WO2022244969A1 - Procédé de préparation d'un composé à base de lactone de méthylène - Google Patents

Procédé de préparation d'un composé à base de lactone de méthylène Download PDF

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Publication number
WO2022244969A1
WO2022244969A1 PCT/KR2022/004436 KR2022004436W WO2022244969A1 WO 2022244969 A1 WO2022244969 A1 WO 2022244969A1 KR 2022004436 W KR2022004436 W KR 2022004436W WO 2022244969 A1 WO2022244969 A1 WO 2022244969A1
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based compound
phosphine
metal
methylene lactone
formula
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PCT/KR2022/004436
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English (en)
Korean (ko)
Inventor
이충렬
박태은
한창훈
나용호
이재란
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주식회사 자경케미칼
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Publication of WO2022244969A1 publication Critical patent/WO2022244969A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/58—One oxygen atom, e.g. butenolide

Definitions

  • the present invention relates to an improved process for the preparation of methylene lactone-based compounds and similar derivatives.
  • MBL Alpha methylene gamma butyrolactone
  • Tulipalin A is a natural product contained in tulip flowers.
  • MBL is a ⁇ -butyrolactone compound having an exomethylene group and is an important compound in the pharmaceutical industry because it has various physiological activities such as antitumor, antibacterial, and antifungal properties.
  • Japanese Patent Laid-open Publication No. 2001-247560 discloses alpha-methylene-gamma-butyrolactone by reacting gamma butyrolactone and methanol under a manganese/magnesium oxide (Mn/MgO) catalyst.
  • Mn/MgO manganese/magnesium oxide
  • a method for preparing rolactone is disclosed.
  • this method has a limitation in that it is difficult to use commercially because the conversion rate to formaldehyde is low.
  • Korean Patent Registration No. KR 10-1427092 introduces a method of making enolate, an intermediate suggested by Murray, using sodium ethoxide and ethyl formate, but this technology is also difficult to apply to mass production due to poor filterability. is hard
  • the present invention was made to solve the problems of the prior art, and does not require expensive manufacturing equipment such as a high-pressure reactor, and the reaction and post-reaction treatment are simple, and the intermediate manufacturing process is unnecessary, while reducing the process cost accordingly. , It is an object to provide a method for producing a methylene lactone-based compound in high yield.
  • a method for preparing a methylene lactone-based compound involves mixing and reacting an alpha halo lactone-based compound, a phosphine-based compound, and an organic solvent, followed by cooling to obtain phospho-phosphorus represented by Formula 1 below.
  • Step 1 of preparing a nium salt A second step of preparing a solution containing a methylene lactone-based compound and a phosphine-based oxide by mixing the phosphonium salt, a base, paraformaldehyde or formaldehyde, and an organic solvent, and then reacting in situ; A third step of adding a metal salt to the solution of step 2 and reacting the phosphine oxide with the metal salt to form a complex; and a fourth step of obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex from the solution in step 3 and then performing a concentration process and a vacuum distillation process.
  • R 1 to R 3 are each independently a C 3 ⁇ C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group A oxyphenyl group or a phenoxy group, X is -F, -Cl, -Br or -I, Y is And, R 4 is a hydrogen atom or a C 1 ⁇ C 5 linear alkyl group.
  • R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 linear alkyl group.
  • the alpha halo lactone-based compound in step 1 may include a lactone-based compound represented by Formula 3 below.
  • R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 linear alkyl group, and X is -F, -Cl, -Br or -I.
  • the alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
  • the phosphine-based compound of step 1 is tris (C 3-4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine Pyne, tris(3-methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and It may include at least one selected from diphenoxyphenylphosphine.
  • the organic solvent in step 1 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
  • the reaction in the first step, may be performed after mixing the alpha halolactone-based compound and the phosphine-based compound in a weight ratio of 1:0.9 to 3.0.
  • the first step of the reaction may be performed at 60 to 80 ° C. for 8 to 16 hours.
  • the base in step 2 may include at least one selected from organic bases and inorganic bases.
  • the organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine.
  • the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide Side, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may include at least one selected from.
  • the organic solvent in step 2 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
  • the in-situ reaction in the second step is performed after mixing 30 to 100 parts by weight of the base and 15 to 50 parts by weight of paraformaldehyde or formaldehyde with respect to 100 parts by weight of the upper phase phosphonium salt. can be performed.
  • the two-step in-situ reaction may be performed at 60 to 80° C. for 1 to 4 hours.
  • the metal salt of step 3 is a metal halide, metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt, a hydrate or These organic sorbates may be included.
  • the metal of the metal salt may be an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal.
  • the metal salt in step 3 may be added in an amount of 1.50 to 3.00 equivalents per 1 equivalent of the phosphine compound in step 1.
  • the methylene lactone-based compound represented by Formula 2 having a yield of 70% or more and a purity of 98% or more can be prepared through the above-described preparation method.
  • the manufacturing method of the present invention can effectively purify (or remove) reaction byproducts generated during the manufacturing process in the same manufacturing process without a separate purification process, and a separate intermediate synthesis process through an in-situ synthesis process. And since a drying process is not performed, a methylene lactone-based compound with a high yield and high purity can be produced with high productivity and commerciality, while the manufacturing process is simple.
  • the present invention relates to an invention in which the purification (or removal) of impurities is easier than in the conventional methylene lactone-based compound manufacturing process, suitable for producing high-purity methylene lactone-based compounds in high yield, and advantageous for large-scale synthesis processes, phosphonium salts Step 1 to prepare;
  • the phosphonium salt in step 1 is a process of mixing and reacting an alpha halolactone-based compound and a phosphine-based compound, followed by cooling to obtain a phosphonium salt represented by Formula 1 below.
  • each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4- A methoxyphenyl group or a phenoxy group, preferably each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group or a phenoxy group, more preferably each of R 1 to R 3 is independently C It is a 3 -C 4 straight-chain alkyl group or a phenyl group.
  • X in Formula 1 is -F, -Cl, -Br or -I, preferably -Cl, -Br or -I, more preferably -Br.
  • Y in Formula 1 is to be.
  • R 4 is a hydrogen atom or a C 1 to C 5 linear alkyl group, preferably a hydrogen atom or a C 1 to C 2 linear alkyl group.
  • the alpha halo lactone-based compound of step 1 may include a lactone-based compound represented by Formula 3 below.
  • R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group.
  • X is -F, -Cl, -Br or -I, preferably X is -Cl, -Br or -I.
  • alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
  • the phosphine-based compound of step 1 is tris (C 3 ⁇ 4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine, tris (3- methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine It includes at least one selected from among, preferably at least one selected from tris (C 3 ⁇ 4 alkyl) phosphine, triphenylphosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine, More preferably, at least one selected from tris(C 3-4 alkyl)phosphine and trip
  • the organic solvent in step 1 may include at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone.
  • the alpha halolactone compound and the phosphine compound are mixed at a weight ratio of 1:0.9 to 3.0, preferably at a weight ratio of 1:1.2 to 2.5, and more preferably at a weight ratio of 1:1.5 to 2.0.
  • the reaction can be carried out.
  • the mixing amount of the phosphine-based compound is less than 0.9 weight ratio, there may be a problem in that the yield of the desired final reaction product is low, and when it is used in excess of 3.0 weight ratio, a large amount of impurities are generated by the unreacted phosphine-type compound, resulting in the desired final reaction product. There may be a problem with low purity.
  • the reaction of the first step is carried out with slow stirring at 60 ⁇ 80 °C for 8 ⁇ 16 hours, preferably 60 ⁇ 75 °C for 8 ⁇ 14 hours, more preferably 65 ⁇ 72 °C for 9 ⁇ 13 hours
  • the reaction temperature is less than 60 °C, the reaction time takes too long and there is a problem of poor commerciality, and if it exceeds 80 °C, the phosphonium salt synthesis time is short, but a large amount of unwanted reaction products (impurities) may be generated. It is preferable to carry out the reaction within the above range.
  • step 2 is a process of synthesizing a methylene lactone-based compound through an in-situ reaction, in which the phosphonium salt, base, paraformaldehyde or formaldehyde and an organic solvent obtained in step 1 are mixed. Then, when an in-situ reaction is performed, a methylene lactone-based compound and a phosphine-based oxide are formed.
  • step 1 alpha-bromo butyrolactone is used as an alpha halolactone-based compound and triphenylphosphine is used as a phosphine-based compound to prepare a phosphonium salt.
  • phosphonium salt and a base are reacted, phosphonium ylide is synthesized, and phosphonium ylide reacts with aldehyde to synthesize a methylene lactone-based compound.
  • An in-situ reaction is performed in the second step will perform
  • a phosphine-based oxide is formed as an addition reaction product as a reaction product in addition to the methylene lactone-based compound.
  • the phosphine-based oxide is an oxide of a phosphine-based compound used in step 1, for example, tris (C 3-4 alkyl) phosphine oxide, triphenylphosphine oxide, tris (3-chlorophenyl) phosphine oxide, Tris (4-chlorophenyl) phosphine oxide, tris (3-methylphenyl) phosphine oxide, tris (4-methylphenyl) phosphine oxide, tris (3-methoxyphenyl) phosphine oxide, tris (4-methoxy- Phenyl) may include at least one selected from phosphine oxide, phenoxydiphenylphosphine oxide and diphenoxyphenylphosphine oxide.
  • the base may include at least one selected from organic bases and inorganic bases.
  • the organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine, and preferably one selected from triethylamine, dimethylamine and diethylamine. may contain more than
  • the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide, lithium methoxide, lithium It may contain at least one selected from among ethoxide, sodium hydroxide and potassium hydroxide, preferably sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, sodium hydroxide and potassium hydroxide It may include one or more selected from rockside.
  • the amount of the base may be 30 to 100 parts by weight, preferably 30 to 60 parts by weight, more preferably 40 to 55 parts by weight, based on 100 parts by weight of the phosphonium salt. If it is less than 30 parts by weight, there may be a problem in that the synthesis yield of the methylene lactone-based compound is low due to the small amount of ylide synthesis, and if the amount of base used exceeds 100 parts by weight, the unreacted base acts as an impurity due to excessive use, resulting in methylene lactone-based Since there may be a problem of lowering the purity of the compound, it is good to use it within the above range.
  • the amount of paraformaldehyde or formaldehyde used is 15 to 50 parts by weight, preferably 15 to 30 parts by weight, more preferably 18 to 30 parts by weight based on 100 parts by weight of the phosphonium salt. , If the amount thereof is less than 15 parts by weight, there may be a problem in that the synthesis yield for the methylene lactone-based compound is lowered, and if the amount thereof exceeds 50 parts by weight, the unreacted aldehyde acts as an impurity rather than the methylene lactone-based compound. Since there may be a problem of lowering the purity, it is good to use it within the above range.
  • the organic solvent of the second step is selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, ethyldichloroethane, diisopropyl ether, t-butylmethyl ether and ethyl acetate It may include one or more, preferably one or more selected from tetrahydrofuran, 1,4-dioxane, and acetonitrile.
  • the second-step in-situ reaction is carried out at 60 to 80 ° C for 1 to 4 hours, preferably at 60 to 75 ° C for 1 to 3 hours, more preferably at 65 to 75 ° C for 1 to 3 hours. It is preferable, and if the reaction temperature is less than 60 °C, the synthesis time of the methylene lactone-based compound is too long and there may be a problem with low yield, and if the reaction temperature exceeds 80 °C, unwanted impurities are generated and there is a problem of low purity. Therefore, it is preferable to perform the in-situ reaction in the above temperature range.
  • step 3 is a process of synthesizing a complex (or complex) by reacting the phosphine-based oxide, which is an addition reaction product of step 2, with a metal salt.
  • the metal salt is a metal halide (e.g., fluoride, chloride, bromide or iodide), metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt , hydrates thereof or organic sorbates thereof.
  • a metal halide e.g., fluoride, chloride, bromide or iodide
  • the metal of the metal salt may include an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal, and preferably, the metal of the metal salt is lithium, sodium, potassium, magnesium, calcium, barium, strontium, samirium (III ), zinc, iron(II), iron(III), manganese(II), cobalt(II), cobalt(III), nickel, copper(I) or copper(II).
  • the metal salt may include at least one selected from zinc chloride and magnesium chloride.
  • the amount of the metal salt added per equivalent of the phosphine-based compound based on the phosphine-based compound used in the first step may be used in a weight ratio of 0.25 to 5.0, preferably 1.5 to 3.0.
  • the equivalence ratio of the metal salt input is less than 0.25 equivalence ratio, the complex is not sufficiently formed, and the remaining phosphine oxide acts as an impurity, which may cause a problem of low purity of the desired final product.
  • the residual metal salt acts as an impurity, there may be a problem of lowering the purity of the species product, so it is good to use it within the above range.
  • reaction of the phosphine-based oxide and the metal salt in the third step is 0 to 130 ° C, preferably 20 to 120 ° C, more preferably 20 to 40 ° C for 5 to 24 hours, preferably 6 to 18 hours while stirring slowly. can be done over time.
  • Step 4 is a process for obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex formed in the reaction solution in Step 3 and performing a concentration and vacuum distillation process.
  • R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group.
  • step 3 As a method for removing the complex synthesized in step 4 in step 3, methods such as filtration, decantation, and/or centrifugation generally used in the art may be used.
  • each of the four-step concentration process and vacuum distillation process can be performed by a general concentration and vacuum distillation method used in the art.
  • the methylene lactone-based compound represented by Formula 2 prepared by performing the above process has a yield of 60% or more, preferably a yield of 70% or more, more preferably 70 to 95% when calculated based on Equation 1 below A methylene lactone-based compound can be obtained in a yield of
  • the methylene lactone-based compound represented by Formula 2 or Formula 3 prepared by performing the above process has a purity of 98% or more, preferably 98.5% to 99.9%, more preferably 98.8 to 99.9% when analyzed by chromatography.
  • a methylene lactone-based compound can be obtained with a high purity of %.
  • Example 1-1 Preparation of methylene lactone-based compound represented by Chemical Formula 2-1
  • each of R 1 , R 2 , and R 3 is a phenyl group
  • X is -Br
  • Y is And
  • R 4 is a hydrogen atom.
  • R 4 in Formula 2-1 is a hydrogen atom.
  • each of R 1 , R 2 , and R 3 is a phenyl group, X is -Br, and Y is , and R 4 is -CH 3 .
  • R 4 in Formula 2-2 is -CH 3 .
  • a methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 1, but as shown in Tables 1 and 2 below, by varying the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 Examples 3 to 10 and Comparative Examples 1 to 8 were carried out, respectively.
  • a methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 2, but the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 was changed as shown in Table 1 below to obtain Example 11 was carried out.
  • Comparative Example 7 in which the metal salt was used at a weight ratio of less than 0.25 in step 3, compared to Example 9, it was confirmed that there was a problem in that the purity was rapidly lowered, and the metal salt was used at a weight ratio of more than 5.00 Comparative Example In the case of 8, compared to Example 10, there was a problem that the purity was lowered.
  • the method for producing the methylene lactone system described above is not limited to the configuration and method of the above-described embodiments, but all or part of each embodiment is selectively applied so that various modifications can be made. They may be configured in combination.

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Abstract

La présente invention concerne un procédé de préparation d'un composé à base de lactone de méthylène et, plus spécifiquement, par comparaison avec un procédé classique de préparation d'un composé à base de lactone de méthylène, permet la préparation d'un composé à base de lactone de méthylène spécifique avec un rendement élevé et une pureté élevée tout en simplifiant un procédé de préparation.
PCT/KR2022/004436 2021-05-17 2022-03-29 Procédé de préparation d'un composé à base de lactone de méthylène WO2022244969A1 (fr)

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CN116462645A (zh) * 2023-05-06 2023-07-21 上海华默西医药科技有限公司 一种2-呋喃-2-基亚甲基-4-羟基丁酸酯及其制备方法和应用

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KR102379889B1 (ko) * 2021-05-17 2022-03-29 자경케미칼 주식회사 메틸렌 락톤계 화합물의 제조방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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