.

1H NMR (400MHz, MeOD) δ ppm 7.47 – 7.13 (m, 5 H), 5.27 – 5.00 (m, 2 H), 3.88 – 3.58 (m, 3 H), 3.48 – 3.33 (m, 2 H), 3.22 – 3.02 (m, 1 H), 2.89 – 2.63 (m, 1 H), 1.80 (s, 3 H). m/z (ESI, +ve ion) 259.1 (M+H)+.

XAMPLE 23: 5-(((3S)-3-(l-PROPYN-l-YL)-4-(4-(l,2,2,2-TETRAFLUORO-1 -(TRIFLUOROMETHYL)ETHYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE

STEP 1 : 2-(4-((2S)-4-BENZYL-2-(l-PROPYN-l-YL)-l-PIPERAZINYL)PHENYL)-1 , 1 ,1 ,3,3,3-HEXAFLUORO-2-PROPANOL

A 20-mL vial was charged with (3S)-l-benzyl-3-(l-propyn-l-yl)piperazine (2.143 g, 10 mmol, Intermediate B), 2-(4-bromophenyl)-1,1,1, 3,3, 3-hexafluoropropan-2-ol (3.09 g, 11.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium 2-methylpropan-2-olate (1.92 g, 20.0 mmol, Sigma-Aldrich, St. Louis, MO), dioxane (5 mL), RuPhos palladacycle (0.364 g, 0.500 mmol, Strem Chemical Inc., Newburyport, MA), and RuPhos (0.233 g, 0.500 mmol, Strem Chemical Inc., Newburyport, MA). The vial was sealed and heated at 100 °C for 1 h. The mixture was allowed to cool to rt, and diluted with water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under a vacuum to give a solid that was purified by silica gel column chromatography (0 to 40% EtOAc in hexanes) to afford 2-(4-((2S)-4-benzyl-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3-hexafluoro-2-propanol (1.75 g) as a slightly yellow oil.

STEP 2: l,l,l,3,3,3-HEXAFLUORO-2-(4-((2S)-2-(l-PROPYN-l-YL)-l-PIPERAZINYL)PHENYL)-2-PROPANOL

A 250 mL round-bottomed flask was charged with 2-(4-((2S)-4-benzyl-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2-propanol (1.75 g, 4.35 mmol), potassium carbonate (2.40 g, 17.4 mmol, Sigma-Aldrich, St. Louis, MO), CH2CI2 (25 mL), and 1-chloroethyl chlorocarbonate (1.88 mL, 17.4 mmol, Sigma-Aldrich, St. Louis, MO). After 30 min at rt, the reaction was filtered and the filtrate was concentrated. To the resulting oil was added MeOH (25 mL). This mixture was heated at 75 °C for 1.5 h then concentrated. The residue was triturated with diethyl ether to give l,l,l,3,3,3-hexafluoro-2-(4-((2S)-2-(l-propyn-l-yl)-l-piperazinyl)phenyl)-2-propanol (1.44 g) as a white solid.

STEP 3: TERT-BUTYL (5-(((3S)-3-(l-PROPYN-l-YL)-4-(4-(2,2,2-TRIFLUORO- 1 -HYDROXY- 1 -(TRIFLUOROMETHYL)ETHYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE

A 250-mL round-bottomed flask was charged with 1,1,1,3,3,3-hexaf uoro-2-(4-((2S)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)-2-propanol (18.9 g, 51.6 mmol) and DCM (150 mL) and cooled to 0 °C. TEA was added (14.4 mL, 103 mmol, Sigma-Aldrich, St. Louis, MO) followed by tert-butyl (5- (chlorosulfonyl)pyridin-2-yl)carbamate (15.9 g, 54.2 mmol, Intermediate A) portionwise. After 10 min, the reaction mixture was diluted with water (100 mL) and the organic layer was separated, dried over Na2S04, filtered and concentrated under a vacuum to give a solid that was purified by silica gel column

chromatography (0 to 50% EtO Ac in hexanes) to afford tert-butyl (5 -(((3 S)-3 -( 1 -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinyl)carbamate (19.9 g) as a tan foam.

STEP 4: 5-(((3S)-3-(l-PROPYN-l-YL)-4-(4-(l,2,2,2-TETRAFLUORO-l- (TRIFLUOROMETHYL)ETHYL)PHENYL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE

A 500-mL round-bottomed flask was charged with tert-butyl (5-(((3S)-3-(1 -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 – (trifluoromethyl)ethyl)phenyl)-l-piperazinyl)sulfonyl)-2-pyridinyl)carbamate (19.7 g, 31.6 mmol) and DCM (300 mL) and cooled to 0 °C.

(Diethylamino)sulfur trifluoride (4.18 mL, 31.6 mmol, Matrix Scientific, Columbia, SC) was added, and after 10 min, the reaction was diluted with water (250 mL) and DCM (200 mL). The organic layer was separated, dried over

Na2S04, filtered and concentrated under a vacuum. The resultant foam was taken up in DCM (200 mL) and cooled to 0 °C. TFA (100 mL, 1298 mmol) was added and the reaction mixture was warmed to rt for 1.5 h. The reaction was then re-cooled to 0 °C and solid sodium bicarbonate was added slowly until gas evolution ceased. The mixture was diluted with water (250 mL) and DCM (300 mL) and the organic layer was separated, dried over Na2S04, filtered and concentrated under a vacuum to give a solid that was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to afford 5-(((3S)-3-(l-propyn- 1 -yl)-4-(4-( 1 ,2,2,2-tetrafluoro- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinamine (11.05 g) as a single enantiomer.

1H NMR (400MHz, CD3OD) δ ppm 8.31 (d, J= 2.2 Hz, 1 H), 7.74 (dd, J= 2.4, 8.9 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 9.0 Hz, 2 H), 6.63 (d, J= 8.8 Hz, 1 H), 4.76-4.70 (m, 1 H), 3.76 (dd, J= 1.9, 11.2 Hz, 2 H), 3.66 – 3.52 (m, 1 H), 3.29 – 3.20 (m, 1 H), 2.79 – 2.72 (m, 1 H), 2.66 – 2.53 (m, 1 H), 1.76 (d, J = 2.2 Hz, 3 H). m/z (ESI, +ve ion) 525.2 (M+H)+. GK-GKRP IC50 (Binding) = 0.187 μΜ.

PAPER

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

Department of Therapeutic Discovery—Medicinal Chemistry, Department of Therapeutic Discovery—Molecular Structure and Characterization, §Department of Metabolic Disorders, Department of Pharmacokinetics and Drug Metabolism, Department of Pathology, #Department of Pharmaceutics Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California, 91320 and 360 Binney Street, Cambridge, Massachusetts, 02142, United States
J. Med. Chem., 2014, 57 (2), pp 325–338
DOI: 10.1021/jm4016747
Abstract Image

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

2-(4-((2S)-4-((6-Amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (27)

1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.3 Hz, 1 H), 7.77 (dd, J = 2.5, 8.8 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 2 H), 6.95 (d, J = 9.2 Hz, 2 H), 6.52 (d, J = 8.8 Hz, 1 H), 4.94 (s, 2 H), 4.44 (br s, 1 H), 3.82–3.71 (m, 2 H), 3.58–3.33 (m, 3 H), 2.81 (dd, J = 3.2, 11.1 Hz, 1 H), 2.67 (dt, J = 3.9, 11.0 Hz, 1 H), 1.78 (d, J = 2.2 Hz, 3 H).
m/z (ESI, +ve ion) 523.2 (M + H)+.
REFERENCES
St Jean, D.J. Jr.; Ashton, K.; Andrews, K.; et al.
Small molecule disruptors of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction
34th Natl Med Chem Symp (May 18-21, Charleston) 2014, Abst 4
Small molecule disruptors of the GK-GKRP interaction as potential antidiabetics
247th Am Chem Soc (ACS) Natl Meet (March 16-20, Dallas) 2014, Abst MEDI 214
Use of non-traditional conformational restriction in the design of a novel, potent, and metabolically stable series of GK-GKRP inhibitors
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 267
Small molecule inhibitors for glucokinase-glucokinase regulatory protein (GK-GKRP) binding: Optimization for in vivo target assessment of type II diabetes
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 268

MAKING CONNECTIONS Aleksandra Baranczak (right), a fourth-year grad student in Gary A. Sulikowski’s lab at Vanderbilt University, discusses her efforts to synthesize the core of the diazo-containing natural product lomaiviticin A with Kate Ashton, a medicinal chemist at Amgen
Dr. Kate Ashton

Mark Norman

Mark Norman

Michael Bartberger

Michael Bartberger

Chris Fotsch

Chris Fotsch

David St. Jean

David St. Jean

Klaus Michelsen

Klaus Michelsen

///////////1361224-53-4, AMGEN, AMG 3969, Type 2 Diabetes,  PRECLINICAL
O=S(=O)(c1ccc(N)nc1)N2C[C@H](C#CC)N(CC2)c3ccc(cc3)C(O)(C(F)(F)F)C(F)(F)F

Hoshinolactam, A new antitrypanosomal lactam


Abstract Image
Tropical diseases caused by parasitic protozoa are a threat to human health, mainly in developing countries. Trypanosomiasis (Chagas disease and sleeping sickness) and leishmaniasis, inter alia, are classified as neglected tropical diseases, and over 400 million people are at risk of contracting these diseases.

In addition, a parasite of the Trypanosoma genus, Trypanosoma brucei brucei, is the causative agent of Nagana disease in wild and domestic animals, and this disease is a major obstacle to the economic development of affected rural areas.

Although some therapeutic agents for these diseases exist, they have limitations, such as serious side effects and the emergence of drug resistance. Thus, new and more effective antiprotozoal medicines are needed

Marine natural products have recently been considered to be good sources for drug leads. In particular, secondary metabolites produced by marine cyanobacteria have unique structures and versatile biological activities, and some of these compounds show antiprotozoal activities. For example, coibacin A isolated from cf. Oscillatoria sp. exhibited potent antileishmanial activity, and viridamide A isolated from Oscillatoria nigro-viridis showed antileishmanial and antitrypanosomal activities.

constituents of marine cyanobacteria and reported an antitrypanosomal cyclodepsipeptide, janadolide.

The marine cyanobacterium was collected at the coast near Hoshino, Okinawa.

Image result for OKINAWA

Image result for OKINAWA

Okinawa
沖縄市
Uchinaa
City
Okinawa City downtown.jpg
Flag of Okinawa
Flag

EARLIER MERCK TEAM HAD REPORTED

CAS 159153-15-8
MF C20 H33 N O5
MW 367.48
2-Pyrrolidinone, 3,4-dihydroxy-5-(hydroxymethyl)-3-[3-(2-nonylcyclopropyl)-1-oxo-2-propenyl]-, [3S-[3α,3[E(1S*,2S*)],4β,5α]]-
Image result for AntitrypanosomalImage result for Antitrypanosomal
Antitrypanosomal
Image result for marine cyanobacterium
Marine cyanobacterium
Image result for human fetal lung fibroblast MRC-5 cells
Human fetal lung fibroblast MRC-5 cells
Majusculoic acid.png
Majusculoic acid
Image result for malyngamide A.
Malyngamide A.

PAPER

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b00047

Recently, we isolated a new antitrypanosomal lactam, hoshinolactam (1), from a marine cyanobacterium.Structurally, 1 contains a cyclopropane ring and a γ-lactam ring. So far, some metabolites possessing either a cyclopropane ring or a γ-lactam ring have been discovered from marine cyanobacteria, such as majusculoic acid and malyngamide A. To the best of our knowledge, on the other hand, hoshinolactam (1) is the first compound discovered in marine cyanobacteria that possesses both of these ring systems. In addition, we clarified that 1 exhibited potent antitrypanosomal activity without cytotoxicity against human fetal lung fibroblast MRC-5 cells. Here, we report the isolation, structure elucidation, first total synthesis, and preliminary biological characterization of hoshinolactam (1).

Isolation and Total Synthesis of Hoshinolactam, an Antitrypanosomal Lactam from a Marine Cyanobacterium

Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
Research Center for Tropical Diseases, Kitasato Institute for Life Sciences, and §Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
Org. Lett., Article ASAP
DOI: 10.1021/acs.orglett.7b00047

Abstract Image

In the search for new antiprotozoal substances, hoshinolactam, an antitrypanosomal lactam, was isolated from a marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configuration was determined by the first total synthesis. Hoshinolactam showed potent antitrypanosomal activity with an IC50 value of 3.9 nM without cytotoxicity against human fetal lung fibroblast MRC-5 cells (IC50 > 25 μM).

Table 1. 1H and 13C NMR Data for 1 in C6D6
unit position δCa δHb (J in Hz)
HIMP 1 177.8, C
2 44.1, CH 2.51, dq (5.2, 7.6)
3 80.8, CH 4.94, dd (4.6, 5.2)
4 57.3, CH 3.49, ddd (4.6, 4.7, 9.4)
5a 44.6, CH2 1.21, m
5b 1.36, m
6 25.0, CH 1.61, m
7 21.7, CH3 0.74, d (6.2)
8 23.2, CH3 0.76, d (6.3)
9 15.0, CH3 1.33, d (7.6)
NH 7.65, s
PCPA 1 166.0, C
2 117.4, CH 5.88, d (15.5)
3 155.0, CH 6.59, dd (10.3, 15.5)
4 22.4, CH 0.91, m
5 23.3, CH 0.59, m
6 35.7, CH2 0.96, m
7 22.5, CH2 1.20, tq (7.1, 7.3)
8 14.0, CH3 0.78, t (7.3)
9a 16.1, CH2 0.35, ddd (4.5, 6.0, 8.2)
9b 0.42, ddd (4.5, 4.5, 8.8)
aMeasured at 100 MHz.
bMeasured at 400 MHz.
Positive HRESIMS data (m/z 308.2228, calcd for C18H30NO3 [M + H]+ 308.2225). Table 1 shows the NMR data for 1.
An analysis of the 1H NMR spectrum indicated the presence of four methyl groups (δH 0.74, 0.76, 0.78 and 1.33), four protons of the cyclopropane ring (δH 0.35, 0.42, 0.59 and 0.91), and two olefinic protons (δH 5.88 and 6.59).
The 13C NMR and HMQC spectra revealed the existence of two carbonyl groups (δC 166.0 and 177.8) and two sp2 methines (δC 117.4 and 155.0).
Examination of the COSY and HMBC spectra established the presence of two fragments derived from 4-hydroxy-5-isobutyl-3-methylpyrrolidin-2-one (HIMP) and 3-(2-propylcyclopropyl) acrylic acid (PCPA), respectively. The configuration of the C-2–C-3 olefinic bond in the PCPA was determined to be trans on the basis of the coupling constant (3JH2–H3 = 15.5 Hz). The connectivity of the two partial structures was determined from the HMBC correlation (H-3 of HIMP/C-1 of PCPA).
1H, 13C, COSY, HMQC, HMBC, and NOESY NMR spectra in C6D6 and 1H and 13C NMR spectra in CD3OD for hoshinolactam (1)
1H, 13C, COSY, HMQC, HMBC, and NOESY NMR spectra in C6D6

1H and 13C NMR spectra in CD3OD

1H NMR PREDICT

13 C NMR PREDICT

Image result for OKINAWAImage result for OKINAWA

OKINAWA

///////////Hoshinolactam

CC(C)C[C@@H]2NC(=O)[C@H](C)C2OC(=O)/C=C/[C@H]1C[C@@H]1CCC


Pridopidine.svg

Pridopidine

  • Molecular Formula C15H23NO2S
  • Average mass 281.414 Da
346688-38-8  CAS FREE FORM
882737-42-0 (hydrochloride)
1440284-30-9 HBr
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidin
4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
ACR16
Huntexil
UNII-HD4TW8S2VK;
4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine
ACR 16
  • ASP 2314
FR 310826

Huntingtons chorea

Dopamine D2 receptor antagonist; Opioid receptor sigma agonist 1

Neurosearch INNOVATORS, In 2012, the product was acquired by Teva

In January 2017, pridopidine was reported to be in phase 3 clinical development,  pridopidine for treating or improving cognitive functions and Alzheimer’s disease.

Teva Pharmaceutical Industries, following an asset acquisition from NeuroSearch, is developing pridopidine, a fast-off dopamine D2 receptor antagonist that strengthens glutamate function, for treating HD.
The drug holds orphan drug designation in the U.S. and the E.U. for the treatment of Huntington’s disease

PRIDOPIDINE.png

About Huntington Disease

HD is a fatal neurodegenerative disease for which there is no known cure or prevention. People who suffer from HD will likely have a variety of steadily-worsening symptoms, including uncoordinated and uncontrolled movements, cognition and memory deterioration and a range of behavioral and psychological problems. HD symptoms typically start in middle age, but the disease may also manifest itself in childhood and in old age. Disease progression is characterized by a gradual decline in motor control, cognition and mental stability, and generally results in death within 15 to 25 years of clinical diagnosis. Current treatment is limited to managing the symptoms of HD, as there are no treatments that have been shown to alter the progression of HD. Studies estimate that HD affects about 13 to 15 people per 100,000 in Caucasians, and for every affected person there are approximately three to five people who may carry the mutation but are not yet ill.

Image result for Pridopidine

Pridopidine, also known as ACR16, is a dopamine stabilizer, which improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD.

Figure

Dopamine D2 ligands. Dopamine D2 receptor agonists dopamine (1) and apomorphine (2), classical antagonists haloperidol (3) and olanzapine (4), partial agonists (−)-3-(3-hydroxyphenyl)-Nn-propylpiperidine (5), bifeprunox (6), aripiprazole (7), and 3-(1-benzylpiperidin-4-yl)phenol (9a), and dopaminergic stabilizers S-(−)-OSU6162 (8) and pridopidine (12b).

Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopa-mine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson’s disease and schizophrenia. Currently available dopaminer-gic pharmaceuticals have severe side effects, such as ex-trapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti -Parkinson ‘ s agents. Therapeutic effects are un-satisfactory in many respects. To improve efficacy and reduce side effects of dopaminergic pharmaceuticals, novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for. In this context, also partial dopamine receptor agonists, i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive do-pamine receptor blockade or excessive stimulation.
Compounds belonging to the class of substituted 4- (phenyl-N-alkyl) -piperazine and substituted 4-(phenyl-N-alkyl) -piperidines have been previously reported. Among these compounds, some are inactive in the CNS, some dis-play serotonergic or mixed serotonergic/dopaminergic pharmacological profiles while some are full or partial dopamine receptor agonists or antagonists with high affinity for dopamine receptors.
A number of 4-phenylpiperazines and 4 -phenyl -piperidine derivatives are known and described, for example Costall et al . European J. Pharm. 31, 94, (1975), Mewshaw et al . Bioorg. Med. Chem. Lett., 8, 295, (1998). The reported compounds are substituted 4 -phenyl -piperazine ‘ s, most of them being 2-, 3- or 4 -OH phenyl substituted and displaying DA autoreceptor agonist properties .
Fuller R. W. et al , J. Pharmacol. Exp . Therapeut . 218, 636, (1981) disclose substituted piperazines (e.g. 1- (m-trifluoro-methylphenyl) piperazine) which reportedly act as serotonin agonists and inhibit serotonin uptake.

Fuller R. W. et al , Res. Commun. Chem. Pathol . Pharmacol. 17, 551, (1977) disclose the comparative effects on the 3 , 4-dihydroxy-phenylacetic acid and Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the compara-tive effects on the 5-hydroxyindole acetic acid concentration in rat brain by 1- (p-chlorophenol) -piperazine .
Boissier J. et al Chem Abstr. 61:10691c, disclose disubstituted piperazines. The compounds are reportedly adrenolytics, antihypertensives , potentiators of barbitu-rates, and depressants of the central nervous system.
A number of different substituted piperazines have been published as ligands at 5-HT1A receptors, for example Glennon R.A. et al J. Med. Chem., 31, 1968, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. et al, Arch. Pharm. (Weinheim) 328, 143-148 (1995), and Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R. A. discloses, in international patent applications WO93/00313 and WO 91/09594 various amines, among them substituted piperazines, as sigma receptor ligands. Clinical studies investigating the properties of sigma receptor ligands in schizophrenic patients have not generated evi-dence of antipsychotic activity, or activity in any other CNS disorder. Two of the most extensively studied selective sigma receptor antagonists, BW234U (rimcazole) and BMY14802, have both failed in clinical studies in schizophrenic patients (Borison et al , 1991, Psychopharmacol Bull 27(2): 103-106; Gewirtz et al , 1994, Neuropsycho-pharmacology 10:37-40) .
Further, WO 93/04684 and GB 2027703 also describe specific substituted piperazines useful in the treatment of CNS disorders

Pridopidine (Huntexil, formerly ACR16) is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. These compounds may counteract the effects of excessive or insufficient dopaminergic transmission,[1][2] and are therefore under investigation for application in neurological and psychiatric disorders characterized by altered dopaminergic transmission, such as Huntington’s disease (HD).

Pridopidine is in late-stage development by Teva Pharmaceutical Industries who acquired the rights to the product from its original developer NeuroSearch in 2012. In April 2010, NeuroSearch announced results from the largest European phase 3 study in HD carried out to date (MermaiHD). The MermaiHD study examined the effects of pridopidine in patients with HD and the results showed after six months of treatment, pridopidine improved total motor symptoms, although the primary endpoint of the study was not met. Pridopidine was well tolerated and had an adverse event profile similar to placebo.[3]

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both indicated they will not issue approval for pridopidine to be used in human patients on the basis of the MermaiHD and HART trials, and a further, positive phase 3 trial is required for approval.[4][5]

Image result for Pridopidine

Dopidines

Dopidines, a new class of pharmaceutical compounds, act as dopaminergic stabilizers, enhancing or counteracting dopaminergic effects in the central nervous system.[1][2] They have a dual mechanism of action, displaying functional antagonism of subcortical dopamine type 2 (D2) receptors, as well as strengthening of cortical glutamate and dopamine transmission.[6] Dopidines are, therefore, able to regulate both hypoactive and hyperactive functioning in areas of the brain that receive dopaminergic input (i.e. cortical and subcortical regions). This potential ability to restore the cortical–subcortical circuitry to normal suggests dopidines may have the potential to improve symptoms associated with several neurological and psychiatric disorders, including HD.

SYNTHESIS

Figure

aReagents and conditions: (a) n-butyllithium, 1-Boc-4-piperidone, THF; (b) trifluoroacetic acid, CH2Cl2, Δ; (c) triethylamine, methyl chloroformate, CH2Cl2; (d) m-CPBA, CH2Cl2; (e) Pd/C, H2, MeOH, HCl; (f) HCl, EtOH, Δ; (g) RX, K2CO3, acetonitrile, Δ.

Pharmacology

In vitro studies demonstrate pridopidine exerts its effects by functional antagonism of D2 receptors. However, pridopidine possesses a number of characteristics[1][2][6][7] that differentiate it from traditional D2 receptor antagonists (agents that block receptor responses).

  • Lower affinity for D2 receptors than traditional D2 ligands[8]
  • Preferential binding to activated D2 (D2high) receptors (i.e. dopamine-bound D2 receptors)[8]
  • Rapid dissociation (fast ‘off-rate’) from D2 receptors
  • D2 receptor antagonism that is surmountable by dopamine
  • Rapid recovery of D2-receptor-mediated responses after washout[1][2][6][7]

Pridopidine is less likely to produce extrapyramidal symptoms, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless), than dopamine antagonists (such as antipsychotics).[9] Furthermore, pridopidine displays no detectable intrinsic activity,[9][10] differentiating it from D2 receptor agonists and partial agonists (agents that stimulate receptor responses). Pridopidine, therefore, differs from D2 receptor antagonists, agonists and partial agonists.[6]

As a dopaminergic stabilizer, pridopidine can be considered to be a dual-acting agent, displaying functional antagonism of subcortical dopaminergic transmission and strengthening of cortical glutamate transmission.

Clinical development

The MermaiHD study

In 2009, NeuroSearch completed the largest European HD trial to date, the Multinational EuRopean Multicentre ACR16 study In Huntington’s Disease (MermaiHD) study.

This six-month, phase 3, randomized, double-blind, placebo-controlled trial recruited patients from Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK, and compared two different pridopidine dose regimens with placebo. Patients were randomly allocated to receive pridopidine (45 mg once daily or 45 mg twice daily) or placebo. During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two doses (one morning and one afternoon dose) until the end of the treatment period. The study had a target recruitment of 420 patients; recruitment was finalized in April 2009 with 437 patients enrolled.[14]

The purpose of the study was to assess the effects of pridopidine on a specific subset of HD motor symptoms defined in the modified motor score (mMS).[14] The mMS comprises 10 items relating to voluntary motor function from the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS—TMS).[14] Other study endpoints included the UHDRS—TMS, submotor items, cognitive function, behaviour and symptoms of depression and anxiety.

After six months of treatment, patients who received pridopidine 45 mg twice daily showed significant improvements in motor function, as measured by the UHDRS-TMS, compared with placebo. For the mMS, which was the primary endpoint of the study, a strong trend in treatment effect was seen, although statistical significance was not reached. Pridopidine was also very well tolerated, had an adverse event profile similar to placebo and gave no indication of treatment-associated worsening of symptoms.[3]

The MermaiHD study – open-label extension

Patients who completed the six-month, randomized phase of the MermaiHD study could choose to enter the MermaiHD open-label extension study and receive pridopidine 45 mg twice daily for six months. In total, 357 patients were enrolled into the MermaiHD open-label extension study and of these, 305 patients completed the entire 12-month treatment period.[15]

The objective of this study was to evaluate the long-term safety and tolerability profile of pridopidine and to collect efficacy data after a 12-month treatment period to support the safety evaluation. Safety and tolerability assessments included the incidence and severity of adverse events, routine laboratory parameters, vital signs and electrocardiogram measurements.[15]

Results from the MermaiHD open-label extension study showed treatment with pridopidine for up to 12 months (up to 45 mg twice daily for the first six months; 45 mg twice daily for the last six months) was well tolerated and demonstrated a good safety profile.[3][15]

The HART study

In October 2010, NeuroSearch reported results from their three-month, phase 2b, randomized, double-blind, placebo-controlled study carried out in Canada and the USA – Huntington’s disease ACR16 Randomized Trial (HART). This study was conducted in 28 centres and enrolled a total of 227 patients, who were randomly allocated to receive pridopidine 10 mg, 22.5 mg or 45 mg twice daily) or placebo.[14][16] During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two treatment doses (one morning and one afternoon dose) until the end of the treatment period. Study endpoints were the same as those for the MermaiHD study.

Results from the HART study were consistent with findings from the larger MermaiHD study. After 12 weeks of treatment with pridopidine 45 mg twice daily, total motor function significantly improved, as measured by the UHDRS–TMS. The primary endpoint, improvement in the mMS, was not met.[16]

In both studies, the effects on the UHDRS–TMS and the mMS were driven by significant improvements in motor symptoms such as gait and balance, and hand movements, deemed by the authors to be “clinically relevant”. However, the magnitude of the improvements was small. Pridopdiine demonstrated a favourable tolerability and safety profile, including no observations of treatment-related disadvantages in terms of worsening of other disease signs or symptoms.[15][16]

Compassionate use programme and open-ended, open-label study

To meet requests from patients and healthcare professionals for continued treatment with pridopidine, NeuroSearch has established a compassionate use programme in Europe to ensure continued access to pridopidine for patients who have completed treatment in the MermaiHD open-label extension study. The programme is active in all of the eight European countries where the MermaiHD study was conducted.

NeuroSearch has initiated an open-ended, open-label clinical study in the USA and Canada, called the Open HART study. In this study, all patients who have completed treatment in the HART study are offered the chance to restart treatment with pridopidine until either marketing approval has been obtained in the countries in question, or the drug’s development is discontinued. The first patients were enrolled in March 2011.[3]

Regulatory agency advice

The results of the MermaiHD and HART trials were presented to the American and European regulatory agencies: the FDA in March 2011 and EMA in May, 2011. Both agencies indicated insufficient evidence had been produced to allow approval in human patients, and a further phase 3 trial would be required for approval.[4][5]

PATENT

WO 2001046145

Example 6: 4- (3 -Methanesulfonyl-phenyl ) – 1-propyl -piperidine
m.p. 200°C (HCl) MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp) , 129 (20), 115 (20), 70 (25.

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2510-2520.

Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16)

NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Göteborg, Sweden
J. Med. Chem., 2010, 53 (6), pp 2510–2520
DOI: 10.1021/jm901689v
*To whom correspondence should be addressed. Phone: +(46) 31 7727710. Fax: +(46) 31 7727701. E-mail: fredrik.pettersson@neurosearch.se.

Abstract

Abstract Image

Modification of the partial dopamine type 2 receptor (D2) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D2 antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D2 in vitro, without displaying properties essential for interaction with D2 in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D2 antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D2 antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The “agonist-like” kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D2 antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique “dopaminergic stabilizer” characteristics, differentiating 12b from D2 antagonists and partial D2agonists.

4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (12b)

Purification with flash chromatography using CH2Cl2/MeOH [1:1 (v/v)] as eluent afforded pure 12b (3.28 g, 79%).
MS m/z (relative intensity, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25).
1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.
The amine was converted to the HCl salt and recrystallized in EtOH/diethyl ether: mp 212−214 °C. Anal. (C15H24ClNO2S) C, H, N.

PATENT

WO-2017015609

Pridopidine (Huntexil®) is a unique compound developed for the treatment of patients with motor symptoms associated with Huntington’s disease. The chemical name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-l-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSED:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459. U.S. Patent No. 6,903,120 claims pridopidine for the treatment of Parkinson’s disease, dyskinesias, dystonias, Tourette’s disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington’s disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

US Patent Application Publication Nos. 20140378508 and 20150202302, describe methods of treatment with high doses of pridopidine and modified release formulations of pridopidine, respectively.

EXAMPLES

Example 1: Pridopidine-HCl synthesis

An initial process for synthesizing pridopidine HC1 shown in Scheme 1 and is a modification of the process disclosed in US Patent No. 7,923,459.

The synthesis of Compound 9 started with the halogen-lithium exchange of 3-bromothioanisole (3BTA) in THF employing n-hexyllithium (HexLi) in hexane as the lithium source. Li-thioanisole (3LTA) intermediate thus formed was coupled with 1 -propyl-4-piperidone (1P4P) forming a Li-Compound 9. These two reactions require low (cryogenic) temperature. The quenching of Li-Compound 9 was done in water HCl/MTBE resulting in precipitation of Compound 9-HCl salt. A cryogenic batch mode process for this step was developed and optimized. The 3BTA and THF were cooled to less than -70°C. A solution of HexLi in n-hexane (33%) was added at a temperature below -70°C and the reaction is stirred for more than 1 hour. An in-process control sample was taken and analyzed for completion of halogen exchange, l-propyl-4-piperidone (1P4P) was then added to the reaction at about -70°C letting the reaction mixture to reach -40°C and further stirred at this temperature for about 1 hour. An in-process sample was analyzed to monitor the conversion according to the acceptance criteria (Compound 9 not less than 83% purity). The reaction mixture was added to a mixture of 5N hydrochloric acid (HC1) and methyl teri-butyl ether (MTBE). The resulting precipitate was filtered and washed with MTBE to give the hydrochloric salt of Compound 9 (Compound 9-HCl) wet.

Batch mode technique for step 1 requires an expensive and high energy-consuming cryogenic system that cools the reactor with a methanol heat exchange, in which the methanol is circulated in counter current liquid nitrogen. This process also brings about additional problems originated from the workup procedure. The work-up starts when the reaction mixture is added into a mixture of MTBE and aqueous HC1. This gives three phases: (1) an organic phase that contains the organic solvents MTBE, THF and hexane along with other organic related materials such as thioanisole (TA), hexyl-bromide,

3-hexylthioanisole and other organic side reaction impurities (2) an aqueous phase containing inorganic salts (LiOH and LiBr), and (3) a solid phase which is mostly Compound 9-HCl but also remainders of 1P4P as an HC1 salt.

The isolation of Compound 9-HCl from the three phase work-up mixture is by filtration followed by MTBE washings. A major problem with this work-up is the difficulty of the filtration which resulted in a long filtration and washing operations. The time it takes to complete a centrifugation and washing cycle is by far beyond the normal duration of such a manufacturing operation. The second problem is the inevitable low and non-reproducible assay (purity of -90% on dry basis) of Compound 9-HCl due to the residues of the other two phases. It should be noted that a high assay is important in the next step in order to control the amount of reagents. The third problem is the existence of THF in the wet Compound 9-HCl salt which is responsible for the Compound 3 impurity that is discussed below.

Example 6.2: Pridopidine crude – work-up development

After the reduction, pridopidine HC1 is precipitated by adding HC1/IPA to the solution of pridopidine free base in ΓΡΑ in the process of Example 1. Prior to that, a solvent swap from toluene to ΓΡΑ is completed by 3 consecutive vacuum distillations. The amount of toluene in the ΓΡΑ solution affects the yield and it was set to be not more than 3% (IPC by GC method). The spontaneous precipitation produces fine crystals with wide PSD. In order to narrow the PSD, Example 1 accomplishes HC1/IPA addition in two cycles with cooling/warming profile.

The updated process is advantageous for crystallizing pridopidine free base over the procedure in Example 1 for two reasons.

First, it simplifies the work-up of the crude because the swap from toluene to PA is not required. The pridopidine free base is crystallized from toluene/n-heptanes system. Only one vacuum distillation of toluene is needed (compared to three in the work-up of Example 1) to remove water and to increase yield.

Second, in order to control pridopidine-HCl physical properties. Pridopidine free base is a much better starting material for the final crystallization step compared to the pridopidine HC1 salt because it is easily dissolved in ΓΡΑ which enables a mild absolute (0.2μ) filtration required in the final step of API manufacturing.

Crystallization of pridopidine free base in toluene/n-heptane system

First, crystallization of pridopidine free base in toluene/n-heptane mixture was tested in order to find the right ratio to maximize the yield. In order to obtain pridopidine free base, pridopidine-HCl in water/toluene system was basified with NaOH(aq) to pH>12. Two more water washes of the toluene phase brought the pH of the aqueous phase to <10. Addition of n-heptane into the toluene solution

resulted in pridopidine free base precipitation. Table 21 shows data from the toluene/n-heptane crystallization experiments.

Example 7: Development of the procedure for the purification of Compound 1 in pridopidine free base.

The present example describes lowering Compound 1 levels in pridopidine free base. This procedure involves dissolving pridopidine FB in 5 Vol of toluene at 20-30°C, 5 Vol of water are added and after the mixing phases are separated and the organic phase is washed three times with 5 Vol water. The toluene mixture is then distilled up to 2.5 Vol in the reactor and 4 Vol of heptane are added for crystallization. Experiment No. 2501 was completed using this procedure. Table 24 summarizes the results.

Example 8: Step 4 in Scheme 2: Pridopidine Hydrochloride process

This example discusses the step used to formulate pridopidine-HCl from pridopidine crude. The corresponding stage in Example 1 was part of the last (third) stage in which pridopidine-HCl was obtained directly from Compound 8 without isolation of pridopidine crude. In order to better control pridopidine-HCl physical properties, it is preferable to start with well-defined pridopidine free base which enables control on the exact amount of HC1 and IPA.

Pridopidine-HCl preparation – present procedure

Pridopidine-HCl was prepared according to the following procedure: Solid pridopidine crude was charged into the first reactor followed by 8 Vol of IPA (not more than (NMT) 0.8% water by KF) and the mixture is heated to Tr =40-45°C (dissolution at Tr = 25-28°C). The mixture was then filtered through a 0.2 μιη filter and transferred into the second (crystallizing) reactor. The first hot reactor was washed with 3.8 Vol of IPA. The wash was transferred through the filter to the second reactor. The temperature was raised to 65-67°C and 1.1 eq of IPA/HCl are added to the mixture (1.1 eq of HC1, from IPA/HCl 5N solution, 0.78 v/w). The addition of EPA HCl into the free base is exothermic; therefore, it was performed slowly, and the temperature maintained at Tr = 60-67°C. After the addition, the mixture was stirred for 15 min and pH is measured (pH<4). If pH adjustment is needed,

0.2 eq of HCl (from IPA/HC1 5 N solution) is optional. At the end of the addition, the mixture was stirred for 1 hour at Tr = 66°C to start sedimentation. If sedimentation does not start, seeding with 0.07% pridopidine hydrochloride crystals is optional at this temperature. Breeding of the crystals was performed by stirring for 2.5 h at Tr =64-67°C. The addition HCl line was washed with 0.4 Vol of ΓΡΑ to give~13 Vol solution. The mixture was cooled to Tr =0°C The solid is filtered and washed with cooled 4.6 Vol ΓΡΑ at LT 5°C. Drying as performed under vacuum (P< ) at 30-60°C to constant weight: Dried pridopidine-HCl was obtained as a white solid.

Purification of Compound 4 during pridopidine-HCl process

A relationship between high temperature in the reduction reaction and high levels of Compound 4 impurity have been observed. A reduction in 50°C leads to 0.25% of Compound 4. For that reason the process of Example 1 limits the reduction reaction temperature to 30±5°C since this is the final step and Compound 4 level should be not more than 0.15%. The present process has another crystallization stage by which Compound 4 can be purified.

PATENT

https://www.google.ch/patents/US20130150406

Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, is a drug substance currently in clinical development for the treatment of Huntington’s disease. The hydrochloride salt of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine and a method for its synthesis is described in WO 01/46145. In WO 2006/040155 an alternative method for the synthesis of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine is described. In WO 2008/127188 N-oxide and/or di-N-oxide derivatives of certain dopamine receptor stabilizers/modulators are reported, including the 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine-1-oxide.

1H NMR PREDICTIONS

ACTUAL VALUES

1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J = 7.3 Hz, 3 H), 1.53−1.64 (m, 2 H), 1.89 (dd, J = 9.6, 3.54 Hz, 4 H), 2.03−2.14 (m, 2 H), 2.31−2.41 (m, 2 H), 2.64 (ddd, J = 15.4, 5.7, 5.5 Hz, 1 H), 3.06−3.15 (m, 5 H), 7.51−7.58 (m, 2 H), 7.78−7.86 (m, 2 H).
 
13C NMR (75 MHz, CDCl3) δ ppm 11.98, 20.18, 33.29, 42.59, 44.43, 54.06, 60.93, 124.99, 125.74, 129.39, 132.04, 148.28.

13C NMR PREDICTIONS

References

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REFERENCES CITED:

U.S. Patent No. 6,903,120

U.S. Patent No. 7,923,459

U.S. Publication No. US-2013-0267552-A1

CSED:25948790, http://w .chemspider.com/Chernical-Stmcture.25948790.

CSID:7971505, http://ww.chemspider.com/Chermcal-Stmcture.7971505.html

Ebenezer et al, Tetrahedron Letters 55 (2014) 5323-5326.

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Pridopidine
Pridopidine.svg
Names
IUPAC name

4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine
Identifiers
346688-38-8 Yes
3D model (Jmol) Interactive image
ChemSpider 7971505 
KEGG D09953 
PubChem 9795739
UNII HD4TW8S2VK Yes
Properties
C15H23NO2S
Molar mass 281.41 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////pridopidine, PHASE 3, TEVA, 346688-38-8, orphan drug designation, Neurosearch, ACR16, Huntexil, ASP 2314, FR 310826, UNII-HD4TW8S2VK

CCCN1CCC(CC1)c2cccc(c2)S(C)(=O)=O

OXIDE

Example 5 – Preparation Of Compound 5 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine 1-oxide)

Pridopidine (50.0g, 178mmol, leq) was dissolved in methanol (250mL) and 33% hydrogen peroxide (20mL, 213mmol, 1.2eq). The reaction mixture was heated and kept at 40°C for 20h. The reaction mixture was then concentrated in a rotavapor to give 71g light-yellow oil. Water (400mL) was added and the suspension was extracted with isopropyl acetate (150mL) which after separation contains unreacted pridopidine while water phase contains 91% area of Compound 5 (HPLC). The product was then washed with dichloromethane (400mL) after adjusting the water phase pH to 9 by sodium hydroxide. After phase separation the water phase was washed again with dichloromethane (200mL) to give 100% area of Compound 5 in the water phase (HPLC). The product was then extracted from the water phase into butanol (lx400mL, 3x200ml) and the butanol phases were combined and concentrated in a rotavapor to give 80g yellow oil (HPLC: 100% area of Compound 5). The oil was washed with water (150mL) to remove salts and the water was extracted with butanol. The organic phases were combined and concentrated in a rotavapor to give 43g of white solid which was suspended in MTBE for lhr, filtered and dried to give 33g solid that was melted when standing on air. After high vacuum drying (2mbar, 60°C, 2.5h) 32.23g pure Compound 5 were obtained (HPLC: 99.5% area, 1H-NMR assay: 97.4%).

NMR Identity Analysis of Compound 5

Compound 5:

The following data in Tables 10 and 11 was determined using a sample of 63.06 mg Compound 5, a solvent of 1.2 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΙΠ 400 MHz.

Table 10: Assignment of ¾ NMRa,c

a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.

b Weak signal.

c Spectra is calibrated by the solvent residual peak (2.5 ppm).

Table 11: Assignment of 13C NMRa,b

a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.

b Spectra is calibrated by a solvent peak (39.54 ppm)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016003919&recNum=5&docAn=US2015038349&queryString=EN_ALL:nmr%20AND%20PA:(teva%20pharmaceutical)&maxRec=677#H3

PATENT

http://www.google.bg/patents/WO2013086425A1?cl=en&hl=bg

Preparation of pridopidine HBr

In order to prepare 33 g of pridopidine HBr, 28.5 g of free base was dissolved in 150 ml 99% ethanol at room temperature. 1 .5 equivalents of hydrobromic acid 48% were added. Precipitation occurred spontaneously, and the suspension was left in refrigerator for 2.5 hours. Then the crystals were filtered, followed by washing with 99% ethanol and ether. The crystals were dried over night under vacuum at 40°C: m.p. 196°C. The results of a CHN analysis are presented in Table 2, below.

NMR 1 H NMR (DMSO-d6): 0.93 ( 3H, t), 1 .68-1 .80 ( 2H, m), 1 .99-2.10 ( 4H, m) 2.97-3.14 (5H, m), 3.24 ( 3H, s), 3.57-3.65 ( 2H, d), 7.60-7.68 (2H, m), 7.78-7.86 ( 2H, m) and 9.41 ppm (1 H, bs).

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