WO2014132975A1 - (2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの製造方法 - Google Patents
(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの製造方法 Download PDFInfo
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- WO2014132975A1 WO2014132975A1 PCT/JP2014/054609 JP2014054609W WO2014132975A1 WO 2014132975 A1 WO2014132975 A1 WO 2014132975A1 JP 2014054609 W JP2014054609 W JP 2014054609W WO 2014132975 A1 WO2014132975 A1 WO 2014132975A1
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- lactone
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- fluoro
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- 0 C[C@@]([C@]([C@@](CO)O1)O)(*1=O)F Chemical compound C[C@@]([C@]([C@@](CO)O1)O)(*1=O)F 0.000 description 7
- VNCJYMKHJWVTPK-ZMIZWQJLSA-N C[C@@]([C@@H]([C@@H](CO)O1)O)(C1=O)F Chemical compound C[C@@]([C@@H]([C@@H](CO)O1)O)(C1=O)F VNCJYMKHJWVTPK-ZMIZWQJLSA-N 0.000 description 3
- VNCJYMKHJWVTPK-ALEPSDHESA-N C[C@@]([C@H]([C@@H](CO)O1)O)(C1=O)F Chemical compound C[C@@]([C@H]([C@@H](CO)O1)O)(C1=O)F VNCJYMKHJWVTPK-ALEPSDHESA-N 0.000 description 2
- VNCJYMKHJWVTPK-DUXHBQLLSA-N C[C@]([C@@H](C(CO)O1)O)(C1=O)F Chemical compound C[C@]([C@@H](C(CO)O1)O)(C1=O)F VNCJYMKHJWVTPK-DUXHBQLLSA-N 0.000 description 2
- VNCJYMKHJWVTPK-KODRXGBYSA-N C[C@]([C@@H]([C@@H](CO)O1)O)(C1=O)F Chemical compound C[C@]([C@@H]([C@@H](CO)O1)O)(C1=O)F VNCJYMKHJWVTPK-KODRXGBYSA-N 0.000 description 2
- VNCJYMKHJWVTPK-IWGUZYHVSA-N C[C@]([C@H]([C@@H](CO)O1)O)(C1=O)F Chemical compound C[C@]([C@H]([C@@H](CO)O1)O)(C1=O)F VNCJYMKHJWVTPK-IWGUZYHVSA-N 0.000 description 2
- SUVMKRCKULRYOZ-RFZPGFLSSA-N CC(C)([C@@H]([C@@H](CN=O)O1)N=O)C1=O Chemical compound CC(C)([C@@H]([C@@H](CN=O)O1)N=O)C1=O SUVMKRCKULRYOZ-RFZPGFLSSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Definitions
- the present invention relates to an industrial process for producing (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones.
- (2R) as a diastereomeric mixture by aldol reaction of ethyl 2-fluoropropionate with (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde in the presence of a base
- a method for separating diastereomers by obtaining a substrate-selective hydrolysis reaction with an enzyme after obtaining a -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone precursor has been reported.
- Et represents an ethyl group
- Bz represents a benzoyl group
- An object of the present invention is to provide an industrial process for producing (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones.
- 1,2-diols which are also raw material substrates of the present invention, are disclosed.
- this compound can be produced by a known method, it is stereoselective using a Wittig reaction or a metal reagent. Cost reduction has been somewhat difficult due to the fact that a method of production by a dihydroxylation reaction has been adopted.
- the process can be shortened as compared with the production method of Patent Document 1, but the total yield is low, and reproducibility is achieved by using an enzyme reaction for separation of diastereomers.
- it still has a problem in terms of productivity, and it has been difficult to satisfy the requirements for industrial manufacturing methods (high productivity and good reproducibility).
- Patent Document 3 sufficient selectivity and yield are not obtained, and an efficient separation method is still required. Therefore, in the development of a method for purifying (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone, which is the subject of the present invention, an efficient dialysis by a simpler operation than in the conventional method. Separation of stereomers was strongly desired.
- R 1 represents an alkyl group or a substituted alkyl group
- A represents an oxygen atom, a nitrogen atom or a sulfur atom.
- P 1 and P 2 each represent a protecting group for a hydroxyl group. * Represents an asymmetric carbon. ] [In the formula, * represents an asymmetric carbon. ]
- recrystallization solvent alcohol, nitrile, ester, ether, aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ketone, water can be used alone or in combination. It has been found that optically active 2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone having high purity and high reproducibility can be obtained in high yield.
- the corresponding lactone obtained here can be obtained in good yield by carrying out an acylation reaction.
- the present invention is characterized by the order of performing “recrystallization purification” and “acylation reaction”. That is, the diastereomer is recrystallized from the (3R) -2-acylated (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones in which the 3,5 positions are mixed, ie, first Even if recrystallization was performed after acylation, the product having the desired configuration could not be efficiently separated (see Comparative Example 1 described later). The results show that the diastereomeric separation behavior is clear when the 3,5 position is a hydroxyl group (when the 3,5 position is not acylated) and when the 3,5 position is acylated.
- the present invention provides an industrial process for producing (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones described in [Invention 1]-[Invention 7].
- R 2 represents an acyl group
- R 1 represents an alkyl group or a substituted alkyl group
- A represents an oxygen atom, a nitrogen atom or a sulfur atom.
- P 1 and P 2 each represent a protecting group for a hydroxyl group. * Represents an asymmetric carbon.
- * represents an asymmetric carbon.
- Solvents used for recrystallization of dihydroxy lactone diastereomeric mixtures are alcohols, aromatic hydrocarbons, esters, nitriles, ethers, halogenated hydrocarbons, ketones, water, and aliphatic hydrocarbons
- invention 3 The production method according to invention 1 or 2, wherein the solvent used for recrystallization of the diastereomeric mixture of dihydroxylactone is isopropanol, toluene, ethyl acetate or n-heptane.
- the acid used is acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, paratoluenesulfonic acid, or trifluoroacetic acid, The manufacturing method of the invention 1.
- the present invention by performing recrystallization purification on a diastereomeric mixture of dihydroxylactone, among the diastereomers contained in the mixture, the target (2R) -2-fluoro-2-C-methyl- D-ribono- ⁇ -lactone can be obtained efficiently. Furthermore, (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone with high reproducibility and high purity can be obtained by adopting suitable recrystallization conditions.
- the present invention does not require a substrate-selective hydrolysis reaction using a conventional enzyme, and efficiently separates diastereomers by a simple operation that does not require an enzyme reaction. Has reproducibility and can increase productivity.
- the present invention also satisfies the requirements as an industrial production method.
- the present invention provides a diastereomeric mixture of dihydroxylactone represented by general formula [3] by deprotecting and lactonizing a diastereomeric mixture of lactone precursor represented by general formula [2] under acidic conditions. And by recrystallizing the mixture obtained in the previous step, a high purity (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone represented by the general formula [4] is obtained.
- a step of acylating the (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone obtained in the previous step, and (2R) -2-fluoro-2- This is a method for producing C-methyl-D-ribono- ⁇ -lactones.
- R 1 in the general formula [2] represents an alkyl group or a substituted alkyl group.
- the alkyl group can have a straight chain or branched chain structure having 1 to 12 carbon atoms, or a cyclic structure (when the number of carbon atoms is 3 or more).
- the substituted alkyl group has a substituent in any number and in any combination on any carbon atom of the alkyl group.
- substituents include fluorine, chlorine, bromine, iodine halogen atoms, methyl groups, ethyl groups, propyl groups, butyl groups and other lower alkyl groups, methoxy groups, ethoxy groups, propoxy groups, butoxy groups and other lower alkoxy groups.
- lower means 1 to 6 carbon atoms, and may be linear or branched, or cyclic (when the number of carbon atoms is 3 or more). Among them, an alkyl group having 1 to 6 carbon atoms or a substituted alkyl group is preferable, and a methyl group or an ethyl group is particularly preferable.
- a in the general formula [2] represents an oxygen atom, a nitrogen atom, or a sulfur atom, and together with the definition of R 1 described above, examples of specific structures are as follows (note that a wavy line in the formula represents a binding site) Is).
- P 1 and P 2 of the lactone precursor represented by the general formula [2] each represent a protecting group for a hydroxyl group.
- protecting groups include those described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc.
- P 1 and P 2 can adopt the same protecting group or different protecting groups, and can also adopt one protecting group at the same time. Among them, those which simultaneously take one protecting group are preferable (see below), and those protected with an isopropylidene group or a cyclohexylidene group are particularly preferable.
- the diastereomeric mixture of the lactone precursor represented by the general formula [2] can be similarly produced with reference to Patent Document 2, Non-Patent Document 1, and the like.
- the “diastereomeric mixture of lactone precursors” mentioned here refers to compounds (formula [2a] -formula [2d]) having four different steric configurations whose specific structures are shown below. .
- the “diastereomeric mixture of dihydroxy lactones” mentioned here refers to compounds (formula [3a] -formula [3d]) having four different steric configurations whose specific structures are shown below.
- examples of the acid include acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid, paratoluenesulfonic acid, and trifluoroacetic acid.
- the acid is not limited to these, and includes those generally used in organic synthesis. Of these, acetic acid, sulfuric acid, and hydrochloric acid are particularly preferable. These acids can be used alone or in combination.
- the acid may be used in an amount of 0.05 mol or more per mol of the diastereomeric mixture of the lactone precursor represented by the general formula [2], preferably 0.1 mol to 50 mol, 0.2 mol To 20 mol is particularly preferred.
- Reaction solvents include alcohols such as methanol and ethanol, amides such as N, N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile and propionitrile, water, tetrahydrofuran and dimethyl Examples thereof include sulfoxide. Of these, methanol, ethanol, N, N-dimethylformamide, acetonitrile, water, tetrahydrofuran and dimethyl sulfoxide are preferable, and methanol, ethanol, acetonitrile, water and tetrahydrofuran are particularly preferable. These reaction solvents can be used alone or in combination.
- the reaction temperature may be in the range of ⁇ 20 to + 150 ° C., preferably ⁇ 10 to + 125 ° C., particularly preferably 0 to + 100 ° C.
- the reaction time may be in the range of 96 hours or less, and varies depending on the raw material substrate and reaction conditions. Therefore, the progress of the reaction is traced by analysis means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc.
- the end point is preferably the point at which almost disappeared.
- the recrystallization solvent examples include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, methylene chloride, chloroform, Halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butylmethyl ether, di-propyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl i-butyl ketone, etc.
- aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane
- aromatic hydrocarbons such as benzene, toluene, e
- Ketone ethyl acetate, ester such as n-butyl acetate, acetonitrile Lil, nitrile such as propionitrile, methanol, ethanol, n- propanol, i- propanol, alcohol such as n- butanol, water and the like.
- acetonitrile Lil nitrile such as propionitrile
- methanol ethanol
- n- propanol n- propanol
- i- propanol i- propanol
- alcohol such as n- butanol, water and the like.
- the amount of the recrystallization solvent used is usually 0.5 mL or more per 1 g of the mixture of dihydroxylactones represented by the general formula [3], preferably 1 to 30 mL, more preferably 2 to 10 mL.
- the crystals are sufficiently precipitated in the range of ⁇ 20 to + 20 ° C. over 1 to 48 hours while dissolving with heating and gradually cooling while standing or stirring.
- a method of filtering the precipitated crystals is preferably employed. It is also possible to use seed crystals during crystallization.
- the (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone obtained in the recrystallization step is represented by the general formula [1] by an acylation reaction in the presence of a base ( 2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones.
- Examples of the acylation reaction used in the present invention include acetylation, benzoylation, and formylation.
- Acylating agents include acetic anhydride and acetyl chloride for acetylation, formic acid for formylation, and benzoyl chloride, benzoic anhydride, benzoyl cyanide, trifluoromethanesulfonic acid for benzoylation. Examples include, but are not limited to, benzoyl.
- the acylation reaction is preferably acetylation or benzoylation reaction, more preferably benzoylation reaction.
- the specific reagent in the benzoylation reaction is particularly preferably benzoyl chloride among the reagents described above.
- the amount of the acylating agent to be used is generally 1 to 20 mol, preferably 2 to 10 mol, per 1 mol of (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone. 2 to 5 mol is more preferable.
- reaction solvent used in the acylation reaction examples include aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane, diethyl ether, tetrahydrofuran, Examples thereof include ethers such as t-butyl methyl ether, di-propyl ether and 1,4-dioxane, and nitriles such as acetonitrile and propionitrile. These reaction solvents may be appropriately selected and used depending on the reaction conditions, and may be used alone or in combination.
- Examples of the base that can be used include ammonia, triethylamine, pyridine, lutidine, collidine, amines such as N, N-dimethylaniline, and hydroxides such as sodium hydroxide, potassium hydroxide, and tetramethylammonium hydroxide. And alkali metal carbonates or hydrogen carbonates such as potassium carbonate and sodium hydrogen carbonate. These bases can be used singly or in combination of two or more.
- reaction temperature an appropriate reaction temperature can be selected depending on the reaction conditions.
- R 2 represents an acyl group.
- the acyl group include a benzoyl group, a formyl group, and an acetyl group, and these correspond to the acylating agents described above.
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 15 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 11.90 g of the mer mixture was obtained.
- the 19 F-NMR of the crude product is shown below.
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 15 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 13.90 g of a mer mixture was obtained.
- the 19 F-NMR of the crude product was the same as in Example 1.
- 13.90 g of the diastereomeric mixture of dihydroxylactone obtained above was recrystallized from a mixed solvent of 20.9 ml (1.5 vol) of isopropanol, 69.5 ml (5 vol) of toluene and 27.8 ml (2 vol) of n-heptane.
- the gas chromatographic purity of the crystals was 99.1%, and the diastereomer represented by the above formula [5] as the main impurity was 0.4%.
- the total amount of the crude product obtained above (7.09 g, referred to as 17.9 mmol for convenience) was 10.6 ml (1.5 vol) of ethyl acetate, 10.6 ml (1.5 vol) of isopropanol, and 63.8.4 ml of n-heptane. Recrystallization from a mixed solvent of (9 vol), washing with 13.8 ml of n-heptane, and vacuum drying gave (2R) -2-fluoro-2-C-methyl-D-ribono- 6.17 g (16.6 mmol) of white crystals of ⁇ -lactones were obtained. The yield was 92.6%. The gas chromatographic purity of the crystals was 99.8%.
- reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 30 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 24.80 g of the mer mixture was obtained.
- the total amount of the crude product obtained above (13.81 g, referred to as 35.6 mmol for convenience) was 20.7 ml (1.5 vol) of ethyl acetate, 20.7 ml (1.5 vol) of isopropanol, and 124.3 ml (9 vol) of n-heptane. ), And the crystals collected by filtration are washed with 27.4 ml of n-heptane and dried under vacuum to give (2R) -2-fluoro-2-C-methyl-D represented by the above formula. -11.99 g (32.2 mmol) of white crystals of ribono- ⁇ -lactones were obtained. The yield was 90.5%. The gas chromatographic purity of the crystals was 95.8%.
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 15 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 8.72 g of a mer mixture was obtained.
- the 19 F-NMR of the crude product was the same as in Example 1. 8.72 g of the diastereomeric mixture of dihydroxylactone obtained above was recrystallized from a mixed solvent of isopropanol 13.1 ml (1.5 vol), toluene 43.6 ml (5 vol) and n-heptane 8.7 ml (1 vol).
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 10 ml of toluene, and vacuum-dried to obtain a dihydroxylactone diastereomer represented by the following formulas [4], [5], [10] and [11].
- 0.52 g of the mer mixture was obtained.
- the 19 F-NMR of the crude product was the same as in Example 1.
- 0.52 g of the mixture of dihydroxylactone obtained above was recrystallized from a mixed solvent of 0.8 ml (1.5 vol) of isopropanol, 2.6 ml (5 vol) of toluene and 0.5 ml (1 vol) of n-heptane, and collected by filtration.
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 15 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 8.72 g of a mer mixture was obtained.
- the 19 F-NMR of the crude product was the same as in Example 1. 6.84 g of the diastereomeric mixture of dihydroxylactone obtained above was recrystallized from a mixed solvent of 10.3 ml (1.5 vol) of isopropanol, 34.2 ml (5 vol) of toluene and 6.8 ml (1 vol) of n-heptane.
- the reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure five times with 55 ml of toluene, and vacuum-dried, thereby diastereoisomers of dihydroxylactones represented by the following formulas [4], [5], [10] and [11]. 70.27 g of a mer mixture was obtained.
- the 19 F-NMR of the crude product was the same as in Example 1.
- (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactones represented by the following formulas [1] and [28]-[31] by concentration under reduced pressure and vacuum drying 131.74 g [[1]: 75.7 mmol, [20]: 69.8 mmol, [21] + [22]: 24.2 mmol (quantified by internal standard method by 19 F-NMR)] was obtained. It was.
- the mixture was recrystallized from a mixed solvent of 197 ml (1.5 vol) of ethyl acetate, 197 ml (1.5 vol) of isopropanol and 1180 ml (9 vol) of n-heptane, and the crystals collected by filtration were washed with 132 ml of ice-cooled methanol. By vacuum drying, 40.36 g of white crystals were obtained. When the crystals were analyzed by gas chromatography, they contained [1]: 61% and [20]: 33%.
- the crystals were recrystallized again from a mixed solvent of 60 ml (1.5 vol) of ethyl acetate, 60 ml (1.5 vol) of isopropanol and 364 ml (9 vol) of n-heptane, and the crystals collected by filtration were ice-cooled.
- the crystals were washed with 81 ml of methanol and vacuum-dried to obtain 33.25 g of white crystals.
- the crystals were analyzed by gas chromatography, they contained [1]: 67% and [20]: 33%.
- the (2R) -2-fluoro-2-C-methyl-D-ribono- ⁇ -lactone targeted in the present invention is 2′-deoxy-2′-fluoro-2′-C-methyl having antiviral activity. It can be used as an important intermediate for cytidine.
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Abstract
Description
一般式[1]で表される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の製造方法において、一般式[2]で表されるラクトン前駆体のジアステレオマー混合物を、酸性条件下で脱保護し、続いてラクトン化させることにより、一般式[3]で表されるジヒドロキシラクトンのジアステレオマー混合物を得る工程と、得られた混合物を再結晶することにより、一般式[4]で表される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンを分離精製する工程と、分離精製されたラクトンをアシル化する工程と、を含む、(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の製造方法。
ジヒドロキシラクトンのジアステレオマー混合物の再結晶に用いる溶媒が、アルコール系、芳香族炭化水素系、エステル系、ニトリル系、エーテル系、ハロゲン化炭化水素系、ケトン系、水、および脂肪族炭化水素系からなる群より選ばれる少なくとも1種の溶媒である、発明1に記載の製造方法。
ジヒドロキシラクトンのジアステレオマー混合物の再結晶に用いる溶媒が、イソプロパノール、トルエン、酢酸エチルまたはn-ヘプタンである、発明1または2に記載の製造方法。
一般式[2]におけるR1が、炭素数が1から6の直鎖または枝分れのアルキル基または置換アルキル基である、発明1に記載の製造方法。
一般式[2]におけるP1およびP2が、イソプロピリデン基またはシクロヘキシリデン基である、発明1に記載の製造方法。
ラクトン前駆体のジアステレオマー混合物を、酸性条件下で脱保護し、続いてラクトン化させる際、用いる酸が酢酸、硫酸、塩酸、メタンスルホン酸、パラトルエンスルホン酸、またはトリフルオロ酢酸である、発明1に記載の製造方法。
一般式[1]におけるR2が、ベンゾイル基、ホルミル基、またはアセチル基である、発明1に記載の製造方法。
100mlナスフラスコに下記式[6]-[9]で示されるラクトン前駆体のジアステレオマー混合物17.47g[[6]:22.3mmol、[7]:16.1mmol、[8]+[9]:9.9mmol(19F-NMRによる内部標準法で定量)]、メタノール24ml(0.5L/mol)、12N塩酸1.5ml(18mmol、0.37eq)を加え、室温で18時間攪拌した。
19F-NMR[基準物質;C6F6、重溶媒;CD3CN]、
[4]:δ ppm;-6.60(m、1F)、
[5]:δ ppm;6.51(m、1F)、
[10]または[11]:δ ppm;-8.70(m、1F)、
[10]または[11]:δ ppm;7.70(m、1F)。
上記で得られたジヒドロキシラクトンのジアステレオマー混合物11.90gをイソプロパノール17.9ml(1.5vol)とトルエン59.5ml(5vol)、n-ヘプタン11.9ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したn-ヘプタン11.9mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を3.17g(19.3mmol)得た。収率は86.5%であった。結晶のガスクロマトグラフィー純度は94.4%で、主な不純物である上記式[5]で示されるジアステレオマーは3.7%であった。
上記で得られた(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン3.17g(19.3mmol)に、アセトニトリル19.3ml(1L/mol)、とピリジン3.51g(44.4mmol、2.30eq)を加えて、ベンゾイルクロリド5.97g(42.5mmol、2.20eq)を氷冷下で加えて、室温で2時間攪拌した。反応終了液に水18mlを氷冷下で加え、室温で10分攪拌し、酢酸エチル36mlで抽出し、回収有機層を5%炭酸水素ナトリウム水溶液18mlで洗浄し、5%食塩水18mlで洗浄し、減圧濃縮し、真空乾燥することにより下記式[28]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類を7.52g得た。
19F-NMR[基準物質;C6F6、重溶媒;CDCl3]δ ppm;-5.44(m、1F)
上記で得られた粗生成物全量7.18g(便宜上19.3mmolとする)を酢酸エチル10.8ml(1.5vol)、イソプロパノール10.8ml(1.5vol)、n-ヘプタン64.6ml(9vol)の混合溶媒から再結晶し、濾取した結晶をn-ヘプタン14.9mlで洗浄し、真空乾燥することにより、上記式で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の白色結晶を6.52g(17.5mmol)得た。収率は90.7%であった。結晶のガスクロマトグラフィー純度は99.3%であった。
100mlナスフラスコに下記式[12]-[15]で示されるラクトン前駆体のジアステレオマー混合物20.58g[[12]:23.1mmol、[13]:16.2mmol、[14]+[15]:6.7mmol(19F-NMRによる内部標準法で定量)]、メタノール23ml(0.5L/mol)、12N塩酸1.4ml(16.8mmol、0.37eq)を加え、室温で18時間攪拌した。
上記で得られたジヒドロキシラクトンのジアステレオマー混合物13.90gをイソプロパノール20.9ml(1.5vol)とトルエン69.5ml(5vol)、n-ヘプタン27.8ml(2vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン13.9mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を3.73g(22.7mmol)得た。収率は98.3%であった。結晶のガスクロマトグラフィー純度は90.3%で、主な不純物である上記式[5]で示されるジアステレオマーは6.3%であった。この結晶3.73gを用いて再度イソプロパノール5.6ml(1.5vol)とトルエン18.7ml(5vol)、n-ヘプタン3.7ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン3.7mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡黄色結晶を2.94g(17.9mmol)得た。回収率は78.8%であった。結晶のガスクロマトグラフィー純度は99.1%で、主な不純物である上記式[5]で示されるジアステレオマーは0.4%であった。
上記で得られた(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン2.94g(17.9mmol)に、アセトニトリル17.9ml(1L/mol)、とピリジン3.26g(41.2mmol、2.30eq)を加えて、ベンゾイルクロリド5.54g(39.4mmol、2.20eq)を氷冷下で加えて、室温で2時間攪拌した。反応終了液に水17mlを氷冷下で加え、室温で10分攪拌し、酢酸エチル34mlで抽出し、回収有機層を5%炭酸水素ナトリウム水溶液17mlで洗浄し、5%食塩水17mlで洗浄し、減圧濃縮し、真空乾燥することにより下記式[28]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類を7.09g得た。
上記で得られた粗生成物全量7.09g(便宜上17.9mmolとする)を酢酸エチル10.6ml(1.5vol)、イソプロパノール10.6ml(1.5vol)、n-ヘプタン63.8.4ml(9vol)の混合溶媒から再結晶し、n-ヘプタン13.8mlで洗浄し、真空乾燥することにより、上記式で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の白色結晶を6.17g(16.6mmol)得た。収率は92.6%であった。結晶のガスクロマトグラフィー純度は99.8%であった。
100mlナスフラスコに下記式[6]-[9]で示されるラクトン前駆体のジアステレオマー混合物35.26g[[6]:44.4mmol、[7]:31.7mmol、[8]+[9]:22.7mmol(19F-NMRによる内部標準法で定量)]、水79ml(0.8L/mol)、酢酸88.99g(1.48mol、15eq)を加え、90度で1時間攪拌した。
上記で得られた(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン5.85g(35.6mmol)に、アセトニトリル35.8ml(1L/mol)、とピリジン6.48g(81.9mmol、2.30eq)を加えて、ベンゾイルクロリド11.01g(78.3mmol、2.20eq)を氷冷下で加えて、室温で2時間攪拌した。反応終了液に水33mlを氷冷下で加え、室温で10分攪拌し、酢酸エチル66mlで抽出し、回収有機層を5%炭酸水素ナトリウム水溶液33mlで洗浄し、5%食塩水33mlで洗浄し、減圧濃縮し、真空乾燥することにより下記式[28]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類を13.81g得た。
上記で得られた粗生成物全量13.81g(便宜上35.6mmolとする)を酢酸エチル20.7ml(1.5vol)、イソプロパノール20.7ml(1.5vol)、n-ヘプタン124.3ml(9vol)の混合溶媒から再結晶し、濾取した結晶をn-ヘプタン27.4mlで洗浄し、真空乾燥することにより、上記式で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の白色結晶を11.99g(32.2mmol)得た。収率は90.5%であった。結晶のガスクロマトグラフィー純度は95.8%であった。
100mlナスフラスコに下記式[16]-[19]で示されるラクトン前駆体のジアステレオマー混合物16.73g[[16]:18.5mmol、[17]:12.0mmol、[18]+[19]:8.9mmol(19F-NMRによる内部標準法で定量)]、メタノール19.7ml(0.5L/mol)、12N塩酸1.2ml(14.4mmol、0.36eq)を加え、室温で18時間攪拌した。
上記で得られたジヒドロキシラクトンのジアステレオマー混合物8.72gをイソプロパノール13.1ml(1.5vol)とトルエン43.6ml(5vol)、n-ヘプタン8.7ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン8.7mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を2.45g(14.9mmol)得た。収率は80.5%であった。結晶のガスクロマトグラフィー純度は81.8%で、主な不純物である上記式[5]で示されるジアステレオマーは8.0%であった。この結晶2.31gを用いて再度イソプロパノール3.5ml(1.5vol)とトルエン11.6ml(5vol)、n-ヘプタン2.3ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン2.3mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡黄色結晶を1.78g(10.8mmol)得た。収率は77%であった。結晶のガスクロマトグラフィー純度は99.7%で、主な不純物である上記式[5]で示されるジアステレオマーは0.3%であった。
上記で得られた(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン1.78g(10.8mmol)に、アセトニトリル10.8ml(1L/mol)、とピリジン1.96g(24.8mmol、2.30eq)を加えて、ベンゾイルクロリド3.34g(23.7mmol、2.19eq)を氷冷下で加えて、室温で2時間攪拌した。反応終了液に水10mlを氷冷下で加え、室温で10分攪拌し、酢酸エチル20mlで抽出し、回収有機層を5%炭酸水素ナトリウム水溶液10mlで洗浄し、5%食塩水10mlで洗浄し、減圧濃縮し、真空乾燥することにより下記式[28]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類を4.16g得た。
上記で得られた粗生成物全量4.16g(便宜上10.8mmolとする)を酢酸エチル6.2ml(1.5vol)、イソプロパノール6.2ml(1.5vol)、n-ヘプタン37.4ml(9vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したメタノール8.3mlで洗浄し、真空乾燥することにより、上記式で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の白色結晶を3.63g(9.7mmol)得た。収率は89.8%であった。結晶のガスクロマトグラフィー純度は99.1%であった。
100mlナスフラスコに下記式[20]-[23]で示されるラクトン前駆体のジアステレオマー混合物1.01g[[20]:1.08mmol、[21]:0.77mmol、[22]+[23]:0.54mmol(19F-NMRによる内部標準法で定量)]、メタノール1.2ml(0.5L/mol)、12N塩酸1.2ml(0.9mol、0.36eq)を加え、室温で18時間攪拌した。
上記で得られたジヒドロキシラクトンの混合物0.52gをイソプロパノール0.8ml(1.5vol)とトルエン2.6ml(5vol)、n-ヘプタン0.5ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したn-ヘプタン3.0mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を0.14g(0.84mmol)得た。収率は77.5%であった。結晶のガスクロマトグラフィー純度は87.6%で、主な不純物である上記式[5]で示されるジアステレオマーは5.3%であった。この結晶2.31gを用いて再度イソプロパノール3.5ml(1.5vol)とトルエン11.6ml(5vol)、n-ヘプタン2.3ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン2.3mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を1.78g(10.8mmol)得た。回収率は72%であった。結晶のガスクロマトグラフィー純度は99.7%で、主な不純物である上記式[5]で示されるジアステレオマーは0.3%であった。
100mlナスフラスコに下記式[24]-[27]で示されるラクトン前駆体のジアステレオマー混合物13.80g[[24]:13.9mmol、[25]:11.0mmol、[26]+[27]:6.2mmol(19F-NMRによる内部標準法で定量)]メタノール15.6ml(0.5L/mol)、12N塩酸0.96ml(11.5mmol、0.37eq)を加え、室温で18時間攪拌した。
上記で得られたジヒドロキシラクトンのジアステレオマー混合物6.84gをイソプロパノール10.3ml(1.5vol)とトルエン34.2ml(5vol)、n-ヘプタン6.8ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したn-ヘプタン6.8mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色色結晶を1.80g(11.0mmol)得た。収率は78.8%であった。結晶のガスクロマトグラフィー純度は81.8%で、主な不純物である上記式[5]で示されるジアステレオマーは8.0%であった。この結晶2.31gを用いて再度イソプロパノール3.5ml(1.5vol)とトルエン11.6ml(5vol)、n-ヘプタン2.3ml(1vol)の混合溶媒から再結晶し、濾取した結晶を氷冷したトルエン2.3mlで洗浄し、真空乾燥することにより、上記式[4]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンの淡褐色結晶を1.78g(10.8mmol)得た。回収率は72%であった。結晶のガスクロマトグラフィー純度は99.7%で、主な不純物である上記式[5]で示されるジアステレオマーは0.3%であった。
100mlナスフラスコに下記式[6]-[9]で示されるラクトン前駆体のジアステレオマー混合物79.03g[[6]:73.6mmol、[7]:62.1mmol、[8]+[9]:30.4mmol(19F-NMRによる内部標準法で定量)]、メタノール83ml(0.5L/mol)、12N塩酸5.1ml(61.4mmol、0.37eq)を加え、室温で18時間攪拌した。
上記で得られたジヒドロキシラクトンの混合物70.27g(便宜上166.1mmolとする)に、アセトニトリル166.1ml(1L/mol)、とピリジン30.29g(382.9mmol、2.31eq)を加えて、ベンゾイルクロリド51.60g(367.1mmol、2.21eq)を氷冷下で加えて、室温で2時間攪拌した。反応終了液に水150mlを氷冷下で加え、室温で10分攪拌し、酢酸エチル300mlで抽出し、回収有機層を5%炭酸水素ナトリウム水溶液150mlで洗浄し、5%食塩水150mlで洗浄し、減圧濃縮し、真空乾燥することにより下記式[1]および[28]-[31]で示される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類を含むジアステレオマー混合物131.74g[[1]:75.7mmol、[20]:69.8mmol、[21]+[22]:24.2mmol(19F-NMRによる内部標準法で定量)]を得た。
Claims (7)
- 一般式[1]で表される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の製造方法において、一般式[2]で示されるラクトン前駆体のジアステレオマー混合物を、酸性条件下で脱保護し、続いてラクトン化させることにより、一般式[3]で表されるジヒドロキシラクトンのジアステレオマー混合物を得る工程と、得られた混合物を再結晶することにより、一般式[4]で表される(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトンを分離精製する工程と、分離精製されたラクトンをアシル化する工程と、を含む、(2R)-2-フルオロ-2-C-メチル-D-リボノ-γ-ラクトン類の製造方法。
- ジヒドロキシラクトンのジアステレオマー混合物の再結晶に用いる溶媒が、アルコール系、芳香族炭化水素系、エステル系、ニトリル系、エーテル系、ハロゲン化炭化水素系、ケトン系、水、および脂肪族炭化水素系からなる群より選ばれる少なくとも1種の溶媒である、請求項1に記載の製造方法。
- ジヒドロキシラクトンのジアステレオマー混合物の再結晶に用いる溶媒が、イソプロパノール、トルエン、酢酸エチルまたはn-ヘプタンである、請求項1または2に記載の製造方法。
- 一般式[2]におけるR1が、炭素数が1から6の直鎖または枝分れのアルキル基または置換アルキル基である、請求項1に記載の製造方法。
- 一般式[2]におけるP1およびP2が、イソプロピリデン基またはシクロヘキシリデン基である、請求項1に記載の製造方法。
- ラクトン前駆体のジアステレオマー混合物を、酸性条件下で脱保護し、続いてラクトン化させる際、用いる酸が酢酸、硫酸、塩酸、メタンスルホン酸、パラトルエンスルホン酸、またはトリフルオロ酢酸である、請求項1に記載の製造方法。
- 一般式[1]におけるR2が、ベンゾイル基、ホルミル基、またはアセチル基である、請求項1に記載の製造方法。
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JP6394588B2 (ja) | 2018-09-26 |
JPWO2014132975A1 (ja) | 2017-02-02 |
CN105026382B (zh) | 2016-10-19 |
CN105026382A (zh) | 2015-11-04 |
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