WO2016124722A1

WO2016124722A1 - A process for the preparation of 3-5-{[(1r,2s)-2-[(2,2-difluoropropanyl)amino]-1 -(2,3-dihydro-1,4-benzodioxin-6-yl]propyl]oxy}-1h-indazol-1-yl)-n-[(3r)-tetrahydrofuran-3-yl] benzamide

Info

Publication number: WO2016124722A1
Application number: PCT/EP2016/052453
Authority: WO
Inventors: Michael Golden; Rifahath Mon NEYYA PPADATH; Vidya NANDIALATH; Anandan MUTHUSAMY; Ranganayakulu NEPPALLI; Rashmi HOLENARASIPURA VASUDEV
Original assignee: Astrazeneca Ab
Priority date: 2015-02-06
Filing date: 2016-02-05
Publication date: 2016-08-11

Abstract

The technical field relates to a process for the preparation of 3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoy)amino]-1-(2,3-dihydro-1,4- benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide (XIV), to products of said process and the use thereof.

Description

A PROCESS FOR THE PREPARATION OF 3-(5-{[(lR,2S)-2-[(2,2- DIFLUOROPROPANYL) AMINO] - 1 -(2,3-DIHYDRO- 1 ,4-BENZODIOXIN-6- YL]PROPYL]OXY} - IH-INDAZOL- 1 -YL)-N-[(3i?)-TETRAHYDROFURAN-3-YL] BENZAMIDE

TECHNICAL FIELD

The technical field relates to a process for the preparation of 3-(5-{[(li?,25)-2-[(2,2- difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i? -tetrahydrofuran-3-yl]benzamide (XIV),

to products of said process and the use thereof.

BACKGROUND

The compound (XIV) is disclosed as a glucocorticoid receptor (GR) modulator in WO2009/142571, where its use as a medicament, particularly for the treatment of respiratory conditions such as asthma and COPD, is described. An alternative synthi (XIV) and the synthesis of compound (VIII) is described in WO2009/142571.

SUMMARY

There is provided a process for preparing 3-(5- {[(li?,25)-2-[(2,2- difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol-

1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (XIV),

comprising the steps of

(a) reacting a compound of formula (VII),

with a compound of formula (X)

wherein PG^ and PG^ are selected to enable protection of the amine (e.g. PG^ and PG^ are independently selected from vinyl, allyl, benzyl or PG^ is selected from nosyl, trifluoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and PG^ is hydrogen) to deliver a compound of formula (XI),

(b) following removal of the protecting groups PG^ and PG^, reacting a compound of formula (XI) with a compound of formula (XIII),

by activation of the acid functionality of (XIII), to deliver 3-(5- {[(li?,25)-2-[(2,2- difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol-

1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (XIV).

A compound of formula (X) may be prepared from a compound of formula (IX),

wherein PG^ and PG^ are as described above, by reacting the compound of formula (IX) with e.g. a sulfonyl chloride in the presence of a base.

A compound of formula (IX) may be prepared from a compound of formula (VIII), by treatment with a benzyl halide, a vinyl halide, an allyl halide, or a substituted sulfonyl chloride.

The process is particularly useful for large-scale production of 3-(5- {[(li?,25)-2- [(2,2-difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - 1H- indazol-l-yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (XIV) by providing for example higher yields, less amounts of chemicals used in the process (or excluded), better volume capacity, shorter manufacturing time, more robust process with the possibility of recovery of solvents used in the resolution and by removing the need for chromatography in the synthesis.

Scheme A illustrates the process for preparation of 3-(5-hydroxy-lH-indazol-l-yl)- N-[(3i?)-tetrahydrofuran-3-yl]benzamide (VII). R may, for example, be C 1 . alkyl.

Scheme A

Scheme B illustrates the process for preparation of 3-(5- {[(li?,25)-2-[(2,2- difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol- l-yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (XIV) via 3-(5-hydroxyindazol-l-yl)-N- [(3i?)-tetrahydrofuran-3-yl]benzamide (VII). Non-limiting examples of PG^ and PG² may be, i.e., vinyl, allyl, benzyl or PG! is selected from nosyl, trifluoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and PG² is hydrogen.

Scheme B

In one embodiment, there is provided a process for the preparation of 3-(5- {[(lR,2S)-2-[(2,2-difluoropropanoyl)amino]-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (XIV),

In a further embodiment, there is provided a compound of formula (VII), 3-(5- hydroxy- lH-indazol- 1 - -N-[(3i?)-tetrahydrofuran-3-yl]benzamide,

In still a further embodiment, there is provided a compound of formula (IX),

wherein PG^ and PG^ are selected to enable protection of the amine (e.g. PG^ and PG^ are independently selected from vinyl, allyl, benzyl or PG^ is selected from nosyl, trifluoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and PG^ is hydrogen). In still a further embodiment, there is provided a compound of formula (IXa), N-[(IR,2S)- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)- 1 -hydroxypropan-2-yl]-N-(prop-2-en- 1 -yl)prop-2- en-l-aminium chloride,

a further embodiment, there is provided a compound of formula (X),

wherein PG^ and PG^ are selected to enable protection of the amine (e.g. PG^ and PG^ are independently selected from vinyl, allyl, benzyl or PG^ is selected from nosyl, trifluoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and PG^ is hydrogen). In still a further embodiment, there is provided a compound of formula (Xa), (2R,3S)-2- (2,3-dihydro- 1 ,4-benzodioxin-6-yl)-3 -methyl- 1 , 1 -di(prop-2-en- 1 -yl)aziridinium,

a further embodiment, there is provided a compound of formula (XI),

wherein PG^ and PG^ are selected to enable protection of the amine (e.g. PG^ and PG^ are independently selected from vinyl, allyl, benzyl or PG^ is selected from nosyl, trifluoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and PG^ is hydrogen). In still a further embodiment, there is provided a compound of formula (XIa), 3-[5- ( {( IR,2S)- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-2- [di(prop-2-en- 1 -yl)amino]propyl}oxy)- lH-indazol- 1 -yl]-N-[(3i?)-tetrahydrofuran-3-yl]benzamide,

In still a further embodiment, there is provided a compound of formula (XII), 3-(5- { [( li?,25)-2-amino- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy } - lH-indazol- 1 -yl)-N- [(3i?)-tetrahydrofuran-3-yl]benzamide,

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the X-ray powder diffraction pattern for Example 8: 3-(5- {[(li?,25)-2-[(2,2-Difluoropropanoyl)amino]-l-(2,3-dihydro-l ,4-benzodioxin-6- yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide.

Figure 2 shows the melting point, as analysed by DSC, for Example 8: 3-(5- {[(li?,25)-2-[(2,2-Difluoropropanoyl)amino]-l-(2,3-dihydro-l ,4-benzodioxin-6- yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide.

EXAMPLES

The disclosure will now be further explained by reference to the following non limiting examples.

(i) Unless stated otherwise, 1H NMR spectra were recorded on Bruker Avance III spectrometers operating at a field strength of 400, 500 or 600 MHz. Either the central peaks of chloroforn (CDCI3; δ £ 7.27 ppm) or dimethylsulfoxide- g (dg-DMSO; 5JJ 2.50 ppm) were used as references.

(ii) Unless stated otherwise, NMR spectra were recorded on Bruker Avance III spectrometers operating at a field strength of 400, 500 or 600 MHz. Either the central peaks of chloroform-d (CDCI3; 5JJ 77.0 ppm) or dimethylsulfoxide- g (dg-DMSO; 39.5

5jj ppm) were used as references.

(iii) The title and sub-title compounds of the examples and preparations were named using the IUPAC name program ACD/Name 2012 from Acdlabs.

(iv) Unless stated otherwise, starting materials were commercially available, and all solvents and commercial reagents were of laboratory grade and used as received. Unless stated otherwise, operations were carried out at ambient temperature, i.e. in the range between 17 - 28 °C and, where appropriate, under an atmosphere of an inert gas such as nitrogen.

(iv) The X-ray diffraction analysis was performed according to standard methods, which can be found in e.g. Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

Samples were mounted on single silicon crystal (SSC) wafer mounts and powder X-ray diffraction was recorded with a PANalytical X'Pert PRO (reflection geometry, wavelength of X-rays 1.5418 A nickel-filtered Cu radiation, Voltage 45 kV, filament emission 40 niA). Automatic variable divergence and anti scatter slits were used and the samples were rotated during measurement. Samples were scanned from 2 - 50 °2Theta using a 0.013° step width and 116 seconds count time using a PIXCEL detector (active length 3.35 °2Theta).

It is known in the art that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure (for further information see Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996).

Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately plus or minus 0.1 °2-theta, and such a degree of a measurement error should be taken into account when considering the X-ray powder diffraction data. Furthermore, it should be understood that intensities might fluctuate depending on experimental conditions and sample preparation (e.g. preferred orientation). The following definitions have been used for the relative intensity (%): 81 - 100%, vs (very strong); 41 - 80%, str (strong); 21 - 40%, med (medium); 10 - 20%, w (weak); 1 - 9%, vw (very weak).

(v) Thermal events were analysed by differential scanning calorimetry using a TA DSC Q2000 instrument. 2.2 mg of material contained in a standard aluminium closed cup with a pinhole was measured over the temperature range 20 °C to 230 °C at a constant heating rate of 5 °C per minute. A purge gas using nitrogen was used (flow rate 50 mL per minute). The melting point onset temperatures presented are not to be taken as absolute values. It is known that the melting point onset temperature may be affected by several parameters such as impurity content and particle size.

The following abbreviations are used:

BOC tert-butyloxycarbonyl

Nosyl 2- or 4-nitrobenzenesulfonyl

FMOC Fluorenylmethyloxycarbonyl

Example 1

-Methylpropyl 3-iodobenzoate

3-Iodobenzoic acid (100 g, 403 mmol, 1.0 eq) was mixed with 2-methyl-l-propanol (500 mL) and sulfuric acid (2.15 mL, 40.3 mmol, 0.1 eq) and heated to 100 °C overnight. The mixture was concentrated at atmospheric pressure to remove 400 ml of solvent. After cooling to ambient temperature, a solution of sodium bicarbonate (10.2 g, 121 mmol, 0.3 eq) in water (200 mL) was added, tert-butyl methyl ether (200 mL) was added and the phases separated. The organic phase was washed with water (200 mL) and concentrated to a light yellow oil (124.8 g, 97.2%, w/w assay = 98.3% yield).

!H NMR (500 MHZ, CDCI3) δ 1.02 (d, J=6.72 Hz, 6 H) 2.04 - 2.13 (m, 1 H) 4.11 (d, J=6.64 Hz, 2 H) 7.18 (t, J=7.82 Hz, 1 H) 7.88 (d, J=7.84 Hz, 1 H) 8.01 (d, J=7.77 Hz, 1 H) 8.37 (t, J=1.61 Hz, 1 H).

Example 2

-(5-Hydroxy- lH-indazol- 1 -yDbenzoic acid

Cesium carbonate (48.6 g, 149 mmol, 2.0 eq) was mixed with 5-hydroxyindazole (10.3 g, 74.6 mmol, 1.0 eq), tris(dibenzylideneacetone)dipalladium(0) (2.05 g, 2.24 mmol, 0.03 eq) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.94 g, 4.47 mmol, 0.06 eq). The vessel was flushed with nitrogen, and 2-methyltetrahydrofuran (70.0 mL) added. After heating to 70 °C, a solution of 2-methylpropyl 3-iodobenzoate (Example 1, 23.5 g, 74.6 mmol, 1.0 eq) in 2-methyltetrahydrofuran (20.0 mL) was added over 30 mins via syringe pump. The reaction mixture was stirred for 30 mins at 70 °C, and then cooled to 5 °C. Water (80.0 mL) was added and the mixture filtered through Celite. The filter pad was washed twice with 2-methyltetrahydrofuran (10.0 mL). The aqueous phase was removed at ambient temperature. After cooling to 10 °C, 10% aqueous sodium hydroxide (100 mL, 297 mmol) was added. The solution was heated to 50 °C and stirred for 2 hours, before cooling to rt. After separation, the aqueous phase was retained. Hydrochloric acid in IPA (60.0 mL, 330 mmol) was added over 10 mins. The mixture was heated to 65-70 °C and 2- propanol (20.0 mL) added, followed by 1 M hydrochloric acid in 2-propanol (40.0 mL, 40 mmol) over 1 hour at 65-70 °C. The reaction mixture was cooled to 5 °C and held for 1 hour before filtering. After washing twice with a mixture of 2-propanol (10.0 mL) and water (10.0 mL), the product was dried to yield an off-white solid (14.6 g, 96.5% w/w = 75% yield).

!H NMR (400 MHz, DMSO-d₆) δ 7.08 (dd, J=9.05, 2.37 Hz, 1 H) 7.15 (d, J=2.15 Hz, 1

H) 7.69 - 7.76 (m, 2 H) 7.93 (d, J=7.95 Hz, 1 H) 8.04 (d, J=8.03 Hz, 1 H) 8.23 (s, 1 H) 8.28 (t, J=1.83 Hz, 1 H). Example 3

-(5-Hydroxy- lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide

3-(5-Hydroxy-lH-indazol-l-yl)benzoic acid (Example 2, 40.0 g, 155 mmol, 1.0 eq) was mixed with [(3i?)-tetrahydrofuran-3-yl]ammonium chloride (22.9 g, 185 mmol, 1.2 eq). Dichloromethane (600 mL) and triethylamine (46.9 g, 464 mmol, 3.0 eq) was added and the mixture was stirred for 1 hour at ambient temperature. After cooling to 0 °C, propylphosphonic anhydride solution (50% in EtOAc) (138 mL, 232 mmol, 1.5 eq) was added dropwise over 30 mins. The mixture was warmed to ambient temperature and held for 30 mins. Saturated aqueous sodium bicarbonate (400 mL) was added over 30 min and the mixture was stirred at ambient temperature for 30 mins. After filtering, the product was washed twice with dichloromethane (80.0 mL), then washed twice with water (80.0 mL) before drying to yield an off- white solid (39.4 g, 93.0% w/w assay = 73% yield).

! H NMR (500 MHz, DMSO-d₆) δ 1.92 - 2.00 (m, 1 H) 2.13 - 2.22 (m, 1 H) 3.63 (dd,

J=8.92, 4.28 Hz, 1 H) 3.71 - 3.75 (m, 1H) 3.84 - 3.91(m, 2 H) 4.47 - 4.54 (m, 1 H) 7.07 (dd, J=9.00, 2.16 Hz, 1 H) 7.14 (d, J=2.28 Hz, 1 H) 7.66 (t, J=7.90 Hz, 1 H) 7.73 (d, J=9.04 Hz, 1 H) 7.86 (d, J=7.75 Hz, 1 H) 7.91 (d, J=7.94 Hz, 1 H) 8.22 (s, 2 H) 8.74 (d, J=6.44 Hz, 1 H)

Example 4

N-[(1R,2S)- l-(2,3-Dihydro- 1 ,4-benzodioxin-6-yl)- 1 -hydroxypropan-2-yl]-N-(prop-2-en- 1 - yl)prop-2-en-l-aminium chloride

(IR, 25)-2-Amino-l-(2,3-dihydro-l ,4-benzodioxin-6-yl)propan-l-ol (10 g, 40.7 mmol, 1.0 eq) was mixed with potassium carbonate (19.7 g, 142 mmol, 3.5 eq), acetonitrile (60 mL) and water (30 mL). The mixture was agitated, and allyl bromide (12.3 g, 102 mmol, 2.5 eq) was added slowly. After stirring overnight at ambient temperature, water (50 mL) was added, and the phases separated, retaining the organic phase. Toluene (60 mL) and water (20 mL) was added and then the phases separated. The organic phase was concentrated under vacuum, to a volume of 30 mL and toluene (80 mL) added. The mixture was concentrated again under vacuum, to a volume of 30 mL and further toluene (30 mL) added. To the solution, 5.5 M hydrochloric acid in 2-propanol (6.7 g, 40.7 mmol, 1.0 eq) was added over 1 hour. Toluene (60 mL) was added, the mixture cooled to 5°C, held for 15 mins, then filtered. The residue was washed twice with toluene (2.00 L/kg, 20 mL) and dried under vacuum, to yield a white solid (10. Og, 98.6% w/w = 75% yield).

!H NMR (500 MHz, D₂0) δ 1.00 (d, J=6.88 Hz, 3 H) 3.43 - 3.52 (m, 2 H) 3.68 (m, 2 H)

3.76 (dd, J=13.75, 6.68 Hz, 1 H) 4.05 (s, 4 H) 4.95 (d, J=3.54 Hz, 1 H) 5.33 - 5.40 (m, 4 H) 5.64 - 5.73 (m, 2 H) 6.63 - 6.71 (m, 3 H).

Example 5

3-[5-(((ϋ?,2^-1-(2,3-Ρ^νάΓθ-1 ,4^6ηζοάίοχίη-6-ν1 -2-[άί(ρΓορ-2-6η-1- yl)amino]propyl}oxy)-lH-indazol-l-yl]-N-[(3i?)-tetrahydrofuran-3-yl]benzamide

N-[(IR,2S)- l-(2,3-Dihydro- 1 ,4-benzodioxin-6-yl)- 1 -hydroxypropan-2-yl]-N-(prop-2-en- 1 - yl)prop-2-en-l-aminium chloride (Example 4, 10.0 g, 30.1 mmol, 1.0 eq) was mixed with

2- methyltetrahydrofuran (150 mL), N,N-diisopropylethylamine (18.4 mL, 105 mmol, 3.5 eq) and cooled to 0 °C. Methanesulfonyl chloride (6.90 g, 60.2 mmol, 2.0 eq) was added over 10 mins, and then stirred for 30 mins at 0 °C. A solution of lithium hydroxide monohydrate (5.05 g, 120 mmol, 4.0 eq) in water (50.00 mL) was added over 5 mins, and then held at 0 °C for 5 mins. A pre-made solution of 3-(5-hydroxy-lH-indazol-l-yl)-N- [(3i?)-tetrahydrofuran-3-yl]benzamide (Example 3, 9.42 g, 27.1 mmol, 0.9 eq), lithium hydroxide monohydrate (2.53 g, 60.2 mmol, 2.0 eq) and water (100.0 mL) was added over 5 mins. The mixture was stirred at 0°C for 3 hours, then separated, retaining the organic phase. Water (100 ml) was added and the pH adjusted to 7 with 37% aqueous hydrochloric acid and the phases separated. The organic phase was washed with water (100 mL) and dried over magnesium sulphate to yield the product as a pale yellow 0.177 M solution (146 ml, 25.9 mmol, 86% yield).

!JT NMR (500 MHz, DMSO-d₆) δ 1.1 1 (d, J=6.72 Hz, 3 H) 1.93 - 1.98 (m, 1 H) 2.13 -

2.21 (m, 1 H) 3.04 - 3.15 (m, 3 H) 3.15 - 3.24 (m, 2 H) 3.63 (dd, J=8.92, 4.28 Hz, 1 H) 3.73 (td, J=8.09, 5.88 Hz, 1 H) 3.84 - 3.90 (m, 2 H) 4.20 (s, 4 H) 4.47 - 4.53 (m, 1 H) 5.05 (d, J=10.76 Hz, 2 H) 5.14 (d, J=18.03 Hz, 2 H) 5.34 (d, J=5.34 Hz, 1 H) 5.63 (m, 2 H) 6.78

- 6.85 (m, 3 H) 7.20 - 7.24 (m, 2 H) 7.65 (t, J=7.92 Hz, 1 H) 7.74 (d, J=9.14 Hz, 1 H) 7.85

- 7.91 (m, 2 H) 8.19 - 8.23 (m, 2 H) 8.73 (d, J=6.48 Hz, 1 H).

Example 6

3- (5- {[(lR,2S)-2- Amino- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol- 1 - l)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide

A 0.177 M solution of 3-[5-({(li?,25)-l-(2,3-dihydro-l ,4-benzodioxin-6-yl)-2-[di(prop-2- en- 1 -yl)amino]propyl}oxy)- lH-indazol- 1 -yl]-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (Example 5, 36.5 mL, 6.46 mmol, 1.0 eq) (in methyltetrahydrofuran) was mixed with Ι,Γ- bis(di-tert-butylphosphino)ferrocene palladium dichloride (100 mg, 0.15 mmol, 0.02 eq) and 1,3-dimethylbarbituric acid (2.40 g, 15.05 mmol, 2.0 eq) under nitrogen atmosphere. The mixture was heated to 75°C for 30 mins, then cooled to ambient temperature. 1 M aqueous hydrochloric acid (25 mL) was added, the reaction briefly stirred and the phases separated, retaining the aqueous phase. The aqueous phase was washed with

methyltetrahydrofuran (25 ml), then adjusted to pH 11 with 50% aqueous sodium hydroxide. The solution was extracted twice with dichloromethane (25 ml), then the combined organics were washed with water (25 ml). The organic solution was dried over magnesium sulphate and concentrated to an off- white foam (3.1 g, 78.7%w/w assay = 73% yield).

!H NMR (500 MHz, DMSO-d₆) δ 1.19 (d, J=6.56 Hz, 3 H) 1.91 - 1.98 (m, 1 H) 2.31 -

2.38 (m, 1 H) 3.30 - 3.35 (m, 1 H) 3.78 - 3.84 (m, 2 H) 3.91 (dd, J=9.47, 5.42 Hz, 1 H) 3.98 (q, J=7.78 Hz, 1 H) 4.11 (q, J=7.19 Hz, 2 H) 4.19 - 4.25 (m, 4 H) 4.69 - 4.74 (m, 1 H) 4.87 (d, J=4.99 Hz, 1 H) 6.78 (d, J=7.27 Hz, 1 H) 6.81 - 6.86 (m, 2 H) 6.89 (s, 1 H) 6.98 (d, J=2.12 Hz, 1 H) 7.12 (dd, J=9.23, 2.31 Hz, 1 H) 7.51 (t, J=7.78 Hz, 1 H) 7.59 (d, J=9.58 Hz, 1 H) 7.70 (d, J=7.51 Hz, 1 H) 7.77 (d, J=8.05 Hz, 1 H) 7.96 (s, 1 H) 8.05 (s, 1 H).

Example 7

3-(5-{[(li?,26 -2-[(2,2-Difluoropropanoyl)amino]-l -(2,3-dihydro- 1 ,4-benzodioxin-6- yPpropyljoxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide

3-(5- {[(lR,2S)-2- Amino- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - lH-indazol- 1 - yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (Example 6, 1 g, 1.943 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). Triethylamine (0.813 mL, 5.83 mmol, 3.0 eq) and difluoropropionic acid (13) (0.321 g, 2.915 mmol, 1.5 eq) was added. The mixture was cooled to 0 °C and added propylphosphonic anhydride solution (50%> in EtOAc) (1.39 mL, 2.332 mmol, 1.2 eq) dropwise over 2 mins. After stirring for 10 mins at 0 °C, water (15 mL) was added over 5 mins at ambient temperature. The mixture was stirred for 15 mins, then filtered and washed twice with water (2 mL) and then once with ethanol (2 mL). Dried under vacuum to yield the product as an off- white solid (0.82 g, 92.1%w/w assay = 64% yield).

!H NMR (400 MHz, DMSO-d₆) δ 1.30 (d, J=6.47 Hz, 3 H) 1.55 (t, J=19.40 Hz, 3 H) 1.89 - 1.98 (m, 1 H) 2.12 - 2.21 (m, 1 H) 3.61 (dd, J=8.94, 4.20 Hz, 1 H) 3.71 (td, J=7.21, 6.79 Hz, 1 H) 3.83 - 3.89 (m, 2 H) 4.12 - 4.23 (m, 5 H) 4.44 - 4.53 (m, 1 H) 5.18 (d, J=7.00 Hz, 1 H) 6.78 - 6.89 (m, 3 H) 7.13 (d, J=2.43 Hz, 1 H) 7.21 (dd, J=9.05, 2.32 Hz, 1 H) 7.64 (t, J=7.54 Hz, 1 H) 7.76 (d, J=9.37 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 8.19 (s, 1 H) 8.23 (s, 1 H) 8.65 (d, J=8.84 Hz, 1 H) 8.70 (d, J=6.25 Hz, 1 H).

Example 8

Purification of 3-(5-{[(li?,26 -2-[(2,2-difluoropropanoyl)amino]-l-(2,3-dihydro-l,4- benzodioxin-6-yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide

3-(5-{[(li?,25)-2-[(2,2-Difluoropropanoyl)amino]-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (Example 7, 84.4 g, 139.2 mmol) was dissolved in 2-butanone (2.1 L) at 75 °C, and held for 1 hour. The solution was then screened through a filter, concentrated to 12-13 rel vols and then heated to 75 °C. The solution was then cooled to 62 °C over 30 mins and seeded with 3-(5- {[(li?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy}-lH-indazol-l-yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (Example 7, 0.5 g). Stirred for 3-6 hours at 62 °C, then cooled to 45 °C over 10 hours. Warmed to 55 °C and held for 1-2 hours, before cooling to 45 °C over 5 hours. Warmed to 55 °C and held for 1-2 hours, before cooling to 40 °C over 6 hours. Warmed to 52 °C and held for 1-2 hours, before cooling to 33 °C over 6 hours. Warmed to 46 °C over 6 hours and held for 1- 2 hours, before cooling to 21 °C over 6 hours. Warmed to 36 °C and held for 1-3 hours, before cooling to 5 °C over 6 hours. Held at 5 °C for 20 hours before filtering and washing twice with 2-butanone (160 mL). Dried at 45 °C under vacuum to yield 3-(5-{[(li?,25)-2- [(2,2-difluoropropanoyl)amino]- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - 1H- indazol-l-yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide (70.6 g, 116.4 mmol, 83.6%).

!H NMR (400 MHz, DMSO-d₆) δ 1.30 (d, J=6.47 Hz, 3 H) 1.55 (t, J=19.40 Hz, 3 H) 1.89

- 1.98 (m, 1 H) 2.12 - 2.21 (m, 1 H) 3.61 (dd, J=8.94, 4.20 Hz, 1 H) 3.71 (td, J=7.21, 6.79 Hz, 1 H) 3.83 - 3.89 (m, 2 H) 4.12 - 4.23 (m, 5 H) 4.44 - 4.53 (m, 1 H) 5.18 (d, J=7.00 Hz, 1 H) 6.78 - 6.89 (m, 3 H) 7.13 (d, J=2.43 Hz, 1 H) 7.21 (dd, J=9.05, 2.32 Hz, 1 H) 7.64 (t, J=7.54 Hz, 1 H) 7.76 (d, J=9.37 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 8.19 (s, 1 H) 8.23 (s, 1 H) 8.65 (d, J=8.84 Hz, 1 H) 8.70 (d, J=6.25 Hz, 1 H).

¹³C NMR (101 MHz, DMSO-d₆) δ ppm 15.73 (s) 21.00 (t, J=25.4 Hz) 31.80 (s) 50.01 (s)

50.40 (s) 63.93 (s) 63.97 (s) 66.49 (s) 72.20 (s) 81.11 (s) 104.22 (s) 111.56 (s) 117.08 (t, J=248.5 Hz) 115.44 (s) 116.79 (s) 119.63 (s) 119.92 (s) 120.58 (s) 124.20 (s) 125.26 (s) 125.53 (s) 129.58 (s) 131.41 (s) 133.93 (s) 135.37 (s) 135.74 (s) 139.63 (s) 142.85 (s) 142.93 (s) 152.96 (s) 162.97 (t, J=29.4 Hz) 165.58 (s).

¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -98.59 (dq, J=247.3, 19.4 Hz) -97.73 (dq, J=247.3, 19.4 Hz).

Melting point = 181°C

XRPD (X-ray powder diffraction)

Table 1. Peaks and intensities of Example 8

Position Intensity

°2Θ

6.7 vw

8.5 vw

12.8 vs

13.4 med

14.2 med

15.3 vw

18.0 vw

18.9 vw

19.3 w

19.6 s

20.2 w 20.6 vw

21.0 w

21.6 vw

21.9 vw

22.2 vw

24.0 vw

24.3 w

25.4 vw

25.7 vw

26.0 vw

Table 2. Five selected peaks of Example 8

Position Intensity °2Θ

12.8 vs

13.4 med

14.2 med

19.6 s

21.0 w

Table 3. Three selected peaks of Example 8

Position Intensity °2Θ

12.8 vs

14.2 med

Claims

1. A process for preparing 3-(5- {[(li?,25)-2-[(2,2-difluoropropanoyl)amino]-l-(2,3- dihydro- 1 ,4-benzodioxin-6-yl)propyl]oxy} - IH-indazol- 1 -yl)-N-[(3 ?)-tetrahydrofuran-3- 5 yljbenzamide (XIV),

with a compound of formula (X),

wherein PG* and PG^ are independently selected from vinyl, allyl, benzyl or PG is selected from nosyl, trifiuoromethylbenzenesulfonyl, tolylsulfonyl, BOC and FMOC and i s PG^ is hydrogen, to deliver a compound of formula (XI),

by activation of the acid functionality of (XIII).

2. A process according to claim 1, wherein PG^ and PG^ are allyl.

3. A process according to claim 1, wherein the solvent in step (a) is 2- methyltetrahydrofuran.

4. A process according to claim 1, wherein the base in step (a) is N,N- diisopropy lethy lamine .

5. The compound of formula (VII), 3-(5-hydroxy-lH-indazol-l-yl)-N-[(3i?)- tetrahydrofuran-3-yl]benzamide,

(VII).

6. The compound of formula (IXa), N-[(li?,25)-l-(2,3-dihydro-l,4-benzodioxin-6-yl)- 1 -hydroxypropan-2-yl]-N-(prop-2-en- 1 -yl)prop-2-en- 1 -aminium chloride,

7. The compound of formula (Xa), (2i?,35)-2-(2,3-dihydro-l,4-benzodioxin-6-yl)-3- methyl- 1 , 1 -di(prop-2-en- 1 -yl aziridinium,

8. The compound of formula (XIa), 3-[5-({(li?,25)-l-(2,3-dihydro-l,4-benzodioxin-6- yl)-2- [di(prop-2-en- 1 -yl)amino]propyl} oxy)- lH-indazol- 1 -yl] -N- [(3i?)-tetrahydrofuran-3 - yljbenzamid

9. The compound of formula (XII), 3-(5-{[(li?,25)-2-amino-l-(2,3-dihydro-l,4- benzodioxin-6-yl)propyl]oxy} - lH-indazol- 1 -yl)-N-[(3i?)-tetrahydrofuran-3-yl]benzamide,

