WO2018152949A1 - 一种光学纯的(r)-4-正丙基-二氢呋喃-2(3h)-酮的制备方法 - Google Patents

一种光学纯的(r)-4-正丙基-二氢呋喃-2(3h)-酮的制备方法 Download PDF

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WO2018152949A1
WO2018152949A1 PCT/CN2017/081556 CN2017081556W WO2018152949A1 WO 2018152949 A1 WO2018152949 A1 WO 2018152949A1 CN 2017081556 W CN2017081556 W CN 2017081556W WO 2018152949 A1 WO2018152949 A1 WO 2018152949A1
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formula
group
acid
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optically pure
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马良
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北京艾百诺医药股份有限公司
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Priority to PL17897655T priority Critical patent/PL3543229T3/pl
Priority to ES17897655T priority patent/ES2875551T3/es
Priority to US16/485,138 priority patent/US10975050B2/en
Priority to EP17897655.1A priority patent/EP3543229B1/en
Priority to SI201730810T priority patent/SI3543229T1/sl
Publication of WO2018152949A1 publication Critical patent/WO2018152949A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/12—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to a process for the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.
  • Benoit M. Kenda et al. J. Med. Chem. 2004, 47, 530-549.
  • J. Med. Chem. 2004, 47, 530-549. describe the preparation of 2-oxo-pyrrolidine with racemic 4-n-propyl-dihydrofuran-2(3H)-one. -1-based method. Due to the use of racemic 4-n-propyl-dihydrofuran-2(3H)-one, the product obtained is a pair of diastereomers, since the isomers are similar in nature to the principal components and are difficult to pass conventional weights. The crystallization method is removed, and therefore, it must be separated by chiral column preparation to obtain a qualified product.
  • Patent CN105646319 reports the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one, and a process for preparing bovistam. Since optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one is used, the obtained product has high chiral purity, so that a cloth with high optical purity can be obtained without chiral separation. Vasitan.
  • Olof Ceder et al. (Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry. 1977, 31, 189-192.) reported an optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.
  • the synthetic route uses a chiral substituted cyclohexenoic acid as a starting material, and a chiral lactone is prepared by reduction, oxidation and electrolysis. This route not only uses a chiral intermediate which is not easily commercially available as a starting material, but also finally obtains a product by electrolytic reaction, and the cost is high, and the reaction conditions are not suitable for large production.
  • the route is as follows:
  • Patent CN105646319 reports a route for the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.
  • the route uses diphenyl malonate and (R)-epichlorohydrin as starting materials, and the chiral lactone is obtained by ring closure, Grignard reaction and decarboxylation.
  • the starting materials are readily available, the third step of the decarboxylation reaction needs to be carried out above 130 ° C, and the reaction time is long, and the product may be racemized under prolonged heating conditions, affecting product purity.
  • the route is as follows:
  • Patent CN105837535 reports a route for the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.
  • the route uses valeryl chloride, chiral oxazolinone and tert-butyl 2-bromoacetate as starting materials, and is subjected to condensation, substitution, reduction and hydrolysis to obtain a chiral lactone.
  • the intermediates in this route are purified by column chromatography, which is costly and cumbersome to operate.
  • the route is as follows:
  • the new process route has the advantages that the starting materials are easy to obtain, the reaction yield is high, the by-products in the reaction can be recycled, the operation is simple, the enantioselectivity is good, and the like, and the industrial application prospect is broad.
  • the present invention provides a simple and economical process for the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one (Formula I).
  • Formula (V) undergoes cyano hydrolysis and lactonization under acidic conditions to obtain optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one as shown in Formula I, or Cyano hydrolysis under basic conditions, re-acidification lactonization to give optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one as shown in Formula I;
  • the acid used for the hydrolysis or/and lactonization of the cyano group is an organic acid or a mineral acid, and the organic acid is p-toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid or propionic acid; the inorganic acid is hydrochloric acid or sulfuric acid. , nitric acid or phosphoric acid.
  • the acid used for the cyano hydrolysis or/and lactonization is preferably hydrochloric acid or sulfuric acid.
  • the base used for the hydrolysis of the cyano group is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate.
  • the base used for the hydrolysis of the cyano group is preferably sodium hydroxide.
  • the cyano hydrolysis reaction temperature is 0 to 100 °C.
  • the method for preparing the formula (V) in the step (1) is to prepare an optically pure (R)-3-(hydroxyl group) represented by the formula (V) in the presence of a reducing agent in the compound of the formula (IV).
  • ())Hexonitrile, and (S)-4-substituted oxazol-2-one represented by Formula VI as a prosthetic group is recovered.
  • X is a substituted or unsubstituted C 1-20 alkyl group, a C 1-20 alkenyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, an arylalkyl group or a heteroarylalkyl group.
  • X is C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, aryl, heteroaryl, substituted aryl, arylalkyl or substituted arylalkyl.
  • X is C 1-6 alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
  • X is preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, substituted benzyl, phenyl or substituted phenyl.
  • X is phenyl, isopropyl or benzyl.
  • the reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, lithium L-selectride or K-selectride.
  • the molar ratio of the formula (IV) to the reducing agent is 1:0.5-5.
  • the reaction solvent to be reduced by the formula (IV) is water, tetrahydrofuran, methanol, ethanol, isopropanol single solvent or a mixed solvent with water, and the reaction temperature is 0 to 100 °C.
  • the preparation method of the compound of the formula (IV) comprises the following steps:
  • Y is a leaving group selected from the group consisting of a halogen, a sulfonate group, -S + Me 2 or -N 2 + .
  • the base used in the alkylation is lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilazide (KHMDS), hexamethyldisilazide Sodium (NHMDS).
  • LHMDS lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • KHMDS potassium hexamethyldisilazide
  • NHS hexamethyldisilazide Sodium
  • the molar ratio of the formula (II) to the formula (III) in the step B) is 1:0.9-5, and the molar ratio of the formula (II) to the base used is 1:0.9-3.
  • the alkylation reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran, and the alkylation reaction temperature is 20 to 80 °C.
  • the Y is fluorine, chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.
  • Y is bromine, fluorine or chlorine.
  • the formula (II) is obtained by reacting a compound of the formula (VI) with a mixed anhydride of n-valeric acid or n-pentanoyl chloride or n-valeric acid.
  • the present invention uses optically pure (R)-3-(hydroxymethyl)hexronitrile under acidic or basic conditions, hydrolyzed by cyano, and then lactonized under acidic conditions to obtain the target product of the present invention, and The chiral center configuration did not change during the reaction.
  • the overall reaction process is as follows:
  • Step (1) optically pure (S)-3-n-pentanoyl-4-substituted oxazol-2-one represented by formula (II) and substituted acetonitrile represented by formula (III) in an alkaline reagent
  • An alkyl substitution reaction occurs in the presence of a compound of the formula (IV).
  • Step (2) preparing the optically pure (R)-3-(hydroxymethyl)hexonitrile represented by the formula (V) in the presence of a reducing agent in the compound of the formula (IV) obtained in the step (1). Simultaneously recovering (S)-4-substituted oxazol-2-one as a chiral auxiliary group represented by formula (VI);
  • Step (3) the optically pure (R)-3-(hydroxymethyl)hexonitrile obtained in the step (2) is subjected to cyano hydrolysis under acidic conditions and Conversion of the esterification, or cyano hydrolysis under basic conditions, followed by acidification to produce optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one.
  • alkyl as used in the present invention is defined to include a saturated monovalent hydrocarbon group having a linear, branched or cyclic chain moiety or a combination thereof and having 1 to 20 carbon atoms, and the acyclic alkyl group preferably has 1 to 6 The carbon atom and the cyclic alkyl group preferably have 3 to 8 carbon atoms.
  • alkenyl as used in the present invention is defined as an unsubstituted or substituted branched, unbranched or cyclic hydrocarbon group having at least one double bond or a combination thereof. Preferred alkenyl groups contain from 2 to 4 carbons.
  • the "alkenyl” moiety can be optionally substituted with from 1 to 5 substituents independently selected from halo, hydroxy, alkoxy, ester, acyl, cyano, acyloxy, carboxylic acid, amide or amino.
  • aryl as used in the present invention includes a group derived from the removal of one hydrogen atom from an aryl hydrocarbon, such as a phenyl group or a naphthyl group.
  • heterocycloalkyl denotes a cyclic alkyl (cycloalkyl) group containing at least one O, S and/or N atom interrupting a carbocyclic structure, such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl. , piperazinyl, morpholino and pyrrolidinyl.
  • heteroaryl denotes an "aryl” group as defined above containing at least one O, S and/or N atom interrupting a carbocyclic structure, such as pyridinyl, furyl, pyrrolyl, thienyl, isothiazolyl.
  • halogen as used in the present invention includes a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.
  • cyano as used in the present invention represents a group of the formula -CN.
  • hydroxy as used in the present invention represents a group represented by the formula -OH.
  • the compound of the formula (II) used in the present invention can be produced by any suitable method.
  • the (S)-3-n-pentanoyl-4-substituted oxazol-2-one represented by the formula (II) is preferably produced by such a method: optically pure (S)-4 represented by the formula (VI) -
  • a substituted oxazol-2-one is prepared by reacting a mixed anhydride of n-pentanoic acid or n-pentanoyl chloride or n-valeric acid.
  • the base used in the alkylation reaction of the step (1) is selected from lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and potassium hexamethyldisilazide.
  • KHMDS lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • KHMDS potassium hexamethyldisilazide
  • NHS sodium hexamethyldisilazide
  • LHMDS lithium hexamethyldisilazide
  • LHMDS lithium hexamethyldisilazide
  • LDA lithium diisopropylamide
  • the recrystallization solvent is selected from the group consisting of methanol, ethanol, isopropanol, methyl tert-butyl ether, acetone, methyl ethyl ketone, and diisopropyl ether.
  • Chiral oxazolinones are known as Evans prosthetic groups and are a common class of chiral auxiliary groups. After N-acylation of the prosthetic group, if an alkyl side chain is introduced at the alpha position of the side chain amide, the selectivity of the newly formed chiral center can be well controlled.
  • the reaction mechanism is that under low temperature conditions, a base such as lithium diisopropylamide forms an enol form with a substrate, and then reacts with a halogenated alkane, and the reaction has good enantioselectivity, and the obtained product has high optical purity.
  • a compound of formula II and a compound of formula III are used to prepare a novel compound of formula IV which, when reacted at low temperatures, contains a chiral center of the compound of formula II.
  • the construction of a new chiral center can be induced stereospecifically, no diastereomers are observed, the stereoselectivity of the reaction is very good, and the amount of diastereomers formed during the reaction is small, and these Very small amounts of diastereomers can also be removed by simple recrystallization.
  • the reaction does not produce structurally similar by-products and has a high conversion rate. Therefore, the problem of poor reaction selectivity and low yield in the prior art is largely solved.
  • the reducing agent used in the reduction reaction of the step (2) is selected from the group consisting of lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tri-tert-butoxide, and tri-sec-butyl boron.
  • Lithium hydride (L-selectride), potassium K-selectride preferably selected from sodium borohydride, potassium borohydride, lithium borohydride; optimally selected from sodium borohydride, potassium borohydride.
  • the alkaline reagent used in the step (3) cyano hydrolysis reaction is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate; preferably selected from sodium hydroxide and potassium hydroxide.
  • the acid used in the esterification reaction in the step (3) is selected from the group consisting of organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, propionic acid; or inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid. , phosphoric acid; the best choice of hydrochloric acid.
  • organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, propionic acid
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid. , phosphoric acid; the best choice of hydrochloric acid.
  • the acid used in the step (3) in the simultaneous occurrence of cyano hydrolysis and lactonization under the acidic reagent condition is selected from the group consisting of inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; Sulfuric acid or hydrochloric acid.
  • the molar ratio of the formula (II) to the formula (III) in the step (1) is from 1:0.9 to 5, preferably from 1:1.1 to 1.5.
  • the molar ratio of the formula (II) to the base used in the step (1) is from 1:0.9 to 3, preferably from 1:1.0 to 1.5.
  • the molar ratio of the formula (IV) to the reducing agent in the step (2) is 1:0.5 to 5, preferably 1:1.0. 2.0.
  • the reaction solvent for alkylation in the step (1) is tetrahydrofuran or 2-methyltetrahydrofuran.
  • the reaction solvent reduced in the step (2) is a mixed solvent of water/tetrahydrofuran, water/methanol, and water/ethanol.
  • the reaction solvent for the cyano hydrolysis in the step (3) is water or a mixed solvent with tetrahydrofuran.
  • the reaction temperature for the alkylation of step (1) is from 20 to -80 °C.
  • the reaction temperature of the reduction in the step (2) is from 0 to 100 °C.
  • the reaction temperature of the step (3) cyano acid hydrolysis is from 0 to 100 ° C, preferably from 80 to 100 ° C.
  • the reaction temperature of the step (3) cyano base hydrolysis is from 0 to 100 ° C, preferably from 70 to 90 ° C.
  • the process of the invention is particularly suitable for the preparation of 4-n-propyl-dihydrofuran-2(3H)-one of the (R) configuration.
  • (R) as used herein refers to a compound which has an enantiomeric composition of 50% or more, more preferably 90% or more.
  • Tetrahydrofuran 50 mL was added to the reaction flask, (S)-4-phenyloxazol-2-one (5.0 g, 30.6 mmol) was added, and the temperature was lowered to -70 ° C; under nitrogen, the internal temperature was maintained at -65 °.
  • a 2.5 M solution of n-butyllithium (12.9 mL, 32.2 mmol, 1.05 eq) was added dropwise, and the reaction was allowed to stand for half an hour; the internal temperature was maintained at -65 to -75 ° C, and valeryl chloride was added dropwise.
  • Tetrahydrofuran (100.0 mL) was added to the reaction flask, and (S)-4-benzyl-3-pentanoyloxazol-2-one (10.0 g, 38.3 mmol, 1.0 eq) was added and cooled to -70 ° C; Under the protection, keep the internal temperature -65 ⁇ -75 °C, add a concentration of 1.0M LHMDS in tetrahydrofuran solution (49.8mL, 49.8mmol, 1.3eq), drop, heat preservation reaction for 1 hour; maintain internal temperature -65 ⁇ - At 75 ° C, bromoacetonitrile (6.9 g, 57.5 mmol, 1.5 eq) was added dropwise, and the reaction was incubated for 1-2 hours.
  • Tetrahydrofuran (100.0 mL) was added to the reaction flask, and (S)-4-benzyl-3-pentanoyloxazol-2-one (10.0 g, 38.3 mmol) was added, and the temperature was lowered to -70 ° C; The internal temperature was maintained at -65 to -75 ° C, and a solution of 1.6 M LDA in tetrahydrofuran (28.7 mL, 45.9 mmol, 1.2 eq) was added dropwise, and the reaction was kept for 1 hour; the internal temperature was maintained at -65 to -75 ° C.
  • Tetrahydrofuran (50.0 mL) was added to the reaction flask, and (S)-4-isopropyl-3-pentanoyloxazol-2-one (5.0 g, 23.4 mmol) was added, and the temperature was lowered to -70 ° C; , keep the internal temperature -65 ⁇ -75 ° C, add a concentration of 1.0M LHMDS in tetrahydrofuran solution (28.1mL, 28.1mmol, 1.2eq), drop, heat preservation reaction for 1 hour; maintain internal temperature -65 ⁇ -75 °C Bromoacetonitrile (4.2 g, 35.0 mmol, 1.5 eq) was added dropwise, and the reaction was incubated for 1-2 hours.
  • Tetrahydrofuran (16.0 mL) and water (4.0 mL) were added to the reaction flask, and (R)-3-((S)-4-benzyl-2-oxooxazolidinyl-3-carbonyl)hexanenitrile was added. (2.4 g, 8.0 mmol), maintaining the internal temperature below 40 ° C, sodium borohydride (0.60 g, 15.86 mmol, 1.98 eq).
  • Tetrahydrofuran (8.0 mL) and water (2.0 mL) were added to the reaction flask, and (R)-3-((S)-4-phenyl-2-oxooxazolidinyl-3-carbonyl)capronitrile was added. (1.20 g, 4.85 mmol), maintaining the internal temperature below 40 ° C, sodium borohydride (0.37 g, 9.78 mmol, 2.0 eq).
  • Tetrahydrofuran (8.0 mL) and water (2.0 mL) were added to the reaction flask, and (R)-3-((S)-4-isopropyl-2-oxooxazolidinyl-3-carbonyl) was added.
  • Nitrile (1.20 g, 4.76 mmol) was maintained at an internal temperature below 40 ° C and sodium borohydride (0.36 g, 9.52 mmol, 2.0 eq).
  • the reaction was kept at room temperature for 2 hours; the TLC was used to detect the disappearance of the starting material, and the treatment was carried out; and the controlled internal temperature was not higher than 40 ° C, and saturated ammonium chloride (6.0 mL) was added dropwise to quench.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

本发明涉及一种光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法，属于化学合成领域。该本发明方法以光学纯的(S)-3-正戊酰基-4-取代的噁唑-2-酮为原料，经过烷基化、还原、氰基水解、酯化等步骤制备得到光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮。本发明提供的制备方法原料易得，价格低廉，且总收率高、所得产物光学纯度高、反应条件和操作过程简单。

Description

一种光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法 技术领域
本发明涉及一种光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法。
背景技术
2-氧代-吡咯烷-1-基的制备方法和作为药物的用途在公开号WO01/62726的国际专利申请中进行了描述，尤其适用于治疗神经紊乱。尤其是(2S)-2-((4R)-2-氧代-4-正丙基-1-吡咯烷基)丁酰胺(又名布瓦西坦)被欧洲专利号EP0162036公开作为保护剂治疗和预防中枢神经系统缺氧和缺血型损害，以其为原料药制成的布瓦西坦制剂已经被欧洲药品管理局(EMA)批准作为辅助治疗药物用于16岁以上癫痫患者部分性癫痫发作治疗。
Figure PCTCN2017081556-appb-000001
Benoit M.Kenda等人(J.Med.Chem.2004,47,530-549.)描述了用消旋的4-正丙基-二氢呋喃-2(3H)-酮制备2-氧代-吡咯烷-1-基的方法。由于使用消旋的4-正丙基-二氢呋喃-2(3H)-酮，得到的产品是一对非对映异构体，因为异构体与主成分性质相似，很难通过常规重结晶方法去除，因此，必须经过手性柱制备分离才能得到合格的产品。专利CN105646319报道了一种制备光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮，以及用其制备布瓦西坦的方法。由于使用了光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮，所得产品手性纯度高，因此，无需经过手性制备分离即可得到高光学纯度的布瓦西坦。
目前，文献报道的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法共有七条合成路线。
Kosugi,H等人(J.Chem.Soc.Perkin Trans.I.1989,935-943.)报道了一条光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的合成路线。该路线以手性亚砜为起始物料，经金属铑催化还原得到顺式烯烃，后在锌粉催化下与三氯乙酰氯关环，再经脱氯和脱硫得到产品，该方法不仅起始物料不易购买，且用到贵重的金属铑催化剂和毒性很大的金属锡催化剂，因此不适于工业化生产。路线如下：
Figure PCTCN2017081556-appb-000002
Mukaiyama,T等人(Chemistry Letters.1980,635-638.)报道了一条光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的合成路线。该路线以手性的七元环作为起始物料，经加成、甲基化、脱除和水解反应得到手性内酯。该路线不仅采用复杂的中间体作为起始物料，不易商业化购买，且产生较多副产物，原子经济性较差，因此不适于工业化生产。路线如下：
Figure PCTCN2017081556-appb-000003
Chamberlin,R等人(J.O.C.1993,58,2725-2737.)报道了一条光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的合成路线。该路线以双取代的手性噁唑啉酮和溴乙酰氯作为起始物料，经七步反应制备得到手性内酯，最后一步还用到剧毒的汞试剂，路线长且对环境污染严重，因此，不适于工业化生产。路线如下：
Figure PCTCN2017081556-appb-000004
Olof Ceder等人(Acta Chemica Scandinavica,Series B:Organic Chemistry and Biochemistry.1977,31,189-192.)报道了一条光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的合成路线。该路线以手性的取代环己烯酸为起始物料，经还原、氧化、电解反应制备得到手性内酯。该路线不仅采用不易商业化购买到的手性中间体作为起始物料，且最后经电解反应得到产品，成本高，反应条件也不适于大生产。路线如下：
Figure PCTCN2017081556-appb-000005
专利CN105646319报道了一种制备光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的路线。该路线以丙二酸二苯酯和(R)-环氧氯丙烷为起始物料，经关环、格氏反应和脱羧得到手性内酯。虽然起始物料易于购得，但是第三步脱羧反应需要在130℃以上进行，且反应时间较长，产品在长时间加热条件下可能发生消旋，影响产品纯度。路线如下：
Figure PCTCN2017081556-appb-000006
专利CN105837535报道了一种制备光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的路线。该路线以戊酰氯、手性噁唑啉酮和2-溴乙酸叔丁酯为起始物料，经缩合、取代、还原和水解反应得到手性内酯。该路线中的中间体都经过柱层析纯化，成本高，操作繁琐。路线如下：
Figure PCTCN2017081556-appb-000007
Arnaud Schülé等人(Org.Process Res.Dev.2016,20,1566-1575.)报道了一种制备光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的路线。该路线以消旋的取代丙二酸酯为起始物料，经酶拆分后，得到(R)型异构体，后经还原和关环得到手性内酯。因酶催化对反应条件要求苛刻，且价格昂贵，因此，该路线成本较高。路线如下：
Figure PCTCN2017081556-appb-000008
为了克服已报道路线中问题，本发明人设计出新的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮制备方法，并且通过实验验证其可行性。新工艺路线具有起始物料易得，反应收率高，反应中的副产物可以回收利用，操作简单，对映选择性好等优点，具有广泛的工业应用前景。
发明内容
本发明提供一种简单和经济地光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮(式I)的制备方法。
一种光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法，包括如下步骤：
1)制备式(V)所示的光学纯的(R)-3-(羟甲基)己腈化合物；
2)式(V)在酸性条件下发生氰基水解及内酯化得到如式I所示的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮，或者在碱性条件发生氰基水解，再酸化内酯化得到如式I所示的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮；
Figure PCTCN2017081556-appb-000009
所述氰基水解或/和内酯化所用的酸为有机酸或无机酸，所述有机酸为对甲苯磺酸、三氟乙酸、甲酸、乙酸或丙酸；所述无机酸为盐酸、硫酸、硝酸或磷酸。
所述氰基水解或/和内酯化所用的酸优选盐酸或硫酸。
所述氰基水解所用的碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾或碳酸钠。
所述氰基水解所用的碱优选氢氧化钠。
所述氰基水解反应温度为0～100℃。
所述步骤(1)中制备式(V)的方法为式(IV)所述的化合物在还原剂存在的条件下制备光学纯的式(V)所示的(R)-3-(羟甲基)己腈，同时回收作为辅基的式VI所示的(S)-4-取代的噁唑-2-酮。
Figure PCTCN2017081556-appb-000010
X是取代或未取代的C1-20烷基、C1-20链烯基、芳基、杂芳基、杂环烷基、芳基烷基或杂芳基烷基。
优选：
X是C1-6烷基、取代的C1-6烷基、C2-6链烯基、芳基、杂芳基、取代的芳基、芳基烷基或取代芳基烷基。
X是C1-6烷基、芳基、取代芳基、芳基烷基或取代芳基烷基。
X优选甲基、乙基、正丙基、异丙基、叔丁基、苄基、取代苄基、苯基、取代苯基。
X是苯基、异丙基或苄基。
所述还原剂为硼氢化锂、硼氢化钠、硼氢化钾，三仲丁基硼氢化锂(L-selectride)或三仲丁基硼氢化钾(K-selectride)。
所述式(IV)与还原剂的用量摩尔比是1:0.5～5。
所述式(IV)被还原的反应溶剂为水、四氢呋喃、甲醇、乙醇、异丙醇单一溶剂或和水混合溶剂，反应温度为0～100℃。
所述式(IV)所述的化合物的制备方法包括如下步骤：
A)提供式(II)所述的光学纯的(S)-3-正戊酰基-4-取代的噁唑-2-酮化合物，
B)使式(II)与式(III)所示的取代乙腈在碱性试剂的存在下发生烷基取代反应，生成 式(IV)所示的化合物，
Figure PCTCN2017081556-appb-000011
其中，
Y是选自卤素、磺酸酯基团、-S+Me2或-N2 +的离去基团。
所述烷基化采用的碱为二异丙基氨基锂(LDA)、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基氨基钾(KHMDS)、六甲基二硅基氨基钠(NHMDS)。
所述步骤B)中式(II)与式(III)的用量摩尔比是1:0.9～5，式(II)与所用碱的用量摩尔比是1:0.9～3。
所述烷基化的反应溶剂为四氢呋喃或2-甲基四氢呋喃，烷基化的反应温度为20～-80℃。
所述Y是氟、氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基。
优选：Y是溴、氟、氯。
所述式(II)采用如下方法制得：式(VI)所示化合物与正戊酸或正戊酰氯或正戊酸的混合酸酐反应制得。
本发明采用光学纯的(R)-3-(羟甲基)己腈在酸性或碱性条件下，氰基水解，然后再于酸性条件下内酯化，得到本发明的目标产物，并且在反应过程中，手性中心构型不发生变化。总反应过程如下：
步骤(1)：使式(II)所示光学纯的(S)-3-正戊酰基-4-取代的噁唑-2-酮与式(III)所示的取代的乙腈在碱性试剂的存在下发生烷基取代反应，生成式(IV)所示的化合物。
Figure PCTCN2017081556-appb-000012
步骤(2)：使步骤(1)所得式(IV)所示化合物在还原剂存在的条件下制备光学纯的式(V)所示的(R)-3-(羟甲基)己腈，同时回收如式(VI)所示作为手性辅基的(S)-4-取代的噁唑-2-酮；
Figure PCTCN2017081556-appb-000013
步骤(3)：使步骤(2)所得光学纯的(R)-3-(羟甲基)己腈在酸性条件下发生氰基水解及内 酯化的转化，或者在碱性条件发生氰基水解、然后再酸化制备光学纯(R)-4-正丙基-二氢呋喃-2(3H)-酮。
整个合成路线如下：
Figure PCTCN2017081556-appb-000014
本发明所用术语“烷基”定义为包括带有直链、支链或环链部分或其组合并含有1～20个碳原子的饱和一价烃基，非环状烷基优选含有1～6个碳原子，环状烷基优选含有3～8个碳原子。
本发明所用术语“链烯基”定义为具有至少一个双键的未取代或取代的支化、未支化或环状烃基或其组合。优选的链烯基包含2～4个碳。“链烯基”结构部分可以任选被独立选自卤素、羟基、烷氧基、酯、酰基、氰基、酰氧基、羧酸、酰胺或氨基的1～5个取代基取代。
本发明所用术语“芳基”包括芳基烃脱去一个氢原子而产生的基团，例如苯基、萘基。
本发明所用术语“杂环烷基”代表含有至少一个O、S和/或N原子中断碳环结构的环状烷基(环烷基)，例如四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉子基和吡咯烷基。
本发明所用术语“杂芳基”代表含有至少一个O、S和/或N原子中断碳环结构的上述定义的“芳基”，例如吡啶基、呋喃基、吡咯基、噻吩基、异噻唑基、咪唑基、苯并咪唑基、四唑基、吡嗪基、嘧啶基、喹啉基、异喹啉基、异苯并呋喃基、苯并噻吩基、吡唑基、吲哚基、异吲哚基、嘌呤基、咔唑基、异噁唑基、噻唑基、噁唑基、苯并噻唑基或苯并噁唑基。
本发明所用的术语“卤素”包括氯原子、溴原子、碘原子、氟原子。
本发明所用术语“氰基”代表式-CN所示的基团。
本发明所用术语“羟基”代表式-OH所示的基团。
本发明所用的式(II)所示化合物可通过任何合适的方法制备。
式(II)所示(S)-3-正戊酰基-4-取代的噁唑-2-酮最好是由这样的方法制成：式(VI)所示光学纯的(S)-4-取代的噁唑-2-酮与正戊酸或正戊酰氯或正戊酸的混合酸酐反应制得。
Figure PCTCN2017081556-appb-000015
在本发明的方法中，步骤(1)烷基化反应采用的碱选自二异丙基氨基锂(LDA)、六甲基二硅基氨基锂(LHMDS)、六甲基二硅基氨基钾(KHMDS)、六甲基二硅基氨基钠(NHMDS)；优先选自六甲基二硅基氨基锂(LHMDS)或二异丙基氨基锂(LDA)。
在本发明的方法中，式(IV)所示化合物，当X为苄基时其重结晶溶剂选自甲醇、乙醇、异丙醇、甲基叔丁基醚、丙酮、丁酮、异丙醚单一溶剂或正庚烷/乙酸乙酯、甲醇/水、乙醇/水、异丙醇/水、乙腈/水混合溶剂；优选乙醇、异丙醇。
手性噁唑啉酮(式IV所示化合物)称作埃文斯辅基，是一类常用的手性辅基。辅基发生N-酰基化后，如果在侧链酰胺的α位引入烷基侧链，可以很好地控制新生成手性中心的选择性。反应机理是在低温条件下，二异丙基氨基锂等碱与底物形成烯醇式，后与卤代烷烃反应，反应对映选择性好，所得产物光学纯度高。
申请人在研究过程中发现，本发明的新路线中，使用式II化合物和式III所示的化合物制备获得新的式IV所示化合物，在低温下反应时，式II化合物含有的手性中心可以立体专一性地诱导新手性中心的构建，没有观察到非对映异构体的产生，反应立体选择性非常好，反应过程中生成的非对映异构体的量很少，且这些极少量的非对映异构体也只需经过简单的重结晶即可去除。另外，该反应不产生结构类似的副产物，转化率高。因此，极大程度上解决了现有技术中反应选择性不好，收率不高的问题。
在本发明的方法中，步骤(2)还原反应采用的还原剂选自四氢铝锂、硼氢化锂、硼氢化钠、硼氢化钾，三叔丁氧基氢化锂铝，三仲丁基硼氢化锂(L-selectride)，三仲丁基硼氢化钾(K-selectride)；优先选自硼氢化钠、硼氢化钾、硼氢化锂；最优选自硼氢化钠、硼氢化钾。
申请人在研究过程中发现，本发明的新路线中，使用式IV所示的化合物制备获得新的式V所示化合物，该反应的化学选择性非常好，还原位点仅发生在噁唑啉酮的酰胺键上，没有观察到氰基被还原的副产物，并且反应后可以通过重结晶来回收式VI化合物，这样大大提高了原子经济性，降低了成本。
在本发明的方法中，步骤(3)氰基水解反应所用的碱性试剂选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠；优先选自氢氧化钠、氢氧化钾；最优选择氢氧化钠。
在本发明的方法中，步骤(3)内酯化反应所用的酸选自有机酸，例如对甲苯磺酸、三氟乙酸、甲酸、乙酸、丙酸；或无机酸，例如盐酸、硫酸、硝酸、磷酸；最优选择盐酸。
在本发明的方法中，当步骤(3)中在酸性试剂条件下同时先后发生氰基水解及内酯化所时所用的酸选自无机酸，例如盐酸、硫酸、硝酸、磷酸；最优选择硫酸或盐酸。
在本发明的方法中，步骤(1)中式(II)与式(III)的用量摩尔比是1:0.9～5，优选1:1.1～1.5。
在本发明的方法中，步骤(1)中式(II)与所用碱的用量摩尔比是1:0.9～3，优选1:1.0～1.5。
在本发明的方法中，步骤(2)中式(IV)与还原剂的用量摩尔比是1:0.5～5，优选1:1.0～ 2.0。
在本发明的方法中，步骤(1)烷基化的反应溶剂为四氢呋喃、2-甲基四氢呋喃。
在本发明的方法中，步骤(2)还原的反应溶剂为水/四氢呋喃、水/甲醇、水/乙醇的混合溶剂。
在本发明的方法中，步骤(3)氰基水解的反应溶剂为水，或与四氢呋喃的混合溶剂。
在本发明的方法中，步骤(1)烷基化的反应温度为20～-80℃。
在本发明的方法中，步骤(2)还原的反应温度为0～100℃。
在本发明的方法中，步骤(3)氰基酸水解的反应温度为0～100℃，优选80～100℃。
在本发明的方法中，步骤(3)氰基碱水解的反应温度为0～100℃，优选70～90℃。
应用本发明的方法可制备光学纯(R)-4-丙基二氢呋喃-2(3H)-酮。
本发明的方法特别适合制备(R)构型的4-正丙基-二氢呋喃-2(3H)-酮。此处所用的术语(R)指的是这样的化合物：它有50％以上，更好90％以上的对映异构体组成。
以下是实例仅起着举例说明本发明的目的，并不以任何方式意味着或者解释为对本发明的限制。本领域技术人员在不超过本发明的精神和范围内可对以下实施例做常规变换和改进。
实施例
实施例1：(S)-4-苄基-3-戊酰基噁唑-2-酮的合成
Figure PCTCN2017081556-appb-000016
将四氢呋喃(6.3L)加到反应瓶中，加入(S)-4-苄基噁唑-2-酮(422.0g,2.38mol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为2.5M正丁基锂(1.0L,2.5mol,1.05eq)溶液，滴毕，保温反应半小时；保持内温-65～-75℃，滴加戊酰氯(315.9g,2.62mol,1.1eq)，滴毕，反应1小时，TLC检测(S)-4-苄基噁唑-2-酮消失，处理；升至0℃，加入2L饱和氯化铵水溶液，淬灭丁基锂，分相。减压浓缩有机相，浓缩至干，浓缩物用3L二氯甲烷溶解，然后用水洗涤(500mL×2)两次，有机相用300.0g无水硫酸钠干燥2小时；过滤，减压浓缩至干，得到621.3g目标化合物，为白色固体，收率99.9％。
1H NMR(400MHz,CDCl3)δ7.33(t,J＝7.2Hz,2H),7.28(d,J＝7.3Hz,1H),7.21(d,J＝7.2Hz,2H),4.67(ddd,J＝10.6,7.1,3.6Hz,1H),4.26–4.08(m,2H),3.29(dd,J＝13.4,3.1Hz,1H),3.04–2.84(m,2H),2.77(dd,J＝13.3,9.6Hz,1H),1.68(ddd,J＝16.9,11.0,6.1Hz,2H),1.41(dt,J＝15.0,7.7Hz,2H),0.96(t,J＝7.4Hz,3H).MS(ESI):m/z 262.1[M+H]+.[α]D 20+54.0°(c＝1.0g/100mL，CHCl3).
实施例2：(S)-4-苯基-3-戊酰基噁唑-2-酮
Figure PCTCN2017081556-appb-000017
将四氢呋喃(50mL)加到反应瓶中，加入(S)-4-苯基噁唑-2-酮(5.0g,30.6mmol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为2.5M的正丁基锂溶液(12.9mL,32.2mmol,1.05eq)，滴毕，保温反应半小时；保持内温-65～-75℃，滴加戊酰氯(4.1g,34.0mmol,1.11eq)，滴毕，反应1小时，TLC检测(S)-4-苯基噁唑-2-酮消失，处理；升至0℃，加入20mL饱和氯化铵水溶液，淬灭丁基锂，分相，减压浓缩有机相。浓缩物用50mL二氯甲烷溶解，然后用水洗涤(25mL×2)，有机相用10.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到7.4g目标化合物，为白色固体，收率97.6％。
1H NMR(600MHz,CDCl3)δ7.38(dd,J＝8.2,6.6Hz,2H),7.35–7.31(m,1H),7.31–7.27(m,2H),5.42(dd,J＝8.7,3.7Hz,1H),4.68(t,J＝8.8Hz,1H),4.27(dd,J＝8.9,3.7Hz,1H),2.93(td,J＝7.4,2.6Hz,2H),1.63–1.53(m,3H),1.33(dtd,J＝15.1,7.6,5.5Hz,2H),0.89(t,J＝7.4Hz,3H).MS(ESI):m/z 248.1[M+H]+.[α]D 19+60.0°(c＝1.0g/100mL，CHCl3).
实施例3：(S)-4-异丙基-3-戊酰基噁唑-2-酮
Figure PCTCN2017081556-appb-000018
将四氢呋喃(50mL)加到反应瓶中，加入(S)-4-异丙基噁唑-2-酮(5.0g,38.7mmol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为2.5M的正丁基锂溶液(16.2mL,40.5mmol,1.05eq)，滴毕，保温反应半小时；保持内温-65～-75℃，滴加戊酰氯(5.1g,42.3mmol,1.09eq)，滴毕，反应1小时，TLC检测(S)-4-异丙基噁唑-2-酮消失，处理；升至0℃，加入20mL饱和氯化铵水溶液，淬灭丁基锂，分相，减压浓缩有机相。浓缩物用50mL二氯甲烷溶解，然后用水洗涤(25mL×2)，有机相用10.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到8.0g目标化合物，为淡黄色油状物，收率96.8％。
1H NMR(600MHz,CDCl3)δ4.44(ddd,J＝8.4,3.9,3.1Hz,1H),4.26(t,J＝8.7Hz,1H),4.20(dd,J＝9.1,3.0Hz,1H),2.99(ddd,J＝16.6,8.7,6.3Hz,1H),2.86(ddd,J＝16.5,8.6,6.4Hz,1H),2.37(dtd,J＝14.0,7.0,3.9Hz,1H),1.69–1.58(m,3H),1.39(h,J＝7.5Hz,2H),0.96–0.90 (m,7H),0.88(d,J＝7.0Hz,3H).MS(ESI):m/z 214.1[M+H]+.[α]D 19+75.0°(c＝1.0g/100mL，CHCl3).
实施例4：(R)-3-((S)-4-苄基-2-氧代噁唑烷基-3-羰基)己腈的合成
方法一：
Figure PCTCN2017081556-appb-000019
将四氢呋喃(100.0mL)加到反应瓶中，加入(S)-4-苄基-3-戊酰基噁唑-2-酮(10.0g,38.3mmol,1.0eq)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为1.0M的LHMDS的四氢呋喃溶液(49.8mL,49.8mmol,1.3eq)，滴毕，保温反应1小时；保持内温-65～-75℃，滴加溴乙腈(6.9g,57.5mmol,1.5eq)，滴毕，保温反应1-2小时，TLC检测(S)-4-苄基-3-戊酰基噁唑-2-酮消失，处理；升至0℃，加入200.0mL饱和氯化铵水溶液，分相，减压浓缩有机相。浓缩至干，用100.0mL二氯甲烷溶解，然后用水洗涤(50.0mL×2)，有机相用30.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到12.0g粗品，向粗品中加入22.0mL乙醇，加热至回流，溶解后降温析晶，降至0～5℃保温搅拌1小时，过滤，滤饼用少量乙醇淋洗，洗毕，固体放入真空干燥箱中干燥4小时，得到9.9g目标化合物，为白色固体，收率86.1％。
1H NMR(400MHz,CDCl3)δ7.34(t,J＝7.1Hz,2H),7.31–7.25(m,1H),7.22(d,J＝7.0Hz,2H),4.69(qd,J＝6.9,3.5Hz,1H),4.32–4.19(m,2H),4.19–4.05(m,1H),3.33(dd,J＝13.5,3.0Hz,1H),2.83(dd,J＝13.4,9.6Hz,1H),2.73(dd,J＝16.8,7.8Hz,1H),2.61(dd,J＝16.8,5.5Hz,1H),1.81(ddd,J＝20.2,11.7,7.1Hz,1H),1.69–1.50(m,1H),1.49–1.30(m,2H),0.95(t,J＝7.3Hz,3H).MS(ESI):m/z 302.1[M+H]+.[α]D 19+67.0°(c＝1.0g/100mL，CHCl3).
方法二：
Figure PCTCN2017081556-appb-000020
将四氢呋喃(100.0mL)加到反应瓶中，加入(S)-4-苄基-3-戊酰基噁唑-2-酮(10.0g,38.3mmol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为1.6M的LDA的四氢呋喃溶液(28.7mL,45.9mmol,1.2eq)，滴毕，保温反应1小时；保持内温-65～-75℃，滴加溴乙腈(6.9g,57.5mmol,1.5eq)，滴毕，保温反应1-2小时，TLC检测(S)-4-苄基-3-戊酰基噁唑-2-酮消失，处理；升至0℃，加入200.0mL饱和氯化铵水溶液，分相，减压浓缩有机相。 浓缩至干，用100.0mL二氯甲烷溶解，然后用水洗涤(50.0mL×2)，有机相用30.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到12.0g粗品，向粗品中加入22.0mL乙醇，加热至回流，溶解后降温析晶，降至0～5℃保温搅拌1小时，过滤，滤饼用少量乙醇淋洗，洗毕，固体放入真空干燥箱中干燥4小时，得到9.8g目标化合物，为白色固体，收率85.2％。
实施例5：(R)-3-((S)-4-苯基-2-氧代噁唑烷基-3-羰基)己腈的合成
Figure PCTCN2017081556-appb-000021
将四氢呋喃(50.0mL)加到反应瓶中，加入(S)-4-苯基-3-戊酰基噁唑-2-酮(5.0g,20.2mmol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为1.0M的LHMDS的四氢呋喃溶液(24.3mL,24.3mmol,1.2eq)，滴毕，保温反应1小时；保持内温-65～-75℃，滴加溴乙腈(3.6g,30.0mmol,1.49eq)，滴毕，保温反应1-2小时，TLC检测(S)-4-苯基-3-戊酰基噁唑-2-酮消失，处理；升至0℃，加入25.0mL饱和氯化铵水溶液，分相，减压浓缩有机相。浓缩至干，用50.0mL二氯甲烷溶解，然后用水洗涤(25.0mL×2)，有机相用10.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到5.6g目标化合物，为淡黄色固体，收率96.7％。
1H NMR(600MHz,CDCl3)δ7.40(ddd,J＝9.0,7.3,1.5Hz,2H),7.37–7.33(m,1H),7.32–7.28(m,2H),5.42(dt,J＝9.1,2.7Hz,1H),4.72(tt,J＝8.8,1.3Hz,1H),4.35–4.27(m,1H),4.15(p,J＝7.5Hz,1H),2.57(ddt,J＝16.8,7.4,1.2Hz,1H),2.49(ddt,J＝16.8,6.0,1.2Hz,1H),1.79(tdd,J＝15.0,6.3,1.6Hz,1H),1.66–1.56(m,1H),1.45–1.32(m,2H),0.95(tt,J＝7.3,1.2Hz,3H).MS(ESI):m/z 287.1[M+H]+.[α]D 19+87.0°(c＝1.0g/100mL，CHCl3).
实施例6：(R)-3-((S)-4-异丙基-2-氧代噁唑烷基-3-羰基)己腈的合成
Figure PCTCN2017081556-appb-000022
将四氢呋喃(50.0mL)加到反应瓶中，加入(S)-4-异丙基-3-戊酰基噁唑-2-酮(5.0g,23.4mmol)，降温至-70℃；氮气保护下，保持内温-65～-75℃，滴加浓度为1.0M的LHMDS的四氢呋喃溶液(28.1mL,28.1mmol,1.2eq)，滴毕，保温反应1小时；保持内温-65～-75℃，滴加溴乙腈(4.2g,35.0mmol,1.5eq)，滴毕，保温反应1-2小时，TLC检测(S)-4-异丙基-3-戊酰基噁唑-2-酮消失，处理；升至0℃，加入25.0mL饱和氯化铵水溶液，分相，减压浓缩有机相。浓缩至干，用50.0mL二氯甲烷溶解，然后用水洗涤(25.0mL×2)，有机相用10.0g无水硫酸钠干燥2小时；过滤，减压浓缩，得到5.8g目标化合物，为淡黄色油状物，收率98.3％。
1H NMR(600MHz,CDCl3)δ4.46(ddd,J＝8.3,3.8,2.9Hz,1H),4.31(dd,J＝9.2,8.2Hz,1H),4.25(dd,J＝9.2,3.0Hz,1H),4.15(dtd,J＝7.7,6.7,5.5Hz,1H),2.71(dd,J＝16.7,7.9Hz,1H),2.60(dd,J＝16.7,5.4Hz,1H),2.43(pd,J＝7.0,3.8Hz,1H),1.78(ddt,J＝13.6,10.0,6.2Hz,1H),1.63–1.51(m,1H),1.44–1.29(m,2H),0.99–0.86(m,9H).MS(ESI):m/z 275.1[M+Na]+.[α]D 19+74.0°(c＝1.0g/100mL，CHCl3).
实施例7：(R)-3-(羟甲基)己腈的合成
方法一：
Figure PCTCN2017081556-appb-000023
将四氢呋喃(16.0mL)和水(4.0mL)加到反应瓶中，加入(R)-3-((S)-4-苄基-2-氧代噁唑烷基-3-羰基)己腈(2.4g,8.0mmol)，保持内温低于40℃，分批加入硼氢化钠(0.60g,15.86mmol,1.98eq)。保持室温下反应2小时；TLC检测(R)-3-((S)-4-苄基-2-氧代噁唑烷基-3-羰基)己腈消失，处理；控制内温不高于40℃条件下滴加饱和氯化铵(12.0mL)。分液，水相用甲基叔丁基醚(10.0mL)萃取，合并有机相，40℃条件下减压蒸馏减压浓缩至干。向浓缩物中加入甲基叔丁基醚/正己烷(2.4mL,2:1,v/v)，降至0-10℃搅拌1小时，过滤，回收(S)-4-苄基噁唑-2-酮，得到1.05g，为白色粉末。母液浓缩至干，柱层析纯化后得到0.91g目标化合物，为无色油状物，收率89.2％。
1H NMR(400MHz,CDCl3)δ3.72(dd,J＝10.8,4.4Hz,1H),3.55(dd,J＝10.8,7.5Hz,1H),2.49(d,J＝5.8Hz,2H),2.01(s,1H),1.97–1.85(m,1H),1.51–1.30(m,4H),0.94(dd,J＝9.5,4.0Hz,3H).MS(ESI):m/z 128.2[M+H]+.[α]D 19+13.5°(c＝1.0g/100mL，MeOH).
方法二：
Figure PCTCN2017081556-appb-000024
将四氢呋喃(8.0mL)和水(2.0mL)加到反应瓶中，加入(R)-3-((S)-4-苯基-2-氧代噁唑烷基-3-羰基)己腈(1.20g,4.85mmol)，保持内温低于40℃，分批加入硼氢化钠(0.37g,9.78mmol,2.0eq)。保持室温下反应2小时；TLC检测(R)-3-((S)-4-苯基-2-氧代噁唑烷基-3-羰基)己腈消失，处理；控制内温不高于40℃条件下滴加饱和氯化铵(6.0mL)淬灭。40℃条件下减压蒸馏至无馏分，加入乙酸乙酯(10.0mL)萃取，分相，有机相用2.0g无水硫酸钠干燥。过滤，滤液减压浓缩，柱层析纯化后得到0.57g目标化合物，为无色油状物，收率91.9％。
方法三：
Figure PCTCN2017081556-appb-000025
将四氢呋喃(8.0mL)和水(2.0mL)加到反应瓶中，加入(R)-3-((S)-4-异丙基-2-氧代噁唑烷基-3-羰基)己腈(1.20g,4.76mmol)，保持内温低于40℃，分批加入硼氢化钠(0.36g,9.52mmol,2.0eq)。保持室温下反应2小时；TLC检测原料消失，处理；控制内温不高于40℃条件下滴加饱和氯化铵(6.0mL)淬灭。40℃条件下减压蒸馏至无馏分，加入乙酸乙酯(10.0mL)萃取，分相，有机相用2.0g无水硫酸钠干燥。过滤，滤液减压浓缩，柱层析纯化后得到0.52g目标化合物，为无色油状物，收率86.7％。
实施例8：(R)-4-正丙基-二氢呋喃-2(3H)-酮的合成
方法一：
Figure PCTCN2017081556-appb-000026
取(R)-3-(羟甲基)己腈(0.90g)，加入6N HCl(6.0mL)水溶液，加热至75±5℃搅拌反应1小时。TLC检测原料消失，停止加热，将反应降至室温，加入甲基叔丁基醚萃取(10.0mL×2)，有机相合并，水洗一次，加入2.0g无水硫酸钠干燥，过滤，减压浓缩得0.87g目标化合物，为无色油状物，收率95.6％。
1H NMR(400MHz,CDCl3)δ4.42(dd,J＝8.9,7.2Hz,1H),3.92(dd,J＝8.9,7.0Hz,1H),2.68-2.50(m,2H),2.18(dd,J＝16.6,7.6Hz,1H),1.46(q,J＝6.9Hz,2H),1.36(dqd,J＝14.3,7.3,4.6Hz,2H),0.94(t,J＝7.3Hz,3H).MS(EI,70eV)：m/e(rel.inten.)128(M+,4),110(2),97(29),70(55),69(42),56(100),55(92).[α]D 19+6.88°(c＝1.22g/100mL，CHCl3).
方法二：
Figure PCTCN2017081556-appb-000027
取(R)-3-(羟甲基)己腈(0.90g)，加入四氢呋喃(2.0mL)和4N氢氧化钠(8.0mL)，加热至75±5℃搅拌反应5小时。TLC检测原料消失，停止加热，将反应降至室温，有机相用甲基叔丁基醚萃取(5.0mL×2)，弃去有机相。向水相加入浓盐酸(15.0mL)，加热至40±5℃搅拌反应1小时。停止反应，降至室温，加入甲基叔丁基醚萃取(5.0mL×2)，有机相合并，水洗一次，加入2.0g无水硫酸钠干燥，过滤，减压浓缩得0.85g目标化合物，为无色油状物，收率93.4％。

Claims (21)

  1. 一种光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备方法，包括如下步骤：
    1)制备式(V)所示的光学纯的(R)-3-(羟甲基)己腈化合物；
    2)式(V)在酸性条件下发生氰基水解及内酯化的转化得到如式(I)所示的光学纯(R)-4-正丙基-二氢呋喃-2(3H)-酮，或者在碱性条件发生氰基水解再酸化内酯化得到如式(I)所示的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮；
    Figure PCTCN2017081556-appb-100001
  2. 根据权利要求1所述的制备方法，所述氰基水解或/和内酯化所用的酸为有机酸或无机酸，所述有机酸为对甲苯磺酸、三氟乙酸、甲酸、乙酸或丙酸；所述无机酸为盐酸、硫酸、硝酸或磷酸。
  3. 根据权利要求2所述的制备方法，所述氰基水解或/和内酯化所用的酸为盐酸或硫酸。
  4. 根据权利要求1所述的制备方法，所述氰基水解所用的碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾或碳酸钠。
  5. 根据权利要求4所述的制备方法，所述氰基水解所用的碱为氢氧化钠。
  6. 根据权利要求1－5任一所述的制备方法，所述氰基水解的反应溶剂为水，或水与四氢呋喃的混合溶剂，氰基水解反应温度为0～100℃。
  7. 根据权利要求6所述的制备方法，其中氰基酸水解的反应温度为80～100℃，氰基碱水解的反应温度为70～90℃。
  8. 根据权利要求1所述的制备方法，所述步骤1)中制备式(V)的方法为式(IV)所述的化合物在还原剂存在的条件下制备光学纯的式(V)所示的(R)-3-(羟甲基)己腈，同时回收作为辅基的式(VI)所示的(S)-4-取代的噁唑-2-酮；
    Figure PCTCN2017081556-appb-100002
    X是取代或未取代的C1-20烷基、C1-20链烯基、芳基、杂芳基、杂环烷基、芳基烷基或杂芳基烷基。
  9. 根据权利要求8所述的制备方法，X是甲基、乙基、正丙基、异丙基、叔丁基、苄基、取代苄基、苯基、取代苯基。
  10. 根据权利要求9所述的制备方法，X是苯基、异丙基或苄基。
  11. 根据权利要求8所述的制备方法，所述还原剂为硼氢化锂、硼氢化钠、硼氢化钾， 三仲丁基硼氢化锂或三仲丁基硼氢化钾。
  12. 根据权利要求11所述的制备方法，所述式IV被还原的反应溶剂为水、四氢呋喃、甲醇、乙醇、异丙醇中的一种或多种，反应温度为0～100℃，所述式(IV)与还原剂的用量摩尔比是1:0.5～5。
  13. 根据权利要求12所述的制备方法，所述式IV被还原的反应溶剂为水/四氢呋喃、水/甲醇、水/乙醇的混合溶剂，所述式IV与还原剂的用量摩尔比是1:1.0～2.0。
  14. 根据权利要求8所述的制备方法，所述式IV所述的化合物的制备方法包括如下步骤：
    A)提供式(II)所述的光学纯的(S)‐3-正戊酰基-4-取代的噁唑-2-酮，
    B)使式(II)与式(III)所示的取代乙腈在碱性试剂的存在下发生烷基取代反应，生成式(IV)所示的化合物，
    Figure PCTCN2017081556-appb-100003
    其中，
    Y是选自卤素、磺酸酯基团、-S+Me2或-N2+的离去基团。
  15. 根据权利要求14所述的制备方法，所述烷基化采用的碱为二异丙基氨基锂、六甲基二硅基氨基锂、六甲基二硅基氨基钾、六甲基二硅基氨基钠。
  16. 根据权利要求15所述的制备方法，所述烷基化的反应溶剂为四氢呋喃或2-甲基四氢呋喃，所述烷基化的反应温度为20～-80℃，所述式(II)与式(III)的用量摩尔比是1:0.9～5，式(II)与所用碱的用量摩尔比是1:0.9～3。
  17. 根据权利要求16所述的制备方法，所述烷基化的反应温度-60～-75℃，所述式(II)与式(III)的用量摩尔比是1:1.1～1.5，式(II)与所用碱的用量摩尔比是1:1.0～1.5。
  18. 根据权利要求14所述的制备方法，所述Y是氟、氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基。
  19. 根据权利要求18所述的制备方法，所述Y是溴。
  20. 根据权利要求14所述的制备方法，X是苄基，式(IV)纯化重结晶的溶剂为甲醇、乙醇、异丙醇、甲基叔丁基醚、丙酮、丁酮、异丙醚单一溶剂或正庚烷/乙酸乙酯、甲醇/水、乙醇/水、异丙醇/水、乙腈/水混合溶剂。
  21. 根据权利要求20所述的制备方法，X是苄基，式(IV)重结晶溶剂优选乙醇、异丙醇。
PCT/CN2017/081556 2017-02-24 2017-04-23 一种光学纯的(r)-4-正丙基-二氢呋喃-2(3h)-酮的制备方法 WO2018152949A1 (zh)

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