Specification
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
METHOD FOR PRODUCING DIAMINE COMPOUND;
TAKASAGO INTERNATIONAL CORPORATION, A CORPORATION ORGANIZED AND EXISTING UNDER THE LAWS OF JAPAN, WHOSE ADDRESS IS 37-1, KAMATA 5-CHOME, OTA-KU, TOKYO 1448721, JAPAN
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
Description
Technical Field
The present invention relates to a method for producing a diamine compound useful for forming a ruthenium-diamine complex important as an asymmetric reduction catalyst. Background Art
Many asymmetric reactions including asymmetric reduction have been developed, and many asymmetric reactions have been reported in which asymmetric metal complexes having optically active phosphine ligands are used. On the other hand, many reports have shown that complexes in which optically active nitrogen compounds are coordinated to transition metals, such as ruthenium, rhodium, and iridium, for example, have excellent performances as catalysts for asymmetric synthesis reactions. Moreover, to enhance the performances of these catalysts, various optically active nitrogen compounds have been developed (Non Patent Literatures 1, 2, 3, 4, etc.). In particular, M. Wills et al. have reported that complexes in which a diamine moiety and an aromatic ring (arene) moiety coordinated to the ruthenium metal are linked by a carbon chain exhibit higher activities than conventional catalysts (Non Patent Literatures 5, 6, 7, 8, 9, 10, etc.). Citation List Non Patent Literatures
Non Patent Literature 1: Chem Rev. (1992) p. 1051 Non Patent Literature 2: J. Am. Chem. Soc. 117 (1995) p. 7562 Non Patent Literature 3: J. Am. Chem. Soc. 118 (1996) p. 2521 Non Patent Literature 4: J. Am. Chem. Soc. 118 (1996) p. 4916
Non Patent Literature 5: J. Am. Chem. Soc. 127 (2005) p. 7318
Non Patent Literature 6: J. Org. Chem. 71 (2006) p. 7035
Non Patent Literature 7: Org. Biomol. Chem. 5 {2007) p. 1093
Non Patent Literature 8: Org. Lett. 9 (2007) p. 4659
Non Patent Literature 9: J. Organometallic. Chem. 693 (2008)
p. 3527
Non Patent Literature 10: Dalton. Trans. 39 (2010) p. 1395
Summary of Invention
However, these complexes have the following problems. Specifically, these complexes are produced through hazardous processes such as the Birch reduction of an alcohol having an aromatic ring, the subseguent conversion to an aldehyde under a low temperature of -80°C, and the subsequent synthesis using pyrophoric NaBH4 or LiAlH4. Moreover, the yields of these complexes are low.
To solve the above problems, the present inventors have developed a production method which is performed under mild conditions and hence can be carried out industrially.
Specifically, the present invention includes the following contents.
[ 1 ] A method for producing a compound represented by the following general formula (1):
wherein R1 represents an alkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having 1 to 10 carbon atoms and optionally substituted with a halogen atom; an arenesulfonyl
group optionally substituted with an alkyl group having 1 to
10 carbon atoms, a halogenated alkyi group having 1 to 10 carbon
atoms, or a halogen atom; an alkoxycarbdnyl group having 2 to
11 carbon atoms in total; or a benzoyl group optionally
substituted with an alkyl group having 1 to 10 carbon atoms,
R2 and R3 each independently represent an alkyi group having
1 to 10 carbon atoms; a phenyl group optionally substituted with
an alkyl group having 1 to 10 carbon atoms, an alkoxy group having
1 to 10 carbon atoms, or a halogen atom; or a cycloalkyl group
having 3 to 8 carbon atoms, or R2 and R3 may together form a
ring, R10 to R14 each independently represent a hydrogen atom,
an alkyi group having 1 to 10 carbon atoms, an alkoxy group having
1 to 10 carbon atoms, or a trisubstituteq alkylsilyl group, A1
and A3 represent methylene, A2 represents an oxygen atom or
methylene, and n1 and n2 are each independently l to 3, the method
comprising:
reacting a compound represented by the following general formula (2):
wherein R10 to R14 ,A1 to A3, m, and n2 are the same as those defined in the general formula (1) , and B, represents a halogen atom, an alkanesulfonyloxy group, or an arenesulfonyloxy group, with a diamine compound represented by the following general formula (3):
wherein R1 to R3 are the same as those defined in the general
formula (1).
[2] The production method according to [1], wherein
the compound represented by the general formula (2) is reacted with the diamine compound represented by the general formula {3) at a temperature of 100°C to 200°C. [3] A compound represented by the following general formula (2) :
wherein R10 to R14 each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a trisubstituted alkylsilyl group, A1 and A3 represent methylene, A2 represents an oxygen atom or methylene, B represents a halogen atom, an alkanesulfonyloxy group, or an arenesulfonyloxy group, and n1 and n2 are each independently 1 to 3.
The present invention provides a method for producing a diamine compound in which a diamine moiety and an arene moiety to be coordinated to a ruthenium metal are linked by a carbon chain. The above-described conventional methods for producing a diamine compound have the following problems: the complexity of the synthesis method; the use of the Birch reduction which necessitates the use of toxic ammonia gas and an ultra
low-temperature apparatus; the inevitable use of the Swern oxidation which causes problems, in industrial application, associated with the odor of by-produced dimethyl sulfide, the hazardous nature of carbon monoxide, the need for a cryogenic reactor, and the like; low yields in some reactions; and the like. In contrast, the present invention makes it possible to simply and efficiently produce a highly active ruthenium-diamine complex by the production method which uses a novel intermediate obtained by halogenating or sulfonylating an alcohol synthesized by the Diels-Alder reaction. Description of Embodiments
Hereinafter, the present invention will be described in further detail.
In the present invention, a compound represented by the following general formula (1) is produced by reacting a compound represented by the following general formula (2) with a diamine compound represented by the following general formula (3):
wherein R1 represents an alkyl group having 1 to 10 carbon atoms; an alkanesulfonyl group having 1 to 10 carbon atoms and optionally substituted with a halogen atom; an arenesulfonyl group optionally substituted with an alkyl group having 1 to
10 carbon atoms, a halogenated alkyl group having 1 to 10 carbon
atoms, or a halogen atom; an alkoxycarbonyl group having 2 to
11 carbon atoms in total; or a benzoyl group optionally
substituted with an alkyl group having 1 to 10 carbon atoms,
R2 and R3 each independently represent an alkyl group having 1 to 10 carbon atoms; a phenyl group optionally substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom; or a cycloalkyl group having 3 to 8 carbon atoms, or R2 and R3 may together form a ring, R10 to R14 each independently represent a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a trisubstituted alkylsilyl group, A1 and A3 represent methylene. A2 represents an oxygen atom or methylene, and n1 and n2 are each independently 1 to 3,
wherein R10 to R14, A1 to A3, n1, and n2 are the same as those defined in the general formula (1) , and B represents a halogen atom, an alkanesulfonyloxy group, or an arenesulfonyloxy group, and
wherein R1 to R3 are the same as those defined in the general formula (1).
The alkyl group having 1 to 10 carbon atoms represented by R1 is a linear or branched alkyl group having 1 to 10 carbon atoms, and preferably having 1 to 5 carbon atoms. Specific examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group,
an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, and the like.
The alkanesulfonyl group having 1 to 10 carbon atoms represented by R1 includes a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, and the like. The alkanesulfonyl group is optionally substituted with one or multiple halogen atoms. The halogen atom includes chlorine atoms, bromine atoms, fluorine atoms, and the like. The alkanesulfonyl group having 1 to 10 carbon atoms and substituted with a halogen atom includes a trifluoromethanesulfonyl group and the like.
The arenesulfonyl group represented by R1 includes a
benzenesulfonyl group and the like. The arenesulfonyl group
is optionally substituted with one or multiple alkyl groups
having 1 to 10 carbon atoms, halogenated alkyl groups having
1 to 10 carbon atoms, or halogen atoms. The alkyl group having
1 to 10 carbon atoms includes those listed as the alkyl group
having 1 to 10 carbon atoms represented by R1, and the like.
The halogenated alkyl group having 1 to 10 carbon atoms includes
halides (the halogen atom includes a chlorine atom, a bromine
atom, a fluorine atom, and the like) of those listed as the alkyl
group having 1 to 10 carbon atoms represented by R1, and the
like. The halogen atom includes a chlorine atom, a bromine atom,
a fluorine atom, and the like. The arenesulfonyl group
substituted with an alkyl group having 1 to 10 carbon atoms,
a halogenated alkyl group having 1 to 10 carbon atoms, or a
halogen atom includes a p-toluenesulfonyl group, a
2,4,6-trimethylbenzenesulfonyl group, a
4-trifluoromethylbenzenesulfonyl group, a
pentafluorobenzenesulfonyl group, and the like.
The alkoxycarbonyl group having 2 to 11 carbon atoms in total represented by R1 is a linear or branched alkoxycarbonyl group having 2 to 11 carbon atoms in total, and preferably having 2 to 5 carbon atoms in total. Specific examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and the like.
The benzoyl group represented by R1 is optionally substituted with one or multiple alkyl groups having 1 to 10 carbon atoms. The alkyl group having 1 to 10 carbon atoms includes those listed as the alkyl group having 1 to 10 carbon atoms represented1 by R1, and the like. The benzoyl group optionally substituted with an alkyl groub having 1 to 10 carbon atoms includes a benzoyl group, a p-toluoyl group, an o-toluoyl group, and the like.
The alkyl group having 1 to 10 carbon atoms represented by each of R2 and R3 includes those listed as the alkyl group having 1 to 10 carbon atoms represented by R1, and the like.
The phenyl group represented by each of R2 and R3 is optionally substituted with one or multiple alkyl groups having 1 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, or halogen atoms. The alkyl group having 1 to 10 carbon atoms includes those listed as the alkyl group having 1 to 10 carbon atoms represented by R1, and the like. The alkoxy groups having 1 to 10 carbon atoms are each a linear or branched alkoxy group having 1 to 10 carbon atoms, and preferably having 1 to 5 carbon atoms. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a
n-heptyloxy group, a n-octyloxy group, a n-nonyloxy group, a n-decyloxy group, and the like. The halogen atom includes a chlorine atom, a bromine atom, a fluorine atom, and the like. The phenyl group substituted with an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, or a halogen atom includes a 2,4,6-trimethylphenyl group, a 4-methoxyphenyl group, a 2,4,6-trimethoxyphenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group, and the like.
The cycloalkyl group having 3 to 8 carbon atoms represented by each of R2 and R3 is a monocyclic, polycyclic, or cross-linked cycloalkyl group having 3 to 8 carbon atoms, and preferably having 5 to 8 carbon atoms. Specific examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
These cycloalkyl groups are optionally substituted with alkyl groups such as methyl groups, isopropyl groups, and t-butyl groups; or the like.
Regarding the ring formed by R2 and R3 together, R2 and R3 together form a linear or branched alkylene group having 2 to 10 carbon atoms, and preferably 3 to 10 carbon atoms, and thus form a preferably 4- to 8-membered, more preferably 5- to 8-membered, cycloalkane ring together with the adjacent carbon atoms. Preferred examples of the cycloalkane ring include a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring. These rings may have, as substituents, alkyl groups such as methyl groups, isopropyl groups, and t-butyl groups, and the like.
The alkyl group having 1 to 10 carbon atoms represented by each of R10 to R14 is a linear or branched alkyl group having 1 to 10 carbon atoms, and preferably having 1 to 5 carbon atoms. Specific examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, and the like.
The alkoxy group having 1 to 10 carbon atoms represented by each of R10 to R14 is a linear or branched alkoxy group having 1 to 10 carbon atoms, and preferably having 1 to 5 carbon atoms. Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a n-heptyloxy group, a n-octyloxy group, a n-nonyloxy group, a n-decyloxy group, and the like.
The alkyl groups of the trisubstituted alkylsilyl group represented by each of R10 to R14 are alkyl groups having 1 to 10 carbon atoms. Specific examples thereof include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, s-butyl groups, t-butyl groups, n-pentyl groups, n-hexyl groups, n-heptyl groups, n-octyl groups, n-nonyl groups, n-decyl groups, and the like. Specific examples of the trisubstituted alkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, and the like.
The halogen atom represented by B includes a chlorine atom, a bromine atom, an iodine atom, and the like.
The alkanesulfonyloxy group represented by B is preferably a linear or branched alkanesulfonyloxy group having 1 to 5 carbon atoms. Specific examples of the alkanesulfonyloxy group include a methanesulfonyloxy group, a trifluoromethanesulfonyl group, an ethanesulfonyloxy group, an isopropanesulfonyloxy group, a n-propylsulfonyloxy group, a n-butylsulfonyloxy group, a tert-butylsulfonyloxy group, a n-pentanesulfonyloxy group, and the like.
The arenesulfonyloxy group represented by B includes a phenylsulfonyloxy group, a naphthylsulfonyloxy group, and the like. The arenesulfonyloxy group may have 1 to 3 substituents on the phenyl ring of the phenylsulfonyloxy group or on the naphthalene ring of the naphthylsulfonyloxy group.
The substituents include linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, halogen atoms, and the like. Specific examples of the phenylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and the like. Specific examples of the naphthylsulfonyloxy group include cc-naphthylsulfonyloxy and (3-naphthylsulfonyloxy groups, and the like.
Subsequently, description is given of a step of obtaining the compound represented by the general formula (1) by reacting the compound represented by the general formula (2) with the diamine compound represented by the general formula (3) (Scheme
1) . Scheme 1
wherein R1 to R3, R10 to R14, A1, A2, A3, ni, n2, and B are the same as described above.
A solvent used for synthesizing the compound represented by the general formula (1) from the compound represented by the general formula (2) and the compound of the general formula (3) , which is a diamine compound, is preferably an aromatic hydrocarbon such as toluene, xylene, or mesitylene; a halogenated aromatic hydrocarbon such as chlorobenzene; an ether such as 1,4-dioxane; an aprotic polar solvent such as N,N-dimethylformamide or dimethyl sulfoxide, or the like, and is particularly preferably dimethyl sulfoxide, toluene, xylene, or mesitylene. In addition, the reaction can also be performed in a mixture of an organic solvent with water by using water as another solvent. Meanwhile, a base used for the reaction is preferably an inorganic base such as sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, lithium hydroxide, lithium hydrogen carbonate, lithium carbonate, cesium carbonate, magnesium hydroxide, magnesium carbonate, calcium hydroxide, or calcium carbonate; or a tertiary organic amine such as trimethylamine, triethylamine, triisopropylamine, tributylamine, or diisopropylethylamine, and is particularly preferably triethylamine or diisopropylethylamine. The amount of the base used is 0.2 to 2.0 equivalents, and preferably 1.0 to 1.5 equivalents to the compound represented by the general formula (2) . The reaction
temperature is, for example, 100°C to 200°C, and preferably 100°C to 160°C. The reaction time is 30 minutes to 30 hours, and preferably 1 hour to 12 hours, although it varies depending on the reaction substrate used. The reaction is preferably performed in an inert gas such as nitrogen gas or argon gas. Moreover, an additive such as sodium iodide, potassium iodide, lithium iodide, sodium bromide, potassium bromide, lithium bromide, potassium chloride, or lithium chloride may be added. The additive is preferably potassium iodide or lithium iodide. The amount of the additive is 0 to 10 equivalents, and preferably 0.1 to 1 equivalents to the compound represented by the general formula (2).
The compound represented by the general formula (2) can be synthesized, for example, by a method described in Scheme 2 below. Scheme 2
wherein R10 to R14, A1, A2, A3, ni, n2, and B are the same as described above.
The alcohol (c) can be synthesized by the Diels-Alder reaction between the diene (a) having substituents and the alkyne (b) having a substituent. The reagent used includes
metal complexes such as
[1,2-bis(diphenylphosphino)ethane]cobalt{II} dibromide,
1,5-cyclooctadiene(naphthalene)rhodium(I) tetrafluoroborate,
dichloro(l,4-diaza-l,3-diene)iron(II) , and
dichlorobis(tri-o-biphenylphosphite)nickel(II). A solvent used for the Diels-Alder reaction is not particularly limited, unless the reaction is adversely affected. The solvent includes ethers such as diethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as toluene and xylene; halogen-containing hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; aprotic polar solvents such as acetonitrile, ethyl acetate, and acetone; and the like. Dichloromethane or tetrahydrofuran is particularly preferable. Although the reaction temperature of the Diels-Alder reaction naturally varies depending on the substrate used, the reaction temperature is in a range of generally -20°C to 100°C, and preferably 10°C to 40°C. In addition, although the reaction time of the Diels-Alder reaction naturally varies depending on the substrate used, the reaction time is generally 30 minutes to 30 hours, and preferably 1 hour to 20 hours. Note that the Diels-Alder reaction is preferably performed in an inert gas such as nitrogen or argon.
Next, the hydroxyl group moiety of the alcohol (c) is converted to a leaving group such as a halogen atom, an alkanesulfonyloxy group, or an arenesulfonyloxy group, and thus the compound represented by the general formula (2) is synthesized. The reagent used here for the conversion to the leaving group includes hydrogen chloride, thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus trichloride,
phosphorus pentachloride, hydrogen bromide, phosphorus tribromide, phosphorus pentabromide, carbon tetrabromide, dimethylbromosulfonium bromide, thionyl bromide, hydrogen iodide, phosphorus triiodide, triphenyl phosphite methiodide, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. The reaction solvent includes, but not particularly limited, ethers such as diethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; halogen-containing hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane; aprotic polar solvents such as N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide; alcohols such as methanol, ethanol, and 2-propanol; and the like. In particular, dichloromethane, tetrahydrofuran, and toluene are preferable. Note that, for some reaction systems, it is preferable to perform the reaction in the presence of a base in an amount of 1 to 2 equivalents to the reaction substrate. Although the reaction temperature naturally varies depending on the substrate used, the reaction temperature is in a range of generally -30°C to 200°C, and preferably 10°C to 100°C. In addition, although the reaction time naturally varies depending on the substrate used, the reaction time is generally 30 minutes to 30 hours, and preferably 1 hour to 20 hours. Note that the reaction is preferably performed in an inert gas such as nitrogen or argon.
The compound represented by the general formula (2) can also be synthesized, for example, according to Scheme 3. Scheme 3
wherein R10 to R14, A1, A2, A3, n1, n2, and B are the same as described above.
As shown in scheme 3, the hydroxyl group moiety of the alkyne (b) having a substituent is converted to a leaving group such as a halogen atom, an alkanesulfonyloxy group, or an arenesulfonyloxy group. After that, the compound represented by the general formula (2) is synthesized by a Diels-Alder reaction of the compound represented by the general formula (e) with the diene (a) having substituents. A reagent for the conversion to the leaving group, a solvent, and reaction conditions are the same as described in scheme 2 above.
From the compound of the general formula (1} , a ruthenium-diamine complex (5) can be produced according to the description in Org. Lett. 9 (2007) p. 4659, for example.
wherein R1 to R3, R10 to R14, A1, A2, A3, n1, and n2 are the same as described above).
A solvent used for synthesizing a complex of the general formula (4) from the compound of the general formula (1) and ruthenium(III) chloride or hydrate thereof includes, but not particularly limited, aliphatic alcohols such as 2-propanol, n-butanol, 2-butanol, n-pentanol, 2-pentanol, 3-pentanol, 3-methyl-l-butanol, cyclopentanol, 3-methoxy-l-propanol, 2-methoxyethanol, 2-ethoxyethanol, 2-isopropoxyethanol, n-hexanol, 3-methoxy-l-butanol, 3-methoxy-3-methyl-l-butanol, 2-hexanol, 3-hexanol, cyclohexanol, n-heptanol, 2-heptanol, 3-heptanol, cycloheptanol, n-octanol, 2-octanol, 3-octanol, 4-octanol, and cyclooctanol; aromatic alcohols such as phenol, benzyl alcohol, 1-phenylethanol, 2-phenylethanol, o-cresol, m-cresol, p-cresol, 2-methylbenzyl alcohol, 3-methylbenzyl alcohol, and 4-methylbenzyl alcohol; diols such as ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, ethylene glycol-n-butyl ether, ethylene glycol-iso-butyl ether, and ethylene glycol-n-hexyl
ether; derivatives thereof; and the like. One of these solvents may be used alone, or two or more thereof may be used as a mixture . By using two or more solvents in combination, the boiling point of the solvent can be adjusted in a desired range, so that the reaction temperature can be controlled for a reaction under reflux. For example, an alcohol with which a small amount of water is mixed may be used. The amount of the compound of the general formula (1) used is 1 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents, to the ruthenium atoms. The amount of the solvent used is not particularly limited, as long as ruthenium chloride or hydrate thereof can be dissolved therein at the reaction temperature. For example, the amount of the solvent is 2 to 50 times volume (i.e., 2 to 50 mL of the solvent relative to 1 g of ruthenium chloride or hydrate thereof), preferably 2 to 30 times volume, and more preferably 5 to 20 times volume of ruthenium chloride or hydrate thereof. Although the reaction temperature varies depending on the solvent used, the reaction temperature is 60°C or above, and preferably 100°C or above, and also 200°C or below, and preferably 160°C or below, from the viewpoint of the reaction efficiency.
A solvent used for synthesizing the complex of the general formula (5) from the complex of the general formula (4) includes, but not particularly limited, halogenated solvents such as methylene chloride, dichloroethane, chloroform, and trifluoroethanol; aromatic hydrocarbons such as toluene and xylene; ethers such as diisopropyl ether and tetrahydrofuran; alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2-butanol, and n-pentanol; and the like. Dichloromethane or isopropanol is particularly preferable. One of these solvents
maybe used alone, or two or more thereof may be used as a mixture. By using two or more solvents in combination, the boiling point of the solvent can be adjusted in a desired range, so that the reaction temperature can be controlled for a reaction under reflux. For example, an alcohol with which a small amount of water is mixed may be used. The base used here includes inorganic bases such as sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, lithium hydroxide, lithium hydrogen carbonate, lithium carbonate, cesium carbonate, magnesium hydroxide, magnesium carbonate, calcium hydroxide, and calcium carbonate; amines such as triethylamine, tripropylamine, tributylamine, pyridine, and triisopropylamine; and the like. Triethylamine is particularly preferable. The amount of the base used is 0.2 to 2 equivalents, and preferably 1 to 1.5 equivalents to the ruthenium atoms. Although the reaction time varies depending on the reaction substrate used, the reaction time is 30 minutes to 20 hours, and preferably 1 hour to 12 hours. This reaction is preferably performed in an inert gas such as nitrogen gas or argon gas. Examples
Hereinafter, the present invention will be described in detail based on Examples. However, the present invention is not limited to these Examples.
Note that, in the following Examples and the like, NMR spectra used for identification of complexes and determination of purities thereof were measured with Mercury Plus 300 4N model apparatus manufactured by Varian Technologies Japan Ltd., or Bruker BioSpin Avance III 500 System. For GC analysis,
Chirasil-DEX CB (0 . 25 mm x 25 m, 0.25 μm) (manufactured by Varian, Inc.) or HP-1 (0. 32 mmx30 m, 0.2 5 urn) (manufactured by Agilent Technologies, Inc.) was used. For HPLC analysis, YMC-Pack Pro C18 (250x4.6 mm, 5 μm, 12 nm) (manufactured by YMC) was used. Meanwhile, for MS measurement, JMS-TlOOGCV manufactured by JEOL Ltd. or LCMS-IT-TOF manufactured by Shimadzu Corporation was used.
In addition, the meanings of abbreviations in Examples are as follows. THF: tetrahydrofuran
Msdpen: N-raethanesulfonyl-1,2-diphenylethylenediamine Tsdpen: N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine o-TFTs-DPEN:
N-(o-trifluoromethylbenzenesulfonyl)-1,2-diphenylethylenedi amine
TIPPs-DPEN:
N-(2, 4 , 6-triisopropylbenzenesulfonyl)-1,2-diphenylethylened iamine
DIPEA: diisopropylethylamine MIBK: methyl isobutyl ketone
S/C represents a value represented by the number of moles of the substrate ketone/the number of moles of the catalyst. [Example 1]
Production of
4-(4-methylcyclohexa-l,4-dienyl)butan-1-ol and
4-{5-methylcyclohexa-l,4-dienyl)butan-1-ol
In 45 mL of THF, 1, 2-bis (diphenylphosphino) ethane (0.77 g, 1.93 mmol), cobalt bromide (0.41 g, 1.87 mmol), zinc iodide (1.19 g, 3.7 3 mmol) , and zinc (0.24 g, 3. 67 mmol) were dissolved, followed by stirring at 70°C for 15 minutes. After cooling to room temperature, isoprene {7.55 g, 110.83 mmol) was added. Then, 5-hexyn-l-ol (8.94 g, 91.09 mmol) was slowly added dropwise with cooling in a water bath. After stirring at 35°C for 1 hour, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography {hexane/ethyl acetate=3/l) . Thus, 13.34 g of the title compounds, alcohols, were obtained as a colorless oily substance. Yield: 88.1% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the mixture of the two isomers.
1H-NMR (CDC13, 300 MHz): δ 5.61-5.57 (m, 2H' ), 5.43-5.41 (m, 2H), 3.67-3.63 (m, 2H+2H' ), 2.58 (brs, 4H) , 2.10 (brs, 4H'), 2.08 (t, J=6.9Hz, 2H' ), 2.00 (t, J=7.2Hz, 2H) , 1.76 (s, 3H' ) , 1.67 (s, 3H), 1.61-1.43 (m, 5H+5H');
HRMS(ESI): calcd for C11H19O [M+H]+ 167.1430, found 167.1432 [Example 2]
Production of 4-(4-methylcyclohexa-l,4-dienyl)butyl
4-methylbenzenesulfonate and
4-(5-methylcyclohexa-l,4-dienyl)butyl 4-methylbenzenesulfonate
The alcohols (12.19 g, 73.32 mmol, isomer ratio: 1,4 type/1, 5 type=77/23) obtained in Example 1, triethylamine (8.90 g, 87. 98 mmol) , and 1-methyl imidazole (7 .22 g, 87.98 mmol) were dissolved in 10 mL of toluene. With cooling in an ice-bath, a toluene solution (40 ml) of p-toluenesulfonyl chloride (15.94 g, 83.58 mmol) was slowly added dropwise, followed by stirring at room temperature for 1 hour. Water was added thereto, and the resultant layers were separated from each other. The obtained organic layer was washed with 2 M hydrochloric acid and water. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/l-4/l) . Thus, 20.25 g of the title compounds, tosylates, were obtained as a colorless oily substance. Yield: 8 6.2% (isomer ratio: 1,4 type/1,5 type=77/23) . Note that the following NMR spectrum data are those of the mixture of the two isomers. 1H-NMR (CDC13, 300 MHz): δ 7.80-7.77 (m, 2H+2H'), 7.36-7.33 (m, 2H+2H'), 5.58-5.56 (m, 1H'), 5.51-5.49 (m, 1H'), 5.39-5.38 (m, 1H) , 5.35-5.34 (m, 1H) , 4.05-4.01 (m, 2H+2H' ) , 2.53 (brs, 4H) , 2.45 (s, 3H +3H'), 2.05 (brs, 4H'), 1.99 (t, J=7.4 Hz, 2H'), 1.91 (t, J=7.4 Hz, 2H), 1.76 (s, 3H') , 1.66 (s, 3H) , 1.67-1.58 (m, 2H+2H'), 1.49-1.37 (m, 2H+2H');
HRMS (ESI) : calcd for C18H24O3SNa [M+Na]+ 343.1338, found 343.1330 [Example 3]
Production of
4-methyl-N-((1S,2S)-2-(4-(4-methylcyclohexa-l,4-dienyl)buty
lamino)-1,2-diphenylethyl)benzenesulfonamide and
4-methyl-N-{(1S,2S)-2-(4-(5-methylcyclohexa-l,4-dienyl)buty lamino)-1,2-diphenylethyl)benzenesulfonamide
The tosylates (10.45 g, 32.61 mmol, isomer ratio: 1,4 type/1,5 type=77/23) obtained in Example 2 were dissolved in 40 ml of toluene, and DIPEA (4.79 g, 32. 61 mmol) and (S,S) -TsDPEN (11.95 g, 32.61 mmol) were added thereto, followed by stirring at 135°C for 14 hours. After that, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate-2/1) . Thus, 9.31 g of the title compounds were obtained as a yellow oily substance. Yield: 55.5% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the mixture of the two isomers.
1H-NMR (CDC13, 300 MHz): δ 7.38-7.36 (m, 2H+2H' ) , 7.14-7.12 (m, 3H+3H'), 7.05-7.00 (m, 5H+5H'), 6.96-6.88 (m, 4H+4H'), 6.30 (brs, 1H+1H'), 5.60-5.58 (m, 1H'), 5.53-5.51 (m, 1H' } , 5.41-5.40 (m, 1H) , 5.37-5.36 (m, 1H) , 4.24-4.22 (m, 1H+1H'), 3.60-3.58 (m, 1H+1H'), 2.55 (brs, 4H) , 2.46-2.37 (m, 1H+1H'), 2.34 (s, 3H+3H'), 2.32-2.23 (m, 1H+1H'), 2.01 {brs, 4H' ) , 2.01-1.88 (m, 2H+2H'), 1.77 (s, 3H'), 1.67 (s, 3H) , 1.46-1.28 (m, 5H+5H');
HRMS (ESI): calcd for C32H39N2O2S [M+H] + 515. 2727, found 515 . 2747 [Example 4]
Production of
4-methyl-N-((IS,2S)-2-(4-(4-methylcyclohexa-l,4-dienyl)buty lamino)-1,2-diphenylethyl}benzenesulfonamide hydrochloride and
4-methyl-N-((IS,2S)-2-(4-(5-methylcyclohexa-l,4-dienyl)buty lamino)-1,2-diphenylethyl)benzenesulfonamide hydrochloride
The amides {8. 55 g, 16. 61 mmol, isomer ratio: 1,4 type/1, 5 type=77/23) obtained in Example 3 were dissolved in 33 ml of toluene. Under ice-cooling, a IN HC1 (methanolic solution) (3.46 g, 33.22 mmol) was added, followed by stirring at room temperature for 20 minutes. After that, the solvent was evaporated under reduced pressure. Thus, 8.85 g of the title compounds, diamine hydrochlorides, were obtained as a white solid. Yield: 96.7% (isomer ratio: 1, 4 type/1,5 type-77/23). 1H-NMR (d6-DMSO, 300 MHz) δ:
9.61 (brs, 1H+1H'), 9.15 (brs, 1H+1H'), 8.85 (d, 1H+1H'), 7.29-6.79 (m, 14H+14H'), 5.55 (m, 1H' ) , 5.48 (m, 1H' ) , 5.36 (m, 1H) , 5.31 (m, 1H), 4.82 (m, 1H+1H' ) , 4.54 (m, 1H+1H' ) , 2.66 (brs, 4H), 2.20 (s, 3H+3H'), 1.99 (brs, 4H'), 1.98-1.90 (m, 2H'), 1.90-1.82 (m, 2H), 1.71(s, 3H'), 1.70-1.52 (m, 2H+2H'), 1.61(s, 3H), 1.38-1.18 (m, 2H+2H');
HRMS (ESI) : calcd for C32H39N2O2S [M-Cl] + 515.2727, found 515.2728 [Example 5]
Production of
N-[(1S,2S)-1,2-diphenyl-2-(4-(4-methylphenyl)butylamino)eth
yl] -4-methylbenzenesulfonamide amnionium chloride ruthenium
dimer and
N-[(IS, 2S)-l,2-diphenyl-2-(4-(3-methylphenyl)butylamino)eth yl]-4-methylbenzenesulfonamide ammonium chloride ruthenium dimer
The hydrochlorides (7.42 g, 13. 46 mmol, isomer ratio: 1,4 type/1,5 type=77/23) obtained in Example 4 and ruthenium trichloride.trihydrate (3.20 g, 12.25 mmol) were dissolved in a mixture solvent of 110 ml of 3-methoxypropanol and 37 ml of water, followed by stirring at 120°C for 1 hour. The solvent was evaporated under reduced pressure, and diethyl ether was added to the obtained residue, followed by stirring at room temperature for 15 minutes. The precipitated crystals were filtered. Thus, 10.15 g of the title compounds, ruthenium dimers, were obtained. Yield: 52.3%. The following NMR spectrum data are those of the major product (1,4 type). 1H NMR (d6-DMSO, 500 MHz): δ 9.61 (brs, 2H), 9.11 (brs, 2H), 8.78 (d, J=9.1Hz, 2H), 7.30-6.88 (m, 28H) , 6.82-6.81 (m, 8H) , 4.83 (m, 2H), 4.56 (m, 2H) , 2.71 (brs, 4H) , 2.35 (t, J=7.5 Hz, 4H), 2.22 (s, 6H), 2.10 (s, 6H), 1.80-1.60 (m, 4H), 1.60-1.42
(m, 4H);
HRMS (FD): calcd for C32H35CIN2O2RUS [M/2-2HCl] + - 648.1156, found
648.1182
[Example 6]
Production of
N-[(lS,2S)-l,2-diphenyl-2-(4-(4-methylphenyl)butylamino)eth
yl]-4-methylbenzenesulfonamide ammonium chloride ruthenium
monomer and
N-[(IS, 2S) -1, 2-diphenyl-2-(4-(3-methylphenyl)butylamino)eth yl]-4-methylbenzenesulfonamide ammonium chloride ruthenium monomer
The ruthenium dimers (9.12 g, 6.32 mmol) obtained in Example 5 were dissolved in 155 ml of 2-propanol, and triethylamine (2.53 g, 25.29 mmol) was added thereto, followed by stirring at 60°C for 1 hour. After that, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography {chloroform/methanol-20/1). Thus, 6.77 g of the title compounds, ruthenium monomers, were obtained. Yield: 82.6%
(the chemical purity based on HPLC was 97.2%). The following NMR spectrum data are those of the major product (1,4 type). 1H NMR (CD2C12/ 500 MHz): δ 7.17 (d, J=7.9 Hz, 2H), 7.10-7.05 (m, 3H), 6.86 (d, J=7.9Hz, 2H), 6.82-6.79 (m, 1H), 6.74 (d, J=6.4 Hz, 2H) , 6.68 (dd, J=7. 9 Hz, 2H) , 6.56 (d, J=7. 9 Hz, 2H) , 6.18 (d, J=5.6Hz, 1H), 5.55 (d, J=6.3Hz, 1H) , 5.35 (d, J=6.3 Hz, 1H), 5.29 (d, J=5.6 Hz, 1H), 4.73-4.70 (m, 1H), 3.97 (d, J=11.0 Hz, 1H), 3.81 (dd, J=11.0, 12.2 Hz, 1H) , 3.52-3.47 (m, 1H), 3.13-3.07 (m, 1H) , 2.85-2.81 (m, 1H) , 2.75-2.69 (m, 1H) , 2.44 (s, 3H), 2.26 (s, 3H), 2.28-2.17 (m, 1H), 2.15-2.04 (m, 1H), 1.96-1.88 (m, 1H) , 1.67-1.60 (m, 1H);
HRMS (ESI): calcd for C32H36ClN202RuS [M+H]+ 649.1224, found 649.1224 [Example 7]
Production of
N-((1S,2S)-2-(4-(4-methylcyclohexa-l,4-dienyl)butylamino)-1
,2-diphenylethyl)methanesulfonamide and
N-((IS,2S)-2-(4-(5-methylcyclohexa-l,4-dienyl)butylamino)-1 ,2-diphenylethyl)methanesulfonamide
The tosylates (5.11 g, 15.95 mmol) obtained in Example 2 were dissolved in 20 ml of toluene, and DIPEA (2.05 g, 15.95 mmol) and (S,S)-MsDPEN (4.63 g, 15.95 mmol) were added thereto, followed by stirring at 135°C for 16 hours. After that, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate-2/1). Thus, 5,72 g of the title
compounds, diamines, were obtained as a yellow oily substance. Yield: 81.8% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the mixture of the two isomers.
1H NMR (CDC13, 300 MHz): δ 7.26-7.19 (m, 10H+10H' ) , 6.23 (brs, 1H+1H'), 5.59-5.58 (m, 1H'), 5.52-5.51 (m, 1H'), 5.40 (m, 1H) , 5.36 (m, 1H), 4.47-4.44 (m, 1H+1H'), 3.75-3.72 (m, 1H+1H'), 2.55 (brs, 4H), 2.46-2.37 (m, 1H+1H'), 2.34 (s, 3H+3H'), 2.32-2.23 (m, 1H+1H'), 2.01 (brs, 4H'), 2.01-1.88 (m, 2H+2H'), 1.77 (s, 3H'), 1.67 (s, 3H), 1.46-1.28 {m, 5H+5H');
HRMS (ESI) : calcd for C26H35N2O2S [M+H]+ 439.2414, found 439.2409 [Example 8]
Production of
N-((IS,2S)-2-(4-(4-methylcyclohexa-l,4-dienyl)butylamino)-1 ,2-diphenylethyl)methanesulfonamide hydrochloride and N-((IS, 2S)-2-(4-{5-methylcyclohexa-l,4-dienyl)butylamino)-1 , 2-diphenylethyl)methanesulfonamide hydrochloride
The diamines (5.11 g, 11.65 mmol) obtained in Example 7 were dissolved in 20 ml of toluene. Under ice-cooling, a IN HC1 (methanolic solution) (2.43 g, 23.30 mmol) was added thereto, followed by stirring at room temperature for 20 minutes. After that, the solvent was evaporated under reduced pressure. Thus, 5.14 g of the title compounds, diamine hydrochlorides, were obtained as a white solid. Yield: 92.9% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the mixture of the two isomers.
1H-NMR (d6-DMSO, 300 MHz) δ:
9.94 {brs, 1H+1H'), 9.08 (brs, 1H+1H'), 8.34 (d, 1H+1H'),
7.39-7.00 (m, 10H+10H') , 5.54 (m, 1H') , 5.47 (m, 1H' ) , 5.35 (m,
1H), 5.30 (m, 1H), 4.90 (m, 1H+1H') , 4.56 (m, 1H+1H' ) , 2.72-2.56
(m, 6H+2H'), 2.47 (s, 3H+3H' ) , 1.98 (brs, 4H' ) , 1.93 (t, J=6.9
Hz, 2H'), 1-85 (t, J=7.2 Hz, 2H) , 1.71 (s, 3H' ) , 1.70-1.52 (m,
2H+2H'), 1.61 (sf 3H), 1.38-1.18 (m, 2t|+2H' ) ;
HRMS (ESI) : calcd for C26H35N202S [M-Cl]+ 4 39.2414, found
439.2422
[Example 9]
Production of
N-[(1S, 2S)-1,2-diphenyl-2-(4-(4methylphenyl)butylamino]-et hyl]-methanesulfonamide ammonium chloriqe ruthenium dimer and N-[(lS,2S)-l,2-diphenyl-2-(4-(3-methylphenyl)butylamino)-et hyl]-methanesulfonamide ammonium chloride ruthenium dimer
The diamine hydrochlorides (4.05 g, 8.52 mmol) obtained in Example 8 and ruthenium trichloride-trihydrate (2.03 g, 7.76 mmol) were dissolved in a mixture solvent of 60 ml of 3-methoxypropanol and 19 ml of water, followed by stirring at 120°C for 1 hour. The solvent was evaporated under reduced pressure, and diethyl ether was added to the obtained residue, followed by stirring at room temperature for 15 minutes. The
precipitated crystals were filtered. Thus, 5.49 g of the title
compounds, ruthenium dimers, were obtained. Yield: 49.9%.
The following NMR spectrum data are those of the major product
(1,4 type).
1H NMR (d6-DMSO, 500 MHz): δ 9.87 (brs, 2H), 9.04 {brs, 2H) ,
8.27 (d, J=9.4 Hz, 2H) , 7.39-7.01 (m, 20H) , 5.76-5.73 (m, 8H) ,
4.91 (m, 2H), 4.59 (m, 2H) , 2.70 (brs, 4H) , 2.62 (s, 6H) , 2.35
(t, J=7.7 Hz, 4H), 2.09 (s, 6H) , 1.80-1.60 (m, 4H) , 1.60-1.41
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1681-MUMNP-2013-CORRESPONDENCE(11-10-2013).pdf |
2013-10-11 |
| 2 |
1681-MUMNP-2013-AFR-14-10-2013.pdf |
2013-10-14 |
| 3 |
Form 3 [04-03-2017(online)].pdf |
2017-03-04 |
| 4 |
1681-MUMNP-2013-FORM 3 [08-11-2017(online)].pdf |
2017-11-08 |
| 5 |
ABSTRACT1.jpg |
2018-08-11 |
| 6 |
1681-MUMNP-2013.pdf |
2018-08-11 |
| 7 |
1681-MUMNP-2013-WO INTERNATIONAL PUBLICATION REPORT A1.pdf |
2018-08-11 |
| 8 |
1681-MUMNP-2013-OTHER DOCUMENT.pdf |
2018-08-11 |
| 9 |
1681-MUMNP-2013-MARKED COPY.pdf |
2018-08-11 |
| 10 |
1681-MUMNP-2013-INTERNATIONAL APPLICATION STATUS REPORT.pdf |
2018-08-11 |
| 11 |
1681-MUMNP-2013-GENERAL POWER OF ATTORNEY.pdf |
2018-08-11 |
| 12 |
1681-MUMNP-2013-GENERAL POWER OF ATTORNEY(2-12-2013).pdf |
2018-08-11 |
| 13 |
1681-MUMNP-2013-FORM PCT-ISA-210.pdf |
2018-08-11 |
| 14 |
1681-MUMNP-2013-FORM PCT-IB-304.pdf |
2018-08-11 |
| 15 |
1681-MUMNP-2013-FORM PCT-IB-301.pdf |
2018-08-11 |
| 16 |
1681-MUMNP-2013-FORM 5.pdf |
2018-08-11 |
| 17 |
1681-MUMNP-2013-FORM 3.pdf |
2018-08-11 |
| 18 |
1681-MUMNP-2013-Form 3-160516.pdf |
2018-08-11 |
| 19 |
1681-MUMNP-2013-Form 3-040915.pdf |
2018-08-11 |
| 20 |
1681-MUMNP-2013-FORM 3(4-3-2014).pdf |
2018-08-11 |
| 21 |
1681-MUMNP-2013-FORM 3(12-9-2014).pdf |
2018-08-11 |
| 22 |
1681-MUMNP-2013-FORM 3(10-3-2014).pdf |
2018-08-11 |
| 23 |
1681-MUMNP-2013-FORM 2.pdf |
2018-08-11 |
| 24 |
1681-MUMNP-2013-FORM 2(TITLE PAGE).pdf |
2018-08-11 |
| 25 |
1681-MUMNP-2013-FORM 13.pdf |
2018-08-11 |
| 26 |
1681-MUMNP-2013-FORM 1.pdf |
2018-08-11 |
| 27 |
1681-MUMNP-2013-FER.pdf |
2018-08-11 |
| 28 |
1681-MUMNP-2013-ENGLISH TRANSLATION.pdf |
2018-08-11 |
| 29 |
1681-MUMNP-2013-DESCRIPTION(COMPLETE).pdf |
2018-08-11 |
| 30 |
1681-MUMNP-2013-CORRESPONDENCE.pdf |
2018-08-11 |
| 31 |
1681-MUMNP-2013-Correspondence-160516.pdf |
2018-08-11 |
| 32 |
1681-MUMNP-2013-Correspondence-040915.pdf |
2018-08-11 |
| 33 |
1681-MUMNP-2013-CORRESPONDENCE(4-3-2014).pdf |
2018-08-11 |
| 34 |
1681-MUMNP-2013-CORRESPONDENCE(2-12-2013).pdf |
2018-08-11 |
| 35 |
1681-MUMNP-2013-CORRESPONDENCE(12-9-2014).pdf |
2018-08-11 |
| 36 |
1681-MUMNP-2013-CORRESPONDENCE(10-3-2014).pdf |
2018-08-11 |
| 37 |
1681-MUMNP-2013-CLAIMS.pdf |
2018-08-11 |
| 38 |
1681-MUMNP-2013-ABSTRACT.pdf |
2018-08-11 |
| 39 |
1681-MUMNP-2013-AbandonedLetter.pdf |
2018-10-31 |
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