WO2009154276A1 - スピロケタール誘導体の結晶およびその製造方法 - Google Patents
スピロケタール誘導体の結晶およびその製造方法 Download PDFInfo
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- WO2009154276A1 WO2009154276A1 PCT/JP2009/061226 JP2009061226W WO2009154276A1 WO 2009154276 A1 WO2009154276 A1 WO 2009154276A1 JP 2009061226 W JP2009061226 W JP 2009061226W WO 2009154276 A1 WO2009154276 A1 WO 2009154276A1
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- 0 CC1(C(*)C(*I)C(*I)C(C*)*1)c1c(C*)ccc(Cc2ccccc2)c1 Chemical compound CC1(C(*)C(*I)C(*I)C(C*)*1)c1c(C*)ccc(Cc2ccccc2)c1 0.000 description 1
- DLYCINLLALMWOI-AVGHQTNXSA-N CCc1ccc(CC(C2)=CC=C(CO3)C2[C@@]3([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 Chemical compound CCc1ccc(CC(C2)=CC=C(CO3)C2[C@@]3([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 DLYCINLLALMWOI-AVGHQTNXSA-N 0.000 description 1
- VWVKUNOPTJGDOB-BDHVOXNPSA-N CCc1ccc(Cc2cc([C@]([C@@H]([C@H]3O)O)(OC4)O[C@H](CO)[C@H]3O)c4cc2)cc1 Chemical compound CCc1ccc(Cc2cc([C@]([C@@H]([C@H]3O)O)(OC4)O[C@H](CO)[C@H]3O)c4cc2)cc1 VWVKUNOPTJGDOB-BDHVOXNPSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
Definitions
- the present invention relates to a process for the preparation of spiroketal derivatives, synthetic intermediates useful for the preparation of spiroketal derivatives, and crystalline substances of spiroketal derivatives.
- Patent Document 1 WO2006 / 080421A1
- Patent Document 1 discloses a method for producing a compound represented by Formula (A), and in Scheme 3 (Patent Document 1, page 24), after making a dibromobenzene derivative react with an alkyllithium reagent, The method of coupling with a lactone and further converting into a tin compound, followed by a coupling reaction in the presence of a palladium catalyst to obtain a target compound is described.
- a dihalotoluene derivative is n-BuLi. After treatment with s-BuLi, t-BuLi or Mg, etc., coupled with a lactone, and after several steps, converted to a tin compound and coupled with a benzyl halide derivative to obtain a target compound Is described.
- An object of the present invention is to provide an efficient and convenient method for industrially producing spiroketal derivatives used as an active ingredient of pharmaceuticals, and to provide useful synthetic intermediates, and storage stability as pharmaceuticals or pharmaceutical raw materials It is an object of the present invention to provide a crystal having excellent properties in terms of properties, ease of handling at the time of preparation and the like.
- the present inventors have found a method for regioselectively halogen-exchanging one of a plurality of halogen atoms on a benzene ring.
- the coupling reaction proceeds smoothly by passing through a novel organometallic compound which is easy to prepare as an intermediate, and according to this method, two successive coupling reactions are efficiently performed as a one-pot reaction. It is found that the present invention is possible.
- the present invention provides a method for producing a target spiroketal derivative without using heavy metals such as tin and organic transition metal complexes in carrying out carbon-carbon bond formation.
- the method using heavy metals such as tin and organic transition metal complexes requires a step of carefully removing the reagent that may contaminate as an impurity, whereas the production method does not require such a step. It is particularly excellent as an industrial process for producing pharmaceutical raw materials.
- the present inventors have found that the crystal form of the compound represented by the formula (I) and the process for producing the same, and that the crystal has excellent properties as a medicine or pharmaceutical raw material, and completed the present invention.
- X 1 and X 2 are each independently selected from a bromine atom and an iodine atom; P 1 is a metal ion, a hydrogen atom or a hydroxy protecting group; R 41 is a group already defined as R 1 , provided that the group may have one or more protecting groups; n is as already defined. Is treated with an organometallic reagent, and then the compound of formula (III):
- P 2 , P 3 , P 4 and P 5 are each independently selected from hydroxy protecting groups; or P 2 and P 3 , P 3 and P 4 , and P 4 and P 4 5 may be a divalent group which together form a ring by independently protecting each two hydroxy groups.
- R 41 , n, X 2 , P 1 , P 2 , P 3 , P 4 and P 5 are as defined above;
- P 6 is a metal ion, a hydrogen atom or a protecting group of a hydroxy group
- R 42 is a group already defined as R 2 , provided that the group may have one or more protecting groups, and m is as defined above] Reacting with the compound of And the step of introducing a protecting group, and / or removing the protecting group at any step during and / or before and / or after the above process is provided. .
- the method comprises Process c) Formula (VI):
- halogen atom as used herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
- C 1-10 alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl and s- Butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropylmethyl, cyclohexylmethyl and the like.
- C 1-10 alkyl further includes linear or branched C 1-6 alkyl, and C 1-4 alkyl.
- C 3-10 cycloalkyl means a cyclic alkyl group having 3 to 10 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl and the like.
- C 3-10 cycloalkyl further includes C 3-8 cycloalkyl and C 3-7 cycloalkyl.
- C 2-10 alkenyl means a linear or branched alkenyl group having 2 to 10 carbon atoms, and examples thereof include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl) and propene-2 -Yl, 3-butenyl (homoallyl), 1,4-pentadien-3-yl and the like.
- C 2-10 alkenyl further includes linear or branched C 2-6 alkenyl, and C 2-4 alkenyl.
- C 3-10 cycloalkenyl means a cyclic alkenyl group having 3 to 10 carbon atoms, and examples include cyclopentenyl, cyclohexenyl and the like, and C 5-10 cycloalkenyl and the like.
- C 2-10 alkynyl means a linear or branched alkynyl group having 2 to 10 carbon atoms, and includes, for example, ethynyl, 1-propynyl, 2-propynyl and the like.
- C 2-10 alkynyl further includes linear or branched C 2-6 alkynyl, and C 2-4 alkynyl.
- C 1-10 alkoxy refers to an alkyloxy group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methoxy, ethoxy, n-propoxy and i-propoxy , N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methyl pen Toxy, 3-methyl pentoxy, 2-methyl pentoxy, 1-methyl pentoxy, 3-ethyl butoxy, 2-ethyl butoxy and the like.
- C 1-10 alkoxy further includes linear or branched C 1-6 alkoxy, and C 1-4 alkoxy.
- C 1-10 alkylamino means an alkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methylamino, ethylamino and n-propylamino. And i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino and the like.
- C 1-10 alkylamino further includes linear or branched C 1-6 alkylamino, and C 1-4 alkylamino.
- di (C 1-10 alkyl) amino means a dialkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and the alkyl moieties may be the same.
- Di (C 1-10 alkyl) amino further includes linear or branched di (C 1-6 alkyl) amino, and di (C 1-4 alkyl) amino.
- C 1-10 alkylthio means an alkylthio group having a linear or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and examples thereof include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio and the like are included.
- C 1-10 alkylthio further includes linear or branched C 1-6 alkylthio, and C 1-4 alkylthio.
- saturated, partially unsaturated or unsaturated heterocyclyl as used herein is, for example, saturated, partially unsaturated, comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Or unsaturated 4 to 10 membered heterocyclic group is meant.
- heterocyclyl examples include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl and morpholinyl and the like.
- aryl is not particularly limited, but means an aryl group having an aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, and examples thereof include phenyl, 1-naphthyl and 2-naphthyl. And so on.
- heteroaryl means a 4- to 10-membered aromatic heterocyclic group, including but not limited to, for example, one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms.
- heteroaryl include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and the like.
- carrier as used herein is not particularly limited, but means a hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, and includes, for example, benzene, naphthalene and the like.
- heterocycle means a 4- to 10-membered heterocycle, including but not limited to, for example, one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. Do.
- heterocycles include pyridine, pyrimidine, pyrazine, triazine, quinoline, quinoxaline, quinazoline, furan, thiophene, pyrrole, pyrazole, imidazole, and triazole.
- the group defined as R 1 and R 2 has one or more protectable groups such as hydroxy, carboxy, carbonyl, amino, mercapto and the like, the group is protected by a protecting group It is also good.
- the selection of the protective group introduced into each group and the desorption operation can be carried out, for example, based on the description of "Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006)". .
- R 51 is each independently aryl optionally substituted by one or more R 56, C 1-10 alkoxy optionally substituted by one or more aryl, C 1-10 alkylthio, and aryl Selected from serenyl;
- R 52 is independently selected from C 1-10 alkoxy;
- R 53 and R 55 are each independently selected from C 1-10 alkyl and aryl;
- R 54 is a hydrogen atom, C 1-10 alkyl, aryl optionally substituted by one or more C 1-10 alkoxy, heteroaryl, amino optionally substitute
- Preferred examples of the hydroxy protecting group include methyl, benzyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiophenyl and 1-ethoxyethyl.
- the protecting group of the amino group which may be contained in R 1 and / or R 2 , C 1-10 alkyl optionally substituted by one or more R 51 , even substituted by one or more R 52 Good saturated, partially unsaturated or unsaturated heterocyclyl, C 2-10 alkenyl, —Si (R 53 ) 3 , —C (OO) R 54 and the like, wherein R 51 to R 54 are already As defined.
- R 51 to R 54 are already As defined.
- benzyl etc. are mentioned, Moreover, a primary amino group can also be converted and protected to a phthalimido group and a succinimide group.
- Examples of the protecting group of the carboxy group which may be contained in R 1 and / or R 2 include C 1-10 alkyl optionally substituted by one or more R 51 , C 2-10 alkenyl, -Si (R 53 An ester-forming group such as 3 (where R 51 and R 53 are as previously defined), or an amide-forming group such as -NR 58 R 59 (where R 58 and R 59 are each independently , C 1-10 alkyl optionally substituted by one or more R 51 , C 2-10 alkenyl, -Si (R 53 ) 3 , wherein R 51 and R 53 are as defined above A) etc.
- Preferred examples of the conversion of carboxy by the introduction of a protecting group include ethyl ester, benzyl ester, t-butyl ester and the like.
- Groups formed by introducing one or more protecting groups into groups defined as R 1 and R 2 are included in the definition of R 41 and R 42 .
- R 1 and R 2 defined in the present invention are not particularly limited, but for example, each is independently substituted by C 1-10 alkyl optionally substituted by one or more of Ra, one or more of Ra Optionally C 3-10 cycloalkyl, C 2-10 alkenyl optionally substituted by one or more Ra, C 3-10 cycloalkenyl optionally substituted by one or more Ra, one or more Ra C 2-10 alkynyl which may be substituted, aryl which may be substituted by one or more Ras, saturated, partially unsaturated or unsaturated heterocyclyl which may be substituted by one or more Ras, and -Selected from SiR 12 R 13 R 14 More preferably, R 1 and R 2 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and —SiR 12 R 13 R 14 . In the present invention, when n or m is 0, R 1 or R 2 is not present on the benzene ring respectively. In one aspect of the invention, n
- the halogen atom defined as R 1 and R 2 is preferably a fluorine atom or a chlorine atom.
- the metal ion defined in P 1 , P 6 and X means a metal ion which is a counter ion of alkoxide ion, and, for example, an alkali metal such as lithium ion, sodium ion, potassium ion, cesium ion, magnesium ion Ions, alkaline earth metal ions, etc. may be mentioned, and they may form complexes with other metals.
- the metal ions also include, for example, metal ions (eg, lithium ions) generated by causing an organometallic reagent used in the present invention to act on a hydroxy group.
- the “hydroxy protecting group” included in the definition of P 1 to P 6 is not particularly limited as long as it is a group generally used as a hydroxy protecting group.
- the selection of the protective group to be introduced into the hydroxy group and the introduction operation can be carried out, for example, based on the description of "Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006) .
- a divalent group that protects two hydroxy groups to form a ring is a divalent group that links the oxygen atoms of the two hydroxy groups, eg, C 1-10 alkylene.
- a group eg, methylene, methyl methylene, dimethyl methylene and the like
- a carbonyl group and the like are meant.
- the organometallic reagent used in the present invention is not particularly limited as long as it is an organometallic reagent suitable for performing a halogen transmetallation reaction on a benzene ring, and examples thereof include C 1-10 alkyllithium (eg, n-butyl) Lithium, s-butyllithium, t-butyllithium etc., aryllithium (eg phenyllithium, naphthyllithium, dimethoxyphenyllithium etc.), C 1-10 alkyl magnesium halide (eg n-butylmagnesium chloride, isopropylmagnesium chloride Etc.), di (C 1-10 alkyl) magnesium (eg, di (n-butyl) magnesium etc.) and the like.
- C 1-10 alkyllithium eg, n-butyl
- aryllithium eg phenyllithium, naphthyllithium, dimethoxypheny
- the organometallic reagent is used in the presence of an inorganic salt or an organic salt (eg, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, magnesium triflate, etc.) It may also be used as a mixture with inorganic or organic salts.
- an inorganic salt or an organic salt eg, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, magnesium triflate, etc.
- examples of the organometallic reagent include a mixture or reaction product of a magnesium compound and an organic lithium compound described in, for example, pages 11 to 17 of WO 2001/057046, for example, butyl magnesium chloride and butyl lithium, isopropyl magnesium Bromide and butyllithium, isopropylmagnesium bromide and lithium chloride, dibutylmagnesium and butyllithium, dibutylmagnesium and ethoxylithium, dibutylmagnesium and t-butoxylithium, dibutylmagnesium and lithium hexamethyldisilazide, butylmagnesium bromide and butyllithium, isopropyl Magnesium bromide and butyllithium and lithium chloride, butylmagnesium chloride and butyllithium and ethoxylithium, A mixture or reaction product of magnesium chloride and butyl lithium and lithium hexamethyl disilazide, isopropyl
- n-butyllithium is used as the organometallic reagent.
- the organometallic reagent may be used by sequentially reacting two or more kinds of reagents to form a metal complex. For example, after treating a compound represented by formula (II) with butyllithium, butylmagnesium chloride and butyllithium may be added to the system and then reacted with a compound represented by formula (III).
- the substituted silyl group specified by the formula -SiR 12 R 13 R 14 , the formula -SiR 23 R 24 R 25 , and the formula -Si (R 53 ) 3 in the present specification is not particularly limited. Triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl and the like.
- X 1 and X 2 are, for example, both bromine atoms.
- P 1 include, for example, lithium ion, hydrogen atom, and, for example, C 1-6 alkoxyC 1-6 alkyl (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-l) Methylethyl etc., arylmethyloxy C 1-6 alkyl (eg benzyloxymethyl etc.) tetrahydropyranyl, group -Si (R 53 ) 3 (eg trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethyl Examples include protecting groups such as silyl, t-butyldiphenylsilyl and the like), aralkyl (eg, benzyl, 4-methoxybenzyl, trityl and the like),
- the treatment of the compound of formula (II) with the organometallic reagent in step a) can be carried out using a solvent suitable for a halogen transmetallation reaction.
- the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and the like), hydrocarbons (for example, And pentane, hexane, heptane, benzene, toluene and the like), N, N-tetramethylethylenediamine, N, N-tetramethylpropanediamine, and a mixed solvent containing two or more of the above-mentioned solvents.
- ethers for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether,
- the organometallic reagent is 0.5 to 1.5 equivalents, for example, 0.8 to 1.1 equivalents, and when P 1 is a hydrogen atom, an organometallic reagent May use 1.5 to 3.0 equivalents, for example 1.8 to 2.2 equivalents.
- the organic metal reagent may be added little by little, for example, by dropping over 15 minutes or more, preferably 15 to 300 minutes, more preferably 30 to 300 minutes. You may add. Also, the addition of the organometallic reagent may be performed intermittently.
- the above addition time may include one or more interruption times, for example, two or three additions across one or two interruption times (eg, 5 to 300 minutes, preferably 15 to 120 minutes) It may be divided into
- a predetermined amount for example, 0.05 to 0.5 equivalents, preferably relative to the amount of the reaction substrate contained in the reaction mixture from the beginning (0.1 to 0.4 equivalents) of an aryl halide may be added to the reaction mixture.
- an aryl halide for example, iodobenzene, diiodotoluene, dibromotoluene, and a reaction substrate (eg, 2,4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene etc.), preferably a reaction substrate Can be used.
- the organometallic reagent is, for example, added little by little (for example, dropwise Can be added.
- the reaction may be completed by stirring at an appropriate temperature, for example, -80 to 0 ° C, preferably -15 to 0 ° C, for a certain time (for example, 0.1 to 5 hours) .
- the organometallic reagent is added in an amount of less than 1 equivalent, for example 0.4 to 0.9 equivalent, preferably 0.8 equivalent.
- a suitable temperature for example, -80 to 30 ° C, preferably -60 to 25 ° C, especially -15 to 0 ° C, for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2
- the reaction mixture may be stirred for a period of time, and then an additional organometallic reagent is added, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, for example, -80 to 30 ° C., preferably -60 to
- the reaction mixture may be stirred at 25 ° C., in particular at ⁇ 15 to 0 ° C., for a certain time, for example 0.1 to 5 hours, preferably 0.5 to 2 hours.
- the number of equivalents represents a molar equivalent to the compound of the formula (II) which is a reaction substrate.
- "equivalent” means molar equivalent unless otherwise stated.
- the organometallic reagent is suitably added by adding less than 2 equivalents, for example 1.4 to 1.9 equivalents, preferably 1.8 equivalents.
- the reaction is carried out at a temperature, for example, -80 to 30 ° C, preferably -60 to 25 ° C, particularly -15 to 0 ° C, for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours.
- the mixture may be stirred, and then an additional organometallic reagent is added, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, for example, -80 to 30 ° C, preferably -60 to 25 ° C,
- the reaction mixture may be stirred at ⁇ 15 to 0 ° C. for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours.
- the number of equivalents represents a molar equivalent to the compound of the formula (II) which is a reaction substrate.
- a halogen transmetalation reaction occurs preferentially in X 1 of the compound of the formula (II) having a plurality of reaction points, and as a result, byproducts derived from the halogen transmetalation reaction in X 2 This gives a greater amount of the desired compound of formula (IVa).
- the reaction is a regioselective reaction.
- the regioselectivity in step a) is not particularly limited, for example, the ratio of target product: byproduct is 10: 1 or more, preferably 30: 1 or more.
- C 1-10 alkyllithium eg, n-butyllithium, s-butyllithium or t-butyllithium etc.
- aryllithium eg, phenyllithium, naphthyllithium, dimethoxyphenyllithium etc.
- another type of organometallic reagent such as n-butylmagnesium chloride and n-butyllithium or dibutylmagnesium
- the complex may be formed after stirring the reaction mixture at -60 to 25 ° C., particularly at -15 to 0 ° C., for a fixed time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours .
- step a compounds of formula (II) are used in step a), wherein P 1 is a hydrogen atom.
- examples of P 2 , P 3 , P 4 and P 5 include, for example, C 1-6 alkoxy C 1-6 alkyl (eg, methoxymethyl, ethoxymethyl 1-methoxyethyl, 1-methoxy-1-methylethyl, etc., arylmethyloxy C 1-6 alkyl (eg, benzyloxymethyl etc.), tetrahydropyranyl, group -Si (R 53 ) 3 (eg, trimethylsilyl) , Triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl etc., aralkyl (eg benzyl, 4-methoxybenzyl, triphenylmethyl etc.), group -B (OR 55 ) 2 , C 1 -6 alkyl carbonyl (eg, acetyl, propion
- P 4 and P 5 are combined to protect two hydroxy groups to form a ring (eg, —CH 2 —, —CH (CH 3 ) —, —C (CH 3) 2 )-, -CHPh-, etc. may be used.
- Reaction of a compound of formula (II) treated with an organometallic reagent with a compound of formula (III) can be carried out, for example, by reacting a solution of the compound of formula (II) in a suitable solvent at a suitable temperature, for example Into a reaction mixture containing a compound of formula (III) (for example 1.0 to 1.1 equivalents) at a temperature of -0 ° C, preferably -90 to -30 ° C, especially -80 to -40 ° C (Dropwise) can be added.
- a compound of formula (III) for example 1.0 to 1.1 equivalents
- Suitable solvents include, for example, ethers (eg, tetrahydrofuran (THF), methyl tetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbons And the like (eg, hexane, heptane, benzene, toluene, etc.) and mixed solvents containing two or more of the above-mentioned solvents.
- the reaction may be completed by stirring at an appropriate temperature, for example, ⁇ 80 to ⁇ 40 ° C. for a certain period of time (for example, 0.5 to 5 hours).
- the reaction can be post-treated by a conventional method, and the resulting product can be purified by a conventional method to give a compound of the formula (IVa), but simplification of the production process, solvent used From the viewpoint of suppression of the amount, suppression of the production cost, etc., it is preferable to carry out the following step without post-treatment of the present reaction.
- the production method of the present invention may include the step of introducing a protecting group into the compound of formula (IVa) to obtain a compound of formula (IVb) in which P 6 is a protecting group of hydroxy group.
- the introduction of the protective group in the step may be carried out, for example, by adding a compound of the formula (II) treated with an organometallic reagent to the compound of the formula (III), a reagent for introducing the protective group into the reaction mixture (eg, 1.0 to 2.0 equivalents) and, if necessary, an appropriate amount (for example, 0.1 to 1.0 equivalents) of a base such as triethylamine, N-methylmorpholine, ethyldiisopropylamine etc.
- a base such as triethylamine, N-methylmorpholine, ethyldiisopropylamine etc.
- the reaction may be completed by stirring for a certain period of time (for example, 0.1 to 5 hours).
- silylating agents such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and the like, methyl iodide, benzyl bromide alkyl halides such as acid halide, such as pivaloyl chloride, methoxymethyl chloride, a C 1-6 alkoxy C 1-6 alkyl halide such as ethoxymethyl chloride.
- silylating agents such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and the like, methyl iodide, benzyl bromide alkyl halides such as acid halide, such as pival
- step b) a compound of (IVb) is used wherein P 6 is a protecting group of a hydroxy group.
- the protective group introduction reaction can be post-treated by a conventional method, and the resulting product can be purified by a conventional method to give a compound of the formula (IVb).
- Treatment of the compound of formula (IVb) with the organometallic reagent in step b) may be carried out using a solvent suitable for halogen transmetallation.
- the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane and the like), hydrocarbons (for example, And pentane, hexane, heptane, benzene, toluene and the like, and mixed solvents containing two or more of the above-mentioned solvents.
- the solvent of the previous step can be used as it is.
- the organometallic reagent can be used in an amount of 0.3 to 4.0 equivalents, for example, 1.0 to 3.0 equivalents, preferably 1.1 to 2.1 equivalents.
- the organometallic reagent can be added in small portions (for example, dropwise) to the system at a temperature of, for example, -100 to 30 ° C, preferably -90 to -10 ° C, especially -90 to -70 ° C. .
- a temperature for example, -100 to 30 ° C, preferably -90 to -10 ° C, especially -90 to -70 ° C.
- the reaction may be stirred, preferably for 0.5 to 2 hours.
- the reaction of a compound of formula (IVb) with a compound of formula (V) treated with an organometallic reagent can be carried out, for example, by reacting a solution of the compound of formula (V) in a suitable solvent under suitable temperature, for example C., preferably -90 to -10.degree. C., in particular -80 to -70.degree. C., by adding it to the reaction mixture containing the compound of formula (IVb).
- the compound of the formula (V) can be used in an amount of 1.0 to 15.0 equivalents, for example, 1.0 to 5.0 equivalents, preferably 1.1 to 2.2 equivalents.
- Suitable solvents include, for example, ethers (eg, tetrahydrofuran (THF), methyl tetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbons And the like (eg, pentane, hexane, heptane, benzene, toluene, etc.), and mixed solvents containing two or more of the aforementioned solvents.
- the reaction may be completed by stirring at a suitable temperature, for example, -90 to 0 ° C., for a fixed time (for example, 0.1 to 5 hours).
- step b) can be worked up by conventional techniques and the resulting product can be purified by conventional procedures to give compounds of formula (VI). From the viewpoint of simplification of the production process, suppression of the amount of solvent used, suppression of the production cost, etc., it is preferable to carry out the next step without particularly purifying the crude product obtained by post-treatment.
- step c) when P 1 is a protecting group for a hydroxy group, deprotection is carried out before step (1) of step c) to convert the compound into a compound wherein P 1 is a hydrogen atom .
- said deprotection also removes the protecting groups introduced as P 2 -P 6 .
- Deprotection can be carried out by methods known in the art, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, tri odor Acids or Lewis acids such as borohydride; bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate; organometallic reagents such as butyllithium, Grignard reagents; lithium aluminum hydride, lithium boron hydride, hydrogen Metal hydride reagents such as diisobutylaluminum halide; boron trifluoride diethyl etherate complex-ethanethiol, aluminum halide-sodium iodide, aluminum halide-thiol, aluminum halide-sulfide, etc.
- bases such as sodium hydroxide, lithium hydroxide, potassium hydrox
- step (1) forms a spiro ring structure.
- the reaction of step (1) can be carried out using a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Methyl pyrrolidone, acetone, acetic acid ester (eg, ethyl acetate, methyl acetate, isopropyl acetate etc.), methylene chloride, chloroform, dichloroethane, water, or a mixed solvent containing two or more of the above solvents at an appropriate temperature, for example, It can be carried out at ⁇ 20 to 100 ° C., preferably 0 to 80 ° C., in particular 20 to 30 ° C.
- a suitable solvent such as tetrahydrofuran (THF), methyltetra
- the reaction time can be set appropriately, and is, for example, about 0.5 to 15 hours, preferably about 2 to 10 hours.
- the acid which can be used is not particularly limited, and a Lewis acid may be used. Specific examples thereof include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, boron tribromide and the like.
- the treatment under the acidic conditions of step (1) can simultaneously remove the protecting group introduced as P 1 to P 6 and form the spiro ring.
- the reduction reaction in step (2) of step c) may be carried out using a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetic acid ester (eg, ethyl acetate, methyl acetate) (Eg, isopropyl acetate), acetone, water, or a mixed solvent containing two or more of the above-mentioned solvents under an appropriate temperature, for example, ⁇ 80 to 80 ° C., preferably ⁇ 30 to 70 ° C., particularly ⁇ 20 to 60 ° C.
- a suitable solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetic acid ester (eg, ethyl acetate, methyl acetate) (Eg
- the reaction time can be set appropriately, and is, for example, about 0.5 to 24 hours, preferably about 5 to 15 hours.
- the reduction reaction is not particularly limited as long as it uses a suitable reducing agent and / or catalyst to remove the hydroxy group on the carbon atom linking the two benzene rings of the compound of formula (VI).
- metal catalysts under hydrogen atmosphere eg, palladium supported on carbon, platinum, homogeneous palladium complex, homogeneous ruthenium complex, homogeneous rhodium complex
- hydride type reducing agent combined with Lewis acid eg aluminum chloride-hydrogen
- Lewis acid eg aluminum chloride-hydrogen
- Sodium borohydride borohydride, trifluoroacetic acid-triethylsilane
- the reduction reaction of step (2) can simultaneously remove the protecting group introduced to P 1 to P 6 and removing the hydroxy group. Any of steps (1) and (2) in step c) may precede, and if deprotection of P 1 or P 1 to P 6 is performed, any step prior to step (1) may be performed. Can be done with
- the production method of the present invention may further include the step of removing any protective group contained in the compound obtained in step c), and the compound of formula (I) obtained by the production method of the present invention May be further converted to another compound of formula (I).
- steps a) and b) can be carried out by a so-called one-pot reaction, that is, sequentially adding necessary reagents and the like without performing post-treatment or purification. Therefore, the production method of the present invention is capable of simplifying the production process, suppressing the amount of solvent used, and suppressing the production cost, etc., by performing the one-pot reaction, in addition to obtaining the desired product in a good yield. It is also very good in that it can be
- the “hydroxy protecting group” defined as P 7 is not particularly limited as long as it is a group generally used as a hydroxy protecting group, and examples thereof include “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(No. 4), John Wiley & Sons, 2006).
- P 7 is selected from C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, -SiR 23 R 24 R 25 and R 23 , R 24 and R 25 are as defined above. As you did.
- the protecting group introduction reaction of step d) can be carried out by methods known in the art, for example, “Greene and Wuts,” Protective Groups in Organic Synthesis “(4th edition, John Wiley & Sons 2006).
- the solvent used in the reaction include ethers (eg, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane etc.), hydrocarbon (Eg, benzene, toluene etc.), acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetone, acetate (eg, ethyl acetate, methyl acetate, isopropyl acetate etc.), chloride
- reagents for introducing the protective group can be selected, and examples thereof include C 1-6 alkylcarbonyl chloride, C 1-6 alkoxycarbonyl chloride, Cl-SiR 23 R 24 R 25 and the like.
- the amount can be 1.0 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to the hydroxyl group, and a base may be used as needed.
- bases examples include triethylamine, pyridine, N, N-dimethylaniline, 4- (dimethylamino) pyridine, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, morpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Can be mentioned. Preferably, 1-methylimidazole may be used.
- the reaction temperature is not particularly limited, but may be, for example, -20 to 50 ° C, preferably -10 to 25 ° C, and the reaction may be stirred for a predetermined time, for example, 1 to 10 hours, preferably 2 to 4 hours. Good.
- the crystallization in step e) may be carried out by using a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxymethane Ethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene or water, or a mixed solvent containing two or more of the above solvents Can be done.
- a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl
- recrystallization in this step may be carried out using a suitable solvent, such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxymethane Ethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene or water, or a mixed solvent containing two or more of the above solvents Can be carried out by methods known in the art.
- a suitable solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, is
- Deprotection can be carried out by selecting methods known in the art depending on the protecting group to be removed, for example, “Greene and Wuts,” Protective Groups in Organic Synthesis “(4th Edition, John Wiley & Sons 2006). Year) can be used.
- acid or Lewis acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, etc .
- sodium hydroxide, lithium hydroxide, water Bases such as potassium oxide and potassium carbonate
- Organometallic reagents such as butyllithium and Grignard reagents
- Metal hydride reagents such as lithium aluminum hydride, lithium boron hydride and diisobutylaluminum hydride
- Boron trifluoride diethyl etherate complex-ethanethiol Combination reagent of Lewis acid and nucleophile such as aluminum halide-sodium iodide, aluminum halide-thiol, aluminum halide-sulfide; carbon-supported palladium, platinum, homogeneous palladium complex, homo
- the crude product obtained by the process comprising steps a) to c) as defined herein is used as a compound of formula (I) in step d). Since the above steps a) to c) can produce the target without purification, it is possible to combine the steps d) to f), which can perform a high degree of purification, in the efficiency of production. From the point of view of Steps d) to f) may also be combined with other methods for the preparation of compounds of formula (I).
- high purity means that the purity is improved compared to the compound of the formula (I) used as a raw material of step d).
- a compound of formula (I) having a purity of 90.0% by weight or more, preferably 97.0% by weight or more can be mentioned.
- the process of the invention comprises the step of further crystallizing the compound of formula (I) of high purity obtained in step f).
- the solvent used in the crystallization for example, water, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1-hexanol), ethers (eg, tetrahydrofuran, t-butyl methyl ether, Cyclopentyl methyl ether, 1,2-dimethoxyethane, diisopropyl ether), esters (eg, ethyl acetate, propyl acetate, hexyl acetate), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N -Methylpyrrolidone, N, N-dibutylformamide), halogenated hydrocarbons (eg, 1-chlorohexane), hydro
- the compound of formula (I) obtained may be further purified by recrystallization.
- a solvent that can be used for recrystallization for example, water, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol or 1-hexanol), ethers (eg, tetrahydrofuran, t-butyl methyl ether, cyclopentyl) Methyl ether, 1,2-dimethoxyethane or diisopropyl ether), esters (for example, ethyl acetate, propyl acetate or hexyl acetate), amides (for example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or N, N-dibutylformamide), halogens (eg 1-chlorohexane), hydrocarbons (eg n-propylbenzene, he
- highly pure compounds of formula (I) are prepared, wherein n is 0, m is 0 or 1, and R 2 is C 1-4 alkyl.
- crystals of the compound of formula (I) of high purity are prepared, wherein n is 0, m is 0 or 1, and R 2 is C 1-4 alkyl.
- the production method of the present invention including the above steps d) to f) is complicated in operation and requires a large amount of solvent and adsorbent, without performing purification methods such as column chromatography and the like.
- the compound of the present invention can be produced, which is useful from the viewpoint of improving the efficiency of the production method and suppressing the production cost.
- a method for efficiently removing impurities from a compound used as a pharmaceutical is very important, and the production method of the present invention is also useful for stably providing a safe pharmaceutical.
- the crystals are monohydrate.
- the monohydrate is not particularly limited as long as it is a crystal that stably holds about 1 equivalent of water under the environment (temperature, relative humidity, etc.) in which the pharmaceutical product is usually stored and used.
- the crystals are provided as sodium acetate co-crystal or potassium acetate co-crystal.
- a monohydrate crystal of a compound of formula (XI) of high purity is provided.
- the sodium acetate co-crystal of the present invention has a powder X-ray diffraction pattern of 4.9 °, 14.7 °, 16.0 °, 17.1 ° and around 19.6 °, more specifically 4.9. °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 And a peak at a diffraction angle (2 ⁇ ) around 22.0 °.
- the potassium acetate co-crystal of the present invention has a powder X-ray diffraction pattern of 5.0 °, 15.1 °, 19.0 °, 20.1 ° and 25.2 °, more specifically 5.0 °.
- Diffraction angles around 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 °, and 25.2 ° It is characterized by having a peak at (2 ⁇ ).
- the powder X-ray diffraction pattern can be measured by a conventional method.
- the value of the diffraction angle of the powder X-ray diffraction peak of the crystal of the present invention is expected to have an error depending on the measurement conditions and the state of the sample. For example, an error of about ⁇ 0.2 is expected.
- the monohydrate crystal of the present invention is a crystal from water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, and a mixed solvent of 1,2-dimethoxyethane and water Can be obtained by
- the sodium acetate co-crystals of the present invention are, for example, methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, propyl acetate, hexyl acetate, 2-butanone, 2-heptanone, n-propylbenzene, hexylbenzene, and 1-chloro It can be obtained by crystallization from a solvent selected from hexane or a mixed solvent of two or more of the solvents, preferably from a mixed solvent of methanol and isopropanol.
- the potassium acetate co-crystals of the present invention may be prepared, for example, from a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, N, N-dibutylformamide, acetone and diisopropyl ether, or of two or more such solvents. It can be obtained from a mixed solvent, preferably from a mixed solvent of methanol and isopropanol.
- the monohydrate crystal of the present invention has the property that the water content becomes almost constant under a certain range of relative humidity, and the handling of the compound in the preparation process is easy.
- the monohydrate crystals, sodium acetate co-crystal and potassium acetate co-crystal of the present invention are also useful for producing a pharmaceutical preparation having good storage stability.
- the monohydrate crystal, sodium acetate co-crystal, and potassium acetate co-crystal of the present invention can be used to efficiently and highly purify the compound of formula (XI), and a pharmaceutical comprising the compound It is also useful from the viewpoint of efficient production of
- FIG. 1 is an example of the measurement result of the water adsorption isotherm measured in Test Example 1.
- FIG. 2 is an example of the measurement results of powder X-ray diffraction of monohydrate crystals measured under measurement condition 1 of Test Example 5.
- FIG. 3 is an example of the measurement results of powder X-ray diffraction of monohydrate crystals measured under measurement condition 2 of Test Example 5.
- FIG. 4 is an example of the measurement result of powder X-ray diffraction of the amorphous body measured in Test Example 5.
- FIG. 5 is an example of the measurement result of powder X-ray diffraction of sodium acetate co-crystal measured in Test Example 5.
- FIG. 6 is an example of the measurement result of powder X-ray diffraction of potassium acetate co-crystal measured in Test Example 5.
- NMR was measured using a nuclear magnetic resonance apparatus JNM-ECP-500 (manufactured by JEOL) or JNM-ECP-400 (manufactured by JEOL).
- Mass spectrometry was measured using a mass spectrometer LCT Premier XE (manufactured by Waters).
- Preparative high performance liquid chromatography used the GL Science preparative system.
- Agilent 1100 manufactured by Agilent
- the water content was measured using a KF analyzer type KF-100 (a trace water content measuring device manufactured by Mitsubishi Chemical Corporation).
- Trimethylsilyl chloride 29.1 kg was added to a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) at 40 ° C. or less After that, the mixture was stirred at 30 to 40 ° C. for 2 hours. The solution was cooled to 0 ° C., toluene (34 kg) and water (39 kg) were added and the organic layer was separated. The organic layer was washed twice with a 5% aqueous sodium dihydrogen phosphate solution (39.56 kg) and once with water (39 kg), and the solvent was evaporated under reduced pressure to give the title compound as an oil. The product was used in step 3 below without further purification.
- Step 2 Synthesis of 2,4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene
- Step 3 2,3,4,5-Tetrakis (trimethylsilyloxy) -6-trimethylsilyloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) Synthesis of phenyl) tetrahydropyran
- this solution is made up of 3,4,5-tris (trimethylsilyloxy) -6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol)
- the solution was added dropwise to a tetrahydrofuran solution (507 ml) at -78.degree. C. and stirred at the same temperature for 2 hours.
- Triethylamine (5.8 ml, 41 mmol) and trimethylsilyl chloride (29.6 ml, 232 mmol) are added to this solution, the temperature is raised to 0 ° C., and the mixture is stirred for 1 hour to give 2,3,4,5-tetrakis (trimethylsilyloxy)-
- a solution containing 6-trimethylsilyloxymethyl-2- (5-bromo-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran was obtained.
- Step 4 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
- the aqueous layer was further washed twice with n-heptane (693 ml), and the water was evaporated under reduced pressure to give an oil containing water and the title compound (diastereomer mixture) (187 g).
- the product was used in the next step without further purification.
- Step 5 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (crude product)
- the organic layer was washed 3 times with a 3% aqueous potassium hydrogen sulfate solution-20% aqueous sodium chloride solution, washed with a 20% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Ethanol (943 ml) was added to the obtained residue, and the mixture was heated to 75 ° C. to dissolve the residue. After cooling to 60 ° C. and adding seed crystals of the title compound, the mixture was cooled to room temperature and stirred for 1 hour. After confirming the solid precipitation, water (472 ml) was added, and the mixture was stirred at room temperature for 2 hours.
- Step 7 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
- the removed organic layer was washed with 25% aqueous sodium chloride solution (40 kg), and the solvent was evaporated under reduced pressure.
- the purity of the obtained residue was calculated as the ratio of the area measured by high performance liquid chromatography to be 98.7%.
- Acetone (32.0 kg) and water (0.8 kg) were added to the residue, and the solvent was evaporated under reduced pressure.
- Acetone (11.7 kg) and water (15.8 kg) were added to the residue to dissolve, and the solution was cooled to 5 ° C. or less. After adding water (64 kg) to this solution at 10 ° C. or less and stirring at 10 ° C. or less for 1 hour, the obtained crystals are centrifuged and mixed with acetone (1.3 kg) and water (8.0 kg) It was washed.
- This wet powder is dried by passing through for 8 hours under the conditions of passing temperature of 13 to 16 ° C and relative humidity of 24 to 33%, and the title compound (3.94 kg) is crystallized from monohydrate (water content: 4.502%) Got as.
- the purity of the obtained compound was calculated as the ratio of the areas measured by high performance liquid chromatography to be 99.1%.
- reaction mixture is subjected to workup, and the resulting residue is purified by high performance liquid chromatography (column; Inertsil ODS-3, 20 mm ID ⁇ 250 mm; acetonitrile, 30 mL / min) to give the title compound 2 Isolated as a class of diastereomers.
- Diastereomer 5 1 H-NMR (500 MHz, CDCl 3 ) ⁇ : -0.30 (9 H, s), 0.095 (9 H, s), 0.099 (9 H, s), 0.16 (9 H, s), 0 17 (9H, s), 1.41 (3H, s), 1.43 (3H, s), 3.20 (3H, s), 3.37-3.44 (2H, m), 3.
- Tetrahydrofuran (154 kg) was added to the residue and the solvent was evaporated under reduced pressure, and then tetrahydrofuran (154 kg) was added again and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (253 kg) to give the title compound as a tetrahydrofuran solution.
- the purity was calculated from the area ratio measured by high performance liquid chromatography, the purity was 99.0% (conversion rate 99.1%).
- High performance liquid chromatography measurement condition column YMC-Pack ODS-AM 4.6 mm I. D. ⁇ 150 mm, 3 ⁇ m (WEM)
- Mobile phase A liquid: 2 mM AcONH 4 / H 2 O, B liquid: 50% (v / v) MeCN / MeOH Gradient operation: Solution B: 50% to 95% (15 minutes), 95% hold (15 minutes), 95% to 100% (5 minutes) 100% (15 minutes)
- Flow rate 1.0 ml / min Column temperature: 40 ° C.
- the reaction mixture was added to 20% aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with water and the solvent was evaporated under reduced pressure to give an oil containing the title compound (879 g). The product was used in the next step without further purification.
- Step 3 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
- the organic layer was washed with 10% aqueous potassium hydrogen sulfate-5% aqueous sodium chloride solution (800 ml). Subsequently, the organic layer was washed twice with a 20% aqueous sodium chloride solution (800 ml), and the solvent was evaporated under reduced pressure. To the resulting residue were added ethanol (1200 ml), t-butyl methyl ether (200 ml) and 2-propanol (130 ml). The mixture was heated to 74 ° C. to dissolve the residue, then cooled to 55 ° C. and stirred for 1 hour. After confirming the solid precipitation, the solution was cooled from 55 ° C. to 25 ° C. over 1.5 hours.
- Step 5 Synthesis of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose
- the organic layer was washed with 18% aqueous sodium dihydrogen phosphate dihydrate-12% aqueous solution of disodium hydrogen phosphate dihydrate (410 ml), and then ethyl acetate (410 ml) was added.
- the organic layer was washed twice with 25% aqueous sodium chloride solution (410 ml), and the solvent was evaporated under reduced pressure.
- Acetone (410 ml) and water (8.2 ml) were added to the residue, and the solvent was evaporated under reduced pressure.
- Acetone (164 ml) and water (655 ml) were added to the obtained residue, and the temperature was raised to 28 ° C. to dissolve the residue.
- the mixture was cooled to 25 ° C., and after adding seed crystals (82 mg) of the title compound, it was cooled from 25 ° C. to 20 ° C. over 24 minutes and stirred at 20 ° C. for 1 hour. After confirming the solid precipitation, the temperature was raised to 25 ° C., and the mixture was stirred at 25 ° C. for 1 hour. Subsequently, it was cooled from 25 ° C. to ⁇ 5 ° C. over 2.4 hours, and the crystals were filtered. Water (246 ml) was added to the obtained crystals, and after stirring for 1 hour at 4 ° C., the crystals were filtered.
- the resulting wet powder is dried under reduced pressure for 20 minutes (pressure: 1 hPa, outside temperature: 20-25 ° C.) to reach a moisture content of 8.249%, and subsequently dried for 30 minutes under reduced pressure ( Pressure: 25 hPa, external temperature: 20-25 ° C.) to give the title compound (44 g, yield 82%) as monohydrate crystals (water content: 4.470%).
- the purity of the obtained compound was calculated as the ratio of the areas measured by high performance liquid chromatography to be 99.9%.
- Example 8 Preparation of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose sodium acetate co-crystal 1,1 -Anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose monohydrate crystal (200 mg) and sodium acetate (40 mg) in methanol After dissolving in (1 ml) at 80 ° C. and cooling to room temperature, isopropanol (2 ml) was added.
- the seed crystals used in the above preparation were obtained by the following method. Hydrate crystals of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (8 mg) and sodium acetate (2 mg) ) was dissolved in methanol (0.1 ml) at 80 ° C. The solvent was completely evaporated from the solution at 80 ° C. to obtain the desired crystalline substance.
- isopropanol (2 ml) was added. After distilling off the solvent (about 2 ml) under reduced pressure, seed crystals of the title co-crystal are added and stirred at room temperature overnight, and the precipitated crystals are collected by filtration, washed with isopropanol (4 ml) and dried. The title co-crystal (melting point about 176 ° C.) was obtained.
- the seed crystals used in the above preparation were obtained by the following method. Hydrate crystal of 1,1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl] - ⁇ -D-glucopyranose (8 mg) and potassium acetate (2 mg) ) was dissolved in methanol (0.1 ml) at 80 ° C. The solvent was completely evaporated from the solution at 80 ° C. to obtain the desired crystalline substance. The melting point was measured in the same manner as in Example 7. [Test Example 1] Measurement of water adsorption isotherm of monohydrate crystal Formula (XI):
- the water adsorption isotherm was measured as follows using a dynamic water adsorption isotherm: DVS-1 (Surface Measurement Systems) for monohydrate crystals of the compound of
- the monohydrate crystal (about 10 mg, water content 4.5%) of the said compound ground on a sample pan was accurately weighed and used as a measurement sample.
- An empty sample pan served as a control sample.
- Set the measurement sample and control sample in the device 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0% at a constant temperature around 25 ° C
- the relative humidity (RH) was changed in order, and the mass change of the measurement sample was measured.
- the measurement results are shown in FIG. It has been found that the compounds of the formula (XI) are stably present in the monohydrate in the range of 10-90% relative humidity.
- Test Example 2 Storage stability test of monohydrate crystal The storage stability test was conducted using the monohydrate crystal of the compound of the formula (XI) of the present invention and the amorphous of the compound.
- the monohydrate crystal of the compound of formula (XI) was produced according to the method described in step 7 of Example 1.
- the amorphous of the compound of formula (XI) was prepared by the following method. Monohydrated crystal (15 g) of the compound is heated on a hot stage, and after melting, it is allowed to cool at room temperature in a humidity controller (25 ° C./dry), and solidified by grinding in a mortar. The sample was used as a sample. Each sample was stored in a thermostat set at 25 ° C. and 40 ° C., and the purity of the sample was confirmed after one month, three months and six months.
- the purity was confirmed by the following procedure.
- the sample (about 6 mg) was weighed, dissolved in a water / methanol mixture (1: 1) to make exactly 10 mL, and used as a sample solution.
- Each prepared solution (10 ⁇ L) was subjected to HPLC analysis under the following conditions, and the total amount of impurities was calculated according to the following equation.
- Test Example 3 Storage Stability Test of Sodium Acetate Co-Crystal Using the sodium acetate co-crystal of the compound of the formula (XI) of the present invention, a storage stability test was conducted according to the method of Test Example 2. Sodium acetate co-crystal of the compound of formula (XI) was prepared according to the method described in Example 5. The samples were stored in thermostatic baths set at 25 ° C. and 40 ° C., and the purity of the samples was confirmed after 1 and 3 months. The obtained measurement results were compared with the amorphous results obtained in Test Example 2.
- Test Example 4 Storage Stability Test of Potassium Acetate Co-Crystal Using the potassium acetate co-crystal of the compound of the formula (XI) of the present invention, a storage stability test was conducted according to the method of Test Example 2. Potassium acetate co-crystal of the compound of formula (XI) was prepared according to the method described in Example 6. The samples were stored in thermostatic baths set at 25 ° C. and 40 ° C., and the purity of the samples was confirmed after 1 and 3 months. The obtained measurement results were compared with the amorphous results obtained in Test Example 2.
- Test Example 5 Powder X-Ray Diffraction Measurement Powder X-ray diffraction of a monohydrate crystal, amorphous, sodium acetate co-crystal and potassium acetate co-crystal of the compound of formula (XI) was measured. The measurement conditions are shown below.
- Measurement condition of monohydrate crystal (measurement condition 1) Measuring device: RINT1100 (manufactured by Rigaku) Anticathode: Cu Tube voltage: 40kV Tube current: 40 mA Scanning speed: 2.000 ° / min Sampling width: 0.020 ° Divergence slit: 1 ° Scattering slit: 1 ° Light receiving slit: 0.15 mm Scanning range: 3 to 35 ° Measurement condition of monohydrate crystal (measurement condition 2) Measuring device: X'Pert-Pro MPD (manufactured by PANalytical) Anticathode: Cu Tube voltage: 45kV Tube current: 40 mA Scanning method: Continuous Step width: 0.017 Scanning axis: 2 ⁇ Sampling time per step: 30 seconds Scanning range: 2 to 35 ° Measurement condition measuring device for amorphous : RINT 1100 (manufactured by Rigaku) Anticathode: Cu Tube voltage: 40k
Abstract
Description
R1およびR2は、それぞれ独立に、1以上のRaにより置換されていてもよいC1-10アルキル、1以上のRaにより置換されていてもよいC3-10シクロアルキル、1以上のRaにより置換されていてもよいC2-10アルケニル、1以上のRaにより置換されていてもよいC3-10シクロアルケニル、1以上のRaにより置換されていてもよいC2-10アルキニル、1以上のRaにより置換されていてもよいアリール、1以上のRaにより置換されていてもよい飽和、部分不飽和、または不飽和のへテロシクリル、シアノ、ハロゲン原子、ニトロ、メルカプト、-OR3、-NR4R5、-S(O)pR6、-S(O)qNR7R8、-C(=O)R35、-CR36=NOR37、-C(=O)OR9、-C(=O)NR10R11、および-SiR12R13R14から選択され;nが2以上の場合、R1はそれぞれ同一であっても、異なっていてもよく;mが2以上の場合、R2はそれぞれ同一であっても、異なっていてもよく;または、隣接する炭素原子上に存在する2つのR1は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;隣接する炭素原子上に存在する2つのR2は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;
pは、0~2から選択される整数であり;qは、1および2から選択される整数であり;
R3は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R4およびR5は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R6は、C1-10アルキル、C3-10シクロアルキル、アリール、またはヘテロアリールであり、ただし、pが0の場合、R6はさらに-SiR12R13R14、または-C(=O)R15であってもよく;
R7、R8、R10およびR11は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R9は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、または-SiR12R13R14であり;
Raは、それぞれ独立に、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、ヒドロキシ、ハロゲン原子、-NR21R22、-OR38、-SR26、-S(O)2R27、-SiR23R24R25、カルボキシ、-C(O)NR28R29、-C(=O)R30、-CR31=NOR32、シアノ、および-S(O)rNR33R34から選択され;
rは、1および2から選択される整数であり;
R12、R13、R14、R23、R24、およびR25は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R15およびR30は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、C1-10アルキルアミノ、ジ(C1-10アルキル)アミノ、C1-10アルキルチオ、アリール、およびヘテロアリールから選択され;
R21、R22、R28、R29、R33およびR34は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR23R24R25、および-C(=O)R30から選択され;
R26は、水素原子、C1-10アルキル、C1-10アルコキシ、C3-10シクロアルキルオキシ、アリールオキシ、C3-10シクロアルキル、アリール、ヘテロアリール、-C(=O)R30、または-SiR23R24R25であり;
R27は、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R31は、水素原子、C1-10アルキル、またはC3-10シクロアルキルであり;
R32は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R35は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、またはヘテロアリールであり;
R36は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、またはC2-10アルキニルであり;
R37は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R38は、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30である]
の化合物を製造する方法であって;
工程a)式(II):
P1は、金属イオン、水素原子またはヒドロキシ基の保護基であり;
R41は、R1として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく;nは既に定義したとおりである]
の化合物を有機金属試薬で処理し、その後、式(III):
を反応させて、式(IVa):
P6は、金属イオン、水素原子またはヒドロキシ基の保護基である]
の化合物を、有機金属試薬で処理し、その後、式(V):
の化合物と反応させる工程;
を含み、さらに、上記工程中、および/またはその前後の任意の段階において、保護基を導入する工程、および/または保護基を除去する工程を含んでいてもよい、前記製造方法が提供される。
工程c)式(VI):
の化合物を、以下の2段階
段階(1):P1が水素原子である式(VI)の化合物を、酸性条件下で処理する工程(但し、P1が保護基である場合は、当該処理前の脱保護工程をさらに含む);および、
段階(2):還元反応により、工程b)の反応により生じたヒドロキシ基を除去する工程;
(但し、いずれの段階を先に行ってもよい)に付し、式(VII):
ここで、R51は、それぞれ独立に、1以上のR56により置換されていてもよいアリール、1以上のアリールにより置換されていてもよいC1-10アルコキシ、C1-10アルキルチオ、およびアリールセレニルから選択され;
R52は、それぞれ独立に、C1-10アルコキシから選択され;
R53およびR55は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R54は、水素原子、C1-10アルキル、1以上のC1-10アルコキシにより置換されていてもよいアリール、ヘテロアリール、1以上のR57により置換されていてもよいアミノ、1以上のアリールにより置換されていてもよいC1-10アルコキシ、または1以上のニトロにより置換されていてもよいアリールオキシであり;
R56は、それぞれ独立に、C1-10アルキル、C1-10アルコキシ、アリール、およびヘテロアリールから選択され;
R57は、それぞれ独立に、C1-10アルキル、およびアリールから選択される。
工程d)式(I)の化合物を、式(X):
の化合物に変換する工程;
工程e)式(X)の化合物を結晶化し、再結晶により精製する工程;
工程f)式(X)の化合物から保護基を除去し、高純度の式(I)の化合物を得る工程;
を含む、前記製造方法が提供される。
工程1:3,4,5-トリス(トリメチルシリルオキシ)-6-トリメチルシリルオキシメチル-テトラヒドロピラン-2-オンの合成
1H-NMR(500MHz,CDCl3)δ:-0.47(4.8H,s)、-0.40(4.2H,s)、-0.003~0.004(5H,m)、0.07-0.08(13H,m)、0.15-0.17(18H,m)、1.200および1.202(3H,eacht,J=8.0Hz)、1.393および1.399(3H,each s)、1.44(3H,s)、2.61(2H,q,J=8.0Hz)、3.221および3.223(3H,eachs)、3.43(1H,t,J=8.5Hz)、3.54(1H,dd,J=8.5,3.0Hz)、3.61-3.66(1H,m)、3.80-3.85(3H,m)、4.56および4.58(1H,each d,J=12.4Hz)、4.92および4.93(1H,each d,J=12.4Hz)、5.80および5.82(1H,each d,J=3.0Hz)、7.14(2H,d,J=8.0Hz)、7.28-7.35(3H,m)、7.50-7.57(2H,m)。
1H-NMR(500MHz,トルエン-d8,80℃)δ:-0.25(4H,s)、-0.22(5H,s)、0.13(5H,s)、0.16(4H,s)、0.211および0.214(9H,each s)、0.25(9H,s)、0.29(9H,s)、1.21(3H,t,J=7.5Hz)、1.43(3H,s)、1.45(3H,s)、2.49(2H,q,J=7.5Hz)、3.192および3.194(3H,each s)、3.91-4.04(4H,m)、4.33-4.39(2H,m)、4.93(1H,d,J=14.5Hz)、5.10-5.17(1H,m)、5.64および5.66(1H,each s)、7.03(2H,d,J=8.0Hz)、7.28-7.35(3H,m)、7.59-7.64(1H,m)、7.87-7.89(1H,m)。
カラム:Cadenza CD-C18 50mm P/NCD032
移動相:A液:H2O,B液:MeCN
グラジェント操作:B液:5%から100%(6分間)、100%(2分間)
流速:毎分1.0mL
温度:35.0℃
検出波長:210nm
工程6:1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-2,3,4,6-テトラ-O-メトキシカルボニル-β-D-グルコピラノースの合成
カラム:Capcell pack ODS UG-120(4.6mmI.D.×150mm,3μm,資生堂製)
移動相:A液:H2O、B液:MeCN
移動相の送液:A液およびB液の混合比を次のように変えて濃度勾配制御した。
温度:25.0℃
検出波長:220nm
水分量の測定方法:
分析法:電量滴定法
KF分析装置:微量水分測定装置 三菱化学社製 型式KF-100
陽極液:アクアミクロンAX(三菱化学製)
陰極液:アクアミクロンCXU(三菱化学製)
[実施例2]2,3,4,5-テトラキス(トリメチルシリルオキシ)-6-トリメチルシリルオキシメチル-2-(5-ブロモ-2-(1-メトキシ-1-メチルエトキシメチル)フェニル)テトラヒドロピランの合成
1H-NMR(500MHz,CDCl3)δ:-0.30(9H,s)、0.095(9H,s)、0.099(9H,s)、0.16(9H,s)、0.17(9H,s)、1.41(3H,s)、1.43(3H,s)、3.20(3H,s)、3.37-3.44(2H,m)、3.62(1H,dd,J=10.5,7.5Hz)、3.81-3.89(3H,m)、4.62(1H,d,J=13.2Hz)、4.81(1H,d,J=13.2Hz)、7.38(1H,dd,J=8.8,2.5Hz)、7.46(1H,d,J=8.8Hz)、7.70(1H,d,J=2.5Hz)。
1H-NMR(500MHz,トルエン-d8,80℃)δ:-0.16(9H,s)、0.18(9H,s)、0.22(9H,s)、0.23(9H,s)、0.29(9H,s)、1.405(3H,s)、1.412(3H,s)、3.16(3H,s)、3.87(1H,dd,J=10.5,4.3Hz)、3.98(1H,dd,J=4.3,1.5Hz)、4.02(1H,dd,J=10.5,2.5Hz)、4.14(1H,s)、4.26(1H,brs)、4.38(1H,brs)、4.90-4.96(2H,m)、7.34(1H,dd,J=8.5,1.5Hz)、7.70(1H,d,J=8.5Hz)、7.97(1H,s,brs)。
カラム:YMC-Pack ODS-AM 4.6mm I.D.×150mm、3μm (ワイエムシィ)
移動相:A液:2mM AcONH4/H2O, B液:50%(v/v)MeCN/MeOH
グラジェント操作:B液:50%から95%(15分間)、95%ホールド(15分間)、95%から100%(5分間)100%(15分間)
流速:1.0ml/分
カラム温度:40℃
検出波長:200nm
[実施例5]1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-β-D-グルコピラノースの合成
工程1:2,3,4,5-テトラキス(トリメチルシリルオキシ)-6-トリメチルシリルオキシメチル-2-(5-(4-エチルフェニル)ヒドロキシメチル-2-(1-メトキシ-1-メチルエトキシメチル)フェニル)テトラヒドロピランの合成
カラム:Ascentis Express C18,3.0mm I.D.×100mm, 2.7μm(Supelco)
移動相:A液:2mM AcONH4水溶液、B液:MeCN
グラジェント操作:B液:30%から98%(25分間)、98%(5分間)
流速:毎分1.0mL
温度:40℃
検出波長:210nm
工程2:1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)ヒドロキシメチル-2-(ヒドロキシメチル)フェニル]-β-D-グルコピラノースの合成
カラム:Atlantis dC18,4.6mm I.D.×75mm,3μm(Waters)
移動相:A液:H2O,B液:MeCN
グラジェント操作:B液:2%から20%(3分間)、20%から28%(5分間)、28%(12分間)、28%から100%(7分間)、100%(8分間)
流速:毎分1.2mL
温度:35℃
検出条件:210nm
工程4:1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-2,3,4,6-テトラ-O-メトキシカルボニル-β-D-グルコピラノースの合成
水分量の測定方法:
分析法:電量滴定法
KF分析装置:微量水分測定装置 三菱化学社製 型式KF-100
陽極液:アクアミクロンAX(三菱化学製)
陰極液:アクアミクロンCXU(三菱化学製)
実施例5工程5にて使用した種結晶は、以下の方法により得た結晶の一部を使用した。
カラム:ZORBAX Eclipse XDB-C18,4.6mm I.D. x 50mm,1.8μm(Agilent)
移動相:A液:H2O,B液:MeOH
グラジェント操作:B液:40%から60%(11.5分間)、60%から80%(7分間)、80%から95%(4分間)、95%(5分間)
流速:毎分1.0ml
温度:50℃
検出波長:220nm
[実施例6]2,4-ジブロモ-1-(1-メトキシ-1-メチルエトキシメチル)ベンゼンのハロゲン金属交換反応
以下の条件(条件1~4)において2,4-ジブロモ-1-(1-メトキシ-1-メチルエトキシメチル)ベンゼンのハロゲン金属交換反応を行い、反応の位置選択性を生成物の1H-NMR分析により確認した。
1H-NMR(CDCl3)δ:1.41(6H,s)、3.24(3H,s)、4.43(2H,s)、7.21-7.24(2H,m)、7.44-7.47(2H,m)。
1H-NMR(CDCl3)δ:1.46(6H,s)、3.24(3H,s)、4.55(2H,s)、7.10-7.14(1H,m)、7.29-7.33(1H,m)、7.51-7.55(2H,m)。
1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-2,3,4,6-テトラ-O-メトキシカルボニル-β-D-グルコピラノース(湿性粉末88.2g)の1,2-ジメトキシエタン(285ml)溶液に、水酸化ナトリウム水溶液(5M、285ml)を室温にて加えて、同温で1時間攪拌した。この溶液に硫酸水溶液(1M、713ml)加えた後、さらに水(100ml)を加え、酢酸エチル(500ml)で2回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液(1000ml)で洗浄し、さらに無水硫酸ナトリウム(250g)で乾燥後、減圧下で溶媒をおよそ半量留去し、析出した生成物を結晶性粉末として得た(10.3g)。得られた結晶性粉末の一部(4mg)をジメチルスルホキシド(0.02ml)に溶解させ、当該溶液を-20℃で2日間凍結乾燥し、ジメチルスルホキシドを除去した。残渣に水(0.02ml)を加えた後、ごく少量の上記の結晶性粉末を種結晶として加え、室温にて10日間振とう攪拌(100rpm、TAITEC社製DOUBLE SHAKER NR-3)し、表題の化合物を結晶として得た。得られた結晶の粉末X線回折を測定し、ピークが試験例5で測定した1水和物の回折パターンと同じ回折角(2θ)に観測されたことにより、当該結晶が1水和物であることを確認した。
1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-β-D-グルコピラノースの1水和物結晶(200mg)と酢酸ナトリウム(40mg)をメタノール(1ml)に80℃にて溶解させ、室温に冷却した後、イソプロパノール(2ml)を加えた。減圧下に溶媒(約2ml)を留去した後、標題の共結晶の種結晶を加え、室温にて一夜撹拌し、析出した結晶をろ取し、イソプロパノール(4ml)で洗浄後、乾燥し、標題の共結晶(融点約162℃)を得た。共結晶の1H-NMR[(CD3)2SO]分析より、表題の化合物のエチル基のCH3のプロトン(δ1.12-1.16(3H,t))のピークと酢酸ナトリウムのCH3(δ1.56(3H,s))の積分比から存在比を算出したところ1:1の共結晶であった。
分析法:示差走査熱量測定(DSC)
装置:DSC6200R エスアイアイ・ナノテクノロジー社製
走査速度:10℃/分
走査範囲:30~210℃
試料量:3~4mg
[実施例9]1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-β-D-グルコピラノース酢酸カリウム共結晶の調製
1,1-アンヒドロ-1-C-[5-(4-エチルフェニル)メチル-2-(ヒドロキシメチル)フェニル]-β-D-グルコピラノースの1水和物結晶(200mg)と酢酸カリウム(48mg)をメタノール(1ml)に80℃にて溶解させ、室温に冷却した後、イソプロパノール(2ml)を加えた。減圧下に溶媒(約2ml)を留去した後、標題の共結晶の種結晶を加え、室温にて一夜撹拌し、析出した結晶をろ取し、イソプロパノール(4ml)で洗浄後、乾燥し、標題の共結晶(融点約176℃)を得た。共結晶の1H-NMR[(CD3)2SO]分析より、表題の化合物のエチル基のCH3のプロトン(δ1.13-1.16(3H,t))のピークと酢酸カリウムのCH3(δ1.53(3H,s))の積分比から存在比を算出したところ1:1の共結晶であった。
[試験例1]1水和物結晶の水分吸着等温線の測定
式(XI):
本発明の式(XI)の化合物の1水和物結晶および当該化合物のアモルファスを用い、保存安定性試験を行った。式(XI)の化合物の1水和物結晶は、実施例1の工程7に記載の方法に準じて製造した。式(XI)の化合物のアモルファスは以下の方法で製造した。当該化合物の1水和結晶(15g)をホットステージ上で加熱し、融解後、調湿デシケーター(25℃/dry)内で室温にて放冷し、固化したものを乳鉢で粉砕することにより得たものを試料として使用した。各試料を25℃および40℃に設定した恒温槽に保存し、1ヶ月後、3ヶ月後および6ヶ月後に試料の純度を確認した。
使用機器:2695 Separations Module(Waters製)、2487 Dual λ Absorbance Detector(Waters製)または996 Photodiode Array Detector(Waters製)
カラム:YMC-Pack ODS-AM AM-302-3、内径4.6 mm×長さ15 cm、粒子径3μm(YMC製)
溶出液:A液=メタノール、B液=水
グラジェント操作:A液:55%(15分間)、A液55から100%(10分間)、100%(5分間)
流量:1.0mL/分
検出波長:220nm
サンプルクーラー温度:5℃
面積測定範囲:溶液注入後30分間
結果を表2に示す。25℃および40℃のいずれにおいても、アモルファスの不純物総量は経時的に増加したのに対し、25℃および40℃のいずれにおいても1水和物結晶の不純物総量は6ヶ月間ほぼ一定であった。
本発明の式(XI)の化合物の酢酸ナトリウム共結晶を用い、保存安定性試験を試験例2の方法に準じて行った。式(XI)の化合物の酢酸ナトリウム共結晶は、実施例5に記載の方法に準じて製造した。試料を25℃および40℃に設定した恒温槽に保存し、1ヶ月後、および3ヶ月後に試料の純度を確認した。得られた測定結果を試験例2で得られたアモルファスの結果と比較した。
本発明の式(XI)の化合物の酢酸カリウム共結晶を用い、保存安定性試験を試験例2の方法に準じて行った。式(XI)の化合物の酢酸カリウム共結晶は、実施例6に記載の方法に準じて製造した。試料を25℃および40℃に設定した恒温槽に保存し、1ヶ月後、および3ヶ月後に試料の純度を確認した。得られた測定結果を試験例2で得られたアモルファスの結果と比較した。
測定装置:RINT1100(Rigaku社製)
対陰極:Cu
管電圧:40kV
管電流:40mA
走査速度:2.000°/分
サンプリング幅:0.020°
発散スリット:1°
散乱スリット:1°
受光スリット:0.15mm
走査範囲:3~35°
1水和物結晶の測定条件(測定条件2)
測定装置:X’Pert-Pro MPD(PANalytical社製)
対陰極:Cu
管電圧:45kV
管電流:40mA
走査方式:連続
ステップ幅:0.017
走査軸:2θ
ステップあたりのサンプリング時間:30秒
走査範囲:2~35°
アモルファスの測定条件
測定装置:RINT1100(Rigaku社製)
対陰極:Cu
管電圧:40kV
管電流:20mA
走査速度:2.000°/分
サンプリング幅:0.020°
発散スリット:1°
散乱スリット:1°
受光スリット:0.15mm
走査範囲:2~35°
酢酸ナトリウム共結晶および酢酸カリウムの測定条件
測定装置:X’Pert MPD(PANalytical社製)
対陰極:Cu
管電圧:45kV
管電流:40mA
走査速度:1.000°/分
サンプリング幅:0.050°
発散スリット:0.25°
散乱スリット:0.25°
受光スリット:0.2mm
走査範囲:3~35°
1水和結晶の結果を図2に示す。3.5°、6.9°、10.4°、13.8°、16.0°、17.2°、18.4°、20.8°、21.4°、および24.4°付近の回折角(2θ)にピークが観測された。酢酸ナトリウム共結晶の結果を図4に示す。4.9°、8.7°、9.3°、11.9°、12.9°、14.7°、16.0°、17.1°、17.7°、19.6°、21.6°、および22.0°付近の回折角(2θ)にピークが観測された。酢酸カリウム共結晶の結果を図5に示す。5.0°、10.0°、10.4°、12.4°、14.5°、15.1°、19.0°、20.1°、21.4°、および25.2°付近の回折角(2θ)にピークが観測された。
Claims (35)
- 式(I):
R1およびR2は、それぞれ独立に、1以上のRaにより置換されていてもよいC1-10アルキル、1以上のRaにより置換されていてもよいC3-10シクロアルキル、1以上のRaにより置換されていてもよいC2-10アルケニル、1以上のRaにより置換されていてもよいC3-10シクロアルケニル、1以上のRaにより置換されていてもよいC2-10アルキニル、1以上のRaにより置換されていてもよいアリール、1以上のRaにより置換されていてもよい飽和、部分不飽和、または不飽和のへテロシクリル、シアノ、ハロゲン原子、ニトロ、メルカプト、-OR3、-NR4R5、-S(O)pR6、-S(O)qNR7R8、-C(=O)R35、-CR36=NOR37、-C(=O)OR9、-C(=O)NR10R11、および-SiR12R13R14から選択され;nが2以上の場合、R1はそれぞれ同一であっても、異なっていてもよく;mが2以上の場合、R2はそれぞれ同一であっても、異なっていてもよく;または、隣接する炭素原子上に存在する2つのR1は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;隣接する炭素原子上に存在する2つのR2は、それらが結合する炭素原子と一緒になって、ベンゼン環に縮合する炭素環またはヘテロ環を形成してもよく;
pは、0~2から選択される整数であり;qは、1および2から選択される整数であり;
R3は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R4およびR5は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R6は、C1-10アルキル、C3-10シクロアルキル、アリール、またはヘテロアリールであり、ただし、pが0の場合、R6はさらに-SiR12R13R14、または-C(=O)R15であってもよく;
R7、R8、R10およびR11は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR12R13R14、および-C(=O)R15から選択され;
R9は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、または-SiR12R13R14であり;
Raは、それぞれ独立に、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、アリール、ヘテロアリール、ヒドロキシ、ハロゲン原子、-NR21R22、-OR38、-SR26、-S(O)2R27、-SiR23R24R25、カルボキシ、-C(O)NR28R29、-C(=O)R30、-CR31=NOR32、シアノ、および-S(O)rNR33R34から選択され;
rは、1および2から選択される整数であり;
R12、R13、R14、R23、R24、およびR25は、それぞれ独立に、C1-10アルキル、およびアリールから選択され;
R15およびR30は、それぞれ独立に、水素原子、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、C1-10アルキルアミノ、ジ(C1-10アルキル)アミノ、C1-10アルキルチオ、アリール、およびヘテロアリールから選択され;
R21、R22、R28、R29、R33およびR34は、それぞれ独立に、水素原子、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、C1-10アルコキシ、アリール、ヘテロアリール、-SiR23R24R25、および-C(=O)R30から選択され;
R26は、水素原子、C1-10アルキル、C1-10アルコキシ、C3-10シクロアルキルオキシ、アリールオキシ、C3-10シクロアルキル、アリール、ヘテロアリール、-C(=O)R30、または-SiR23R24R25であり;
R27は、ヒドロキシ、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R31は、水素原子、C1-10アルキル、またはC3-10シクロアルキルであり;
R32は、水素原子、C1-10アルキル、C3-10シクロアルキル、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30であり;
R35は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、ヘテロアリールであり;
R36は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、またはC2-10アルキニルであり;
R37は、水素原子、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、アリール、ヘテロアリール、-SiR12R13R14、または-C(=O)R15であり;
R38は、C1-10アルキル、C3-10シクロアルキル、C2-10アルケニル、C3-10シクロアルケニル、C2-10アルキニル、C1-10アルキルチオ、アリール、ヘテロアリール、-SiR23R24R25、または-C(=O)R30である]
の化合物を製造する方法であって;
工程a)式(II):
P1は、金属イオン、水素原子またはヒドロキシ基の保護基であり;
R41は、R1として既に定義した基であり、ただし当該基は1以上の保護基を有していてもよく;nは既に定義したとおりである]
の化合物を有機金属試薬で処理し、その後、式(III):
の化合物を反応させて、式(IVa):
Xは、金属イオン、または水素原子である]
の化合物を得る工程;
工程b)式(IVb):
P6は、金属イオン、水素原子またはヒドロキシ基の保護基である]
の化合物を、有機金属試薬で処理し、その後、式(V):
の化合物と反応させる工程;
を含み、さらに、上記工程中、および/またはその前後の任意の段階において、保護基を導入する工程、および/または保護基を除去する工程を含んでいてもよい、前記製造方法。 - 工程c)式(VI):
の化合物を、以下の2段階
段階(1):P1が水素原子である式(VI)の化合物を、酸性条件下で処理する段階(但し、P1が保護基である場合は、当該処理前の脱保護工程をさらに含む);および、
段階(2):工程b)の反応により生じたヒドロキシ基を還元反応により除去する段階;
(但し、いずれの段階を先に行ってもよい)に付し、式(VII):
の化合物を得る工程;
をさらに含む、請求項1に記載の製造方法。 - 工程a)において、有機金属試薬を15~300分かけて添加する、請求項1または2に記載の製造方法。
- 工程a)において、有機金属試薬の添加を断続的に行う、請求項1~3のいずれか1項に記載の製造方法。
- 工程a)において、P1が金属イオンまたは保護基の場合、有機金属試薬を式(II)の化合物に対して0.4~0.9当量添加した後に添加を中断し、その後さらに有機金属試薬を式(II)の化合物に対して0.1~0.7当量添加する、請求項1~4のいずれか1項に記載の製造方法。
- 工程a)において、P1が水素原子の場合、有機金属試薬を式(II)の化合物に対して1.4~1.9当量添加した後に添加を中断し、その後さらに有機金属試薬を式(II)の化合物に対して0.1~0.7当量添加する、請求項1~4のいずれか1項に記載の製造方法。
- 工程a)において、P1が金属イオンまたは保護基である式(II)の化合物を含む反応系に有機金属試薬を添加し、その後、式(II)の化合物をさらに加える、請求項1~5のいずれか1項に記載の製造方法。
- 工程a)において、P1がヒドロキシ基の保護基である式(II)の化合物を使用する、請求項1~5および7のいずれか1項に記載の製造方法。
- 工程b)において、P6がヒドロキシ基の保護基である式(IVb)の化合物を使用する、請求項1~8のいずれか1項に記載の製造方法。
- nが0であり、mが0または1であり、R2がC1-4アルキルである、請求項1~9のいずれか1項に記載の製造方法。
- 工程a)およびb)をワンポット反応で行う、請求項1~10のいずれか1項に記載の方法。
- 工程d)の式(I)の化合物が、請求項1~11のいずれか1項に記載の製造方法により得られる粗生成物である、請求項12に記載の製造方法。
- メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、エチレングリコール、1-ヘキサノール、テトラヒドロフラン、t-ブチルメチルエーテル、シクロペンチルメチルエーテル、1,2-ジメトキシエタン、ジイソプロピルエーテル、酢酸エチル、酢酸プロピル、酢酸ヘキシル、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、N,N-ジブチルホルムアミド、1-クロロヘキサン、n-プロピルベンゼン、ヘキシルベンゼン、ヘプタン、トルエン、アセトン、2-ブタノン、2-ヘプタノン、アセトニトリル、ジメチルスルホキシド、および水から選択される溶媒、または2以上の前記溶媒を含む混合溶媒を用いて、得られた式(I)の化合物を結晶化する工程をさらに含む、請求項12または13に記載の製造方法。
- 工程d)の変換において、1-メチルイミダゾールを塩基として使用する、請求項12~14のいずれか1項に記載の製造方法。
- P7が、C1-6アルキルカルボニル、C1-6アルコキシカルボニル、-SiR23R24R25から選択され、R23、R24、およびR25は、請求項1に定義したとおりである、請求項12~15のいずれか1項に記載の製造方法。
- P7が、t-ブチルカルボニルおよびメトキシカルボニルから選択される、請求項12~16のいずれか1項に記載の製造方法。
- 式(I)において、nが0であり、mが0または1であり、R2がC1-4アルキルである、請求項12~17のいずれか1項に記載の製造方法。
- 1水和物である、請求項21に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、3.5°、6.9°、および13.8°付近の回折角(2θ)にピークを有する、請求項21または22に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、3.5°、6.9°、13.8°、16.0°、17.2°、および18.4°付近の回折角(2θ)にピークを有する、請求項21~23のいずれか1項に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、3.5°、6.9°、10.4°、13.8°、16.0°、17.2°、18.4°、20.8°、21.4°、および24.4°付近の回折角(2θ)にピークを有する、請求項21~24のいずれか1項に記載の式(XI)の化合物の結晶。
- アセトンおよび水の混合溶媒からの結晶化により得られる、請求項21~25のいずれか1項に記載の式(XI)の化合物の結晶。
- アセトン:水の容積比が1:3.5から1:7である、アセトンおよび水の混合溶媒を使用する、請求項26に記載の式(XI)の化合物の結晶。
- 酢酸ナトリウム共結晶である、請求項21に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、4.9°、14.7°、16.0°、17.1°、および19.6°付近の回折角(2θ)にピークを有する、請求項21または28に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、4.9°、8.7°、9.3°、11.9°、12.9°、14.7°、16.0°、17.1°、17.7°、19.6°、21.6°、および22.0°付近の回折角(2θ)にピークを有する、請求項21、28または29に記載の式(XI)の化合物の結晶。
- メタノールおよびイソプロパノールの混合溶媒からの結晶化により得られる、請求項21、28~30のいずれか1項に記載の式(XI)の化合物の結晶。
- 酢酸カリウム共結晶である、請求項21に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、5.0°、15.1°、19.0°、20.1°および25.2°付近の回折角(2θ)にピークを有する、請求項21または32に記載の式(XI)の化合物の結晶。
- 粉末X線回折パターンにおいて、5.0°、10.0°、10.4°、12.4°、14.5°、15.1°、19.0°、20.1°、21.4°、および25.2°付近の回折角(2θ)にピークを有する、請求項21、32および33のいずれか1項に記載の式(XI)の化合物の結晶。
- メタノールおよびイソプロパノールの混合溶媒からの結晶化により得られる、請求項21、32~34のいずれか1項に記載の式(XI)の化合物の結晶。
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EP22155547.7A EP4036100A1 (en) | 2008-06-20 | 2009-06-19 | Spiroketal derivatives and process for preparation of spiroketal derivatives |
AU2009261129A AU2009261129A1 (en) | 2008-06-20 | 2009-06-19 | Crystal of spiroketal derivative, and process for production thereof |
NZ589961A NZ589961A (en) | 2008-06-20 | 2009-06-19 | Crystal of spiroketal derivative, and process for production thereof |
EP16202285.9A EP3170834B8 (en) | 2008-06-20 | 2009-06-19 | Crystalline forms of (1s,3'r,4's,5's,6'r)-6-[(4-ethylphenyl)methyl]-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro[isobenzofuran-1(3h) 2'-[2h]pyran]-3',4',5'-triol |
US13/000,208 US8569520B2 (en) | 2008-06-20 | 2009-06-19 | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
KR1020117000778A KR101856784B1 (ko) | 2008-06-20 | 2009-06-19 | 스피로케탈 유도체의 결정 및 그 제조 방법 |
PL16202285T PL3170834T3 (pl) | 2008-06-20 | 2009-06-19 | Krystaliczne postacie (1s,3’r,4’s,5’s,6’r)-6-[(4-etylofenylo)metylo]-3’,4’,5’,6’-tetrahydro-6’-(hydroksymetylo)spiro[izobenzofurano-1(3h) 2’-[2h]pirano]-3’,4’,5’-triolu |
CA2727923A CA2727923A1 (en) | 2008-06-20 | 2009-06-19 | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
JP2010517979A JP4823385B2 (ja) | 2008-06-20 | 2009-06-19 | スピロケタール誘導体の結晶およびその製造方法 |
EP09766724.0A EP2308886B1 (en) | 2008-06-20 | 2009-06-19 | Process for the production of a spiroketal derivative |
CN200980119081.4A CN102046645B (zh) | 2008-06-20 | 2009-06-19 | 螺酮缩醇衍生物的结晶及其制备方法 |
MX2010014023A MX2010014023A (es) | 2008-06-20 | 2009-06-19 | Cristal de derivados de espirocetal, y procedimiento para la preparacion de derivados de espirocetal. |
IL210098A IL210098A0 (en) | 2008-06-20 | 2010-12-19 | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
MA33442A MA32530B1 (fr) | 2008-06-20 | 2010-12-20 | Dérivés de spirocétals cristallins et procédé pour la préparation de dérivés de spirocétals |
ZA2011/00016A ZA201100016B (en) | 2008-06-20 | 2011-01-03 | "crystal of spiroketal derivatives and process for preparation of spiroketal derivatives" |
HK11108698.5A HK1154589A1 (en) | 2008-06-20 | 2011-08-17 | Crystal of spiroketal derivative, and process for production thereof |
US14/034,880 US9163051B2 (en) | 2008-06-20 | 2013-09-24 | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
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US14/034,880 Division US9163051B2 (en) | 2008-06-20 | 2013-09-24 | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
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WO2015099139A1 (ja) | 2013-12-27 | 2015-07-02 | 中外製薬株式会社 | トホグリフロジンを含有する固形製剤及びその製造方法 |
WO2018073154A1 (en) | 2016-10-19 | 2018-04-26 | Boehringer Ingelheim International Gmbh | Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof |
WO2019201752A1 (en) | 2018-04-17 | 2019-10-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
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UA114490C2 (uk) * | 2011-10-06 | 2017-06-26 | Байєр Інтеллектуал Проперті Гмбх | Гетероциклілпіри(mі)динілпіразоли як фунгіциди |
CN106188190B (zh) * | 2016-07-28 | 2020-08-25 | 迪嘉药业集团有限公司 | 一种托格列净一水合物的制备方法 |
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KR20210082557A (ko) | 2013-12-27 | 2021-07-05 | 추가이 세이야쿠 가부시키가이샤 | 토포글리플로진을 함유하는 고형 제제 및 그 제조 방법 |
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