Method for producing 3-methyl-4-halo-indole derivatives

Abstract

To provide a method for producing 3-methyl-4-halo-indole derivatives, which is an industrially useful and novel production method including a novel method for reducing formyl-halo-indole derivatives.SOLUTION: In production of 3-methyl-4-halo-indole derivatives, there has been found a novel method for reducing a formyl group using a Lewis acid and a hydride reducing agent. And it has been found that, according to the method, demethylation and / or dehalogenation of the derivatives become suppressed, and thereby, aftertreatments become easy or the derivatives are obtained in high yields.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for preparing 3-methyl-4-halo-indole derivatives, and in particular to a novel method for reducing formyl-halo indole derivatives using a Lewis acid and a hydride reducing agent. [Background technology]

[0002] 3-Methyl-4-halo-indole derivatives are useful as pharmaceuticals or raw materials for their production, and are known to be useful in treating tumors (Patent Document 1).

[0003] Patent Document 1 discloses various 3-methyl-4-halo-indole derivatives and methods for producing the same. The method for producing a 3-methyl-4-halo-indole derivative disclosed in the document involves, for example, using 3-formyl-4-bromo-7-fluoroindole as a raw material and subjecting it to a reduction reaction with sodium bis(2-methoxyethoxy)aluminum hydride to obtain a 3-methylindole derivative (Patent Document 1, Reference Example E-14).

[0004] However, this method has problems such as a moderate yield, difficulty in handling due to the generation of Hartz and other compounds derived from sodium bis(2-methoxyethoxy)aluminum hydride during post-treatment, and the high cost of the reagents. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2016 / 052697 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an industrially useful novel method for producing 3-methyl-4-halo-indole derivatives, which method comprises a novel method for reducing formyl-halo indole derivatives. [Means for solving the problem]

[0007] As a result of intensive research conducted by the present inventors to achieve the above-mentioned object, they have found that, in the production of a 3-methyl-4-halo-indole derivative, reduction of the formyl group using a Lewis acid and a hydride reducing agent can produce the derivative in high yield, or can suppress demethylation or dehalogenation of the derivative, facilitating post-treatment. They have also found that a crystalline polymorph of mono(2-methylpropane-2-ammonium)(2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate can be produced using an intermediate produced by this method, and have thus completed the present invention.

[0008] That is, the present invention relates to the following (1) to (17). (1) Formula (I):

[0009] [ka]

[0010] or a pharmaceutically acceptable salt thereof, using a Lewis acid having one metal ion selected from Li ion, Mg ion, Ca ion, Sc ion, Bi ion, Ti ion, Fe ion, Cu ion, Ce ion, La ion, and Yb ion, and a hydride reducing agent, Formula (II):

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof. [X represents a halogen atom.] (2) The method according to (1), wherein X is a bromine atom. (3) The method according to (1) or (2), wherein the Lewis acid is a Lewis acid containing one metal ion selected from Mg ions, Sc ions, Bi ions, Ti ions, La ions, and Yb ions. (4) The method according to (1) or (2), wherein the Lewis acid is a Lewis acid containing a Ti ion. (5) The method according to (1) or (2), wherein the Lewis acid is Ti(OR)4, where R represents a C1-C4 alkyl group. (6) The method according to any one of (1) to (5), wherein R is an ethyl group, an isopropyl group, or a butyl group. (7) A compound represented by formula (II) produced by the production method according to any one of (1) to (6), reacting with tert-butyl acrylate using a palladium catalyst. Formula (III):

[0013] [ka]

[0014] or a pharmaceutically acceptable salt thereof. (8) The compound represented by formula (III) produced by the production method described in (7), condensing with a compound of formula (IV),

[0015] [ka]

[0016] Formula (V):

[0017] [ka]

[0018] A method for producing a compound represented by the formula: (9) Hydrolyzing the compound represented by formula (V) produced by the production method according to (8). Formula (VI):

[0019] [ka]

[0020] or a pharmaceutically acceptable salt thereof. (10) A method for producing a compound represented by formula (VI), characterized by using a compound represented by formula (II) produced by any one of the production methods according to (1) to (6) as an intermediate. (11) The compound represented by formula (VI) produced by the production method according to (9) or (10), salification with tert-butylamine; and crystallization in a mixed solution of acetone and 2-propanol; A method for preparing the tert-butylamine salt of the compound of formula (VI). (12) Crystal of mono(2-methylpropan-2-ammonium) = (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which is detected by copper Kα radiation (λ = 1.54 Å) ), a tBA1 type crystal having at least three peaks at diffraction angles (2θ) selected from 5.81±0.2, 10.31±0.2, 11.09±0.2, 11.54±0.2, 15.56±0.2, 16.19±0.2, 19.24±0.2, 23.16±0.2, 25.80±0.2, and 26.28±0.2. (13) Crystals of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which were irradiated with copper Kα radiation (λ = 1.54 Å). In a powder X-ray diffraction pattern obtained by the method of claim 1, a tBA2 type crystal has at least three peaks at diffraction angles (2θ) selected from 3.23±0.2, 6.35±0.2, 9.51±0.2, 12.64±0.2, 15.79±0.2, 16.67±0.2, 18.99±0.2, 20.62±0.2, 25.42±0.2, 28.06±0.2, and 28.42±0.2. (14) A crystal of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which is a P1 type crystal having at least three peaks at diffraction angles (2θ) selected from 3.15±0.2, 14.92±0.2, 15.55±0.2, 18.70±0.2, 20.40±0.2, 23.20±0.2, 25.13±0.2, 26.13±0.2, 27.86±0.2, and 28.81±0.2 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ=1.54 angstroms). (15) A P2 type crystal of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which has at least three peaks at diffraction angles (2θ) selected from 3.04±0.2, 9.08±0.2, 18.23±0.2, 24.38±0.2, 24.66±0.2, and 27.18±0.2 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ=1.54 angstroms). (16) A crystal of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which is a P3 type crystal having at least three peaks at diffraction angles (2θ) selected from 3.10±0.2, 6.23±0.2, 9.39±0.2, 12.55±0.2, 15.71±0.2, 18.15±0.2, 18.91±0.2, 25.32±0.2, 27.10±0.2, and 27.94±0.2 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ=1.54 angstroms). (17) A pharmaceutical composition containing the crystal according to (12) to (16) as an active ingredient. [Effects of the Invention]

[0021] The present invention provides a novel, industrially useful method for producing 3-methyl-4-halo-indole derivatives. In particular, it provides a high-yield production method that includes a novel method for reducing formyl groups using a Lewis acid and a hydride reducing agent to suppress dehalogenation and / or demethylation, thereby facilitating post-treatment. Furthermore, this production method can be used to produce a crystalline polymorph of mono(2-methylpropane-2-ammonium)(2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate. [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows the powder X-ray diffraction pattern of the crystals of the compound prepared in Example 7-1, where the vertical axis represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. [Figure 2]8 shows the powder X-ray diffraction pattern of the crystals of the compound prepared in Example 8-1, where the vertical axis represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ. [Figure 3] 8 shows the powder X-ray diffraction pattern of the crystals of the compound prepared in Example 8-2. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the value of the diffraction angle 2θ. [Figure 4] 8 shows the powder X-ray diffraction pattern of the crystals of the compound prepared in Example 8-3. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the value of the diffraction angle 2θ. [Figure 5] 8 shows the powder X-ray diffraction pattern of the crystals of the compound prepared in Example 8-4. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the value of the diffraction angle 2θ. DETAILED DESCRIPTION OF THE INVENTION

[0023] (Production method of the present invention) The present invention relates to the following production method.

[0024] Formula (I):

[0025] [ka]

[0026] or a pharmaceutically acceptable salt thereof, using a Lewis acid and a hydride reducing agent, Formula (II):

[0027] [ka]

[0028] or a pharmaceutically acceptable salt thereof. [X represents a halogen atom].

[0029] As will be shown in the Examples below, this method is an industrially useful novel production method including a novel method for reducing formyl-haloindole derivatives (for example, a production method that allows the derivatives to be obtained in high yield, a production method that suppresses demethylation and / or dehalogenation of the derivatives and facilitates post-treatment).

[0030] In the present invention, the term "Lewis acid" refers to a substance containing a metal ion and capable of accepting an electron pair. Examples of metal ions contained in Lewis acids include Li ion, Mg ion, Ca ion, Al ion, Sc ion, In ion, Bi ion, B ion, Ti ion, Fe ion, Co ion, Cu ion, Zn ion, Ce ion, La ion, and Yb ion. From the viewpoint of easily obtaining a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in high yield, Li ion, Mg ion, Ca ion, Sc ion, Bi ion, Ti ion, Fe ion, Cu ion, Ce ion, La ion, or Yb ion is preferred, Mg ion, Ca ion, Sc ion, Bi ion, Ti ion, Cu ion, La ion, or Yb ion is more preferred, Mg ion, Sc ion, Bi ion, Ti ion, La ion, or Yb ion is even more preferred, and Ti ion is particularly preferred. In the present invention, "high yield" refers to an HPLC area ratio, as shown in the examples below, of preferably 75 area% or more.

[0031] The metal ion contained in the Lewis acid in the present invention is, for example, Li + , Mg2 + , Ca 2+ , Al 3+ ,Sc. 3+ , In 3+ , Bi 3+ , B 3+ , Ti 4+ , Fe 2+ , Fe 3+ , Co 2+ , Co 3+ , Cu + , Cu 2+ , Zn 2+ , Ce 3+ , Ce4+ , La 3+ , and Yb 3+ The preferred valence of each metal ion is Li + , Mg 2+ , Ca 2+ , Al 3+ ,Sc. 3+ , In 3+ , Bi 3+ , B 3+ , Ti 4+ , Fe 3+ , Co 2+ , Cu + , Zn 2+ , Ce 3+ , La 3+ , and Yb 3+ is.

[0032] Examples of Lewis acids containing Li ions include LiCl, LiBr, LiI, and LiOTf. Examples of Lewis acids containing Mg ions include MgCl2, MgBr2, and MgI2. MgCl2 is preferred. Examples of Lewis acids containing Ca ions include CaCl2, CaBr2, and CaI2. CaCl2 is preferred. Examples of Lewis acids containing Al ions include AlCl 3、Examples of Lewis acids containing Sc ions include AlBr3 and AlI3. Preferably, AlCl3. Examples of Lewis acids containing Sc ions include Sc(OTf)3. Examples of Lewis acids containing In include InCl3, InBr3, and InI3. Examples of Lewis acids containing Bi ions include BiCl3, BiBr3, and Bi(OTf)3. Preferably, BiCl3. Examples of Lewis acids containing B ions include BF3·Et2O. Examples of Lewis acids containing Ti ions include TiCl4 and Ti(OR)4 (e.g., Ti(OEt)4, Ti(OiPr)4, Ti(OBu)4). Preferably, Ti(OR)4, more preferably Ti(OEt)4, Ti(OiPr)4, or Ti(OBu)4. Here, R represents a C1-C4 alkyl group as described below. Examples of Lewis acids containing Fe ions include FeCl2, FeBr2, FeI2, FeCl3, FeBr3, and FeI3. Preferably, FeCl3. Examples of Lewis acids containing Co ions include CoCl2, CoBr2, and CoI2. Preferably, CoCl2. Examples of Lewis acids containing Cu ions include CuCl, CuBr, CuI, CuCl2, CuBr2, and CuI2. Preferably, CuI. Examples of Lewis acids containing Zn ions include ZnCl2, ZnBr2, Zn(OTf)2, and ZnO. Examples of Lewis acids containing Ce ions include CeCl3 and CeCl4. Examples of Lewis acids containing La ions include La(OTf)3. Examples of Lewis acids containing Yb ions include Yb(OTf)3.

[0033] As described above, more preferred Lewis acids in the present invention are Lewis acids containing Mg ions, Lewis acids containing Ca ions, Lewis acids containing Sc ions, Lewis acids containing Bi ions, Lewis acids containing Ti ions, Lewis acids containing Cu ions, Lewis acids containing La ions, and Lewis acids containing Yb ions. Among these Lewis acids, MgCl, MgBr, MgI, CaCl, Sc(OTf), BiCl, Ti(OEt), Ti(OiPr), Ti(OBu), CuI, La(OTf), and Yb(OTf), and more preferably Ti(OEt), Ti(OiPr), and Ti(OBu).

[0034] In the production of 3-methyl-4-halo-indole derivatives, the impurity (imp. 2) shown in the Examples below is difficult to remove by purification. Therefore, in the present invention, from the viewpoint of easily suppressing the formation of imp. 2, i.e., demethylation of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, preferred Lewis acids of the present invention are Lewis acids containing Mg ions, Lewis acids containing Al ions, Lewis acids containing Sc ions, Lewis acids containing In ions, Lewis acids containing Bi ions, Lewis acids containing B ions, Lewis acids containing Ti ions, Lewis acids containing Fe ions, Lewis acids containing Co ions, Lewis acids containing Cu ions, Lewis acids containing La ions, and Lewis acids containing Yb ions. Furthermore, from the viewpoints of facilitating the production of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in high yield while facilitating the suppression of the formation of imp. 2, more preferred are Lewis acids containing Mg ions, Lewis acids containing Sc ions, Lewis acids containing Bi ions, Lewis acids containing Ti ions, Lewis acids containing Fe ions, Lewis acids containing Cu ions, Lewis acids containing La ions, and Lewis acids containing Yb ions, and even more preferred are MgCl, MgBr, MgI, Sc(OTf), BiCl, Ti(OEt), Ti(OiPr), Ti(OBu), FeCl, CuI, La(OTf), and Yb(OTf). In the present invention, "suppressing the formation of imp. 2" means that the HPLC area ratio of imp. 2 shown in the Examples below is preferably 3 area% or less, more preferably 2 area% or less.

[0035] Similarly, in the production of 3-methyl-4-halo-indole derivatives, from the viewpoint of easily suppressing the formation of imp. 1, i.e., dehalogenation of the compound represented by Formula (II) or a pharmaceutically acceptable salt thereof, a Lewis acid containing Bi ions, a Lewis acid containing Cu ions, a Lewis acid containing Ti ions, a Lewis acid containing Li ions, a Lewis acid containing Zn ions, a Lewis acid containing Ca ions, a Lewis acid containing Yb ions, a Lewis acid containing Sc ions, or a Lewis acid containing Mg ions is preferred, with a Lewis acid containing Bi ions, a Lewis acid containing Cu ions, a Lewis acid containing Ti ions, a Lewis acid containing Li ions, or a Lewis acid containing Zn ions being more preferred, and BiCl3, Bi(OTf)3, BiBr3, CuI, TiCl4, LiI, LiBr, LiCl, LiOTf, or ZnO being even more preferred. In the present invention, "suppressing the formation of imp. 1" means that the HPLC area ratio of imp. 1 shown in the Examples below is preferably 10 area% or less, more preferably 5 area% or less.

[0036] In the present invention, the term "C1-C4 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, and a t-butyl group. An ethyl group, an isopropyl group, or a butyl group is preferred. An ethyl group is more preferred.

[0037] In the present invention, examples of the "hydride reducing agent" that can be used include sodium borohydride, lithium borohydride, calcium borohydride, sodium triacetate borohydride, and lithium triethylborohydride. Sodium borohydride is preferred.

[0038] The solvent that can be used in the present invention may be any solvent that is inert to each reaction. In the reduction reaction using a hydride reducing agent, for example, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, isopropanol, tetrahydrofuran, etc., or a mixed solvent thereof can be used. N-methyl-2-pyrrolidone, isopropanol, tetrahydrofuran, or a mixed solvent thereof is preferably used.

[0039] In the present invention, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is reduced using the above-mentioned Lewis acid, hydride reducing agent, and solvent to produce a compound represented by formula (II) or a pharmaceutically acceptable salt thereof. Specific reaction conditions are described in detail in the Examples below (see, in particular, Examples 1-1 to 1-3). Therefore, a person skilled in the art can prepare a compound represented by formula (II) or a pharmaceutically acceptable salt thereof by appropriately referring to the reaction conditions. However, the reaction conditions of the present invention should not be construed as being limited to these.

[0040] The present invention also provides a compound represented by formula (II) produced by the above-mentioned production method, reacting with tert-butyl acrylate using a palladium catalyst. Formula (III):

[0041] [ka]

[0042] or a pharmaceutically acceptable salt thereof.

[0043] Furthermore, the present invention relates to a compound represented by formula (III) produced by the above-mentioned production method, condensing with a compound of formula (IV),

[0044] [ka]

[0045] Formula (V):

[0046] [ka]

[0047] The present invention relates to a method for producing a compound represented by the formula:

[0048] The present invention also provides a method for producing a compound represented by formula (V) by hydrolyzing the compound represented by formula (V) produced by the above-mentioned production method. Formula (VI):

[0049] [ka]

[0050] or a pharmaceutically acceptable salt thereof.

[0051] Furthermore, the present invention relates to a method for producing a compound represented by formula (VI), which comprises using, as an intermediate, a compound represented by formula (II) produced by the above-mentioned production method.

[0052] The compound represented by formula (VI) produced by the above production method can also be salification with tert-butylamine; and crystallization in a mixed solution of acetone and 2-propanol; The present invention relates to a method for producing the tert-butylamine salt of the compound represented by formula (VI).

[0053] A method for producing the tert-butylamine salt of the compound represented by formula (VI) from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is also described in detail in the Examples below (see, in particular, Examples 4-1 to 8-4). It is also described in detail in Patent Document 1. Therefore, a person skilled in the art can also produce the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, the compound represented by formula (V), and the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof by appropriately referring to these descriptions. However, the methods for producing these compounds in the present invention should not be construed as being limited to these descriptions.

[0054] In the production method of the present invention, functional groups of the compounds may be protected with appropriate protecting groups. Examples of such functional groups include hydroxyl, carboxy, and amino groups. The types of protecting groups and the conditions for introducing and removing these protecting groups can be found, for example, in Protective Groups in Organic Synthesis (T.W. Green and P.G.M. Butts, John Wiley & Sons, Inc., New York, 2006).

[0055] (Compounds according to the present invention) Next, the compounds represented by formulas (I) to (VI) or pharmaceutically acceptable salts thereof, which are reactants, intermediates and products in the above-mentioned production methods, will be described.

[0056] "X" in the compound represented by formula (I) and the compound represented by formula (II) of the present invention is a halogen atom, such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., and is preferably a bromine atom.

[0057] The compound represented by formula (III) or a pharmaceutically acceptable salt thereof, the compound represented by formula (V), and the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof of the present invention each encompasses geometric isomers of each compound.

[0058] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is not significantly toxic and can be used in pharmaceutical compositions.

[0059] The compounds of formula (I), (II), and (III) of the present invention can be converted into salts by reaction with an acid. Examples of such salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; C1-C6 alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and adipate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate.

[0060] The compound of the present invention represented by formula (IV) and the compound of formula (VI) can be converted into a salt by reacting with a base. Examples of such salts include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt; and amine salts such as t-butylamine salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and organic salts such as tris(hydroxymethyl)aminomethane salt.

[0061] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, the compound represented by formula (V), and the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof of the present invention may each incorporate water molecules to become a hydrate when left in the air or upon recrystallization, and such hydrates are also encompassed by the present invention.

[0062] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, the compound represented by formula (V), and the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof of the present invention may each absorb a certain type of solvent and become a solvate when left in a solvent or recrystallized, and such solvates are also encompassed by the present invention.

[0063] Furthermore, the tert-butylamine salt of the compound represented by formula (VI) of the present invention also includes the following crystals: Crystals of mono(2-methylpropan-2-ammonium) = (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which show a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ = 1.54 angstroms). and tBA1 type crystals having at least three peaks (e.g., three, five, six, seven, eight, nine, or ten peaks) at diffraction angles (2θ) selected from 5.81±0.2, 10.31±0.2, 11.09±0.2, 11.54±0.2, 15.56±0.2, 16.19±0.2, 19.24±0.2, 23.16±0.2, 25.80±0.2, and 26.28±0.2. A crystal of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which has a powder X-ray diffraction pattern of 3.23 in the case of irradiation with copper Kα radiation (λ=1.54 angstroms). A tBA2 type crystal having at least three peaks (e.g., three, five, six, seven, eight, nine, ten, or eleven peaks) at a diffraction angle (2θ) selected from the following: ±0.2, 6.35±0.2, 9.51±0.2, 12.64±0.2, 15.79±0.2, 16.67±0.2, 18.99±0.2, 20.62±0.2, 25.42±0.2, 28.06±0.2, and 28.42±0.2. Crystals of mono(2-methylpropan-2-ammonium) = (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which show a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ = 1.54 angstroms). and P1 type crystals having at least three peaks (e.g., three, five, six, seven, eight, nine, or ten peaks) at diffraction angles (2θ) selected from 3.15±0.2, 14.92±0.2, 15.55±0.2, 18.70±0.2, 20.40±0.2, 23.20±0.2, 25.13±0.2, 26.13±0.2, 27.86±0.2, and 28.81±0.2. A P2 type crystal of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which has at least three peaks (e.g., three, five, or six peaks) at diffraction angles (2θ) selected from 3.04±0.2, 9.08±0.2, 18.23±0.2, 24.38±0.2, 24.66±0.2, and 27.18±0.2 in a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ=1.54 angstroms). Crystals of mono(2-methylpropan-2-ammonium) = (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate, which have a powder X-ray diffraction pattern obtained by irradiation with copper Kα radiation (λ = 1.54 angstroms). A P3 type crystal having at least three peaks (e.g., three, five, six, seven, eight, nine, or ten peaks) at diffraction angles (2θ) selected from 3.10±0.2, 6.23±0.2, 9.39±0.2, 12.55±0.2, 15.71±0.2, 18.15±0.2, 18.91±0.2, 25.32±0.2, 27.10±0.2, and 27.94±0.2.

[0064] Furthermore, the compound of the present invention represented by formula (VI) or a pharmaceutically acceptable salt thereof can be prepared as a pharmaceutical composition or as a reagent for research purposes (see Patent Document 1).

[0065] When the compound of the present invention or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition, examples of pharmaceutically acceptable carriers used include, but are not limited to, sterile water, physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, fragrance, excipient, vehicle, preservative, binder, diluent, isotonicity agent, soothing agent, bulking agent, disintegrant, buffer, coating agent, lubricant, colorant, sweetener, thickener, flavoring agent, solubilizing agent, and other additives. The compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated in various forms, such as tablets, powders, granules, capsules, and liquids, depending on the therapeutic purpose. It can also be administered in the form of, for example, a liposome delivery system. The liposome can also be loaded with the above-mentioned auxiliary moieties (e.g., antibodies, ligands, etc.) that enhance useful therapeutic properties.

[0066] Furthermore, the target diseases of the pharmaceutical composition of the present invention are not particularly limited, but are preferably cancers such as brain tumors (including gliomas), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, peripheral T-cell lymphoma, chondrosarcoma, osteosarcoma, bile duct cancer, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, prostate cancer, colon cancer, and thyroid cancer, as well as Ollier's disease and Maffucci syndrome. That is, the pharmaceutical composition of the present invention can be suitably used as an antitumor agent.

[0067] Furthermore, the active ingredient of the pharmaceutical composition of the present invention is not particularly limited as long as it is the compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, but is preferably a tert-butylamine salt of the compound represented by formula (VI), more preferably at least one crystal selected from the group consisting of the tBA1-type crystal, tBA2-type crystal, P1-type crystal, P2-type crystal, and P3-type crystal of the tert-butylamine salt, and preferably the tBA1-type crystal, tBA2-type crystal, P1-type crystal, P2-type crystal, and P3-type crystal. [Example]

[0068] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples. The abbreviations used in the examples and reference examples have the following meanings. mg: milligram, g: gram, ml: milliliter, L: liter, MHz: megahertz. NMP: N-methylpyrrolidone.

[0069] In the following examples and reference examples, nuclear magnetic resonance (hereinafter referred to as 1 H NMR (500 MHz) spectra were recorded using tetramethylsilane as the standard, with chemical shifts expressed as δ values ​​(ppm). Splitting patterns were indicated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). In this example, liquid chromatography was performed using an HPLC 10A (Shimadzu) or ACQUITY UPLC H-Class (Waters).

[0070] In the present examples, the equipment and measurement conditions for powder X-ray diffraction measurement are as follows: Model: Rigaku MiniFlex600 Sample: appropriate amount X-ray generation conditions: 40 kV, 15 mA Wavelength: 1.54Å (copper Kα line) Measurement temperature: room temperature Scanning speed: 10° / min Scanning range: 3~40° Sampling width: 0.02° Generally, the positions of peaks in an X-ray diffraction spectrum are expected to vary by approximately ±0.2° 2θ. That is, when the difference in 2θ values ​​between two peaks being compared is within a range of approximately ±0.2° 2θ, the two peaks are considered to be the same peak.

[0071] Reference Example 1-1: Preparation of methyl 5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carboxylate

[0072] [ka]

[0073] Under a nitrogen atmosphere, acetonitrile (120 mL) and 1,1-carbonyldiimidazole (64.19 g, 0.3959 mol) were added to Reactor 1 and stirred at room temperature. A solution of 2-fluoro-2-methylpropanoic acid (40 g) in acetonitrile (40 mL) was added dropwise over 30 minutes and stirred for an additional 30 minutes. Next, under a nitrogen atmosphere, acetonitrile (200 mL) and monomethyl potassium malonate (70.66 g, 0.4524 mol) were added to Reactor 2, and magnesium chloride (28.72 g, 0.3016 mol) was added while controlling the internal temperature at 10-40 °C. The solution from Reactor 1 was then added dropwise to Reactor 2 at 50 °C over 40 minutes and washed with acetonitrile (40 mL). The mixture was cooled to room temperature, and a mixture of concentrated hydrochloric acid (100 mL) and water (280 mL) was added dropwise over 15 minutes. The mixture was stirred for 5 minutes, allowed to stand for 5 minutes, and then separated to obtain a solution of methyl 4-fluoro-4-methyl-3-oxopentanoate in acetonitrile.

[0074] Separately, under a nitrogen atmosphere, dimethylformamide (70 mL) and N-hydroxy-1-(2,4,6-trichlorophenyl)methanimine (10 g) were added to a reaction vessel and stirred at room temperature. A solution of trichloroisocyanuric acid (3.73 g, 0.0160 mol) in ethyl acetate (25.0 mL) was added dropwise while controlling the internal temperature at 10-40°C, and the mixture was washed with ethyl acetate (5.0 mL). After stirring at room temperature for 30 minutes, a solution of sodium chloride (5.0 g) in normal water (45.0 mL) was added, stirred for 5 minutes, allowed to stand for 5 minutes, and then the mixture was separated and the aqueous layer was discarded. Next, normal water (50 mL) was added, stirred for 5 minutes, allowed to stand for 5 minutes, and then the mixture was separated and the aqueous layer was discarded. Finally, a solution of sodium chloride (10.0 g) in normal water (40.0 mL) was added, stirred for 5 minutes, allowed to stand for 5 minutes, and then separated to obtain an ethyl acetate solution of 2,4,6-trichloro-N-hydroxybenzene-1-carboximidoyl chloride.

[0075] Under a nitrogen atmosphere, an acetonitrile solution of methyl 4-fluoro-4-methyl-3-oxopentanoate (0.068 mol equivalent) was added to the reaction vessel, and the internal temperature was adjusted to 15°C. A 28% (w / w) solution of sodium methoxide in methanol (12.0 g, 0.0623 mol) was added at 15°C, followed by a dropwise addition of an ethyl acetate solution of 2,4,6-trichloro-N-hydroxybenzene-1-carboximidoyl chloride (0.0445 mol equivalent) over 1 hour, followed by rinsing with ethyl acetate (5 mL). After dropwise addition, the mixture was stirred at an internal temperature of 15°C for 1 hour. Then, ordinary water (25 mL) was added at room temperature, and the pH was adjusted to 7-9 with 2 mol / L hydrochloric acid. After stirring for 15 minutes and allowing to stand for 5 minutes, the mixture was separated and the aqueous layer was discarded. A solution of sodium chloride (10.0 g) in water (40.0 mL) was then added, stirred for 15 minutes, and allowed to stand for 5 minutes. The mixture was then separated and the aqueous layer was discarded. The resulting organic layer was concentrated under reduced pressure to 50 mL or less at 50°C or below. 2-Propanol (200 mL) was added, and the mixture was further concentrated under reduced pressure to 50 mL or less at 50°C or below. The volume was adjusted to 60 mL with 2-propanol, yielding 55.79 g of a 2-propanol solution. A portion of this solution was withdrawn, adjusted to an internal temperature of 5°C, and stirred. After confirming crystallization, the mixture was stirred for 30 minutes. Water (10.6 mL) was added dropwise over 2 hours and stirred for 30 minutes. The resulting suspension was filtered, and the crystals were washed with a mixture of cooled 2-propanol (4 mL) and water (4 mL). They were then dried overnight at 40°C under reduced pressure to yield the title compound (2.55 g, 0.00696 mol). 1 H NMR (500MHz, DMSO-d6) δ2.14 (d, J = 20 Hz, 6H) 3.90 (s, 3H), 8.18 (s, 2H); ESI MS m / z 366 ([M+1]+).

[0076] Reference Example 1-2: Preparation of methyl 5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carboxylate

[0077] [ka]

[0078] Under a nitrogen atmosphere, acetonitrile (348 g) and methyl 2-fluoro-2-propionate (145 g) were added to Reactor 1 and stirred at 0°C. 1,1-carbonyldiimidazole (244.1 g) was added dropwise in five portions over one hour while maintaining the internal temperature below 10°C. The inlet was rinsed with acetonitrile (20 g), and the mixture was stirred for another hour. The temperature of the reaction vessel was then adjusted to 25°C under a nitrogen atmosphere, and acetonitrile (435 g) and monomethyl potassium malonate (235 g) were added to Reactor 2. While maintaining the internal temperature below 40°C, magnesium chloride (143.5 g) was added in four portions. The inlet was rinsed with acetonitrile (145 g), and the mixture was stirred at 25°C for one hour. The solution obtained in Reactor 1 was then added dropwise to Reactor 2 at 30°C over one hour, followed by rinsing with acetonitrile (20 g). The mixture was stirred at 30°C for 3 hours and then cooled to 20°C. A mixture of concentrated hydrochloric acid (428g) and water (362.5g) was added dropwise over 1 hour and stirred for 30 minutes. After standing for 30 minutes, the mixture was separated, and 10% aqueous sodium chloride solution (725g) was added. The mixture was stirred for 30 minutes, and then stood for 30 minutes before being separated again. The same procedure was repeated three times to obtain a solution of methyl 4-fluoro-4-methyl-3-oxopentanoate in acetonitrile.

[0079] Under a nitrogen atmosphere, dimethylacetamide (900 g) and N-hydroxyl-1-(2,4,6-trichlorophenyl)methyleneimine (215 g) were added to the reactor, and the inlet was rinsed with dimethylacetamide (37 g). The mixture was stirred at 50°C until clear. While maintaining the internal temperature below 55°C, N-chlorosuccinimide (126 g) was added in 21 portions over 3 hours, and the mixture was stirred at 50°C for 1 hour. After stirring for 30 minutes at 25°C, a solution of methyl tert-butyl ether (1450 g) and sodium chloride (100 g) in normal water (900 mL) was added, stirred for 30 minutes, and allowed to stand for 30 minutes before separation. The aqueous layer was discarded. The above brine wash and separation procedures were then repeated twice, yielding a final solution of 2,4,6-trichloro-N-hydroxybenzene-1-carboximide chloride in methyl tert-butyl ether.

[0080] Under a nitrogen atmosphere, a solution of methyl 4-fluoro-4-methyl-3-oxopentanoate in acetonitrile was added to the reactor, followed by the addition of water (188.5 mL). The internal temperature was then adjusted to 5°C. A solution of sodium methoxide in methanol (223.3 g) was added within 2 hours at 30°C or below, and the pH was adjusted to 12-14. A solution of 2,4,6-trichloro-N-hydroxybenzene-1-carboximide chloride in methyl tert-butyl ether was added dropwise at 20°C over 2 hours, followed by washing with acetonitrile (145 g). After the dropwise addition, the mixture was stirred for 1 hour at 20°C, and then a solution of ethyl acetate (1450 g) and sodium chloride (145 g) in water (1305 g) was added at room temperature. The mixture was stirred for 30 minutes, allowed to stand for 30 minutes, and then separated. The aqueous layer was discarded. The same brine washing procedure was repeated twice. The resulting organic layer was concentrated under reduced pressure to less than 400 mL at 45°C or below. Methanol (725 g) was added, and the mixture was concentrated under reduced pressure at 45°C or below until the volume was 400 mL or less. A second addition of methanol (725 g) was made, and the mixture was concentrated under reduced pressure at 45°C until the volume was 400 mL or less. After adding methanol (478.5 g), the mixture was stirred at 40°C for 20 minutes, and then water (101.5 mL) was added dropwise to the reaction vessel within 1 hour. Seed crystals (0.435 mg, the seed crystals were prepared according to Reference Example 1-1) were added, and the mixture was stirred for 2 hours. Regular water (350 mL) was added dropwise over 3 hours, and the mixture was stirred for 2 hours. The mixture was cooled to 20°C over 4 hours, and then stirred for 4 hours. The resulting suspension was filtered, and the crystals were washed with a cooled mixture of methanol (232 g) and regular water (145 g). They were then dried under reduced pressure at 40°C for 24 hours to obtain the target compound (295.0 g, 0.80 mol, yield 88.1%). The obtained target compound 1 The 1 H-NMR values ​​were compared with those shown in Reference Example 1-1, and it was confirmed that they were the same compound.

[0081] Reference Example 2-1: Preparation of 5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carboxylic acid

[0082] [ka]

[0083] Methanol (30 mL) was added to a reaction vessel under a nitrogen atmosphere and stirred, followed by the addition of the compound (5 g) obtained in Reference Example 1. 40 (w / w)% aqueous tetrabutylammonium hydroxide solution (9.73 g, 0.0150 mol) was added and stirred at 72 °C for 3 hours. The temperature was adjusted to 40 °C, and 2 mol / L hydrochloric acid (5.1 mL) was added. After crystallization was confirmed, the mixture was stirred for 1 hour. 2 mol / L hydrochloric acid (2.7 mL) was added dropwise over 10 minutes and stirred for 10 minutes. Furthermore, ordinary water (20 mL) was added dropwise over 10 minutes and stirred for 10 minutes. After cooling to room temperature, the mixture was stirred for 30 minutes. The resulting suspension was filtered, and the crystals were washed with a mixture of methanol (7.5 mL) and ordinary water (7.5 mL). They were then dried overnight under reduced pressure at 40 °C to obtain the title compound (4.44 g, 0.0126 mol, yield 92.3%). 1 H NMR(500MHz,DMSO-d6)δ1.89(d,J=20Hz,6H),7.89(s,2H);ESI MS m / z 350([M-1]-).

[0084] Reference Example 2-2: Preparation of 5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carboxylic acid

[0085] [ka]

[0086] Under a nitrogen atmosphere, methanol (440.0 g) was added to a reaction vessel and stirred, and then the compound (5 g) obtained in Reference Example 1-2 and a 40 (w / w)% aqueous solution of tetrabutylammonium hydroxide (195.0 g) were added, followed by stirring at 45°C for 20 hours. The temperature was adjusted to 40°C, and 2 mol / L hydrochloric acid (145.0 g) was added. After confirming crystallization, the mixture was stirred for 1 hour. 2 mol / L hydrochloric acid (75.0 g) was added dropwise over 1 hour, followed by stirring for 2 hours. Regular water (600 g) was then added dropwise over 1 hour, followed by stirring for 1 hour. The mixture was cooled to 20°C, followed by stirring for 1 hour. The resulting suspension was filtered, and the crystals were washed with a mixture of methanol (120 g) and regular water (150 g). They were then dried under reduced pressure at 40°C for 20 hours to obtain the target compound (yield 95.3%). The target compound obtained was 1 The 1 H-NMR values ​​were compared with those shown in Reference Example 2-1, and it was confirmed that they were the same compound.

[0087] (Example 1-1) Preparation of 4-bromo-3-methyl-1H-indole

[0088] [ka]

[0089] Under a nitrogen atmosphere, N-methylpyrrolidone (70 mL), tetraisopropyl orthotitanate (19.03 g, 0.06695 mol), and sodium borohydride (6.75 g, 0.178 mol) were added to a reaction vessel and stirred at room temperature for 1 hour. After cooling to 0°C, 4-bromo-1H-indole-3-formaldehyde (20 g) dissolved in N-methylpyrrolidone (20 mL) was added dropwise. The mixture was heated to 80°C and stirred at 80°C for 2 hours. After cooling to 0°C again, acetone (39.5 mL) was added dropwise and the mixture was stirred at 0°C for 13.5 hours. Lactic acid (37.5 g) was then added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour and then warmed to room temperature. Ambient water (60 mL) and sodium chloride (6 g) were added, followed by ethyl acetate (300 mL). The mixture was stirred at room temperature and the aqueous layer was removed. Ambient water (60 mL) and sodium chloride (12 g) were added to the organic layer, followed by stirring at room temperature, and then the aqueous layer was removed. Ambient water (60 mL) and sodium bicarbonate (4.8 g) were added to the organic layer, followed by stirring at room temperature, and then the aqueous layer was removed to obtain a solution of the title compound (16.72 g, 0.07959 mol, yield 89.2%) in ethyl acetate and N-methylpyrrolidone. 1 H NMR (500MHz, CDCl3) δ2.54 (s, 3H), 6.95-6.98 (m, 2H), 7.23 (d, J = 7.8Hz, 2H), 7.88 (br s, 1H).

[0090] (Example 1-2) Preparation of 4-bromo-3-methyl-1H-indole

[0091] [ka]

[0092] Under a nitrogen atmosphere, tetrahydrofuran (2.08 kg), the raw materials 4-bromo-1H-indole-3-formaldehyde (0.80 kg, 3.571 mol), and isopropanol (3.76 kg) were added to reactor 1 and stirred for 1 hour at 25°C. Purified water was added until the solution KF (water content in the system) reached 0.5%, and the system was cooled to 5°C. Sodium borohydride (144.0 g, 1.06 eq) was added in several portions to prepare a mixture of the intermediate (4-bromo-1H-indol-3-yl)methanol in tetrahydrofuran and isopropanol, which was then stored at 5°C or below. Simultaneously, tetrahydrofuran (2.08 kg) and isopropanol (3.76 kg) were added to reactor 2, and sodium borohydride (152.0 g, 1.13 eq) and CaCl (400.0 g, 1.1 eq) were added at 25°C. The solution was stirred at 25°C for 0.5 hours, then heated to 60°C. The intermediate (4-bromo-1H-indol-3-yl)methanol reaction solution was added dropwise and reacted at 60°C for 36 hours. After the reaction was completed, the temperature of reactor 2 was lowered to 25°C, toluene (7.04 kg, 8.8 equivalents relative to the raw materials) was added, the temperature of the reactor was adjusted to 5°C, and 14.91 kg of aqueous AcOH solution (0.51 kg AcOH solution and 14.40 kg water) was added to quench the excess sodium borohydride. The quench temperature was maintained at 25°C while maintaining it below 30°C, and the mixture was stirred for 1 hour. After standing for 0.5 hours, the aqueous layer was discarded. Purified water (8 kg) was added to the organic layer, and the mixture was stirred at 25°C for 1 hour, after which the aqueous layer was discarded. 4.20 kg of aqueous sodium bicarbonate solution (0.20 kg of sodium bicarbonate dissolved in 4.00 kg of water) was added to the organic layer, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was then removed, and the organic layer was concentrated to 2.4 L. Toluene (2.00 kg) was then added again, and the mixture was concentrated to 2.4 L, yielding a toluene solution of the target compound.

[0093] (Example 2-1) Examination of various Lewis acids 1 In the reaction to obtain compound (2) from compound (1) shown in the following chemical reaction formula, Lewis acid screening was performed under the same reaction conditions as in Example 1-1, and the changes in the amounts of various compounds were examined from the HPLC area ratios. The results are shown in Table 1. In the following table, "Imp." stands for impurity.

[0094] [ka]

[0095] [Table 1]

[0096] HPLC conditions Detection: 225 nm Column: YMC Triart C8 (4.6 mm ID x 150 mm, 3 μm) Column temperature: 40℃ Mobile phase: A: 10 mM ammonium acetate aqueous solution, B: acetonitrile Gradient conditions:

[0097] [Table 2]

[0098] Flow rate: 1.0mL / min Injection volume: 1μL Sample dissolution medium: acetonitrile / water (8:2).

[0099] (Example 2-2) Examination of various Lewis acids 2 For some of the Lewis acids examined in Table 1, the Lewis acid equivalent was examined under the same reaction conditions as in Example 1. The results are shown in Table 3. The HPLC conditions were the same as in Example 2-1. Furthermore, the reaction system is preferably in a solution state rather than a slurry state, as this results in a more uniform reaction state.

[0100] [ka]

[0101] [Table 3]

[0102] (Example 3) Examination of various Lewis acids 3 The type of titanium alkoxide was investigated under the same reaction conditions as in Example 1-1. The results are shown in Table 4. Note that No. 1-3 shown in the table were all solutions.

[0103] [ka]

[0104] [Table 4]

[0105] (Example 4-1) Preparation of tert-butyl (2E)-3-(3-methyl-1H-indol-4-yl)prop-2-enoate

[0106] [ka]

[0107] Under a nitrogen atmosphere, acetonitrile (25 mL), an N-methylpyrrolidone solution of the compound (5 g) obtained in Example 1-1, palladium acetate (0.053 g, 0.00024 mol), tris(o-toluyl)phosphine (0.145 g, 0.000476 mol), triethylamine (2.89 g, 0.0286 mol), and tert-butyl acrylate (3.66 g, 0.0286 mol) were added to a reaction vessel and stirred at 80°C for 3 hours. After cooling to 50°C, ordinary water (12.5 mL) was added dropwise and the mixture was cooled to room temperature. Seed crystals (5 mg) of the title compound were added and the mixture was stirred at room temperature for 1 hour. Subsequently, ordinary water (37.5 mL) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 1 hour. The resulting suspension was filtered, and the crystals were washed with a mixture of acetonitrile (10 mL) and ordinary water (15 mL) and dried overnight at 40° C. under reduced pressure to obtain the title compound (5.56 g, 0.0216 mol, yield 90.8%). 1 H NMR(500MHz,DMSO-d6)δ1.50(s,9H),2.46(s,3H),3.33(s,1H),6.42(d,J=16.0Hz,1H),7.08(t,J=8. 1Hz,1H),7.23(s,1H),7.39(d,J=8.1Hz,1H),7.44(d,J=7.5Hz,1H),8.39(d,J=16.1Hz,1H),10.98(br s,1H). The seed crystals were obtained by leaving the title compound purified by column chromatography to stand.

[0108] (Example 4-2) Preparation of tert-butyl (2E)-3-(3-methyl-1H-indol-4-yl)prop-2-enoate

[0109] [ka]

[0110] Under a nitrogen atmosphere, N,N-dimethylformamide (3.04 kg), a toluene solution of the compound obtained in Example 1-2 (0.80 kg), palladium acetate (8.0 g, 0.0357 mol), tris(p-tolyl)phosphine (28.0 g, 0.107 mol), diisopropyltriethylamine (0.64 kg, 4.95 mol), and tert-butyl acrylate (0.64 kg, 4.93 mol) were added to a reaction vessel and stirred at 100 °C for 12 hours. After cooling to 50 °C, purified water (0.12 kg) was added dropwise and the mixture was concentrated to 5.6 L, reducing the toluene content to 2% or less. The mixture was then cooled to 25 °C, and acetonitrile (2.80 kg) was added. Purified water was then added and replenished until the water content in the system reached 10%. Seed crystals of the target compound (40.0 g) were added, and the mixture was stirred at 25 °C for 2 hours. Further, purified water (1.20 kg) was slowly added dropwise over 4 hours, followed by rapid addition of purified water (5.60 kg) over 4 hours, followed by stirring at room temperature for 4 hours. The resulting suspension was filtered, and the crystals were washed twice with acetonitrile (1.20 kg) and purified water (2.40 kg), and dried under reduced pressure at 40°C for 40 hours to obtain the target compound (0.70 kg, 2.72 mol, yield 76.0%). Seed crystals were obtained by leaving the target compound after purification in a column. In addition, the obtained target compound 1 The 1 H-NMR values ​​were compared with those shown in Example 4-1, and it was confirmed that this was the same compound.

[0111] (Example 5-1) Preparation of tert-butyl (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate

[0112] [ka]

[0113] Under a nitrogen atmosphere, acetonitrile (100 mL), the compound obtained in Reference Example 2-1 (10 g), and 1,1-carbonyldiimidazole (5.06 g, 0.0284 mol) were added to a reaction vessel and stirred at 40°C for 3.5 hours. After cooling to room temperature and degassing under reduced pressure for 10 minutes, the compound obtained in Example 4-1 (8.19 g) and diazabicycloundecene (0.86 g, 0.0057 mol) were added. After stirring at room temperature for 2 hours, acetic acid (0.85 g, 0.014 mol) was added. Subsequently, ordinary water (43 mL) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 15 hours. The resulting suspension was filtered, and the crystals were washed with a mixture of acetonitrile (24 mL) and ordinary water (16 mL). They were then dried overnight under reduced pressure at 40°C to obtain the title compound (15.94 g, 0.02693 mol, yield 95.0%). 1 H NMR(500MHz,DMSO-d6)δ1.49(s,9H),1.83(d,J=21.8Hz,6H),2.37(s,3H),6.50(d,J=15.5Hz,1H),7.34(t,J =8.0Hz,1H),7.44(s,1H),7.73(d,J=7.5Hz,1H),7.84(s,2H),8.24(d,J=16.1Hz,1H),8.25(d,J=8.0Hz,1H).

[0114] (Example 5-2) Preparation of tert-butyl (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate

[0115] [ka]

[0116] Under a nitrogen atmosphere, toluene (36 kg), the compound obtained in Reference Example 2-2 (4.0 kg, 11.3 mol), and 1,1-carbonyldiimidazole (2.28 kg, 14.1 mol) were added to a reaction vessel and stirred at 40°C for 2 hours. After cooling to 25°C, purified water (24 kg) was added and stirred for 1 hour. After allowing to stand, the aqueous layer was removed. The organic layer was concentrated to 20 L. When the water content in the system was less than 0.3%, the compound obtained in Example 4-2 (3.03 kg, 11.8 mol), acetonitrile (28 kg), and diazabicycloundecene (346 g, 2.27 mol) were added. After stirring at 25°C for 6 hours, acetic acid (340 g, 5.66 mol) was added. The reaction mixture was then concentrated to 20 L, isopropanol (32 kg) was added, and the mixture was stirred at 25°C for 1.5 hours. The mixture was further concentrated to 20 L, and isopropanol (32 kg) was added, followed by concentration to 30 L. Finally, isopropanol (16 kg) was added, and the mixture was stirred at 25°C for 0.5 hours, cooled to -5°C over 4 hours, and stirred for 4 hours. The residual rate of the supernatant was 0.38%. The resulting suspension was filtered, and the crystals were washed with isopropanol (10 kg), and then dried under reduced pressure at 40°C for 18 hours to obtain the target compound (yield 92%). 1 The 1 H-NMR values ​​were compared with those shown in Example 5-1, and it was confirmed that this was the same compound.

[0117] (Example 6-1) Preparation of (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid

[0118] [ka]

[0119] Under a nitrogen atmosphere, acetonitrile (100 mL) and the compound (10 g) obtained in Example 5-1 were added to a reaction vessel and stirred at 50°C to completely dissolve the mixture. A 12 mol / L aqueous hydrochloric acid solution (4.2 mL) was added, and the mixture was stirred for 3 hours and then cooled to room temperature. Subsequently, ordinary water (80 mL) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 3 hours. The resulting suspension was filtered, and the crystals were washed with a mixture of acetonitrile (22 mL) and ordinary water (18 mL). They were then dried overnight at 40°C under reduced pressure to obtain the title compound (8.35 g, 0.0558 mol, yield 92.2%). 1 H NMR(500MHz,DMSO-d6)δ1.83(d,J=21.8Hz,6H),2.37(s,3H),6.50(d,J=16.0Hz,1H),7.35(t,J=8.0Hz ,1H),7.43(s,1H),7.70(d,J=7.5Hz,1H),7.84(s,2H),8.25(d,J=15.5Hz,1H),8.26(d,J=8.6Hz,1H).

[0120] (Example 6-2) Preparation of (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid

[0121] [ka]

[0122] Under a nitrogen atmosphere, acetone (25.8 kg) and the compound obtained in Example 5-2 (3.1 kg) were added to a reaction vessel and stirred at 25°C to completely dissolve the mixture. A 12 mol / L aqueous hydrochloric acid solution (7.4 kg) was added, and the mixture was stirred at 40°C for 3 hours, followed by cooling to room temperature (20°C). Purified water (6.2 kg) was then added dropwise over 1 hour, and seed crystals (15.2 g, produced according to Example 6-1) were added, followed by stirring at room temperature for 1 hour. Purified water (12.4 kg) was then added dropwise over 4 hours, followed by stirring at 25°C for 2 hours. The resulting suspension was filtered, and the crystals were washed with a mixture of acetone (6.8 kg) and purified water (9.9 kg), and dried under reduced pressure at 35°C for 8 hours to obtain the target compound (yield 94.0%). The target compound obtained was 1 The 1 H-NMR values ​​were compared with those shown in Example 6-1, and it was confirmed that this was the same compound.

[0123] Example 7-1: Preparation of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate (also referred to as (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)propa-2-enoate t-butylamine salt

[0124] [ka]

[0125] Under a nitrogen atmosphere, acetone (255 mL) and 2-propanol (255 mL) were added to the compound obtained in Example 6 (30 g) in a reaction vessel and stirred at 30°C for 30 minutes to completely dissolve the mixture. Activated carbon (0.3 g) was added and stirred for 30 minutes. The activated carbon was filtered and washed with a mixture of acetone (45 mL) and 2-propanol (45 mL), and the filtrate was collected. The resulting solution was heated to 40°C, and a mixture of tert-butylamine (1.2 g), acetone (13 mL), and 2-propanol (13 mL) was added and stirred for 30 minutes. After confirming the precipitation of crystals of the title compound, a mixture of tert-butylamine (1.4 g), acetone (15 mL), and 2-propanol (15 mL) was added dropwise over 30 minutes. After stirring for 30 minutes, the mixture was heated to 60°C. A mixture of tert-butylamine (1.6 g), acetone (17 mL), and 2-propanol (17 mL) was added dropwise over 2 hours. The mixture was then stirred for 2 hours, cooled to 0°C over 1.5 hours, and stirred for 3 hours. The resulting suspension was filtered, and the crystals were washed with a mixture of chilled acetone (45 mL) and chilled 2-propanol (45 mL). The crystals were then dried overnight at 40°C under reduced pressure to obtain tBA2-type crystals (15.5 g) of the title compound. Figure 1 shows the powder X-ray diffraction pattern, and Table 5 lists the diffraction angle (2θ), interplanar spacing (d value), and relative intensity of the powder X-ray diffraction spectrum. 1 H NMR(500MHz,DMSO-d6)δ1.20(s,9H),1.83(d,J=22.4Hz,6H),2.35(s,3H),6.39(d,J=15.7Hz,1H),7.30(t,J =7.9Hz,1H),7.34(s,1H),7.54(d,J=7.9Hz,1H),7.85(s,2H),7.93(d,J=15.7Hz,1H),8.17(d,J=8.5Hz,1H).

[0126] [Table 5]

[0127] (Example 7-2) Preparation of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate

[0128] [ka]

[0129] In a nitrogen atmosphere, acetone (32.9 kg) and 2-propanol (32.9 kg) were added to the compound (4.9 kg) obtained in Example 6-2 in a reaction vessel, and the mixture was stirred at 30°C for 30 minutes to completely dissolve the compound. TM The mixture was filtered through a Cuno Filtration SAS, and the ZetaCarbon was washed with a mixture of acetone (5.9 kg) and 2-propanol (5.9 kg) to obtain a solution. The resulting solution was heated to 40°C, and tert-butylamine (200.9 g) was added and stirred for 1 hour. After confirming the crystallization of the target compound, tert-butylamine (236.0 g) was added dropwise, and the mixture was stirred with seed crystals (18.5 g, the seed crystals were produced according to Example 7-1) for 1 hour, and then heated to 60°C. tert-butylamine (169.5 g) was added dropwise, and the mixture was charged into the pipeline together with acetone (2.5 kg) and 2-propanol (2.5 kg). The mixture was then stirred for 3 hours, cooled to 0°C over 10 hours, and stirred for 4 hours. The resulting suspension was filtered, and the crystals were washed with a mixture of acetone (5.9 kg) and 2-propanol (5.9 kg). After drying under reduced pressure at 35°C for 20 hours, tBA2-type crystals of the target compound were obtained (yield 87.9%). 1 The 1 H-NMR values ​​were compared with those shown in Example 7-1, and it was confirmed that this was the same compound.

[0130] Example 8: Polymorphism of mono(2-methylpropan-2-ammonium) (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate The title compound has multiple crystal polymorphs (tBA1, tBA2, P1, P2, and P3), and the preparation of four crystal forms, excluding the tBA2 crystal shown in Examples 7-1 and 7-2, is shown in Examples 8-1, 8-2, 8-3, and 8-4.

[0131] (Example 8-1) Production of tBA1-type crystals Acetone (52 mL) and 2-propanol (52 mL) were added to the compound (10 g) obtained in Example 7-1 and stirred at 30°C for 30 minutes to completely dissolve the compound. Activated carbon (0.1 g) was added and stirred for 30 minutes. The activated carbon was filtered and washed with a mixture of acetone (13 mL) and 2-propanol (13 mL), and the filtrate was obtained. The resulting solution was heated to 40°C, and 2-propanol (80 mL) was added. A mixture of tert-butylamine (0.2 g), acetone (1.3 mL), and 2-propanol (3 mL) was then added. Subsequently, tert-butylamine (1.2 g) was added, stirred for 30 minutes, and then cooled to 0°C. After stirring for 2 hours, the resulting suspension was filtered, and the crystals were washed with a mixture of chilled acetone (15 mL) and chilled 2-propanol (15 mL) and dried overnight at 40°C under reduced pressure to obtain tBA1-type crystals (9.8 g) of the title compound. Figure 2 shows the powder X-ray diffraction pattern, and Table 6 lists the diffraction angle (2θ), interplanar spacing (d value), and relative intensity in the powder X-ray diffraction spectrum.

[0132] [Table 6]

[0133] (Example 8-2) Preparation of P1 type crystals Acetone (21 mL) and purified water (3 mL) were added to the compound obtained in Example 7-1 (3 g) and stirred at 40 °C for 30 minutes to completely dissolve the mixture. tert-Butylamine (0.1 g) was added three times every 15 minutes. After confirming the precipitation of crystals of the title compound, tert-butylamine (0.1 g) was added. After cooling to 5 °C and stirring for 30 minutes, the resulting suspension was filtered, and the crystals were washed with a mixture of chilled acetone (1.5 mL) and chilled purified water (2.6 mL). They were then dried overnight at 40 °C under reduced pressure to obtain P1-type crystals of the title compound (2.9 g). Figure 3 shows the powder X-ray diffraction pattern, and Table 7 lists the diffraction angle (2θ), interplanar spacing (d value), and relative intensity of the powder X-ray diffraction spectrum.

[0134] [Table 7]

[0135] (Example 8-3) Preparation of P2 type crystals Acetone (104 mL) and 2-propanol (104 mL) were added to the compound obtained in Example 7-1 (20 g) and stirred at 30 °C for 30 minutes to completely dissolve the mixture. Activated carbon (0.2 g) was added and stirred for 30 minutes. The activated carbon was filtered and washed with a mixture of acetone (26 mL) and 2-propanol (26 mL), and the filtrate was obtained. The resulting solution was heated to 40 °C, and 2-propanol (160 mL) was added. A mixture of tert-butylamine (0.4 g), acetone (2.6 mL), and 2-propanol (6 mL) was then added. Subsequently, tert-butylamine (0.9 g) was added and stirred for 30 minutes. The resulting suspension was filtered, and the crystals were washed with a mixture of acetone (30 mL) and 2-propanol (30 mL). They were then dried overnight at 40 °C under reduced pressure to obtain P2-type crystals (17.7 g) of the title compound. FIG. 4 shows the powder X-ray diffraction pattern, and Table 8 shows the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum.

[0136] [Table 8]

[0137] (Example 8-4) Preparation of P3 type crystals Acetone (52 mL) and 2-propanol (52 mL) were added to the compound obtained in Example 7-1 (10 g) and stirred at 30°C for 30 minutes to completely dissolve the compound. Activated carbon (0.1 g) was added and stirred for 30 minutes. The activated carbon was filtered and washed with a mixture of acetone (13 mL) and 2-propanol (13 mL), and the filtrate was obtained. The resulting solution was heated to 60°C, and 2-propanol (80 mL) and tert-butylamine (0.5 g) were added. After stirring for 1 hour, precipitation of the title compound was confirmed. tert-butylamine (0.3 g) was added, cooled to 25°C, and stirred overnight. The resulting suspension was filtered, and the crystals were washed with a mixture of acetone (15 mL) and 2-propanol (15 mL). They were then dried overnight at 40°C under reduced pressure to obtain P3-type crystals of the title compound (7.2 g). FIG. 5 shows the powder X-ray diffraction pattern, and Table 9 shows the diffraction angle (2θ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction spectrum.

[0138] [Table 9] [Industrial Applicability]

[0139] As described above, according to the present invention, in the production of 3-methyl-4-halo-indole derivatives, the derivatives can be obtained in high yield, and further, demethylation or dehalogenation of the derivatives can be suppressed, facilitating post-treatment. 3-methyl-4-halo-indole derivatives are useful as pharmaceuticals such as antitumor agents or as raw materials for their production, and therefore can be used particularly in the medical field.

Claims

1. Formula (I): 【Chemical 1】 The compound represented by the formula Ti(OR) ４ and reducing the compound with a hydride reducing agent, Formula (II): 【Chemistry 2】 and reacting the compound with tert-butyl acrylate using a palladium catalyst. Formula (III): 【Chemistry 3】 A method for producing a compound represented by the formula: [X represents a halogen atom, and R represents a C 1 -C 4 alkyl group.]

2. A step of producing a compound represented by formula (III) by the production method according to claim 1; and condensing the compound with a compound of formula (IV), 【Chemistry 4】 Formula (V): 【Chemistry 5】 A method for producing a compound represented by the formula:

3. A step of producing a compound represented by formula (V) by the production method according to claim 2; and hydrolyzing the compound. Formula (VI): 【Chemistry 6】 A method for producing a compound represented by the formula:

4. A step of producing a compound represented by formula (VI) by the production method according to claim 3; salifying the compound with tert-butylamine; and crystallization in a mixed solution of acetone and 2-propanol; A method for producing the tert-butylamine salt of the compound of formula (VI).

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