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HK1154589B - Crystal of spiroketal derivative, and process for production thereof - Google Patents

Crystal of spiroketal derivative, and process for production thereof Download PDF

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Publication number
HK1154589B
HK1154589B HK11108698.5A HK11108698A HK1154589B HK 1154589 B HK1154589 B HK 1154589B HK 11108698 A HK11108698 A HK 11108698A HK 1154589 B HK1154589 B HK 1154589B
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Hong Kong
Prior art keywords
formula
group
compound
alkyl
solution
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Application number
HK11108698.5A
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Chinese (zh)
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HK1154589A1 (en
Inventor
Murakata Masatoshi
Ikeda Takuma
Kimura Nobuaki
Kawase Akira
Nagase Masahiro
Yamamoto Keisuke
Takata Noriyuki
Yoshizaki Shinichi
Takano Koji
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Priority claimed from PCT/JP2009/061226 external-priority patent/WO2009154276A1/en
Publication of HK1154589A1 publication Critical patent/HK1154589A1/en
Publication of HK1154589B publication Critical patent/HK1154589B/en

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Description

Crystal of spiroketal derivative and process for producing the same
Technical Field
The present invention relates to a method for producing a spiroketal (spiroketal) derivative, a synthetic intermediate suitable for producing a spiroketal derivative, and a crystalline substance of a spiroketal derivative.
Background
Spiroketal derivatives having a specific structure are known to be useful for the prevention or treatment of diabetes (patent documents 1 to 4). For example, WO2006/080421A1 (patent document 1) discloses a compound represented by the formula (A)
[ solution 1]
The compound and use thereof as a therapeutic agent for diabetes.
Further, patent document 1 discloses a method for producing a compound represented by formula (a), and a process for obtaining a target compound by reacting a dibromobenzene derivative with an alkyllithium reagent, then coupling the resultant product with a lactone, further converting the coupled product into a tin compound, and then carrying out a coupling reaction in the presence of a palladium catalyst is described in a flowchart 3 (patent document 1, page 24).
In addition, in a flow chart 4 (patent document 2, pages 24 to 25, fig. 4) of WO2007/140191a2 (patent document 2) and corresponding U.S. patent publication US2007/0275907a1 (patent document 3), there is described a method in which a dihalotoluene derivative is treated with n-BuLi, s-BuLi, t-BuLi, Mg or the like, then coupled with a lactone, and after several steps, further converted into a tin compound, and further coupled with a benzyl halide derivative to obtain a target compound.
Patent document 1 describes a compound represented by the formula (B)
[ solution 2]
The compound and the compound have excellent SGLT2 inhibitory activity.
Documents of the prior art
Patent document
Patent document 1: WO2006/080421A1
Patent document 2: WO2007/140191A2
Patent document 3: US2007/0275907A1
Patent document 4: WO2008/013280A1
Disclosure of Invention
Problems to be solved by the invention
As described above, although the flow charts of the production of a compound having a spiroketal skeleton from a dihalobenzene derivative are shown in the flow chart 3 of patent document 1 and the flow chart 4 of patent document 2, a synthetic method using a tin compound is complicated in operation, and a step for carefully removing a tin compound which may be mixed as an impurity is required, and therefore, is not suitable as an industrial production method. In addition, the above patent documents do not disclose any specific examples relating to the preparation schemes, and do not report an efficient and simple preparation method suitable for industrial production of the compounds of the formulae (a) and (B) used as active ingredients of pharmaceuticals.
Further, with respect to the compound of formula (B) having an excellent SGLT2 inhibitory activity, the presence of its crystal is not reported.
The purpose of the present invention is to provide a highly efficient and simple process for the industrial production of spiroketal derivatives which are useful as active ingredients in pharmaceuticals, and useful synthetic intermediates; and crystals which are useful as a pharmaceutical product or a raw material for a pharmaceutical product and have excellent characteristics in terms of storage stability, ease of handling in the preparation, and the like.
Means for solving the problems
The present inventors have made intensive studies to solve the above problems, and as a result, have found a method of selectively exchanging a halogen metal at one position among a plurality of halogen atoms on a benzene ring. Further, the present inventors have completed the present invention by going through a process in which a novel organometallic compound which is easily prepared is used as an intermediate to allow a coupling reaction to proceed smoothly, and further, according to this process, two coupling reactions in series can be efficiently performed as a one-pot synthesis (one-pot synthesis). The present invention provides a process for producing a spiroketal derivative as a target product without using a heavy metal such as tin or an organic transition metal complex for forming a carbon-carbon bond. In contrast to the method using a heavy metal such as tin and an organic transition metal complex, which requires a step of carefully removing the reagent that may be mixed as an impurity, the production method of the present invention does not require such a step, and is particularly excellent as an industrial production method of a raw material for pharmaceuticals.
Further, the present inventors have found that a crystal form of a compound represented by formula (I), a method for producing the same, and the crystal have excellent properties as a pharmaceutical product or a pharmaceutical raw material, and have completed the present invention.
That is, according to 1 aspect of the present invention, there is provided a process for the preparation of a compound of formula (I),
[ solution 3]
[ in the formula, n is an integer selected from 0 to 3; m is an integer selected from 0 to 5;
R1and R2Each independently selected from C which may be substituted by 1 or more Ra1-10Alkyl, C which may be substituted by more than 1 Ra3-10Cycloalkyl, C which may be substituted by more than 1 Ra2-10Alkenyl, C which may be substituted by 1 or more Ra3-10Cycloalkenyl radical, C which may be substituted by more than 1 Ra2-10Alkynyl, aryl which may be substituted by 1 OR more Ra, saturated, partially unsaturated, OR unsaturated heterocyclic group which may be substituted by 1 OR more Ra, cyano, halogen atom, nitro, mercapto, -OR3、-NR4R5、-S(O)pR6、-S(O)qNR7R8、-C(＝O)R35、-CR36＝NOR37、-C(＝O)OR9、-C(＝O)NR10R11and-SiR12R13R14(ii) a When n is 2 or more, R1May be the same or different from each other; when m is 2 or more, R2May be the same or different from each other; or 2R present on adjacent carbon atoms1Together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring fused to a benzene ring; 2R present on adjacent carbon atoms2Together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring fused to a benzene ring;
p is an integer selected from 0 to 2; q is an integer selected from 1 and 2;
R3is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl radical, C2-10Alkynyl, aryl, heteroaryl, -SiR12R13R14or-C (═ O)15；
R4And R5Each independently selected from hydrogen atom, hydroxyl group, C1-10Alkyl radical, C3-10Cycloalkyl radical, C1-10Alkoxy, aryl, heteroaryl, -SiR12R13R14and-C (═ O) R15；
R6Is C1-10Alkyl radical, C3-10Cycloalkyl, aryl, or heteroaryl, wherein, when p is 0, R6May also be-SiR12R13R14or-C (═ O) R15；
R7、R8、R10And R11Each independently selected from hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, -SiR12R13R14and-C (═ O) R15；
R9Is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, or-SiR12R13R14；
Ra is independently selected from C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl radical, C2-10Alkynyl, aryl, heteroaryl, hydroxy, halogen atom, -NR21R22、-OR38、-SR26、-S(O)2R27、-SiR23R24R25Carboxy, -C (O) NR28R29、-C(＝O)R30、-CR31＝NOR32Cyano and-S (O)rNR33R34；
r is an integer selected from 1 and 2;
R12、R13、R14、R23、R24and R25Each independently selected from C1-10Alkyl, and aryl;
R15and R30Each independently selected from hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl radical, C1-10Alkoxy radical, C1-10Alkylamino radical, di (C)1-10Alkyl) amino, C1-10Alkylthio, aryl, and heteroaryl;
R21、R22、R28、R29、R33and R34Each independently selected from hydrogen atom, hydroxyl group, C1-10Alkyl radical, C3-10Cycloalkyl radical, C1-10Alkoxy, aryl, heteroaryl, -SiR23R24R25and-C (═ O) R30；
R26Is a hydrogen atom, C1-10Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, aryloxy, C3-10Cycloalkyl, aryl, heteroaryl, -C (═ O) R30or-SiR23R24R25；
R27Is hydroxy, C1-10Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, -SiR23R24R25or-C (═ O) R30；
R31Is a hydrogen atom, C1-10Alkyl, or C3-10A cycloalkyl group;
R32is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, -SiR23R24R25or-C (═ O) R30；
R35Is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl radical, C2-10Alkynyl, C1-10Alkylthio, aryl, or heteroaryl;
R36is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl group, or C2-10An alkynyl group;
R37is a hydrogen atom, C1-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl, aryl, heteroaryl, -SiR12R13R14or-C (═ O) R15；
R38Is C1-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkenyl radical, C3-10Cycloalkenyl radical, C2-10Alkynyl, C1-10Alkylthio, aryl, heteroaryl, -SiR23R24R25or-C (═ O) R30]；
The method comprises a process step a) and a process step b):
step a) is a step of treating the compound of formula (II) with an organometallic reagent, and then reacting it with the compound of formula (III) to obtain a compound of formula (IVa):
[ solution 4]
[ in the formula, X1And X2Each independently selected from a bromine atom and an iodine atom;
P1a protecting group which is a metal ion, a hydrogen atom or a hydroxyl group;
R41is as above for R1A group as defined, wherein the group may also have more than 1 protecting group; n is as defined above.
[ in the formula, P2、P3、P4And P5Each independently selected from protecting groups for hydroxyl groups; or, P2And P3、P3And P4And P4And P5Together independently are 2-valent radicals which respectively protect 2 hydroxyl groups and form a ring]
[ solution 6]
[ in the formula, R41、n、X2、P1、P2、P3、P4And P5Is as defined above;
x is a metal ion or a hydrogen atom ];
step b) is a step of treating the compound of formula (IVb) with an organometallic reagent and then reacting it with the compound of formula (V):
[ solution 7]
[ in the formula, R41、n、X2、P1、P2、P3、P4And P5Is as defined above;
P6protecting groups for metal ions, hydrogen atoms, or hydroxy groups]
[ solution 8]
[ in the formula, R42Is as above for R2Is determined byA group of the above, wherein the group may also have 1 or more protecting groups; m is as defined above]；
Further, the step of introducing a protecting group and/or the step of removing a protecting group may be included in the above-mentioned step and/or at any stage before or after the step.
In 1 embodiment of the above aspect of the present invention, the above production method further comprises a process c):
step c) the compound of formula (VI) is subjected to the following 2 stages:
stage (1): will P1A step of treating a compound of the formula (VI) which is a hydrogen atom under acidic conditions (wherein P is1When the group is a protecting group, a deprotection step before the treatment is further included); and the number of the first and second groups,
stage (2): removing a hydroxyl group formed by the reaction in the step b) by a reduction reaction;
(wherein, any stage may be performed first), thereby obtaining a compound of formula (VII):
[ solution 9]
[ in the formula, R41、R42、m、n、P1、P2、P3、P4、P5And P6Is as defined above]。
[ solution 10]
[ in the formula, R41、R42、m、n、P2、P3、P4And P5Is as defined above]。
The term "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
The term "C1-10The alkyl group "means a linear or branched alkyl group having 1 to 10 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropylmethyl, cyclohexylmethyl and the like. C1-10Also included in the alkyl group are straight or branched chain C1-6Alkyl group, and C1-4An alkyl group.
The term "C3-10The cycloalkyl group 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. C3-10Cycloalkyl also includes C3-8Cycloalkyl group, and C3-7A cycloalkyl group.
The term "C2-10The alkenyl group means a linear or branched alkenyl group having 2 to 10 carbon atoms, and includes, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group (allyl group), a propen-2-yl group, a 3-butenyl group (homoallyl group), a1, 4-pentadien-3-yl group and the like. C2-10Alkenyl also includes straight or branched C2-6Alkenyl, and C2-4An alkenyl group.
The term "C3-10Cycloalkenyl refers to C3-10 cyclic alkenyl groups, including cyclopentenyl, cyclohexenyl, and the like, and further including C5-10Cycloalkenyl groups, and the like.
The term "C2-10The alkynyl group means a linear or branched alkynyl group having 2 to 10 carbon atoms, and includes, for example, ethynyl, 1-propynyl, and 2-propynyl groups. C2-10Alkynyl also includes straight or branched C2-6Alkynyl group and C2-4Alkynyl.
The term "C1-10The "alkoxy group" refers to an alkoxy group having a linear or branched alkyl group having 1 to 10 carbon atoms as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, 3-methylbutyloxy, 2-methylbutyloxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3-ethylbutoxy, and 2-ethylbutoxy groups. C1-10Also included in the alkoxy group are straight or branched C1-6Alkoxy group, and C1-4An alkoxy group.
The term "C1-10The "alkylamino group" refers to an alkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as an alkyl moiety, and includes, for example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, a sec-butylamino group, an isobutylamino group, a tert-butylamino group, and the like. C1-10Also included in alkylamino are straight or branched chain C1-6Alkylamino group, and C1-4An alkylamino group.
The term "di (C)1-10The "alkyl) amino group" refers to a dialkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as an alkyl moiety, and the alkyl moieties may be the same or different, and includes, for example, a dimethylamino group, a diethylamino group, a di (n-propyl) amino group, a di (isopropyl) amino group, a di (n-butyl) amino group, a di (sec-butyl) amino group, a di (isobutyl) amino group, a di (tert-butyl) amino group, an ethyl (methyl) amino group, a methyl (n-propyl) amino group, a methyl (isopropyl) amino group, a n-butyl (methyl) amino group, a sec-butyl (methyl) amino group, an isobutyl (methyl) amino group, a tert-butyl (methyl) amino group, and. Two (C)1-10Alkyl) amino also includes straight or branched chain di (C)1-6Alkyl) amino, and di (C)1-4Alkyl) amino.
The term "C1-10The "alkylthio group" refers to an alkylthio group having a straight or branched alkyl group having 1 to 10 carbon atoms as the alkyl moiety, and includes, for example, methylthio, ethylthio, n-propylthio, n-propyl,Isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio and the like. C1-10Also included in alkylthio are straight or branched chain C1-6Alkylthio group, and C1-4An alkylthio group.
The term "saturated, partially unsaturated, or unsaturated heterocyclic group" as used in the present specification means a saturated, partially unsaturated, or unsaturated 4-to 10-membered heterocyclic group containing, for example, 1 or more heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Examples of the heterocyclic group include a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinoxalinyl group, a quinazolinyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a homopiperidinyl group, a homopiperazinyl group, and a morpholinyl group.
The term "aryl" is not particularly limited, and means an aryl group having an aromatic hydrocarbon ring having 6 to 14 carbon atoms, for example, 6 to 10 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
The term "heteroaryl group" is not particularly limited, and means a 4 to 10-membered aromatic heterocyclic group containing 1 or more heteroatoms selected from, for example, nitrogen atom, oxygen atom and sulfur atom. Examples of the heteroaryl group include a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinoxalyl group, a quinazolinyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, and a triazolyl group.
The term "carbocyclic ring" used herein is not particularly limited, and means a hydrocarbon ring having 6 to 14 carbon atoms, for example, 6 to 10 carbon atoms, and includes, for example, benzene, naphthalene, etc.
The term "heterocycle" used herein is not particularly limited, and means a 4-to 10-membered heterocycle containing 1 or more hetero atoms selected from, for example, a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the heterocyclic ring include pyridine, pyrimidine, pyrazine, triazine, quinoline, quinoxaline, quinazoline, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, and the like.
In the present invention, R is1And R2The defined group has 1 or more groups which can be protected, and for example, a hydroxyl group, a carboxyl group, a carbonyl group, an amino group, a mercapto group, or the like, the group may be protected with a protecting group. The choice of protecting Groups to be introduced into the respective Groups and the operation of removing them can be made, for example, according to "Greene and Wuts," Protective Groups in organic Synthesis "(4 th edition, John Wiley&Sons, 2006) ".
As R1And/or R2Examples of the protecting group of the hydroxyl group which may be contained in (1) include groups which are optionally substituted by 1 or more R51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C-(＝O)R54、-B(OR55)2And the like;
here, R51Each independently selected from the group consisting of56Substituted aryl, C which may be substituted by more than 1 aryl1-10Alkoxy radical, C1-10Alkylthio, and arylhydrogenseleno groups;
R52each independently selected from C1-10An alkoxy group;
R53and R55Each independently selected from C1-10Alkyl, and aryl;
R54is a hydrogen atom, C1-10Alkyl, optionally substituted by 1 or more C1-10Aryl, heteroaryl, optionally substituted by 1 or more R57Substituted amino, C which may be substituted by more than 1 aryl group1-10An alkoxy group or an aryloxy group which may be substituted with 1 or more nitro groups;
R56each independently selected from C1-10Alkyl radical, C1-10Alkoxy, aryl, and heteroaryl;
R57each independently of the otherIs selected from C1-10Alkyl groups, and aryl groups.
Preferable examples of the protective group for a hydroxyl group include a methyl group, a benzyl group, a methoxymethyl group, a methylthiomethyl group, a 2-methoxyethoxymethyl group, a benzyloxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a 1-ethoxyethyl group, a 1-methoxy-1-methylethyl group, a tert-butyl group, an allyl group, a vinyl group, a triphenylmethyl group (trityl group), a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldiphenylsilyl group, an isobutyryl group, a pivaloyl group, a benzoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a benzyloxycarbonyl group, and a tert-butoxycarbonyl group.
As R1And/or R2Examples of the protecting group of amino group which may be contained in (1) include groups which are optionally substituted by 1 or more R51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C(＝O)R54Etc. here, R51～R54Is as defined above. Preferable examples of the protecting group of the amino group include benzyl group, etc., and the primary amino group may be protected by converting it into a phthalimide group or a succinimidyl group.
As R1And/or R2Examples of the protecting group of the carboxyl group which may be contained in (1) include groups which are optionally substituted by 1 or more R51Substituted C1-10Alkyl radical, C2-10Alkenyl, -Si (R)53)3Iso ester forming group (here, R)51And R53As defined above), or-NR58R59Isoamide forming group (here, R)58And R59Each independently selected from the group consisting of51Substituted C1-10Alkyl radical, C2-10Alkenyl, -Si (R)53)3Here, R51And R53As defined above), etc. As by introduction into carboxyl groupsPreferable examples of the conversion of the protecting group include ethyl ester, benzyl ester, and tert-butyl ester.
To be as R1And R2Groups formed by introducing more than 1 protecting group into a defined group, including in R41And R42In the definition of (1).
R as defined in the invention1And R2Not specifically defined, for example, each is independently selected from C which may be substituted by 1 or more Ra1-10Alkyl, C which may be substituted by more than 1 Ra3-10Cycloalkyl, C which may be substituted by more than 1 Ra2-10Alkenyl, C which may be substituted by 1 or more Ra3-10Cycloalkenyl radical, C which may be substituted by more than 1 Ra2-10Alkynyl, aryl which may be substituted with 1 or more Ra, saturated, partially unsaturated, or unsaturated heterocyclic group which may be substituted with 1 or more Ra, and-SiR12R13R14. More preferably, R1And R2Each independently selected from C1-6Alkyl radical, C3-6Cycloalkyl, aryl, and-SiR12R13R14. In the present invention, when n or m is 0, R is not present on the benzene ring1Or R2. In 1 embodiment of the invention, n is 0, m is 0 or 1, R2Is C1-4An alkyl group.
As R1And R2The halogen atom defined is preferably a fluorine atom or a chlorine atom.
P1、P6The metal ion defined as X is a metal ion constituting a counter ion of the alkoxide ion, and examples thereof include an alkali metal ion such as a lithium ion, a sodium ion, a potassium ion, a cesium ion and a magnesium ion, an alkaline earth metal ion, and the like, and a complex can be formed with other metals. The metal ions include, for example, metal ions (for example, lithium ions) generated by reacting a hydroxyl group with the organometallic reagent used in the present invention.
P1～P6The "protecting group for hydroxyl group" contained in the definition of (1) is not particularly limited as long as it is a group generally used as a hydroxyl groupThe group used for the protecting group is not particularly limited. The choice of protecting groups introduced into the hydroxyl groups and the procedure for introduction may be as follows, for example, "Greene and Wuts," protective groups in Organic Synthesis "(4 th edition, John Wiley&Sons, 2006) ". Examples of the protecting group for a hydroxyl group include groups which can be substituted by 1 or more R51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C(＝O)R54、-B(OR55)2And the like.
The term "2-valent group which protects 2 hydroxyl groups and forms a ring" as used herein means a 2-valent group in which oxygen atoms of 2 hydroxyl groups are bonded, for example, C1-10Alkylene groups (e.g., methylene, methylmethylene, dimethylmethylene, etc.), and carbonyl groups, and the like.
The organometallic reagent used in the present invention is not particularly limited as long as it is an organometallic reagent suitable for conducting a halogen metal exchange reaction on a benzene ring, and includes, for example, C1-10Alkyl lithium (e.g., n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.), aryl lithium (e.g., phenyl lithium, naphthyl lithium, dimethoxyphenyl lithium, etc.), C1-10Alkyl magnesium halides (e.g., n-butyl magnesium chloride, isopropyl magnesium chloride, etc.), bis (C)1-10Alkyl) magnesium (e.g., di (n-butyl) magnesium, etc.), and the like. The organometallic reagent may be used in the presence of an inorganic salt or an organic salt (for example, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium trifluoromethanesulfonate, magnesium chloride, magnesium bromide, magnesium trifluoromethanesulfonate, or the like), or may be used as a mixture with an inorganic salt or an organic salt. The organometallic reagent includes, for example, a mixture or a reaction product of a magnesium compound and an organolithium compound as described in WO2001/057046 on pages 11 to 17, for example, butylmagnesium chloride and butyllithium, isopropylmagnesium bromide and lithium chloride, dibutylmagnesium and butyllithium, dibutylmagnesium and lithium ethoxide, dibutylmagnesium and lithium tert-butoxideDibutyl magnesium and hexamethyldisilazane lithium amide, butyl magnesium bromide and butyl lithium, isopropyl magnesium bromide and butyl lithium and lithium chloride, butyl magnesium chloride and butyl lithium and lithium ethoxide, butyl magnesium chloride and butyl lithium and hexamethyldisilazane lithium amide, a mixture or reaction product of isopropyl magnesium bromide and butyl lithium and lithium ethoxide, zinc chloride and butyl lithium, diethyl zinc and butyl lithium, an organic zinc complex described in Japanese patent laid-open publication No. 2004-292328A, and the like.
For example, in the steps a) and b) of the present invention, n-butyllithium is used as the organometallic reagent. Further, as the organometallic reagent, a metal complex formed by sequentially reacting 2 or more kinds of reagents may be used. For example, after the compound represented by the formula (II) is treated with butyl lithium, butyl magnesium chloride and butyl lithium may be added to the system, and then, the mixture may be reacted with the compound represented by the formula (III).
In the present specification, the compound represented by the formula-SiR12R13R14Of the formula-SiR23R24R25And formula-Si (R)53)3The specific substituted silyl group is not particularly limited, and includes, for example, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldiphenylsilyl group and the like.
In the compound of the formula (II) used in step a), X1And X2For example, both are bromine atoms. In addition, as P1Examples of (3) include, for example, lithium ions, hydrogen atoms, and, for example, C1-6Alkoxy radical C1-6Alkyl (e.g., methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl, etc.), arylmethoxy C1-6Alkyl (e.g., benzyloxymethyl, etc.), tetrahydropyranyl, a group-Si (R)53)3(e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyl (e.g., benzyl, 4-methoxybenzyl, tris (t-butyl-phenyl-ethyl-phenyl-methyl-phenyl-ethyl-phenyl-methyl-phenyl-Benzyl, etc.), group-B (OR)55)2And the like.
The treatment of the compound of formula (II) in step a) with an organometallic reagent can be carried out using a solvent suitable for the halogen metal exchange reaction. Examples of the solvent include ethers (e.g., Tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, etc.), hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.), N-tetramethylethylenediamine, N-tetramethylpropylenediamine, and mixed solvents containing 2 or more of the above solvents. When P is present1When the metal ion or the protecting group is used, 0.5 to 1.5 equivalents, for example, 0.8 to 1.1 equivalents of the organometallic reagent is used, when P is1In the case of hydrogen atoms, 1.5 to 3.0 equivalents, for example, 1.8 to 2.2 equivalents of an organometallic reagent may be used.
In addition, the organometallic reagent may be added little by little from the viewpoint of improving the site selectivity of the reaction, and for example, may be added dropwise over 15 minutes, preferably 15 to 300 minutes, more preferably 30 to 300 minutes. The addition of the organometallic reagent may be carried out intermittently. The addition time may include 1 or more times of the interruption time, and for example, the addition may be performed in 2 or 3 times with 1 or 2 times of the interruption time (for example, 5 to 300 minutes, preferably 15 to 120 minutes) interposed.
In addition, from the viewpoint of improving the site selectivity of the reaction, an aryl halide may be added to the reaction mixture in a predetermined amount (for example, 0.05 to 0.5 equivalents, preferably 0.1 to 0.4 equivalents, relative to the amount of the reaction substrate contained in the initial reaction mixture) after the addition of the organometallic reagent is completed. As the aryl halide, for example, iodobenzene, diiodotoluene, dibromotoluene, and a reaction substrate (for example, 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene) can be used, with preference given to the reaction substrate.
From the viewpoint of improving the site selectivity of the reaction, the organometallic reagent may be added little by little (for example, dropped) to the system at a temperature of, for example, -80 to 30 ℃, preferably-60 to 25 ℃, particularly preferably-15 to 0 ℃. After the addition of the reagent, the reaction is preferably completed by stirring at a suitable temperature, for example, -80 to 0 ℃, preferably, -15 to 0 ℃ for a certain period of time (for example, 0.1 to 5 hours).
When P is present in view of improving the site selectivity of the reaction1In the case of a metal ion or a protective group, an organometallic reagent may be added in an amount of less than 1 equivalent, for example, 0.4 to 0.9 equivalent, preferably 0.8 equivalent, and the reaction mixture may be stirred at an appropriate temperature, for example, 80 to 30 ℃, preferably 60 to 25 ℃, particularly preferably 15 to 0 ℃ for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours; then, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, of an organometallic reagent may be added thereto, and the reaction mixture may be stirred at-80 to 30 ℃, preferably-60 to 25 ℃, particularly preferably-15 to 0 ℃ for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours. Here, the equivalent number means a molar equivalent relative to the compound of formula (II) as a reaction substrate. In the present specification, unless otherwise specified, "equivalent" means a molar equivalent.
When P is present in view of improving the site selectivity of the reaction1In the case of a hydrogen atom, an organometallic reagent of less than 2 equivalents, for example, 1.4 to 1.9 equivalents, preferably 1.8 equivalents, may be added, and the reaction mixture may be stirred at an appropriate temperature, for example, at-80 to 30 ℃, preferably-60 to 25 ℃, particularly preferably-15 to 0 ℃ for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours; then, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, of an organometallic reagent may be added thereto, and the reaction mixture may be stirred at-80 to 30 ℃, preferably-60 to 25 ℃, particularly preferably-15 to 0 ℃ for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours. Here, the equivalent number means a molar equivalent relative to the compound of formula (II) as a reaction substrate.
In the reaction of the step a), it is preferable to have a large amount ofX of a compound of formula (II) having a single reaction site1Causes a halogen metal exchange reaction, and as a result, the amount of the compound of the formula (IVa) obtained as the target product exceeds that due to the reaction at X2The amount of by-products produced by the metal exchange reaction of the halogen. From this, it can be considered that the reaction is a site-selective reaction. The site selectivity in the step a) is not particularly limited, and for example, the ratio of the target product to the by-product may be 10: 1 or more, preferably 30: 1 or more.
In addition, C may be used1-10After a halogen metal exchange reaction is performed with alkyllithium (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium, etc.) and aryllithium (e.g., phenyllithium, naphthyllithium, dimethoxyphenyllithium, etc.), another organometallic reagent (e.g., n-butylmagnesium chloride, n-butyllithium, dibutylmagnesium, etc.) is added, and the reaction mixture is stirred at an appropriate temperature, for example, from-80 to 30 ℃, preferably from-60 to 25 ℃, particularly preferably from-15 to 0 ℃ for a certain period of time, for example, from 0.1 to 5 hours, preferably from 0.5 to 2 hours, to form a complex.
In 1 embodiment of the invention, P is used in process step a)1A compound of formula (II) which is a hydrogen atom.
In the compounds of the formula (III) used in process a), as P2、P3、P4And P5Examples of (3) include, for example, C1-6Alkoxy radical C1-6Alkyl (e.g., methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl, etc.), arylmethoxy C1-6Alkyl (e.g., benzyloxymethyl, etc.), tetrahydropyranyl, a group-Si (R)53)3(e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyl (e.g., benzyl, 4-methoxybenzyl, triphenylmethyl, etc.), group-B (OR)55)2、C1-6Alkylcarbonyl (e.g., acetyl, propionyl, pivaloyl, etc.), C1-6Alkoxycarbonyl (e.g. methoxy)Carbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.), tert-butyl, etc. In addition, P may be used4And P5Together represent a 2-valent group (e.g., -CH) capable of protecting 2 hydroxyl groups and forming a ring2-、-CH(CH3)-、-C(CH3)2-, -CHPh-, etc.).
The reaction of the compound of the formula (II) treated with the organometallic reagent with the compound of the formula (III) can be carried out, for example, by adding a solution of the compound of the formula (II) in an appropriate solvent little by little (for example, dropwise) to a reaction mixture containing the compound of the formula (III) (for example, 1.0 to 1.1 equivalents) at an appropriate temperature, for example, at-100 to 0 ℃, preferably-90 to-30 ℃, and particularly preferably-80 to-40 ℃. Examples of suitable solvents include ethers (e.g., Tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, etc.), hydrocarbons (e.g., hexane, heptane, benzene, toluene, etc.), and mixed solvents containing 2 or more of the above solvents. After the compound of formula (II) is added, the reaction may be completed by stirring at an appropriate temperature, for example, at-80 to-40 ℃ for a certain period of time (for example, 0.5 to 5 hours).
The present reaction may be post-treated by a conventional method, and the obtained product may be purified by a conventional method, whereby the compound of formula (IVa) can be obtained, and from the viewpoint of simplification of the production process, suppression of the amount of solvent used, suppression of the production cost, and the like, it is preferable to directly perform the subsequent process without performing the post-treatment of the present reaction.
The preparation process of the present invention may also comprise obtaining P by introducing a protecting group into the compound of formula (IVa)6A step of preparing a compound of formula (IVb) which is a protecting group for a hydroxyl group. The introduction of the protecting group in this step can be carried out by: for example, a compound of the formula (II) treated with an organometallic reagent is added to a compound of the formula (III), and then at an appropriate temperature, for example at-100 to 0 ℃, preferably-90 to-60 ℃, particularly preferably-80 to-75 ℃,to the reaction mixture, a reagent for introducing a protecting group (for example, 1.0 to 2.0 equivalents) and an appropriate amount of a base (for example, 0.1 to 1.0 equivalent) as required, for example, triethylamine, N-methylmorpholine, ethyldiisopropylamine, etc. are added. Preferably, after the addition of the reagent or after the addition of the reagent and subsequent temperature rise, the reaction is completed by stirring for a certain period of time (for example, 0.1 to 5 hours).
Examples of the reagent for introducing a protecting group include silylating agents such as trimethylsilyl chloride, triethylsilane chloride, t-butyldimethylsilane chloride, isopropyldimethylsilane chloride and t-butyldiphenylsilane chloride; alkyl halides such as methyl iodide and benzyl bromide; acyl halides such as pivaloyl chloride; c such as methoxymethyl chloride, ethoxymethyl chloride, etc1-6Alkoxy radical C1-6Alkyl halides, and the like. When P is a compound of formula (IVa)1In the case of a metal ion or a hydrogen atom, P can be obtained by introducing a protecting group at the position by using an appropriate amount of a reagent in the step1A compound of formula (IVb) which is a protecting group for a hydroxy group. Thus, in 1 embodiment of the invention, in step b), P is used6(IVb) which is a protecting group for a hydroxyl group.
The above-mentioned protecting group-introducing reaction may be post-treated by a conventional method, and the obtained product may be purified by a conventional method, whereby the compound of formula (IVb) can be obtained. However, from the viewpoint of simplification of the production process, suppression of the amount of solvent used, suppression of production cost, and the like, it is also preferable to directly perform the subsequent process without performing post-treatment for the reaction.
The treatment in step b) with the organometallic reagent of the compound of formula (IVb) may also be carried out using a solvent suitable for the halogen metal exchange reaction. Examples of the solvent include ethers (e.g., Tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, etc.), hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.), etc., and a mixed solvent containing 2 or more of the above solvents. When the post-treatment is not performed in the previous step, the solvent of the previous step may be used as it is.
As the organometallic reagent, 0.3 to 4.0 equivalents, for example, 1.0 to 3.0 equivalents, preferably 1.1 to 2.1 equivalents, can be used.
The organometallic reagent can be added (for example, dropped) to the system little by little at a temperature of, for example, -100 to 30 ℃, preferably, -90 to-10 ℃, and particularly preferably, -90 to-70 ℃. After the addition of the organometallic reagent, the reaction can be stirred at an appropriate temperature, for example, from-100 to 30 ℃, preferably from-90 to-10 ℃, and particularly preferably from-90 to-70 ℃ for a certain period of time, for example, from 0.1 to 5 hours, preferably from 0.5 to 2 hours.
The reaction of the compound of formula (IVb) treated with the organometallic reagent with the compound of formula (V) can be carried out, for example, by adding a solution of the compound of formula (V) in a suitable solvent to the reaction mixture containing the compound of formula (IVb) at a suitable temperature, for example at-100 to 30 ℃, preferably-90 to-10 ℃, particularly preferably-80 to-70 ℃. Here, 1.0 to 15.0 equivalents, for example, 1.0 to 5.0 equivalents, preferably 1.1 to 2.2 equivalents, of the compound of the formula (V) may be used. Examples of suitable solvents include ethers (e.g., Tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, etc.), hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.), etc., and mixed solvents containing 2 or more of the above solvents. After the addition of the formula (V), the reaction may be completed by stirring at an appropriate temperature, for example, at-90 to 0 ℃ for a certain period of time (for example, 0.1 to 5 hours).
The reaction in step b) may be worked up by a conventional method, and the obtained product may be purified by a conventional method to obtain the compound of formula (VI). From the viewpoints of simplification of the production process, suppression of the amount of solvent used, suppression of production cost, and the like, it is preferable to directly perform the subsequent process without performing post-treatment and without particularly purifying the obtained crude product.
When P is present in the compound of formula (VI)1In the case of a hydroxyl-protecting group, the protecting group is converted to P by deprotection before the stage (1) of the step c)1A compound which is a hydrogen atom. In 1 embodiment of the present invention, P can also be removed by this deprotection2～P6Introduced protecting groups. Deprotection can be carried out by a method known in the art, for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate, boron trichloride, boron tribromide, or like acids or lewis acids can be used; bases such as sodium hydroxide, lithium hydroxide, potassium carbonate, etc.; organic metal reagents such as butyl lithium and grignard reagents; metal hydride reagents such as lithium aluminum hydride, lithium boron hydride, and diisobutylaluminum hydride; boron trifluoride diethyl etherate-ethanethiol, aluminum halide-sodium iodide, aluminum halide-mercaptan, aluminum halide-thioether and other reagents which are formed by combining Lewis acid and nucleophilic reagent; hydrogenation is carried out using a catalyst such as palladium, platinum, a homogeneous palladium complex, a homogeneous ruthenium complex, or a homogeneous rhodium complex supported on carbon.
By the treatment of the stage (1), a spiro ring structure is formed. The reaction in the stage (1) can be carried out in an appropriate solvent, for example, Tetrahydrofuran (THF), methyltetrahydrofuran, 1, 2-dimethoxyethane, acetonitrile, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetone, an acetate (for example, ethyl acetate, methyl acetate, isopropyl acetate, etc.), dichloromethane, chloroform, dichloroethane, water, or a mixed solvent containing 2 or more of the above solvents, at an appropriate temperature, for example, from-20 to 100 ℃, preferably from 0 to 80 ℃, particularly preferably from 20 to 30 ℃. The reaction time may be suitably set, for example, to about 0.5 to 15 hours, preferably about 2 to 10 hours. The acid to 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 etherate, boron trichloride, boron tribromide and the like.
In 1 variant of the invention, the treatment under acidic conditions is carried out by stage (1)It is also possible to remove P simultaneously1～P6Introduced protecting groups and the formation of spiro rings.
The reduction reaction in the step (2) of the step c) may be carried out in a suitable solvent such as Tetrahydrofuran (THF), methyltetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, isopropanol, an acetate (e.g., ethyl acetate, methyl acetate, isopropyl acetate, etc.), acetone, water, or a mixed solvent containing 2 or more of the above solvents at a suitable temperature, for example, from-80 ℃ to 80 ℃, preferably from-30 ℃ to 70 ℃, and particularly preferably from-20 ℃ to 60 ℃. The reaction time may be suitably set, for example, to 0.5 to 24 hours, preferably about 5 to 15 hours. The reduction reaction is not particularly limited as long as it is a reaction using an appropriate reducing agent and/or catalyst for removing the hydroxyl group on the carbon atom linking the 2 benzene rings of the compound of formula (VI), and for example, a metal catalyst (for example, palladium on carbon, platinum, a homogeneous palladium complex, a homogeneous ruthenium complex, a homogeneous rhodium complex) in a hydrogen atmosphere can be used; hydride type reducing agents (for example, aluminum chloride-sodium borohydride, trifluoroacetic acid-triethylsilane) in combination with a lewis acid, and the like.
In the 1 embodiment of the present invention, the introduction of P into the reaction mixture can be simultaneously removed by the reduction reaction in the stage (2)1～P6And a step of removing a hydroxyl group. In the step c), the step (1) or the step (2) may be performed first, and when P is performed1Or P1～P6The deprotection of (2) may be carried out at any stage prior to the stage (1).
The production method of the present invention may further include a step of removing any protecting group contained in the compound obtained in the step c), and may further include a step of converting the compound of the formula (I) obtained by the production method of the present invention into another compound of the formula (I).
In 1 embodiment of the present invention, the steps a) and b) can be carried out by a so-called one-pot reaction, in which necessary reagents and the like are sequentially added without carrying out post-treatment or purification. Therefore, the production method of the present invention is excellent in that the target product can be obtained in a good yield and the target product can be obtained by performing the one-pot reaction, and thus the production process can be simplified, the amount of the solvent used can be suppressed, and the production cost can be suppressed.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula (I) as described in the specification, of high purity, which comprises:
step d): a step of converting the compound of formula (I) into a compound of formula (X):
[ solution 11]
[ in the formula, R41、R42M and n are as defined in the specification, P7Being protecting groups for hydroxy groups]；
Step e): a step of crystallizing the compound of formula (X) and purifying the crystal by recrystallization;
step f): removing the protecting group from the compound of formula (X) to obtain a high-purity compound of formula (I).
Among the compounds of the above formula (X), for example, compounds of the formulae (Xa) and (Xb);
[ solution 12]
As P7The "protecting group for hydroxyl group" as defined is not particularly limited as long as it is a group usually used as a protecting group for hydroxyl group, and includes, for example, those described in "Greene and Wuts," Protective Groups in Organic Synthesis "(4 th edition, John Wiley&Sons, 2006) ". As examples of the protecting group for a hydroxyl group,can be represented by 1 or more R51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C(＝O)R54、-B(OR55)2Etc. group, R51～R55Is as defined above.
In 1 embodiment of the invention, P7Is selected from C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, -SiR23R24R25，R23、R24And R25Is as defined above.
The protecting group-introducing reaction in step d) can be carried out by a method known in the art, and for example, reagents and reaction conditions described in "Greene and Wuts," Protective Groups in organic Synthesis "(4 th edition, John Wiley & Sons, 2006)" can be used. Examples of the solvent used in the reaction include ethers (e.g., Tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, etc.), hydrocarbons (e.g., benzene, toluene, etc.), acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetone, acetates (e.g., ethyl acetate, methyl acetate, isopropyl acetate, etc.), dichloromethane, chloroform, dichloroethane, water, etc., and mixed solvents containing 2 or more of the above solvents.
Depending on the protecting group to be introduced, a reagent for introducing a protecting group may be selected, and for example, 1.0 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents, of C may be used with respect to the hydroxyl group1-6Alkyl carbonyl chloride, C1-6Alkoxycarbonyl chlorides, Cl-SiR23R24R25And the like, and a base may be used as necessary. Examples of the base include triethylamine, pyridine, N-dimethylaniline, 4- (dimethylamino) pyridine, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, morpholine, potassium carbonate, sodium carbonate, and hydrogen carbonateSodium, and the like. Preference is given to using 1-methylimidazole. The reaction temperature is not particularly limited, and may be, for example, -20 to 50 ℃, preferably, -10 to 25 ℃, and the reaction may be carried out with stirring for a certain period of time, for example, 1 to 10 hours, preferably 2 to 4 hours.
The crystallization in step e) can be carried out using an appropriate solvent, for example, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diisopropyl ether, acetonitrile, acetone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene, or water, or a mixed solvent containing 2 or more of the above solvents. The recrystallization in this step can be carried out by a method known in the art using an appropriate solvent, for example, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diisopropyl ether, acetonitrile, acetone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene, or water, or a mixed solvent containing 2 or more of the above solvents.
Deprotection may be carried out by selecting a method known in the art suitable for removing a protecting group, and for example, reagents and reaction conditions described in "Greene and Wuts," Protective Groups in organic Synthesis "(4 th edition, John Wiley & Sons, 2006)" may be used. For example, there can be used a method using an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate, boron trichloride, boron tribromide or the like, or a lewis acid; bases such as sodium hydroxide, lithium hydroxide, potassium carbonate, etc.; organic metal reagents such as butyl lithium and grignard reagents; metal hydride reagents such as lithium aluminum hydride, lithium boron hydride, and diisobutylaluminum hydride; boron trifluoride diethyl etherate-ethanethiol, aluminum halide-sodium iodide, aluminum halide-mercaptan, aluminum halide-thioether and other Lewis acids and nucleophilic reagents; hydrogenation of catalysts such as palladium on carbon, platinum, homogeneous palladium complexes, homogeneous ruthenium complexes, and homogeneous rhodium complexes.
In 1 embodiment of the invention, as the compound of formula (I) in step d) is used a crude product obtained by employing a preparation method comprising steps a) to c) as defined in the present specification. Since the above-mentioned steps a) to c) can produce the target product without purification, it is very advantageous to combine the steps d) to f) which can be highly purified from the viewpoint of high efficiency of production. In addition, the steps d) to f) can also be combined with other methods for the preparation of the compounds of the formula (I).
In the present invention, "high purity" means a purity higher than that of the compound of formula (I) used as a raw material in the step d). Examples of the high-purity compound of the formula (I) include compounds of the formula (I) having a purity of 90.0 wt% or more, preferably 97.0 wt% or more.
In 1 embodiment of the present invention, the production method of the present invention comprises a step of further crystallizing the high purity compound of formula (I) obtained in step f). Examples of the solvent used in the crystallization process include solvents selected from water, alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1-hexanol), ethers (e.g., tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diisopropyl ether), esters (e.g., ethyl acetate, propyl acetate, hexyl acetate), amides (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-dibutylformamide), halogenated hydrocarbons (e.g., 1-chlorohexane), hydrocarbons (e.g., N-propylbenzene, hexylbenzene, heptane, toluene), ketones (e.g., acetone, 2-butanone, 2-heptanone), acetonitrile, and dimethylsulfoxide, Or a mixture thereof.
The compound of formula (I) obtained may be further purified by recrystallization. Examples of the solvent that can be used for recrystallization include solvents selected from water, alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, or 1-hexanol), ethers (e.g., tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, or diisopropyl ether), esters (e.g., ethyl acetate, propyl acetate, or hexyl acetate), amides (e.g., N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or N, N-dibutylformamide), halogens (e.g., 1-chlorohexane), hydrocarbons (e.g., N-propylbenzene, hexylbenzene, heptane, or toluene), ketones (e.g., acetone, 2-butanone, 2-heptanone), acetonitrile, and dimethyl sulfoxide, Or a mixed solvent containing 2 or more of the above solvents.
In another embodiment of the invention, n is 0, m is 0 or 1, R2Is C1-4Highly pure compounds of formula (I) of alkyl. In another embodiment of the invention, n is 0, m is 0 or 1, R2Is C1-4Crystals of the compound of formula (I) with high purity of the alkyl group.
The production method of the present invention including the steps d) to f) is useful from the viewpoint of increasing the efficiency of the production method and suppressing the production cost, because the production method can produce a compound of formula (I) with high purity without carrying out a purification method such as column chromatography which is complicated in operation and requires a large amount of solvent and adsorbent. In addition, 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.
According to another aspect of the invention, there is provided a compound of formula (IVb):
[ solution 13]
[ in the formula, R41、n、X2、P1、P2、P3、P4、P5And P6Is as defined above]。
The compounds are useful as synthetic intermediates for compounds of formula (I).
According to another aspect of the invention, there is provided a compound of formula (VI):
[ solution 14]
[ in the formula, R41、R42、m、n、P1、P2、P3、P4、P5And P6Is as defined above]. Furthermore, the compounds are useful as synthesis intermediates for compounds of formula (I).
According to another aspect of the present invention there is provided a crystal of the compound of formula (XI):
[ solution 15]
In 1 embodiment of the invention, the crystal is a monohydrate. The monohydrate is not particularly limited as long as it is a crystal that is stable in an environment (temperature, relative humidity, etc.) in which a pharmaceutical product is usually stored or used and retains about 1 equivalent of water. In 1 version of the above aspect, the crystals are provided as sodium acetate co-crystals or potassium acetate co-crystals. Further, according to another aspect of the present invention, there is provided a monohydrate crystal of the compound of formula (XI) having high purity.
The monohydrate crystal of the present invention has peaks at diffraction angles (2 θ) in the powder X-ray diffraction pattern in the vicinity of 3.5 °, 6.9 °, and 13.8 °, specifically in the vicinity of 3.5 °, 6.9 °, 13.8 °, 16.0 °, 17.2 °, and 18.4 °, more specifically in the vicinity of 3.5 °, 6.9 °, 10.4 °, 13.8 °, 16.0 °, 17.2 °, 18.4 °, 20.8 °, 21.4 °, and 24.4 °. The sodium acetate co-crystal of the present invention has peaks at diffraction angles (2 θ) in the powder X-ray diffraction pattern in the vicinity of 4.9 °, 14.7 °, 16.0 °, 17.1 °, and 19.6 °, more specifically in the vicinity of 4.9 °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 °, and 22.0 °. The potassium acetate co-crystal of the present invention has peaks at diffraction angles (2 θ) in the powder X-ray diffraction pattern in the vicinity of 5.0 °, 15.1 °, 19.0 °, 20.1 ° and 25.2 °, more specifically in the vicinity of 5.0 °, 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 ° and 25.2 °. Here, the powder X-ray diffraction pattern can be measured by a usual method. The value of the diffraction angle of the powder X-ray diffraction peak of the crystal of the present invention has a certain error depending on the measurement conditions and the state of the sample. For example, there is an error of about ± 0.2.
The monohydrate crystal of the present invention can be obtained by crystallization from a solvent such as water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, or a mixed solvent of 1, 2-dimethoxyethane and water. The crystallization can be carried out using, for example, a mixed solvent of acetone and water, and the volume ratio of acetone to water is preferably 1: 3.5 to 1: 7, more preferably 1: 4 to 1: 7.
The sodium acetate cocrystal of the present invention can be obtained by crystallization using a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, propyl acetate, hexyl acetate, 2-butanone, 2-heptanone, n-propylbenzene, hexylbenzene, and 1-chlorohexane, or a mixed solvent of 2 or more of these solvents, preferably a mixed solvent of methanol and isopropanol. The potassium acetate cocrystal of the present invention can be obtained by crystallization using, for example, a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, N-dibutylformamide, acetone, and diisopropyl ether, or a mixed solvent of 2 or more of these solvents, preferably a mixed solvent of methanol and isopropanol.
The monohydrate crystals of the present invention have the property of having a substantially constant water content over a range of relative humidities, and the compound is easy to handle during the formulation process. In addition, the monohydrate crystal, the sodium acetate cocrystal, and the potassium acetate cocrystal of the present invention are suitable for the preparation of a pharmaceutical preparation having good storage stability. Further, the monohydrate crystal, the sodium acetate co-crystal, and the potassium acetate co-crystal of the present invention are suitable for efficiently and highly purifying the compound of formula (XI), and therefore are also useful from the viewpoint of efficiently producing a pharmaceutical product containing the compound.
Drawings
Fig. 1 is an example of the measurement result of the moisture adsorption isotherm measured in test example 1.
Fig. 2 shows an example of the measurement results of the powder X-ray diffraction of the monohydrate crystal measured under the measurement condition 1 of test example 5.
Fig. 3 shows an example of the measurement results of the powder X-ray diffraction of the monohydrate crystal measured under the measurement condition 2 of test example 5.
Fig. 4 shows an example of the measurement result of the powder X-ray diffraction of the amorphous material measured in test example 5.
Fig. 5 shows an example of the results of the powder X-ray diffraction measurement of sodium acetate cocrystals measured in test example 5.
Fig. 6 shows an example of the results of powder X-ray diffraction measurement of the potassium acetate cocrystal measured in test example 5.
Detailed Description
Examples
Preferred examples of the present invention will be described in more detail below, but the present invention is not limited to these examples.
NMR measurement was carried out using JNM-ECP-500 (manufactured by JEOL) or JNM-ECP-400 (manufactured by JEOL) as a nuclear magnetic resonance apparatus. The mass analysis was performed using a mass spectrometer LCT PremierXE (manufactured by Waters). Preparative HPLC uses GL-Science preparative separation system. Agilent 1100 (manufactured by Agilent) was used as the HPLC. The moisture content was measured using a KF analyzer (model KF-100) (micro-moisture measuring device, manufactured by Mitsubishi chemical corporation). In the case where the product is used in the subsequent step without purification, a part of the product is taken out and used for NMR measurement, or another product prepared by the same method is suitably purified and used for NMR measurement.
EXAMPLE 1 Synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
Step 1: synthesis of 3, 4, 5-tris (trimethylsilyloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-one
[ solution 16]
Trimethylsilyl chloride (29.1kg) was added to a tetrahydrofuran (70kg) solution of D- (+) -glucono-1, 5-lactone (7.88kg) and N-methylmorpholine (35.8kg) at a temperature of 40 ℃ or lower, followed by stirring at 30 to 40 ℃ for 2 hours. The solution was cooled to 0 ℃ and toluene (34kg) and water (39kg) were added to separate an organic layer. The organic layer was washed 2 times with 5% aqueous sodium dihydrogenphosphate solution (39.56kg), 1 time with water (39kg), and the solvent was distilled off under reduced pressure to obtain the title compound as an oil. This product was used in the subsequent step 3 without further purification.
1H-NMR(CDCl3)：0.13(9H，s)，0.17(9H，s)，0.18(9H，s)，0.20(9H，s)，3.74-3.83(3H，m)，3.90(1H，t，J＝8.0Hz)，3.99(1H，d，J＝8.0Hz)，4.17(1H，dt，J＝2.5，8.0Hz)
And a step 2: synthesis of 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene
[ solution 17]
To a tetrahydrofuran solution (300ml) of 2, 4-dibromobenzyl alcohol (40g, 0.15mol) was added 2-methoxypropene (144ml, 1.5mol) at room temperature under a nitrogen atmosphere, and then cooled to 0 ℃. At 0 ℃, adding p-toluenesulfonic acid pyridine(75mg, 0.30mmol) and stirred at the same temperature for 1 hour. Subsequently, the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution which had been cooled to 0 ℃ and extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain quantitative title compound as an oil. The product was used in the subsequent steps without further purification.
1H-NMR(CDCl3)：1.44(6H，s)，3.22(3H，s)，4.48(2H，s)，7.42(1H，d，J＝8.0Hz)，7.44(1H，dd，J＝1.5，8.0Hz)，7.68(1H，d，J＝1.5Hz)
Step 3: synthesis of 2, 3, 4, 5-tetrakis (trimethylsiloxy) -6-trimethylsiloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran
[ solution 18]
2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (70g, 207mmol) obtained in the previous step was dissolved in toluene (700mL) and methyl t-butyl ether (70mL) under a nitrogen atmosphere, and a hexane solution of n-butyllithium (1.65M, 138mL, 227mmol) was added dropwise thereto over 30 minutes at 0 ℃. After stirring at 0 ℃ for 1.5 hours, the solution was dropped into a tetrahydrofuran solution (507ml) of 3, 4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-one (example 1, 108g, 217 mo) at-78 ℃ and stirred at the same temperature for 2 hours. To the solution were added triethylamine (5.8ml, 41mmol) and trimethylsilyl chloride (29.6ml, 232mmol), and the mixture was stirred at 0 ℃ for 1 hour to obtain a solution containing 2, 3, 4, 5-tetrakis (trimethylsilyloxy) -6-trimethylsiloxymethyl-2- (5-bromo-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran.
The resulting solution was cooled to-78 ℃ and a hexane solution of n-butyllithium (1.65M, 263ml, 434mmol) was added dropwise thereto, followed by stirring at the same temperature for 30 minutes. 4-ethylbenzaldehyde (62ml, 455mmol) was added dropwise at-78 ℃ and stirred at the same temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain the product (238g) containing the title compound as an oil. The product was used in the subsequent steps without further purification.
A part of the obtained oily substance was purified by high performance liquid chromatography (column: InertsilODS-3, 20mm I.D. times.250 mm; acetonitrile, 30mL/min) to obtain the title compound as 4 diastereomers (2 mixtures containing 2 diastereomers each).
Mixture of diastereomers 1 and 2:
1H-NMR(500MHz，CDCl3): -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 and 1.202(3H, each t, J ═ 8.0Hz), 1.393 and 1.399(3H, each s), 1.44(3H, s), 2.61(2H, q, J ═ 8.0Hz), 3.221 and 3.223(3H, each s), 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 and 4.58(1H, d, 4.12, J ═ 4.12 Hz), 3.61-3.58 (3H, m), 4.56 and 4.58(1H, d ═ 8.5Hz)92 and 4.93(1H, each d, J-12.4 Hz), 5.80 and 5.82(1H, each d, J-3.0 Hz), 7.14(2H, d, J-8.0 Hz), 7.28-7.35(3H, m), 7.50-7.57(2H, m).
MS(ESI+)：875[M+Na]+。
Mixture of diastereomers 3 and 4:
1H-NMR (500MHz, toluene-d)880 ℃ C.): -0.25(4H, s), -0.22(5H, s), 0.13(5H, s), 0.16(4H, s), 0.211 and 0.214(9H, 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 and 3.194(3H, 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 and 5.66(1H, s), 7.03(2H, d, J ═ 14.5Hz), 7.10-5.17 (1H, m), 5.64 and 5.66(1H, s), 7.03(2H, d, 8J ═ 14.5.5H, 7.59, 7.7.7.5H, 7.87, 7.9H, 7.87H, 7.9H, m)
MS(ESI+)：875[M+Na]+。
And step 4: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
[ solution 19]
The oily substance (238g) containing 2, 3, 4, 5-tetrakis (trimethylsilyloxy) -6-trimethylsiloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran obtained in the preceding step was dissolved in acetonitrile (693ml) under a nitrogen atmosphere, and water (37ml) and a 1N aqueous HCl solution (2.0ml) were added thereto, followed by stirring at room temperature for 5.5 hours. Water (693ml) and n-heptane (693ml) were added to the reaction mixture, and the aqueous layer was separated. After the aqueous layer was further washed with n-heptane (693ml) for 2 times, water was distilled off under reduced pressure to obtain an oil (187g) containing water and the title compound (diastereomer mixture). The product was used in the subsequent steps without further purification.
1H-NMR(500MHz，CD3OD): 1.200(3H, t, J ═ 7.7Hz), 1.201(3H, t, J ═ 7.7Hz), 2.61(2H, q, J ═ 7.7Hz), 3.44-3.48(1H, m), 3.63-3.68(1H, m), 3.76-3.84(4H, m), 5.09(1H, d, J ═ 12.8Hz), 5.15(1H, d, J ═ 12.8Hz), 5.79(1H, s), 7.15(2H, d, J ═ 7.7Hz), 7.24 and 7.25(1H, d, J ═ 8.4Hz), 7.28(2H, d, J ═ 7.7Hz), 7.36(1H, dd, J ═ 8.4, 1.5, 7.40H, 7.42H, 42-42 m)
MS(ESI+)：425[M+Na]+。
Step 5: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose (crude product)
[ solution 20]
5% Pd/C (26g, 6.2mmol, water content 53%) was added to a solution of the oily 1, 2-dimethoxyethane (187g) containing 1, 1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose obtained in the previous step in 693ml, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure to obtain an oil (59g) containing the title compound. The purity of the compound calculated from the area ratio measured by high performance liquid chromatography was 85.7%. The product was used in the subsequent steps without further purification.
1H-NMR(CD3OD)：1.19(3H，t，J＝7.5Hz)，2.59(2H，q，J＝7.5Hz)，3.42-3.46(1H，m)，3.65(1H，dd，J＝5.5，12.0Hz)，3.74-3.82(4H，m)，3.96(2H，s)，5.07(1H，d，J＝12.8Hz)，5.13(1H，d，J＝12.8Hz)，7.08-7.12(4H，m)，7.18-7.23(3H，m)
MS(ESI+)：387[M+1]+
Measurement conditions of the high performance liquid chromatograph:
column: cadenza CD-C1850 mm P/NCD032
Mobile phase: solution A: h2O, liquid B: MeCN
Gradient operation: the B liquid is from 5% to 100% (6 minutes), 100% (2 minutes)
Flow rate: 1.0mL/min
Temperature: 35.0 deg.C
Detection wavelength: 210nm
Step 6: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-methoxycarbonyl-beta-D-glucopyranose
[ solution 21]
Methyl chloroformate (95ml, 1231mmol) was added dropwise to a solution of the oily 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose (59g) obtained in the preceding step and 4- (dimethylamino) pyridine (175g, 1436mmol) in acetonitrile (1040ml) under a nitrogen atmosphere at 0 ℃ and stirred for 3 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with isopropyl acetate. The organic layer was washed 3 times with a 3% aqueous solution of potassium hydrogensulfate-20% aqueous solution of sodium chloride, washed with a 20% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (943ml) was added to the resulting residue, and the residue was dissolved by heating to 75 ℃. Cooled to 60 ℃, seeded with the title compound, cooled to room temperature and stirred for 1 hour. After the precipitation of the solid was confirmed, water (472ml) was added and the mixture was stirred at room temperature for 2 hours. The obtained crystals were filtered, washed with a mixed solvent of water and ethanol (1: 1), and dried under reduced pressure to obtain the title compound (94 g). Ethanol (1092ml) was added again to the obtained title compound (91g), and the mixture was heated to 75 ℃ to dissolve it. Cooled to 60 ℃, seeded with the title compound, cooled to room temperature and stirred for 1 hour. After confirming that a solid was precipitated, water (360ml) was added and the mixture was stirred at room temperature for 2 hours. The obtained crystals were filtered, washed with a mixed solvent of water and ethanol (1: 1), and dried under reduced pressure to obtain the title compound [83g, 68% yield from 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene used in step 3 ].
1H-NMR(CDCl3)：1.20(3H，t，J＝7.5Hz)，2.60(2H，q，J＝7.5Hz)，3.50(3H，s)，3.76(3H，s)，3.77(3H，s)，3.81(3H，s)，3.96(2H，s)，4.23(1H，dd，J＝2.5，11.8Hz)，4.33(1H，dd，J＝4.5，12.0Hz)，4.36-4.40(1H，m)，5.11-5.20(3H，m)，5.41(1H，d，J＝10.0Hz)，5.51(1H，t，J＝10.0Hz)，7.07-7.11(4H，m)，7.14(1H，d，J＝7.5Hz)，7.19(1H，dd，J＝1.5，7.8Hz)，7.31(1H，d，J＝1.5Hz)
MS(ESI+)：619[M+1]+，636[M+18]+
The title compound was obtained as crystals by the same method as in step 6 except that no seed crystal was used.
Step 7: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
[ solution 22]
To an aqueous solution of 1, 2-dimethoxyethane (28kg) containing 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-methoxycarbonyl-. beta. -D-glucopyranose (wet powder 8.92kg, converted to dry powder 8.00kg) was added an aqueous sodium hydroxide solution (4mol/L, 30.02kg) at 20 ℃ and the mixture was stirred for 1 hour. To the mixture was added water (8.0kg), followed by liquid separation, and then 25% aqueous sodium chloride solution (40kg) and ethyl acetate (36kg) were added to the organic layer. The organic layer thus obtained was washed with a 25% aqueous solution (40kg) of sodium chloride, and the solvent was distilled off under reduced pressure. The purity of the obtained residue was 98.7% as calculated from the area ratio measured by high performance liquid chromatography. To the residue were added acetone (32.0kg) and water (0.8kg), and the solvent was distilled off under reduced pressure. Acetone (11.7kg) and water (15.8kg) were added to the residue to dissolve it, and the solution was cooled to 5 ℃ or lower. Water (64kg) was added to the solution at 10 ℃ or lower, and after stirring at 10 ℃ or lower for 1 hour, the resulting crystals were centrifuged and washed with a mixture of acetone (1.3kg) and water (8.0 kg). The wet powder was dried by aeration at an aeration temperature of 13 to 16 ℃ and a relative humidity of 24 to 33% for 8 hours to obtain the title compound (3.94kg) as monohydrate crystals (water content: 4.502%). The purity of the obtained compound was 99.1% as calculated from the area ratio measured by high performance liquid chromatography.
1H-NMR(CD3OD)：1.19(3H，t，J＝7.5Hz)，2.59(2H，q，J＝7.5Hz)，3.42-3.46(1H，m)，3.65(1H，dd，J＝5.5，12.0Hz)，3.74-3.82(4H，m)，3.96(2H，s)，5.07(1H，d，J＝12.8Hz)，5.13(1H，d，J＝12.8Hz)，7.08-7.12(4H，m)，7.18-7.23(3H，m)
MS(ESI+)：387[M+1]+
Measurement conditions of the high performance liquid chromatograph:
column: capcell pack ODS UG-120(4.6 mmI.D.. times.150 mm, 3 μm, manufactured by Zishengtang)
Mobile phase: solution A: h2O, liquid B: MeCN
Liquid feeding of mobile phase: the concentration gradient was controlled by changing the mixing ratio of the solution A and the solution B according to the following table.
[ Table 1]
Flow rate: 1.0mL/min
Temperature: 25.0 deg.C
Detection wavelength: 220nm
The water content determination method comprises the following steps:
analysis method: electric quantity titration method
KF analysis device: trace moisture measuring device Mitsubishi chemical model KF-100
Anode liquid: aquamiron AX (manufactured by Mitsubishi chemical)
And (3) catholyte: aquamiron CXU (Mitsubishi chemical)
EXAMPLE 2 Synthesis of 2, 3, 4, 5-tetrakis (trimethylsilyloxy) -6-trimethylsiloxymethyl-2- (5-bromo-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran
[ solution 23]
2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene was treated with a hexane solution of n-butyllithium, 3, 4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-one, triethylamine, and trimethylsilylchloride in accordance with the procedure of step 3 of example 1. The reaction mixture was subjected to post-treatment, and the obtained residue was purified by high performance liquid chromatography (column: Inertsil ODS-3, 20mm I.D. times.250 mm; acetonitrile, 30mL/min) to isolate the title compound as 2 diastereomers.
Diastereomer 5:
1H-NMR(500MHz，CDCl3)：-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)
MS(ESI+)：819[M+Na]+
diastereomer 6:
1H-NMR (500MHz, toluene-d)8，80℃)：-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)
MS(ESI+)：819[M+Na]+
EXAMPLE 3 Synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-pivaloyl-. beta. -D-glucopyranose
[ solution 24]
Pivaloyl chloride (7.8ml, 63.5mmol) was added dropwise to a solution of monohydrate (3.95g, 9.77mmol) of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose and 4- (dimethylamino) pyridine (8.36g, 68.4mmol) in dichloromethane (40ml) under ice-cooling, and then stirred at room temperature for about 24 hours. To the resulting reaction mixture was added water, followed by extraction with hexane, and then the organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and saturated brine in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 150g, hexane: ethyl acetate 20: 1 to 10: 1) to obtain an oily residue (7.74 g). The residue (500mg) was dissolved in isopropanol (4ml), and water (1.5ml) and isopropanol (1ml) were added in this order at room temperature, followed by stirring for 1 hour. Water (0.5ml) was added thereto, the mixture was stirred for 1 hour, and further at 0 ℃ for 1 hour, and then the precipitated crystals were collected by filtration, washed with a mixture (4ml) of water and isopropanol (1: 1), and dried to obtain the title compound (403 mg).
1H-NMR(CDCl3)：0.71(9H，s)，1.11(9H，s)，1.17(9H，s)，1.20(9H，s)，1.20(3H，t，J＝7.5Hz)，2.60(2H，q，J＝7.5Hz)，3.93(2H，s)，4.09(1H，dd，J＝4.0，12.5Hz)，4.16(1H，dd，J＝2.0，12.5Hz)，4.37(1H，ddd，J＝2.0，4.0，10.0Hz)，5.12(1H，d，J＝12.2Hz)，5.21(1H，d，J＝12.2Hz)，5.37(1H，t，J＝10.0Hz)，5.57(1H，d，J＝10.0Hz)，5.69(1H，t，J＝10.0Hz)，7.07(2H，d，J＝8.2Hz)，7.10(2H，d，J＝8.2Hz)，7.11(1H，d，J＝8.0Hz)，7.17(1H，dd，J＝1.2，8.0Hz)，7.25(1H，brs)
MS(ESI+)：723[M+1]+
EXAMPLE 4 Synthesis of 3, 4, 5-tris (trimethylsiloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-one
[ solution 25]
Trimethylsilyl chloride (79.1kg) was added to a tetrahydrofuran (192kg) solution of D- (+) -glucono-1, 5-lactone (21.6kg) and N-methylmorpholine (98.2kg) at a temperature of 40 ℃ or lower, and the resulting mixture was stirred at 30 to 40 ℃ for 4 hours. The reaction mixture was cooled to 17 ℃ and toluene (93.6kg) and water (109kg) were added and the organic phase was separated. The organic layer was washed 2 times with a 5% sodium dihydrogenphosphate aqueous solution (108kg), 1 time with water (108kg), and the solvent was distilled off under reduced pressure. Tetrahydrofuran (154kg) was added to the residue, and after the solvent was distilled off under reduced pressure, tetrahydrofuran (154kg) was added again, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (253kg) to obtain the title compound as a tetrahydrofuran solution. The purity calculated from the area ratio measured by a high performance liquid chromatograph was 99.0% (conversion rate 99.1%).
Measurement conditions of the high performance liquid chromatograph:
column: YMC-Pack ODS-AM 4.6mm I.D. times 150mm, 3 μm (YMC)
Mobile phase: solution A: 2mM AcONH4/H2O, liquid B: 50% (v/v) MeCN/MeOH
Gradient operation: and B, liquid B: 50% -95% (15 minutes), 95% -100% (5 minutes), and 100% (15 minutes)
Flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 200nm
EXAMPLE 5 Synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
Step 1: synthesis of 2, 3, 4, 5-tetrakis (trimethylsiloxy) -6-trimethylsiloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran
[ solution 26]
2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (277g, 820mmol) was dissolved in a mixed solvent of toluene (2616mL) and methyl tert-butyl ether (262mL) under argon atmosphere, and a hexane solution of n-butyllithium (1.54M, 426mL, 656mmol) was added dropwise at-10 ℃ and stirred at-10 ℃ for 0.5 hour. Subsequently, a hexane solution of n-butyllithium (1.54M, 160ml, 246mmol) was added dropwise at-10 ℃ and stirred at-10 ℃ for 1 hour. In order to confirm the positional selectivity of the halogen metal exchange reaction, a small amount was taken out from the reaction mixture and added to a saturated aqueous ammonium chloride solution. The ratio of 4-bromo-1- (1-methoxy-1-methylethoxymethyl) benzene to 2-bromo-1- (1-methoxy-1-methylethoxymethyl) benzene contained in the resulting mixture, calculated from the area ratio by HPLC, was 53: 1 (98% conversion).
The resulting reaction mixture was cooled to-48 ℃ and then dropped into a solution of 3, 4, 5-tris (trimethylsilyloxy) -6-trimethylsiloxymethyl-tetrahydropyran-2-one (402g, 862mmol) in tetrahydrofuran (2012ml) cooled to-77 ℃ and stirred at-70 ℃ for 1.5 hours. To the solution were added triethylamine (24ml, 172mmol) and trimethylsilyl chloride (98g, 903mmol), and the temperature was raised to 0 ℃ to obtain a solution containing 2, 3, 4, 5-tetrakis (trimethylsiloxy) -6-trimethylsiloxymethyl-2- (5-bromo-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran. The solution was cooled to-78 ℃ and a hexane solution of n-butyllithium (1.54M, 1119mL, 1724mmol) was added dropwise thereto at the same temperature, followed by stirring for 1 hour. 4-ethylbenzaldehyde (242g, 1806mmol) was added dropwise at-78 ℃ and stirred at the same temperature for 2.5 hours. The reaction mixture was added to a 20% ammonium chloride aqueous solution, and the organic layer was separated. The organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain an oil (879g) containing the title compound. The product was used in the subsequent steps without further purification.
Measurement conditions of the high performance liquid chromatograph:
column: ascentis Express C18, 3.0mm I.D. x 100mm, 2.7 μm (Supelco)
Mobile phase: solution A: 2mM AcONH4/H2O, liquid B: MeCN
Gradient operation: and B, liquid B: 30% -98% (25 minutes), 98% (5 minutes)
Flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 210nm
And a step 2: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
[ solution 27]
628g of the oily substance containing 2, 3, 4, 5-tetrakis (trimethylsilyloxy) -6-trimethylsiloxymethyl-2- (5- (4-ethylphenyl) hydroxymethyl-2- (1-methoxy-1-methylethoxymethyl) phenyl) tetrahydropyran obtained in the preceding step was dissolved in tetrahydrofuran (991ml) under a nitrogen atmosphere, and water (63ml) and a 1N HCl solution (23ml) were added thereto, followed by stirring at 28 ℃ for 7 hours. Triethylamine (3.8ml, 25.8mmol) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. To the residue were added water (198ml) and 1, 2-dimethoxyethane (396ml), the layers were separated, and the aqueous layer was washed with n-heptane (595 ml). To the aqueous layer were added water (99ml) and 1, 2-dimethoxyethane (198ml), and after washing with n-heptane (595ml), the aqueous layer was concentrated under reduced pressure. To the obtained residue was added 1, 2-dimethoxyethane (793ml), and the solvent was distilled off under reduced pressure to obtain an oil (247g) containing the title compound. The product was used in the subsequent steps without further purification.
Step 3: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
[ solution 28]
125g of the oily substance containing 1, 1-anhydro-1-C- [5- (4-ethylphenyl) hydroxymethyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose obtained in the previous step was dissolved in 1, 2-dimethoxyethane (400ml), and water (150ml) and 5% Pd/C (water content: 50%, 19g, 4.5mmol) were added thereto, followed by stirring at room temperature for 6 hours under a hydrogen atmosphere. After the reaction mixture was filtered, the residue was washed with a mixed solvent of 1, 2-dimethoxyethane (250ml) and water (250ml), and a washing solution was added to the filtrate. To the mixture was added 1, 2-dimethoxyethane (500ml), and the mixture was washed 2 times with n-heptane (1000 ml). To the aqueous layer were added ethyl acetate (500ml) and 25% aqueous sodium chloride solution (600g), and the product was extracted into the organic layer. The organic layer was washed with a 15% aqueous solution (600g) of sodium chloride, and the solvent was distilled off under reduced pressure. Acetone (500ml) was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain a product (106g) containing the title compound. The purity of the obtained compound was 93.9% as calculated from the area ratio measured by high performance liquid chromatography. The product was used in the subsequent steps without further purification.
Measurement conditions of the high performance liquid chromatograph:
column: atlantis dC18, 4.6mm I.D. X75 mm, 3 μm (Waters)
Mobile phase: solution A: h2O, liquid B: MeCN
Gradient operation: and B, liquid B: 2% -20% (3 minutes), 20% -28% (5 minutes), 28% (12 minutes), 28% -100% (7 minutes), and 100% (8 minutes)
Flow rate: 1.2mL/min
Column temperature: 35 deg.C
Detection wavelength: 210nm
And step 4: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-methoxycarbonyl-beta-D-glucopyranose
[ solution 29]
The 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose (106g) obtained in the previous step and 1-methylimidazole (318ml, 3994mmol) were dissolved in acetone (400 ml). Methyl chloroformate (182ml, 2367mmol) was added dropwise to the solution at 15 ℃ under a nitrogen atmosphere, and the mixture was stirred for 3 hours while raising the temperature to 18 ℃. Water (800ml) was added to the reaction mixture, which was subjected to extraction with ethyl acetate (800 ml). The organic layer was washed with 10% potassium hydrogensulfate-5% aqueous sodium chloride solution (800 ml). Subsequently, the organic layer was washed 2 times with a 20% aqueous solution (800ml) of sodium chloride, and the solvent was distilled off under reduced pressure. To the resulting residue were added ethanol (1200ml), methyl t-butyl ether (200ml) and 2-propanol (130 ml). The mixture was heated to 74 ℃ to dissolve the residue, cooled to 55 ℃ and stirred for 1 hour. After confirming that the solid was precipitated, it took 1.5 hours to cool from 55 ℃ to 25 ℃. 2-propanol (270ml) was added and stirred at 25 ℃ for 1 hour. The resulting crystals were filtered, and washed with a mixed solvent (300ml) of ethanol: 2-propanol (3: 1). Then, the residue was washed with a mixed solvent (300ml) of ethanol and water (1: 1) to obtain the title compound as a wet powder (122g, loss by drying: 14%, converted to 104g of a dry powder, and yield 57% based on 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene used in step 1).
Step 5: synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
[ solution 30]
A4N aqueous sodium hydroxide solution (265ml, 1060mmol) was added dropwise to a1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-methoxycarbonyl-. beta. -D-glucopyranose (wet powder 96g, 82g in terms of dry powder) in 1, 2-dimethoxyethane (328ml) at 40 ℃ under a nitrogen atmosphere, and then stirred at 40 ℃ for 4.5 hours. Water (82ml) was added to the reaction mixture, and the organic layer was separated. Subsequently, the organic layer was washed with an aqueous solution (410ml) of 18% sodium dihydrogenphosphate 2 hydrate-12% disodium hydrogenphosphate 12 hydrate, and then ethyl acetate (410ml) was added thereto. The organic layer was washed 2 times with a 25% aqueous solution (410ml) of sodium chloride, and the solvent was distilled off under reduced pressure. Acetone (410ml) and water (8.2ml) were added to the residue, and the solvent was distilled off under reduced pressure. To the resulting residue were added acetone (164ml) and water (655ml), and the temperature was raised to 28 ℃ to dissolve the residue. After cooling to 25 ℃ and addition of seed crystals (82mg) of the title compound, it took 24 minutes to cool from 25 ℃ to 20 ℃ and stir at 20 ℃ for 1 hour. After the precipitation of the solid was confirmed, the temperature was raised to 25 ℃ and the mixture was stirred at 25 ℃ for 1 hour. Then, it took 2.4 hours to cool from 25 ℃ to-5 ℃ and the crystals were collected by filtration. To the resulting crystals, water (246ml) was added, and after stirring at 4 ℃ for 1 hour, the crystals were collected by filtration. The obtained wet powder was dried under reduced pressure for 20 minutes (pressure: 1hPa, external temperature: 20 to 25 ℃ C.) so that the water content of the wet powder became 8.249%, and then dried under reduced pressure for 30 minutes (pressure: 25hPa, external temperature: 20 to 25 ℃ C.) to obtain the title compound (44g, yield 82%) as monohydrate crystals (water content: 4.470%). The purity of the obtained compound was 99.9% as calculated from the area ratio measured by high performance liquid chromatography.
The water content determination method comprises the following steps:
analysis method: electric quantity titration method
KF analysis device: trace moisture measuring device Mitsubishi chemical model KF-100
Anode liquid: aquamiron AX (manufactured by Mitsubishi chemical)
And (3) catholyte: aquamiron CXU (Mitsubishi chemical)
As the seed crystal used in step 5 of example 5, a part of the crystal obtained by the following method was used.
Water (250ml) and acetone (250ml) were added to 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose (180.4g), and dissolved at 25 ℃ followed by filtration to remove insoluble matter. A mixture of water (326ml) and acetone (326ml) was added to the filtrate, and then the mixture was cooled to 4 ℃ and water (2.31L) was added thereto at 11 ℃ or lower with stirring to obtain a precipitate. The precipitate thus obtained was collected by filtration, washed with a mixture of water (289ml) and acetone (59ml), and dried under aeration to obtain crystals (160.7 g).
Measurement conditions of the high performance liquid chromatograph:
column: ZORBAX Eclipse XDB-C18, 4.6mm I.D. x 50mm, 1.8 μm (Agilent)
Mobile phase: solution A: h2O, liquid B: MeOH
Gradient operation: and B, liquid B: 40-60% (11.5 min), 60-80% (7 min), 80-95% (4 min), 95% (5 min)
Flow rate: 1.0ml/min
Column temperature: 50 deg.C
Detection wavelength: 220nm
EXAMPLE 6 halogen Metal exchange reaction of 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene
The halogen metal exchange reaction of 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene was carried out under the following conditions (conditions 1 to 4), and the product was used1H-NMR analysis confirmed the positional selectivity of the reaction.
Condition 1: 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (500mg, 1.48mmol) was dissolved in toluene (3.65ml) and methyl t-butyl ether (0.35ml) under a nitrogen atmosphere, and a hexane solution of n-butyllithium (1.6M, 1.01ml, 1.62mmol) was added dropwise at 0 ℃ over 3 minutes. After the completion of the addition, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a mixture containing 4-bromo-1- (1-methoxy-1-methylethyl) ether as an oily substanceProduct of oxymethyl) benzene (hereinafter also referred to as 4-bromide) and 2-bromo-1- (1-methoxy-1-methylethoxymethyl) benzene (hereinafter also referred to as 2-bromide) (376 mg). Based on the products1H-NMR analysis showed that the presence ratio calculated from the integral ratio of the peaks of protons at the benzyl position (4-bromide: 4.43, 2-bromide: 4.55) was 16: 1 for 4-bromide: 2-bromide.
4-bromo-1- (1-methoxy-1-methylethoxymethyl) benzene:
1H-NMR(CDCl3)：1.41(6H，s)，3.24(3H，s)，4.43(2H，s)，7.21-7.24(2H，m)，7.44-7.47(2H，m)。
2-bromo-1- (1-methoxy-1-methylethoxymethyl) benzene:
1H-NMR(CDCl3)：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)。
condition 2: 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (500mg, 1.48mmol) was dissolved in toluene (3.65ml) and methyl t-butyl ether (0.35ml) under a nitrogen atmosphere, and a hexane solution of n-butyllithium (1.6M, 1.01ml, 1.62mmol) was added dropwise at 0 ℃ over 3 minutes. A solution of 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (150mg, 0.44mmol) in toluene (1.1ml) and methyl t-butyl ether (0.11ml) was added dropwise to the reaction mixture. After the completion of the dropwise addition, the mixture was stirred at 0 ℃ for 30 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a product containing 4-bromide and 2-bromide as an oil (458 mg). Based on the products1In the H-NMR analysis, the presence ratio of 4-bromide to 2-bromide calculated from the integral ratio of the peaks of protons at the benzylic positions was 220: 1, 4-bromide: 2-bromide.
Condition 3: 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (150mg, 0.44mmol) was dissolved in toluene (1.1ml), methyl tert-butyl in a nitrogen atmosphereTo butyl ether (0.11ml), a hexane solution of n-butyllithium (1.6M, 0.3ml, 0.48mmol) was added dropwise at 0 ℃ over 3 minutes. After the end of the dropwise addition, the reaction mixture was stirred at 0 ℃ for 30 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a product containing 4-bromide and 2-bromide as an oil (108 mg). Based on the products1According to the H-NMR analysis, the existence ratio of 4-bromide to 2-bromide calculated according to the integral ratio of the proton peak at the benzyl position is 16: 1.
Condition 4: 2, 4-dibromo-1- (1-methoxy-1-methylethoxymethyl) benzene (500mg, 1.48mmol) was dissolved in toluene (3.65ml) and methyl t-butyl ether (0.35ml) under a nitrogen atmosphere, and a hexane solution of n-butyllithium (1.6M, 1.01ml, 1.62mmol) was added dropwise at 0 ℃ over 30 minutes. After the completion of the dropwise addition, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a product containing 4-bromide and 2-bromide as an oil (373 mg). Based on the products1In the H-NMR analysis, the presence ratio of 4-bromide to 2-bromide calculated from the integral ratio of the proton peaks at the benzylic positions was 40: 1, 4-bromide: 2-bromide.
EXAMPLE 7 Synthesis of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose
To a solution of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -2, 3, 4, 6-tetra-O-methoxycarbonyl-. beta. -D-glucopyranose (wet powder 88.2g) in 1, 2-dimethoxyethane (285ml) was added an aqueous sodium hydroxide solution (5M, 285ml) at room temperature, followed by stirring at the same temperature for 1 hour. To the solution was added aqueous sulfuric acid (1M, 713ml), and water (100ml) was further added to conduct extraction with ethyl acetate (500ml) for 2 times. The combined organic layers were washed with a saturated aqueous sodium chloride solution (1000ml), and further dried over anhydrous sodium sulfate (250g), and then about half of the amount of the solvent was distilled off under reduced pressure to obtain a precipitated product (10.3g) as a crystalline powder. A part (4mg) of the obtained crystalline powder was dissolved in dimethyl sulfoxide (0.02ml), and the solution was lyophilized at-20 ℃ for 2 days to remove the dimethyl sulfoxide. After water (0.02ml) was added to the residue, a very small amount of the above crystalline powder was added as seed crystals, and the mixture was stirred with shaking at room temperature for 10 days (100rpm, DOUBLESHAKER NR-3 manufactured by TAITEC) to obtain the title compound as crystals. The powder of the obtained crystal was analyzed by X-ray diffraction, and a peak was observed at the diffraction angle (2 θ) which was the same as the diffraction pattern of the monohydrate measured in test example 5, whereby it was confirmed that the crystal was a monohydrate.
EXAMPLE 8 preparation of sodium 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose acetate cocrystals
1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl at 80 deg.C]Crystalline monohydrate of β -D-glucopyranose (200mg) and sodium acetate (40mg) were dissolved in methanol (1ml), cooled to room temperature, and isopropyl alcohol (2ml) was added. After the solvent (about 2ml) was distilled off under reduced pressure, the title co-crystal seed crystal was added, stirred at room temperature overnight, and the precipitated crystal was collected by filtration, washed with isopropyl alcohol (4ml), and dried to obtain the title co-crystal (melting point about 162 ℃). Based on para-cocrystallization1H-NMR[(CD3)2SO]Analysis according to the CH of the ethyl group of the title compound3Peaks of protons (1.12-1.16(3H, t)) with CH of sodium acetate3(1.56(3H, s)) was calculated as a cocrystal having a presence ratio of 1: 1.
The seed crystal used in the above preparation is obtained by the following method. Crystalline monohydrate of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose (8mg) and sodium acetate (2mg) were dissolved in methanol (0.1ml) at 80 ℃. The solvent in the solution was completely evaporated at 80 ℃ to obtain the objective crystalline substance.
Melting point determination conditions:
analysis method: differential Scanning Calorimetry (DSC)
The device comprises the following steps: DSC6200R (SII Nanotechnology Inc.)
Scanning speed: 10 ℃/min
Scanning range: 30 to 210 DEG C
Sample amount: 3-4 mg
EXAMPLE 9 preparation of Potassium 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] -beta-D-glucopyranose acetate cocrystal
1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl at 80 deg.C]Crystalline monohydrate of β -D-glucopyranose (200mg) and potassium acetate (48mg) were dissolved in methanol (1ml), cooled to room temperature, and isopropyl alcohol (2ml) was added. After the solvent (about 2ml) was distilled off under reduced pressure, seed crystals of the title co-crystal were added, stirred at room temperature overnight, and the precipitated crystal was collected by filtration, washed with isopropyl alcohol (4ml), and dried to obtain the title co-crystal (melting point about 176 ℃). Based on para-cocrystallization1H-NMR[(CD3)2SO]Analysis according to the CH of the ethyl group of the title compound3Peak of proton (1.13-1.16(3H, t)) and CH of potassium acetate3(1.53(3H, s)) was calculated as a cocrystal having a presence ratio of 1: 1.
The seed crystal used in the above preparation is obtained by the following method. Crystalline monohydrate of 1, 1-anhydro-1-C- [5- (4-ethylphenyl) methyl-2- (hydroxymethyl) phenyl ] - β -D-glucopyranose (8mg) and potassium acetate (2mg) were dissolved in methanol (0.1ml) at 80 ℃. The solvent in the solution was completely evaporated at 80 ℃ to obtain a crystalline substance as an object product. The melting point was measured by the same method as in example 7.
Test example 1 measurement of moisture adsorption isotherm of monohydrate crystals
[ solution 31]
For the monohydrate crystal of the compound of formula (XI), a moisture adsorption isotherm was measured as follows using a dynamic moisture adsorption isotherm device DVS-1(Surface Measurement Systems).
The pulverized monohydrate crystals of the above-mentioned compound (about 10mg, water content 4.5%) were precisely weighed in a sample pan as a measurement sample. An empty sample pan was used as a control sample. The measurement sample and the control sample were mounted on the apparatus, and the change in mass of the measurement sample was measured by changing Relative Humidity (RH) in the order of 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0% at a certain temperature around 25 ℃. The measurement results are shown in FIG. 1. It was confirmed that the compound of formula (XI) stably existed as a monohydrate at a relative humidity of 10 to 90%.
Test example 2 storage stability test of monohydrate Crystal
The storage stability test was performed using the monohydrate crystal of the compound of formula (XI) of the present invention and an amorphous form of the compound. The monohydrate crystal of the compound of formula (XI) was prepared according to the method described in step 7 of example 1. An amorphous form of the compound of formula (XI) is prepared according to the following method. The monohydrate crystals (15g) of this compound were heated on a heating table, melted, cooled at room temperature in a humidity-controlled dryer (25 ℃/dry), and the solidified material was pulverized in a mortar, and the pulverized material thus obtained was used as a sample. The samples were stored in a thermostat set at 25 ℃ and 40 ℃ and the purity of the samples was confirmed after 1 month, 3 months, and 6 months, respectively.
The purity was confirmed in the following manner. A sample (about 6mg) was weighed, dissolved in a water/methanol mixture (1: 1), and adjusted to 10mL accurately to prepare a sample solution. Each prepared solution (10. mu.L) was subjected to HPLC analysis under the following conditions, and the total amount of impurities was calculated from the following formula.
[ solution 32]
HPLC determination conditions:
the instrument comprises the following steps: 2695 separators Module (manufactured by Waters), 2487 Dual λ Absorbance Detector (manufactured by Waters) or 996 Photoodidearray Detector (manufactured by Waters)
Column: YMC-Pack ODS-AM-302-3, 4.6mm I.D. times.15 cm, particle size 3 μm (manufactured by YMC)
Dissolving liquid: liquid A is methanol; liquid B is water
Gradient operation: solution A: 55% (15 min), solution a: 55% -100% (10 min), 100% (5 min)
Flow rate: 1.0mL/min
Detection wavelength: 220nm
Sample cooler temperature: 5 deg.C
Area measurement range: 30 minutes after the solution injection
The results are shown in Table 2. The total amount of impurities of the amorphous material increased with time at any of 25 ℃ and 40 ℃, compared to approximately constant total amount of impurities of the monohydrate crystals over 6 months at any of 25 ℃ and 40 ℃.
[ Table 2]
[ test example 3] test of storage stability of sodium acetate cocrystal
The storage stability test was carried out in the same manner as in test example 2 using the sodium acetate cocrystal of the compound of formula (XI) of the present invention. Sodium acetate co-crystals of the compound of formula (XI) were prepared according to the method described in example 5. The samples were stored in an incubator set at 25 ℃ and 40 ℃ and the purity of the samples was confirmed after 1 month and 3 months, respectively. The measurement results obtained were compared with those of the amorphous material obtained in test example 2.
The results are shown in Table 3. The impurity amount of the amorphous substance was increased with time at any one of 25 ℃ and 40 ℃, compared to that at any one of 25 ℃ and 40 ℃, the total amount of impurities of sodium acetate co-crystallization was approximately constant over 3 months.
[ Table 3]
[ test example 4] storage stability test of Potassium acetate cocrystal
The storage stability test was carried out in the same manner as in test example 2 using the potassium acetate co-crystal of the compound of formula (XI) of the present invention. A 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 an incubator set at 25 ℃ and 40 ℃ and the purity of the samples was confirmed after 1 month and 3 months, respectively. The measurement results obtained were compared with those of the amorphous material obtained in test example 2.
The results are shown in Table 4. The amount of impurities of the amorphous material increased with time at any one of 25 ℃ and 40 ℃, compared to the total amount of impurities of the potassium acetate co-crystal which was approximately constant over 3 months at any one of 25 ℃ and 40 ℃.
[ Table 4]
[ test example 5] powder X-ray diffraction measurement
Powder X-ray diffraction of monohydrate crystals, amorphous, sodium acetate co-crystals and potassium acetate co-crystals of the compound of formula (XI) was determined. The measurement conditions are shown below.
Measurement conditions for monohydrate Crystal (Condition 1)
A measuring device: RINT 1100 (manufactured by Rigaku corporation)
And (3) for a cathode: cu
Tube voltage: 40kV
Tube current: 40mA
Scanning speed: 2.000 degree/min
Sampling range: 0.020 °
Divergent slit: 1 degree
Scattering slit: 1 degree
Receiving a slit: 0.15mm
Scanning range: 3 to 35 DEG
Measurement conditions for monohydrate Crystal (Condition 2)
A measuring device: x' Pert-Pro MPD (product of PANALYTICAL Co., Ltd.)
And (3) for a cathode: cu
Tube voltage: 45kV
Tube current: 40mA
The scanning mode is as follows: continuous
Step width: 0.017
Scanning shaft: 2 theta
Sampling time of each step: 30 seconds
Scanning range: 2 to 35 DEG
Conditions for measuring amorphous substance
A measuring device: RINT 1100 (manufactured by Rigaku corporation)
And (3) for a cathode: cu
Tube voltage: 40kV
Tube current: 20mA
Scanning speed: 2.000 degree/min
Sampling range: 0.020 °
Divergent slit: 1 degree
Scattering slit: 1 degree
Receiving a slit: 0.15mm
Scanning range: 2 to 35 DEG
Determination conditions of sodium acetate cocrystallization and potassium acetate cocrystallization:
a measuring device: x' Pert MPD (product of PANALYTICAL Co., Ltd.)
And (3) for a cathode: cu
Tube voltage: 45kV
Tube current: 40mA
Scanning speed: 1.000 degree/min
Sampling range: 0.050 °
Divergent slit: 0.25 degree
Scattering slit: 0.25 degree
Receiving a slit: 0.2mm
Scanning range: 3 to 35 DEG
The results of the monohydrate crystallization are shown in figure 2. Peaks were observed at diffraction angles (2 θ) in the vicinity of 3.5 °, 6.9 °, 10.4 °, 13.8 °, 16.0 °, 17.2 °, 18.4 °, 20.8 °, 21.4 °, and 24.4 °. The results of sodium acetate co-crystallization are shown in figure 4. Peaks were observed at diffraction angles (2 θ) in the vicinity of 4.9 °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 °, and 22.0 °. The results of potassium acetate co-crystallization are shown in fig. 5. Peaks were observed at diffraction angles (2 θ) in the vicinity of 5.0 °, 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 °, and 25.2 °.

Claims (30)

1. A process for the preparation of a compound of formula (I),
[ solution 1]
Wherein n is 0; m is an integer selected from 0 and 1;
R2is C1-4An alkyl group;
the method comprises a step a), a step b) and a step c),
step a) is a step of treating the compound of formula (II) with an organometallic reagent, and then reacting it with a compound of formula (III) to obtain a compound of formula (IVa):
[ solution 2]
In the formula, X1And X2Each independently selected from a bromine atom and an iodine atom;
P1a protecting group which is a metal ion, a hydrogen atom or a hydroxyl group;
the definition of n is as described above,
[ solution 3]
In the formula, P2、P3、P4And P5Each independently selected from protecting groups for hydroxyl groups; alternatively, P may be used2And P3Together, P3And P4Together, and P4And P5Together are each independently a 2-valent radical which protects 2 hydroxyl groups and forms a ring,
[ solution 4]
In the formula, n, X2、P1、P2、P3、P4And P5Is as defined above;
x is a metal ion or a hydrogen atom;
step b) is a step of treating the compound of formula (IVb) with an organometallic reagent, and then reacting it with the compound of formula (V) to obtain a compound of formula (VI):
[ solution 5]
In the formula, n, X2、P1、P2、P3、P4And P5Is as defined above;
P6protecting groups for metal ions, hydrogen atoms, or hydroxy groups
[ solution 6]
In the formula, R42Is as above for R2A defined group, m is as defined above,
[ solution 7]
In the formula, R42、m、n、P1、P2、P3、P4、P5And P6Is as defined above;
step c) is a step of converting the compound of formula (VI) into a compound of formula (I);
further comprising introducing a protecting group into the compound of formula (IVa) to obtain P6A step of preparing a compound of formula (IVb) which is a protecting group for a hydroxyl group.
2. The production process according to claim 1, wherein,
in step c), the compound of formula (VI) is subjected to the following 2 stages:
stage (1): will P1A stage in which the compound of formula (VI) which is a hydrogen atom is treated under acidic conditions, in which P is present1When the protecting group is a protecting group, a deprotection step before the treatment is also included; and the number of the first and second groups,
stage (2): removing the hydroxyl group formed by the reaction in step b) by a reduction reaction;
wherein the step of obtaining the compound of formula (I) may be carried out at any stage,
[ solution 7]
In the formula, R42、m、n、P1、P2、P3、P4、P5And P6Is as defined in claim 1.
3. The production method according to claim 1 or 2, wherein in the step a), the organometallic reagent is added for 15 to 300 minutes.
4. The production method according to claim 1 or 2, wherein in the step a), the organometallic reagent is added intermittently.
5. The process according to claim 1 or 2, wherein in step a), when P is1In the case of a metal ion or a protective group, 0.4 to 0.9 equivalent of the organometallic reagent is added to the compound of the formula (II), the addition is suspended, and then 0.1 to 0.7 equivalent of the organometallic reagent is added to the compound of the formula (II).
6. The process according to claim 1 or 2, wherein in step a), when P is1In the case of hydrogen atoms, 1.4 to 1.9 equivalents of the organometallic reagent is added to the compound of formula (II), the addition is interrupted, and then 0.1 to 0.7 equivalents of the organometallic reagent is added to the compound of formula (II).
7. The process according to claim 1 or 2, wherein in the step a), P is added1An organometallic reagent is added to the reaction system of the compound of the formula (II) which is a metal ion or a protecting group, and then the compound of the formula (II) is added.
8. The process according to claim 1 or 2, wherein in step a), P is used1A compound of formula (II) which is a protecting group for a hydroxyl group.
9. The process according to claim 1 or 2, wherein in step b), P is used6A compound of formula (IVb) which is a protecting group for a hydroxy group.
10. The process of claim 1 or 2, wherein the step a) and the step b) are carried out as a one-pot reaction.
11. The production method according to claim 1 or 2, wherein,
P1and P6Each independently selected from alkali metal ions, alkaline earth metal ions, hydrogen atoms, optionally substituted with 1 or more R51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated 4-to 10-membered heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C(＝O)R54、-B(OR55)2；
P2、P3、P4And P5Each independently selected from the group consisting of51Substituted C1-10Alkyl, optionally substituted by 1 or more R52Substituted saturated, partially unsaturated, or unsaturated 4-to 10-membered heterocyclic group, C2-10Alkenyl, -Si (R)53)3、-C(＝O)R54、-B(OR55)2(ii) a Or, P2And P3Together, P3And P4Together, and P4And P5Together may each independently be C which protects 2 hydroxyl groups and forms a ring1-10Alkylene or carbonyl;
here, R51Each independently selected from the group consisting of56Substituted C6-14Aryl, optionally substituted by 1 or more C6-14Aryl substituted C1-10Alkoxy radical, C1-10Alkylthio groupAnd C6-14An arylhydrogenseleno group;
R52each independently selected from C1-10An alkoxy group;
R53and R55Each independently selected from C1-10Alkyl and C6-14An aryl group;
R54each independently is a hydrogen atom, C1-10Alkyl, optionally substituted by 1 or more C1-10Alkoxy-substituted C6-14Aryl, 4-to 10-membered heteroaryl, optionally substituted with more than 1R57Substituted amino, optionally substituted by 1 or more C6-14Aryl substituted C1-10Alkoxy, or C which may be substituted by 1 or more nitro groups6-14An aryloxy group;
R56each independently selected from C1-10Alkyl radical, C1-10Alkoxy radical, C6-14Aryl, and 4-10 membered heteroaryl;
R57each independently selected from C1-10Alkyl and C6-14An aryl group;
x is an alkali metal ion, an alkaline earth metal ion, or a hydrogen atom.
12. The production method according to claim 1 or 2, wherein,
P1selected from lithium ions, hydrogen atoms, C1-6Alkoxy radical C1-6Alkyl, (C)6-14Aryl) methoxy group C1-6Alkyl, tetrahydropyranyl, the radical-Si (R)53)3Benzyl, 4-methoxybenzyl, trityl, and the group-B (OR)55)2；
P2、P3、P4And P5Each independently selected from C1-6Alkoxy radical C1-6Alkyl, (C)6-14Aryl) methoxy group C1-6Alkyl, tetrahydropyranyl, the radical-Si (R)53)3Benzyl, 4-methoxybenzyl, trityl, radical-B (OR)55)2、C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, benzyloxycarbonyl, and tert-butyl; or, P4And P5Together can be 2 for protectionA hydroxyl group and forms a 2-valent group of a ring, the 2-valent group being selected from the group consisting of-CH2-、-CH(CH3)-、-C(CH3)2-, and-CHPh-;
X、P6、R53and R55As defined in claim 12.
13. The production method according to claim 1 or 2, wherein,
P1is C1-6Alkoxy radical C1-6An alkyl group;
P2、P3、P4、P5and P6Each independently selected from the group-Si (R)53)3，R53Each independently selected from C1-10Alkyl and C6-14An aryl group;
x is an alkali metal ion.
14. A process for the preparation of a compound of formula (I) according to claim 1 having a purity of 90.0% by weight or more,
[ solution 1]
In the formula, n, m and R2As defined in claim 1;
the method comprises the following steps:
step d): a step of converting the compound of formula (I) into a compound of formula (X):
[ solution 9]
In the formula, R42M and n are as defined in claim 1, P7Is selected from C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, -SiR23R24R25Wherein R is23、R24And R25Each independently selected from C1-10Alkyl and C6-14An aryl group;
step e): a step of crystallizing the compound of formula (X) and purifying the crystal by recrystallization;
step f): and (c) removing the protecting group from the compound of formula (X) to obtain a compound of formula (I) having a purity of 90.0 wt% or more.
15. The process according to claim 14, wherein the compound of formula (I) in step d) is a crude product obtained by the process according to claim 1 or 2.
16. The production method according to claim 14 or 15, further comprising a step of crystallizing the obtained compound of formula (I) using a solvent selected from the following solvents, or a mixed solvent containing 2 or more of the following solvents: methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, 1-hexanol, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diisopropyl ether, ethyl acetate, propyl acetate, hexyl acetate, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-dibutylformamide, 1-chlorohexane, N-propylbenzene, hexylbenzene, heptane, toluene, acetone, 2-butanone, 2-heptanone, acetonitrile, dimethyl sulfoxide, and water.
17. The process according to claim 14 or 15, wherein 1-methylimidazole is used as a base in the conversion in step d).
18. The process according to claim 14 or 15, wherein P is7Selected from the group consisting of tert-butylcarbonyl and methoxycarbonyl.
19. The process according to claim 14 or 15, wherein, in the formula (I), n is 0, m is 0 or 1, R2Is C1-4An alkyl group.
20. A compound of formula (IVb):
[ solution 10]
In the formula, n and X2As defined in claim 1, the first and second,
P1is C1-6Alkoxy radical C1-6An alkyl group;
P2、P3、P4、P5and P6Each independently selected from the group-Si (R)53)3，R53Each independently selected from C1-10Alkyl and C6-14And (4) an aryl group.
21. The compound of claim 20, wherein,
P1is C1-6Alkoxy radical C1-6An alkyl group;
P2、P3、P4、P5and P6Is a trimethylsilyl group.
22. A compound of formula (VI):
[ solution 11]
In the formula, R42M and n are as defined in claim 1, P1、P2、P3、P4、P5And P6As defined in claim 20.
23. The compound of claim 22, wherein,
P1is C1-6Alkoxy radical C1-6An alkyl group;
P2、P3、P4、P5and P6Is a trimethylsilyl group.
24. A crystal of the compound of formula (XI) which is a monohydrate,
[ solution 12]
It has peaks at diffraction angles (2 θ) near 3.5 °, 6.9 °, 10.4 °, 13.8 °, 16.0 °, 17.2 °, 18.4 °, 20.8 °, 21.4 °, and 24.4 ° in a powder X-ray diffraction pattern.
25. The crystal of the compound of the formula (XI) according to claim 24, which is obtained by crystallization from a mixed solvent of acetone and water.
26. The crystal of the compound of the formula (XI) according to claim 25, wherein a mixed solvent of acetone and water is used in a volume ratio of acetone to water of 1: 3.5 to 1: 7.
27. A crystal of the compound of formula (XI) which is a sodium acetate co-crystal,
it has peaks at diffraction angles (2 θ) in the vicinity of 4.9 °, 8.7 °, 9.3 °, 11.9 °, 12.9 °, 14.7 °, 16.0 °, 17.1 °, 17.7 °, 19.6 °, 21.6 °, and 22.0 ° in a powder X-ray diffraction pattern.
28. The crystal of the compound of formula (XI) according to claim 27, which is obtained by crystallization from a mixed solvent of methanol and isopropanol.
29. A crystal of the compound of formula (XI) which is a potassium acetate co-crystal,
it has peaks at diffraction angles (2 θ) near 5.0 °, 10.0 °, 10.4 °, 12.4 °, 14.5 °, 15.1 °, 19.0 °, 20.1 °, 21.4 ° and 25.2 ° in a powder X-ray diffraction pattern.
30. The crystal of the compound of formula (XI) according to claim 29, which is obtained by crystallization from a mixed solvent of methanol and isopropanol.
HK11108698.5A 2008-06-20 2009-06-19 Crystal of spiroketal derivative, and process for production thereof HK1154589B (en)

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