PROCESS FOR THE PREPARATION OF PANOBINOSTAT

Abstract

The present invention relates to a new process for the preparation of Panobinostat and intermediates thereof.

Claims

1. A process for the production of (2E)-N-hydroxy-3-[4-({ [2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enamide of formula (I): ##STR00011## which comprises the following steps: a) reacting a compound of formula (II) ##STR00012## wherein PG is an amino protecting group and X is halogen or an activating group, with an alkyl or an aryl acrylate of formula (III) ##STR00013## in which R is selected from Me, Et, t-Bu, iPr, Ph, or Bn to obtain a compound of formula (IV) ##STR00014## wherein PG and R are as defined above; b) reacting a compound of formula (IV) with NH.sub.2OH (V) and further deprotection of the amino protecting group to obtain a compound of formula (VI) ##STR00015## c) reacting the compound of formula (VI), preferably in the form of the trifluoroacetic acid salt, with a compound of formula (VII) ##STR00016## d) optionally, salifying the compound of formula (I) with lactic acid to form the corresponding lactate salt.

2. The process according to claim 1, characterized in that the amino protecting group is selected from Boc, Cbz, Bz, Alloc, Noc, Troc, Poc, Ac, SES.

3. The process according to claim 1, characterized in that the compound of formula (II) is obtained by protecting the corresponding primary benzylamine or a salt thereof in a solvent and in the presence of an organic or inorganic base.

4. The process according to claim 1, characterized in that the step a) is performed in a solvent, in the presence of a transition metal catalyst, a phosphine-based ligand, and an organic or inorganic base.

5. The process according to claim 4, characterized in that the transition metal catalyst is used in an amount ranging from about 0.01 to about 0.10 equivalents, the phosphine-based ligand is used in an amount ranging from about 0.02 to about 0.2 equivalents, the organic or inorganic base is used in an amount ranging from about 1.0 to about 2.0 equivalents.

6. The process according to claim 1, characterized in that the step b) is performed at room temperature.

7. The process according to claim 1, characterized in that the reaction with NH.sub.2OH of step b) is performed in a polar solvent or in a mixture of polar solvents, preferably in a molar ratio ranging from 1:2 to 2:1.

8. The process according to claim 1, characterized in that the deprotection of the amino protecting group in step b) is performed in a solvent in the presence of a strong acid, or by thermal decomposition.

9. The process according to claim 1, characterized in that the compound of formula (VII) is obtained from 2-(2-methyl-1H-indol-3-yl)ethanol via IBX oxidation.

10. The process according to claim 1, characterized in that the step c) is carried out in a mixture of polar and non-polar solvents, preferably in a molar ratio ranging from 1:10 to 1:1, in the presence of a reducing agent.

11. The process according to claim 1, characterized in that the pH of step c) is from 4.8 to 6.2.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0022] According to a first aspect, the present invention relates to a new process for preparing (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1 H-indol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enamide of formula (I), preferably as lactate salt,

##STR00005##

which comprises the steps of: [0023] a) reacting a compound of formula (II) [00006] [0024] wherein PG is an amino protecting group and X is halogen or an activating group, with an alkyl or an aryl acrylate of formula (III) [00007] [0025] in which R is selected from Me, Et, t-Bu, iPr, Ph or Bn to obtain a compound of formula (IV) [00008] [0026] wherein PG and R are as defined above; [0027] b) reacting a compound of formula (IV) with NH.sub.2OH (V) and further deprotection of the amino protecting group to obtain a compound of formula (VI) [00009] [0028] c) reacting the compound of formula (VI), preferably in the form of the trifluoroacetic acid salt, with a compound of formula (VII) [00010] to obtain the compound of formula (I) and [0029] d) optionally, salifying the compound of formula (I) with lactic acid to form the corresponding lactate salt.

[0030] In a preferred embodiment of the process, the amino protecting group PG is selected from tert-Butyloxycarbonyl (Boc), Carbobenzyloxy (Cbz), Benzoyl (Bz), Allyloxycarbonyl (Alloc), p-Nitrocinnamyloxycarbonyl (Noc), 2,2,2-Trichloroethoxycarbonyl (Troc), Propargyloxycarbonyl (Poc), Acetyl (Ac), or 2-Trimethylsilylethanesulfonyl (SES).

[0031] In a preferred embodiment of the process, X is halogen, preferably bromine. In another embodiment, X is an activating group, preferably, trifluoromethanesulfonate (OTf) or nonaflate (ONf).

[0032] In one preferred embodiment, the compound of formula (II) is obtained by protecting the corresponding primary benzylamine or a salt thereof in a solvent and in the presence of an organic or inorganic base.

[0033] Preferably, the solvent is selected from polar, non-polar solvents or mixtures thereof. More preferably, water, DCM, tBuOH, ACN, Ethyl acetate, Dioxane, THF, HFIP, toluene or mixtures thereof.

[0034] Preferably, the organic or inorganic base is selected from TEA, DlEA, DBU, DBN, DMAP, NaOH, NaOAc, Na.sub.2CO.sub.3, NaHCO.sub.3.

[0035] In another embodiment of the process, the step a) is performed in a solvent, in the presence of a transition metal catalyst, a phosphine-based ligand, and an organic or inorganic base.

[0036] Alternative ligands to the phosphine-based ligands that can be used in the present process are NHC or Pincer ligands.

[0037] Preferably, the solvent used in the step a) is selected from acetonitrile, DMF, DMSO, Toluene, NMP, DMA or mixtures thereof.

[0038] Preferably, the transition metal catalyst is Pd(OAc).sub.2.

[0039] Preferably, the phosphine-based ligand is P(o-tolyl).sub.3.

[0040] Preferably, the organic or inorganic base used in the step a) is selected from TEA, DIEA, DBU, DMAP, NaOH, NaOAc, K.sub.2CO.sub.3, Na.sub.2CO.sub.3.

[0041] In a preferred embodiment of the process, the transition metal catalyst used in the step a) is in an amount ranging from about 0.01 to about 0.10 equivalents, the phosphine-based ligand is used in an amount ranging from about 0.02 to about 0.2 equivalents, the organic or inorganic base is used in an amount ranging from about 1.0 to about 2.0 equivalents.

[0042] In another embodiment, the step b) is performed at room temperature.

[0043] In a preferred embodiment of the process, the reaction with NH.sub.2OH of step b) is performed in a polar solvent or in a mixture of polar solvents, preferably in a molar ratio ranging from 1:2 to 2:1.

[0044] Preferably, the polar solvent is selected from water, DMSO, DMF, MeOH, THF, pyridine or mixtures thereof.

[0045] In another preferred embodiment of the process, the deprotection of the amino protecting group in step b) is performed in a solvent in the presence of a strong acid, or by thermal decomposition.

[0046] Preferably, the deprotection of the amino protecting group is performed in methylene chloride in the presence of trifluoroacetic acid, or in dioxane in the presence of hydrochloric acid 4M.

[0047] Preferably, the deprotection phase is performed at room temperature.

[0048] In another embodiment, the compound of formula (VII) is obtained from 2-(2-methyl-1H-indol-3-yl)ethanol via IBX oxidation.

[0049] 2-methyl-1H-indol-3-yl)ethanol is obtained from carboxylic acid reduction of commercially available 2-methyl-1H-indol-3-yl) acetic acid.

[0050] In a preferred embodiment of the process, the step c) is carried out in a mixture of polar and non-polar solvents, preferably in a molar ratio ranging from 1:10 to 1:1, in the presence of a reducing agent.

[0051] Preferably, the mixture of polar and non-polar solvents is selected from methanol/methylene chloride, methanol/toluene, methanol/IPA, Acetonitrile/methylene chloride, Acetonitrile/toluene, or Acetonitrile/IPA. Preferably, the reducing agent is a boron-based reducing agent. More preferably, sodium triacetoxyborohydride, sodiumborohydride or sodium cyanoborohydride. In another embodiment, the pH of step c) is from 4.8 to 6.2.

EXAMPLES

Example 1: Preparation of 2-(2-methyl-1H-indol-3-yl)ethanol

[0052] The 2-methyl-1H-indol-3-yl) acetic acid 2 g (1.0 equiv 10.5 mmol) was dissolved in anhydrous THF 10 mL and cooled 0° C. A suspension of LiAlH.sub.41.6 g (4.0 equiv 42.0 mmol) in THF was added dropwise, and the mixture was stirred at 10° C. After 30 min the LiAIH4 was quenched by adding in this order: H.sub.2O, NaOH (10%) and H.sub.2O (1 g of LiAIH4 = 1 mL of H.sub.2O, 1.5 mL of NaOH). The resulting powder was washed with ethyl acetate and evaporated to obtained a clear oil in 92% yield. The desired product was obtained with 96% of purity (1-H NMR).

[0053] .sup.1H NMR (300 MHz, CD.sub.3CN) δ 2.36(s, 3 H); 2.84 (t, J = 6.4 Hz, 1 H); 3.65 (q, J = 6.4 Hz, 1 H) 7.04 ( dd, J = 8.4 Hz, 1.9, 1 H), 7.26 ( d, J = 1.4 Hz, 1 H), 7.48 ( d, J = 8.4 Hz,1 H) 8.93 (br s, 1H) ppm.

[0054] .sup.13 C NMR (75.0 MHz, CD.sub.3CN) δ 120.3,118.5,117.9,117.9,117.5,110.1,62.0,27.6,10.5.

[0055] IR (neat) 3401,3055,2934,1622,1585,1462,1433,1338,1300,1239,1239,1154,1138,1108, 1043,1010,863,742.

Example 2: Preparation of 2-(2-methyl-1H-indol-3-yl)acetaldehyde

[0056] IBX 7.4 g (1.1 equiv 27.0 mmol) was added to a solution of 2-(2-methyl-1H-indol-3-yl)ethanol 2 g (11.0 mmol) in DMSO (57 mL). After 6 h, the reaction mixture was diluted with water, the resulting white solid was filtered, and the resulting two layers were extracted with Et.sub.2O (3 x 100 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and volatiles were removed under reduced pressure. The crude mixture was purified by flash chromatography (n-hexane/ AcOEt 6:4) to give the desired product in 55% yield.

[0057] .sup.1H NMR (300 MHz, CD.sub.3CN) δ 2.36 (s, 3 H) 3.7(s, 2 H) 7.02-7.13 (m, 2 H) 7.13-7.41(m, 2 H) 9.1(br s, 1 H) 9.6 (s, 1 H) ppm.

[0058] .sup.13C NMR (75.0 MHz, CD3CN) δ 199.4,135.5,133.9,128.6,119.0,117.3,110.4,101.3,38.9, 10.5

[0059] IR (neat) 3397,1718,1654,1560,1508,1460,130,3743.

Example 3: Preparation of Tert-butyl 4-bromobenzylcarbamate

[0060] To a solution of 4-bromobenzylamine hydrochloride 1 g (1 equiv 5.0 mmol) in anhydrous DCM (10 mL), Et.sub.3N 1.25 mL (2.0 equiv 9.0 mmol) was added followed by di-tert-butyl dicarbonate 1 mL (1.0 equiv 0.005 mol). The reaction mixture was stirred at room temperature under N.sub.2 overnight.

[0061] The reaction was quenched with water (10 mL) and the resulting mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The desired product was obtained in 91% yield. M.p.80° C.

[0062] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.47 (s, 9 H) 4.27 (s, 2 H) 4.9 (br s, 1 H) 7.17 (d, J=0.5 Hz 2 H) 7.4 (d, J=0.5 Hz 2H) ppm.

[0063] .sup.13 C NMR (75.0 MHz, CD.sub.3CN) δ 155.7,137.9,131.5,129.0,121.0,77.3,77.1,76.9,43.9,28.2.

[0064] IR (neat) 3364,2921,2360,1682,1455,1377,1246,1169,1068,1049,1011,879,839,810, 781,722

Example 4: Preparation of Tert-butyl 4-((E)-2-(methoxycarbonyl)vinyl) benzylcarbamate

[0065] To a solution of tert-butyl 4-bromobenzylcarbamate 0.6 g (1.0 equiv 2.0 mmol) in MeCN ( 3 ml ), methyl acrylate 152 ∟L (1.2 equiv), P(o-tolyl).sub.3 0,026.00 g (2% mol), DIEA 0.286 mL (1.2 equiv), and Pd(OAc).sub.2 0.013 g (1% mol) were added and the resulting mixture was stirred under N.sub.2 at room temperature for 10 min, the temperature was increased at 100° C. and then stirred for 6.5 h.

[0066] After cooling, H.sub.2O (100 mL) was added, and the mixture was extracted with AcOEt (100 mL x 3). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced pressure.

[0067] The crude product was purified through flash chromatography (n-hexane/ AcOEt 8/2) to give the desired product in 67% yield.

[0068] M.p.90° C.

[0069] .sup.1H NMR (300 MHz, CD.sub.3CN) δ 1.42 (s, 9 H) 3.77 (s, 3 H) 4.25 (d , J=0.3 Hz 2 H) 5.78 (br s, 1 H) 6.5 (d, , J=0.8 Hz 1 H) 7.21 (d, , J=0.5 Hz 2 H) 7.6 (d, , J=0.5 Hz 2 H) 7.6 (d, , J=0.8 Hz 1 H) ppm.

[0070] .sup.13C NMR (75.0 MHz, CD.sub.3CN) δ 169.7,146.8,135.7,130.9,130.2,120.2,120.0,53.8,46.1, 30.2.

[0071] IR (neat) 3333,2920,2359,1714,1687,1681,1651,1469,1455,1366,1285,1169,1040,985, 955,935,869,815,723.

Example 5: Preparation of Tert-butyl 4-((E)-2-(hydroxycarbamoyl)vinyl) benzylcarbamate

[0072] Hydroxylamine (20 mL of 50% aqueous solution) was added to a solution of tert-butyl 4-((E)-2-(methoxycarbonyl)vinyl)benzylcarbamate 1 g (1.0 equiv 3.0 mol) in 20 mL of MeOH/THF (1:1). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was then poured onto ice/6M HCl (50 mL), extracted with DCM (1 x 20 mL) and EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and filtered. The resulting solution was concentrated in vacuo to afford a colorless oil, which was triturated with ether until crystallization occurred. The solid was isolated by filtration to give the desired product in 75% yield. M.p.155° C.

[0073] .sup.1H NMR (300 MHz, DMSO) δ 1.38 (s, 9 H) 4.11 (d, J=0.03 Hz 2 H) 6.56 (d, J=0.08 Hz 1 H) 7.24 (d, J=0.04 Hz 2 H) 7.43 (m, 2 H) 7.49 (d, J=0.0.04 Hz 2 H) ppm.

[0074] .sup.13C NMR (75.0 MHz, CD.sub.3CN) δ 162.7,155.7,141.6,138.0,133.2,127.4,118.5,77.8, 43.1,28.2.

[0075] IR (neat) 2927,1682,1460,1376,1155,1047,967,722.

Example 6: Preparation of (E)-3-(4-(aminomethyl)phenyl)-N-hydroxyacrylamide ammonium trifluoroacetate salt.

[0076] The tert-butyl 4-((E)-2-(hydroxycarbamoyl)vinyl)benzylcarbamate 0.4 g (1.3 mmol ) was added to a solution of TFA 0,524.00 mL (5.0 equiv 7.0 mmol) in DCM (13 mL) and stirred for 1 h at room temperature. Volatiles (TFA and DCM) were removed under reduced pressure to obtain a solid product in quantitative yield.

[0077] M.p.160° C.

[0078] .sup.1H NMR (300 MHz, DMSO) δ 4.05 (d, J=0.03 Hz 2 H) 4.43 (br s, 1 H) 6.49 (d, J=0.08 Hz 1 H) 7.45 (m, 4 H) 7.5 (d, J=0.08 Hz 1 H) 8.23 (s, 2 H) ppm.

[0079] .sup.13C NMR (75.0 MHz, CD.sub.3CN) δ 162.4,158.4,158.0,137.56,135.1,134.9,129.3,127.6, 119.7,41.9.

[0080] IR (neat) 2920,1778,1681,1651,1557,1520,1505,1455,1378,1199,1065,1005,972, 854,827,798,696.

Example 7: Preparation of Panobinostat

[0081] Solution of 2-(2-methyl-1H-indol-3-yl)acetaldehyde 2 g (1.0 equiv 11.0 mmol) and (E)-3-(4-(aminomethyl)phenyl)-N-hydroxyacrylamide ammonium trifluoroacetate salt 2.6 g (1.2 equiv 13.0 mmol) in MeOH/DCM 0.1 M was stirred at room temperature for five minutes. The pH of the reaction mixture is buffered around ⅚ by addition of solid NaHCO.sub.3.

[0082] NaB(OAc).sub.3H (3 equiv, 33.0 mol,) was added and the resulting reaction mixture was stirred for 12 h.

[0083] The reaction mixture was concentrated in vacuo, after solubilization of solids with water was filtered through a reverse phase silica pad by washing with methanol. The filtrate was collected and volatiles were removed in vacuo to afford an oil, which until crystallization with EtOAc and MeOH 9:1 give the final product in 45% yield. The desired product was obtained with 88% of purity determined by UHPLC-LC-MS analysis.

[0084] M.p.115° C.

[0085] .sup.1H NMR (300 MHz, DMSO) δ 2.7 (dd, J=0.03 Hz 0.06, 4 H) 2.30 (s, 3 H) 3.72 (s, 2 H) 6.4 (d, J=0.0.08 Hz 1 H) 6.90 (m, 2 H) 7.19 (d, J=0.04 Hz 1 H) 7.21 (d, J=0.04 Hz 2 H) 7.42 (t, J=0.04 Hz 3 H) 10.65 (s, 1 H) ppm.

[0086] .sup.13C NMR (75.0 MHz, CD.sub.3CN) δ 166.1, 140.7, 137.8,137.5, 134.2,131.8, 129.7,129.5,122.1,120.2,118.2,111.9,105.88,52.1,22.5,11.5.

Example 8: Preparation of Panobinostat Lactate

[0087] DL-Lactic acid 0,042.00 mL (1.0 equiv 573.0 mmol) was added to a solution of Panobinostat 0.2 g (1.0 equiv 573.0 mmol) in 7:3 acetone/water (1 mL). The resulting suspension was heated at 50° C. under vigorous stirring for 1 h to form a clear solution.

[0088] The solution was cooled at 10° C., filtered, dried under vacuum to obtain the final product in 89% yield.

[0089] The process of the invention lays on a convergent reductive amination between indole-derivative aldehyde and benzylic amine in which the key hydroxamic moiety has been already installed. The latter has been synthesized via a low palladium catalytic loading, 1% mole, Heck reaction which afforded N-BOC protected 4-bromobenzylcarbamate in 67% isolated yield.

[0090] The experiments performed on palladium catalyst shown that using the same conditions in each entry changing only the catalyst loading, the desired product in 67% of yield was obtained using only 1.0 % mol of catalyst. The experiments performed are summarized in the table below.

TABLE-US-00001 Heck reaction optimization Temperature (°C) Time Pd Catalyst Yield% 100 12 h 5.0 % mol 65% 100 12 h 3.0 % mol 61% 100 12 h 2.0 % mol 63% 100 12 h 1.0 % mol 67%

[0091] Moreover, hydroxamic acid formation was carried out at room temperature avoiding the use of cryogenic conditions and highly toxic solvents. At this stage of synthetic sequence, no significant impurities have been detected with UHPLC-LC-HESI-MS analysis. In particular, no significant amount of impurity was detected in the TFA salt obtained after BOC deprotection.

[0092] The last synthetic step (i.e. the reductive amination) in the Panobinostat synthesis was performed in DCM as a solvent under mild conditions, in particular was used the non-toxic NaB(OAc).sub.3H as a reductive agent instead of toxic NaBH.sub.3CN used in the prior art. Notably, the reaction was carried out without any carbocation scavenger.

[0093] In this step, the most relevant impurities were the residual amine, the selfcondensation product of aldehyde and the Panobinostat oligomerization (in traces amount). However, these impurities were completely removed with standard chromatographic techniques followed by Panobinostat crystallization.