This application claims the benefit of U.S. Provisional Applications 61/754,516 filed on January 18, 2013

FIELD OF THE INVENTION

The present invention relates a new process to synthesize 6-(7-((l-aminocyclo-propyl)- methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl- 1 -naphthamide (AL3810) by deprotection of substituted benzyl 1 -((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinol in-7-yloxy)- methyl)cyclopropylcarbamate (Formula I) under a diluted or weak acidic condition. A stable crystalline form of 6-(7-((l-aminocyclo-propyl)-methoxy)-6-methoxyquinolin-4-ylo xy)-N- methyl- 1 -naphthamide has also been prepared.

BACKGROUND OF THE INVENTION

6-(7-((l -Aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-met hyl- 1 -naphthamide (AL3810), or a pharmaceutically acceptable salt (such as hydrochloride salt) thereof, has been developed as an anti-tumor agent also named as E3810 and lucitanib, see "Journal of Cellular and Molecular Medicine vol. 16 issue 10 October 2012. p. 2321-2330 ", "Cancer Res February 15, 2011 vol. 71 no A 1396-1405 ".

This compound has been structurally disclosed in WO20081 12408 as an agiogenesis inhibitor with few preparation methods. A new process has been disclosed in WO2010105761 with the removal of use of sodium azide. Both above disclosed processes have involved a deprotection of benzyl carbmate protected precursor by HBr/Acetic acid solution that is a strong, fuming and high corrosive acidic condition. No crystalline form has been disclosed.

SUMMARY OF THE INVENTION

Abbreviations

The following abbreviations are used and have the meaning below for ease of reference. EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature, DIPEA: diisopropylethylamine, DCM: Dichloromethane, DMF: NN-dimethylformamide, NMP: 1 -Methyl-2-pyrrolidinone, ACN: acetonitrile, DEAD: Diethyl azodicarboxylate, DIAD: Diisopro- pyl azodicarboxylate, CDI: Ι, -Carbonyldiimidazole, MeNH ₂ .HCl: methylamine hydrochloride, TSA.H20: 4-toluensulfonic acid monohydrate, DMAP: 4-N,N-dimethylaminopyridine, MsCl: methanesulfonyl chloride, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TEA: triethylamine, DPPA: diphenyl phosphoryl azide, eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minutes

Definitions

The term "halogen", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. such as fluoro and chloro.

The term "halogeno-Ci-Cealkyl", as used herein, unless otherwise indicated, includes 1 to 6 halogen substituted alkyl, such as trifluoromethyl.

The term "Ci-Cealkyl", as used herein, unless otherwise indicated, includes 1 to 6 saturated monovalent hydrocarbon radicals having straight or branched moieties, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, tert-butyl, and the like.

The term "Ci-Cealkoxy", as used herein, unless otherwise indicated, includes -OCi-Cealkyl groups wherein Ci-Cealkyl is as defined above, such as methoxy and ethoxy.

The term "cyano", as used herein, unless otherwise indicated, includes -CHST.

The term "nitro", as used herein, unless otherwise indicated, includes -N0 ₂ .

Methods of Preparation

The present invention relates to a process for preparing 6-(7-((l-aminocyclopropyl)- methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl- 1 -naphthamide (AL3810) by deprotection of substituted benzyl 1 -((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinol in-7-yloxy)- methyl)cyclopropylcarbamate Formula I under a diluted or weak acidic condition according to Process A.

Process A

Wherein

P i is selected from H, halogen, halogeno-Ci-C ₆ alkyl, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, cyano or nitro; Pv ₂ is selected from Ci-C ₆ alkoxy, or nitro. The present invention relates to the compound of Formula I.

The present invention relates to the methods of preparing a compound having the Formula I.

The present invention also relates to various intermediates useful in the preparation of a compound having the Formula I, and the present invention further relates to the methods of preparing such intermediates.

The present invention relates to the methods of preparing a crystalline form of 6-(7-((l- aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-meth yl- l -naphthamide.

DESCRIPTION OF DRAWINGS

Fig 1 provides a HI nuclear magnetic resonance (NMR) graph of a crystalline form of 6- (7-((l -aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-met hyl- 1 -naphthamide.

Fig 2 provides a differential scanning calorimetric (DSC) graph of a crystalline form of 6-(7-((l -aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-met hyl- 1 -naphthamide.

Fig 3 provides a thermogravimetric analysis (TGA) graph of a crystalline form of 6-(7- (( 1 -aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-met hyl- 1 -naphthamide.

Fig 4 provides an X-ray powder diffraction (XRPD) graph of a crystalline form of 6-(7- (( 1 -aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-met hyl- 1 -naphthamide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing 6-(7-((l-aminocyclo-propyl)- methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl- 1 -naphthamide (AL3810) by deprotection of substituted benzyl 1 -((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinol in-7-yloxy)- methyl)cyclopropylcarbamate Formula I under a diluted or weak acidic condition according to above Process A.

Wherein

Ri is selected from H, halogen, halogeno-Ci-Cealkyl, Ci-Cealkyl, Ci-Cealkoxy, cyano or nitro; preferably selected from H, Ci-Cealkoxy, or nitro;

R ₂ is selected from Ci-Cealkoxy, or nitro; preferably R ₂ is methoxy.

A diluted or weak acidic condition is selected from 5-50% TFA in CH ₂ C1 ₂ or CH ₃ CN, 10% HC1 in ethanol, 4NHC1 in dioxane, HCOOH in CH ₃ CN or p-toluenesulfonic acid monohydrate in CH ₃ CN; preferably the acid is 10% TFA in CH ₂ C1 _2. The total volume ratio of solvent to reactant is from 2 to 20 folds by weight. The reaction temperature is selected from 0 to 80°C and the reaction time is selected from 0.5 to 24 hours. A preferred procedure is shown in Scheme I.

The present invention relates to a process for preparing 6-(7-((l-aminocyclo-propyl)- methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl- 1 -naphthamide (AL3810) by deprotection of 4- methoxybenzyl l-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)-quin olin-7-yloxy)- methyl)cyclopropylcarbamate Formula II according to Process B.

Process B

The present invention relates to the compound of Formula II.

The present invention relates to the methods of preparing a compound having the Formula II.

The present invention also relates to various intermediates useful in the preparation of a compound having the Formula II, and the present invention further relates to the methods of preparing such intermediates.

Process B of the invention comprises preparing AL3810, a preferred procedure is shown in Scheme II via:

(a) under a condition of 10% TFA in CH ₂ C1 _2, preferably at 0°C to 50°C for 3- 10 hours with 5-20 folds volume of 10% TFA in CH ₂ CI ₂ as the solvent, or

(b) under a condition of 2-4 eq TSA.H ₂ 0 _; preferably at room temperature to 80°C for 10-24 hours with CH ₃ CN as the solvent.

The present invention relates to a compound of Formula I or Formula II and the method preparing Formula I or Formula II according to Process C. Process C

Formula III Scheme IV

Wherein

Ri is selected from H, halogen, halogeno-Ci-Cealkyl, Ci-Cealkyl, Ci-Cealkoxy, cyano or nitro; R ₂ is selected from Ci-C ₆ alkoxy, or nitro.

Process C of the invention comprises preparing Formula I, a preferred procedure is shown in Scheme III via the reaction between formula 14 and Formula VI using a base, such as: Na ₂ C0 ₃ , Cs ₂ C0 ₃ or K ₂ C0 ₃ , or between formula 14 and Formula V using a base, such as: Na ₂ C0 ₃ , Cs ₂ C0 ₃ or K ₂ C0 ₃ , and KI or Nal to give Formula I, preferably the reaction is at a heated condition, such as 60- 120 °C in acetone, DMF or NMP.

Formula 14 can be prepared by following steps:

(a) A direct acylation of formula 10 without any protection by methylamine hydrochloride with heat pre-activation of formula 10 at the presence of CDI gives formula 1 1 , preferably the reaction is carried out in DMF or dioxane for 2-8 hours with 1.5-4 eq CDI at a heated condition, such as at 50- 120 °C,

(b) (i) Coupling formula 1 1 with formula 12 (WO20081 12408) at 100- 160 °C in lutidine, such as 1 ,6-lutidine, or pyridine with 1.5-3 eq DMAP for 2-24 hours gives formula 13, or

(ii) Coupling formula 1 1 with formula 12 under similar Ullmann reaction conditions, such as: a base, Cul and 2-picolinic acid gives formula 13, preferably a base is one of Na ₂ C0 ₃ , Cs ₂ C0 ₃ and K ₂ C0 ₃ , Cul amount is catalytic amount at 1 -50% eq and 2-piclinic acid is at 1 -50% eq. The reaction is at 100- 160 °C in DMF or NMP for 10-36 hours, or

(iii) Coupling formula 1 1 with formula 12 under similar Ullmann reaction conditions, such as: a base, Cul and pentanedione gives formula 13, preferably a base is one of Na ₂ C0 ₃ , Cs ₂ C0 ₃ and K ₂ C0 ₃ , Cul amount is catalytic amount at 1 -50% eq and pentanedione is 1 ,4-pentanedione. The reaction is at 100- 160 °C in DMF or NMP for 10-36 hours.

(c) Deprotecting formula 13 with TFA gives formula 14 as a TFA salt, preferably at 60- 100 °C for 0.5-8 hours.

Formula VI or Formula V can be prepared by following steps:

(d) Reacting formula 15 with Ri, R ₂ substituted benzyl alcohol with DPPA and triethylamine gives Formula III, preferably using 2-4 eq DPPA and 2-4 eq TEA in toluene or dioxane at a heated condition for 10-28 hours through Curtis rearrangement.

(e) Reducting Formula III by NaBH ₄ gives Formula IV, preferably at reflux condition in THF with addition of methanol.

(f) Reacting Formula IV with CH ₃ S0 ₂ C1 gives Formula V, preferably in a basic condition at - 10 °C -25°C. (g) Reacting Formula V with KI or Nal gives Formula VI, preferably refluxing in acetone or acetonitrile. This step can be modified as one pot reaction without isolation as Scheme III described.

Process C of the invention comprises preparing Formula II, a preferred procedure is shown in Scheme IV via the reaction between formula 14 and formula 15f using a base, such as: Na ₂ C0 ₃ , CS ₂ CO ₃ or K ₂ CO ₃ , or between formula 14 and formula 15d using a base, such as: Na ₂ C03, CS ₂ CO ₃ or K ₂ CO ₃ , and KI or Nal at a heated condition, such as at 60- 120 °C of one pot reaction in acetone, DMF or NMP to give Formula II.

The present invention relates to the compound of Formula I and the method preparing Formula I according to Process D.

Process D

Formula I

Process D of the invention comprises preparing Formula I, a preferred procedure is shown in Scheme V via acylazide formula 17 reacting with Ri, R ₂ substituted benzyl alcohol in a heated condition, preferably toulene or dioxane refluxing condition.

Formula 17 can be prepared by reacting formula 16 with ethyl chloroformate at 0°C in DMF or THF at the presence of TEA or DIPEA to form a mixed anhydride that can be reacted with NaN ₃ /DMF solution at similar temperature. Formula 16 can be prepared according to WO20081 12408.

The present invention relates to the compound of Formula I and the method preparing Formula I according to Process E. Process E

⁰ Formula VIII

Wherein

Ri is selected from H, halogen, halogeno-Ci-Cealkyl, Ci-Cealkyl, Ci-Cealkoxy, cyano or nitro; R ₂ is selected from Ci-C ₆ alkoxy, or nitro.

Process E of the invention comprises preparing Formula I, a preferred procedure is shown in Scheme VI via acylation of Formula VIII with methylamine hydrochloride with heat pre- activation of formula VIII at the presence of CDI gives Formula I, preferably the reaction is carried out in DMF or dioxane for 2-8 hours withl .5-4 eq CDI at 50- 120 °C. Formula VII can be similarly prepared by reacting formula 19 with Formula VI with a base, such as: Na ₂ C0 ₃ , CS ₂ CO ₃ or K ₂ CO ₃ , or with Formula V in one pot KI or Nal with a base, such as: Na ₂ C0 ₃ , Cs ₂ C0 ₃ or K ₂ CO ₃ , as described in Scheme III. Formula VIII can be prepared by hydrolysis of Formula VII under a strong basic condition, such as a mixture of an aqueous NaOH solution and EtOH. Formula 19 can be prepared according to WO20081 12408 from formula 18.

The present invention relates to the compound of Formula I or Formula II and the method preparing Formula I or Formula II according to Process F. Process F

Formula I

Formula II

Wherein

Ri is selected from H, halogen, halogeno-Ci-Cealkyl, Ci-Cealkyl, Ci-Cealkoxy, cyano or nitro; R ₂ is selected from Ci-C ₆ alkoxy, or nitro.

Process F of the invention comprises preparing Formula I, a preferred procedure is shown in Scheme VII via:

(a) Coupling formula 1 1 with Formula IX at 100- 160 °C in lutidine, such as 1 ,6-lutidine, or pyridine with 1.5-3 eq DMAP for 2-24 hours gives Formula I, or (b) coupling formula 1 1 with Formula IX under similar Ullmann reaction conditions, such as: a base of Na ₂ C03, CS ₂ CO ₃ and K ₂ CO ₃ with catalytic amount of Cul (1-50% eq) and 2-piclinic acid (1-50% eq) at 100-160 °C in DMF or NMP for 10-36 hours gives Formula I, or

(c) coupling formula 1 1 with Formula IX under similar Ullmann reaction conditions, such as: a base of Na ₂ C03, CS ₂ CO ₃ and K ₂ CO ₃ with catalytic amount of Cul (1-50% eq) and pentanedione (1-50% eq), such as 1 ,4-pentanedione, at 100-160 °C in DMF or NMP for 10-36 hours gives Formula I.

Formula IX can be prepared by reacting Formula IV with formula 21 under Mitusnobu reaction condition in THF at 0-40°C for 2-24 hours by use of Mitusnobu reagents, such as: DEAD or DIAD at the presence of a Mitsunobu ligand, such as triphenylphosphine. Formula 21 can be prepared by deprotection of formula 20 with TFA at 60-100 °C for 0.5-8 hours to give a TFA salt that can be neutralized by aqueous NaHC03 solution, and then filtered off.

Process F of the invention comprises preparing Formula II, a preferred procedure is shown in Scheme VIII via:

(a) Coupling formula 1 1 with formula 21b at 100-160°C in lutidine, such as 1,6-lutidine, or pyridine with 1.5-3 eq DMAP for 2-24 hours gives Formula II, or

(b) coupling formula 1 1 with formula 21b under similar Ullmann reaction conditions, such as: a base of Na ₂ C03, CS ₂ CO ₃ and K ₂ CO ₃ with catalytic amount of Cul (1-50% eq) and 2-picolinic acid (1-50% eq) at 100- 160 °C in DMF or NMP for 10-36 hours gives Formula II, or

(c) coupling formula 1 1 with formula 21b under similar Ullmann reaction conditions, such as: a base of Na ₂ C03, CS ₂ CO ₃ and K ₂ CO ₃ with catalytic amount of Cul (1-50% eq) and pentanedione (1-50% eq), such as 1 ,4-pentanedione, at 100- 160°C in DMF or NMP for 10-36 hours gives Formula II.

Formula 21b can be prepared by reacting formula 15c with formula 21 under Mitusnobu reaction condition in THF at 0-40°C for 2-24 hours with use of Mitsunobu reagents, such as: DEAD or DIAD, at the presence of a Mitsunobu ligand, such as triphenylphosphine.

The present invention relates to the methods of preparing a crystalline form of 6-(7-((l- aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-meth yl- 1 -naphthamide (AL3810) by recrystallizing the crude product from isopropanol to give a stable crystalline form. The crude product was dissolved at refluxing condition for 15 minutes to 3 hours in isopropanol with certain amount of active carbon. The reaction was filtered at hot condition and cooled to room temperature (optionally cooled at 4°C) for 4 to 48 hours. The precipitate was filtered and dried under high vacuum at 25°C-80°C to give a stable crystalline form with melting point at 185°C- 205 C. The crystalline form has no observable endotherm from about 40 C to about 185 C as determined by DSC. It has observable endotherm from about 185°C to about 210°C as determined by DSC. The crystalline form has a TGA themogram that doesn't exhibit significant weight loss until at 210°C to 250°C to indicate that it is an unsolvated material. The crystalline form has 20- 40 characteristic peaks on XRPD graph.

The following examples further illustrate the present invention, but should not construed as in any way to limit its scope.

Example 1

Representation of Process A and Process B

Process for preparation of 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxy-quinolin-4- yloxy)-N-methyl- 1 -naphthamide (AL3810)

To a stirred mixture of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarbamoyl)- naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropylcarba mate Formula II (150 g) in DCM (1.5 L) was added TFA (150 ml) through an additional funnel for about 30 min at RT. The reaction was stirred at 30°C for 4 hours and added into water (3 L). The aqueous layer was extracted with DCM twice (1.5L X 2) and basified with 3N NaOH (620 ml) to adjust pH 1 1-12 with a fine white solid precipitation. The solid was filtered and washed with water, further suction dry. The solid was dissolved into a mixture of chloroform/methanol (5 L, 3.5L/1.5L) and further washed with brine (2 L). It was dried with MgS0 ₄ and filtered. The solution was evaporated with EtOAc (2 L) three times to a slurry solution and cooled to RT. It was filtered and the filter cake was washed with ether, further air dried to give the crude titled compound 105g, yield: 95.9%. MS: (M+l) 444.

Example 2

Representation of Process A and Process B

Process for preparation of 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxy-quinolin-4- yloxy)-N-methyl- 1 -naphthamide (AL3810)

To a stirred mixture of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarbamoyl)naph- thalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropylcarbamate Formula II (1 g) in ACN (15 ml) was added TSA.H ₂ 0 (3 eq). The reaction was stirred at RT for 24 hours and it was basified with 3N NaOH. The solution was extracted with DCM three times, washed with brine and dried with MgS04. The solution then was filtered and evaporated, further recrystalized from IPA to give pure titled compound 550 mg, yield: 75%. MS: (M+l) 444. Example 3

Representation of Process C

Process for preparation of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarbamoyl)- naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropylcarba mate Formula II

To a stirred mixture of 6-hydroxy- 1 -naphthoic acid (19 g, formula 10) in DMF (150 ml) was added CDI (22 g). The reaction was heated at 80°C for 30 min and CH ₃ NH ₂ .HC1 (40 g) was added into the reaction. The reaction was heated for 3 hours at 80°C and cooled to RT and further diluted with water (300 ml). It was acidified with IN HC1 to pH 2-3 and extracted three times with EtOAc (150 ml). The combined organic layer was washed with saturated NaHC0 ₃ solution followed by water and brine. The solution was dried with Na ₂ S0 ₄ and evaporated to give the 4- rmula 1 1 compound 12 g.

(i) To a mixture of formula 1 1 (6.5 g), formula 12 (6.5 g) and DMAP (5.5 g) was added 1,6- lutidine (20 ml). The reaction was stirred and heated at 135°C for 5 hours from heterogeneous to homogeneous. The reaction was cooled and IPA (35 ml) was added into the reaction under slow stirring for 2 hours at RT. The solid was filtered and further washed with IPA, dried to give the formula 13 compound 5.8 g as a gray solid, yield 57%, or

(ii) To a mixture of formula 1 1 (500 mg), formula 12 (500 mg), Cul (80 mg), Cs ₂ C0 ₃ (1 g) and 1-picolinic acid (150 mg) was added DMF (0.5 ml). The reaction was stirred and heated at 120 °C for 24 hours. It was directed loaded on silica gel column to purify to give the formula 13 compound 370 mg, yield 48%, or (iii) To a mixture of formula 1 1 (500 mg), formula 12 (500 mg), Cul (80 mg), CS ₂ CO ₃ (1 g) and 2,4-pentanedione (10 mg) was added DMF (0.5 ml). The reaction was stirred and heated at 120 °C for 24 hours. It was directed loaded on silica gel column to purify to give the formula 13

A mixture of formula 13 (5.8 g) and TFA (12 ml) was heated at 90°C for one hour. The reaction was evaporated under reduced pressure and triturated with EtOAc. The solid was filtered e formula 14 as a TFA salt 5.5 g, yield 95%.

To a mixture of acid-ester (8.2 g, formula 15) and 4-methoxybenzyl alcohol (9.5 g) in toluene (50 ml) was added DPPA (15 g), the reaction was stirred and TEA was added into the reaction through an additional funnel at RT. The reaction then was refluxed for 20 hours and cooled to RT. To the reaction was added 2N NaOH (30 ml) and followed by extraction with EtOAc three times. The combined organic layer was washed with water to neutral and dried with Na ₂ SOzt. The solution was filtered and evaporated followed by addition of EtOAc/PE (petroleum ether) and stored in a refrigerator overnight. The crystals were filtered and washed with cold EtOAc/PE to give an off white powder. The product formula 15b was vacuum oven dried at 30°C to give 8.0 g as ethyl l-((4-methoxybenzyloxy)carbonylamino)cyclopropanecarboxylate (formula

294.

To a mixture of formula 15b (8.0 g) and THF (50 ml) was added NaBH ₄ (8 g). The reaction was refluxed for 12 hours. Methanol (15 ml) was slowly added to the reaction and refluxed for 4 hour. The solvent was evaporated and cooled. NH ₄ C1 (6.3 g) and water (60 ml) were added and stirred. The mixture was extracted with DCM three times and dried with Na ₂ S0 ₄ . The solution was filtered and evaporated followed by addition of ethanol to recrystalize overnight. The crystal was filtered to give an off white powder and further dried in oven to give the product 4.0 g as 4-methoxybenzyl l-(hydroxymethyl)cyclopropylcarbamate (formula 15c),

To a stirred mixture of formula 15c (100 g) and DCM (400 ml) was added DIPEA (78g). The result solution was cooled to 0-5°C with ice/water and further stirred under this temperature for 15 min. MsCl (60g) was added via an addition funnel dropwise keeping temperature below 5°C for about 1.5 hours. After completion of addition, the reaction mixture was allowed stirring at 0-5°C for 30 min and quenched with saturated NaHC0 ₃ (300 ml). The solution was extracted with 200 ml DCM twice. The combined DCM layer was washed with 0.1 N HC1 (400 ml) followed by brine. It was dried over Na ₂ S0 ₄ and concentrated to obtain an off- white solid 123 g

330.

To a stirred mixture of formula 15d (3.3 g) and KI (3.3 g) was added acetone (30 ml), the reaction was refluxed for 2 hours and cooled. The reaction was evaporated and extracted with EtOAc (30 ml) twice and washed with brine, further evaporated under reduced pressure to give the crude product 2.3 g of formula 15e, MS: (M+l) 362.

Formula II Method A:

To a stirred mixture of formula 14 (500 mg), formula 15d (450 mg), K ₂ C0 ₃ (400 mg) and Nal (180 mg) was added acetone (10 ml), the reaction suspension was heated to reflux for 20 hours as one pot reaction. The reaction was evaporated and purified on silica gel column to give the product 510 mg of Formula II. MS: (M+1) 608. ^l H NMR (DMSO-d6): δ: 8.53-8.54 (m, 2H), 8.37-8.39 (d, 1H), 8.00-8.02 (d, 1H), 7.83-7.88 (m, 2H), 7.53-7.61 (m, 4H), 7.42 (s, 1H), 7.22- 7.24 (d, 2H), 6.83-6.85 (d, 2H), 6.61-6.62 (d, 1H), 4.91 (s, 2H), 4.23 (s, 2H), 3.95 (s, 3H), 3.70 (s, 3H), 2.86-2.87 (d, 3H), 0.83-0.93 (d, 4H).

Method B:

To a stirred mixture of formula 14 (500 mg), formula 15e (500 mg) and K ₂ C0 ₃ (400 mg) was added acetone (10 ml), the reaction suspension was heated to reflux for 20 hours. The reaction was evaporated and purified on silica gel column to give the product 560 mg of Formula II. MS: (M+1) 608. ¾ NMR conforms to Formula II from above Method A.

Method C:

To a stirred mixture of formula 14 (33 g), formula 15d (43 g), K ₂ C0 ₃ (41 g) and KI (16.6 g) was added acetone (400 ml). The reaction suspension was heated to reflux for about 30 hr. The reaction was concentrated and to the residue was added water (700 ml). The result suspension was stirred for 1 hour slowly to get a brown solid. The solid was filtered and rinsed with water twice further rinsed with ethanol. The crude product was dried in oven at 40°C for 2-3 hours. The product was purified with IPA by recrystalization to give 29 g of Formula II. MS: (M+1) 608. ^l H NMR conforms to Formula II from above Method A.

Example 4

Representation of Process D

Process for preparation of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarba- moyl)naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropyl -carbamate Formula II

A mixture of 2-(l-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)qu ino-lin-7- yloxy)methyl)cyclopropyl)acetyl azide formula 17 (WO2008112408, 150 mg) and 4-methoxybenzyl alcohol (0.15 ml) in toluene (10 ml) was refluxed for 1.5 hour. The reaction was evaporated and purified with silica gel column to give the titled product. Mass: (M + 1), 608

Example 5

Representation of Process E Process for preparation of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarba- moyl)naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropyl carbamate Formula II

A mixture of 6-Hydroxy- 1 -naphthoic acid (1 g) and H ₂ SO ₄ (0.2ml) in EtOH (25 ml) was refluxed overnight and evaporated, followed by dissolving into EtOAc. The solution was washed with water, IN NaHC0 ₃ solution and brine, further dried by Na ₂ S0 ₄ . The solution was evaporated to give crude ethyl 6-hydroxy- 1 -naphthoate 0.9 g which was reacted with formula 12 at similar preparation conditions to formula 13 of Example 3 to give the above product of formula 18. Formula 19 was similarly prepared to formula 14 of Example 3.

A reaction between formula 19 and formula 15d similarly to the preparation of Formula II of Method A gave ethyl 6-(6-methoxy-7-((l-((4-methoxybenzyloxy)carbonylamino)cyclop ro- pyl)methoxy)quinolin-4-yloxy)- 1 -naphthoate which was hydro lyzed with 10% NaOH in EtOH at RT to give 6-(6-methoxy-7-((l-((4-methoxybenzyloxy)carbonylamino)cyclop ropyl)methoxy)- quinolin-4-yloxy)-l -naphthoic acid. The resulting acid was acylated similarly to the preparation of formula 1 1 of Example 3 with CH ₃ NH ₂ .HC1 under the heat pre- activation at the presence of CDI to give the titled product.

Example 6

Representation of Process F

Process for preparation of 4-methoxybenzyl l-((6-methoxy-4-(5-(methylcarbamoyl)- naphthalen-2-yloxy)-quinolin-7-yloxy)methyl)cyclopropylcarba mate Formula II

To a mixture of 4-chloro-6-methoxyquilolin-7-ol (formula 21, 5.2g), l-((4-methoxyben- zyloxy)carbonylamino)cyclopropanecarboxylate (formula 15b, 8.3g) and triphenylphosphine (9.8 g) in THF (250 ml) was added DEAD (6.5 g) dropwise at RT in 1.5 hours, the reaction was further stirred for 20 hours at RT and evaporated. The residue was purified with silica gel column to give the 4-methoxybenzyl 1 -((4-chloro-6-methoxy-quinolin-7-yloxy)methyl)cyclopropylcar ba- mate formula 21b product 6.5 g.

The titled compound of Formula II was then similarly prepared by using formula 21b to react with 4-hydroxy-N-methyl-naphamide formula 1 1 according to formula 13 of Example 3.

Example 7

Preparation of the crystalline form of 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxy- quinolin-4-yloxy)-N-methyl- 1 -naphthamide (AL3810)

The crude product from Example 1 (105 g) was mixed with isopropanol (2.5 L) and active carbon (5 g), the mixture was heated to reflux for 0.5 hour to dissolve all crude product followed by filtration while it was hot, then the filtrate was refluxed again for 10 minutes and it was cooled to room temperature overnight under a slow stirring condition. The precipitate was filtered and washed with ethyl ether (500 ml x 2), further dried under high vacuum at 80°C to give the pure product (85 g) with melting point at 192°C- 196°C.

HI NMR shown in Fig 1.

DSC shown in Fig 2 having observable endotherm from about 193°C-202°C

TGA shown in Fig 3 demonstrating as an unsolvated material with weight loss at about 230°C

XRPD shown in Fig 4 having pattern compromising thirty three characteristic peaks with all intensity and intensity% expressed in d values and angles as follows:

NO. Angle d value NO. Angle d value NO. Angle d value

1 10.429 8.476 14 20.545 4.320 27 29.137 3.062

2 1 1 .81 1 7.487 15 21 .214 4.185 28 30.331 2.944

3 12.287 7.198 16 21 .843 4.066 29 31 .172 2.867

4 13.293 6.655 17 22.058 4.026 30 31 .803 2.81 1

5 13.658 6.478 18 22.682 3.917 31 32.613 2.743

6 15.778 5.612 19 23.453 3.790 32 37.959 2.369

7 16.186 5.472 20 24.065 3.695 33 39.470 2.281

8 16.682 5.310 21 24.708 3.600

9 17.102 5.181 22 25.072 3.549

10 17.907 4.949 23 25.435 3.499

1 1 18.631 4.759 24 25.886 3.439

12 19.027 4.661 25 27.929 3.192

13 19.847 4.470 26 28.420 3.138

And HI NMR shown in Fig 1.

DSC shown in Fig 2 having observable endotherm from about 193°C-202°C

TGA shown in Fig 3 demonstrating as an unsolvated material with weight loss at about 230°C

XRPD shown in Fig 4 having pattern compromising characteristic peaks with intensity% greater than 10% expressed in d values and angles as follows: