Process for preparing quinoline derivatives.

(54) Title: PROCESS FOR THE PREPARATION OF QUINOLINE DERIVATIVES. (54) Title: PROCESS FOR PREPARING QUINOLINE DERIVATIVES.

(57) Summary

A process for preparing a compound of formula I is described, comprising the steps: Wherein R1 is halo R2 is halo; R3 is (C1-C6) alkyl or C1-C6 alkyl) optionally substituted with heterocycloalkyl; R4 is (C1-C6) alkyl; and Q is CH or N which comprises: (a) contacting 1,1-cyclopropanedicabolxylic acid with thionyl chloride in a polar aprotic solvent; (b) (b) adding H2N (r2) n and a tertiary amine base to the mixture of step (a) to form a compound of formula A; and.

(57) Abstract

A processfor preparing a compound of Formula I is disclosed, comprising thesteps: where: R1 is halo; R2 is halo; R3 is (C1-C6) alkyl or (C1-C6) alkyl optionally substituted with heterocycloalkyl; R4 is (C1-C6) alkyl; and Q is CH orN; Comprising: (a) contacting 1,1 -cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; (b) adding and a tertiary amine base to the mixture of step (a) to form a compound of Formula A; and (c) coupling a compound of Formula A with an amine of Formula B to form a compound of Formula I.

I KNOW

Mexican Institute of Industrial Property

<img file="MX343288B_D0001.tif" />

PATENT TITLE NO. 343288

Owner (s): EXELIXIS, INC.

Address: 210 East Grand Avenue, South San Francisco, California, 94080, USA

Name: PROCESS FOR THE PREPARATION OF QUINOLINE DERIVATIVES. Classification: lnt.CI.8: C07C231 / 02; C07C233 / 59; C07D215 / 22; C07D413 / 12

Inventor (s); JO ANN WILSON; SRIRAM NAGANATHAN; MATTHEW PFEIFFER; NEIL G. ........ ANDERSEN

REQUEST

Number:

MX / a / 2014/004583

Country:

US

Validity: Twenty years

Int Presentation Date October 2012

PRIORITY

Date:

October 2011

Number:

61/549,312

Expiration Date: October 22, 2032

The reference patent is granted based on articles 1, 2 fraction V, 6 fraction III, and 59 d to the Industrial Property Law.

In accordance with Article 23S of the Industrial Property Law, this patent has UBBMeWÜfefefe years of expiration, counted from the date of filing of the international application and will be subject to the payment of the fee to keep the rights in force.

polish subscribes this title does so based on the provisions of article · 6 “sections III and 7 ° bis 2 of the Industrial Property Law (Official Gazette of the Federation (DOF.) 06/27/1991, amended the 08/02/1994. 25 / 1C / 1996, 12/26/1997, 05/17/1999, 01/26/2004, 06/16/2001, 01/25/2002 ^ 16, 06/05/2009, 06/01/2010, 06/18/2010, 06/28/39/10, 274HC012 and 04/09/2012); Articles 1, 3, section V, subsection a), 4, and 12, sections I and III of the Regulations of the Mexican Institute of Industrial Property (DOF) 12/14/1999, amended on 07/01/2002, 07/15/2004, 07/28/2004 and 09/07/2007); articles 1 ° 3 °, 4 °, 5 ° fraction V inciBO B), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, rWWttsWvel 4W10 / 2002, 07/29/2004, 08/04/2004 and 13909/2007); 1, 3 and 5 subsection a) of the Agreement that delegates powers to the Deputy Directors General, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subaltems of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

Issue Date: November 1, 2016

THE DIVISIONAL DIRECTOR OF PATENTS

<img file="MX343288B_D0002.tif" />

MX / 2016/89155

<img file="MX343288B_D0003.tif" />

/ V / ^ o / 9/72&gt; 83 / ¿£

<img file="MX343288B_D0004.tif" />

PROCESS FOR THE PREPARATION OF DERIVATIVES OF QUINOLTNA

Field of the Invention

The present description relates to a process of preparing compounds useful for modulating the enzymatic activity of protein kinases. More specifically, the present description relates to a process for the preparation of compounds useful for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemoinvasion.

Background of the Invention

Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes necessary for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024) is an attractive target for the development of small molecule drugs. Antiangiogenic therapy represents a potentially important methodology for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including coronary artery disease, diabetic retinopathy, psoriasis, and rheumatoid arthritis. Also, antiproliferative agents are desirable to slow or stop the growth of tumors.

One of the targets for modulation with molecules

REF: 248017

IMPI

MEXICAN INSTITUTE OF THE EitOEILLMD

INDUSTRIAL

<img file="MX343288B_D0005.tif" />

Small of the antiangiogenic and antiproliferative activity is c-Met. C-Met kinase is the prototype member of a heterodimeric receptor tyrosine kinase subfamily (RTKs) including Met, Ron and Sea. C-Met expression occurs in a wide variety of cell types including epithelial, endothelial, and mesenchymal cells, where receptor activation induces migration, invasion, cell proliferation, and other biological activities associated with cell growth. invasive. As such, signal translation through c-Met receptor activation is responsible for many of the characteristics of tumor cells.

N- (4- {[6,7-bis (methyloxy) quinolin-4-yl] oxy} phenyl) -N '(4-fluorophenyl) cyclopropan-1,1-dicarboxamide and N- [3fluoro-4- ({6- (Methyloxy) -7 - [(3-morpholin-4ylpropyl) oxy] quinolin-4-yl} oxy) phenyl] -Ν '- (4-fluorophenyl) cyclopropan-1,1-dicarboxamide are two inhibitors of A small molecule of c-Met that is currently under clinical investigation as treatments for a range of cancers. Consequently, there is a current need for new and efficient processes for the development of these two promising cancer therapies.

Summary of the Invention

These and other needs are covered by this invention, which relates to a process for the preparation of

<img file="MX343288B_D0006.tif" />

in which R² is H, F, Cl or Breque comprises (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent; and (b) add

<img file="MX343288B_D0007.tif" />

of tertiary amine to the mixture of that of step (a).

The compound of Formula A is used to form a compound

Formula I:

<img file="MX343288B_D0008.tif" />

where:

R¹ is halo;

R² is halo;

R³ is alkyl (Ci-C₆) or alkyl (Ci-C₆) optionally substituted with heterocycloalkyl;

R⁴ is alkyl (Ci-C₆); and Q is CH or N.

IMPI

MBXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343288B_D0009.tif" />

In one embodiment, the compound of Formula I eg. .ftl · · compound 1: γ-j χτ'ΫΫ'α,

H3C-0

<img file="MX343288B_D0010.tif" />

Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is known as N- (4- {[6,7-bis (methyloxy) quinolin-4yl] oxy} phenyl) -Ν '- (4-fluorophenyl) cyclopropane-1,1dicarboxamide. WO 2005/030140 describes the synthesis of N- (4- {[6,7-bis (methyloxy) quinolin-4yl] oxy} phenyl) -Ν '- (4-fluorophenyl) cyclopropan-1,1-dicarboxamide (Example 12, 37, 38 and 48) and also describes the therapeutic activity of this molecule to inhibit, regulate and / or modulate the translation of kinase signals, (Assays, Table 4, entry 289). Example 48 is as in paragraph [0353] of WO 2005/030140, the contents of which are incorporated by reference in their entirety.

In another embodiment, the compound of Formula I is compound 2:

<img file="MX343288B_D0011.tif" />

or a pharmaceutically acceptable salt thereof. Compound 2 is

IMPI

MEXICAN INSTITUTE M INDUSTRIAL PROPERTY

<img file="MX343288B_D0012.tif" />

known as N- [3-fluoro-4 - ({6- (methyloxy) -7 - [(3-morpholin-4ylpropyl) oxy] quinolin-4-yl} oxy) phenyl] -Ν '- (4-fluorophenyl) cyclopropan-1,1-dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) ​​and also describes the therapeutic activity of this molecule to inhibit, regulate and / or modulate the translation of signals from kinases, (Assays, Table 4, entry 312). The IC value has been measured₅₀ of the c-Met of Compound 2 at approximately 0.6 nanomolar (nM). Document PCT / US09 / 064341, which claims priority over the US provisional application. 61 / 199,088, filed November 13, 2008, describes an enlarged-scale synthesis of compound 2.

Therefore, in another aspect, the invention relates to a process for the preparation of a compound of Formula I as defined above:

<img file="MX343288B_D0013.tif" />

which includes the stages of:

(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent;

(b) add

<img file="MX343288B_D0014.tif" />

a tertiary amine base to the

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343288B_D0015.tif" />

mixing step (a) to form a compound of formula A;

<img file="MX343288B_D0016.tif" />

(c) coupling a compound of Formula A with an amine of Formula B to form a compound of Formula I

<img file="MX343288B_D0017.tif" />

<img file="MX343288B_D0018.tif" />

The compound of Formula B can be prepared as described in WO 2005/030140, as previously mentioned, the content of which is incorporated by reference in its entirety. Some alternative methodologies for the synthesis of the compound of Formula I, of compound A, compound B, and of Compounds 1 and 2 are described in additional applications PCT / 2009/643411 and PCT / US2010 / 021194, and the contents of each they are described in this document for reference in their entirety.

The monoamidation process described and claimed in this document has several significant processing advantages. The previous methodologies for the elaboration of Compound A required the mixing of acid 1.17

IMPI

MEXICAN INSTITUTE ”Dt LA ER &lt;

INDUSTRIAL

<img file="MX343288B_D0019.tif" />

cyclopropanedicarboxylic acid with triethyl amine, and then the addition of thionyl chloride followed by aniline. The reaction was typically and undesirably exothermic. The inventors have found that the exotherm was eliminated by rearranging the reagent addition sequence. Reaction times are significantly reduced, and the resulting product does not require any further purification. Furthermore, the process of the invention as described herein is highly selective for the formation of the monoamidation product of Compound A.

<img file="MX343288B_D0020.tif" />

Bis-amide, if present, is easily removed by using the treatment conditions developed by the inventors.

The process claimed in this document is generalizable for the selective monoamidation of symmetric dicarboxylic acids through the use of a set of primary or secondary amines. Therefore, in another aspect, the invention provides a process for making a mono-amide from the corresponding dicarboxylic acid, comprising:

(a) contacting a dicarboxylic acid with thionyl chloride in a polar aprotic solvent; and

IMPI

MEXICAN INSTITUTE OF THE INDUSTRIAL PRCPIEUAU

<img file="MX343288B_D0021.tif" />

(b) adding a primary amine- and tertiary amine base to the resulting mixture.

There are many different aspects and modalities of the present which are described below, and each aspect and each modality is not limiting with respect to the scope of the description. The terms aspects and modalities are not intended to be limiting regardless of where the terms aspect or modality appear in this description. The term "transitional" comprising, as used herein, which is synonymous with including, containing, or characterized by, is inclusive or open, and does not exclude any additional uncited elements.

Detailed Description of the Invention Abbreviations and definitions

The following abbreviations and terms have the meanings indicated in their entirety:

<td>Abbreviation</td><td>Meaning</td>

<td>Ac</td><td>Acetyl</td>

<td>br</td><td>Width</td>

<td>° C</td><td>Celsius degrees</td>

<td>c-</td><td>Cycle</td>

<td>CBZ</td><td>CarboBenZoxi = benzyloxycarbonyl</td>

<td>d</td><td>Doublet</td>

<td>dd</td><td>Doublet doublet</td>

<td>dt</td><td>Triplet doublet</td>

IMPI

MEXICAN INSTITUTE

<td>Abbreviation</td><td>Meaning ^{, NDUSTR1AL}</td>

<td>DCM</td><td></td>

<td>DMA</td><td>N, N-dimethylacetamide</td>

<td>DME</td><td>1,2-dimethoxyethane</td>

<td>DMF</td><td>N, N-Dimethylformamide</td>

<td>DMSO</td><td>Dimethylsulfoxide</td>

<td>Dppf</td><td> 1.1 ¹-bis (diphenylphosphan) ferrocene</td>

<td>DSC</td><td>Differential scanning calorimetry</td>

<td>The</td><td>Electronic impact ionization</td>

<td>Et</td><td>Ethyl</td>

<td>g</td><td>Gram (s)</td>

<td>GVS</td><td>Gravimetric Sorption of Vapor</td>

<td>h</td><td>Hours)</td>

<td>HPLC</td><td>High resolution liquid chromatography</td>

<td>KF</td><td>Determination of water content by Karl Fisher</td>

<td>kg</td><td>Kilogram</td>

<td>kV</td><td>Kilovolt</td>

<td>L</td><td>Liter (s)</td>

<td>LCMS</td><td>Liquid chromatography - spectrometry masses</td>

<td>mA</td><td>Milliamp</td>

<td>I</td><td>Methyl</td>

<td>M</td><td>Molar or molarity</td>

<td>m</td><td>Multiplet</td>

<td>Mm</td><td>Millimeter</td>

<td>MEK</td><td>Methyl ethyl ketone</td>

<td>mg</td><td>Milligram (s)</td>

<td>MHz</td><td>Megahertz (frequency)</td>

<img file="MX343288B_D0022.tif" />

<img file="MX343288B_D0023.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>Abbreviation</td><td>Meaning</td>

<td>Min</td><td>Minute (s)</td>

<td>me</td><td>Milliliter (s)</td>

<td>μβ</td><td>Microliter (s)</td>

<td>um</td><td>Micrometer</td>

<td>μΜ</td><td>Micromol (s) or micromolar</td>

<td>mM</td><td>Millimolar</td>

<td>mmol</td><td>Millimol (s)</td>

<td>Mol</td><td>Mol (s)</td>

<td>MS</td><td>Mass spectral analysis</td>

<td>MTBE</td><td>Methyl t-butyl ether</td>

<td>N</td><td>Normal or normal</td>

<td>nM</td><td>Nanomolar</td>

<td>TA</td><td>Room temperature</td>

<td>NMR</td><td>Nuclear Magnetic Resonance Spectroscopy</td>

<td>what</td><td>Quartet</td>

<td>psi</td><td>Pounds per square inch</td>

<td>rpm</td><td>Revolutions per minute</td>

<td>HR</td><td>RH</td>

<td>s</td><td>Singlet</td>

<td>to tr</td><td>Triplet</td>

<td>TFA</td><td>Trifluoroacetic acid</td>

<td>TGA</td><td>Thermogravimetric analysis</td>

<td>THF</td><td>Tetrahydrofuran</td>

<td>TLC</td><td>Thin layer chromatography</td>

<td>XRPD</td><td>X-ray powder diffraction</td>

<td>Θ</td><td>Rotation angle in radians</td>

IMPI

<img file="MX343288B_D0024.tif" />

MEXICAN INSTITUTE OF PROflEDAp

The symbol means a simple link; í ^^BUSTSl^Lgn a double bond.

When representing or describing chemical structures, unless explicitly stated otherwise, it is assumed that all carbons have hydrogens substituted to make a valence of four. For example, in the structure to the left of the following reaction scheme there are nine implicit hydrogens. The nine hydrogens are represented in the structure on the right. Sometimes, a particular atom of a structure is described in a textual formula as a carrier for hydrogen or hydrogens as a substitution (specifically defined hydrogen), for example, -CH₂CH₂-. One of ordinary skill in the art will understand that the descriptive techniques mentioned above are common in the chemical art to provide brevity and simplicity to the description of otherwise complex structures.

OR?

H H

If a group R is represented as floating in a ring system, such as in the formula:

R

<img file="MX343288B_D0025.tif" />

i

<img file="MX343288B_D0026.tif" />

IMPI

INSTITUTO MEXICANO Dt LA «INDUSTRIAL OPIETTY then, unless otherwise defined, a substituent

R can reside on any atom in the ring system, assuming the substitution of a hydrogen represented, implicitly or expressly defined of one of the ring atoms, provided that a stable structure is formed.

If a group R is represented as floating in a merged ring system, such as in the formulas:

<img file="MX343288B_D0027.tif" />

<img file="MX343288B_D0028.tif" />

, 0 then, unless otherwise defined, a substituent R may reside on any atom of the fused ring system, assuming the substitution of a represented hydrogen (eg, -NH- in the formula above), of an implicit hydrogen (eg, as in the formula above, where hydrogens are not shown but understood to be present), or an expressly defined hydrogen (eg, when in the formula above, Z equals = CH-) of one of the ring atoms, provided that a stable structure is formed. In the example depicted, group R can reside on either the 5-membered or 6-membered rings of the fused ring system. When it is represented that a group R exists on a ring system that contains saturated carbons, as for example, in the formula:

<img file="MX343288B_D0029.tif" />

<img file="MX343288B_D0030.tif" />

where, in this example, and can be more than one, assuming each replaces a hydrogen currently represented, implied or expressly defined by the ring; then, unless otherwise defined, when the resulting structure is stable, two R's may reside on the same carbon. A simple example is when R is a methyl group; a geminal dimethyl may exist on a carbon in the depicted ring (an annular carbon). In another example, two R's on the same carbon, including that carbon, can form a ring, thereby creating a spirocyclic ring structure (a spirocyclyl group) with the ring represented as, for example, in the formula.

HN

Alkyl (Ci-C₆) or "alkyl" means a linear or branched hydrocarbon group with between one and six carbon atoms. Some examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like. Alkyl C₆ refers, for example, to n-hexyl, iso-hexyl, and the like.

Heterocycloalkyl means a monocyclic group

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY monovalent saturated or partially unsaturated with 3 to 8 atoms

<img file="MX343288B_D0031.tif" />

in the ring, or a saturated or partially unsaturated monovalent fused bicyclic group of 5 to 12 ring atoms, in which one or more, for example, one, two, three or 5 four ring heteroatoms independently selected from -0 -, -S (0)_n- (n is 0, 1 or 2), -N =, -N (R^and) - (where R^and it is hydrogen, alkyl, hydroxy, alkoxy, acyl or alkylsulfonyl), the rest of the ring atoms being carbon. One or two carbon atoms in the ring may be replaced by a group -C (O) -, -C (S) - or -C (= NH) -. The fused bicyclic radical includes ring bridge systems. Unless otherwise indicated, the valence of the group can be located on any atom of any ring of the radical, allowing the valence norms. In particular, when the 15 valence point is located on a nitrogen atom, R^andhe's absent. In another embodiment the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2oxopirrolidinilo, 2.5-dihydro-lH-pyrrolyl, piperidinyl, 4piperidonilo, morpholinyl, piperazinyl, 2-oxopiperazinyl, 20 tetrahydropyranyl, 2-oxopiperidinyl, perhydroazepinyl, imidazolidinyl , oxazolinyl, thiomorpholinyl, pyrazolidinyl, dihydropyridinyl, oxazolidinyl, thiamorpholinyl, imidazolinyl, tetrahydropyridinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl derivatives thereof, and a derivative thereof.

Halogen or halo refers to

N - oxide r&gt;

fluorine, chlorine, bromine, or iodine.

Yield, for each of the reactions described herein, is expressed as a percentage of the theoretical yield.

Patient, for the purposes of this invention, includes humans and other animals, particularly mammals, and other organisms. Therefore, the processes are applicable in both human therapy and veterinary applications. In another embodiment, the patient is a mammal, and in another embodiment the patient is a human.

A pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable that possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17^to ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference, or in SM Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977; 66: 1-19, both being incorporated herein by reference.

<img file="MX343288B_D0032.tif" />

IMPI Mexican InsrrruTo • r the currency »

Some examples of addiction salts © fl *^,* '' Pharmaceutically acceptable acids include those ΓυΐΙΙΙά '£ 13ΕΓ ~ 0ο “inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, acid malic, citric acid, benzoic acid, cinnamic acid, 3 - (4-hydroxybenzoyl) benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, acid

1,2-Ethanedisulfonic Acid, 2-Hydroxyethanesulfonic Acid, Benzenesulfonic Acid, 4-Chlorobenzenesulfonic Acid, 2-Naphthalenesulfonic Acid, 4-Toluenesulfonic Acid, Camphor Sulfonic Acid, Glucoheptonic Acid, 4,4'-Methylene Bis- (3-Hydroxy-2-ene-l Acid -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid and salicylic acid, and the like.

Prodrug refers to compounds that are transformed (typically rapidly) in vivo to produce the parent compound of the above formulas, by

INínWTOMSXICANQ

<img file="MX343288B_D0033.tif" />

IMPI example, by hydrolysis in the blood. AÍ ^ h! A®ssTx © g &lt;

Common include, but are not limited to,

FROPIF.DAD,

<img file="MX343288B_D0034.tif" />

amide of a compound with an active form bearing a carboxylic acid moiety. Some examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (eg, with from about one to about six carbons). The alkyl group is a straight or branched chain. Some acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to, benzyl. Some examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (eg, with from about one to about six carbons). The amides and esters of the compounds of this invention can be prepared according to conventional processes. A comprehensive prodrug analysis is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 from the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both being incorporated herein by reference for all purposes.

Therapeutically effective amount is an amount of a

IMPI mexican institute / Λ,,,, PE LA WpFIEDAD Oesa-Si 'compound of the invention, that when adminiiBfesraxL to ^ * 5jS7 "patient, improves a symptom of the disease ·?' A "therapeutically effective amount" is intended to include an amount of a compound alone or in conjunction with other active ingredients effective in modulating c-Met and / or VEGFR2, or effective in treating or preventing cancer. The amount of a compound of the invention that constitutes a therapeutically effective amount will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined by one of ordinary skill in the art based on his knowledge and this report.

Treating or treating a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from appearing in a human, that is, causing clinical symptoms of the disease, disorder or syndrome do not develop in an animal that may be exposed or predisposed to the disease, disorder or syndrome, but has not yet experienced or displays the symptoms of the disease, the disorder or syndrome;

(ii) inhibit the disease, disorder or syndrome, that is, stop its development; and (iii) alleviating the disease, disorder, or syndrome, that is, causing regression of the disease, disorder, or syndrome. How is it

IMPI

<img file="MX343288B_D0035.tif" />

MEXICAN INSTITUTE

OE PROPERTY and known in the art, may be required • for systemic versus localized administration, age, body weight, general health, sex, diet, administration time, drug interactions, and severity of the condition, and can be ascertained through routine experience.

Process

In one aspect, the present description relates to a process for the preparation of a compound of Formula A:

<img file="MX343288B_D0036.tif" />

in which R² it is H, F, Cl or Br; comprising (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent: and jQ (b) add Y^a tertiary amine base to the mixture of step (a).

In the process, 1,1-cyclopropanedicarboxylic acid combines with a polar aprotic solvent to form a mixture. In one embodiment, the polar aprotic solvent is chosen from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or

<img file="MX343288B_D0037.tif" />

combinations of these. In another modal id $ 3 ^ ° mouros aprotic polar is chosen from the group consisting of.

dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, and acetonitrile, or combinations thereof. In another embodiment, the polar aprotic solvent is chosen from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, and isopropyl acetate, or combinations thereof. In one embodiment, the polar aprotic solvent is isopropyl acetate.

The volume of the polar aprotic solvent used will vary depending on the scale of the reaction. Typically, about 5 to 10 volumes of polar aprotic acid are used relative to the volume of 1,1-cyclopropanedicarboxylic acid used. More typically, 6 to 9 volumes of polar aprotic acid are used. More typically, between 7.5 and 8.5 volumes of polar aprotic acid are used. Preferably about 8 volumes of polar aprotic acid are used.

Thionyl chloride is then added to the mixture comprising 1,1-cyclopropanedicarboxylic acid and polar aprotic acid. A molar excess of thionyl chloride is used relative to the number of moles of 1,1-cyclopropanedicarboxylic acid used. Typically, approximately 1.01 to 1.5 molar equivalents of thionyl chloride are used relative to the number of moles of acid.

<img file="MX343288B_D0038.tif" />

1,1-cyclopropanedicarboxylic acid used. More typically, approximately 1.01 to 1.2 molar equivalents of thionyl chloride are used. More typically, approximately 1.01 to 1.1 molar equivalents of thionyl chloride are used. More typically, approximately 1.05 molar equivalents of thionyl chloride are used.

The mixture comprising 1,1-cyclopropanedicarboxylic acid, thionyl chloride and the polar aprotic solvent is stirred for 2 to 24 hours. Ambient temperature generally means that no external heating device, such as a heating jacket, heating liner, or the like, is used to increase the temperature of the mixture. Typically, the temperature is between approximately 23 and 27 ° C. More typically, the temperature is between about 24 and 26 ° C. Typically, the temperature is approximately 25 ° C. Stirring at room temperature typically continues for between about 6 and 16 hours. More typically, stirring continues for between about 13-15 hours at about 25 ° C.

Then a mixture of an aniline is added to the mixture.

<img file="MX343288B_D0039.tif" />

optionally substituted aniline and a tertiary amine base in a polar aprotic solvent. Typically, with respect to the cyclopropanedicarboxylic number.

MEXICAN INSTITUTE of the property ..

optionally substituted is 4-fluoroamine. industrial

A molar excess of aniline with roapootium is used at ηάπτ of moles of 1,1-cyclopropanedicarboxylic acid. Typically, between about 1.01 and 1.5 molar equivalents of aniline are used relative to the number of moles of 1,1cyclopropanedicarboxylic acid used. More typically, between about 1.01 and 1.2 molar equivalents of aniline are used. More typically, approximately 1.05 to 1.15 molar equivalents of aniline are used. More typically, approximately 1.1 molar equivalents of aniline are used.

The tertiary amine base is typically a trialkyl amine, in which the alkyl groups are the same or different and can be linear or branched. The use of trialkyl amine bases is well known to the skilled artisan, and many are commercially available, such as triethylamine, di-isopropylethyl amine, or the like. Typically, the tertiary amine base is triethyl amine. A molar excess of tertiary amine base is used with 1.1 mole of acid. Typically, between about 1.01 and 1.5 molar equivalents of tertiary amine base are used relative to the number of moles of 1,1cyclopropanedicarboxylic acid used. More typically, approximately 1.01 to 1.2 molar equivalents of tertiary amine base are used. More typically, they are used between

<img file="MX343288B_D0040.tif" />

IMPI instituto mkicano approximately 1.05 and 1.15 equivalents molai? EsiNaae * '* &amp; ni!

More typically, approximately ___1 - Ί —ja qu i va 1 gTTCgg ^ are used³tertiary amine base molars.

The optionally substituted aniline and tertiary amine base are typically combined in a polar aprotic solvent before being added to the 1,1-cyclopropanedicarboxylic acid / thionyl chloride / isopropyl acetate mixture. The polar aprotic solvent used is typically the same solvent that was used to form the 1,1-cyclopropanedicarboxylic acid mixture, and is chosen from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone , dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof. In another embodiment, the polar aprotic solvent is chosen from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, and acetonitrile, or combinations thereof. In another embodiment, the polar aprotic solvent is chosen from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, and isopropyl acetate, or combinations thereof. In one embodiment, the polar aprotic solvent is isopropyl acetate.

The volume of polar aprotic solvent used to form the aniline / tertiary amine base mixture will vary depending on the scale of the reaction. Typically, they are used

IMPI itC ktttf 1ΓΛΝΟ

<img file="MX343288B_D0041.tif" />

between about 1 and 5 volumes of polar acetic acid relative to the volume of the optionally substituted aniline used. More typically, 1.5 to 3 volumes of polar acetic acid are used. More typically, approximately 2 volumes of polar acetic acid are used.

The resulting combined mixture is allowed to mix at room temperature for between 0.5 and 5 hours and more preferably for between 1 and 3 hours. More typically the mixture is left to mix for 2 hours.

The mixture, which at this point is typically a suspension comprising Compound A, is then quenched by treatment with a concentrated aqueous base such as NaOH, KOH or K₃PO₄ aqueous 5N, or the like. In one embodiment, the base is NaOH. The amount of aqueous base used to quench the reaction will vary depending on the scale of the reaction. For the scale described above, approximately 4-6 volumes of 5N NaOH are typically used. The organic phase of the resulting biphasic mixture is subsequently extracted with multiple washes of 0.5N NaOH and the aqueous phases are combined. The combined basic extracts are back extracted with an aprotic solvent such as heptane. The combined aqueous bases are then subsequently acidified with an aqueous mineral acid such as HCI, H₂SW₄, or the like.

Typically the acid used is 30 percent HCI in i

IMPI

MEXICAN INSTITUTE Dt LA FROFIEDAD agua. The acid is added to the aqueous comb'Tíacfás phases to form a suspension. Then it is isolated^- Useful Compound by filtration.

In a further embodiment, a process is provided for the preparation of a compound of Formula A:

<img file="MX343288B_D0042.tif" />

<img file="MX343288B_D0043.tif" />

A where R² it is H, F, Cl or Br; comprising (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature: and (b) adding a mixture comprising H2N (Rto-amine in isopropyl acetate to the resulting mixture.

In a further embodiment, a process is provided for the preparation of a compound of Formula A:

<img file="MX343288B_D0044.tif" />

<img file="MX343288B_D0045.tif" />

A where R² it is H, F, Cl or Br; comprising (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature: and (b) adding

<img file="MX343288B_D0046.tif" />

and a triethyl amine to the mixture;

(c) quenching the mixture from step (b) with concentrated aqueous sodium hydroxide;

<img file="MX343288B_D0047.tif" />

(d) extracting compound A with a dilute haae aminse— (e) acidifying the mixture with HCl; and (f) isolating Compound A by filtration.

In a further embodiment, a process is provided for the preparation of a compound of Formula Al:

HO

Al which comprises (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; and (b) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the resulting mixture.

In a further embodiment, a process is provided for the preparation of a compound of Formula Al:

HO

Al which comprises (a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature;

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343288B_D0048.tif" />

(b) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the resulting mixture;

(c) quench the mixture with concentrated aqueous sodium hydroxide;

(d) extracting compound Al with a dilute aqueous base;

(e) acidifying the mixture with HCl; and (f) isolating Compound A by filtration.

In another embodiment, the invention relates to a process for the preparation of Compound 1:

<img file="MX343288B_D0049.tif" />

Compound 1 comprising the steps of:

(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent;

(b) adding 4-fluororaniline and triethyl amine to the mixture of step (a) to form a compound of Formula A; and

<img file="MX343288B_D0050.tif" />

By (c) coupling a compound of Formula Al with an amine of

Formula Bl to form Compound 1

IMPIOUS?

Mexican INSTITUTE __________ of the «ο ™↓?

INDUSTRIAL

<img file="MX343288B_D0051.tif" />

In another embodiment, the invention relates to a process for the preparation of Compound 1:

<img file="MX343288B_D0052.tif" />

Compound 1 comprising the steps of:

(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent;

(b) adding 4-fluororaniline and triethyl amine to the mixture of step (a) to form a compound of Formula A;

<img file="MX343288B_D0053.tif" />

(c) quench the mixture with concentrated aqueous sodium hydroxide;

(d) extracting compound Al (e) acidifying the mixture with (f) isolating the compound

IMPIéUB Mexican Institute Kj -— = &amp; · .; OF THE PROPERTY with a base acuoSS ^ dTluictar; · HCI;^------- of Formula Al by filtration; and (g) coupling a compound of Formula Al with an amine of

Formula Bl to form Compound 1.

<img file="MX343288B_D0054.tif" />

In another embodiment, the invention relates to a process for the preparation of Compound 2:

<img file="MX343288B_D0055.tif" />

Compound 2 comprising the steps of:

(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent;

(b) adding 4-fluororaniline and triethyl amine to the mixture of step (a) to form a compound of Formula A; and

<img file="MX343288B_D0056.tif" />

MEXICAN INSTITUTE OF IA TRONERAD

INDUSTRIAL

<img file="MX343288B_D0057.tif" />

<img file="MX343288B_D0058.tif" />

(c) coupling a compound of Formula Al with an amine of Formula B-2 to form Compound 1.

<img file="MX343288B_D0059.tif" />

In another embodiment, the invention relates to a process for the preparation of Compound 1:

<img file="MX343288B_D0060.tif" />

Compound 2 comprising the steps of:

(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar aprotic solvent;

(b) adding 4-fluororaniline and triethyl amine to the mixture of step (a) to form a compound of Formula A;

HO

<img file="MX343288B_D0061.tif" />

Ai

<img file="MX343288B_D0062.tif" />

(c) quench the mixture with concentrated aqueous sodium hydroxide;

(d) extracting compound Al with a dilute aqueous base;

(e) acidifying the mixture with HCI;

(f) isolating the compound of Formula Al by filtration; and (g) coupling a compound of Formula Al with an amine of Formula Bl to form Compound 1.

HO '

A-1

B-2

<img file="MX343288B_D0063.tif" />

'F

As described herein, the reaction of thionyl chloride with 1,1cyclopropanedicarboxylic acid in a polar aprotic solvent as described herein offers a significant advantage over previous processes, where the reaction does not it is exothermic. A previous variant of the reaction in which SOC1 was added₂ to a mixture of 1,1-cyclopropanedicarboxylic acid and Et₃N in tetrahydrofuran was

MEXICAN INSTITUTE OF PROPERTY very exothermic. The process of the invention follows^Nn^^,TOdescribed in this document it is worth noting that ¹ lU ^ 5 Carboxylic acids do not normally convert to the corresponding acyl chloride when treated with SOC1₂at room temperature.

The process of the invention as disclosed herein is highly selective for the formation of the monoamidation product of Compound A relative to bis-amide.

<img file="MX343288B_D0064.tif" />

Typically, less than 5 percent, or more typically less than 1 percent, of the bis-amide is formed through the process claimed herein, as evidenced by HPLC analysis of control samples during the process. Furthermore, bis-amide, if present, is normally completely removed by using the isolation conditions.

Advantageously, the described process also considerably shortens the time required for the production of a batch of Compound A. Currently, the process for the large-scale production of Compound A requires several days and a subsequent purification by recrystallization. Using the improved process, the typical production time is expected to be one to two days, and does not require recrystallization.

<img file="MX343288B_D0065.tif" />

Experimental procedures ---— «-» »

The invention is now further illustrated by the following examples of Reaction Scheme 1 and the description thereof, and the scope or spirit of the invention should not be construed as being limited to the specific procedures described. Those skilled in the art will recognize that starting materials can be modified and that additional steps can be employed to produce the compounds encompassed by the invention, as demonstrated by the following examples. Those skilled in the art will also recognize that it may be necessary to use different solvents or reagents to achieve some of the above transformations.

Unless otherwise specified, all reagents and solvents are of standard commercial grade and are used without further purification. The appropriate atmosphere to carry out the reaction, for example, in air, nitrogen, argon, and the like, will be apparent to those skilled in the art.

Preparation of 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (Compound Al)

HO

<img file="MX343288B_D0066.tif" />

MEXICAN INSTITUTE ^INm^ ÍAPRCPIEPAD _ ___

The 1,1-cyclopropanedicarboxylic acid of partiToa was treated with thionyl chloride (1.05 equivalents) in 8 volumes of isopropyl acetate at 25 ° C for 5 hours. The resulting mixture was then treated with a solution of 4fluoroaniline (1.1 equivalents) and triethylamine (1.1 equivalents) in isopropyl acetate (2 volumes) for 1 hour. The suspension product was quenched with a 5N NaOH solution (5 volumes) and the aqueous phase was discarded. The organic phase was extracted with a 0.5N NaOH solution (10 volumes) and the basic extract was washed with heptane (5 volumes) and subsequently acidified with a 30% HCl solution to give a suspension. Compound Al was isolated by filtration.

Compound Al was prepared on a 1.00 kg scale using 1,1-cyclopropanedicarboxylic acid as a limiting reagent to form 1.32 kg of Compound Al (77% isolated yield; 84% mass balance) with a purity of 99.92 % (HPLC) and a 100.3% test.

Preparation of N- (4- {[6,7-bis (methyloxy) quinolin-4yl] oxyphenyl) -Ν '- (4-fluorophenyl) cyclopropan-1,1-dicarboxamide (Compound 1) and the salt of (L ) -maltum of this.

A synthetic route that can be used for the preparation of N- (4 - {[6,7-bis (methyloxy) quinolin-4-yl] oxy} phenyl) -Ν '- (4fluorophenyl) cyclopropan-1,1-dicarboxamide and the (L) malate salt thereof is represented in Reaction Scheme 1.

<img file="MX343288B_D0067.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Reaction scheme 1

<img file="MX343288B_D0068.tif" />

(L} -malcic acid

MEK

-0.

.C * Hg0s

Another synthetic route that can be used for the preparation of N- (4- {[6,7-bis (methyloxy) quinolin-4-yl] oxy} phenyl) -Ν '- (4-fluorophenyl) cyclopropan-1,1 -dicarboxamide and the (L) -mate salt thereof is represented in Reaction Scheme 2.

Reaction scheme 2

<img file="MX343288B_D0069.tif" />

CHO,

IMPI _ .-,., - r,,. . . . , MEXICAN INSTITUTE

Preparation of 4-chloro-6,7-dimethoxyquinolin «LA« oFiEDAD

A reactor took over

INDUSTRIAL sequentially with

<img file="MX343288B_D0070.tif" />

dimethoxyquinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 ° C and phosphorus oxychloride (POC1) was added.₃, 130.6 kg). After the addition of POC1₃, the temperature of the reaction mixture was increased to approximately 77 ° C. The reaction was considered complete (approximately 13 hours) when less than 3% of the starting material remained (analysis by high performance liquid chromatography [HPLC] during the process). The reaction mixture was cooled to about 2 to 7 ° C and then quenched with a chilled solution of dichloromethane (DCM, 482.8 kg), NH₄26% OH (251.3 kg) and water (900 1). The resulting mixture was heated to approximately 20 to 25 ° C and the phases were separated. The organic phase was filtered through an AW hyflo super-cel NF bed (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 1). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of the solvent (residual volume of approximately 95 1). DCM (686.5 kg) was charged into the reactor containing the organic phase and concentrated by vacuum distillation with removal of the solvent (residual volume of approximately 90 1).

IMPI 'NSTITUT · MIXICANO • f LA IAOPISDAD IN »USTXIAL

<img file="MX343288B_D0071.tif" />

Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to between -20 and -25 ° C and held for 2.5 hours, resulting in a solid precipitate, which was then filtered and washed with nheptane (92.0 kg), and dried on a filter at approximately 25 ° C under nitrogen to provide the title compound (35.6 kg).

Preparation of 4- (6,7-dimethoxy-quinoline-4-yloxy) -phenylamine

4-Aminophenol (24.4 kg) of dissolved in N, Ndimethylacetamide (DMA, 184.3 kg) was charged into a reactor containing

4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at between 20 and 25 ° C. This mixture was then heated at between 100 and 105 ° C for approximately 13 hours. After the reaction was deemed complete, as determined by using HPLC analysis during the process (less than 2% of the remaining starting material), the contents of the reactor were cooled to between 15 and 20 ° C and it charged water (previously cooled to between 2 and 7 ° C, 587 1) at a speed such that a temperature of between 15 and 30 ° C was maintained. The resulting precipitated solid was filtered, washed with a mixture of water (47 1) and DMA (89.1 kg) and finally with water (214 1). The filter cake was then dried at about 25 ° C on a filter to produce crude 4 (6,7-dimethoxy-quinoline-4-yloxy) -phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD) . The 425

<img file="MX343288B_D0072.tif" />

(6,7-dimethoxy-quinoline-4-yloxy) -phenylamine

INSTITU

<img file="MX343288B_D0073.tif" />

<img file="MX343288B_D0074.tif" />

heated at reflux (approximately 75 ° tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour and then cooled to between 0 and 5 ° C and aged for approximately 1 hour, after which time the solid was Filtered, washed with THF (147.6 kg) and dried on a vacuum filter at approximately 25 ° C to produce 4 - (6,7-dimethoxy-quinoline-4-yloxy) -phenylamine (34.0 kg).

Alternative preparation of 4- (6,7-dimethoxy-quinoline-4-yloxy) -phenylamine

4-Chloro-6,7-dimethoxyquinoline (34.8 kg) and 4aminophenol (30.8 kg) and sodium tert-pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent THF) were charged into a reactor, followed by N, N -dimethylacetamide (DMA, 293.3 kg). This mixture was then heated at 105-115 ° C for approximately 9 hours. After the reaction was deemed complete, as determined by using HPLC analysis during the process (less than 2% of the remaining starting material), the reactor contents were cooled to between 15 and 25 ° C and added water (315 kg) over a period of two hours, while maintaining the temperature between 20 and 30 ° C. The reaction mixture was then stirred for an additional hour at 20-25 ° C. The crude product was collected by filtration and washed

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343288B_D0075.tif" />

with a mixture of 88 kg of water and 82.1 kg of DMA, followed by 175 kg of water. The product was dried in a filter drier for 53 hours. The LOD showed less than 1% w / w.

In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 110 to 120 ° C. Furthermore, the cooling temperature was increased from 35 to 40 ° C and the starting temperature of the added water was adjusted to between 35 and 40 ° C, with an exotherm allowed up to 45 ° C.

Preparation of l- (4-fluoro-phenylcarbamoyl) cyclopropanecarbonyl chloride

Oxalyl chloride (12.6 kg) was added to a solution of 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, Ndimethylformamide (DMF; 0.23 kg) at a speed such that the batch temperature does not exceed 25 ° C. This solution was used in the next stage without further processing.

Alternative preparation of l- (4-fluorophenylcarbamoyl) -cyclopropanecarbonyl chloride

A reactor was charged with l- (4-fluorophenylcarbamoyl) -cyclopropanecarboxylic acid (35 kg), 344 g of DMF and 175 kg of THF. The reaction mixture was adjusted to between 12 and 17 ° C and then the reaction mixture was charged with 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was allowed to stir at between 12 and 17 ° C for between

ΙΜΡΪ ep

MEXICAN INSTITUTE

OF THE PROPERTY and 8 hours. This solution was used in the S ^ guieníC^!and'^ST^ top '· additional processing. ^J

Preparation of [4- (6,7-dimethoxy-quinoIin-4-yloxy) -phenyl] (4-fluoro-phenyl) -amido of cyclopropane-1,1-dicarboxylic acid

The solution from the previous step, containing 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarbonyl chloride was added to a mixture of compound 4- (6,7-dimethoxy-quinoline-4-yloxy) phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 1) at a speed such that the batch temperature did not exceed 30 ° C. When the reaction was complete (in about 20 minutes) water (653 1) was added. The mixture was stirred at 20-25 ° C for about 10 hours, which resulted in product precipitation. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 1), and dried first on a filter under nitrogen at approximately 25 ° C and then at approximately 45 ° C in vacuo, to provide the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Alternative preparation of [4 - (6,7-dimethoxy-quinolin-4yloxy) -phenyl] -amide (4-fluoro-phenyl) -cyclopropane-1,1-dicarboxylic acid amide

A reactor was charged with 4- (6,7-dimethoxy-quinoline-441

IMPI injtttvto Mexicano i loxi) -f eni lamina (35.7 kg, 1 equivalent) ', I know' ^ 'úá ^ RtO &amp; e' kg of THF. The reaction mixture was charged with a Bn1iici¿) n of

48.3 K₂CO₃ in 169 kg of water. The acid chloride solution described in the 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarbonyl chloride Alternative Preparation was transferred to the reactor containing the 4- (6,7-dimethoxyquinoline-4-yloxy) -phenylamine while kept the temperature between 20 and 30 ° C for a minimum of two hours. The reaction mixture was stirred at 20-25 ° C for a minimum of three hours. The reaction temperature was then adjusted to between 30 and 25 ° C, and the mixture was stirred. Stirring was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the rest of the upper organic phase, 804 kg of water were added. The reaction was allowed to stir at 15-25 ° C for a minimum of 16 hours.

The product precipitated. The product was filtered and washed with a mixture of 179 kg of water and 157.9 THF in two portions. The crude product was dried under vacuum for at least two hours. The dry product was then collected in

285.1 kg THF. The resulting suspension was transferred to a reaction vessel and stirred until the suspension became a clear solution (dissolved), requiring heating to between 30 and 35 ° C for approximately 30 minutes. Then

<img file="MX343288B_D0076.tif" />

'· ΙΜΡ „,,

INSTITUTO MEXICANO A added 456 kg of water / assisj to the solution

SDAG-1 ethanol (ethanol denatured with methanol for two hours). The mixture was stirred at 15-25 ° C for at least 16 hours. The product was filtered and washed with a mixture of 143 kg of water and 126.7 THF in two portions. The product was dried at a set point of maximum temperature at 40 ° C.

In an alternative procedure, the temperature of the reaction during the formation of the acid chloride was adjusted to between 10 and 15 ° C. The recrystallization temperature was changed from between 15 and 25 ° C to between 45 and 50 ° C for 1 hour, and then cooled to between 15 and 25 ° C for 2 hours.

Preparation of (L) Malate Salt of [4- (6,7-Dimethoxyquinine-4-yloxy) -phenyl] -amide (4-fluoro-phenyl) -cyclopropane-1,1-dicarboxylic acid amide, XL184

Cyclopropane1,1-dicarboxylic acid (1 - 5; 13.3 kg), L-acid was loaded with [4 - (6,7-dimethoxy-quinolin-4-yloxy) phenyl] -amide (4-fluoro-phenyl) -amide. -malic (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) in a reactor and the mixture was heated under reflux (approximately 74 ° C) for approximately 2 h. The reactor temperature was reduced to between 50 and 55 ° C and the contents of the reactor were filtered. The sequential steps described above were repeated two more times

IMPI

MEXICAN INSTITUTE starting from similar amounts of l^THEVímS ™ AÍl L-malic acid (4.96 kg), MEK (198.6 kg) and acni fniJcgl.,., The mixture was azeotropically dried at atmospheric pressure by using MEK (1,133.2 kg) (approximate residual volume of 711 1 ; KF &lt;0.5% w / w) at approximately 74 ° C. The temperature of the reactor contents was reduced to between 20 and 25 ° C and held for approximately 4 hours, resulting in a solid precipitate that was filtered, washed with MEK (448 kg) and vacuum dried at 50 ° C to provide the title compound (45.5 kg). Alternative preparation of (4) (6,7-dimethoxy-quinolin-4-yloxy) -phenyl] -amide (4-fluorophenyl) -amide of cyclopropane-1,1-dicarboxylic acid

Cyclopropane-1,1-dicarboxylic acid amide (4-fluoro-phenyl) -amide (47.9 kg), L-malic acid (17.2) were charged. , 658.2 kg of methyl ethyl ketone and 129.1 kg of water (37.3 kg) in a reactor and the mixture was heated to between 50 and 55 ° C for approximately 1 to 3 hours and then between 55 and 60 ° C for 4 to 5 additional hours. The mixture was clarified by filtration through a 1 μτη cartridge. The reactor temperature was adjusted to between 20 and 25 ° C and vacuum distilled with a vacuum of between 150 and 200 mm Hg with a maximum jacket temperature of 55 ° C at a volume range of between

558 and 731 1.

IMPI _____

MEXICAN INSTITUTE,

OF THE PROPERTY

Vacuum distillation was carried out twice '^N? K§'K^{TO THE}I took 3 80 kg and 3 8 0.2 kg of methyl and LeLwie-r respectively. After the third distillation, the batch volume was adjusted to 18 v / w of [4 - (6,7-dimethoxyquinoline-4-yloxy) -phenyl] -amide (4-fluoro-phenyl) -cyclopropane acid amide- 1,1-dicarboxylic acid loading 159.9 kg of methyl ethyl ketone to give a total volume of 880 1. Further vacuum distillation was performed adjusting 245.7 of methyl ethyl ketone. The reaction mixture was left with moderate stirring at 20-25 ° C for at least 24 hours. The product was filtered and washed with 415.1 kg of methyl ethyl ketone in three portions. The product was vacuum dried at a set temperature point of the sheath at

45 ° C.

In an alternative procedure, the order of addition was changed, so that a solution of 17.7 kg of L-malic acid dissolved in 129.9 kg of water was added to the [4- (6,7dimethoxy-quinoline-4-yloxy) - cyclopropane-1,1-dicarboxylic acid phenyl] -amide (4-fluoro-phenyl) amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound 2

Compound 2 was prepared as provided in Reaction Scheme 3 and in the accompanying experimental examples.

Reaction scheme 3

<img file="MX343288B_D0077.tif" />

<img file="MX343288B_D0078.tif" />

POCIj

CHiCN

HCO₂H hco₂k

EtOH

H, N „

KjCOg, Bu₄NBr ^ toluene

Οό ^^ νη₂ or

NaOEt

HCO₂Et

EtOH

Cl ^H3C° XVtS ^H0 or&gt;

X&gt;

2,6-lutidine

<img file="MX343288B_D0079.tif" />

Ηϊθθχ_νχ- &lt;55_ϊ^ χ4 ^

<img file="MX343288B_D0080.tif" />

Mexican IMPI ° E THE INDUSTRIAL FRORITY

<img file="MX343288B_D0081.tif" />

In Reaction Scheme 3, Xb is Br or Cl. With respect to the names of the intermediates described in the description of Reaction Scheme 3, below, Xb is called halo, where it is understood that the halo group for these intermediates stands for Br or Cl.

IMPI

MEXICAN INSTITUTE Dt LA «OtlEDAO

<img file="MX343288B_D0082.tif" />

Preparation of 1- [5 methoxy-4 (3-halopropoxy) -2 ηίϊ ^ ο ^ 'ϊβηΤ ethanone

Water (70 1) was charged into the l- [4- (3-halo propoxy) -3-methoxy phenyl] ethanone solution (both the bromine and chlorine compounds are commercially available). The solution was cooled to approximately 4 ° C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 ° C. The resulting solution was cooled to approximately 5 ° C and 7 0 percent nitric acid (75.8 kg) was added at such a rate that the batch temperature did not exceed approximately 10 ° C. Methylene chloride, water, and ice were charged into a separate reactor. The acidic reaction mixture was then added to this mixture. The methylene chloride layer was separated, and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with an aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1-Butanol was added and the mixture was concentrated again by vacuum distillation. The resulting solution was stirred at about 20 ° C, during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to provide the compound with the title compound, which was isolated as a solvent-wet cake and was

IMPI

INSTITUTO MEXICANO used directly in the next stage. NMR-^to^ rNr $ £ ¡}) 2 DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4. »» ·· (m, SU), (s, 3H), 3.78 (t) - 3.65 (t) (2H), 2.51 (s, 3H), 2.30 - 2.08 (m, 2H) LC / MS calculated for [M (Cl) + H]⁺ 288.1, found 288.0; calculated for [M (Br) + H]⁺ 332.0, 334.0, found 331.9, 334.0.

<img file="MX343288B_D0083.tif" />

Preparation of 1- [5-methoxy-4- (3-morpholin-4-yl-propoxy) -2nitro-phenyl] -ethanone

The solvent-moistened cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) were added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting biphasic mixture was heated at about 85 ° C for about 9 hours. The mixture was then cooled to room temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were sequentially washed with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. NMR-¹!! (400 MHz, DMSO-d6): δ 7.64 (s, 1H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H ), 2.44 - 2.30 (m, 6H),

1.90 (quin, 2H); LC / MS calculated for [Μ + H]⁺ 339.2, found 339.2.

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MEXICAN INSTITUTE IX) *. ·

Preparation of 1- [2-amino-5-methoxy-4- (3 propoxy) -phenyl] -ethanone

The solution from the previous step was concentrated under reduced pressure to approximately half the original volume. Ethanol and 10 percent Pd / C (50 percent aqueous moisture, 5.02 kg) were added; The resulting suspension was heated to approximately 48 ° C, and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction was deemed complete by thin layer chromatography (TLC), water was added to dissolve the saline by-product. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure, and toluene was added. The mixture was basified (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the resulting solution was used in the next step without further processing. NMR-¹!! (400 MHz, DMSO-d6): δ 7.11 (s, 1H) „7.01 (sa, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s,

3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44 - 2.30 (m, 6H), 1.91 (quin, 2H LC / MS calculated for [Μ + H]⁺ 3 09.2, found

309.1.

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Preparation of the sodium salt of 6-methoxy-7- (3-πί &amp; ϊϊ'όΊτη-Ι ^ yl-propoxy) -quinolin- 4-ol

A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution of the previous step. The mixture was heated at approximately 44 ° C for approximately 3 hours. The reaction mixture was cooled to approximately 25 ° C. Methyl t-butyl ether (MTBE) was added, causing the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at room temperature. The dried product was ground through a mesh screen to provide 60.2 kg of the title compound. ΗΜΝ- ^ Ή (400 MHz, DMSO-d6): δ 11.22 (sa, IH), 8.61 (d, IH), 7.55 (s, IH),

7.54 (s, IH), 7.17 (d, IH), 4.29 (t, 2H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.11 (m,

2H), 2.35 (m, 2H), LC / MS calculated for [Μ + H]⁺ 319.2, found 319.1.

Preparation of 4-chloro-6-methoxy-7- (3 morpholin-4-yl) -quinoline

Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin4-ol (5.00 kg) in acetonitrile which was heated to between 50 and 55 ° C . When the addition was complete, the mixture was heated to reflux (about 82 ° C) and held at that temperature, with stirring for about 18 hours, after which time a sample was taken for a

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MEXICAN INSTITUTE 'fe?' '- DELA PROPIEDAD V' «-: 7X¡ '

INDUSTRIAL ^ * 13 '6ίΤ ^ · ^ in-process analysis using HPLC. The reaction was considered complete when no more than 5 percent of the starting material remained. The reaction mixture was then cooled to between 20 and 25 ° C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting biphasic mixture was separated, and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated to a solid. The solids were dried at 30 to 40 ° C under reduced pressure to provide the title compound (1,480 kg). NMR-¹H (400 MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H),

4.21 (t, 2H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50 - 2.30 (m, 6H), 1.97 (quin, 2H) LC / MS calculated for [Μ + H]⁺ 458.2, found 458.0.

Preparation of 4- (2-fluoro-4-nitro-phenoxy) -6-methoxy-7- (3morfolin-4-yl propoxy) quinoline

A solution of 4-chloro-6-methoxy-7- (3 morpholin-4-yl) quinoline (2,005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1,169 kg, 7.44 mol) in 2.6-lutidine was heated to between 140

<img file="MX343288B_D0085.tif" />

IMPI nwrnvro Mexican DE. LA RROE11OAD INDUSTRIAL y 145 ° C, with stirring, for approximately 2 hours, after which time a sample was taken for in-process analysis by HPLC. The reaction was considered complete when no more than 5 percent of the starting material remained. The reaction mixture was then cooled to approximately 75 ° C and water was added. Potassium carbonate was added to the mixture, which was then stirred at room temperature overnight. The precipitating solids were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 ° C under reduced pressure to provide the title compound (1.7 kg). NMR-¹H (400 MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd,

1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s,

1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t,

4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H), LC / MS calculated for [Μ + H]⁺ 337.1, 339.1, found 337.0,

339.0.

Preparation of 3-fluoro-4- [6-methoxy-7- (3-morpholin-4-ylpropoxy) -quinolin-4-yloxy] -phenylamine

A reactor containing 4- (2-fluoro-4-nitro-phenoxy) -6 methoxy-7- (3-morpholin-4-yl propoxy) quinoline (2.5 kg) and 10 percent palladium on carbon (at 50 percent aqueous humidity, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 1) was pressurized with hydrogen gas (approximately 40 psi). The mixture is

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INSTITUTO MEXICANO stirred at room temperature. When reaction (typically 2 hours), as evidenced by in-process analysis by HPLC, hydrogen was blown in and the reactor was made inert with argon. The reaction mixture was filtered through a pad of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 ° C for approximately 1 hour. The solids were collected by filtration, washed with water, and dried at 50 to 60 ° C under reduced pressure to provide the compound of the

<img file="MX343288B_D0086.tif" />

<td colspan="2">title (1.</td><td> 164</td><td>kg).</td><td>NMR-^XH (400 MHZ, DMSO-d6): δ 8.45</td><td>(d,</td>

<td>1 HOUR) ,</td><td> 7.51</td><td>(s,</td><td>1 HOUR) ,</td><td>7.38 (s, 1H), 7.08 (t, 1H), 6.55 (</td><td>dd,</td>

<td>1 HOUR) ,</td><td> 6.46</td><td>(dd,</td><td>1 HOUR) ,</td><td>6.39 (dd, 1H), 5.51 (bs, 2H), 4.19</td><td>(t,</td>

<td>2H),</td><td> 3.94</td><td>(S,</td><td>3H),</td><td>3.59 (t, 4H), 2.47 (t, 2H), 2.39</td><td>(m,</td>

<td>4H),</td><td> 1.98</td><td>(m,</td><td>2H),</td><td>LC / MS calculated for [M + H]⁺ 428</td><td> .2,</td>

<td colspan="2">found</td><td> 428</td><td> . 1.</td><td></td><td></td>

Preparation of 1- (4-fluoro-phenylcarbamoyl) cyclopropanecarbonyl chloride

Oxalyl chloride (291 ml) was slowly added to a cooled (approximately 5 ° C) solution of 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10 ° C. When the addition was complete, the batch was allowed to warm to room temperature and was maintained with

<img file="MX343288B_D0087.tif" />

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MEXICAN INSTITUTE • and ia «oneoAD

INOE'STRIAL __ stirring for approximately 2 hours, after which an in-process analysis by HPLC indicated that the reaction was complete. The solution was used in the next step without further processing.

Preparation of {3-fluoro-4- [6-methoxy-7- (3-morpholin-4-ylpropoxy) -quinolin-4-ylamino] phenyl} -amide- (4-fiuorophenyl) amide of cyclopropane-1,1 acid -dicarboxylic

The solution from the previous step was added to a mixture of 3-fluoro-4- [6-methoxy-7- (3-morpholin-4-yl-propoxy) quinolin-4-yloxy] -phenylamine (1,160 kg) and carbonate potassium (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 ° C. When the addition was complete, the batch was warmed to room temperature and maintained with stirring for approximately 1 hour, after which time an in-process analysis by HPLC indicated that the reaction was complete. A solution of aqueous potassium carbonate and isopropyl acetate were added to the batch. The resulting biphasic mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water, followed by aqueous sodium chloride, and then suspended with a mixture of magnesium sulfate and activated carbon. The suspension was filtered through Celite®, and the filtrate was concentrated to a

IMPI

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INSTITUTO MEXICANO ds the RXOMDAD INDUSTRIAL oil at approximately 30 ° C under vacuum to provide title compound, which was carried to the next stage without further processing. ΕΜΝ- ^ Ή (400 MHz, DMSO-d6): δ 10.41 (s,

<td>1 HOUR) ,</td><td> 10.03</td><td>(s,</td><td colspan="2">1H), 8.47</td><td>(d, 1H),</td><td> 7.91</td><td>(dd,</td><td>1H), 7.65</td><td>(m,</td>

<td>2H),</td><td> 7.53</td><td>(m,</td><td>2H),</td><td> 7.42</td><td>(m, 2H),</td><td> 7.16</td><td>(t,</td><td>2H), 6.41</td><td>(d,</td>

<td>1 HOUR) ,</td><td> 4.20</td><td>(t,</td><td>2H),</td><td> 3.95</td><td>(s, 3H),</td><td> 3.59</td><td>(t,</td><td>4H), 2.47</td><td>(t,</td>

<td>2H),</td><td> 2.39</td><td>(m,</td><td>4H)</td><td> , 1.98</td><td>(m, 2H)</td><td colspan="2"> , 1.47</td><td colspan="2">(m, 4H), LC / MS</td>

<td colspan="3">calculated for</td><td>[M +</td><td>H]⁺ 633</td><td colspan="2">1.2, found</td><td> 633</td><td> . 1.</td><td></td>

<td colspan="2">Preparation</td><td>of</td><td>the</td><td>Get ouf of</td><td colspan="2">bisphosphate</td><td>the</td><td>{3 -fluoro-4-</td><td> [6-</td>

Cyclopropane-1,1-dicarboxylic acid methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-amino-phenyl} -amide (4-fluoro-phenyl) -amide

Cyclopropane-1 acid (3-fluoro-4- (6-methoxy-7-3-morpholin-4-propoxy) -quinolin-4-ylamino] phenyl} -amide- (4-fluoro-phenyl) -amide was dissolved. , 1-dicarboxylic acid from the previous stage in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 ° C. The batch was kept at about 15 to 30 ° C with stirring for 1 hour, during which time the product precipitated. The solids were collected by filtration, washed with acetone, and dried at approximately 60 ° C in vacuo to provide the title compound (1,533 kg). The title compound had an IC value₅₀ of c-Met less than 50 nM. Bisphosphate salt is not shown in Reaction Scheme 3.

<img file="MX343288B_D0089.tif" />

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Mexican INSTNvro OF industrial property

NMR-¹H (400 MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H),

<td> 10</td><td> . 02</td><td>(s,</td><td>1 HOUR) ,</td><td> 8.48</td><td>i (d, 1H),</td><td>7.93 (dd, 1H), 7.65</td><td>(m,</td><td>2H),</td>

<td> 7 .</td><td> 53</td><td>(d,</td><td>2H), 7</td><td> .42</td><td>(m, 2H), 7.</td><td>.17 (m, 2H), 6.48 (d,</td><td>1 HOUR)</td><td> , 5.6</td>

<td>(s</td><td>to,</td><td>6H)</td><td> , 4.24</td><td>(t,</td><td>2H), 3.95</td><td>(s, 3H), 3.69 (sa,</td><td>4H),</td><td> 2.73</td>

<td>(s</td><td>to,</td><td>6H)</td><td> , 2.09</td><td>(t,</td><td>2H), 1.48</td><td>(d, 4H).</td><td></td><td></td>

Procedure for direct coupling

<img file="MX343288B_D0090.tif" />

Solid sodium tert-butoxide (1.20 g; 12.5 mmol) was added to a suspension of chloroquinoline (3.37 g; 10 mmol) in dimethylacetamide (35 ml), followed by solid 2-fluoro-4-hydroxyaniline. The dark green reaction mixture was heated at 95-100 ° C for 18 hours. HPLC analysis showed that approximately 18 percent of the starting material and approximately 79 percent of the product remained. The reaction mixture was cooled to below 50 ° C, sodium tert-butoxide (300mg; 3.125mmol) and additional aniline (300mg; 2.36mmol) were added and heating to 95-100 ° C was terminated. Analysis by HPLC after 18 hours revealed that less than 3 percent of the starting material remained. The reaction was cooled to below 30 ° C, and ice water (50 ml) was added while maintaining the temperature for

1ΜΡΪ below 30 ° C. After shaking dur ^ g ^ eroMaicAi ^^{D £} Ά íimusTT ·¹ *^L At room temperature, the product was collected by filtration, washed with water (2 x 10 ml) and dried under vacuum in the filter funnel, to produce 4.11 g of the coupled product as a brown solid (96% yield; 89%, corrected for water content). NMR'ή and MS: consistent with the product; 97.8% LCAP; about 7 weight percent water by KF. Preparation of Compound 2 in hydrated form

The hydrate of Compound 2 was prepared by adding 4.9614 g of Compound 1 and 50 ml of n-propanol to a 250 ml beaker. The suspension was heated to 90 ° C with stirring by means of a magnetic stir bar at 200 rpm. After 2 hours, the solids completely dissolved in an amber colored solution. At the 1 hour and 2 hour time points 10 ml of npropanol was added to compensate for the effects of evaporation, and the volume of the solution was returned to 50 ml. The solution was then filtered hot through a 1.6 μιη fiberglass filter. The solution was then allowed to dry overnight in the beaker to a powder, which was then redissolved in 150 ml of a 1: 1 mixture of acetone and water and suspended overnight (16 hours) with an aluminum cap to avoid evaporation. The suspended solids were then collected by filtration at

<img file="MX343288B_D0091.tif" />

<img file="MX343288B_D0092.tif" />

ΙΜΡΙ empty. The final weight recovered was performance). This batch was stored under ambient conditions for several days before analysis.

Water content determinations by Karl Fisher were made using a standard procedure. The water content was measured with a Brinkmann KF1V4 Metrohm 756 coulometer equipped with a 703 Ti stirrer and using the Hydranal Coulomat AG reagent. The samples were introduced into the container as a solid. Approximately 30 to 35 mg of sample were used per titration. A crystalline sample of Compound (I) prepared in Example 1.1.2 was measured in duplicate, and was found to have an average water content of 2.5% w / w, with each duplicate matching 0.1%.

A Gravimetric Vapor Sorption (GVS) study was conducted using a standard procedure. The samples were analyzed on a dynamic vapor sorption analyzer (Surface Measurement Systems) with a DVSCFR software. Sample sizes were typically 10 mg. A moisture desorption-absorption isotherm was performed, according to the chalk reaction scheme below. The standard isotherm experiment, performed at 25 ° C, is a two-cycle analysis, starting with 40% RH (relative humidity), increasing humidity up to 90% RH, decreasing humidity up to 0% RH, increasing the humidity up to 90% RH and finally^NR3ÍSthinuyenao humidity up to 0% RH at intervals- dül 10% de — MR. The

Crystalline compound 1 prepared in Example 1.1.1 showed a weight gain of 2.5% at 25 ° C and a humidity of 90%. GVS sorption and desorption curves showed signs that the hydrate behaves like an isomorphic solvent (Stephenson, GA; Groleau, EG; Kleeman, RL; Xu, W .; Rigsbee, DRJ Pharm. Sci. 1998, 87, 536 - 42).

The X-ray powder diffraction pattern of the crystalline hydrate of Compound 1 prepared above was acquired using a PANalytical X'Pert Pro diffractometer. The sample was gently flattened on a sample holder with a zero-bottom silicon insert. A continuous sweep at 20 from 2 ° to 50 ° was used with a CuKa radiation source and a generator power of 40 kV and 45 mA. A jump size of 20 of 0.017 degrees / jump with a jump time of 40.7 seconds was used. The samples were rotated at 30 rpm. The experiments were carried out at room temperature and at ambient humidity. WO 2011/112896, the entirety of the content of which is incorporated herein by reference, shows the XRPD pattern of the crystalline hydrate of N- [3-fluoro-4 - ({6- (methyloxy) -7- [ (3morpholin-4-ylpropyl) oxy] quinolin-4-yl} oxy) phenyl] -N¹- (4fluorophenyl) cyclopropane-1,1-dicarboxamide. The following peaks were identified in an experimental ° 20 + 0.1 ° 20 in the

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<img file="MX343288B_D0093.tif" />

XRPD pattern: 6.6, 9.0, 10.2, 12.0, 12.2, 13.1, 13.3, 14.6, 15.6, 16.2, 17.0, 17.1, 17.4, 18.2, 18.4, 20.0, 2θ7Τ7 20.8, 21.7, 22.1, 23.1, 23.4, 23.8, 24.2 , 24.5, 25.0.

Only peaks below 25 ° 20 are provided as these are generally preferred for the identification of crystalline dosage forms. The complete list of peaks, or a subset of these, may be sufficient to characterize the hydrate of Compound 1.

DSC thermograms were acquired using a TA Instruments Q2000 differential scanning calorimeter. A sample mass of 2.1500 mg of the crystalline hydrate of Compound 1 was weighed directly into an aluminum crucible for DSC. The crucible was sealed tightly by applying pressure by hand and pushing each part of the crucible against the other (also known as a loose cap configuration). The temperature increased from 25 ° C to 225 ° C at 10 ° C / minute. A peak melting temperature of 137.4 ° C and a heat flux of 44.2 J / g were measured for the melting endotherm. After the melting event, recrystallization occurs to an anhydrous form, which then melts at 194.1 ° C.

TGA thermograms were acquired using a TA Instruments Q500 thermogravimetric analyzer. The sample crucible was tarred and 9.9760 milligrams of the crystalline hydrate of Compound (I) was placed on the crucible. The

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10 ° C / minute. A weight loss of '2.9)% IilluIw * was observed

<img file="MX343288B_D0094.tif" />

160 ° C, with additional weight loss beyond 200 ° C due to decomposition.

Preparation of the crystalline hydrate of Compound 2 with different states of hydration.

Five 150 mg aliquots of the crystalline hydrate batch prepared above were taken and placed in vials with a 10 ml screw cap. With the vial stoppers removed, these aliquots were each stored in chambers with desiccant (Dri-Rite®, tricalcium silicate, 2 to 3% RH), saturated lithium bromide (6% RH), saturated lithium chloride (11% RH), saturated magnesium chloride (33% RH), and saturated sodium chloride (75% RH). Samples were removed after 2 weeks and immediately sealed with a stopper for analysis, and characterized.

The foregoing description has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to the person skilled in the art that changes and modifications can be made to the

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MEXICAN INSTITUTE OF PROPERTY

<img file="MX343288B_D0095.tif" />

scope of the appended claims. By 'T'áñtb, you understand that the above description is intended to sel¹ llUSLldLiva · and not restrictive. The scope of the invention should therefore not be determined with reference to the foregoing description, but should instead be determined with reference to the following appended claims, together with the full scope of equivalents to which the claims are entitled .

It is noted that in relation to this date, the best method known by the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.

$ &lt;ο5Μ

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industrial

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