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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4


Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4

Ahmedabad, February 24, 2017

Zydus Cadila, a research-driven, global healthcare provider has received approvals from the Drug Controller General of India (DCGI), Central Drugs Standard Control Organization (CDSCO) and the Central Drug Laboratory (CDL) to market the Tetravalent Inactivated Influenza vaccine for seasonal flu, VaxiFlu – 4. With this, Zydus Cadila will become the first Indian pharma company and second in the world to launch a Tetravalent Inactivated Influenza vaccine. The vaccine provides protection from the four influenza viruses- H1N1, H3N2, Type B (Brisbane) and Type B (Phuket).

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VaxiFlu – 4 will be marketed by Zydus Vaxxicare – a division of the group focussing on preventives. The Tetravalent Inactivated Influenza vaccine has been developed at the Vaccine Technology Centre (VTC) in Ahmedabad which has proven capabilities in researching, developing, and manufacturing of safe and efficacious vaccines. The group was also the first to indigenously develop, manufacture and launch India’s first vaccine against H1N1 – Vaxiflu-S.

VTC further plans to develop a wide spectrum of vaccines against bacterial, viral and protozoal infections and has a robust pipeline of vaccines like Pentavalent (DTP-Hib-HepB), Conjugated Typhoid Vaccine, HPV, MMRV, Malaria and Hepatitis B vaccines. The group also markets the anti-rabies vaccine and the typhoid vaccine.

Speaking on the development Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “Disease prevention is the key to public health in both the developing and the developed world and vaccines have the potential to improve the quality of life in both spectrums. In countries such as India, there is a pressing need for low cost, high quality vaccines that can address healthcare challenges. With the launch of vaccines like VaxiFlu – 4 we are serving the cause of public health and meeting the twin challenge of affordability and accessibility.”

Influenza, or the “flu” as it is commonly called, is an infection of the respiratory tract. It is a dreaded disease and the morbidity and mortality rates associated with influenza are especially high during pandemics. Annually it is estimated that it attacks 5-10% of adults and 20-30% of children globally and causes significant levels of illness, hospitalization and death. In India, the 2009 swine flu pandemic infected more than 10 million people and resulted in more than 18000 deaths worldwide.

The last major outbreak in India occurred in 2015 with more than 33000 registered cases of influenza and over 2000 deaths. There are different strains of influenza viruses that infect human beings, the predominant ones being influenza A and influenza B. The common subtypes of influenza A found in general circulation amongst people are H1N1 (which was responsible for the devastating swine flu pandemic) and H3N2.

The subtypes of influenza B commonly found in circulation are influenza B (Brisbane – Victoria lineage) and influenza B (Phuket – Yamagata lineage). Vaccination against influenza is the most effective way to protect oneself against the dangers of influenza. Majority of the influenza vaccines available in India are inactivated trivalent influenza vaccines.

These vaccines provide protection against 2 strains of influenza A and 1 strain of influenza B. Protection against only 1 subtype of influenza B often leads to a vaccine mismatch i.e. the antigen of influenza B present in the trivalent vaccine may not match the influenza B subtype circulating during the season, leading to suboptimal protection. A quadrivalent vaccine, by virtue of having a comprehensive coverage against 2 strains of both influenza A and influenza B, provides a broader protection and significantly reduces the risk of vaccine mismatch. Vaxiflu – 4 is the first quadrivalent influenza vaccine in india.

About Zydus Zydus Cadila is an innovative, global pharmaceutical company that discovers, develops, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 19,500 people worldwide, including 1200 scientists engaged in R & D, and is dedicated to creating healthier communities globally. For more information, please visit http://www.zyduscadila.com

Zydus’ vaccine research programme The Vaccine Technology Centre (VTC) is the vaccine research centre of the Zydus Group. The group has two state-of-the-art R & D Centers, one located in Catania, Italy and the other in Ahmedabad, in the western part of India. The goup has been developing vaccines for the basic vaccine programmes such as Diphtheria, Pertussis, Tetanus, Haemophilus Influenzae type B, Hepatitis B, Measles, Mumps, Rubella, Varicella, Influenza and Typhoid fever. In addition, it is developing new vaccines such as Human Papilloma Virus, Leishmaniasis, Malaria, Haemorrhagic Congo Fever, Ebola and Japanese Encephalitis.

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Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4 Read more: https://goo.gl/xuSTfK #ZydusAnnouncement

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Image result for Trivalent Inactivated Influenza vaccine

///////////Zydus Cadila, Tetravalent Inactivated,  Influenza vaccine, VaxiFlu – 4

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Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC)


Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC) Read more: https://goo.gl/eugRnZ #ZydusAnnouncement

Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC)

Ahmedabad, India, February 23, 2017

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Zydus Cadila, a research-driven, global healthcare provider, today announced that the USFDA has approved the group’s plans to initiate a Phase 2 clinical trial of Saroglitazar Magnesium (Mg) in patients with Primary Biliary Cholangitis (PBC) of the liver. This randomized, double-blind Phase 2 trial will evaluate Saroglitazar Magnesium 2mg and 4 mg Vs. Placebo.

Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “We are very thankful to the USFDA for their timely and useful feedback on the clinical trial designs of Saroglitazar Mg in patients with Primary Biliary Cholangitis (PBC). This development underlines our commitment to bridging unmet healthcare needs with innovative therapies.”

Primary Biliary Cholangitis (PBC) is a liver disease, caused due to progressive destruction of the bile ducts in the liver which leads to reduction of bile flow – a condition referred to as cholestasis. PBC is often discovered incidentally due to abnormal results on routine liver blood tests. Progression of PBC leads to symptoms of cirrhosis like yellowing of the skin, swelling of legs and feet (edema), ascites, internal bleeding (varices) and thinning of the bones (osteoporosis). The buildup of toxic bile in the liver leads to liver inflammation and fibrosis which can progress to cirrhosis. People with cirrhosis are at increased risk of hepatocellular carcinoma or liver cancer, which is a leading cause of liver transplants or death.

With an increasing number of people being affected by PBC which can lead to progressive cholestasis and even turn fatal, there is a pressing need to develop therapies which help to achieve an adequate reduction in alkaline phosphotase (ALP) or bilirubin and bring in better tolerance and efficacy.

About Lipaglyn™ Lipaglyn™ is a prescription drug authorized for sale in India only. Lipaglyn™ was launched in India during Sept 2013 for the treatment of Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Saroglitazar Mg is an investigational new drug with the USFDA, and is currently under clinical investigation for three significant unmet medical needs in the United States – Primary Biliary Cholangitis (PBC), Non-alcoholic Steatohepatitis (NASH) and Severe Hypertriglyceridemia (TG>500).

About Zydus Zydus Cadila is an innovative, global healthcare provider that discovers, develops, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 19,500 people worldwide, including 1200 scientists engaged in R & D, and is dedicated to creating healthier communities globally. For more information, please visit http://www.zyduscadila.com

http://zyduscadila.com/wp-content/uploads/2017/02/USFDA-approval-for-clinical-trial-of-Saro-Mg.pdf

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Image result for Saroglitazar Magnesium

Saroglitazar magnesium
CAS: 1639792-20-3

Molecular Formula, 2C25-H28-N-O4-S.Mg,

Molecular Weight, 901.4354

Magnesium, bis((alphaS)-alpha-(ethoxy-kappaO)-4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)benzenepropanoato-kappaO)-, (T-4)-

(2S)-2-Ethoxy-3-(4-(2-(2-methyl-5-(4-(methylsulfanyl)phenyl)-1H-pyrrol-1-yl(ethoxy)phenyl)propanoic acid, magnesium salt (2:1)

Image result for RANJIT DESAI ZYDUS

DR RANJIT DESAI

ZYDUS

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//////////Zydus,  USFDA, Phase II,  clinical studies, Saroglitazar Magnesium,  Primary Biliary Cholangitis,  (PBC)

[Mg+2].CCO[C@@H](Cc1ccc(OCCn2c(C)ccc2c3ccc(SC)cc3)cc1)C(=O)[O-].CCO[C@@H](Cc4ccc(OCCn5c(C)ccc5c6ccc(SC)cc6)cc4)C(=O)[O-]

AZD 8931, Sapitinib,


AZD8931 (Sapitinib)Figure imgf000027_0003

AZD 8931, Sapitinib, SAPATINIB

PHASE 2, at AstraZeneca for the treatment of non-small cell lung cancer.

CAS 848942-61-0,

MF C23H25ClFN5O3, MW 473.9,

pan-EGFR/pan-erbB inhibitor

4-[[4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-methyl-1-piperidineacetamide

4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[[1-(N-methylcarbamoylmethyl)piperidin-4-yl] oxy]quinazoline

4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy]quinazoline

2-[4-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-N-methyl-acetamide

AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling.

WO 2005028469

Inventors Robert Hugh Bradbury, Laurent Francois Andre Hennequin, Bernard Christophe Barlaam
Applicant Astrazeneca Ab, Astrazeneca Uk Limited

Image resultDeregulation of the HER receptor family, comprising four related receptor tyrosine kinases (EGFR, HER2, HER3, and HER4), promotes proliferation, invasion, and tumor cell survival.Such deregulation has been observed in many human cancers, including lung, head and neck, and breast. Numerous small molecules have been investigated for inhibition of tyrosine kinases with the aminoquinazoline motif coming to the forefront as a privileged scaffold. Three of the clinically available treatments, gefitinib (1),lapatinib (2), and erlotinib (3),as well as the candidate drug dacomitinib (4), contain this arrangement

Figure

Figure 1. Structure of gefitinib (1), lapatinib (2), erlotinib (3), dacomitinib (4), and AZD8931 (5).

SYNTHESIS

PATENT

https://www.google.com/patents/WO2005028469A1?cl=en

PAPER

The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling
Bioorganic & Medicinal Chemistry Letters (2014), 24, (18), 4455-4459.

Image for unlabelled figure

Synthesis of the reference standard AZD8931 (11a) and its precursor ...

Synthesis of the reference standard AZD8931 (11a)

Reagents and conditions: (a) SnCl2·H2O, concd HCl; (b) formamide, 168–170 °C; (c) l-methionine, methanesulfonic acid, 120 °C; (d) Ac2O, pyridine, DMAP, 100 °C; (e) POCl3, DEA, 100 °C; (f) 3-chloro-2-fluoroaniline, i-PrOH, refluxing; (g) conc. NH3, MeOH; (h) (1) Boc2O, CH2Cl2, dioxane; (2) methanesulfonyl chloride, Et3N, CH2Cl2; (i) Compound 8, CsF, DMA, 85 °C; (j) TFA; (k) Compound 11a: 2-chloro-N-methylacetamide, KI, K2CO3, CH3CN, refluxing; compound

PAPER

Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
ACS Medicinal Chemistry Letters (2013), 4, (8), 742-746.

Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

Centre de Recherches, AstraZeneca, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France
Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Abstract Image

Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure–activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
(2). 2 as a white solid (60%).1H NMR (CDCl3):
δ 1.98 (m, 2H), 2.08 (m, 2H), 2.46 (m, 2H), 2.85 (m, 2H), 2.87 (d, 3H), 3.07 (s, 2H), 4.02 (s, 3H), 4.49 (m, 1H),
7.16 (m, 4H), 7.31 (m, 2H), 8.49 (m, 1H), 8.71 (s, 1H). MS-ESI m/z MH+ 474 [MH]+. Anal.
(C23H25ClFN5O3
.0.21 H2O) C, H, N. Found C, 57.88; H, 5.45; N, 14.67; Requires C, 57.83; H, 5.36; N, 14.66%.

PATENT

WO 2010122340

Compound (I) is disclosed in International Patent Application Publication number WO2005/028469 as Example 1 therein and is of the structure:

Figure imgf000002_0001

Compound (I)

Compound (I) is an erbB receptor tyrosine kinase inhibitor, in particular compound (I) is a potent inhibitor of EGFR and erbB2 receptor tyrosine kinases. Compound (I) also inhibits erbB3 mediated signalling through the inhibition of phosphorylation of erbB3 following ligand stimulated EGFR/erbB3 and/or erbB2/erbB3 heterodimerisation. Compound (I) is expected to be useful in the treatment of hyperproliferative disorders such as cancer.

WO 03/082831 discloses the preparation of various 4-(3-chloro-2- fluoroanilino)quinazo lines. However, compound (I) is not disclosed therein.

WO2005/028469 discloses as Example 1 therein the preparation of compound (I) as follows: 2-Chloro-N-methylacetamide (32 mg, 0.3 mmol) was added to a mixture of

4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol), potassium iodide (16 mg, 0.1 mmol), and potassium carbonate (50 mg, 0.36 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for one hour. After evaporation of the solvents under vacuum, the residue was taken up in dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 1% to 2% 7 N methanolic ammonia in dichloromethane) to give compound (I).

Scheme 1 :

Figure imgf000008_0001

Example 1 : Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)).

Compound (I) was prepared according to the scheme shown below:

Figure imgf000019_0001

Compound (III) Compound (IV)

Compound (V)

Figure imgf000019_0002

Compound (I)Compound (II)

Step 1. Preparation of tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-l- carboxylate (Intermediate 2). 3-hydroxy-4-methoxybenzonitrile (Compound (X), 6.00 g, 39.62 mmole), tert-butyl (4-methanesulfonyloxy)piperidine-l-carboxylate (16.6 g, 59.44 mmoles) (Chemical & Pharmaceutical Bulletin 2001, 49(7), 822-829); and potassium carbonate (6.71 g, 47.55 mmoles) were suspended in isopropanol (78.98 g) and the mixture was heated at reflux with stirring. Additional tert-butyl (4-methanesulfonyloxy)piperidine-l- carboxylate (2.08 g, 7.43 mmoles) was added to push the reaction to completion. The mixture was then cooled and quenched by the addition of water (100.47 g). Seeding with intermediate 2 followed by cooling to 00C resulted in a crystalline product, which was isolated by filtration. The filter cake was washed with a mixture of water (8.86 g) and isopropanol (6.97 g), followed by water (23.64 g) and then dried to give Intermediate 2 (10.75 g, 80% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 1.48 (m, 2 H) 1.88 (m, 2 H) 3.13 (m, 2 H) 3.67 (m, 2 H) 3.83 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.13 (d, J=8.4 Hz, 1 H) 7.42 (dd, J=8.4, 1.9 Hz, 1 H) 7.51 (d, J=1.9 Hz, 1 H); Mass Spectrum: m/z (M + H)+ 333.1. Step 2. Preparation of 4-methoxy-3-(piperidin-4-yloxy)benzonitrile (Compound

(VI)). Intermediate 2 (39.31 g, 118.26 mmoles) was suspended in ethanol (155.53 g) and heated to 40 0C. To this slurry was slowly added HCl (46.61 g, 573.04 mmoles). The mixture was heated to 60 0C and held for 3 hours. The reaction mixture was cooled to 200C and seed was charged initiating crystallisation. The resulting solid was isolated by filtration at 00C, washed twice with ethanol (62.21 g) and then dried to give compound (VI) as the hydrochloride salt (29.84 g, 77% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H) 2.09 (m, 2 H) 3.02 (ddd, J=12.7, 8.9, 3.4 Hz, 2 H) 3.20 (m, 2 H) 3.84 (s, 3 H) 4.63 (tt, J=7.7, 3.6 Hz, 1 H) 7.15 (d, J=8.5 Hz, 1 H) 7.45 (dd, J=8.5, 1.9 Hz, 1 H) 7.56 (d, J=1.9 Hz, 1 H) 9.16 (br. s, 2 H); Mass Spectrum: m/z (M + H)+ 233.2. Step 3. Preparation of 2-[4-(5-cyano-2-methoxyphenoxy)piperidin-l-yl]-JV- methylacetamide (Compound (V)). Compound (VI) (28.36 g, 95.82 mmoles), 2-chloro-N- methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 200C and water (386.26 g) was charged. The reaction was heated to 75°C and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give compound (V) (27.95 g, 94% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.68 (m, 2 H) 1.91 (m, 2 H) 2.29 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.67 (m, 2 H) 2.88 (s, 2 H) 3.83 (s, 3 H) 4.41 (tt, J=8.3, 4.0 Hz, 1 H) 7.11 (d, J=8.4 Hz, 1 H) 7.40 (dd, J=8.4, 1.9 Hz, 1 H) 7.47 (d, J=I.9 Hz, 1 H) 7.68 (q, J=4.7 Hz, 1 H); Mass Spectrum: m/z (M + H)+ 304.2.

Step 4. Preparation of 2-[4-(5-cyano-2-methoxy-4-nitrophenoxy)piperidin-l-yl]-N- methylacetamide (Compound (IV)). Compound (V) (8.78 g, 26.11 mmoles) was suspended in acetic acid (22.82 g, 364.87 mmoles) and the resulting reaction mixture cooled to 5°C. To this was added sulfuric acid (23.64 g, 234.95 mmoles) maintaining the reaction temperature below 300C. To the resulting solution was added nitric acid (2.40 g, 26.63 mmoles). The reaction mixture was then heated to 35°C and held for 3 hours. Additional nitric acid (117 mg, 1.31 mmoles) and sulphuric acid (1.31 g 13.1 mmoles) were charged and the reaction mixture was heated at 35°C for 30 minutes. The solution was cooled to 200C and quenched with aqueous ammonia (92.45 g 1.36 moles), resulting in an increase in temperature to 500C. To the resulting slurry was added, propionitrile (61.58 g 1.12 moles) and water (19 g). The reaction mixture was heated to 80 0C resulting in a clear solution, which upon settling gave two layers. The bottom layer was removed. The reaction mixture was cooled to 20 0C resulting in a thick slurry. The solid was isolated by filtration, washed with propionitrile (6.16 g 112.0 mmoles) and dried to afford compound (IV) (7.44 g, 82% yield); 1H NMR (400 MHz, DMSO-de) δ ppm 1.72 (m, 2 H) 1.97 (m, 2 H) 2.35 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.90 (s, 2 H) 3.96 (s, 3 H) 4.73 (tt, J=8.4, 4.0 Hz, 1 H) 7.71 (q, J=4.7 Hz, 1 H) 7.82 (s, 1 H) 7.86 (s, 1 H). Mass Spectrum: m/z (M + H)+ 349.2

Step 5. Preparation of 2-[4-(4-amino-5-cyano-2-methoxyphenoxy)piperidin-l-yl]-N- methylacetamide (Compound (III)). Compound (IV) (7.42 g, 19.38 mmoles) was suspended in water (44.52 g) and methanol (5.35 g). To this was added sodium dithionite (11.91 g, 58.15 mmoles) and the resulting reaction mixture was heated to 600C. To the reaction mixture was added hydrochloric acid (46.98 g, 463.89 mmoles)), resulting in a solution, which was held at 60 0C for 3 hours. The reaction mixture was then allowed to cool to 20 0C. Aqueous sodium hydroxide (15.51 g 182.2 mmoles) was charged followed by 2-methyltetrahydrofuran (58.0 g). The reaction mixture was heated to 60 0C, which upon settling gave two layers and the lower aqueous layer was discarded. The volume of the reaction mixture was reduced by vacuum distillation and methyl tert-butyl ether (18.54 g) was added to give a slurry which was cooled to 10 0C. and then the solid was collected by filtration. The solid was washed with 2- methyltetrahydrofuran (5.8 g) and dried to give compound (III) (5.4 g, 78% yield); 1H NMR (400 MHz, DMSO-de) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M + H)+ 319.2.

Step 6. Preparation of 2-[4-(5-cyano-4-{[(dimethylamino)methylene]amino}-2- methoxyphenoxy)piperidin-l-yl]-Λ/-methylacetamide (Compound (H)). Compound (III) (18.21 g, 52.05 mmoles) was suspended in 2-methyltetrahydrofuran (99.62 g). To this was added acetic acid (162.79 mg), and N,N-dimethylformamide dimethyl acetal (DMA) (8.63 g, 70.27 mmoles) and the resulting reaction mixture was heated at 76 0C for 16 hrs. Additional N,N-dimethylformamide dimethyl acetal (639.41 mg, 5.20 mmoles) was added to the reaction mixture to ensure the reaction completed. The reaction mixture was cooled to 300C during which time crystallisation occurred. The resulting solid was isolated by filtration, washed with 2-methyltetrahydrofuran (14.23 g) and dried to afford compound (II) (19.53 g, 97% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.65 (m, 2 H) 1.86 (m, 2 H) 2.24 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.87 (s, 2 H) 2.95 (s, 3 H) 3.04 (s, 3 H) 3.81 (s, 3 H) 4.19 (tt, J=8.2, 3.8 Hz, 1 H) 6.72 (s, 1 H) 7.15 (s, 1 H) 7.67 (q, J=4.7 Hz, 1 H) 7.90 (s, 1 H); Mass Spectrum: m/z (M + H)+ 374.2.

Step 7. Preparation of compound (I). 2-[4-(5-cyano-4-

{ [(dimethylamino)methylene] amino } -2-methoxyphenoxy)piperidin- 1 -yl] -JV-methylacetamide (compound (II), 7.00 g, 17.71 mmoles), was suspended in methoxybenzene (35.8 g). Acetic acid (16.6 g) was charged and to the resulting solution was added 3-chloro-2-fluoroaniline (2.71 g, 18.07 mmoles). The reaction mixture was heated at 90 0C for 20 hours then cooled to 200C. Water (37.04 g) was charged to the reaction mixture, and the organic layer discarded. To the resulting aqueous mixture was charged isopropanol (39.00 g), followed by aqueous ammonia (20.79 g, 25%). The reaction mixture was heated to 30 0C and seeded with compound (I), which induced crystallisation. The reaction was then cooled to 00C and the product isolated by filtration. The filter cake was washed twice with a mixture of water (7.28 g) and isopropanol (4.68 g), then dried to afford the compound (I) (5.65 g, 55% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.79 (m, 2 H) 2.04 (m, 2 H) 2.38 (m, 2 H) 2.62 (d, J=4.5 Hz, 3 H) 2.74 (m, 2 H) 2.94 (s, 2 H) 3.93 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.21 (s, 1 H) 7.28 (m, 1 H) 7.50 (m, 2 H) 7.73 (q, J=4.5 Hz, 1 H) 7.81 (s, 1 H) 8.36 (s, 1 H) 9.56 (br.s, 1 H); Mass Spectrum: m/z (M + H)+ 474.2, 476.2.

Example 2: Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)). Compound (I) was prepared according to the scheme shown below:

Figure imgf000023_0001

Compound (III) Compound (IV)

Compound (V)

Figure imgf000023_0002

Compound (Xl)

Figure imgf000023_0003

Compound (I)

Steps 1, 2, 3 and 4 as set forth in Example 1.

Step 5, alternate 1. Preparation of compound (III). 2-[4-(5-Cyano-2-methoxy-4- nitrophenoxy)piperidin-l-yl]-N-methylacetamide (compound (IV), 15.00 g, 42.50 mmoles) was suspended in water (90.00 g) and methanol (59.38 g). To this was added sodium dithionite (30.47 g, 148.75 mmoles) and water (90.00 g), the resulting reaction mixture was heated to 30 0C and held for 2 hrs. To the reaction mixture was added hydrochloric acid (27.98 g, 276.25 mmoles)), resulting in a solution, which was held at 600C for 2 hours. Aqueous sodium hydroxide (30.60 g 382.49 mmoles) was added followed by a line wash of water (30.00 g). The reaction mixture was cooled to 25°C to give a slurry which was collected by filtration. The solid was washed with water (30.00 g) and dried to give compound (III) (13.50 g, 82% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)+ 319.2.

Step 5, alternate 2. Preparation of compound (III). Compound (IV) (8.00 g, 22.67 mmoles) and 1% platinum + 2 % vanadium catalyst on carbon (1.23 g, 0.023 mmoles) were suspended in Acetonitrile (94.00 g). The reaction mixture was hydrogenated at a pressure of 3 Bar G and at a temperature of 35°C for 3 hrs. Once complete, the reaction mixture was filtered to remove the catalyst which is washed with acetonitrile (31.33 g). The volume of the reaction mixture was reduced by vacuum distillation to give a slurry which was cooled to 00C and then the solid was collected by filtration. The solid was washed with acetonitrile (12.53 g) and dried to give compound (III) (5.88 g, 78% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)+ 319.2.

Step 6. Preparation of N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)). 3-chloro-2-fluroaniline (51.21 g, 341.22 mmoles) was suspended in cyclohexane (87.07 g). To this ethyl orthoformate (22.28 g, 150.32 mmoles) and acetic acid (0.94 g, 15.03 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 48°C for 12 hours. Following this the reaction mixture was cooled to 200C over 12 hours and the solid product was isolated by filtration. The filter cake was washed with cylcohexane (26.12 g) and dried in vacuo at 40 0C to give compound (XI) as a white crystalline product (33.95 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 7.14 (t, 2 H) 7.22 (m, 2 H) 8.14 (s, 1 H), 9,98 (s, 1 H); Mass Spectrum (by GC-MS EI): m/z (M+) 300.0.

Step 7, alternate 1 : Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (10 g, 29.84 mmol) and TV, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (11.46 g, 37.3 mmol) were suspended in 2-methyltetrahydrofuran (30.4 ml) and heated to 800C. To this yellow suspension was added acetic acid (7.6 ml, 127.33 mmol) and the resulting solution was heated to 92°C for 6 hours. 2-methyltetrahydrofuran (66.5 ml) and water (28.5 ml) were added and mixture was cooled to 550C before adding 50%w/w sodium hydroxide (7 ml, 131.29 mmol) resulting in a temperature rise to 63°C. The temperature was raised further to 69°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 20 ml) and each aqueous phase was discarded after settling. 2- methyltetrahydrofuran (100 ml, 997 mmol) was added and the volume reduced by distillation. Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (19 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (12.14 g, 95%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.12 (d, J= 6Hz, 1.3H), 1.26 -1.36 (m, 0.4H), 1.75-1.97 (m, 3.3H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.52-3.59 (m, 0.4H), 3.72-3.87 (m, 0.86H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data above includes signals for the 2-methyltetrahydrofuran solvent which is present in a 0.43 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 1.12, 1.26-1.36, 3.52-3.59 and 3.72-3.87. The cluster at 1.75-1.93 contains signals for the solvent and the parent compound. The XRPD for this compound is shown in Figure 2.

Step 7, alternate 2. Preparation of compound (I). Compound (III) (15 g, 44.76 mmol) and compound (XI) (17.19 g, 55.95 mmol) were suspended in 2-methyltetrahydrofuran (45.6 ml) and heated to 83°C. To this yellow suspension was added acetic acid (11.4 ml, 190.99 mmol) and the resulting solution was heated to 92°C for 3 Vi hours. 2-methyltetrahydrofuran (105 ml) and water (50 ml) were added and mixture was cooled to 49°C before adding 50%w/w sodium hydroxide (10.74 ml, 201.4 mmol), resulting in a temperature rise to 62°C. The temperature was maintained at 62°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 30 ml) and each aqueous phase was discarded after settling. The mixture was cooled to 15°C and seed was added to induce crystallisation. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (21 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (20.12 g, 95%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.75-1.86 (m, 2H), 2.02- 2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The XRPD for this compound is shown in Figure 3.

Step 7, alternate 3. Preparation of compound (I). Compound (III) (15.1 g, 45.06 mmol) and compound (XI) (17.31 g, 56.32 mmol) were suspended in 2-methyltetrahydrofuran (46 ml) and heated to 800C. To this yellow suspension was added acetic acid (12 ml, 458 mmol) and the resulting solution was heated to 92° C for 7 hours. 2-methyltetrahydrofuran (100 ml) and water (43 ml) were added and mixture was cooled to 59°C before adding 50%w/w sodium hydroxide (11 ml, 207 mmol), resulting in a temperature rise to 71.5°C. The temperature was adjusted to 69°C and the aqueous phase was discarded after settling. The organic phase was washed with water (2 x 43 ml) and each aqueous phase was discarded after settling. 2-methyltetrahydrofuran (72 ml) was removed by distillation at atmospheric pressure and was replaced by addition of isopropyl alcohol (72 ml). A further 72 ml of solvent was removed by distillation at atmospheric pressure and replaced by isopropyl alcohol (72 ml). Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The solid was isolated by filtration, washed twice with isopropylalcohol (32 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (20.86 g, 87%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.04 (d, J= 6Hz, 6H),1.75-1.88 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.73-3.84 (m, IH), 3.95 (s, 3H), 4.34 (d, J = 4.2Hz, IH), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data include signals for 1 mole equivalent isopropanol present. The XRPD for this compound is shown in Figure 4.

Example 3. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline di- [(2E)-but-2-enedioate] (compound (I) difumarate salt). Compound (I) difumarate salt was prepared according to the scheme shown below:

Figure imgf000027_0001

Compound (III) Compound (IV) Compound (V)

Figure imgf000027_0002

Compound (Xl)

Figure imgf000027_0003

Difumarate Compound (I)

Steps 1, 2, 3, 4, 5 and 6 were performed as set forth in Example 2. Step 7. Preparation of compound (I) difumarate salt. Compound (III) (17.90 mmoles) and N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (7.04 g, 23.27 mmoles) were suspended in tert-butyl alcohol (88.95 g). To this suspension fumaric acid (10.39 g, 89.52 mmoles) was added and the mixture was heated to 800C, with stirring, for 2.5 hrs. Water (11.40 g, 632.80 mmoles) was charged and the reaction continued for a further 21.5 hrs. The reaction was cooled to 200C over 12 hours, during which time crystallisation occurred. The resulting solid was isolated by filtration and was washed with a mixture of water (1.00) and tert-butyl alcohol (7.80 g) followed by a wash with a mixture of water (0.50 g) and tert-butyl alcohol (7.30 g). The solid was dried in vacuo at 40 0C to give compound (I) difumarate salt (8.17 g, 61.40%) as a mustard yellow powder; 1H NMR (400 MHz, DMSO- dβ) δ ppm 1.83 (m, 2 H, broad) 2.07 (m, 2 H, broad) 2.64 (d, J=5.0 Hz, 3 H) 2.80 (m, 2 H, broad) 3.03 (s, 2 H) 3.94 (s, 3 H) 4.58 (m, 1 H) 6.63 (s, 4 H) 7.22 (s, 1 H) 7.29 (td, J=8.5, 1.0 Hz, 1 H) 7.51 (m, 2 H) 7.82 (m, 2 H) 8.37 (s, 1 H); Mass Spectrum: m/z (M+H)+ 474.0. Example 4. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline (compound (I)).

Compound (I) was prepared according to the scheme shown below:

Figure imgf000029_0001

Compound (III) Compound (IV)

Compound (V)

Figure imgf000029_0002

Compound (XII)

Figure imgf000029_0003

Compound (I)

Steps 1, 2, 3, 4 and 5 were performed as set forth in Example 2.

Step 6. Preparation of N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)). 3-chloro-2-fluroaniline (5.30 g, 35.29 mmoles) was dissolved in 2- methyltetrahydrofuran (52.94 g). To this N,N-dimethylformamide dimethyl acetal (6.07 g, 49.41 mmoles) and acetic acid (0.11 g, 1.76 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 76 0C for 3 hours. Following this the solvent was removed in vacuo at 400C to give compound (XII) as a yellow oil (6.60 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 2.74 (s, 0.29H), 2.89 (s, 0.31H), 2.94 (s, 2.75H), 3.03 (s, 2.66H), 3.34 (br s, 0.70H), 5.48 (s, 0.06H) 6.91-7.10 (m, 3H), 7.79 (s, 1 H), 7.96 (s, 1 H). The NMR data above includes signals for N,N-dimethylformamide dimethyl acetal which is present in a 0.06 molar equivalence. The signals pertaining to N5N- dimethylformamide dimethyl acetal are at δ ppm shifts of 3.75, and 6.90-6.95. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum (by LCMS EI): m/z (M+H)+ 201.2. Step 7: Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (0.50 g, 1.45 mmol) and N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)) (0.32 g, 1.52 mmol) were suspended in methoxybenzene (3.1 ml). To this yellow suspension was added acetic acid (1.52 ml, 25.51 mmol) and the resulting solution was heated to 90 0C for 14 hours. The reaction mixture was cooled to 20 0C and water (2.58 mL) was added. The organic layer was removed and the aqueous layer washed with methoxybenzene (1.4 mL). Ethanol (2.45 mL) and ammonia (1.94 ml, 25.55 mmoles) were added to the aqueous layer. The solution was heated to 900C resulting in the loss of some ethanol by evaporation. The solution was cooled to 40 0C. Seed was added to induce crystallisation and the resulting mixture was cooled to 20 0C. The solid was isolated by filtration to yield compound (I) as a white solid (0.61 g, 73% yield). IH NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.87 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.8Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.35 (s, 5.4H), 3.75 (s, 1.3H), 3.95 (s, 3H), 4.58 (hept., J=4.0Hz, IH), 6.90-6.95 (m, 1.3H), 7.23 (s, 1.8H), 7.26-7.34 (m, IH), 7.45-7.58 (m 2H), 7.72-7.78 (m, IH), 7.83 (s, IH), 8.38 (s, IH), 9.58 (s, IH). The NMR data above includes signals for the methoxybenzene solvent which is present in a 0.40 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 3.75, and 6.90-6.95. The cluster at 7.26-7.34 contains signals for the solvent and the parent compound. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum: m/z (M + H)+ 474.0, 476.0. Example 5. Preparation of compound (I) difumarate Form A – 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (2.7 g, 23.22 mmol) in methanol (95 ml) was added to a mixture of 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (5.62 g at 89% w/w, 10.55 mmol) in isopropanol (100 ml) maintaining the temperature >65°C. The mixture was heated at reflux for one hour before clarification. The reaction mixture was cooled to 300C over 90 minutes and held for 30 minutes to establish crystallisation. The reaction was cooled to 00C over 2 hours and held for 1 hour before isolation by filtration. The filter cake was washed twice with cold isopropanol (2 x 10 ml) and dried in vacuo at 500C to give the title compound as a white solid (5.84 g, 78%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 6. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (1.4 kg, 12.1 mol) in methanol (26.6 kg) was added to a mixture of 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (2.93 kg, 84.8% w/w, 5.24 mol) in isopropanol (39 kg) maintaining the temperature >65°C. A line wash of methanol (3.6 kg) was charged. The mixture was heated at reflux for one hour before clarification, followed by a line wash of methanol (7 kg). The reaction mixture was distilled at atmospheric pressure to remove 47 kg of distillates. Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 00C over 8 hours and held for 1 hour before isolation by filtration. The filter cake was washed with cold 50:50 isopropanol:MeOH (4 kg) followed by cold isopropanol (4 kg) and dried in vacuo at 500C to give the title compound as a white solid (3.64 kg, 98%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 7. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (60.19 g at 88% w/w, 111.8 mmol) was dissolved in ethyl acetate (1550 ml). The solution was clarified by filtration and the filter washed with ethyl acetate (53 ml). The solution was cooled to 400C. A clarified solution of fumaric acid (26.60 g, 257.0 mmol) in isopropanol (408 ml) was then added over 1 hour. The filter used to clarify the fumaric acid solution was then washed with isopropanol (37 ml). After holding for 1 hour at 400C the reaction was cooled to 200C over 1 hour. The reaction mixture was held for 13.5 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (82 ml) : isopropanol (24 ml) and then dried in vacuo at 400C to give the title compound as a white solid (72.32 g, 90%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH). Example 8. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (2.75 g at assumed 100% w/w, 5.80 mmol) was dissolved in ethyl acetate (94 ml) and isopropanol (14 ml). The solution was distilled such that 25.2 ml of distillates were collected. The solution was cooled to 400C. A clarified solution of fumaric acid (1.38 g, 11.90 mmol) in isopropanol (21 ml) was then added over 1 hour. Compound (I) difumarate Form A seed was added (3.7 mg, 5.3 μmol). The filter used to clarify the fumaric acid solution was then washed with isopropanol (2 ml). After holding for 1 hour at 400C the reaction was cooled to 200C over 2 hours. The reaction mixture was held for 15 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (4.3 ml): isopropanol (1.2 ml) and then dried in vacuo at 400C to give the title compound as a white solid (72.32 g, 90%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 9. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (1 g, 1.86 mmoles) and fumaric acid (0.44 g, 3.81 mmoles) were suspended in water (4.4 g) and heated to 85°C. The reaction mixture was cooled to 600C at l°C/minute and compound (I) Form A seed was added when the temperature was 77°C. The resulting solid was isolated by filtration, washed twice with acetone (0.7O g per wash) and dried in a vacuum oven at 400C to afford the title compound (0.89 g, 68% yield), IH NMR (400 MHz, DMSO-d6) d ppm 1.84 (m, 2 H) 2.08 (m, 2 H) 2.55 (m, 2 H) 2.63 (d, J=4.7 Hz, 3 H) 2.86 (m, 2 H) 3.12 (s, 2 H) 3.93 (s, 3 H) 4.59 (tt, J=7.8, 3.7 Hz, 1 H) 6.62 (s, 4 H) 7.21 (s, 1 H) 7.27 (td, J=8.1, 1.3 Hz, 1 H) 7.49 (m, 2 H) 7.86 (m, 2 H) 8.36 (s, 1 H) 9.63 (br. s., 1 H). Compound (I) difumarate Form A is a free flowing powder.

PAPER

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00412

The Development of a Dimroth Rearrangement Route to AZD8931

The Department of Pharmaceutical Sciences, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, United Kingdom
The Department of Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00412

Abstract Image

Recently, the aminoquinazoline motif has been highly prevalent in anticancer pharmaceutical compounds. Synthetic methods are required to make this structure on a multikilo scale and in high purity. The initial route to aminoquinazoline AZD8931 suffered from the formation of late-stage impurities. To avoid these impurities, a new high-yielding Dimroth rearrangement approach to the aminoquinazoline core of AZD8931 was developed. Assessment of route options on a gram scale demonstrated that the Dimroth rearrangement is a viable approach. The processes were then evolved for large-scale production with learning from a kilo campaign and two plant-scale manufactures. Identification of key process impurities offers an insight into the mechanisms of the Dimroth rearrangement as well as the hydrogenation of a key intermediate. The final processes were operated on a 30 kg scale delivering the target AZD8931 in 41% overall yield.

2-[4-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-N-methyl-acetamide IPA solvate (5) as a white solid (38.1 kg, 84.2% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (m, 2 H), 2.06 (m, 2 H), 2.39 (m, 2 H), 2.63 (d, J = 4.7 Hz, 3 H), 2.75 (m, 2 H), 2.95 (s, 2 H), 3.94 (s, 3 H), 4.57 (Dt, J = 8.1, 4.2 Hz, 1 H), 7.22 (s, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.51 (m, 2 H), 7.74 (br d, J = 4.6 Hz, 1 H), 7.83 (s, 1 H), 8.37 (s, 1 H), 9.58 (br.s, 1 H); m/Z ES+ 474.2 [MH]+; HRMS found [MH]+ = 474.1706, C23H25ClFN5O3 requires [MH]+ = 474.1630; Assay (QNMR) 97.5 wt %/wt.

1H NMR PREDICT

13C NMR PREDICT

CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 49, no. 7, 2001, pages 822 – 829
Citing Patent Filing date Publication date Applicant Title
WO2013051883A3 * Oct 5, 2012 Jun 6, 2013 Hanmi Science Co., Ltd. Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein
US8859767 Oct 5, 2012 Oct 14, 2014 Hanmi Science Co., Ltd Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein

////////////////AZD 8931, Sapitinib, pan-EGFR, pan-erbB inhibitor, SAPATINIB, PHASE 2, 848942-61-0

CNC(=O)CN1CCC(CC1)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05)


str1

1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05)

Cas 1835197-63-1
C13 H22 N2 O3, 254.33
Tricyclo[3.3.1.13,7]decane-1-methanol, 3-amino-5-ethyl-, 1-nitrate
Amantadine and its derivatives have a variety of biological activity, in the field of medicine has a wide range of applications. Rimantine (1-aminoethyl adamantane, Rimantadine) is currently widely used in clinical prevention and treatment of influenza drugs. Amantadine is widely used in the treatment of influenza and Parkinson & apos; s Disease (PD) (Schwab et al., J. Am. Med. Asos. 1669, 208: 1168). Memantine is the only NMDA receptor antagonist approved by the US FDA for the treatment of moderate to severe Alzheimer’s disease (AD). NMDA receptors are a subtype of the important excitatory amino acid ionotropic glutamate receptors in the central nervous system and are important receptors in the learning and memory process. NMDA receptor pathway is opened after the non-selective allow some cations, such as Ca 2+ , K + and Na + into the cells, these ions, especially calcium ions can cause a series of biochemical reactions, and ultimately lead to neurotoxicity , Causing neuronal apoptosis. Memantine is a noncompetitive antagonist of the NMDA receptor open channel, which binds to binding sites within the ion channel and blocks the intramolecular flow and acts as a neuroprotective effect. The combination of memantine to NMDA receptors is reversible and has a moderate dissociation rate that ensures both pharmacological effects and ensures that it does not accumulate in the channel and affects normal physiological functions (Lipton et al. Journal of neurochemistry. 2006, 97: 1611-1626). At the same time, the antagonism of memantine to NMDA receptor has a strong voltage dependence, only in the neuronal depolarization can be combined with the receptor, which can block the pathological conditions of neurons continue to depolarize the NMDA receptor Activation, without blocking NMDA receptor activation under normal physiological conditions (Wenk et al., CNS drug reviews. 2003, 9 (3): 275-308; McKeage., Drugs & aging.2010,27 (2): 177-179 ). This protection mechanism is also important for the treatment of other central nervous system diseases such as stroke, PD, ALS and so on, and therefore it has a good prospect for the treatment of these diseases.
Nitric oxide (NO) also has a variety of biological activities in the body, it plays the role of signal molecules. Nitric oxide molecules can penetrate the cell wall into the smooth muscle cells, so that relaxation, expansion of blood vessels, lower blood pressure. But also into the platelet cells, reduce its activity, thereby inhibiting its agglutination and adhesion to the vascular endothelium to prevent thrombosis, prevent atherosclerosis. NO is a free radical gas, with an unpaired electron, the body is very unstable, very easy to react with free radicals, which can reduce the number of free radicals. The accumulation of free radicals can cause nucleic acid cleavage, enzyme passivation, polysaccharide depolymerization, and lipid peroxidation eventually leads to neuronal death (Yan et al. Free Radic. Biol. Med. 2013, 62: 90-101). NO has a strong ability to react with various free radicals, which can effectively reduce the number of free radicals, but its synthesis in vivo requires the participation of nitric oxide synthase (NOS). Under normal circumstances, NOS activity is relatively low, the need for nitro-like molecules or saponins substances activated. The introduction of NO-releasing groups on small molecule drugs can increase NO content in the body and have significant efficacy, such as nitroglycerin.
Because of the complex pathogenesis of AD, at present, the clinical treatment of AD is limited, only four acetylcholinesterase inhibitors and an NMDA receptor inhibitor. These drugs for the role of a single target molecules, can only alleviate some aspects of clinical symptoms of AD can not fundamentally cure the disease, blocking the process of neurodegeneration.
PATENT
Figure 2 depicts the synthesis of compound NM-004.
Example 3, Synthesis of compound NM-004a
A 50 mL round bottom flask was cooled in an ice-water bath and 20 mL of concentrated sulfuric acid, 2 mL of n-hexane and 970 mg (4 mmol) of compound NM-003a were added to the round bottom flask. To maintain the ice bath, slowly add formic acid (1.8mL). After dripping, continue the ice bath reaction for 3 hours. The reaction solution was poured into 100 mL of ice water to precipitate a solid. The mixture was allowed to stand and filtered to give a pale yellow solid. After drying in solid, it is dissolved in ethyl acetate and the aqueous solution of sodium hydroxide is basified to pH to about 9-10. The aqueous layer is separated. The organic layer was extracted with an aqueous solution of sodium hydroxide (30 mL x 3) and the aqueous solution was combined with a dilute hydrochloric acid solution to acidify the aqueous layer to a pH of about 3. Filtered and dried to give the pure compound NM-004a 640 mg (77%). ESI-MS: m / z 207 ([MH] ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.11 (q, 2H, J = 7.5Hz) (M, 2H), 1.47 (s, 2H), 1.51-1.64 (m, 2H), 1.66-1.81 (m, 4H), 2.01 (m, 2H), 11.99 (s, 1H).
Example 4, Synthesis of compound NM-004b
To a 50 mL round bottom flask, 624 mg (3 mmol) of compound NM-004a was added and the mixture was cooled in an ice bath. Add 0.55mL concentrated nitric acid, stir well. To the mixture was added 3.5 mL of concentrated sulfuric acid, and the reaction was carried out in an ice bath for 1 hour. After which 2.5 mL of acetonitrile (4.8 mmol) was added dropwise and the reaction was continued for 1 hour in an ice bath. The reaction solution was poured into 20 mL of ice water and vigorously stirred for 30 minutes and allowed to stand overnight. The precipitate was removed by filtration, and the solid was washed with the appropriate amount of water and dried to obtain the compound NM-004b (580 g, 73%) without further purification. ESI-MS: m / z 266 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.74 (t, 3H, J = 7.5Hz), 1.15 (q, 2H, J = 7.5 Hz, 1.26-1.35 (m, 2H), 1.36-1.47 (m, 2H), 1.52-1.70 (m, 4H), 1.72-1.86 (m, 5H), 1.88-1.98 (m, 2H) M, 1H), 7.43 (s, 1H).
Example 5, Synthesis of compound NM-004c
The compound NM-004b 878 mg (3.3 mmol) was dissolved in 10 mL of dry tetrahydrofuran and cooled in an ice-water bath. 0.5 mL of triethylamine and 0.5 mL of ethyl chloroformate were added to the mixture, followed by an ice bath for 30 minutes. The ice bath was removed and reacted at room temperature for 4 hours. The filtrate was filtered and the filtrate was washed with an appropriate amount of tetrahydrofuran. To the filtrate by adding sodium borohydride 1.5g, dropping funnel slowly dropping 1mL water, 1 hour drop finished. After dripping at room temperature, the reaction was continued for 1 hour. TLC monitoring, the reaction is completed, the reaction system to add water 30mL, dry spin dry tetrahydrofuran. The aqueous layer was extracted with ethyl acetate (20 mL x 4), combined with ethyl acetate, 25 mL of 0.5 N hydrochloric acid, saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude oil. Silica gel column (petroleum ether: ethyl acetate = 1: 1), and finally a white solid, NM-004c, 348 mg (42%) was obtained. ESI-MS: m / z 252.2 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.03-1.20 (m, 4H) 1.28 (m, 4H), 1.58 (m, 4H), 1.75 (m, 5H), 2.09 (s, 1H), 3.02 (d, 2H, J = 5.5 Hz), 4.38 (t, 1H, J = ), 7.33 (s, 1H).
Example 6, Synthesis of compound NM-004d
To a 250 mL round bottom flask was added 1.26 g (5 mmol) of compound NM-004c, 3 g of solid sodium hydroxide, 20 mL of diethylene glycol and refluxed at 170 ° C for 15 hours. After cooling to room temperature, the reaction solution was poured into 40 g of crushed ice and the mixture was stirred. The mixture was extracted with ethyl acetate (20 mL x 4). The combined ethyl acetate layer, 30 mL of water and 30 mL of saturated sodium chloride solution were washed and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give a crude product as a pale yellow oil. The crude product was dissolved in 50 mL of dry ethyl acetate and the resulting dry HCl was passed under stirring to precipitate a large amount of white solid. The solid was washed with an appropriate amount of dry ethyl acetate and dried to give 850 mg (69.4%) of white solid NM-004d. ESI-MS: m / z 210.3 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.74 (t, 3H, J = 7.6 Hz), 1.15 (q, 2H, J = 7.6 Hz, 1.26-1.35 (m, 2H), 1.36-1.47 (m, 2H), 1.53-1.68 (m, 4H), 1.74-1.85 (m, 3H), 1.88-1.96 (m, 2H) M, 1H), 7.43 (s, 3H).
Example 7, Synthesis of compound NM-004e
Take the compound NM-004d 2.45 g, (10 mmol) in 20 mL of water, basify the sodium hydroxide solution to pH 10, and extract with ethyl acetate (30 mL x 4). The combined ethyl acetate was washed with 30 mL of water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1.57 g (7.5 mmol) of free amine as a colorless oil. (15.6 mmol) of triethamine, 2.55 g (11.7 mmol) of Boc anhydride and 10 mg of DMAP were added to 50 mL of distilled steam in tetrahydrofuran, and the reaction was monitored by TLC at room temperature for 5 hours. After completion of the reaction, the reaction solution was quenched by adding 30 mL of saturated ammonium chloride solution to the reaction solution. The solvent was evaporated under reduced pressure and extracted with ethyl acetate (50 mL x 4). The combined ethyl acetate was washed with 30 mL of 0.1 N hydrochloric acid and 30 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude product was separated on a silica gel column (petroleum ether: ethyl acetate = 1: 1) and 1.58 g (68%) of the white solid NM-004e was obtained. ESI-MS: m / z 310.3 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.75 (t, 3H, J = 7.5Hz), 1.03-1.19 (m, 4H) 1.24 (m, 4H), 1.36 (s, 9H), 1.44-1.58 (m, 4H), 1.52-1.73 (m, 2H), 2.08 (s, 1H), 3.02 (d, 2H, J = 5.5 Hz) , 4.38 (t, 1H, J = 5.5 Hz), 6.36 (s, 1H).
Example 8, Synthesis of compound NM-004f
The compound NM-004e (620 mg, 2 mmol) was dissolved in 10 mL of dry water, dichloromethane and cooled in an ice-water bath. Add acetic anhydride and fuming nitric acid mixture (acetic anhydride and fuming nitric acid volume ratio equal to 3: 2) 2mL. Ice bath reaction 10-15 minutes. The reaction solution was poured into 10 mL of 1N sodium bicarbonate solution, and the dichloromethane was separated. The aqueous layer was extracted with dichloromethane (10 mL x 3), combined with dichloromethane and washed with 10 mL of water. Dried over anhydrous sodium sulfate, filtered and the dichloromethane was distilled off under reduced pressure to give the crude product as a colorless oil. Silica gel column separation (petroleum ether: dichloromethane = 10: 1) was obtained as a colorless oil NM-004 f 505 mg (73.4%). ESI-MS: m / z 377.2 ([M + Na] + ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.08-1.23 (m, 4H) 1.26-1.49 (m, 14H), 1.56-1.82 (m, 5H), 2.12 (m, 1H), 4.23 (s, 2H), 6.50 (s, 1H).
Example 9, Synthesis of compound NM-004
To the compound NM-004f710 mg (2 mmol) was added 5 mL of a saturated solution of hydrogen chloride and reacted at room temperature. At the end of the reaction, a white solid precipitates. Filtration, anhydrous ether washing white solid, you can get NM-004 pure. After drying, NM-004380 mg (65.5%) was obtained. ESI-MS: m / z 255.1 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.78 (t, 3H, J = 7.5Hz), 1.15-1.28 (m, 4H) (M, 2H), 1.40-1.55 (m, 4H), 1.57-1.67 (m, 2H), 1.71 (s, 2H), 2.23 (m, 1H), 4.30 (s, 2H) S, 3H).

Med. Chem. Commun., 2017, 8,135-147

DOI: 10.1039/C6MD00509H, Research Article
Zheng Liu, Si Yang, Xiaoyong Jin, Gaoxiao Zhang, Baojian Guo, Haiyun Chen, Pei Yu, Yewei Sun, Zaijun Zhang, Yuqiang Wang
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized

Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases

Zheng Liu,a   Si Yang,a   Xiaoyong Jin,a   Gaoxiao Zhang,a  Baojian Guo,a   Haiyun Chen,a   Pei Yu,a   Yewei Sun,*a  Zaijun Zhang*a and   Yuqiang Wanga  
*Corresponding authors
aInstitute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China
E-mail: yxy0723@163.com, zaijunzhang@163.com
Fax: +86 20 8522 4766
Tel: +86 20 8522 5030
Med. Chem. Commun., 2017,8, 135-147

DOI: 10.1039/C6MD00509H

A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized. These compounds combined the memantine skeleton and a nitrate moiety, and thus inhibited the N-methyl-D-aspartic acid receptor and released NO in the central nervous system. The biological evaluation results revealed that the new memantine nitrates were effective in protecting neurons against glutamate-induced injury in vitro. Moreover, memantine nitrates dilated aortic rings against phenylephrine-induced contraction. The structure–activity relationships of neuroprotection and vasodilation were both analyzed. In further studies, compound MN-05 significantly protected cortical neurons by inhibiting Ca2+ influx, reducing free radical production and maintaining the mitochondrial membrane potential. Further research on MN-05 is warranted.

1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05).

Compound MN- 05 was synthesized using a similar method to that as described for synthesis of compound MN-01 from compound 16. White solid, 65.5% yield. ESI-MS: m/z 255.1 [M + H]+ .

1H NMR (300 MHz, DMSO-d6) δ 0.75-0.80 (t, J = 7.5 Hz, 3H, CH3), 1.16-1.24 (q, J = 7.5 Hz, 2H, CH2), 1.24-1.25 (m, 2H), 1.30-1.39 (m, 2H), 1.43 (s, 2H), 1.45-1.57 (dd, J = 12 Hz, 6 Hz, 2H), 1.57-1.63 (dd, J = 12 Hz, 6 Hz, 2H), 1.71 (s, 2H), 2.23 (m, 1H, CH), 4.30 (s, 2H, CH2O), 8.21 (s, 3H, NH2HCl).

13C NMR (75 MHz, DMSO-d6) δ 7.4, 28.6, 34.5, 35.0, 36.8, 40.3, 41.6, 43.9, 52.3, 80.9. Anal. Calcd for C13H23N2O3Cl·0.3 H2O: C, 52.72%; H, 8.03%; N, 9.46%. Found: C, 52.72%; H, 7.92%; N, 9.51%

//////// memantine nitrates ,  neurodegenerative diseases, MN 05
[O-][N+](=O)OCC12CC3(CC(N)(C1)CC(C2)C3)CC

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Deflazacort


Deflazacort structure.svgChemSpider 2D Image | Deflazacort | C25H31NO6

Deflazacort

  • CAS 14484-47-0
  • Molecular Formula C25H31NO6
  • Average mass 441.517 Da
(11b,16b)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
11b,21-Dihydroxy-2′-methyl-5’bH-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione 21-acetate
2-[(4aR,4bS,5S,6aS,6bS,9aR,10aS,10bS)-5-Hydroxy-4a,6a,8-trimethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]oxazol-6b-yl]-2-oxoethyl acetate
  • 5’βH-Pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, 11β,21-dihydroxy-2′-methyl-, 21-acetate (8CI)
  • (11β,16β)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
  • 2H-Naphth[2′,1′:4,5]indeno[1,2-d]oxazole, 5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione deriv.
  • Azacort
  • Azacortinol
  • Calcort
  • DL 458IT
  • Deflan
Optical Rotatory Power +62.3 ° Conc: 0.5 g/100mL; Solv: chloroform (67-66-3); Wavlength: 589.3 nm

…………..REF, “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)Hoechst Marion Roussel (now Aventis Pharma) has developed and launched Deflazacort (Dezacor; Flantadin; Lantadin; Calcort) a systemic corticosteroid developed for the treatment of a variety of inflammatory conditions .

In March 1990, the drug was approved in Spain, and by January 2013, the drug had been launched by FAES Farma . By the end of 1999, the product had been launched in Germany, Italy, Belgium, Switzerland and South Korea

Deflazacort is a corticosteroid first launched in 1985 by Guidotti in Europe for the oral treatment of allergic asthma, rheumatoid arthritis, arthritis, and skin allergy.

In 2017, an oral formulation developed at Marathon Pharmaceuticals was approved by the FDA for the treatment of Duchenne’s muscular dystrophy in patients 5 years of age and older.

Deflazacort (trade name Emflaza or Calcort among others) is a glucocorticoid used as an anti-inflammatory and immunosuppressant.

In 2013, orphan drug designation in the U.S. was assigned to the compound for the treatment of Duchenne’s muscular dystrophy. In 2015, additional orphan drug designation in the U.S. was assigned for the treatment of pediatric juvenile idiopathic arthritis (JIA) excluding systemic JIA.

Also in 2015, deflazacort was granted fast track and rare pediatric disease designations in the U.S. for the treatment of Duchenne’s muscular dystrophy.

Deflazacort is a glucocorticoid used as an anti-inflammatory and immunosuppressant. It was approved in February, 2017 by the FDA for use in treatment of Duchenne muscular dystrophy (trade name Emflaza).
  • Aventis Pharma (Originator), Lepetit (Originator), Guidotti (Licensee), Shire Laboratories (Licensee)

Image result for deflazacort

February 9, 2017 FDA approved

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.

Corticosteroids are commonly used to treat DMD across the world. This is the first FDA approval of any corticosteroid to treat DMD and the first approval of deflazacort for any use in the United States.

Image result for Deflazacort

“This is the first treatment approved for a wide range of patients with Duchenne muscular dystrophy,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We hope that this treatment option will benefit many patients with DMD.”

DMD is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between 3 and 5 years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

The effectiveness of deflazacort was shown in a clinical study of 196 male patients who were 5 to 15 years old at the beginning of the trial with documented mutation of the dystrophin gene and onset of weakness before age 5. At week 12, patients taking deflazacort had improvements in a clinical assessment of muscle strength across a number of muscles compared to those taking a placebo. An overall stability in average muscle strength was maintained through the end of study at week 52 in the deflazacort-treated patients. In another trial with 29 male patients that lasted 104 weeks, deflazacort demonstrated a numerical advantage over placebo on an assessment of average muscle strength. In addition, although not statistically controlled for multiple comparisons, patients on deflazacort appeared to lose the ability to walk later than those treated with placebo.

The side effects caused by Emflaza are similar to those experienced with other corticosteroids. The most common side effects include facial puffiness (Cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism) and excessive fat around the stomach (central obesity).

Other side effects that are less common include problems with endocrine function, increased susceptibility to infection, elevation in blood pressure, risk of gastrointestinal perforation, serious skin rashes, behavioral and mood changes, decrease in the density of the bones and vision problems such as cataracts. Patients receiving immunosuppressive doses of corticosteroids should not be given live or live attenuated vaccines.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the ninth rare pediatric disease priority review voucher issued by the FDA since the program began.

Emflaza is marketed by Marathon Pharmaceuticals of Northbrook, Illinois.

Medical uses

The manufacturer lists the following uses for deflazacort:[1]

In the United States, deflazacort is only FDA-approved for the treatment of Duchenne muscular dystrophy in people over the age of 5.

Image result for DeflazacortImage result for Deflazacort

Image result for DeflazacortImage result for Deflazacort

Adverse effects

Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushing’s-like appearance, weight gain, and increased appetite.[2]

Pharmacology

Mechanism of action

Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort.[3]

Relative potency

Deflazacort’s potency is around 70–90% that of prednisone.[4] A 2017 review found its activity of 7.5 mg of deflazacort is approximately equivalent to 25 mg cortisone, 20 mg hydrocortisone, 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone or triamcinolone, or 0.75 mg of betamethasone or dexamethasone. The review noted that the drug has a high therapeutic index, being used at initial oral doses ranging from 6 to 90 mg, and probably requires a 50% higher dose to induce the same demineralizing effect as prednisolone. Thus it has “a smaller impact on calcium metabolism than any other synthetic corticosteroid, and therefore shows a lower risk of growth rate retardation in children and of osteoporosis” in the elderly, and comparatively small effects on carbohydrate metabolism, sodium retention, and hypokalemia.[5]

History

In January 2015, the FDA granted fast track status to Marathon Pharmaceuticals to pursue approval of deflazacort as a potential treatment for Duchenne muscular dystrophy, a rare, “progressive and fatal disease” that affects boys.[6] Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017,[7][8] Marathon CEO announced on February 13, 2017 that the launch of deflazacort (Emflaza) would be delayed amidst controversy over the steep price Marathon was asking for the drug – $89,000-a-year. In Canada the same drug can be purchased for around $1 per tablet.[9] Marathon has said that Emflaza is estimated to cost $89,000/year which is “roughly 70 times” more than it would cost overseas.[10] Deflazacort is sold in the United Kingdom under the trade name Calcort;[4] in Brazil as Cortax, Decortil, and Deflanil; in India as Moaid, Zenflav, Defolet, DFZ, Decotaz, and DefZot; in Bangladesh as Xalcort; in Panama as Zamen; Spain as Zamene; and in Honduras as Flezacor.[11]

SYNTHESIS

Worlddrugtracker drew this

1 Protection of the keto groups in pregna-1,4-diene derivative  with NH2NHCOOMe using HCOOH, yields the corresponding methyl ester.

2 Cleavage of epoxide  with NH3 in DMAc/DMF gives amino-alcohol,

3 which on esterification with acetic anhydride in the presence of AcOH furnishes acetate.

4 Cyclization of amine using NaOH, Na2CO3 or K2CO3 produces oxazoline derivative ,

5 which is finally deprotected with HCl to afford Deflazacort 

SYNTHESIS FROM CHEMDRUG

The cyclization of 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione (I) by hydrogenation with H2 over Pt in methanol, followed by a treatment with 10% HCl gives 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (II), which is converted into the semicarbazone (III) by treatment with semicarbazide hydrochloride (A) and pyridine in refluxing methanol. The reduction of one ketonic group of (III) with NaBH4 in refluxing ethanol yields the dihydroxy-semicarbazone (IV), which is hydrolyzed with 10% HCl in refluxing methanol to afford the ketodiol (V). The oxidation of (V) with cyclohexanone and aluminum isopropoxide in refluxing toluene gives 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (VI). The dehydrogenation of (VI) by treatment with Br2 in dioxane-acetic acid, followed by treatment with Li2CO3 in DMF at 140 C yields the corresponding 1,4-diene derivative (VII). Finally, the reaction of (VII) with I2 by means of azobisisobutyronitrile in CH2Cl2 affords the corresponding 21-iodo compound, which is then acetylated with triethylammonium acetate in refluxing acetone.

The monoacetylation of (V) with acetic anhydride and pyridine at 100 C gives the 3-acetoxy-11-hydroxy compound (IX), which is dehydrated by treatment with methanesulfonyl chloride and then with sodium acetate yielding 3beta-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (X). The hydrolysis of (X) with KOH in refluxing methanol affords the corresponding hydroxy compound (XI), which is acetoxylated by treatment with I2 and AZBN as before giving the iodo derivative (XII), and then with triethylammonium acetate also as before, yielding 3beta-hydroxy-21-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (XIII). The oxidation of (XIII) with CrO3 in acetone yields the 3,20-diketone (XIV), which by treatment with Br2 and Li2CO3 as before is dehydrogenated affording the 1,4,9(11)-pregnatriene (XV). Finally, the reaction of (XV) with N-bromoacetamide in THF yields 9alpha-bromo-11beta-hydroxy-21-acetoxy-5alpha-pregna-1,4-dieno-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (XVI), which is then debrominated by reaction with chromous acetate and butanethiol in DMSO.

PAPER

Journal of Medicinal Chemistry (1967), 10(5), 799-802

Steroids Possessing Nitrogen Atoms. III. Synthesis of New Highly Active Corticoids. [17α,16α,-d]Oxazolino Steroids

J. Med. Chem., 1967, 10 (5), pp 799–802
DOI: 10.1021/jm00317a009

PATENT

CN 105622713

PATENT CN 106008660

MACHINE TRANSLATED FROM CHINESE may seem funny

Description of the drawings

[0007] Figure 1 is a map of the traditional method of the combination process;

Figure 2 is a two-step method of the present invention.

detailed description

[0008] In order to more easily illustrate the gist and spirit of the present invention, the following examples illustrate:

Example 1

A: Preparation of hydroxylamine

In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 30 ml of DMF, 300 ml of chloroform was added and incubated at 30-35 ° C with 8 g of ammonia gas at 1-2 atmospheres Reaction 16 ~ 20 hours, TLC detection reaction end point, after the reaction, the vacuum exhaust ammonia gas, add 3x100ml saturated brine washing 3 times, plus 10ml pure water washing times, then, under reduced pressure to chloroform to dry, add 200ml Ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 degrees, hot filter, l-2ml ethyl acetate washing carbon, combined filtrate and lotion, and then below 500C concentrated under pressure 95 % Of ethyl acetate, the system cooled to -5-0 ° C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of approved; filter cake below 70 ° C Drying, get hydroxylamine 18.2g, HPLC content of 99.2%, weight loss of 91%.

[0009] B: Preparation of terracavir

Add 10 g of hydroxylamine, 150 ml of glacial acetic acid and 150 ml of acetic anhydride in a 100 ml three-necked flask. Add 5 g of concentrated sulfuric acid under stirring at room temperature. The reaction was carried out at 30-35 ° C for 12-16 hours. TLC confirmed the end of the reaction. Add 500ml of pure water, and adjust the pH of 7.5.5 with liquid alkali, cool to 10 ~ 15 ° C, stirring crystallization 2-3 hours, filtration, washing to neutral, combined filtrate and lotion, pretreated into Waste water treatment tank, filter cake below 70 V drying, Texaco can be special crude 112.5g, HPLC content of 98.2%, the yield of 112.5% ο the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, Decolorization 1-1.5 hours, hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -5-0 ° C, frozen crystal 2-3 hours, Filtration, filter cake with 4-5ml alcohol washing, 70 ° C below drying, digoxin special product 89.2g, melting point 255.5-256.0 degrees, HPLC content of 99.7%, yield 89.2%. The mother liquor is recycled with solvent and crude.

[0010] Example II

A: Preparation of hydroxylamine

In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 120 ml of toluene was added and incubated at 30-35 ° C with 8 g of ammonia and 16 to 20 at atmospheric pressure The reaction was carried out in the presence of 3 x 50 ml of saturated brine and 50 ml of pure water was added. Then, the toluene was dried under reduced pressure to dryness, and 200 ml of ethyl acetate, Ig activated carbon was added, and the mixture was stirred. Reflux 60-90 minutes, cool to 50-55 ° C, hot filter, l2ml ethyl acetate wash carbon, combined filtrate and lotion, and then below 500C under reduced pressure 95% ethyl acetate, the system cooling To 5-0C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of the next batch; filter cake 70 ° C below drying, hydroxylamine 18.0g, HPLC content 99.1%, 90% by weight.

[0011] B: Preparation of terracavir

Add 10 g of hydroxylamine, 500 ml of chloroform and 150 ml of acetic anhydride in a 100 ml three-necked flask, add 5 g of p-toluenesulfonic acid under stirring at room temperature, and incubate at 30-35 ° C for 12-16 hours. TLC confirms the reaction end, After the addition of 500ml of pure water, and with the liquid alkali pH 7.55, down to 10 ~ 15 ° C, stirring 0.5_1 hours, separate the water layer, washed to neutral, combined with water and lotion, pretreated into Waste water treatment tank, organic layer under reduced pressure concentrated chloroform to near dry, adding 200ml hexane, reflux 0.5-1 hours, slowly cooling to -5 ~ O0C, stirring crystallization 2-3 hours, filter, filter cake with 4-5ml Alcohol washing, the filtrate and lotion combined apply to the next batch, the filter cake below 70 ° C drying, Texaco can crude 110.5g, HPLC content of 98.4%, the yield of 110.5%. The above-mentioned diltiazem crude product dissolved in 800ml alcohol, add 5g activated carbon, temperature reflux bleaching 1-1.5 hours, hot filter, 10ml alcohol washing cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol And then cooled to -500C, frozen crystallization for 2-3 hours, filtration, filter cake with 4-5ml alcohol washing, 70 ° C the following drying, digester can special products 88.6g, melting point 255.0-256.0 degrees, HPLC content of 99.5%, the yield of 88.6%. The mother liquor is recycled with solvent and crude.

[0012] Example 3

A: Preparation of hydroxylamine

Add 20 g of 16 (17) a-epoxy prednisolone to 120 ml of ethanol in a 100 ml three-necked flask and incubate at 30-35 ° C with stirring to give Sg ammonia at 16 to 20 hours , TLC test reaction end point, after the reaction, vacuum exhaust ammonia gas, concentrated ethanol to the near dry, cooling, adding 300ml chloroform, stirring dissolved residue, and then add 3x100ml saturated brine washing, plus 10ml pure water washing, washing And then concentrated to reduce the chloroform to dry, add 200ml of ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 ° C, hot filter, l2ml ethyl acetate washing carbon, combined filtrate and lotion And then concentrated below 50 ° C to 95% ethyl acetate under reduced pressure. The system was cooled to -5-0 0C, stirred for 2 to 3 hours, filtered, 0.5-l of ethyl acetate, washed and filtrate The filter cake was dried at 70 ° C, 18.6 g of hydroxylamine, 99.5% of HPLC, and 93% by weight.

[0013] B: Preparation of terracavir

In a 100ml three-necked flask, add 10g of hydroxylamine, 500ml toluene, 150ml acetic anhydride, stirring at room temperature by adding 5g concentrated sulfuric acid, insulation at 30-35 degrees stirring reaction 12-16 hours, TLC confirmed the end of the reaction, after the reaction, Add 500ml of pure water, and liquid pH adjustment pH 7.5, cooling to 1 ~ 15 ° C, stirring 0.5-1 hours, the water layer, washed to neutral, combined with water and lotion, pretreated into the wastewater The cells were dried and the organic layer was concentrated to dryness under reduced pressure. 200 ml of hexane was added and refluxed

0.5-1 hours, slowly cool to -5 ~ O0C, stirring crystallization 2-3 hours, filtration, filter cake with 4-5ml hexane, the filtrate and lotion combined apply to the next batch, filter cake below 70 ° C Drying, digoxin crude 112.5g, HPLC content of 97.4%, the yield of 112,5% ο will be the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, heating reflux bleaching 1-1.5 hours, while Hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -500C, frozen crystallization for 2-3 hours, filter, filter cake with 4-5ml alcohol Washing, 70 ° C below the dry, Diges can special products 86.2g, melting point 255.5-256.0 degrees, HPLC content of 99.8%, the yield of 86.2%. The mother liquor is recycled with solvent and crude.

PATENT

https://www.google.com/patents/CN101418032A?cl=en

Example 1

21- bromo -ll (3- hydroxy – pregna–l, 4- diene -3, 20-dione [170, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask was added 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw: 178.00; 55 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 20 ° C 0.5 h, the reaction is complete. After completion of the reaction was filtered to remove the white precipitate cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, the solvent was evaporated under reduced pressure to give a pale yellow solid 21.27 g, yield: 92%, HPLC content of greater than 95%.

Example 2

21- bromo -lip- hydroxy – pregna–l, 4- diene -3, 20-dione [17 “16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw : 178.00; 55 mmol), 150 ml of toluene; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 110 ° C 5 h, the reaction is complete. After completion of the reaction was cooled to room temperature, the white precipitate was removed by filtration cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 19.65 g, yield: 85%, HPLC content greater than 95%.

Example 3

21 Jie bromo -11 – hydroxy – pregna-1,4-diene -3, 20-dione [17a, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System Stirring was continued at reflux for 3 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.18 g, yield: 70%, HPLC content greater than 92%.

Example 4

21- bromo -11 Jie – hydroxy – pregna-1,4-diene -3, 20- dione [17c, 16o-d] -2′- methyl-oxazoline (4) Preparation:

A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml dichloromethane; followed by ammonium acetate (0.039 g; Fw: 77.08; 0.0005 mmol) added to the system. System Stirring was continued at reflux for 24 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.41 g, yield: 71%, HPLC content of greater than 92. / 0.

Example 5

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of sodium acetate (8.20g; Fw: 82.03; lOOmmol), 50 mL methanol was added to the system.

Then tetrabutylammonium bromide (O. 81g; Fw: 322.38; 2.5 mmol). Warmed to 50 ° C with stirring

48 h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase washed with 10% aqueous sodium carbonate paint 3 times, saturated sodium chloride once. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, purified ethyl acetate to give the product 9.93g, yield 90%, HPLC content> 990/0.

Example 6

Deflazacort Preparation –

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetone was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.

Example 7

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetonitrile was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.

Example 8

Deflazacort Preparation:

In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (2.45g; Fw: 98.14; 25 mmol), the N, N- dimethylformamide, 50 mL added to the system. Followed by tetrabutylammonium iodide (O.IO g; Fw: 369.37; 0.25 mmol). Warmed to 120. C stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99o / q.

PATENT

https://www.google.com/patents/WO1997021722A1?cl=zh

compound (llβ,16β)-21-(acetyloxy)-11- hydroxy-2 ‘ -methyl-5 ‘H-pregna-1, -dieno[17 , 16-d Joxazole- 3,20-dione, also known, and hereinafter referred to, with the INN (International Nonproprietary Name) deflazacort. Deflazacort is represented by the following formula I

Figure imgf000003_0001

Deflazacort is employed in therapy aince some years as a calcium-sparing corticoid agent. This compound belongs to the more general class of pregneno-oxazolines, for which anti-inflammatory, glucocorticoid and hormone-like pharmacological activities are reported. Examples of compounds of the above class, comprising deflazacort, are disclosed in US 3413286, where deflazacort is referred to as llβ-21-dihydroxy-2 ‘ -methyl-5 ‘ βH-pregna-1,4-dieno.17 , 16- d]oxazole-3,20-dione 21-acetate.

According to the process disclosed by US 3413286, deflazacort is obtained from 5-pregnane-3β-ol-ll , 20- dione-2 ‘-methyloxazoline by 2 , -dibromination with Br2– dioxane, heating the product in the presence of LiBr- iC03 for obtaining the 1,4-diene, and converting this latter into the 21-iodo and then into the desired 21- acetyloxy compound. By hydrolysis of deflazacort, the llβ-21-dihydroxy-2 ‘ -methyl-5 ‘βH-pregna-1, -dieno[ 17 , 16- d-]oxazoline-3, 20-dione of formula II is obtained:

Figure imgf000004_0001

The compound of formula II is preferably obtained according to a fermentation process disclosed in

EP-B-322630; in said patent, the compound of formula II is referred to as llβ-21-dihydroxy-2 ‘-methyl-5 ‘ βH- pregna-1,4-dieno[17,16-d-]oxazoline-3,20-dione.

The present invention provides a new advantageous single-step process for obtaining deflazacort, by acetylation of the compound of formula II.

CLIP

Image result for Deflazacort NMR

tructure of deflazacort and its forced degradation product (A), chromatogram plot of standard deflazacort (B), contour plot of deflazacort (C). Deflazacort was found to be a stable drug under stress condition such as thermal, neutral and oxidative condition. However, the forceddegradation study on deflazacort showed that the drug degraded under alkaline, acid and photolytic conditions.

Mass fragmentation pathway for degradant product of deflazacort.

PATENT

CN 103059096

Figure CN103059096AD00051

Example 1: Protective reaction To the reaction flask was added 20 g of 1,4-diene-11? -hydroxy-16,17-epoxy_3,20-dione pregnone (Formula I) 20% of the aqueous solution of glacial acetic acid 300g, stirring 5 minutes, temperature 10 ° C ~ 15 ° C, adding ethyl carbazate 14g, temperature control 30 ° C reaction 6 hours; TLC detection reaction is complete, cooling to 0 ° C ~ 5 ° C for 2 hours, until dry, washed to neutral; 60 ° C vacuum dry to dry creatures 20. 5g; on P, oxazoline ring reaction The above protective products into the reaction bottle, add 41ml Of the DMAC dissolved, temperature 25 ~ 30 ° C, access to ammonia, to keep the reaction bottle micro-positive pressure, the reaction of 32 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes; 5 ° C, temperature 5 ~ 0 ° C by adding 5ml glacial acetic acid, then add 21ml acetic anhydride, heated to 35 ° C reaction 4 hours, the sample to confirm the reaction completely; slowly add 5% sodium hydroxide solution 610ml and heated to 60 ~ 70 ° C reaction 2 hours; point plate to confirm the end of the reaction, cooling to 50 ° C, half an hour by adding refined concentrated hydrochloric acid 40ml, insulation 50 ~ 55 ° C reaction 10 hours; to the end of the reaction temperature to room temperature, chloroform Extraction, drying and filtration, concentration of at least a small amount of solvent, ethyl acetate entrained twice, leaving a small amount of solvent, frozen crystallization filter high purity [17a, 16a-d] terfu Kete intermediate. Example 2: Protective reaction 20 g of 1,4-diene-l1-la-hydroxy-16,17-epoxy_3,20_dione progestin (Formula I) was added to the reaction flask and 15% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding methyl carbazate 12g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, Suction to dry, washed to neutral; 60 ° C vacuum drying to dry protection of 20g; on P, oxazoline ring reaction The protection of the reaction into the reaction flask, add 30ml of DMF dissolved, temperature control 25 ~ 30 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 30 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooled to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 30 ° C reaction for 5 hours to confirm the reaction is complete; slowly add 20% sodium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 4 hours, the point plate to confirm the reaction The temperature of 55 ~ 60 ° C for 10 hours; to be the end of the reaction temperature to room temperature, chloroform extraction, drying and filtration, concentration of a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues. [0024] Example 3: Protective reaction 20 g of I, 4-diene-16,17-epoxy-3,11,20-triketone pregnone (Formula I) was added to the reaction flask and 20% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding hydrazine carbamate 15g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, To the dry, washed to neutral; 60 ° C vacuum drying to dry protection of 22g; on P, oxazoline ring reaction of the protection of the reaction into the bottle, add 30ml of DMAC dissolved temperature control 35 ~ 40 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 40 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooling to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 40 ° C reaction 5 hours to confirm the reaction is complete; slowly add 20% potassium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 7 hours, the point plate to confirm the reaction The temperature of the reaction to the end of the temperature to room temperature, chloroform extraction, drying filter, concentrated to a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues.

PATENT

CN 102936274

Figure CN102936274BD00041

xample 1

[0028] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 15 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10-15 ° C), 30 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 30.6 g, 102% mass yield, product by HPLC , a purity of 95.2%.

[0029] Example 2

[0030] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mL of pyridine were mixed, added pressure reactor, stirring ammonia gas to the reactor pressure to 0. 15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 15 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 28.6 g, yield 95% by mass, product by HPLC , a purity of 94.8%.

[0031] Example 3

[0032] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction.Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31.2 g, yield 104% quality products by HPLC , a purity of 95.4%.

[0033] Example 4

[0034] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.5 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31. I g, 102% mass yield, product by by HPLC, the purity was 95.2%.

[0035] Example 5

[0036] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 60 mL of acetic acid, 15 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29. 5 g, yield 98% by mass, the product of by HPLC, purity of 95%.

[0037] Example 6

[0038] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. The reaction was complete, the material was transferred to a glass reaction flask until the material temperature drops below 10 ° C, plus acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of maleic dianhydride, the reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 30 g, 100% mass yield, product by HPLC purity of 95.2%.

[0039] Example 7

[0040] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of propionic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 27.6 g, 92% yield of quality products by HPLC , a purity of 93.5%.

[0041] Example 8

[0042] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature is controlled at 50 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29.8 g, 99% yield of quality products by HPLC , a purity of 94.8%.

References

  1. Jump up^ “Refla: deflazacort” (PDF).
  2. Jump up^http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208684s000,208685s000lbl.pdf
  3. Jump up^ Möllmann, H; Hochhaus, G; Rohatagi, S; Barth, J; Derendorf, H (1995). “Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone”. Pharmaceutical Research. 12 (7): 1096–100. PMID 7494809.
  4. ^ Jump up to:a b “Calcort”. electronic Medicines Compendium. June 11, 2008. Retrieved on October 28, 2008.
  5. Jump up^ Luca Parente (2017). “Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids”. BMC Pharmacol Toxicol. doi:10.1186/s40360-016-0111-8.
  6. Jump up^ Ellen Jean Hirst (January 19, 2015), Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016, The Chicago Tribune, retrieved February 13, 2017,has been shown to prolong lives … a progressive and fatal disease that has no drug treatment available in the US
  7. Jump up^ “FDA approves drug to treat Duchenne muscular dystrophy”. http://www.fda.gov. 2017-02-09. Retrieved 2017-02-10.
  8. Jump up^ “Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug”. http://www.wsj.com. 2017-02-10. Retrieved 2017-02-10.
  9. Jump up^ Clifton Sy Mukherjee (February 10, 2017). “Brainstorm Health Daily”. Retrieved February 13, 2017.
  10. Jump up^ Joseph Walker and Susan Pulliam (February 13, 2017), Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug After 70-Fold Increase, The Wall Street Journal, retrieved February 13, 2017,FDA-approved deflazacort treats rare type of disease affecting boys
  11. Jump up^ “Substâncias: DEFLAZACORT” (in Portuguese). Centralx. 2008. Retrieved on October 28, 2008.
Deflazacort
Deflazacort structure.svg
Clinical data
Trade names Emflaza, Calcort, others
AHFS/Drugs.com International Drug Names
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 40%
Metabolism By plasma esterases, to active metabolite
Biological half-life 1.1–1.9 hours (metabolite)
Excretion Renal (70%) and fecal (30%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.034.969
Chemical and physical data
Formula C25H31NO6
Molar mass 441.517 g/mol
3D model (Jmol)
CN102746358A * Apr 22, 2011 Oct 24, 2012 天津金耀集团有限公司 Novel technology for synthesis of pregnane 21-bit bromide
CN102746358B * Apr 22, 2011 Feb 10, 2016 天津金耀集团有限公司 一种合成孕甾21位溴化物的工艺
CN102936274A * Nov 12, 2012 Feb 20, 2013 浙江仙居君业药业有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN102936274B * Nov 12, 2012 Apr 1, 2015 江西君业生物制药有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline

///////FDA 2017, Emflaza, Calcort, Deflazacort, orphan drug designation, FAST TRACK

[H][C@@]12C[C@@]3([H])[C@]4([H])CCC5=CC(=O)C=C[C@]5(C)[C@@]4([H])[C@@]([H])(O)C[C@]3(C)[C@@]1(N=C(C)O2)C(=O)COC(C)=O

FDA approves new psoriasis drug Siliq (brodalumab)


FDA approves new psoriasis drug

The U.S. Food and Drug Administration today approved Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis. Siliq is administered as an injection.

Read more.

For Immediate Release

February 15, 2017

Release

The U.S. Food and Drug Administration today approved Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis. Siliq is administered as an injection.

Siliq is intended for patients who are candidates for systemic therapy (treatment using substances that travel through the bloodstream, after being taken by mouth or injected) or phototherapy (ultraviolet light treatment) and have failed to respond, or have stopped responding to other systemic therapies.

“Moderate-to-severe plaque psoriasis can cause significant skin irritation and discomfort for patients, and today’s approval provides patients with another treatment option for their psoriasis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Patients and their health care providers should discuss the benefits and risks of Siliq before considering treatment.”

Psoriasis is a skin condition that causes patches of skin redness and flaking. Psoriasis is an autoimmune disorder that occurs more commonly in patients with a family history of the disease, and most often begins in people between the ages of 15 and 35. The most common form of psoriasis is plaque psoriasis, in which patients develop thick, red skin with flaky, silver-white scales.

Siliq’s active ingredient (brodalumab) binds to a protein that causes inflammation, inhibiting the inflammatory response that plays a role in the development of plaque psoriasis.

Siliq’s safety and efficacy were established in three randomized, placebo-controlled clinical trials with a total of 4,373 adult participants with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. More patients treated with Siliq compared to placebo had skin that was clear or almost clear, as assessed by scoring of the extent, nature and severity of psoriatic changes of the skin.

Suicidal ideation and behavior, including completed suicides, have occurred in patients treated with Siliq during clinical trials. Siliq users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior compared to users without this history. A causal association between treatment with Siliq and increased risk of suicidal ideation and behavior has not been established.

Because of the observed risk of suicidal ideation and behavior, the labeling for Siliq includes a Boxed Warning and the drug is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Siliq REMS Program. Notable requirements of the Siliq REMS Program include the following:

  • Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
  • Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety or other mood changes.
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Siliq.

Siliq is also approved with a Medication Guide to inform patients of the risk of suicidal ideation and behavior, and that because Siliq is a medication that affects the immune system, patients may have a greater risk of getting an infection, or an allergic or autoimmune condition. Patients with Crohn’s disease should not use Siliq. Health care providers should also evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Siliq. Health care providers should not administer Siliq to patients with active TB infection, and should avoid immunizations with live vaccines in patients being treated with Siliq.

The most common adverse reactions reported with the use of Siliq include joint pain (arthralgia), headache, fatigue, diarrhea, throat pain (oropharyngeal pain), nausea, muscle pain (myalgia), injection site reactions, influenza, low white blood cell count (neutropenia) and fungal (tinea) infections.

Siliq is marketed by Bridgewater, New Jersey-based Valeant Pharmaceuticals.

Award for me, 100 Most Impactful Health care Leaders Global listing


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At award function for my award “100 Most Impactful Health care Leaders Global listing”, conferred on me at Taj lands end, Mumbai, India on 14 Feb 2014 by World Health Wellness congress and awards

 

Lorlatinib, лорлатиниб , لورلاتينيب , 洛拉替尼 , PF-6463922


Lorlatinib.svgChemSpider 2D Image | lorlatinib | C21H19FN6O2

Lorlatinib, PF-6463922

For Cancer; Non-small-cell lung cancer

  • Molecular Formula C21H19FN6O2
  • Average mass 406.413 Da

Phase 2

WO 2013132376

Andrew James Jensen, Suman Luthra, Paul Francis RICHARDSON
Applicant Pfizer Inc.
Image result for pfizer
(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8- methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
(16R)-19-Amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10,12,14,18,20-octaene-3-carbonitrile
(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
CAS 1454846-35-5 [RN]
UNII:OSP71S83EU
лорлатиниб [Russian]
لورلاتينيب [Arabic]
洛拉替尼 [Chinese]

Ros1 tyrosine kinase receptor inhibitor; Anaplastic lymphoma kinase receptor inhibitor

useful for treating cancer mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) receptor tyrosine kinase, particularly NSCLC.  an ATP-competitive inhibitor of ROS1/ALK, for treating NSCLC. In February 2017, lorlatinib was reported to be in phase 2 clinical development.

  • Originator Pfizer
  • Developer Pfizer; The Childrens Hospital of Philadelphia; Yale University
  • Class Antineoplastics; Aza compounds; Benzoxazines; Pyrazoles; Pyrazolones; Small molecules
  • Mechanism of Action Anaplastic lymphoma kinase inhibitors; ROS1-protein-inhibitors
  • Orphan Drug Status Yes – Non-small cell lung cancer

Lorlatinib (PF-6463922) is an experimental anti-neoplastic drug in development by Pfizer. It is a orally-administered small molecule inhibitor of ROS1 and ALK.

In 2015, FDA granted Pfizer orphan drug status for lorlatinib for the treatment of non-small cell lung cancer.[1]

  • 05 Oct 2016 Massachusetts General Hospital plans a phase II trial for Non-small cell lung cancer (Late-stage disease, Metastatic disease) in USA (PO, unspecified formulation) (NCT02927340)
  • 01 Oct 2016 Pfizer completes a phase I trial in pharmacokinetic trial in Healthy volunteers in USA (NCT02804399)
  • 01 Aug 2016 Pfizer initiates a phase I drug-drug interaction trial in Healthy volunteers in Belgium (PO, unspecified formulation) (NCT02838264)

Figure

Structures of ALK inhibitors marketed or currently in the clinic

Synthesis

NEED COLOUR

Clinical studies

Several clinical trials are ongoing. A phase II trial comparing avelumab alone and in combination with lorlatinib or crizotinib for non-small cell lung cancer is expected to be complete in late 2017. A phase II trial comparing lorlatinib with crizotinib is expected to be complete in mid-2018.[2] A phase II trial for treatment of ALK-positive or ROS1-positive non-small cell lung cancer with CNA metastases is not expected to be complete until 2023.[3] Preclinical studies are investigating lorlatinib for treatment of neuroblastoma.

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Due to tumor complexity and development of resistance to treatment, disease progression is a challenge in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). A common site for progression in metastatic NSCLC is the brain. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.

ABOUT LORLATINIB

ALK in NSCLC ROS1 in NSCLC PRECLINICAL DATA CLINICAL STUDIES Originally discovered as an oncogenic driver in a type of lymphoma, ALK gene alterations were also found to be among key drivers of tumor development in cancers, such as NSCLC.1 In ALK-positive lung cancer, a normally inactive gene called ALK is fused with another gene. This genetic alteration creates the ALK fusion gene and ultimately, the production of an ALK fusion protein, which is responsible for tumor growth.1,2 This genetic alteration is present in 3-5% of NSCLC patients.3,4,5 Another gene that can fuse with other genes is called ROS1. Sometimes a ROS1 fusion protein can contribute to cancer-cell growth and tumor survival. This genetic alteration is present in approximately 1% of NSCLC patients.5 Preclinical data showed lorlatinib is capable of overcoming resistance to existing ALK inhibitors and penetrated the blood brain barrier in ALK-driven tumor models.2 Specifically, in these preclinical models, lorlatinib had activity against all tested clinical resistance mutations in ALK.

A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. • The primary objective of the Phase 1 portion was to assess safety and tolerability of single-agent lorlatinib at increasing dose levels in patients with ALK-positive or ROS1-positive advanced NSCLC.6 • Data from the Phase 1 study showed that lorlatinib had promising clinical activity in patients with ALK-positive or ROS1- positive advanced NSCLC. Most of these patients had developed CNS metastases and had received ≥1 prior tyrosine kinase inhibitor.7 o The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

PATENT

WO2014207606

This invention relates to crystalline forms of the macrocyclic kinase inhibitor, (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4, 3-?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, including crystalline solvates thereof, that may be useful in the treatment of abnormal cell growth, such as cancer, in mammals. The invention also relates to compositions including such crystalline forms, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.

Background of the Invention

The compound (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, represented by the formula (I):

(I)

is a potent, macrocyclic inhibitor of both wild type and resistance mutant forms of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) receptor tyrosine kinase. Preparation of the free base compound of formula (I) as an amorphous solid is disclosed in International Patent Publication No. WO 2013/132376 and in United States Patent Publication No. 2013/0252961 , the contents of which are incorporated herein by reference in their entirety.

Human cancers comprise a diverse array of diseases that collectively are one of the leading causes of death in developed countries throughout the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of cancers is caused by a complex series of multiple genetic and molecular events including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan & Weinberg, The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of

cancer are both diverse and complex, each cancer type has been observed to exhibit common traits and acquired capabilities that facilitate its progression. These acquired capabilities include dysregulated cell growth, sustained ability to recruit blood vessels (i.e., angiogenesis), and ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan & Weinberg 2000). Therefore, the ability to identify novel therapeutic agents that inhibit molecular targets that are altered during cancer progression or target multiple processes that are common to cancer progression in a variety of tumors presents a significant unmet need.

Receptor tyrosine kinases (RTKs) play fundamental roles in cellular processes, including cell proliferation, migration, metabolism, differentiation, and survival. RTK activity is tightly controlled in normal cells. The constitutively enhanced RTK activities from point mutation, amplification, and rearrangement of the corresponding genes have been implicated in the development and progression of many types of cancer. (Gschwind et al., The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 2004; 4, 361-370; Krause & Van Etten, Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005; 353: 172-187.)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, grouped together with leukocyte tyrosine kinase (LTK) to a subfamily within the insulin receptor (IR) superfamily. ALK was first discovered as a fusion protein with nucleophosmin (NPM) in anaplastic large cell lymphoma (ALCL) cell lines in 1994. (Morris et al., Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263:1281-1284.) NPM-ALK, which results from a chromosomal translocation, is implicated in the pathogenesis of human anaplastic large cell lymphoma (ALCL) (Pulford et al., Anaplastic lymphoma kinase proteins in growth control and cancer. J. Cell Physiol., 2004; 199: 330-58). The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of ALCL have been defined (Wan et. al., Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large cell lymphoma cells. Blood, 2006; 107:1617-1623). Other chromosomal rearrangements resulting in ALK fusions have been subsequently detected in ALCL (50-60%), inflammatory myofibroblastic tumors (27%), and non-small-cell lung cancer (NSCLC) (2-7%). (Palmer et al., Anaplastic lymphoma kinase: signaling in development and disease. Biochem. J. 2009; 420:345-361 .)

The EML4-ALK fusion gene, comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the ALK gene, was first discovered in NSCLC archived clinical specimens and cell lines. (Soda et al., Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 2007; 448:561-566; Rikova et al., Cell 2007; 131 :1 190-1203.) EML4-ALK fusion variants were demonstrated to transform NIH-3T3 fibroblasts and cause lung adenocarcinoma when expressed in transgenic mice, confirming the

potent oncogenic activity of the EML4-ALK fusion kinase. (Soda et al., A mouse model for EML4-ALK-positive lung cancer. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:19893-19897.) Oncogenic mutations of ALK in both familial and sporadic cases of neuroblastoma have also been reported. (Caren et al., High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumors. Biochem. J. 2008; 416:153-159.)

ROS1 is a proto-oncogene receptor tyrosine kinase that belongs to the insulin receptor subfamily, and is involved in cell proliferation and differentiation processes. (Nagarajan et al. Proc Natl Acad Sci 1986; 83:6568-6572). ROS is expressed, in humans, in epithelial cells of a variety of different tissues. Defects in ROS expression and/or activation have been found in glioblastoma, as well as tumors of the central nervous system (Charest et al., Genes Chromos. Can. 2003; 37(1): 58-71). Genetic alterations involving ROS that result in aberrant fusion proteins of ROS kinase have been described, including the FIG-ROS deletion translocation in glioblastoma (Charest et al. (2003); Birchmeier et al. Proc Natl Acad Sci 1987; 84:9270-9274; and NSCLC (Rimkunas et al., Analysis of Receptor Tyrosine Kinase ROS1 -Positive Tumors in Non-Small Cell Lung Cancer: Identification of FIG-ROS1 Fusion, Clin Cancer Res 2012; 18:4449-4457), the SLC34A2-ROS translocation in NSCLC (Rikova et al. Cell 2007;131 :1 190-1203), the CD74-ROS translocation in NSCLC (Rikova et al. (2007)) and cholangiocarcinoma (Gu et al. PLoS ONE 201 1 ; 6(1 ): e15640), and a truncated, active form of ROS known to drive tumor growth in mice (Birchmeier et al. Mol. Cell. Bio. 1986; 6(9):3109-31 15). Additional fusions, including TPM3-ROS1 , SDC4-ROS1 , EZR-ROS1 and LRIG3-ROS1 , have been reported in lung cancer patient tumor samples (Takeuchi et al., RET, ROS1 and ALK fusions in lung cancer, Nature Medicine 2012; 18(3):378-381).

The dual ALK/c-MET inhibitor crizotinib was approved in 201 1 for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. Crizotinib has also shown efficacy in treatment of NSCLC with ROS1 translocations. (Shaw et al. Clinical activity of crizotinib in advanced rson-smali cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, June 1-5, 2012.) As observed clinically for other tyrosine kinase inhibitors, mutations in ALK and ROS1 that confer resistance to ALK inhibitors have been described (Choi et ai., EML4-ALK Mutations in Lung Cancer than Confer Resistance to ALK Inhibitors, N Engl J Med 2010; 363:1734-1739; Awad et ai., Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1, Engl J Med 2013; 368:2395-2401 ).

Thus, ALK and ROS1 are attractive molecular targets for cancer therapeutic intervention. There remains a need to identify compounds having novel activity profiles against wild-type and mutant forms of ALK and ROS1 .

The present invention provides crystalline forms of the free base of (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2, 5,1 1 ]-benzoxadiazacyclotetradecine-3-carbonitrile having improved properties, such as improved crystallinity, dissolution properties, decreased hygroscopicity, improved mechanical properties, improved purity, and/or improved stability, while maintaining chemical and enantiomeric stability.

Comparative Example 1A

Preparation of (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxadiazacyclo-tetradecine-3-carbonitrile (amorphous)

Example 1A

Step 1 :

Palladium (II) acetate (53 mg, 0.24 mmol) and cataCXium® A (180 mg, 0.5 mmol) were mixed together in toluene (1 .5 mL, de-gassed) and the resulting solution was added via pipette to a stirred solution of compound 7 (0.9 g, 2.4 mmol), compound 15 (1 .0 g, 3.0 mmol) bis-pinacolato diboron (0.9 g, 3.6 mmol) and CsF (1 .9 g, 12.6 mmol) in MeOH/H20 (9:1 , 12 mL, degassed) at 60 °C. The resulting mixture was then stirred at reflux for 3 hrs. A further portion of Palladium (II) acetate (26 mg, 0.12 mmol) and cataCXium® A (90 mg, 0.25 mmol) in toluene (1 .5 mL, de-gassed) was added, and the yellow reaction mixture stirred at 60 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (150 mL) and filtered through CELITE®. The filtrate was washed with water (100 mL), then brine (100 mL), dried (Na2S04) and evaporated. The residue was purified by flash chromatography over silica gel, which was eluted with 1 :1 EtOAc/cyclohexane, to give compound 22 as a yellow oil (570 mg, 43% yield). TLC (Rf = 0.40, 1 :1 EtOAc/cyclohexane). 1H NMR (400 MHz, CDCI3) δ 8.03 (m, 1 H), 7.65 (s, 1 H), 7.27 (dd,1 H, J = 9.9, 2.7 Hz), 7.01 (m, 1 H), 6.68 (m, 1 H), 6.40 (m, 1 H), 4.90 (br s, 2 H), 4.20 – 4.30 (m, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 2.55 – 2.85 (m, 3 H), 1 .68 (d, 3 H, J = 6.6 Hz), 1 .24 (s, 9 H). LCMS ES m/z 539 [M+H]+.

Step 2:

To a solution of compound 22 (69% purity, 0.95 g, assumed 1 .05 mmol) in MeOH (20 mL) was added a solution NaOH (1 .0 g, 25 mmol) in water (2 mL). The mixture was stirred at 40 °C for 3.5 hours. The reaction was diluted with water (80 mL), concentrated by 20 mL to remove MeOH on the rotary evaporator, and washed with MTBE (100 mL). The aqueous layer was then acidified carefully with 1 M aq HCI to approx. pH 2 (pH paper). Sodium chloride (15 g) was added to the mixture and the mixture was extracted with EtOAc (100 mL). The organic layer was separated, dried (Na2S04) and evaporated to give compound 23 as a pale yellow solid (480 mg, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.05 (m, 1 H), 7.45 (s, 1 H), 7.37 (dd,1 H, J = 10.4, 2.8 Hz), 7.10 (dt, 1 H, J = 8.5, 2.4 Hz), 6.50 – 6.60 (m, 2 H), 4.05 – 4.30 (m, 2 H), 3.99 (s, 3 H), 2.60 – 2.80 (m, 3 H), 1 .72 (d, 3 H, J = 6.5 Hz). LCMS ES m/z 525 [M+H]+.

Step 3:

A solution of HCI in dioxane (4 M, 6.0 mL) was added to a solution of compound 23

(480 mg, 0.91 mmol) in MeOH (methanol) (6 mL) and the reaction was stirred at 40 °C for 2.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was taken-up in MeOH (50 mL) and acetonitrile (100 mL) was added and the mixture was then again evaporated to dryness, to give compound 24 as an off white solid (400 mg, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.07 (dd, 1 H, J = 8.9. 5.9 Hz), 7.51 (d, 1 H, J = 1 .7 Hz), 7.42 (dd, 1 H, J = 9.8, 2.6 Hz), 7.23 (d, 1 H, J = 1 .6 Hz), 7.16 (dt, 1 H, J = 8.5, 2.7 Hz), 6.73 (dd, 1 H, J = 1 1 .9, 6.9 Hz), 4.22 (d, 1 H, J = 14.7 Hz), 4.14 (d, 1 H, J = 14.7 Hz), 4.07 (s, 3 H), 2.75 (s, 3 H), 1 .75 (d, 3 H, J = 5.5 Hz). LCMS ES m/z 425 [M+H]+.

Step 4:

A solution of compound 24 (400 mg, assumed 0.91 mmol) as the HCI salt and DIPEA

(diisopropylethylamine) (1 .17 g, 9.1 mmol) in DMF (dimethylformamide) (5.0 mL) and THF (0.5 mL) was added drop-wise to a solution of HATU (2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (482 mg, 1 .27 mmol) in DMF (10.0 mL) at 0 °C over 30 minutes. After complete addition, the mixture was stirred at 0 °C for a further 30 mins. Water (70 mL) was added and the mixture was extracted into EtOAc (2 x 60 mL). The combined organics were washed with saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried over Na2S04, and evaporated. The residue was purified by column chromatography over silica gel, which was eluted with 70% EtOAc/cyclohexane giving 205 mg of a pale yellow residue (semi-solid). The solids were dissolved in MTBE (7 mL) and cyclohexane (20 mL) was added slowly with good stirring to precipitate the product. After stirring for 30 minutes, the mixture was filtered, and Example 1A was collected as an

amorphous white solid (1 10 mg, 29% yield). TLC (Rf = 0.40, 70% EtOAc in cyclohexane). 1H NMR (400 MHz, CDCI3) δ 7.83 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 9.6, 2.4 Hz), 7.21 (dd, 1 H, J = 8.4, 5.6 Hz), 6.99 (dt, 1 H, J = 8.0, 2.8 Hz), 6.86 (d, 1 H, J = 1 .2 Hz), 5.75 – 5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, 1 H, J = 14.4 Hz), 4.35 (d ,1 H, J = 14.4 Hz), 4.07 (s, 3 H), 3.13 (s, 3 H), 1 .79 (d, 3 H, J = 6.4Hz). LCMS ES m/z 407 [M+H]+.

Example 1

Preparation of crystalline hydrate of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo- 10,15,16,17-tetrahvdro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxa-diazacyclo-tetradecine-3-carbonitrile (Form 1)

Example 1A Example 1

(amorphous) (Form 1 }

Amorphous (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2,5,11 ]benzoxa-diazacyclo-tetradecine-3-carbonitrile free base, prepared as described in Example 1A (and Example 2 of United States Patent Publication No. 2013/0252961), was dissolved in 1 .0 : 1 .1 (v:v) H20:MeOH at a concentration of 22 mg/mL at 50°C, then allowed to cool to room temperature . This slurry was granulated for approximately 72 hours. The solids were isolated by filtration and vacuum dried overnight at 60°C to produce crystalline hydrate Form 1 of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-/?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile.

Example 4

Alternative preparation of crystalline acetic acid solvate of (10 ?)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahvdro-2H-8,4-(metheno)pyrazolo[4,3- ?U2,5, 1 1 lbenzoxa-diazacyclotetradecine-3-carbonitrile (Form 3)

Step 1 :

To a reaction vessel under N2 were charged compound 9 (9.97 kg, 17.95 mol), compound 21 (3.52 kg, 18.85 mol) and 2-methyltetrahydrofuran (97 L). Triethylamine (7.45 kg, 73.6 mol) was added while keeping the internal temperature below 35°C. The reaction mixture was held for 30 min and n-propylphosphonic anhydride (T3P), 50% solution in ethyl acetate (22.85 kg, 35.9 mol) was charged slowly, maintaining the internal temperature below 25°C. The reaction mixture was held at 20°C for at least 2 h until reaction was deemed complete. Ethyl acetate (35 L) and water (66 L) were added followed by 0.5N Hydrochloric acid solution (80 L). The aqueous layer was removed and the organic layer was washed with brine solution (80 L). The organic layer was concentrated and solvent exchanged with 2-methyl-2-butanol (80 L) give compound 25 (23 wt/wt%) solution in 2-methyl-2-butanol . This solution was carried forward to the next step directly in three batches, assuming 12.00 kg (100% yield) from this step.

Step 2:

2-Methyl-2-butanol (100 L) was combined with potassium acetate (1 .8 kg, 18.34 mol), palladium(ll) acetate (0.10 kg, 0.46 mol) and water (0.10 kg, 5.73 mol). The resulting mixture was purged with nitrogen. Di(1 -adamantyl)n-butylphosphine (0.23 kg, 0.43 mol) was added. An amount of 20% of compound 25 (3.97 kg active or 17.3 L of step 1 solution in 2-methyl-2-butanol) was added, and the resulting reaction mixture was heated at reflux for 2 h. The remaining solution of compound 25 in 2-methyl-2-butanol was subsequently added to the reaction over a period of 5 h. The resulting mixture was heated until the reaction was deemed complete (typically 16 – 20 h). This reaction step was processed in three batches, and the isolation was done in one single batch. Thus, the combined three batches were filtered through CELITE® to remove insoluble materials. The filtrate was concentrated to a low volume (approximately 20 L). Acetonitrile (60 L) was added. The resulting mixture was heated to reflux for 2 – 4 h, then cooled to RT for granulation. The resulting slurry was filtered to give compound 26 as a crude product. The crude product was combined with ethyl acetate (80 L) and Silicycle thiol (5 kg). The resulting mixture was heated for 2 h, cooled to RT and filtered. The filtrate was concentrated to approx. 20 L, and the resulting slurry was granulated and filtered. The filter cake was rinsed with ethyl acetate (4 L) and dried in a vacuum oven to give compound 26 as a pure product (4.74 kg, 43.5% overall last two steps). 1H NMR (CDCI3) δ 8.25 – 8.23 (m, 1 H), 7.28 (1 H, dd, 2.76 and 9.79 Hz), 7.22 (1 H, dd, 5.52 and 8.53 Hz), 7.18 (1 H, d, J = 1 .76 Hz), 7.01 (1 H, dt, J = 2.50 and 8.03 Hz), 5.78 – 5.70 (m, 1 H), 4.76 (1 H, d, J = 14.3 Hz), 4.13 (s, 3H), 3.16 (s, 3H), 1 .78 (d, 3H, J = 6.02 Hz), 1 .45 (s, 18H); 13C NMR (CDCI3) δ 167.0, 162.9, 160.4, 148.7, 146.3, 143.0, 140.7, 139.9, 135.5, 129.9, 129.8, 126.1 , 123.8, 123.5, 1 19.7, 1 13.8, 1 13.5, 1 1 1 .6, 108.1 , 81 .1 , 70.1 , 45.5, 37.0, 29.7, 26.0, 20.7; LCMS (M+1)+ 607.3, 507.1 , 451 .2.

Step 3:

To a reactor under N2 was added compound 26 (4.74 kg, 7.82 mol) and ethyl acetate (54 L). Hydrochloric acid 37% (5.19 L, 63.2 mol) was charged slowly while keeping the internal temperature below 25°C. The reaction mixture was stirred for 24 – 48 h until the reaction was complete. Ethyl acetate (54L) and water (54 L) were added. The reaction mixture was then treated with triethylamine until pH 8 – 9 was reached. The aqueous layer was removed and then the organic layer was washed water (2 x 54 L). The organic layer was concentrated under reduced pressure to approx. 54 L to give compound 27 (unisolated).

Step 4:

Acetic acid (1 .0 kg, 16.6 mol) was added to the organic layer containing compound 27. The reaction mixture was concentrated and then held for at least 3 h with stirring at RT. The resulted slurry was filtered. The filter cake was washed with ethyl acetate (2 L) and dried under vacuum to give 3.20 kg (87.8% yield) of Example 4 acetic acid solvate (Form 3). The spectroscopic data of this material was identical to that of an authentic sample of the crystalline acetic acid Form 3 of (10R)-7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]-benzoxadiazacyclo-tetradecine-3-carbonitrile prepared according to Example 3.

Preparation of Synthetic Intermediates

7 6 5

Step 1 :

A solution of (-)-DIPCI ((-)-B-chlorodiisopinocampheylborane) (57.1 g, 178 mmol) in THF

(tetrahydrofuran) (100 ml) was cooled to -20 to -30 °C. A solution of compound 1 (31 .3 g, 1 19 mmol) in THF (100 ml) was then added dropwise, via addition funnel (30 min addition). The reaction was left to warm up to room temperature (RT). After 2 h, the reaction was cooled to -30 °C and another portion of (-)-DIPCI (38.0 g, 1 19 mmol) was added. After 30 min, the reaction was allowed to warm to RT and after 1 h, the solvents were removed in vacuo and the residue re-dissolved in MTBE (methyl tertiary-butyl ether) (200 ml). A solution of diethanolamine (31 g, 296 mmol) in ethanol/THF (15 ml/30 ml) was added via addition funnel, to the reaction mixture under an ice bath. The formation of a white precipitate was observed. The suspension was heated at reflux for 2 hours then cooled to room temperature, filtered and the mother liquids concentrated in vacuo. The residue was suspended in heptane/EtOAc (7:3, 200 ml) and again

filtered. This procedure was repeated until no more solids could be observed after the liquids were concentrated. The final yellow oil was purified by column chromatography (eluent: cyclohexane/EtOAc 99:1 to 96:4). The resulting colorless oil was further purified by recrystallization from heptanes, to give alcohol compound 2 (25 g, 80% yield, 99% purity and 96% ee) as white crystals. 1H NMR (400 MHz, CDCI3) δ 7.73 (dd, 1 H), 7.32 (dd, 1 H), 6.74 (ddd, 1 H), 4.99 – 5.04 (m, 1 H), 2.01 (d, 1 H), 1 .44 (d, 3 H). LCMS-ES: No ionization, Purity 99%. Chiral GC (column CP-Chirasil-DexnCB): 96% ee; Rt (minor) 17.7 minutes and Rt (major) 19.4 minutes.

Step 2:

A solution of compound 2 (22 g, 83 mmol) in MTBE (350 mL) was cooled under an ice bath and triethylamine (23 mL, 166 mmol) followed by mesyl chloride (9.6 mL, 124 mmol) were added drop-wise. The reaction was then warmed to RT and stirred for 3 h. The reaction mixture was filtered and the solids washed with EtOAc. The mother liquids were concentrated in vacuo to give compound 3 (35 g, 80% yield) as a pale yellow oil. This material was taken into the following step without further purification. 1H NMR (400 MHz, CDCI3) δ 7.78 (dd, 1 H), 7.24 (dd, 1 H), 6.82 (ddd, 1 H), 2.92 (s, 3 H), 1 .64 (d, 3 H). LCMS-ES no ionization.

Step 3:

A suspension of Cs2C03 (65 g, 201 mmol) and compound 4 (13.3 g, 121 mmol) in 2-CH3-THF (2-methyitetrahydrofuran) (600 mL) and acetone (300 mL) was stirred at RT for 30 minutes then heated at 40 °C before drop-wise addition of a solution of compound 3 (34.4 g, 80 mmol) in 2-CH3-THF (300 mL) via addition funnel. The resulting mixture was left stirring at 75 -80 °C for 24 h. The reaction was then filtered through CELITE® with MTBE, the solvents removed in vacuo and the residue purified by column chromatography over silica gel which was eluted with cyclohexane/EtOAc (9:1 to 1 :1) to give compound 5 (14.3 g, 39 % yield, 90% ee) as a white solid. The solids were then re crystallized from heptane/EtOAc to give compound 5 (10.8 g, 37% yield, 95% ee). 1H NMR (400 MHz, CDCI3) 5 7.38 (dd, 1 H), 7.62 (dd, 1 H), 7.10 (dd, 1 H), 6.75 (ddd, 1 H), 6.44 – 6.51 (m, 2 H), 5.34 – 5.39 (m, 1 H), 4.73 (br s, 2 H), 1 .61 (d, 3 H). LCMS-ES m/z 359 [M+H]+. HPLC (Chiralpak IC 4.6 x 250 mm): 95% ee; Rt (minor) 10.4 minutes; Rt (major) 14.7 minutes; eluent: Heptane 80%/IPA 20% with 0.2% DEA, 0.7 mL/min. Step 4:

Compound 5 (20 g, 57 mmol) was dissolved in methanol (300 mL), and sequentially treated with triethylamine (TEA) (15.4 mL, 1 13 mmol) and PdCI2(dppf) (1 ,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ) (4.1 g, 5.7 mmol). This mixture was heated at 100 °C for 16 hours, under a 100 psi carbon monoxide atmosphere. LCMS indicated consumption of starting material. The reaction mixture was filtered through a pad of CELITE®, and the filtrate evaporated to a brown oil. The crude product was purified by flash

chromatography over silica gel which was eluted with 50% to 75% ethyl acetate in cyclohexane, affording the pure product 6 as a brick-red solid (13.0 g, 79% yield). 1H NMR (400 MHz, CDCI3) δ 1 .65 (d, 3 H), 3.94 (s, 3 H), 4.75 (br s, 2 H), 6.32 (q, 1 H), 6.42 (dd, 1 H), 6.61 (dd, 1 H), 7.00 (ddd, 1 H), 7.28 (dd, 1 H), 7.60 (dd, 1 H), 8.03 (dd, 1 H). LCMS ES m/z 291 for [M+H]+.

Step 5:

Compound 6 (13.0 g, 45 mmol) was dissolved in acetonitrile (195 mL), and cooled to <10 °C in an ice water bath. NBS (N-bromosuccinimide) (7.9 g, 45 mmol) was added drop-wise to the cooled reaction mixture as a solution in acetonitrile (195 mL), monitoring the internal temperature to ensure it did not rise above 10 °C. After addition was complete, the mixture was stirred for 15 minutes. Thin layer chromatography (TLC) (1 :1 cyclohexane/ethyl acetate) showed consumption of starting material. The reaction mixture was evaporated, and the residue redissolved in ethyl acetate (400 mL), and washed with 2M aqueous NaOH (2 x 300 mL), and 10% aqueous sodium thiosulfate solution (300 mL). The organic extracts were dried over MgS04, and evaporated to a red oil (17.6 g). The crude product was purified over silica gel, which was eluted with 10% to 50% ethyl acetate in cyclohexane, which gave compound 7 (12.0 g, 73% yield). 1H NMR (400 MHz, CDCI3) δ 1 .65 (d, 3 H), 3.96 (s, 3 H), 4.74 – 4.81 (br s, 2 H), 6.33 (q, 1 H), 6.75 (d, 1 H), 7.03 (ddd, 1 H), 7.25 (dd, 1 H), 7.66 (d, 1 H), 8.06 (dd, 1 H). LCMS ES m/z 369/371 [M+H]+. A Chiralpak AD-H (4.6 x 100 mm, 5 micron) column was eluted with 10% MeOH (0.1 % DEA) in C02 at 120 bar. A flow rate of 5.0 mL/min gave the minor isomer Rt 0.6 minutes and the major isomer Rt 0.8 minutes (99% ee). Optical rotation: [ ]d20 = -92.4 deg (c=1 .5, MeOH).

Preparation of (/?)-methyl 2-(1 -((N,N-di-Boc-2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoic acid (9)

7

Step 1 :

To a solution of compound 7 (2000 g, 5.4 mol) in dry DCM (dichloromethane) (32000 mL) was added DIPEA (N.N-dsisopropyleibylamine) (2100 g, 16.28 mol) and DMAP (4-dimethylaminopyridine) (132 g, 1 .08 mol). Then Boc20 (di-tert-butyl-dicarbonate) (3552 g, 16.28 mol) was added to the mixture in portions. The reaction was stirred at RT for overnight. TLC (petroleum ether/EtOAc =5:1) show the reaction was complete, the mixture was washed with sat. NH4CI (15 L) two times, then dried over Na2S04and concentrated to give a crude product which was purified by column (silica gel, petroleum ether/EtOAc from 20:1 to 10:1) to give compound 8 (2300 g, 75%) as a white solid.

Step 2:

Compound 8 (50 g, 87.81 mmol, 100 mass%) was charged to a round bottom flask (RBF) containing tetrahydrofuran (12.25 mol/L) in Water (5 mL/g, 3060 mmol, 12.25 mol/L) and sodium hydroxide (1 mol/L) in Water (1 .5 equiv., 131 .7 mmol, 1 mol/L). The biphasic mixture was stirred at RT for 14 hours. 1 N HCI was added to adjust pH to < 2. THF was then removed by vacuum distillation. The product precipitated out was collected by filtration. The filter cake was rinsed with water, pulled dried then dried in vacuum oven to constant weight (48 h, 55°C, 25 mbar). 48.3g isolated, 99% yield. 1H NMR (CDCI3, 400MHz) δ 8.24 (1 H, dd, 1 H, J = 5.76 and 3.0 Hz), 8.16 (1 H, d, J = 2.0 Hz), 7.37 (1 H, dd, J = 2.5 and 9.8 Hz), 7.19 (1 H, d, J = 2 Hz), 7.14 – 7.06 (1 H, m), 6.50 (1 H, q, J = 6.3 Hz), 1 .67 (3H, d, J = 8.4 Hz), 1 .48 (18H, s). 13C NMR (CDCI3, 100 MHz), δ 170.1 , 169.2, 167.6, 165.1 , 150.6, 149.2, 148.6, 141 .4, 140.7, 135.2, 135.1 , 124.2, 122.2,122.1 , 1 19.9, 1 15.4, 1 15.1 , 1 13.4, 1 13.2, 100.0, 83.4, 73.3, 27.9, 23.9. LCMS (M+ +1) 557.2, 555.3, 457.1 , 455.1 , 401 , 0, 399.0.

Step 1 :

Ethyl 1 ,3-dimethylpyrazole-5-carboxylate (5.0 g, 30 mmol) was dissolved in 1 ,2-dichloroethane (200 mL), followed by addition of NBS (5.3 g, 30 mmol) and dibenzoyi peroxide (727 mg, 3.0 mmol), in small portions and stirred at 85 °C for 2 hours. The mixture was allowed to cool, diluted to 400 mL with dichloromethane, and washed with water (2 x 200 mL). The organic layer was dried over MgS04, and evaporated to give compound 10 (4.1 g, 42% yield). TLC (EtOAc/Cyclohexane; 1 :10; KMn04): Rf~0.3. 1H NMR (400 MHz, CDCI3) δ 4.47 (s, 2 H), 4.41 (q, 2 H), 4.15 (s, 3 H), 1 .42 (t, 3 H). LCMS ES m/z 324/326/328 [M+H]+.

Step 2:

Compound 10 (3.0 g, 9.2 mmol) was dissolved in methylamine solution (33% solution in ethanol, 70 mL), and stirred at RT for 16 hours. The mixture was evaporated to give compound 11 (1 .8 g, 71 % yield). 1H NMR (400 MHz, CDCI3) δ 4.39 (q, 2 H), 4.14 (s, 3 H), 4.05 (s, 2 H), 2.62 (d, 3 H), 1 .41 (t, 3 H). LCMS ES m/z 276/278 [M+H]+.

Step 3:

Compound 11 (1 .8 g, 6.5 mmol) was dissolved in dichloromethane (20 mL), and the mixture cooled to 0 °C. A solution of di(fe/?-butyl) dicarbonate (1 .75 g, 8 mmol) in dichloromethane (17.5 mL) was added dropwise. The ice bath was removed and the mixture stirred for 18 hours at room temperature. The mixture was diluted to 100 mL with dichloromethane, and washed with water (2 x 50 mL). Organic extracts were dried over magnesium sulfate, and evaporated to give compound 12 (1 .8 g, 72% yield). 1H NMR (400 MHz, CDCI3) δ 4.48 – 4.44 (m, 2 H), 4.41 (q, 2 H), 4.12 (s, 3 H), 2.82 – 2.79 (m, 3 H), 1 .47 (s, 9 H), 1 .41 (t, 3 H). LCMS ES m/z 376/378 [M+H]+ and 276/278 [M-BOC]+.

Step 4:

Compound 12 (4 g, 1 1 mmol) was dissolved in dioxane (43 mL). Sodium amide (1 g, 27 mmol) was added in one portion. The reaction mixture was stirred at 100 °C for 24 h. After this time, the solvent was removed under reduced pressure to give a white solid. The material was suspended in EtOAc (100 mL) and washed with 5% citric acid solution (100 mL). The organic phase was separated and washed with water (100 mL), dried over MgS04, filtered and the solvent removed in vacuo to give compound 13 as a yellow gum (3.1 g, 84% yield). 1H NMR (400 MHz, DMSO-c/6) δ 4.27 (s, 2 H), 3.92 (s, 3 H), 2.70 (s, 3 H), 1 .40 (s, 9 H). LCMS ES m/z 348/350 [M+H]+ and 248/250 [M-BOC]+.

Step 5:

Compound 13 (3 g, 8.6 mmol) was dissolved in DMF (43 mL, 0.2 M). HOBt (1 .2 g, 8.6 mmol) was added, followed by ammonium chloride (0.9 g, 17.2 mmol). EDCI (2.5 g, 13 mmol) was then added, followed by TEA (2.4 mL, 17 mmol). The reaction mixture was stirred at room temperature. After 18h, the solvent was removed under reduced pressure to give a yellow oil

(8.0 g). The residue was dissolved in EtOAc (75ml_). The organic phase was washed with NaHC03 (sat. solution, 70 ml_) and then brine (100 ml_). The combined organic layers were dried over MgS04 and the solvent removed in vacuo to give compound 14 as a dark yellow oil (2.7 g, 91 % yield). This material was used directly in the next step without further purification. 1H NMR (400 MHz, CDCI3) δ 6.74 (br s, 1 H), 5.95 (br s, 1 H), 4.49 (br s, 2 H), 4.16 (s, 3 H), 2.81 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 347/349 [M+H]+ and 247/249 [M-BOC]+.

Step 6:

Compound 14 (2.7 g, 7.9 mmol) was dissolved in DCM (80 ml_, 0.1 M). TEA (3.3 ml_, 23.8 mmol) was then added and the reaction mixture cooled down to -5 °C. Trifluoroacetic anhydride (2.2 ml_, 15.8 mmol) in DCM (15 ml_) was added dropwise over 30 min. After addition, the reaction mixture was stirred at 0 °C for 1 h. After this time, the solvents were removed under reduced pressure to give a dark yellow oil. This residue was diluted in DCM (100 ml_), washed with 5% citric acid, sat. NaHC03and brine, dried over MgS04, filtered and the solvents removed in vacuo to give a dark yellow oil (2.6 g). The crude product was purified by reverse phase chromatography to give compound 15 as a yellow oil (2.3 g, 87% yield). 1H NMR (400 MHz, CDCI3) δ 4.46 (br s, 2 H), 4.01 (s, 3 H), 2.83 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 331 /329 [M+H]+ and 229/231 [M-BOC]+ as the base ion.

Preparation o/: 1 -methyl-3-((methylamino)methyl)-1 H-pyrazole-5-carbonitrile (21)

Step 1 :

To /V-benzylmethylamine (2.40 kg, 19.8 mol) and ethyldiisopropylamine (2.61 kg, 20.2 mol) in acetonitrile (6 L) at 16°C was added chloroacetone (1 .96 kg, 21 .2 mol) over 60 mins [exothermic, temp kept <30°C]. The mixture was stirred at 22°C for 18 hours then concentrated to an oily solid. The residue was triturated with MTBE (5 L), and then filtered through a pad of CELITE® (600 g, top) and silica (1 .5 kg, bottom), washing with MTBE (8 L). The filtrate was evaporated to afford compound 16 (3.35 kg, 18.9 mol, 95%) as a brown oil.

Step 2:

Compound 16 (1 .68 kg, 9.45 mol), Boc-anhydride (2.1 kg, 9.6 mol) and 20wt% Pd/C (50% H20, 56 g) in ethanol (5 L) were hydrogenated in an 1 1 -L autoclave at 50 psi [exotherm to 40°C with 20°C jacket]. The atmosphere became saturated with carbon dioxide during the reaction and so needed to be vented and de-gassed twice to ensure sufficient hydrogen uptake and completion of the reaction. The total reaction time was ~1 .5 hours. Two runs (for a total of 18.9 mol) were combined and filtered through a pad of SOLKA-FLOC®, washing with methanol. The filtrate was treated with DMAP (45 g, 0.37 mol) and stirred at room temperature overnight to destroy the excess Boc-anhydride. The mixture was then concentrated to dryness, dissolved in MTBE (6 L) and filtered through a pad of magnesol (1 kg), washing with MTBE (4 L). The filtrate was evaporated to afford compound 17 (3.68 kg, ~95 wt%, 18.7 mol, 99%) as an orange-brown oil.

Step 3:

To compound 17 (3.25 kg, -95 wt%, 16.5 mol) and diethyl oxalate (4.71 kg, 32.2 mol) in methanol (12 L) at 15°C was added 25 wt% sodium methoxide in methanol (6.94 kg, 32.1 mol) over 25 mins [temp kept <25°C]. The mixture was stirred at 20°C for 16 hours then cooled to -37°C and 37% hydrochloric acid (3.1 kg, 31 mol) was added over 5 mins [temp kept <-10°C]. The mixture was cooled to -40°C and methylhydrazine (1 .42 kg, 30.8 mol) was added over 7 mins [temp kept <-17°C]. The mixture was warmed to 5°C over 90 minutes, then re-cooled to 0°C and quenched by addition of 2.4M KHS04 (6.75 L, 16.2 mol) in one portion [exotherm to 27°C]. The mixture was diluted with water (25 L) and MTBE (15 L), and the layers separated. The organic layer was washed with brine (7 L) and the aqueous layers then sequentially re-extracted with MTBE (8 L). The combined organics were evaporated and azeotroped with toluene (2 L) to afford crude compound 18. Chromatography (20 kg silica, 10-40% EtOAc in hexane) afforded compound 18 (3.4 kg, ~95 wt%, 11 .4 mol, 69%) as an orange oil.

Step 4:

Ammonia (3 kg, 167 mol) was bubbled in to cooled methanol (24 L) [temp kept <18°C]. A solution of compound 18 (4.8 kg, ~95 wt%, 16.1 mol) in methanol (1 .5 L) was added over 30 minutes and the mixture stirred at 25°C for 68 hours and then at 30°C for 24 hours. Two runs (from a total of 9.68 kg of ~95 wt% Step 3) were combined and concentrated to ~13 L volume. Water (30 L) was slowly added over 80 minutes, keeping the temperature 30 to 40°C. The resulting slurry was cooled to 20°C, filtered, washed with water (12 L) and pulled dry on the filter overnight. The solids were triturated in MTBE (8 L) and hexane (8 L) at 45°C then re-cooled to 15°C, filtered, washed with hexane (4 L) and dried under vacuum to afford compound 19 (7.95 kg, 29.6 mol, 90%) as an off-white solid.

Step 5:

To compound 19 (7.0 kg, 26.1 mol) in DCM (30 L) at 0°C was added triethylamine (5.85 kg, 57.8 mol). The mixture was further cooled to -6°C then trifluoroacetic anhydride (5.85 kg, 27.8 mol) added over 90 minutes [temp kept 0 to 5°C]. TLC assay showed the reaction was incomplete. Additional triethylamine (4.1 kg, 40.5 mol) and trifluoroacetic acid (4.1 kg, 19.5 mol) were added over 2 hours until TLC showed complete reaction. The reaction mixture was quenched in to water (40 L) [temp to 23°C]. The layers were separated and the aqueous re-extracted with DCM (8 L). The organic layers were sequentially washed with brine (7 L), filtered through a pad of silica (3 kg) and eluted with DCM (10 L). The filtrate was evaporated and chromatographed (9 kg silica, eluent 10-30% EtOAc in hexane). Product fractions were evaporated and azeotroped with IPA to afford compound 20 (6.86 kg, -94 wt%, 25.8 mol, 99%) as an orange oil.

Step 6:

To compound 20 (6.86 kg, -94 wt%, 25.8 mol) in IPA (35 L) at 17°C was added 37% hydrochloric acid (6.4 L, 77.4 mol). The mixture was heated to 35°C overnight then concentrated to a moist solid and residual water azeotroped with additional IPA (8 L). The resulting moist solid was triturated with MTBE (12 L) at 45°C for 30 minutes then cooled to 20°C and filtered, washing with MTBE (5 L). The solids were dried under vacuum at 45°C to afford compound 21 (4.52 kg, 24.2 mol, 94%) as a white solid. 1H-NMR was consistent with desired product; mp 203-205°C; HPLC 99.3%. 1H NMR (CD3OD, 400 MHz) δ 7.12 (1 H, s), 4.28 (2H, s), 4.09 (3H, s), 2.77 (3H, s). 13C NMR (CD3OD, 100 MHz) δ 144.5, 177.8, 1 14.9, 110.9, 45.9, 39.0, 33.2. LCMS (M++1) 151 .1 , 138.0, 120.0.

PATENT

WO2013132376

PATENT

WO 2016089208

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017021823&redirectedID=true

Preparation of the free base of lorlatinib as an amorphous solid is disclosed in

International Patent Publication No. WO 2013/132376 and in United States Patent No. 8,680,1 1 1 . Solvated forms of lorlatinib free base are disclosed in International Patent Publication No. WO 2014/207606.

Example 1

Lab Scale Preparation of Form 7 of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 l lbenzoxadiazacyclotetra-decine- -carbonitrile (lorlatinib) Free Base

[AcOH solvate]

Form 7 of lorlatinib free base was prepared by de-solvation of the acetic acid solvate of lorlatinib (Form 3), prepared as described in International Patent Publication No. WO 2014/207606, via an intermediate methanol solvate hydrate form of lorlatinib (Form 2).

The acetic acid solvate of lorlatinib (Form 3) (5 g, 10.72 mmol) was slurried in methanol

(10 mL/g, 1235.9 mmol) at room temperature in an Easymax flask with magnetic stirring to which triethylamine (1 .2 equiv., 12.86 mmol) was added over 10 minutes. The resulting solution was heated to 60°C and water (12.5 mL/g, 3469.3 mmol) was added over 10 minutes, while maintaining a temperature of 60°C. Crystallization was initiated by scratching the inside of the glass vessel to form a rapidly precipitating suspension which was triturated to make the system mobile. The suspension was then cooled to 25°C over 1 hour, then cooled to 5°C and granulated for 4 hours. The white slurry was filtered and washed with 1 mL/g chilled

water/methanol (1 :1) then dried under vacuum at 50°C overnight to provide the methanol solvate hydrate Form 2 of lorlatinib.

Form 7 was then prepared via a re-slurry of the methanol solvate hydrate Form 2 of lorlatinib in heptane. 100 mg of lorlatinib Form 2 was weighed into a 4-dram vial and 3 mL of heptane was added. The mixture was slurried at room temperature on a roller mixer for 2 hours. Form conversion was confirmed by PXRD revealing complete form change to Form 7 of lorlatinib free base.

Paper

http://pubs.acs.org/doi/abs/10.1021/jm500261q

*E-mail: ted.w.johnson@pfizer.com. Phone: (858) 526-4683., *E-mail: paul.f.richardson@pfizer.com. Phone: (858) 526-4290.

Abstract Image

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States
J. Med. Chem., 2014, 57 (11), pp 4720–4744
DOI: 10.1021/jm500261q
(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (8k)
white solid:
TLC Rf = 0.40 (70% EtOAc in cyclohexane);
LC–MS (ESI), m/z 407.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 9.6, 2.4 Hz, 1 H), 7.21 (dd, J = 8.4, 5.6 Hz, 1 H), 6.99 (dt, J = 8.0, 2.8 Hz, 1 H), 6.86 (d, J = 1.2 Hz, 1 H), 5.75–5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, J = 14.4 Hz, 1 H), 4.35 (d, J = 14.4 Hz, 1 H), 4.07 (s, 3 H), 3.13 (s, 3 H), 1.79 (d, J = 6.4 Hz, 3 H).

References

1H NMR PREDICT

13C NMR PREDICT

Lorlatinib
Lorlatinib.svg
Clinical data
Routes of
administration
PO
Legal status
Legal status
  • experimental
Identifiers
CAS Number 1454846-35-5
ChemSpider 32813339
Chemical and physical data
Formula C22H20FN5O2
Molar mass 405.43 g·mol−1
3D model (Jmol) Interactive image

///////////////////Lorlatinib, PF-6463922,  anti-neoplastic,  Pfizer,  ROS1,  ALK, phase 2, UNII:OSP71S83EU, лорлатиниб لورلاتينيب 洛拉替尼 Orphan Drug, PF 6463922

Fc2ccc3C(=O)N(C)Cc1nn(C)c(C#N)c1c4cc(O[C@H](C)c3c2)c(N)nc4

FDA approved Trulance for adults with chronic idiopathic constipation (CIC).


Image result for TrulanceImage result for plecanatide

Plecanatide

FDA approved Trulance on January 19th 2017, a once-daily prescription medication for adults with chronic idiopathic constipation (CIC).

Image result for Trulance

 

Plecanatide (brand name Trulance), is a drug approved on January 2017 by the FDA for the treatment of chronic idiopathic constipation (CIC).[1] Plecanatide is a guanylate cyclase-C agonist. Plecanatide increases intestinal transit and fluid through a buildup of cGMP,.[2][3]

Plecanatide 普卡那肽 ليكاناتيد плеканатид

References

  1. Jump up^ “FDA approves Trulance for Chronic Idiopathic Constipation”. FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017.
  2. Jump up^ “TRULANCE package insert” (PDF). Trulance website. Synergy Pharmaceuticals Inc. 420 Lexington Avenue, Suite 2012 New York, New York 10170. Retrieved 20 January 2017.
  3. Jump up^ Thomas, RH; Luthin, DR (June 2015). “Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents.”. Pharmacotherapy. 35 (6): 613–30. doi:10.1002/phar.1594. PMID 26016701. Retrieved 20 January 2017.
Plecanatide
Clinical data
Trade names Trulance
License data
Routes of
administration
Oral
Legal status
Legal status
Identifiers
Synonyms SP-304
CAS Number 467426-54-6 Yes
PubChem (CID) 70693500
IUPHAR/BPS 9069
ChemSpider 28530494 
UNII 7IK8Z952OK Yes
KEGG D09948 Yes
ChEMBL CHEMBL2103867 
Chemical and physical data
Formula C65H104N18O26S4
Molar mass 1681.887 g/mol
3D model (Jmol) Interactive image

 

/////////Trulance, plecanatide

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

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