LUCITANIB

6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide

6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)- N-methyl- 1 -naphthamide

6-(7-((l- aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-l- naphthamide

1058137-23-7 (E-3810 free base); 1058137-84-0  (E-3810 HCl salt)

A 4-(3-methoxypropoxy)-3-methylpyridinyl derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS.
For in advanced solid tumors.

Lucitanib (E-3810): Lucitanib, also known as E-3810,  is a novel dual inhibitor targeting human vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs) with antiangiogenic activity. VEGFR/FGFR dual kinase inhibitor E-3810 inhibits VEGFR-1, -2, -3 and FGFR-1, -2 kinases in the nM range, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. Both VEGFRs and FGFRs belong to the family of receptor tyrosine kinases that may be upregulated in various tumor cell type

Overview

http://www.clovisoncology.com/products-companion-diagnostics/lucitanib/

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 through 3 (FGFR1-3), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR α-ß). We own exclusive development and commercial rights to lucitanib on a global basis, excluding China. Lucitanib rights to markets outside of the U.S. and Japan have been sublicensed to Les Laboratoires Servier (Servier). We are collaborating with Servier on the global clinical development of lucitanib.

A Phase I/IIa clinical trial of lucitanib was initiated in 2010 and has demonstrated multiple objective responses in FGFR1 gene-amplified breast cancer patients, and objective responses were also observed in patients with tumors often sensitive to VEGFR inhibitors, such as renal cell and thyroid cancer. FGFR amplification is common in a number of tumor types, including breast cancer and squamous non-small cell lung cancer, and we intend to study lucitanib in these cancers as well as other solid tumors exhibiting FGFR pathway activation. A broad Phase II development program has been initiated by us and Servier in multiple indications, including advanced breast cancer and squamous NSCLC. For more information or to participate in the trials, contact the Clovis Oncology Clinical Trial Navigation Service at 1-855-262-3040, or 303-625-5010, or clovistrials@emergingmed.com.

http://www.asianscientist.com/2013/09/pharma/servier-license-lucitanib-simm-china-2013/

WO 2008/112408 Al and US 2008/0227812 Al disclose angiogenesis inhibitors with quinoline structure, useful for the treatment of neoplasias. One of the disclosed products is 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide of formula (I), described in example 3 of the above mentioned patent applications.

According to said documents, compound (I) is prepared by removing the benzyloxycarbonyl protective group from the compound benzyl l-((6- methoxy-4-(5-(methylcarbamoyl)-naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropyl carbamate (II):

in acid medium or by hydrogenolysis, to give compound (I).

Compound (II) is obtained in a number of steps with different processes in which the benzyloxycarbonyl protected 1 -amino- 1-cyclopropylmethyl moiety is introduced by subjecting the acyl azide obtained from l-((6- methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropanecarboxylic acid of formula (III):

to Curtius rearrangement, in the presence of benzyl alcohol, or by alkylation of 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N- methyl-1-naphthamide of formula (IV):

with 1 -benzyloxy carbony lamino- 1 -methylsolfonyloxymethyl- cyclopropane of formula (V):

The above mentioned applications do not provide yields concerning both the preparation of compound (II) by the two above mentioned reactions, and the conversion of compound (II) to (I).

Compound (III) is prepared by a process in which the 1-carboxy-l- cyclopropylmethyl moiety is introduced in 4-hydroxy-3-methoxyacetophenone as in the form of the ethyl ester, followed by formation of the 4- hydroxyquinoline ring and, finally, by the introduction of the 1- naphthylcarboxyamido fragment.

It is well known that the reactions requiring the use of azides, such as the formation of acyl azides, or Curtius rearrangement of the latter, are potentially hazardous as they involve risk of explosions, therefore they are not suitable for use in preparations on large scale. The synthetic methods reported in WO 2008/1 12408 and US

2008/0227812 include, inter alia, a general synthetic scheme in which the cycloalkyl-alkyl portion of the products is introduced by reaction between a cycloalkyl-alkyl mesylate and an hydroxy or amino acetophenone, followed by nitration to give a nitroacetofenone, reduction of the nitro group to amino group, formation of the 4-hydroxyquinoline ring and further work up of the latter to the final products. The above mentioned applications do not provide examples of the use of this process for compound (I) or the other described products.

SYNTHESIS

Patent

http://www.google.com/patents/WO2008112408A1?cl=en

Example 1

Benzyl l-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)cyclo- propylcarbamate Method A:

6-Hydroxy- 1 -naphthoic acid (1 g) was mixed with acetic anhydride (5 ml) and sulfuric acid (5 drops). The mixture was refluxed for 3 hours and cooled at RT for 10 hours then mixed with water (15 ml). The solid was filtered and washed with water and cold MeOH to give the product as 6-acetoxy-l -naphthoic acid (900 mg) that was mixed with EDC (1.5 eq), HOBt (1 eq), MeNH₂-HCl (2.5 eq, methylamine hydrochloride) and DIPEA (2.5 eq) in DCM (25 ml). The reaction was stirred at RT overnight and washed with NaHCO₃ solution, dried. The solution was evaporated and mixed with 15% KOH (2 ml) in MeOH (10 ml) further stirred at RT for 30 minutes. The solvent was evaporated and the residue was adjusted to weak acidic with 2N HCl, the solid was filtered and washed with water twice and cold MeOH to give 6-Hydroxy-N-methyl- 1 -naphthamide (720 mg).

7-Benzyloxy-6-methoxy-quinolin-4-ol (WO2006108059) (1 g) was refluxed with POCl₃ (8 ml) for 3 hours. The reaction was evaporated and dissolved into DCM (80 ml) that was washed with ice water followed by brine. The organic layer was dried with Na₂Sθ₄ and evaporated to dryness to give a dark yellow solid as 4-chloro-7-benzyloxy-6-methoxy-quinoline that was mixed with 6-Hydroxy-N-methyl-l -naphthamide (600 mg), DMAP (1.5 eq) in dioxane (40 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6-methoxyquinolin-4- yloxy)-N-methyl-l -naphthamide (210 mg). This product was mixed with Pd/C (120 mg, 10%), HCONH₄ (210 mg) in EtOH (20 ml). The mixture was refluxed for 1 hour and evaporated then mixed with water (2 ml). The solid was filtered and washed with water twice and cold MeOH as 6- (7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-l -naphthamide for next step without further purification.

N-CBZ-amino-l-(hydroxymethyl)cyclopropane (similarly prepared according to JMC 31, 2004, 1998) (250 mg) was dissolved into DCM (25 ml) with DIPEA (250 1) and stirred at O⁰C for 15 minutes. To the reaction was added MsCl (1.1 eq) and stirred for 30 minutes. The reaction was washed with NaHCO₃ solution, water, brine and dried with Na₂SO₄. The solution was evaporated to give N-CBZ-ammo-l^methylsulfonyloxymethyFjcyclopropane as an off white solid. This solid was mixed with above 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl- 1 – naphthamide and Cs₂CO₃ (250 mg) in DMA (4 ml). The reaction was heated at 100⁰C for 10 hours and mixed with EtOAc and water, then filtered, further extracted with EtOAc. The combined organic layer was evaporated and purified with silica gel column to give the titled product. Mass: (M + 1), 578 Method B:

4-Chloro-7-benzyloxy-6-methoxy-quinoline (3 g) was mixed with 6-Hydroxy- 1 -naphthoic acid (2 g) and KOH (2.5 g) in DMSO (11 ml). The mixture was heated at 130oC for 5 hours and cooled to RT. The reaction was then poured into a stirred water (60 ml) solution slowly to give a precipitate that was filtered to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)- 1 -naphthoic acid (2.8 g). This product was mixed with MeNH₂-HCl (2 g), EDC (3.3 g), HOBt (2 g) and DIPEA (4 ml) in DCM (80 ml). The reaction was stirred at RT overnight and washed with NaHCO₃ solution, dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6- methoxyquinolin-4-yloxy)-N-methyl- 1 -naphthamide. The title compound then was prepared according to the same procedures described in Method A. Method C:

Dimethyl l^-cyclopropanedicarboxylate (5 ml) was mixed with NaOH (1.4 g) in MeOH (40 ml)/water (4 ml). The reaction mixture was stirred at RT overnight and the solvent was evaporated. To the residue was added ether (50 ml), water (50 ml) and extracted once. The aqueous layer was acidified with 6N HCl and extracted three times with ether, the combined organic layer was washed with brine, dried and evaporated to give l-(methoxycarbonyl)cyclopropanecarboxylic acid (4 g).

The above product was mixed with DIPEA (1.2 eq) in THF and stirred at 0⁰C for 10 minutes, to the reaction was added ethyl chloro formate (1 eq) slowly and further stirred for 1.5 hours from 0⁰C to RT. To the reaction cooled at 0⁰C was added NaBH₄ (1.5 eq) slowly followed by MeOH (2 eq) and stirred for 2 hours from 0⁰C to RT. The reaction was diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give methyl 1 -(hydroxymethyl)cyclo- propanecarboxylate (2.5 g).

The above product was dissolved into DCM (40 ml) with DIPEA (4 ml) and stirred at O⁰C for 15 minutes. To the reaction was added MsCl (1.1 eq) and stirred for 30 minutes. The reaction was washed with NaHCθ3 solution, water, brine and dried with Na₂SO₄. The solution was evaporated and mixed with 4-hydroxy-3-methoxy-acetophenone (0.9 eq) and K₂CO3 (1.5 eq) in DMF (20 ml). The reaction was heated at 100⁰C for 6 hours and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried further evaporated to give methyl l-((4-acetyl-2-methoxyphenoxy)methyl)cyclopropane-carboxylate (1.8 g). This product was dissolved into acetic acid (5 ml) and stirred at RT, to the reaction was very slowly added nitric acid (8 ml, 60%) and stirred at RT for 1 hour. The reaction was poured into ice-water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried.

The solution was evaporated and mixed with iron powder (1.5 g) and NH₄Cl (150 mg) in EtOH/H₂O (80 ml, 9/1). The reaction was refluxed for 3 hours and filtered through Celite followed by evaporation. The residue was mixed with EtOAc/H₂O and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give methyl l-((5-amino-4-acetyl-2-methoxyphenoxy)methyl)- cyclopropanecarboxylate (1 g).

The above product was mixed with fresh prepared NaOMe (2 eq) in ethylene glycol dimethyl ether (30 ml) and stirred at RT for 1 hour. To the mixture was added HCOOEt (3 eq), the reaction was stirred at RT overnight and neutralized with 6N HCl. The reaction was evaporated with silica gel to dryness and purified on silica gel column with DCM/MeOH as eluent to give methyl l-((4- hydroxy-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (600 mg). This product was refluxed with POCI3 (4 ml) for 3 hours and evaporated, then dissolved into DCM. The solution was washed with ice water followed by brine. The organic layer was dried with Na₂SC^ and evaporated to give methyl l-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (500 mg).

The above product was mixed with DMAP (1.5 eq), 6-Hydroxy-N-methyl- 1 -naphthamide (300 mg) in dioxane (20 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give methyl 1 -((6-methoxy- 4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)-cyclopropanecarboxylate (200 mg). This product of was mixed with 15% NaOH (3 eq) in MeOH (15 ml) and refluxed for 30 minutes. The reaction was evaporated and adjusted to PH=6, then diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine, dried and evaporated to give l-((6-methoxy-4-(5-(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7- yloxy)methyl)cyclopropanecarboxylic acid (120 mg).

The above product was mixed with DIPEA (0.3 ml) in acetone (5 ml) at 0⁰C. To the reaction was slowly added C1COOCH₂CH(CH₃)₂ (100 1) and stirred for 2 hours from 0⁰C to RT. NaN₃ (0.2 g)/H2O (0.5 ml) was added to the reaction and stirred for 30 minutes. The reaction was diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine, dried and evaporated without further purification. The residue was mixed with benzyl alcohol (150 1) in toluene (10 ml) and refluxed for 1.5 hour. The reaction was evaporated and purified with silica gel column to give the titled product. Mass: (M + 1), 578

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http://www.google.com/patents/WO2010105761A1?cl=en

sequence of intermediates……………

LUCITANIB

Example 1: Preparation of l-[(4-acetyl-2-methoxyphenoxy)methyl]- N-benzyloxycarbonyl-1-aminocyclopropane

A 10 L reactor equipped with mechanical stirrer was loaded with triphenylphosphine (340.0 g, 1.296 mol) and THF (2 L) and the suspension was cooled with an ice bath. The stirred suspension was then slowly added with DIAD (264 g, 1.296 mol) over 30 minutes. After stirring for 30 min at 0⁰C, the stirred suspension was added dropwise with a solution of 4-hydroxy- 3-methoxyacetofenone (180 g, 1.08 mol) and DIPEA (210 g, 1.62 mol) in THF (1500 mL). The suspension was left under stirring for 45 min at 0⁰C, then added dropwise with a solution of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane (China Gateway) (240 g, 1.08 mol) in THF (1500 mL). After Ih, LC-MS analysis of a sample from the reaction mixture showed the complete disappearance of 1-benzyloxycarbonylamino-l- hydroxymethylcyclopropane. The reaction mixture was evaporated and the crude product was recrystallized with EtOH 95% (4000 mL) to give l-[(4- acetyl-2-methoxyphenoxy)methyl]-N-benzyloxycarbonyl- 1 – aminocyclopropane (214 g, yield: 53.5%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.41-7.45 (m, 2 H), 7.26 (s, 5 H), 6.77 (d, 1 H), 5.43 (s, 1 H), 5.00 (s, 2 H), 4.04 (s, 2 H), 3.82 (s, 3 H), 2.49 (s, 3H), 0.92 (m, 4 H).

LC-MS: M+H⁺: 370.4

Example 2: Preparation of l-[(4-acetyl-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l-aminocycIopropane

A solution of HNO₃ (65%, 3 mL) in Ac₂O (2 mL) at 0°C was slowly added with a suspension of the compound of Example 1 (1.1 g, 2.9 mmol) in

Ac₂O (3 mL). After stirring at 0⁰C for 2 h, the reaction mixture was poured into 50 mL of ice/water and the precipitate was recovered by filtration. The resulting yellow solid was recrystallized with 95% EtOH (5 mL) to give l-[(4- acetyl-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane (0.69 g, yield: 56%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ: 7.52 (s, 1 H), 7.26 (s, 5 H), 6.67 (s, 1 H), 5.36 (s, IH), 5.02 (s, 2 H), 4.05 (s, 2 H), 3.86 (s, 3 H), 2.42 (s, 3 H), 0.94 (m, 4 H).

LC-MS: M+H⁺: 414.41

Example 3: Preparation of l-[(4-(3-dimethylaminopropenoyl)-2- methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-l- aminocyclopropane

A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N₅N- dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100⁰C for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried and evaporated to give l-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5- nitrophenoxy)methyl]-N-benzyloxycarbonyl-l -aminocyclopropane (1.9 g, yield: 95%) as a yellow solid. 1H-NMR (300 MHz, CDCl₃): δ: 7.50 (s, 1 H), 7.27 (s, 5 H), 6.75 (s, 1

H), 5.44 (s, 1 H), 5.23 (s, 1 H), 5.1 1 (br, 1 H), 5.01 (s, 2 H), 4.04 (s, 2 H), 3.83 (s, 3 H), 2.78-3.00 (m, 6 H), 0.94 (m, 4 H) LC-MS: M+H⁺: 470.49

Example 4: Preparation of l-[(4-hydroxy-6-methoxyquinolin-7- yloxy)methyl]-N-benzyloxycarbonyl-l-aminocyclopropane

A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron (1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80⁰C for 2 h. The reaction mixture was cooled at room temperature, diluted with AcOEt (150 mL), filtered and washed with 50 ml of AcOEt. The filtration liquors were combined, washed with water (2 x 100 mL) and an NaHCO₃ saturated solution (2 x 100 mL), dried and evaporated to give l-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N- benzyloxycarbonyl-1 -aminocyclopropane (1.2 g, yield: 95%) as a yellow solid.

¹H-NMR (300 MHz, MeOD): δ: 7.75 (d, 1 H), 7.51 (s, 1 H), 7.15 (m, 5 H), 6.80 (br, 1 H), 6.20 (d, 1 H), 4.97 (s,2 H), 4.05 (s, 2 H), 3.84 (s, 3 H), 0.87 (m, 4 H).

LC-MS: M+H⁺: 395.2

Example 5: Preparation of l-[(4-chloro-6-methoxyquinolin-7- yloxy)methyl]-N-benzyIoxycarbonyl-l-aminocyclopropane

a) By chlorination of the compound of Example 4

A 50 ml round-bottom flask fitted with magnetic stirrer, thermometer, condenser and kept under nitrogen atmosphere, was loaded at 20°/25°C with 3.90 g (9.89 mmol) of the compound of Example 4 and 25 ml of POCl₃. The resulting suspension became a solution after stirring for a few minutes. The solution was heated at 85°C inner T and after 30 minutes the reaction was monitored by TLC, showing the disappearance of the starting product. The solution was cooled and dropwise added, over about 30 minutes and keeping the temperature below 10⁰C, to a mixture of 250 ml of DCM and 250 ml of water, cooled at 0⁰C. After completion of the addition, stirring was maintained for 30 minutes at 0°-10°C. The phases were separated and the aqueous phase was washed with 150 ml of DCM; the phases were separated and the organic phases combined. The combined organic phase was added with 150 ml of water, stirred at 20°/25°C for 15 minutes and pH was adjusted to 7-8 with a sodium bicarbonate saturated solution. The phases were separated and the organic phase was washed with 150 ml of water; the phases were separated, the organic phase was dried with sodium sulfate, filtered and the solvent evaporated off by distillation under vacuum. Stripping with ethyl ether afforded 3.8 g of a brownish solid. The solid residue was dissolved in 20 ml of tert-butyl methyl ether, stirring at 20°/25°C for an hour; filtered and washed with ter /-butyl methyl ether, then dried to obtain l-[(4-chloro-6- methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl- l- aminocyclopropane (3.4 g; yield: 87%) having (¹H-NMR) titre of 95%.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.61 (d, 1 H), 7.91 (s, 1 H), 7.56 (s, 1 H), 7.44 (s, 1 H), 7.38 (s, 1 H), 7.29 (m, 5 H), 4.99 (s, 2 H), 4.23 (s, 2 H), 3.97 (s, 3 H), 0.87 (m, 4 H). b) by Mitsunobu reaction between 4-chloro-7-hydroxy-6- methoxyquinoline and 1 -benzyloxycarbonylamino- 1 – hydroxymethylcyclopropane 20 ml of DCM were added with 4-chloro-7-hydroxy-6- methoxyquinoline (300 mg, 1.43 mmol; from China Gateway),

1 -benzyloxycarbonylamino- 1 -hydroxymethylcyclopropane (412 mg,

1.87 mmol, 1.3 eq; from China Gateway) and triphenylphosphine (490 mg,

1.87 mmol, 1.3 eq). The resulting solution was dropwise added with a solution of DEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperature at 0⁰C for 2 hours. The mixture was then left at 10⁰C for 20 hours, then filtered to recover the unreacted 4-chloro-7-hydroxy-6- methoxyquinoline. The filtrate was evaporated under vacuum and the resulting residue was added with 20 ml of 95% EtOH and left under stirring for 30 min. The solid was collected by filtration, washed with 5 ml of 95% EtOH and dried under vacuum to give l-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-

N-benzyloxycarbonyl-1-aminocyclopropane (273 mg; yield: 46%).

LC-MS: M+H⁺: 413.1

Example 6: Preparation of benzyl l-[(6-methoxy-4-(5- (methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II)

A solution of 0.51 g (2.53 mmol) of 6-hydroxy-N-methyl- 1 – naphthamide prepared according to WO2008/112408, 2, 7 ml of 2,6-lutidine and 0.3 g (2.42 mmol) of DMAP, kept at 20°/25°C and under nitrogen atmosphere, was added with the compound of Example 5 (1.0 g, NMR titre 95%, 2.30 mmol). The suspension was heated to 140⁰C inner temperature for

6 hours; then cooled to 20°/25°C and added with 80 ml of water and kept under stirring a 20°/25°C for 1 hour; the suspension was filtered and washed with water, to afford 0.88 g (yield: 66%) of benzyl l-[(6-methoxy-4-(5-

(methylcarbamoyl)naphthalen-2-yloxy)quinolin-7-yloxy)methyl)]cyclopropyl carbamate (II).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: δ: 8.56 (d, 1 H), 8.50 (d, 1 H), 8.39 (d, 1 H), 8.04 (d, 1 H), 7.94 (s, 1 H), 7.87 (s, 1 H), 7.59 (m, 4 H), 7.41 (s, 1 H), 7.44 (s, 1 H), 7.30 (m, 5 H), 6.56 (d, 1 H), 5.01 (s, 2 H), 4.48 (s, 2 H), 4.23 (s, 2 H), 3.95 (s, 3 H), 0.87 (m, 4 H). LC-MS: M+H⁺: 578.3

Example 7: Preparation of 6-(7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4-yloxy)-N-methyl-l-naphthamide (I)

A mixture of the compound of Example 6 (0.24 g, 0.42 mmol) in 2 ml of a solution of 40% HBr in acetic acid was stirred at 30⁰C for 3h, then added with 10 ml of water and the reaction mixture was extracted with AcOEt (2 x 10 mL). The organic phases were removed. The aqueous solution was dropwise added with a solution of 50% NaOH to reach pH 10. The mixture was extracted with DCM (3 x 20 mL) and the combined organic phases were dried and evaporated to give a crude containing 6-(7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4- yloxy)-N-methyl-l-naphthamide (I) with purity higher than >94% by LC-MS analysis. This crude was further purified by chromatography on a silica gel column eluting with DCM/MeOH 10: 1), to afford 6-(7-((l- aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-l- naphthamide (I) having purity higher than 98% by LC-MS analysis (140 mg, yield: 76%).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 8.47 (d, 2 H), 7.87 (d, 1 H), 7.53 (m, 3 H), 7.51 (m, 1 H), 7.44 (d, 1 H), 7.38 (s, 1 H), 6.50 (d, 1 H), 6.16 (d, 1 H), 5.01 (s, 2 H), 4.05 (s, 2 H), 4.03 (s, 3 H), 3.12 (d, 3 H), 2.09 (m, 2 H), 0.80 (m, 4 H).

LC-MS: M+H⁺: 444.0

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http://www.google.com/patents/WO2014113616A1?cl=en

6-(7-((l -Aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl- 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.

A

B

Process C

Formula III Scheme IV

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)cyclopropylcarbamate 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 MgS0₄ 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.H₂0 (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)cyclopropylcarbamate 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 CH₃NH₂.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 NaHC0₃ solution followed by water and brine. The solution was dried with Na₂S0₄ 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), Cs₂C0₃ (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), CS₂CO₃ (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 Na₂SOzt. 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 NaBH₄ (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. NH₄C1 (6.3 g) and water (60 ml) were added and stirred. The mixture was extracted with DCM three times and dried with Na₂S0₄. 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 NaHC0₃ (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 Na₂S0₄ 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), K₂C0₃ (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. ^lH 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 K₂C0₃ (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), K₂C0₃ (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. ^lH 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)quino-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)cyclopropylcarbamate Formula II

A mixture of 6-Hydroxy- 1 -naphthoic acid (1 g) and H₂SO₄ (0.2ml) in EtOH (25 ml) was refluxed overnight and evaporated, followed by dissolving into EtOAc. The solution was washed with water, IN NaHC0₃ solution and brine, further dried by Na₂S0₄. 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)cyclopro- 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)cyclopropyl)methoxy)- quinolin-4-yloxy)-l -naphthoic acid. The resulting acid was acylated similarly to the preparation of formula 1 1 of Example 3 with CH₃NH₂.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)cyclopropylcarbamate 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)cyclopropylcarba- 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

………………………………………….

synthesis…….will be updated

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Patent Reference:

EOS ETHICAL ONCOLOGY SCIENCE S.p.A. in abbreviated form EOS S.p.A.; SPINELLI, Silvano; LIVI, Valeria Patent: WO2010/105761 A1, 2010 ; Location in patent: Page/Page column 21 ;

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide H-NMR spectral analysis

CAS NO. 1058137-23-7, 6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide C-NMR spectral analysis

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