WO2022092247A1 - 3-メチル-4-ハロ-インドール誘導体の製造方法 - Google Patents
3-メチル-4-ハロ-インドール誘導体の製造方法 Download PDFInfo
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- WO2022092247A1 WO2022092247A1 PCT/JP2021/039946 JP2021039946W WO2022092247A1 WO 2022092247 A1 WO2022092247 A1 WO 2022092247A1 JP 2021039946 W JP2021039946 W JP 2021039946W WO 2022092247 A1 WO2022092247 A1 WO 2022092247A1
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
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- 238000005695 dehalogenation reaction Methods 0.000 abstract description 5
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/03—Monoamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J2231/4261—Heck-type, i.e. RY + C=C, in which R is aryl
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
Definitions
- the present invention relates to a novel method for producing a 3-methyl-4-halo-indole derivative, and more particularly to a production method including a novel method for reducing a formyl-haloindole derivative using Lewis acid and a hydride reducing agent.
- the 3-methyl-4-halo-indole derivative is useful as a pharmaceutical product or a raw material for producing the same, and is known to be useful for treating tumors (Patent Document 1).
- 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 present document uses, for example, 3-formyl-4-bromo-7-fluoroindole as a raw material and bis (2-methoxyethoxy) hydride.
- a 3-methylindole derivative is obtained by a reduction reaction with sodium (Patent Document 1, Reference Example E-14).
- the present inventors used Lewis acid and a hydride reducing agent in the production of a 3-methyl-4-halo-indole derivative by reducing the formyl group. It has been found that the derivative can be obtained in a high yield, or demethylation or dehalogenation of the derivative is suppressed, and post-treatment becomes easy, and an intermediate produced by that method is used.
- the compound represented by (1) or a pharmaceutically acceptable salt thereof is 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. It comprises a step of reducing with a Lewis acid having one metal ion and a hydride reducing agent. Equation (II):
- a method for producing a compound represented by the above or a pharmaceutically acceptable salt thereof [X represents a halogen atom. ] (2) The production method according to (1), wherein X is a bromine atom. (3) The production according to (1) or (2), wherein the Lewis acid is a Lewis acid containing one metal ion selected from Mg ion, Sc ion, Bi ion, Ti ion, La ion, and Yb ion. Method. (4) The production method according to (1) or (2), wherein the Lewis acid is a Lewis acid containing Ti ions. (5) The production method according to (1) or (2), wherein the Lewis acid is Ti (OR) 4 .
- a method for producing a compound represented by the above or a pharmaceutically acceptable salt thereof (8) A compound represented by the formula (III) produced by using the production method according to (7). Condensate with the compound of formula (IV),
- a method for producing a compound represented by the above or a pharmaceutically acceptable salt thereof. (10) In the formula (VI), the compound represented by the formula (II) produced by the production method according to any one of (1) to (6) is used as an intermediate. The method for producing the indicated compound. (11) A compound represented by the formula (VI) produced by the production method according to (9) or (10). It comprises a step of chlorinating with tert-butylamine and a step of crystallizing in a mixed solution of acetone and 2-propanol. A method for producing a tert-butylamine salt of a compound represented by the formula (VI).
- a tBA2-type crystal having at least three peaks at a diffraction angle (2 ⁇ ) selected from.
- Diffraction angle (2 ⁇ ) selected from 2, 23.20 ⁇ 0.2, 25.13 ⁇ 0.2, 26.13 ⁇ 0.2, 27.86 ⁇ 0.2, and 28.81 ⁇ 0.2. ), A P1-type crystal having at least three peaks.
- Mono (2-methylpropan-2-ammonium) (2E) -3-(1- ⁇ [5- (2-fluoropropane-2-yl) -3- (2,4,6-trichlorophenyl) ) -1,2-Oxazole-4-yl] carbonyl ⁇ -3-methyl-1H-indole-4-yl)
- Propa-2-enoate crystal, copper K ⁇ -ray ( ⁇ 1.54 angstrom)
- X-ray diffraction pattern obtained by the irradiation of 3.10 ⁇ 0.2, 6.23 ⁇ 0.2, 9.39 ⁇ 0.2, 12.55 ⁇ 0.2, 15.71 ⁇ 0.
- the powder X-ray diffraction pattern of the crystal of the compound produced in Example 7-1 is shown.
- the vertical axis of the figure shows the diffraction intensity as a relative line intensity, and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal of the compound produced in Example 8-1 is shown.
- the vertical axis of the figure shows the diffraction intensity as a relative line intensity
- the horizontal axis shows the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal of the compound produced in Example 8-2 is shown.
- the vertical axis of the figure shows the diffraction intensity as a relative line intensity, and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal of the compound produced in Example 8-3 is shown.
- the vertical axis of the figure shows the diffraction intensity as a relative line intensity, and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal of the compound produced in Example 8-4 is shown.
- the vertical axis of the figure shows the diffraction intensity as a relative line intensity, and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
- the present invention relates to the following manufacturing method.
- [X represents a halogen atom].
- such a method is an industrially useful and novel production method including a novel reduction method for a formyl-haloindole derivative (for example, a production method for obtaining the derivative in high yield).
- a novel reduction method for a formyl-haloindole derivative for example, a production method for obtaining the derivative in high yield.
- This is a production method that suppresses demethylation and / or dehalogenation of the derivative and facilitates post-treatment).
- Lewis acid means a substance containing a metal ion and capable of receiving an electron pair.
- the metal ion contained in Lewis acid 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 and Zn ion. , Ce ion, La ion, Yb ion and the like.
- the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof can be easily obtained with high yield, preferably Li ion, Mg ion, Ca ion, Sc ion, Bi ion, Ti ion and Fe.
- Is Mg ion, Sc ion, Bi ion, Ti ion, La ion, or Yb ion, and Ti ion is particularly preferable.
- the "high yield" in the present invention means that the HPLC area ratio shown in Examples described later is preferably 75 area% or more.
- the metal ions contained in Lewis acid in the present invention are, for example, Li + , Mg2 + , Ca 2+ , Al 3+ , Sc 3+ , In 3+ , Bi 3+ , B 3+ , Ti 4+ , Fe 2+ , Fe 3+ , Co 2+ , Examples thereof include metal ions having valences such as Co 3+ , Cu + , Cu 2+ , Zn 2+ , Ce 3+ , Ce 4+ , La 3+ , and Yb 3+ .
- Preferred valences are 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+ .
- Lewis acids containing Li ions include LiCl, LiBr, LiI, LiOTf and the like.
- Lewis acids containing Mg ions include MgCl 2 , MgBr 2 , and MgI 2 . It is preferably MgCl 2 .
- Lewis acids containing Ca ions include, for example, CaCl 2 , CaBr 2 , CaI 2 and the like. It is preferably CaCl 2 .
- Lewis acids containing Al ions include AlCl 3, AlBr 3 , AlI 3 , and the like. Preferred is AlCl 3 .
- the Lewis acid containing Sc ions include Sc (OTf) 3 .
- Lewis acids containing In examples include InCl 3 , InBr 3 , and InI 3 .
- Lewis acids containing Bi ions include BiCl 3 , BiBr 3 , and Bi (OTf) 3 .
- BiCl 3 is preferred.
- the Lewis acid containing B ion examples include BF 3 , Et 2 O and the like.
- Lewis acids containing Ti ions include TiCl 4 , Ti (OR) 4 (for example, Ti (OEt) 4 , Ti (OiPr) 4 , Ti (OBu) 4 ) and the like. It is preferably Ti (OR) 4 , and more preferably Ti (OEt) 4 , Ti (OiPr) 4 , or Ti (OBu) 4 .
- R represents a C1- C4 alkyl group described later.
- Lewis acids containing Fe ions include FeCl 2 , FeBr 2 , FeI 2 , FeCl 3 , FeBr 3 , and FeI 3 . Preferred is FeCl 3 .
- Lewis acids containing Co ions include CoCl 2 , CoBr 2 , CoI 2 , and the like. It is preferably CoCl 2 .
- Lewis acids containing Cu ions include CuCl, CuBr, CuI, CuCl 2 , CuBr 2 , and CuI 2 . CuI is preferred.
- Lewis acids containing Zn ions examples include ZnCl 2 , ZnBr 2 , Zn (OTf) 2 , and ZnO.
- Lewis acids containing Ce ions examples include CeCl 3 and CeCl 4 .
- Examples of the Lewis acid containing La ion include La (OTf) 3 and the like.
- Examples of the Lewis acid containing Yb ion include Yb (OTf) 3 and the like.
- Lewis acids in the present invention include Lewis acids containing Mg ions, Lewis acids containing Ca ions, Lewis acids containing Sc ions, Lewis acids containing Bi ions, and Ti ions.
- Lewis acids more preferably, MgCl 2 , MgBr 2 , MgI 2 , CaCl 2 , Sc (OTf) 3 , BiCl 3 , Ti (OEt) 4 , Ti (OiPr) 4 , Ti (OiPr) 4 , CuI, It is La (OTf) 3 , or Yb (OTf) 3 , and more preferably Ti (OEt) 4 , Ti (OiPr) 4 , or Ti (OBu) 4 .
- the impurities (imp.2) shown in [Example] described later are difficult to remove by purification. Therefore, in the present invention, imp.
- the preferred Lewis acid of the present invention is a Lewis acid containing Mg ion, Al ion.
- Lewis acid containing Sc ion Lewis acid containing In ion, Lewis acid containing Bi ion, Lewis acid containing B ion, Lewis acid containing Ti ion, Fe ion included It is a Lewis acid, a Lewis acid containing Co ion, a Lewis acid containing Cu ion, a Lewis acid containing La ion, or a Lewis acid containing Yb ion. Further, while it is easy to obtain the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof in high yield, imp.
- Lewis acid containing Mg ion, Lewis acid containing Sc ion, Lewis acid containing Bi ion, Lewis acid containing Ti ion, and Fe ion Lewis acid, Lewis acid containing Cu ion, Lewis acid containing La ion, or Lewis acid containing Yb ion, more preferably MgCl 2 , MgBr 2 , MgI 2 , Sc (OTf) 3 , BiCl 3 , Ti (OEt) 4 , Ti (OiPr) 4 , Ti (OBu) 4 , FeCl 3 , CuI, La (OTf) 3 , or Yb (OTf) 3 .
- “suppressing the generation of imp. 2” means “imp. 2 shown in Examples described later".
- the HPLC area ratio of 2 is preferably 3 area% or less, and more preferably 2 area% or less.
- a Lewis acid containing Mg ions more preferably a Lewis acid containing Bi ions, a Lewis acid containing Cu ions, a Lewis acid containing Ti ions, a Lewis acid containing Li ions, and a Zn ion. It is a Lewis acid, more preferably BiCl 3 , Bi (OTf) 3 , BiBr 3 , CuI, TiCl 4 , LiI, LiBr, LiCl, LiOTf, or ZnO.
- “suppressing the generation of imp. 1" means "imp.”
- the HPLC area ratio of 1 is preferably 10 area% or less, more preferably 5 area% or less.
- the "C1- C4 alkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms, and is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group.
- Groups, isobutyl groups, s-butyl groups, t-butyl groups and the like can be mentioned. It is preferably an ethyl group, an isopropyl group, or a butyl group. More preferably, it is an ethyl group.
- the "hydride reducing agent” for example, sodium borohydride, lithium borohydride, calcium borohydride, sodium triacetoxyborohydride, lithium triethylborohydride and the like can be used.
- sodium borohydride sodium borohydride, lithium borohydride, calcium borohydride, sodium triacetoxyborohydride, lithium triethylborohydride and the like.
- Preferred is sodium borohydride.
- the solvent that can be used in the present invention may be any one that is inert to each reaction.
- a hydride reducing agent for example, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, isopropanol, tetrahydrofuran and the like, or a mixed solvent thereof can be used. It is preferable to use N-methyl-2-pyrrolidone, isopropanol, tetrahydrofuran, or a mixed solvent thereof.
- the above-mentioned Lewis acid and hydride reducing agent and a solvent are used to reduce the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and the compound represented by the formula (II) or a pharmaceutical product thereof.
- the above acceptable salt is produced, and the specific reaction conditions are described in detail in [Examples] described later (particularly, see Examples 1-1 to 3). Therefore, those skilled in the art can produce the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof while appropriately referring to the reaction conditions.
- the reaction conditions and the like of the present invention should not be construed as being limited to these.
- the present invention relates to a method for producing a compound represented by the above or a pharmaceutically acceptable salt thereof.
- the present invention comprises the compound represented by the formula (III) produced by the above-mentioned production method. Condensate with the compound of formula (IV),
- the present invention relates to a method for producing a compound represented by.
- the present invention relates to a method for producing a compound represented by the above or a pharmaceutically acceptable salt thereof.
- the present invention relates to a method for producing a compound represented by the formula (VI), which comprises using the compound represented by the formula (II) produced by the above production method as an intermediate.
- the compound represented by the formula (VI) produced by the above-mentioned production method comprises a step of chlorinating with tert-butylamine and a step of crystallizing in a mixed solution of acetone and 2-propanol.
- the present invention relates to a method for producing a tert-butylamine salt of a compound represented by the formula (VI).
- a method for producing a tert-butylamine salt of the compound represented by the formula (VI) from the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof is also described in detail in [Example] described later. (In particular, see Examples 4-1 to 8-4). Further, it is described in detail in Patent Document 1. Therefore, those skilled in the art will refer to these descriptions as appropriate, and represent the compound represented by the formula (III) or a pharmaceutically acceptable salt thereof, the compound represented by the formula (V), and the formula (VI). It is also possible to produce each of these compounds or pharmaceutically acceptable salts thereof. However, in the present invention, the method for producing these compounds should not be construed as being limited to these descriptions.
- the functional group of the compound may be protected by an appropriate protecting group.
- a functional group include a hydroxyl group, a carboxy group, an amino group and the like, and the types of protecting groups and the conditions for introducing and removing those protecting groups are described in, for example, Protective Groups in Organic Synthesis (T.D.). W. Green and PGM Wuts, John Wiley & Sons, Inc., New York, 2006) can be referred to.
- the "X" in the compound represented by the formula (I) and the compound represented by the formula (II) of the present invention is a halogen atom, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. , Preferably a bromine atom.
- the "pharmaceutically acceptable salt” means a salt that does not have significant toxicity and can be used as a pharmaceutical composition.
- the compound represented by the formula (I), the compound represented by the formula (II), and the compound represented by the formula (III) of the present invention can each be made into a salt by reacting with an acid.
- Such salts include, for example, hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, phosphates and the like.
- Inorganic acid salts C1 - C6 alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate; Allyl sulfonates such as benzene sulfonate, p-toluene sulfonate.
- Acids organic acid salts such as acetates, apple acid salts, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, adipates; and glycine salts, lysines. Examples thereof include salts, arginine salts, ornithine salts, glutamates, amino acid salts such as aspartate and the like.
- the compound represented by the formula (IV) of the present invention and the compound represented by the formula (VI) can each be converted into a salt by reacting with a base.
- Such salts include, for example, 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; ammonium salt and the like.
- Inorganic salts t-butylamine salt, t-octylamine salt, dibenzylamine salt, morpholin salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt , Dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocine salt, prokine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, etc.
- Examples include amine salts such as organic salts.
- the compound represented by the formula (I) or the pharmaceutically acceptable salt of the present invention the compound represented by the formula (II) or the pharmaceutically acceptable salt, the compound represented by the formula (III) or the pharmaceutically acceptable salt.
- the compound represented by the formula (IV) or the pharmaceutically acceptable salt, the compound represented by the formula (V), and the compound represented by the formula (VI) or the pharmaceutically acceptable salt are each left in the air. Or by recrystallizing, water molecules may be taken up and become hydrates, and each such hydrate is also included in the present invention.
- the compound represented by the formula (I) or a pharmaceutically acceptable salt of the present invention the compound represented by the formula (II) or a pharmaceutically acceptable salt, the compound represented by the formula (III) or a pharmaceutically acceptable salt.
- the compound represented by formula (IV) or a pharmaceutically acceptable salt, the compound represented by formula (V), and the compound represented by formula (VI) or a pharmaceutically acceptable salt are each left in a solvent. Or by recrystallizing, it may absorb certain solvents and become solvent compounds, and each such solvent compound is also included in the present invention.
- the tert-butylamine salt of the compound represented by the formula (VI) of the present invention also includes the following crystals.
- a P1-type crystal having at least 3 peaks (eg, 3, 5, 6, 7, 8, 9, or 10 peaks).
- a P2-type crystal having at least three peaks (eg, three, five, or six peaks) at a diffraction angle (2 ⁇ ) selected from 27.18 ⁇ 0.2.
- Mono (2-methylpropan-2-ammonium) (2E) -3-(1- ⁇ [5- (2-fluoropropane-2-yl) -3- (2,4,6-trichlorophenyl) -1) , 2-Oxazole-4-yl] carbonyl ⁇ -3-methyl-1H-indole-4-yl)
- the compound represented by the formula (VI) of the present invention or a pharmaceutically acceptable salt thereof can be prepared as a pharmaceutical composition or as a reagent for research purposes (Patent Document 1). reference).
- the pharmaceutically acceptable carrier used may be, for example, sterile water, physiological saline, vegetable oil, solvent, or group.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be in various forms such as tablets, powders, granules, capsules and liquids, depending on the therapeutic purpose and the like. It can also be administered, for example, in the form of a liposome delivery system.
- the liposome can also be added with the auxiliary moieties (eg, antibodies, ligands, etc.) that enhance therapeutically useful properties.
- the pharmaceutical composition of the present invention is not particularly limited with respect to the target disease, but is preferably brain tumor (including chondrosarcoma), acute myeloid leukemia, myeloproliferative syndrome, myeloproliferative neoplasm, peripheral T. Cancers such as cellular lymphoma, chondrosarcoma, osteosarcoma, bile duct cancer, primordial neuroectodermal tumor, B lymphoblastic lymphoma, malignant melanoma, prostate cancer, colon cancer, thyroid cancer, Orie's disease, Muffch's syndrome. .. That is, the pharmaceutical composition of the present invention can be suitably used as an antitumor agent.
- the active ingredient of the pharmaceutical composition of the present invention is not particularly limited as long as it is the compound represented by the above formula (VI) or a pharmaceutically acceptable salt thereof, but is preferable. It is a tert-butylamine salt of the compound represented by the formula (VI), and more preferably, it is a group consisting of the above-mentioned tBA1 type crystal, tBA2 type crystal, P1 type crystal, P2 type crystal, and P3 type crystal of the tert-butylamine salt. It is at least one crystal selected from, preferably the tBA1 type crystal, the tBA2 type crystal, the P1 type crystal, and the P2 type crystal. And P3 type crystals.
- the nuclear magnetic resonance (hereinafter, 1 H NMR: 500 MHz) spectrum is described with a chemical shift value of ⁇ value (ppm) using tetramethylsilane as a standard material.
- the split pattern is shown by s for the single line, d for the double line, t for the triple line, q for the quadruple line, m for the multiple line, and br for the broad line.
- liquid chromatography used HPLC 10A (SHIMADZU) or ACQUITY UPLC H-Class (WATERS).
- the equipment and measurement conditions in the powder X-ray diffraction measurement are as follows.
- the position of the peak in the X-ray diffraction spectrum is expected to change by about ⁇ 0.2 ° 2 ⁇ . That is, when the difference between the 2 ⁇ values of the two peaks to be compared is within the range of about ⁇ 0.2 ° 2 ⁇ , both peaks are regarded as the same peak.
- Acetonitrile (120 mL) and 1,1-carbonyldiimidazole (64.19 g, 0.3959 mol) were added to the reaction vessel 1 under a nitrogen atmosphere, and the mixture was stirred at room temperature and then 2-fluoro-2-methylpropanoic acid (40 g). The acetonitrile (40 mL) solution of) was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. Next, under a nitrogen atmosphere, acetonitrile (200 mL) and monomethyl potassium malonic acid (70.66 g, 0.4524 mol) were added to the reaction vessel 2, and magnesium chloride (28.72 g, 28.72 g,) was added while controlling the internal temperature at 10-40 ° C.
- dimethylformamide (70 mL) and N-hydroxy-1- (2,4,6-trichlorophenyl) methaneimine (10 g) were added to the reaction vessel under a nitrogen atmosphere, and the mixture was stirred at room temperature and then trichloroisocyanuric acid (3).
- a solution of ethyl acetate (25.0 mL) of .73 g, 0.0160 mol) was added dropwise to 10-40 ° C. while controlling the internal temperature, and the mixture was washed with ethyl acetate (5.0 mL).
- a methanol solution of 28 (w / w)% sodium methoxide (12.0 g, 0.0623 mol) was added at 15 ° C., followed by 2,4,6-trichloro-N-hydroxybenzene-1-carboxyimideyl chloride.
- a solution of ethyl acetate (corresponding to 0.0445 mol) was added dropwise over 1 hour, and the solution was washed with ethyl acetate (5 mL).
- Acetonitrile (348 g) and methyl 2-fluoro-2-propionate (145 g) were added to the reaction vessel 1 under a nitrogen atmosphere, and the mixture was stirred at 0 ° C.
- 1,1-carbonyldiimidazole (244.1 g) was added dropwise while keeping the internal temperature below 10 ° C. in 5 batches over 1 hour.
- the inlet was washed with acetonitrile (20 g) and stirred for another hour.
- the temperature of the reaction kettle was adjusted to 25 ° C., and then acetonitrile (435 g) and monomethylpotassium malonic acid (235 g) were added to the reaction kettle 2 to keep the internal temperature below 40 ° C.
- magnesium chloride 143.5 g was added in 4 portions. The inlet was washed with acetonitrile (145 g) and stirred at 25 ° C. for 1 hour. Further, the solution obtained in the reaction vessel 1 was added dropwise to the reaction vessel 2 at 30 ° C. over 1 hour, and the mixture was washed with acetonitrile (20 g). The mixture was continuously stirred at 30 ° C. for 3 hours and cooled to 20 ° C. A mixture of concentrated hydrochloric acid (428 g) and normal water (362.5) was added dropwise over 1 hour, and the mixture was stirred for 30 minutes.
- dimethylacetamide (900 g) and N-hydroxyl-1- (2,4,6-trichlorophenyl) methyleneimine (215 g) were added to the reaction vessel, and dimethylacetamide (37 g) was added to the inlet. Was washed.
- the mixture was stirred at 50 ° C. until clear, and N-chlorosuccinimide (126 g) was added in 21 portions over 3 hours while keeping the internal temperature below 55 ° C., and the mixture was stirred at 50 ° C. for 1 hour. After stirring at 25 ° C.
- N-Methylpyrrolidone 70 mL
- tetraisopropyl orthotitanate (19.03 g, 0.06695 mol)
- sodium borohydride (6.75 g, 0.178 mol)
- 4-bromo-1H-indole-3-formaldehyde (20 g) dissolved in N-methylpyrrolidone (20 mL) was added dropwise.
- the mixture was stirred at 80 ° C. for 2 hours. The mixture was cooled to 0 ° C.
- Tetrahydrofuran (2.08 kg) raw materials 4-bromo-1H-indole-3-formaldehyde (0.80 kg, 3.571 mol) and isopropanol (3.76 kg) were added to the reaction vessel 1 under a nitrogen atmosphere. Then, the mixture was stirred at 25 ° C. for 1 hour. Purified water is replenished until the solution KF (moisture in the system) reaches 0.5%, cooled to 5 ° C., and then sodium borohydride (144.0 g, 1.06 eq) is added in several portions.
- Example 2-1 Examination of various Lewis acids 1
- Lewis acid screening is performed under the same reaction conditions as in Example 1-1, and how the amounts of various compounds change. It was examined from the HPLC area ratio. The results are shown in Table 1.
- "Imp.” In the following table means Impurity (impurity).
- HPLC condition detection 225 nm
- Example 2-2 Examination of various Lewis acids 2 For some of the Lewis acids examined in Table 1, the Lewis acid equivalents were examined under the same reaction conditions as in Example 1. The results are shown in Table 3. The HPLC conditions are the same as in Example 2-1. Further, it is preferable that the reaction system is in a solution state rather than a slurry state because it is in a more uniform reaction state.
- Example 3 Examination of various Lewis acids 3 The type of titanium alkoxide was examined under the same reaction conditions as in Example 1-1. The results are shown in Table 4. The No. 1 shown in the table. 1-3 were all Solutions.
- N, N-dimethylformamide (3.04 kg), a toluene solution of the compound (0.80 kg) obtained in Example 1-2, and palladium acetate (8.0 g, 0.) were placed in the reaction vessel.
- 0357mo1 tris (p-tolyl) phosphine (28.0 g, 0.107 mol), diisopropyltriethylamine (0.64 kg, 4.95 mol), tert-butyl acrylate (0.64 kg, 4.93 mol) were added, and the temperature was 100 ° C. Was stirred for 12 hours.
- purified water (0.12 kg) was added dropwise and concentrated to 5.6 L to reduce the toluene content to 2% or less. Then, the mixture was cooled to 25 ° C., acetonitrile (2.80 kg) was added, and purified water was added to replenish the system until the water content in the system reached 10%. A seed crystal (40.0 g) of the target compound was 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, then purified water (5.60 kg) was rapidly added over 4 hours, and the mixture was stirred at room temperature for 4 hours.
- the obtained suspension was filtered, 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%) was obtained.
- the seed crystal was obtained by allowing the target compound after purification to stand on a column. Further, the 1 H-NMR value of the obtained target compound was compared with those shown in Example 4-1 to confirm that they were the same compound.
- Diazabicycloundecene (346 g, 2.27 mo1) was added. After stirring at 25 ° C. for 6 hours, acetic acid (340 g, 5.66 mol) was added. Then, the reaction solution was concentrated to 20 L, isopropanol (32 kg) was added, and the mixture was stirred at 25 ° C. for 1.5 hours. Further, it was concentrated to 20 L, isopropanol (32 kg) was added, and it was concentrated to 30 L. Finally, isopropanol (16 kg) was added, and the mixture was stirred at 25 ° C. for 0.5 hour, cooled to ⁇ 5 ° C. in 4 hours, and stirred for 4 hours. The residual rate of the supernatant was 0.38%.
- the obtained suspension was filtered, 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%).
- the 1 H-NMR value of the obtained target compound was compared with those shown in Example 5-1 to confirm that they were the same compound.
- Acetone (25.8 kg) and the compound obtained in Example 5-2 (3.1 kg) were added to the reaction vessel under a nitrogen atmosphere, and the mixture was stirred at 25 ° C. so as to be completely dissolved.
- a 12 mol / L hydrochloric acid aqueous solution (7.4 kg) was added, and the mixture was stirred at 40 ° C. for 3 hours and then cooled to room temperature (20 ° C.).
- purified water (6.2 kg) was added dropwise over 1 hour, seed crystals (15.2 g, produced according to Example 6-1) were added, and the mixture was stirred at room temperature for 1 hour.
- Purified water (12.4 kg) was added dropwise over 4 hours, and the mixture was stirred at 25 ° C. for 2 hours.
- the obtained suspension was filtered, the crystals were washed with a mixed solution 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 1 H-NMR value of the obtained target compound was compared with those shown in Example 6-1 to confirm that they were the same compound.
- Acetone (255 mL) and 2-propanol (255 mL) were added to the compound (30 g) obtained in Example 6 in a reaction vessel under a nitrogen atmosphere, and the mixture was completely dissolved by stirring at 30 ° C. for 30 minutes.
- Activated carbon (0.3 g) was added and stirred for 30 minutes, the activated carbon was filtered, and the activated carbon was washed with a mixed solution of acetone (45 mL) and 2-propanol (45 mL) to obtain a filtrate.
- FIG. 1 shows a powder X-ray diffraction pattern
- Table 5 shows a diffraction angle (2 ⁇ ), a lattice spacing (d value), and a relative intensity in the powder X-ray diffraction spectrum.
- 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 under a nitrogen atmosphere, and the mixture was completely dissolved at 30 ° C. It was stirred for 30 minutes so as to be allowed to.
- the solution was filtered through ZetaCarbon TM (Cuno Filtration S.A.S.), and ZetaCarbon was washed with a mixed solution of acetone (5.9 kg) and 2-propanol (5.9 kg) to obtain a solution.
- the obtained solution was heated to 40 ° C., tert-butylamine (200.9 g) was added, and the mixture was stirred for 1 hour.
- tert-butylamine 236.0 g was added dropwise, and the mixture was stirred with a seed crystal (18.5 g, the seed crystal was produced according to Example 7-1) for 1 hour. Then, it was heated to 60 ° C.
- Example 8-1 Production of tBA1 type crystal Acetone (52 mL) and 2-propanol (52 mL) were added to the compound (10 g) obtained in Example 7-1, and the mixture was stirred at 30 ° C. for 30 minutes to completely dissolve. I let you. Activated carbon (0.1 g) was added and stirred for 30 minutes, the activated carbon was filtered, and the activated carbon was washed with a mixed solution of acetone (13 mL) and 2-propanol (13 mL) to obtain a filtrate.
- the obtained solution was heated to 40 ° C., 2-propanol (80 mL) was added, and a mixed solution of tert-butylamine (0.2 g), acetone (1.3 mL) and 2-propanol (3 mL) was added. .. Subsequently, tert-butylamine (1.2 g) was added, and the mixture was stirred for 30 minutes and then cooled to 0 ° C. After stirring for 2 hours, the resulting suspension was filtered, the crystals washed with a mixture of cooled acetone (15 mL) and cooled 2-propanol (15 mL), and dried under reduced pressure at 40 ° C. overnight.
- FIG. 2 shows the powder X-ray diffraction pattern
- Table 6 shows the diffraction angle (2 ⁇ ), the lattice spacing (d value), and the relative intensity in the powder X-ray diffraction spectrum.
- Example 8-2 Production of P1 type crystals Acetone (21 mL) and purified water (3 mL) were added to the compound (3 g) obtained in Example 7-1, and the mixture was stirred at 40 ° C. for 30 minutes to completely dissolve. rice field. tert-Butylamine (0.1 g) was added 3 times every 15 minutes, and 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 is filtered, the crystals washed with a mixture of cooled acetone (1.5 mL) and cooled purified water (2.6 mL), and under reduced pressure. By drying at 40 ° C.
- FIG. 3 shows the powder X-ray diffraction pattern
- Table 7 shows the diffraction angle (2 ⁇ ), the lattice spacing (d value), and the relative intensity in the powder X-ray diffraction spectrum.
- Example 8-3 Production of P2 type crystal Acetone (104 mL) and 2-propanol (104 mL) were added to the compound (20 g) obtained in Example 7-1, and the mixture was stirred at 30 ° C. for 30 minutes to completely dissolve. I let you. Activated carbon (0.2 g) was added and stirred for 30 minutes, the activated carbon was filtered, and the activated carbon was washed with a mixed solution of acetone (26 mL) and 2-propanol (26 mL) to obtain a filtrate.
- FIG. 4 shows the powder X-ray diffraction pattern
- Table 8 shows the diffraction angle (2 ⁇ ), the lattice spacing (d value), and the relative intensity in the powder X-ray diffraction spectrum.
- Example 8-4 Production of P3 type crystal Acetone (52 mL) and 2-propanol (52 mL) were added to the compound (10 g) obtained in Example 7-1, and the mixture was stirred at 30 ° C. for 30 minutes to completely dissolve. I let you. Activated carbon (0.1 g) was added and stirred for 30 minutes, the activated carbon was filtered, and the activated carbon was washed with a mixed solution of acetone (13 mL) and 2-propanol (13 mL) to obtain a filtrate. The obtained solution was heated to 60 ° C., 2-propanol (80 mL) was added, and tert-butylamine (0.5 g) was added.
- FIG. 5 shows the powder X-ray diffraction pattern
- Table 9 shows the diffraction angle (2 ⁇ ), the lattice spacing (d value), and the relative intensity in the powder X-ray diffraction spectrum.
- the derivative in the production of a 3-methyl-4-halo-indole derivative, the derivative can be obtained in a high yield, and further, the derivative is demethylated or demethylated. Halogenation can be suppressed and post-treatment can be facilitated. Since the 3-methyl-4-halo-indole derivative is useful as a medicine such as an antitumor agent or a raw material for producing the same, it is particularly useful in the medical field.
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Abstract
Description
(1)式(I):
式(II):
[Xは、ハロゲン原子を示す。]
(2)Xが、臭素原子である(1)に記載の製造方法。
(3)ルイス酸が、Mgイオン、Scイオン、Biイオン、Tiイオン、Laイオン、およびYbイオンから選ばれる1種の金属イオンを含むルイス酸である(1)または(2)に記載の製造方法。
(4)ルイス酸が、Tiイオンを含むルイス酸である(1)または(2)に記載の製造方法。
(5)ルイス酸が、Ti(OR)4である(1)または(2)に記載の製造方法。(Rは、C1-C4アルキル基を示す。)
(6)Rが、エチル基、イソプロピル基、またはブチル基である(1)から(5)のいずれか1つに記載の製造方法
(7)(1)から(6)のいずれか1つに記載の製造方法を用いて製造された式(II)で示される化合物を、
パラジウム触媒を用いて、tert-ブチルアクリレートと反応させる工程を包含する
式(III):
(8)(7)に記載の製造方法を用いて製造された式(III)で示される化合物を、
式(IV)で示される化合物と縮合させる、
(9)(8)に記載の製造方法を用いて製造された式(V)で示される化合物を、加水分解する、
式(VI):
(10)(1)から(6)のいずれか1つに記載の製造方法を用いて製造された式(II)で示される化合物を中間体として用いることを特徴とする、式(VI)で示される化合物の製造方法。
(11)(9)または(10)に記載の製造方法を用いて製造された式(VI)で示される化合物を、
tert-ブチルアミンを用いて塩化させる工程、ならびに
アセトンおよび2-プロパノールの混合溶液中で結晶化させる工程を含む、
式(VI)で示される化合物のtert-ブチルアミン塩の製造方法。
(12)モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および26.28±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するtBA1型結晶。
(13)モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.42±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するtBA2型結晶。
(14)モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.81±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP1型結晶。
(15)モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、3.04±0.2、9.08±0.2、18.23±0.2、24.38±0.2、24.66±0.2、および27.18±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP2型結晶。
(16)モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および27.94±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP3型結晶。
(17)(12)に記載の結晶ないし(16)に記載の結晶を有効成分として含有する医薬組成物。
本発明は、下記製造方法に関する。
式(II):
[Xは、ハロゲン原子を示す]。
パラジウム触媒を用いて、tert-ブチルアクリレートと反応させる工程を包含する
式(III):
式(IV)で示される化合物と縮合させる、
式(VI):
tert-ブチルアミンを用いて塩化させる工程、ならびに
アセトンおよび2-プロパノールの混合溶液中で結晶化させる工程を含む、
式(VI)で示される化合物のtert-ブチルアミン塩の製造方法に関する。
次に、上述の製造方法における、反応物、中間体、生成物であるところの、式(I)~(VI)にて各々示される化合物、または製薬上許容されるそれらの塩について説明する。
モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および26.28±0.2から選択される回折角度(2θ)に、少なくとも3つのピーク(例えば、3つ、5つ、6つ、7つ、8つ、9つ、または10個のピーク)を有するtBA1型結晶。
モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.42±0.2から選択される回折角度(2θ)に、少なくとも3つのピーク(例えば、3つ、5つ、6つ、7つ、8つ、9つ、10個、または11個のピーク)を有するtBA2型結晶。
モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.81±0.2から選択される回折角度(2θ)に、少なくとも3つのピーク(例えば、3つ、5つ、6つ、7つ、8つ、9つ、または10個のピーク)を有するP1型結晶。
モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、3.04±0.2、9.08±0.2、18.23±0.2、24.38±0.2、24.66±0.2、および27.18±0.2から選択される回折角度(2θ)に、少なくとも3つのピーク(例えば、3つ、5つ、または6つのピーク)を有するP2型結晶。
モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および27.94±0.2から選択される回折角度(2θ)に、少なくとも3つのピーク(例えば、3つ、5つ、6つ、7つ、8つ、9つ、または10個のピーク)を有するP3型結晶。
mg:ミリグラム,g:グラム,ml:ミリリットル,L:リットル,MHz:メガヘルツ。NMP:N-メチルピロリドン。
機種:Rigaku MiniFlex600
試料:適量
X線発生条件:40kV,15mA
波長:1.54Å(銅のKα線)
測定温度:室温
走査速度:10°/min
走査範囲:3~40°
サンプリング幅:0.02°
なお、概して、X線回析スペクトルにおけるピークの位置は、約±0.2°2θで変化することが予期される。すなわち、比較される2つのピークの2θ値の差が、約±0.2°2θの範囲内にある場合には、両ピークは同一のピークとみなされる。
1H NMR(500MHz,DMSO-d6)δ2.14(d,J=20Hz,6H)3.90(s,3H),8.18(s,2H);ESI MS m/z 366([M+1]+)。
1H NMR(500MHz,DMSO-d6)δ1.89(d,J=20Hz,6H),7.89(s,2H);ESI MS m/z 350([M-1]-)。
1H 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)。
下記化学反応式に示す、化合物(1)から化合物(2)を得る反応において、実施例1-1と同様の反応条件でルイス酸スクリーニングを行い、各種化合物の量がどのように変化するかをHPLC面積比率から検討した。結果を表1に示す。なお、以下の表における「Imp.」とは、Impurity(不純物)であることを表す。
検出:225nm
カラム:YMC Triart C8 (4.6mmID×150mm,3μm)
カラム温度:40℃
移動相:A:10mM酢酸アンモニウム水溶液、B:アセトニトリル
グラジエント条件:
注入量:1μL
試料溶解液:アセトニトリル/水(8:2)。
表1で検討したいくつかのルイス酸に対し、実施例1と同様の反応条件でルイス酸当量の検討を行った。結果を表3に示す。なお、HPLC条件は実施例2-1と同一である。また、反応系は、スラリー(slurry)よりも溶液(Solution)の状態である方が、より均一な反応状態であることから好ましい。
実施例1-1と同様の反応条件でチタンアルコキシドの種類を検討した。結果を表4に示す。なお、当該表に示すNo.1-3は全てSolutionであった。
1H 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)。
なお、種結晶はカラムクロマトグラフィーにて精製した標記化合物を静置して得た。
1H 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)。
1H 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)。
1H 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)。
標記化合物は複数の結晶多形(tBA1型、tBA2型、P1型、P2型、P3型)を有しており、実施例7-1および7-2に示すtBA2型結晶を除く4種類の結晶形の製造を実施例8-1、8-2、8-3、および8-4に示す。
実施例7-1で得られた化合物(10g)にアセトン(52mL)と2-プロパノール(52mL)を加え、30℃で30分間攪拌して完溶させた。活性炭(0.1g)を加えて30分間撹拌し、活性炭を濾過し、アセトン(13mL)と2-プロパノール(13mL)の混合液で活性炭を洗浄し、濾液を取得した。得られた溶液を40℃に昇温し、2-プロパノール(80mL)を添加し、tert-ブチルアミン(0.2g)とアセトン(1.3mL)と2-プロパノール(3mL)の混合液を添加した。続いて、tert-ブチルアミン(1.2g)を添加し、30分間撹拌後、0℃に冷却した。2時間撹拌し、得られた懸濁液を濾過し、結晶を冷却したアセトン(15mL)と冷却した2-プロパノール(15mL)の混合液で洗浄し、減圧下で40℃一晩乾燥することにより標記化合物のtBA1型結晶(9.8g)を得た。図2に粉末X線回折パターンを示し、表6に粉末X線回折スペクトルにおける回折角(2θ)、格子面間隔(d値)、および相対強度を記載する。
実施例7-1で得られた化合物(3g)にアセトン(21mL)と精製水(3mL)を加え、40℃で30分間撹拌して完溶させた。tert-ブチルアミン(0.1g)を15分間毎に3回添加し、標記化合物の結晶の析出を確認後、tert-ブチルアミン(0.1g)を添加した。5℃に冷却し30分間撹拌後、得られた懸濁液を濾過し、結晶を冷却したアセトン(1.5mL)と冷却した精製水(2.6mL)の混合液で洗浄し、減圧下で40℃一晩乾燥することにより標記化合物のP1型結晶(2.9g)を得た。図3に粉末X線回折パターンを示し、表7に粉末X線回折スペクトルにおける回折角(2θ)、格子面間隔(d値)、および相対強度を記載する。
実施例7-1で得られた化合物(20g)にアセトン(104mL)と2-プロパノール(104mL)を加え、30℃で30分間撹拌して完溶させた。活性炭(0.2g)を加えて30分間撹拌し、活性炭を濾過し、アセトン(26mL)と2-プロパノール(26mL)の混合液で活性炭を洗浄し、濾液を取得した。得られた溶液を40℃に昇温し、2-プロパノール(160mL)を添加し、tert-ブチルアミン(0.4g)とアセトン(2.6mL)と2-プロパノール(6mL)の混合液を添加した。続いて、tert-ブチルアミン(0.9g)を添加し、30分間撹拌後、得られた懸濁液を濾過し、結晶をアセトン(30mL)と2-プロパノール(30mL)の混合液で洗浄し、減圧下で40℃一晩乾燥することにより標記化合物のP2型結晶(17.7g)を得た。図4に粉末X線回折パターンを示し、表8に粉末X線回折スペクトルにおける回折角(2θ)、格子面間隔(d値)、および相対強度を記載する。
実施例7-1で得られた化合物(10g)にアセトン(52mL)と2-プロパノール(52mL)を加え、30℃で30分間撹拌して完溶させた。活性炭(0.1g)を加えて30分間撹拌し、活性炭を濾過し、アセトン(13mL)と2-プロパノール(13mL)の混合液で活性炭を洗浄し、濾液を取得した。得られた溶液を60℃に昇温し、2-プロパノール(80mL)を添加し、tert-ブチルアミン(0.5g)を添加した。1時間撹拌し、標記化合物の析出を確認後、tert-ブチルアミン(0.3g)を添加し、25℃に冷却して一晩撹拌した。得られた懸濁液を濾過し、結晶をアセトン(15mL)と2-プロパノール(15mL)の混合液で洗浄し、減圧下で40℃一晩乾燥することにより標記化合物のP3型結晶(7.2g)を得た。図5に粉末X線回折パターンを示し、表9に粉末X線回折スペクトルにおける回折角(2θ)、格子面間隔(d値)、および相対強度を記載する。
Claims (14)
- ルイス酸が、Mgイオン、Scイオン、Biイオン、Tiイオン、Laイオン、およびYbイオンから選ばれる1種の金属イオンを含むルイス酸である請求項1に記載の製造方法。
- ルイス酸が、Tiイオンを含むルイス酸である請求項1に記載の製造方法。
- ルイス酸が、Ti(OR)4である請求項1に記載の製造方法。(Rは、C1-C4アルキル基を示す。)
- 請求項7に記載の製造方法を用いて製造された式(VI)で示される化合物を、
tert-ブチルアミン を用いて塩化させる工程、ならびに
アセトンおよび2-プロパノールの混合溶液中で結晶化させる工程を含む、
式(VI)で示される化合物のtert-ブチルアミン塩の製造方法。 - モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および26.28±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するtBA1型結晶。
- モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.42±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するtBA2型結晶。
- モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および28.81±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP1型結晶。
- モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、3.04±0.2、9.08±0.2、18.23±0.2、24.38±0.2、24.66±0.2、および27.18±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP2型結晶。
- モノ(2-メチルプロパン-2-アンモニウム)=(2E)-3-(1-{[5-(2-フルオロプロパン-2-イル)-3-(2,4,6-トリクロロフェニル)-1,2-オキサゾール-4-イル]カルボニル}-3-メチル-1H-インドール-4-イル)プロパ-2-エノアートの結晶であって、銅のKα線(λ=1.54オングストローム)の照射で得られる粉末X線回折図において、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、および27.94±0.2から選択される回折角度(2θ)に、少なくとも3つのピークを有するP3型結晶。
- 請求項9に記載の結晶ないし請求項13に記載の結晶を有効成分として含有する医薬組成物。
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