WO2011062139A1 - Procédé de fabrication de 3-tert-butoxycarbonylamino-2-fluoro-1-propanol optiquement actif - Google Patents

Procédé de fabrication de 3-tert-butoxycarbonylamino-2-fluoro-1-propanol optiquement actif Download PDF

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WO2011062139A1
WO2011062139A1 PCT/JP2010/070287 JP2010070287W WO2011062139A1 WO 2011062139 A1 WO2011062139 A1 WO 2011062139A1 JP 2010070287 W JP2010070287 W JP 2010070287W WO 2011062139 A1 WO2011062139 A1 WO 2011062139A1
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tert
optically active
butoxycarbonylamino
propanol
fluoro
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PCT/JP2010/070287
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English (en)
Japanese (ja)
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章央 石井
隆司 増田
たか子 山崎
英之 鶴田
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セントラル硝子株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol important as a pharmaceutical intermediate.
  • Patent Documents 1 and 2 disclose a method for producing the compound (see Scheme 1).
  • Bn, Me, Boc, *, THF, Pd (OH) 2 / C, EtOH, (Boc) 2 O and Aqueous dioxane are benzyl group, methyl group, tert-butoxycarbonyl group, asymmetric carbon, respectively.
  • the conventional method for producing optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol has the following problems.
  • Patent Document 2 discloses that “a pure product was obtained as a light brown oil” regarding the color tone and physical properties of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol. It was very different from the high-purity product (white crystals) of the compound obtained in 1.
  • an object of the present invention is to solve the above-mentioned problems of the prior art and to provide an industrial production method of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol.
  • the amount of palladium catalyst used can be remarkably reduced (1 mol% or less), and the reaction can be completed in one time. It has also been found that the dedibenzylation in the first step proceeds very smoothly by adding an acid as an additive.
  • a highly pure product of the compound can be obtained by deriving the optically active 3-amino-2-fluoropropionic acid ester obtained by dedibenzylation in the first step into a salt with an acid and carrying out salt purification.
  • the optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol finally obtained by subjecting this high purity product to tert-butoxycarbonylation in the second step and hydride reduction in the third step It was found that a high purity product of the final target product can be obtained by recrystallization purification.
  • the tert-butoxycarbonylation in the second step was found to proceed very smoothly by adding a base as an additive.
  • the final target optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained as a crystal has a melting point as low as 39 ° C. and is not necessarily a desirable physical property for recrystallization purification. It has also been found that a high-purity product can be recovered with good yield by using it.
  • the present invention includes [Invention 1] to [Invention 5], an industrial production method of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol, and a key intermediate in the production method
  • an optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester is provided.
  • R represents an alkyl group having 1 to 6 carbon atoms
  • Bn represents a benzyl group
  • Boc represents a tert-butoxycarbonyl group
  • * represents an asymmetric carbon.
  • invention 3 The optically active 3-tert-2-butoxycarbonylamino-2 obtained in the third step is subjected to salt purification by derivatizing the optically active 3-amino-2-fluoropropionic acid ester obtained in the first step into a salt with an acid.
  • the production method according to invention 1 or 2 characterized in that recrystallization purification of fluoro-1-propanol is performed.
  • the recrystallization solvent of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol obtained in the third step is an aliphatic hydrocarbon type, an aromatic hydrocarbon type or a mixed solvent thereof.
  • the debenzylation is performed in the first step, the amount of the palladium catalyst used can be remarkably reduced and the reaction can be completed at one time, so that the production cost is low.
  • the final product is crystallized and recrystallized to obtain a high-purity product. Therefore, according to the present invention, all the problems of the prior art can be solved, and optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol can be produced industrially advantageously.
  • the present invention also provides optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester as a key intermediate in the production of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol. it can.
  • the optically active 3-dibenzylamino-2-fluoropropionic acid ester represented by the general formula [1] is dedibenzylated with hydrogen gas in the presence of a palladium catalyst.
  • a first step of converting to an optically active 3-amino-2-fluoropropionic acid ester represented by formula (1) and tert-butoxycarbonyl (Boc) conversion of the ester represented by the general formula [2] with di-t-butyl dicarbonate Thereby converting the optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester represented by the general formula [3] into a lithium borohydride, and converting the ester compound represented by the general formula [3] into lithium borohydride.
  • an optically active 3-tert-butoxycal represented by the general formula [4] by hydride reduction with sodium borohydride
  • R of the optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group can be linear or branched, or cyclic (when the number of carbon atoms is 3 or more).
  • a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group and an n-hexyl group are preferable, and a methyl group, an ethyl group, an n-propyl group and an isopropyl group are particularly preferable.
  • Bn in the optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents a benzyl group.
  • optically active 3-dibenzylamino-2-fluoropropionic acid ester [1] represents an asymmetric carbon
  • the absolute configuration can be R-form or S-form
  • the optical purity is 80% ee (enantiomeric excess Rate) or higher, 90% ee or higher is preferable, and 95% ee or higher is particularly preferable.
  • Palladium catalysts include palladium black, palladium sponge, palladium / activated carbon, palladium / alumina, palladium / calcium carbonate, palladium / strontium carbonate, palladium / barium sulfate, palladium hydroxide / activated carbon, palladium hydroxide / alumina, palladium acetate, chloride. Palladium etc. are mentioned. Among these, palladium / activated carbon, palladium / alumina, palladium hydroxide / activated carbon and palladium hydroxide / alumina are preferable, and palladium / activated carbon and palladium hydroxide / activated carbon are particularly preferable.
  • palladium catalysts can be used alone or in combination.
  • the supported content may be 0.1 to 50% by weight, preferably 0.5 to 40% by weight, and particularly preferably 1 to 30% by weight.
  • a water-containing product can also be used as the palladium catalyst.
  • the one stored in water or an inert liquid can also be used.
  • the amount of the palladium catalyst used may be 0.05 mol or less, preferably 0.00001 to 0.03 mol, relative to 1 mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. 0.0001 to 0.01 mol is particularly preferred.
  • the hydrogen gas may be used in an amount of 2 moles or more per mole of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. Is particularly preferred.
  • the pressure condition of hydrogen gas may be 5 MPa or less, preferably 0.005 to 4 MPa, and particularly preferably 0.01 to 3 MPa. Therefore, it is preferable to use a pressure resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining).
  • SUS stainless steel
  • glass glass lining
  • the first step it is preferable to carry out dedibenzylation by adding an acid as an additive because the reaction proceeds very smoothly ([Invention 2]).
  • an acid as an additive because the reaction proceeds very smoothly ([Invention 2]).
  • the additive examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitric acid, and organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid.
  • inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid
  • organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid.
  • hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and paratoluenesulfonic acid are preferable, and hydrogen chloride, acetic acid, trifluoroacetic acid and paratolu
  • the amount used may be 0.1 mol or more per mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1], preferably 0.2 to 100 mol. 0.3 to 50 mol is particularly preferred.
  • reaction solvent examples include ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2,2,2-triol.
  • ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2,2,2-triol.
  • alcohols such as fluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, water, and the like. Of these, alcohols are preferred, and methanol, ethanol, n-propanol and isopropanol are particularly preferred.
  • the reaction solvent may be used in an amount of 0.05 L (liter) or more, preferably 0.1 to 20 L, based on 1 mol of optically active 3-dibenzylamino-2-fluoropropionic acid ester [1]. .15 to 10 L is particularly preferred.
  • the reaction temperature may be + 150 ° C. or less, preferably ⁇ 30 ° C. to + 100 ° C., particularly preferably ⁇ 20 ° C. to + 50 ° C.
  • the reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance.
  • the end point is preferably the time point at which almost no decrease in the reaction substrate is observed.
  • the target optically active 3-amino-2-fluoropropionic acid ester [2] can be obtained by performing a general post-treatment operation in organic synthesis on the reaction end solution.
  • a general post-treatment operation in organic synthesis on the reaction end solution.
  • an operation of filtering the palladium catalyst in the reaction completion liquid and concentrating the filtrate washing liquid to obtain a residue is effective.
  • the target product having high water solubility can also be recovered with high yield.
  • the stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed. Moreover, it can also refine
  • the optically active 3-amino-2-fluoropropionic acid ester [2] produced in the first step is preferable because it can be obtained as a high-purity product by conducting salt purification by inducing a salt with an acid.
  • the actual operations are “induction to a salt with an acid” and “salt purification”, but they can be performed as general operations in organic synthesis.
  • the specific operation of “induction to a salt with an acid” is not particularly limited, but is preferably performed by adding an acid to the reaction completion liquid, the filtrate washing liquid or the concentrated residue.
  • an acid By adding an acid before the concentration, the target product having a low boiling point can be recovered in a high yield as a salt.
  • an acid when an acid is added to the concentrated residue, it is effective to use a salt-derived solvent.
  • activated carbon treatment, concentration of a salt-derived solvent, and the like can be performed in an arbitrary process as necessary.
  • Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and nitric acid, formic acid, acetic acid, propionic acid, benzoic acid, trifluoroacetic acid, mandelic acid (R-form, S-form or racemic form), oxalic acid, malee
  • examples include acids, fumaric acid, phthalic acid, malic acid (D-form, L-form or racemic form), tartaric acid (D-form, L-form or racemic form), methanesulfonic acid, paratoluenesulfonic acid and the like.
  • hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, phthalic acid, malic acid, tartaric acid, methanesulfonic acid, and paratoluenesulfonic acid are preferred.
  • Hydrogen chloride, acetic acid, trifluoroacetic acid Particularly preferred are oxalic acid, phthalic acid, tartaric acid and paratoluenesulfonic acid. It is also possible to combine the acid of the additive for making the reaction proceed very smoothly and the acid of “derivation to the salt with the acid”. You can handle it.
  • the amount of the acid used may be 0.35 mol or more, preferably 0.4 to 10 mol, preferably 0.45 to 5 per 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2]. Mole is particularly preferred.
  • salt purification is not particularly limited, but is preferably performed by “isolation with crystals”, “washing of isolated crystals” or “recrystallization of isolated crystals”.
  • Salt refining can be applied to non-crystallized salts (for example, oily substances, viscous liquids, cakes, amorphouss, etc.).
  • a method of stirring and washing, a method of separating (or separating) and recovering by adding a poor solvent after dissolving in a rich solvent, and the like can be employed.
  • a salt that crystallizes is preferable because it has a higher purification efficiency, and in particular, “isolation with crystals” and “washing of isolated crystals” are easy to obtain, but easy to obtain a high-purity product.
  • the “salt purification” can be performed by arbitrarily combining arbitrary operations depending on the required degree of purification. Moreover, it can also be purified to a higher purity by repeating the same operation. Furthermore, activated carbon treatment, salt purification solvent concentration, and the like can be performed in an arbitrary process as necessary. In “salt purification”, the chemical purity, optical purity, or both can be increased.
  • Solvents used for “induction to salt with acid” or “salt purification” include aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, n-octane, benzene, toluene, ethylbenzene, xylene, mesitylene Aromatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, acetone, methyl ethyl ketone , Ketone systems such as methyl isobutyl ketone, ester systems such as ethyl acetate and n-butyl acetate, amide systems such as N, N-dimethylformamide, N, N-dimethylacet
  • salt induction solvents or salt purification solvents can be used alone or in combination. Further, the reaction solvent, the salt-inducing solvent, and the salt purification solvent can be combined, and among them, it is preferable to combine any two solvents, and it is particularly preferable to combine three solvents.
  • the amount of the solvent used for the “derivation to a salt with an acid” or “salt purification” is 0.05 L with respect to 1 mol of the optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound. What is necessary is just to use the above, 0.07 to 20L is preferable, and 0.09 to 10L is especially preferable.
  • “Isolation by crystal” or “recrystallization of isolated crystal” may cause the crystal to precipitate smoothly and efficiently by adding a seed crystal (by using a combination of suitable purification conditions, There is no need to add seed crystals).
  • the amount used may be 0.00001 mol or more with respect to 1 mol of the salt of the optically active 3-amino-2-fluoropropionic acid ester [2], and 0.0001 to 0.1 mol. Is preferable, and 0.0002 to 0.05 mol is particularly preferable.
  • the temperature condition of “induction to salt with acid” or “salt purification” may be performed at + 150 ° C. or less, preferably ⁇ 30 to + 125 ° C., particularly preferably ⁇ 20 to + 100 ° C.
  • the time condition of “derivation to salt with acid” or “salt purification” may be within 48 hours, but it varies depending on the basic substance and the induction or purification conditions. Therefore, gas chromatography, thin layer chromatography, liquid chromatography It is preferable that the progress of induction or purification is tracked by analytical means such as chromatography or nuclear magnetic resonance, and that the end point is when no further progress is observed.
  • the operation for recovering the salt obtained by “induction to a salt with an acid” is not particularly limited, but it is preferably used for “salt purification” in a solution or in a concentrated residue.
  • the operation for recovering the salt obtained by “salt purification” is not particularly limited, but preferably a high-purity product can be obtained by filtering, separating or separating crystals, oily substances, viscous liquids, cakes, amorphouss, etc. . Moreover, washing
  • the salt of the optically active 3-amino-2-fluoropropionic acid ester [2] obtained as a high-purity product can be subjected to the tert-butoxycarbonylation in the next step as it is or converted back to the free base.
  • the method for returning to the free base is not particularly limited, but preferably includes an operation in which the salt is neutralized with an aqueous solution of an inorganic base and extracted with an organic solvent, and the recovered organic layer is concentrated to obtain a residue. Moreover, it can also be dried with a desiccant (for example, anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.), a vacuum pump, etc. in arbitrary processes as needed.
  • This inorganic base can be arbitrarily selected from inorganic bases added as an additive in the second step described later.
  • the organic solvent can be arbitrarily selected from those that can be separated from an aqueous solution of an inorganic base from among salt-derived solvents and salt-purifying solvents. However, it is preferable to use the salt as it is in the next step because the operation is simple.
  • the optically active 3-amino-2-fluoropropionic acid ester [2] is left as a salt in this step. It can also be subjected to tert-butoxycarbonylation.
  • Boc of the target optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3] represents a tert-butoxycarbonyl group.
  • the amount of di-t-butyl dicarbonate used may be 0.7 mol or more per 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound. To 5 mol is preferred, and 0.9 to 3 mol is particularly preferred.
  • lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases triethylamine, diisopropylethylamine, tri-n- Butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, And organic bases such as 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
  • sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5 4.0] undec-7-ene is preferred, with sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine and 4-dimethylaminopyridine being particularly preferred.
  • These bases can be used alone or in combination.
  • the amount used may be 0.01 mol or more, preferably 0.03 to 5 mol, based on 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2]. 0.05 to 3 moles is particularly preferred.
  • the optically active 3-amino-2-fluoropropionic acid ester [2] is used in this step in the form of a salt, it must be returned to the free base in the reaction system.
  • a reaction may be performed. This base can be arbitrarily selected from the bases of additives for allowing the reaction to proceed very smoothly, but it is preferable to carry out the reaction with both of them being the same base.
  • reaction solvent examples include aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, and n-octane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene, methylene chloride, chloroform, 1, Halogens such as 2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, acetonitrile, propionitrile, etc.
  • aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane, and n-octane
  • aromatic hydrocarbons such as benzene
  • Nitrile type water and the like.
  • n-hexane, cyclohexane, n-heptane, toluene, ethylbenzene, xylene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, ethyl acetate, acetonitrile and water are preferred, and n-hexane, n- Particularly preferred are heptane, toluene, xylene, methylene chloride, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile and water.
  • reaction solvents can be used alone or in combination. When water is used, the reaction can be performed in a heterogeneous system.
  • the reaction solvent may be used in an amount of 0.05 L or more with respect to 1 mol of optically active 3-amino-2-fluoropropionic acid ester [2] or a salt of the compound, preferably 0.1 to 20 L, .15 to 10 L is particularly preferred.
  • the reaction temperature may be + 150 ° C. or less, preferably ⁇ 30 ° C. to + 125 ° C., particularly preferably ⁇ 20 ° C. to + 100 ° C.
  • the reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance.
  • the end point is preferably the time point at which almost no decrease in the reaction substrate is observed.
  • the target optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3] is obtained by performing a general post-treatment operation in organic synthesis on the reaction end solution. Can do.
  • the operation of washing the reaction end solution with an aqueous solution of an inorganic base and concentrating the recovered organic layer to obtain a residue is effective.
  • the amount of di-t-butyl dicarbonate used for the optically active 3-amino-2-fluoropropionic acid ester [2] is controlled to exactly 1 equivalent, unreacted di-t-butyl dicarbonate is the target product. Remain. If necessary, it can be purified by activated carbon treatment, column chromatography or the like. Further, the stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed.
  • the first step and the second step can produce optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3], which is a novel substance, as a key intermediate in the production method of the present invention. ([Invention 5]).
  • the amount of lithium borohydride or sodium borohydride used may be 0.35 mol or more per 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3]. 4 to 5 mol is preferred, and 0.45 to 3 mol is particularly preferred.
  • reaction solvent examples include ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, and 1,4-dioxane, and alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol. .
  • ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, and 1,4-dioxane
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol.
  • tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol, n-propanol and isopropanol are preferred, and tetrahydrofuran, 1,
  • the reaction solvent may be used in an amount of 0.05 L or more, preferably 0.1 to 20 L, based on 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoropropionic acid ester [3]. 15 to 10 L is particularly preferred.
  • the reaction temperature may be + 150 ° C. or less, preferably ⁇ 50 ° C. to + 125 ° C., particularly preferably ⁇ 40 ° C. to + 100 ° C.
  • the reaction time may be 48 hours or less, but it varies depending on the reaction substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance.
  • the end point is preferably the time point at which almost no decrease in the reaction substrate is observed.
  • the target optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4] is crystallized by subjecting the reaction end solution to a general post-treatment operation in organic synthesis.
  • a general post-treatment operation in organic synthesis can be obtained as Preferably, an operation of adding an aqueous solution of an inorganic base to the reaction completion liquid and concentrating, adding water to the residue and extracting with an organic solvent, washing the recovered organic layer with water, and concentrating to obtain a residue is effective. Even if a reaction substrate in which unreacted di-t-butyl dicarbonate remains is decomposed under the reaction conditions of this step, di-t-butyl dicarbonate does not remain at all in the target product. If necessary, it can be purified by activated carbon treatment, column chromatography or the like. Further, the stereochemistry at the 2-position of the target product is maintained throughout this step, and no decrease in optical purity is observed.
  • the optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol produced in the third step is preferable because it can be obtained as a high purity product by recrystallization purification ([Invention 3]).
  • As an actual operation it can be performed as a general operation in organic synthesis [The Chemical Society of Japan, edited by Fifth Edition, Experimental Chemistry Lecture 1 (Basics I: Basics of Experiments and Information, published by Maruzen in 2003), 4 (Basics Part IV IV Organic / Polymer / Biochemistry, published by Maruzen in 2003), 5 (Basic technology for chemical experiments, published by Maruzen in 2005), etc.]
  • recrystallization purification it can be purified to a higher purity.
  • activated carbon treatment etc. can also be performed as needed.
  • the purity of chemical purity, optical purity, or both can be increased.
  • Recrystallization solvents include n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, cycloheptane, n-octane, cyclooctane and other aliphatic hydrocarbons, benzene, toluene, ethylbenzene, xylene, mesitylene, etc.
  • Aromatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, Ketones such as methyl isobutyl ketone, esters such as ethyl acetate and n-butyl acetate, nitriles such as acetonitrile and propionitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.
  • halogens such as methylene chloride, chloroform, 1,2-dichloroethane
  • ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether
  • aliphatic hydrocarbons, aromatic hydrocarbons and mixed solvents thereof are preferable, and n-hexane, cyclohexane, n-heptane, n-octane, toluene, ethylbenzene, xylene and mixed solvents thereof are particularly preferable.
  • This recrystallization purification is preferable because a high-purity product can be recovered with good yield by using an aliphatic hydrocarbon type, an aromatic hydrocarbon type or a mixed solvent thereof as a recrystallization solvent ([Invention 4]). .
  • These recrystallization solvents can be used alone or in combination.
  • the recrystallization solvent may be used in an amount of 0.05 L or more with respect to 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4], preferably 0.07 to 20 L, 0.09 to 10 L is particularly preferred.
  • the amount used may be 0.00001 mol or more with respect to 1 mol of optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol [4]. 0.1 mole is preferred, with 0.0002 to 0.05 mole being particularly preferred.
  • the temperature condition for recrystallization purification may be + 150 ° C. or less, preferably ⁇ 30 ° C. to + 125 ° C., particularly preferably ⁇ 20 ° C. to + 100 ° C. Moreover, it is preferable to age at + 15 ° C. or lower by gradually cooling or cooling.
  • the recrystallization purification time condition may be within 48 hours, but since it varies depending on the recrystallization substrate and the purification conditions, it can be purified by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable that the progress is tracked and the end point is the point at which no further progress is recognized.
  • the operation for recovering the high-purity product obtained by recrystallization purification is not particularly limited.
  • the precipitated crystal is filtered, washed with a poor solvent as necessary, and dried at 30 ° C. or less to obtain high purity. Goods can be obtained.
  • Example 1 90.4 g of methyl (R) -3-dibenzylamino-2-fluoropropionate represented by the following formula (gas chromatographic purity: 88) produced in the same manner from L-serine with reference to the pamphlet of International Publication No. 2009/133789 0.4%, 265 mmol, 1.00 eq) in methanol solution (solvent usage 300 mL, 0.9 M) and 5% palladium on carbon (water content 50%) 6.38 g (1.50 mmol, 0.00566 eq) Acetic acid 36.0 g (600 mmol, 2.26 eq) was added, the hydrogen gas pressure was set to 0.9 MPa, and the mixture was stirred at room temperature overnight.
  • gas chromatographic purity: 88 gas chromatographic purity
  • the conversion rate was 100% from 19 F-NMR of the reaction completed liquid.
  • the reaction-terminated liquid was filtered through Celite, washed with a small amount of methanol, and 13.0 g (357 mmol, 1.35 eq) of hydrogen chloride gas (HCl) was blown into the filtrate with ice cooling, followed by concentration under reduced pressure.
  • Toluene 200 mL, 1.3 M was added to the residue (crude crystals), and the mixture was stirred and washed under ice cooling (heterogeneous system). The crystals were filtered, washed with toluene (40 mL), and vacuum-dried.
  • the reaction-terminated liquid was washed with an aqueous potassium carbonate solution [prepared from 13.2 g (95.5 mmol, 1.00 eq) of potassium carbonate and 60 mL of water], and the recovered organic layer was concentrated under reduced pressure and vacuum-dried, and expressed by the following formula. 21.4 g of methyl (R) -3-tert-butoxycarbonylamino-2-fluoropropionate (oil) was obtained (theoretical yield 21.1 g). The purity by gas chromatography was 94.7% (3.7% of di-t-butyl dicarbonate remained, and the purity excluding di-t-butyl dicarbonate was 98.4%). 1 H-NMR and 19 F-NMR are shown below.
  • Example 2 Example 1 Using methyl (S) -3-dibenzylamino-2-fluoropropionate represented by the following formula, which was prepared in the same manner from D-serine with reference to the pamphlet of International Publication No. 2009/133789, as a starting material, Example 1 The reaction (debenzylation, tert-butoxycarbonylation, hydride reduction) was carried out in the same manner as described above. As a result, (S) -3-tert-butoxycarbonylamino-2-fluoro-1-propanol represented by the following formula could be produced.
  • Example 1 The color tone, physical properties, yield, total yield, gas chromatography purity, 1 H-NMR and 19 F-NMR of the final product obtained were the same as in Example 1 (other than the absolute configuration of the asymmetric carbon). .
  • the color tone, physical properties, recovery amount, recovery rate, melting point, gas chromatography purity and optical purity in recrystallization purification were also the same as in Example 1. Further, the gas chromatography purity, recovery rate and optical purity in the second recrystallization were also the same as in Example 1.
  • the resulting reaction mixture was stirred under hydrogen gas at a pressure of 0.9 MPa, and the progress of the reaction was followed by 19 F-NMR.
  • the reaction check (1) was performed “after stirring overnight at room temperature”, and the reaction check (2) was performed “after further stirring overnight at 50 ° C.”.
  • the reaction mixture was filtered through Celite, and 70% of the filtrate (to 169 mmol, 1.00 eq) was added to 5.09 g [1.20 mmol, 0% of 5% palladium carbon (water content 50%). .00710 eq (total usage 0.01417 eq)] was added again.
  • the resulting mixture was stirred under hydrogen gas at a pressure of 0.9 MPa, and the progress of the reaction was followed by 19 F-NMR.
  • a reaction check (3) was performed “after 3 hours of stirring at room temperature”, and a reaction check (4) was performed “after further stirring overnight at room temperature”.
  • Table 1 summarizes the composition ratios (dibenzyl: monobenzyl: target) of the reaction mixture in each reaction check.
  • the amount of palladium catalyst used is significantly reduced by performing debenzylation in the first step. Since the reaction can be completed in one time, the production cost is low and the operation is simple. In addition, a high-purity product can be obtained by crystallization of the final target product and recrystallization purification. Therefore, according to the present invention, optically active 3-tert-butoxycarbonylamino-2-fluoro-1-propanol can be produced industrially more advantageously than the prior art.

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Abstract

La présente invention a pour objet un procédé en trois étapes de fabrication de 3-tert-butoxycarbonylamino-2-fluoro-1-propanol optiquement actif. Ce procédé permettra de réduire considérablement la quantité utilisée de catalyseur de palladium et pourra compléter la réaction en un cycle, réduisant ainsi les coûts de fabrication et simplifiant la procédure. En outre, la substance cible finale est cristallisée et purifiée par l'intermédiaire d'une recristallisation, produisant un résultat de pureté élevée. L'invention concerne également un ester de l'acide 3-tert-butoxycarbonylamino-2- fluoropropionique optiquement actif, une nouvelle substance qui est l'intermédiaire clé dans ce procédé de fabrication.
PCT/JP2010/070287 2009-11-18 2010-11-15 Procédé de fabrication de 3-tert-butoxycarbonylamino-2-fluoro-1-propanol optiquement actif WO2011062139A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056280A1 (fr) * 2005-11-03 2007-05-18 Ilypsa, Inc. Composes d'indole presentant des substituants acides c4 et leur utilisation en tant qu'inhibiteurs de phospholipases a2
WO2008136745A1 (fr) * 2007-05-04 2008-11-13 Astrazeneca Ab Synthèse d'acides phosphiniques d'alkyle par amorçage d'une amine et d'un amine-oxyde
WO2008136746A1 (fr) * 2007-05-04 2008-11-13 Astrazeneca Ab Synthèse d'acides phosphiniques alkyle par initiation d'une amine et d'un amine-oxyde

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056280A1 (fr) * 2005-11-03 2007-05-18 Ilypsa, Inc. Composes d'indole presentant des substituants acides c4 et leur utilisation en tant qu'inhibiteurs de phospholipases a2
WO2008136745A1 (fr) * 2007-05-04 2008-11-13 Astrazeneca Ab Synthèse d'acides phosphiniques d'alkyle par amorçage d'une amine et d'un amine-oxyde
WO2008136746A1 (fr) * 2007-05-04 2008-11-13 Astrazeneca Ab Synthèse d'acides phosphiniques alkyle par initiation d'une amine et d'un amine-oxyde

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