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WO2024232593A1 - Procédé de préparation d'hydrocarbure saturé estérifié de mono-tert-butyle, et procédé de préparation cyclique associé - Google Patents

Procédé de préparation d'hydrocarbure saturé estérifié de mono-tert-butyle, et procédé de préparation cyclique associé Download PDF

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WO2024232593A1
WO2024232593A1 PCT/KR2024/005933 KR2024005933W WO2024232593A1 WO 2024232593 A1 WO2024232593 A1 WO 2024232593A1 KR 2024005933 W KR2024005933 W KR 2024005933W WO 2024232593 A1 WO2024232593 A1 WO 2024232593A1
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Prior art keywords
tert
mono
saturated hydrocarbon
producing
butyl
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English (en)
Korean (ko)
Inventor
김원섭
전재훈
전병만
엄인영
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Aminologics Co Ltd
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Aminologics Co Ltd
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Priority to CN202480031212.8A priority Critical patent/CN121100110A/zh
Publication of WO2024232593A1 publication Critical patent/WO2024232593A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/138—Halogens; Compounds thereof with alkaline earth metals, magnesium, beryllium, zinc, cadmium or mercury
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom

Definitions

  • the present invention relates to a method for producing a mono-tert-butyl esterified saturated hydrocarbon and a cyclic method for producing the same.
  • Semaglutide is a representative GLP-1 (glucagon-like peptide-1) analogue and is a medicine used for the treatment or prevention of diabetes.
  • Octadecanedioic acid-mono-tert-butyl-ester (C 22 H 42 O 4 ) is an intermediate for synthesizing semaglutide and is obtained by hydrolyzing di-tert-butyl-octadecanedioate (C 26 H 50 O 4 ).
  • 2011-0306551 discloses a hydrolysis reaction using N,N-dimethylformamide di-tert-butylacetal and toluene as a solvent at 95°C, but due to the high reaction temperature, a large amount of impurities are generated, low purity, and it is difficult to recover the filtrate, so the yield is low.
  • the hydrolysis reaction disclosed in the previous literature 'Giuseppe Bartoli et al., "Selective Deprotection of N-Boc-Protected tert-Butyl Ester Amino Acid by the CeCl 3 7H 2 O-NaI System in Acetonitrile", J. Org. Chem. 2001, 66, 4430', the solvent in which the desired product is difficult to dissolve is used, so the reaction proceeds at a high temperature, resulting in low yield and purity.
  • U.S. Patent No. 1,026,6578 discloses a method using DMAP, 2-Me-THF, t-BuOH, and Boc 2 O; a method using acetic anhydride, DMAP, and t-BuOH under an argon atmosphere; and a method using DMAP, Boc 2 O, and toluene as a solvent.
  • these methods have low purity due to the generation of a large amount of impurities due to the high reaction temperature, and the yield is low because it is difficult to recover the filtrate.
  • it is difficult to apply it to a commercial process because silica gel chromatography is performed to purify the obtained product.
  • 3,321,279 discloses a method using 1 equivalent each of DIC ( N,N′ -diisopropylcarbodiimide) and DMAP[4-(dimethylamino)pyridine]; and initiates a hydrolysis reaction using t-BuOH as a solvent, but is difficult to apply to a commercial process due to the column chromatography performed thereafter to purify the obtained product.
  • the present invention provides a method for producing a mono-tert-butyl esterified saturated hydrocarbon and a cyclic method for producing the same.
  • the first aspect of the present invention provides a method for producing a mono-tert-butyl esterified saturated hydrocarbon, comprising subjecting a di-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 1 to a hydrolysis reaction in the presence of a catalyst to obtain a mono-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 2, wherein the catalyst is at least one selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), zinc iodide (ZnI 2 ), and hydrates thereof:
  • n is an integer greater than or equal to 1.
  • the second aspect of the present invention provides a cyclic method for producing a mono-tert-butyl esterified saturated hydrocarbon, comprising: performing a hydrolysis reaction of a di-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 1 in the presence of a catalyst to obtain a mono-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 2 ; and performing the hydrolysis reaction in the presence of the catalyst on a filtrate of the hydrolysis reaction to additionally obtain a mono-tert-butyl esterified saturated hydrocarbon, at least once; wherein the catalyst is at least one selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), zinc iodide (ZnI 2 ), and hydrates thereof:
  • n is an integer greater than or equal to 1.
  • the method for producing a mono-tert-butyl esterified saturated hydrocarbon according to the embodiments of the present invention is easy to process and can be performed under mild conditions compared to conventional methods.
  • the method for producing a mono-tert-butyl esterified saturated hydrocarbon according to the embodiments of the present invention does not produce impurities compared to conventional methods, so that a mono-tert-butyl esterified saturated hydrocarbon can be easily separated and obtained.
  • the purity of the mono-tert-butyl esterified saturated hydrocarbon obtained by the method for producing a mono-tert-butyl esterified saturated hydrocarbon may be about 90% or more, about 95% or more, about 98% or more, or about 99% or more.
  • the method for producing a mono-tert-butyl esterified saturated hydrocarbon according to the embodiments of the present invention can be applied to a commercial process.
  • the cyclic production method of a mono-tert-butyl esterified saturated hydrocarbon according to the embodiments of the present invention is economical because the mono-tert-butyl esterified saturated hydrocarbon can be additionally obtained by performing the same hydrolysis reaction on the filtrate after the hydrolysis reaction.
  • the cumulative crystallization yield of the mono-tert-butyl esterified saturated hydrocarbon obtained by the cyclical production method of the mono-tert-butyl esterified saturated hydrocarbon according to the embodiments of the present disclosure can be about 40% or more, about 50% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, or about 90% or more.
  • Figure 1 is a reaction scheme for a reaction of obtaining a mono-tert-butyl esterified saturated hydrocarbon by hydrolyzing a di-tert-butyl esterified saturated hydrocarbon in the presence of a zinc bromide catalyst, in one embodiment of the present invention, wherein n is an integer greater than or equal to 1.
  • step of ⁇ or “step of ⁇ ” as used throughout this specification do not mean “step for ⁇ .”
  • the term "combination(s) thereof" included in the expressions in the Makushi format means one or more mixtures or combinations selected from the group consisting of the components described in the Makushi format, and means including one or more selected from the group consisting of said components.
  • references to “A and/or B” mean “A or B, or A and B.”
  • the first aspect of the present invention provides a method for producing a mono-tert-butyl esterified saturated hydrocarbon, comprising subjecting a di-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 1 to a hydrolysis reaction in the presence of a catalyst to obtain a mono-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 2, wherein the catalyst is at least one selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), zinc iodide (ZnI 2 ), and hydrates thereof:
  • n is an integer greater than or equal to 1.
  • n may be an integer from about 4 to about 22, but may not be limited thereto. In one embodiment of the present disclosure, n may be an integer from about 4 to about 22, from about 4 to about 18, from about 4 to about 14, from about 4 to about 10, from about 4 to about 6, from about 8 to about 22, from about 8 to about 18, from about 8 to about 14, from about 8 to about 10, from about 12 to about 22, from about 12 to about 18, from about 12 to about 16, from about 12 to about 14, from about 14 to about 22, from about 14 to about 18, or from about 20 to about 22. In one embodiment of the present disclosure, n may be about 6 to about 18. In one embodiment of the present disclosure, n may be 14. In one embodiment of the present invention, n may be 16.
  • the hydrolysis reaction may be performed in an environment including a catalyst selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), or zinc iodide (ZnI 2 ); and water, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction may be performed in an environment including zinc bromide (ZnBr 2 ) and water.
  • the hydrolysis reaction may be performed including a hydrate of zinc bromide (ZnBr 2 ), a hydrate of zinc chloride (ZnCl 2 ), or a hydrate of zinc iodide (ZnI 2 ), but may not be limited thereto.
  • ZnBr 2 zinc bromide
  • ZnCl 2 zinc chloride
  • ZnI 2 zinc iodide
  • the catalyst may be zinc bromide (ZnBr 2 ). In one embodiment of the present invention, the catalyst may be a hydrate of zinc bromide (as a non-limiting example, a dihydrate, ZnBr 2 2H 2 O).
  • the catalyst may be used in an amount of more than about 0.2 equivalents and less than about 1 equivalent, but may not be limited thereto. In one embodiment of the present invention, the catalyst is present in an amount of from about 0.2 equivalents to about 1 equivalent or less, from about 0.2 equivalents to about 0.9 equivalents or less, from about 0.2 equivalents to about 0.8 equivalents or less, from about 0.2 equivalents to about 0.7 equivalents or less, from about 0.2 equivalents to about 0.6 equivalents or less, from about 0.3 equivalents to about 1 equivalent or less, from about 0.3 equivalents to about 0.9 equivalents or less, from about 0.3 equivalents to about 0.8 equivalents or less, from about 0.3 equivalents to about 0.7 equivalents or less, from about 0.3 equivalents to about 0.6 equivalents or less, from about 0.4 equivalents to about 1 equivalent or less, from about 0.4 equivalents to about 0.9 equivalents or less, from about 0.4 equivalents to about 0.8 equivalents or less, from about 0.4 equivalents to about 1 equivalent or less, from about 0.4 equivalent
  • n 14
  • about 100 mg to about 200 mg of zinc bromide may be used based on 1 mmol of the compound represented by the chemical formula 2.
  • the reaction time may be shortened, but all of the di-tert-butyl-ester groups of the compound represented by the chemical formula 1 may be hydrolyzed.
  • the hydrolysis reaction may be performed at a temperature range of about 0°C to about 40°C, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction is performed at a temperature of about 0°C to about 40°C, about 0°C to about 37°C, about 0°C to about 34°C, about 0°C to about 31°C, about 0°C to about 28°C, about 3°C to about 40°C, about 3°C to about 37°C, about 3°C to about 34°C, about 3°C to about 31°C, about 3°C to about 28°C, about 6°C to about 40°C, about 6°C to about 37°C, about 6°C to about 34°C, about 6°C to about 31°C, about 6°C to about 28°C, about 9°C to about 40°C, about 9°C to about 37°C, about 9°C to about 34°C, about 9°C to about 31°C, about
  • the hydrolysis reaction may be preferably performed at about 25° C.
  • the hydrolysis reaction may be performed for about 12 hours to about 36 hours, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction is carried out for about 12 hours to about 36 hours, about 12 hours to about 34 hours, about 12 hours to about 32 hours, about 12 hours to about 30 hours, about 12 hours to about 28 hours, about 12 hours to about 26 hours, about 14 hours to about 36 hours, about 14 hours to about 34 hours, about 14 hours to about 32 hours, about 14 hours to about 30 hours, about 14 hours to about 28 hours, about 14 hours to about 26 hours, about 16 hours to about 36 hours, about 16 hours to about 34 hours, about 16 hours to about 32 hours, about 16 hours to about 30 hours, about 16 hours to about 28 hours, about 16 hours to about 26 hours, about 18 hours to about 36 hours, about It can be performed for about 18 hours to about 34 hours, about 18 hours to about 32 hours, about 18 hours to about 30 hours, about 18 hours to about 28 hours, about 18 hours to about 26 hours, about 20 hours to about 36 hours, about
  • the hydrolysis reaction when using about 0.5 equivalents of the catalyst, may be performed for about 12 hours to about 36 hours. In one embodiment of the present invention, when using about 0.5 equivalents of the catalyst, the hydrolysis reaction may be preferably performed for about 24 hours. In one embodiment of the present invention, when using about 1 equivalent of the catalyst, the hydrolysis reaction may be preferably performed for about 12 hours.
  • it may be performed under solution conditions including a solvent, but may not be limited thereto.
  • the solvent may be at least one selected from a hydrochloric organic solvent, an aliphatic hydrocarbon solvent, and an aromatic hydrocarbon solvent.
  • the hydrochloric organic solvent may be at least one selected from carbon tetrachloride, chloroform, dichloromethane, and dichloroethane.
  • the aliphatic hydrocarbon organic solvent may be at least one selected from n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the aromatic hydrocarbon solvent may be at least one selected from benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, and n-amylnaphthalene.
  • the solvent may be at least one selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, n-amylnaphthalene, n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the toluene may be substituted or unsubstituted and may be selected from toluene, fluorotoluene, 1,2-difluorotoluene, 1,3-difluorotoluene, 1,4-difluorotoluene, trifluorotoluene, 1,2,4-trifluorotoluene, chlorotoluene, 1,2-dichlorotoluene, 1,3-dichlorotoluene, 1,4-dichlorotoluene, 1,2,4-trichlorotoluene, iodotoluene, 1,2-diiodotoluene, 1,3-diiodotoluene, 1,4-diiodotoluene, or 1,2,4-triiodotoluene.
  • n-hexane may be substituted or unsubstituted and may be selected from n-hexane, 1-chlorohexane, 1-bromohexane, 1-iodohexane, 1,6-dichlorohexane, 1,6-dibromohexane, 1,6-diiodohexane, and 1-hydroxyhexane.
  • the solvent may be at least one selected from dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. In one embodiment of the present invention, it may be preferable that the solvent is dichloromethane or chloroform.
  • a crystallization process may be additionally included after the hydrolysis reaction, but may not be limited thereto.
  • the solvent used in the crystallization process may be at least one selected from an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, and an alcohol solvent.
  • the aliphatic hydrocarbon solvent used in the crystallization process may be at least one selected from n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the aromatic hydrocarbon solvent used in the crystallization process may be at least one selected from benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, and n-amylnaphthalene.
  • the alcohol solvent used in the crystallization process may be at least one selected from methanol, ethanol, iso-propyl alcohol, butanol, and octanol.
  • the solvent used in the crystallization process may be n-heptane.
  • the present invention may further include, but is not limited to, performing a concentration process and a filtration process after the hydrolysis reaction.
  • the mono-tert-butyl-esterified saturated hydrocarbon can be obtained as a solid compound using a conventional separation method.
  • the hydrolysis reaction is a reaction in which no impurities are generated, a mono-tert-butyl esterified saturated hydrocarbon can be easily separated and obtained.
  • the purity of the mono-tert-butyl esterified saturated hydrocarbon obtained by the method for producing the mono-tert-butyl esterified saturated hydrocarbon may be about 90% or more, about 95% or more, about 98% or more, or about 99% or more.
  • the method for producing the mono-tert-butyl esterified saturated hydrocarbon can be applied to a commercial process.
  • the second aspect of the present invention provides a cyclic method for producing a mono-tert-butyl esterified saturated hydrocarbon, comprising: performing a hydrolysis reaction of a di-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 1 in the presence of a catalyst to obtain a mono-tert-butyl esterified saturated hydrocarbon represented by the following chemical formula 2 ; and performing the hydrolysis reaction in the presence of the catalyst on a filtrate of the hydrolysis reaction to additionally obtain a mono-tert-butyl esterified saturated hydrocarbon, at least once; wherein the catalyst is at least one selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), zinc iodide (ZnI 2 ), and hydrates thereof:
  • n is an integer greater than or equal to 1.
  • n may be an integer from about 4 to about 22, but may not be limited thereto. In one embodiment of the present disclosure, n may be an integer from about 4 to about 22, from about 4 to about 18, from about 4 to about 14, from about 4 to about 10, from about 4 to about 6, from about 8 to about 22, from about 8 to about 18, from about 8 to about 14, from about 8 to about 10, from about 12 to about 22, from about 12 to about 18, from about 12 to about 16, from about 12 to about 14, from about 14 to about 22, from about 14 to about 18, or from about 20 to about 22. In one embodiment of the present disclosure, n may be about 6 to about 18. In one embodiment of the present disclosure, n may be 14. In one embodiment of the present invention, n may be 16.
  • the hydrolysis reaction may be performed in an environment including a catalyst selected from zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), or zinc iodide (ZnI 2 ); and water, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction may be performed in an environment including zinc bromide (ZnBr 2 ) and water.
  • the hydrolysis reaction may be performed including a hydrate of zinc bromide (ZnBr 2 ), zinc chloride (ZnCl 2 ), or zinc iodide (ZnI 2 ), but may not be limited thereto.
  • the catalyst may be zinc bromide (ZnBr 2 ). In one embodiment of the present invention, the catalyst may be a hydrate of zinc bromide (as a non-limiting example, a dihydrate, ZnBr 2 2H 2 O).
  • the catalyst may be used in an amount of more than about 0.2 equivalents and less than about 1 equivalent, but may not be limited thereto. In one embodiment of the present invention, the catalyst is present in an amount of from about 0.2 equivalents to about 1 equivalent or less, from about 0.2 equivalents to about 0.9 equivalents or less, from about 0.2 equivalents to about 0.8 equivalents or less, from about 0.2 equivalents to about 0.7 equivalents or less, from about 0.2 equivalents to about 0.6 equivalents or less, from about 0.3 equivalents to about 1 equivalent or less, from about 0.3 equivalents to about 0.9 equivalents or less, from about 0.3 equivalents to about 0.8 equivalents or less, from about 0.3 equivalents to about 0.7 equivalents or less, from about 0.3 equivalents to about 0.6 equivalents or less, from about 0.4 equivalents to about 1 equivalent or less, from about 0.4 equivalents to about 0.9 equivalents or less, from about 0.4 equivalents to about 0.8 equivalents or less, from about 0.4 equivalents to about 1 equivalent or less, from about 0.4 equivalent
  • n 14
  • about 100 mg to about 200 mg of zinc bromide may be used based on 1 mmol of the compound represented by the chemical formula 2.
  • the reaction time may be shortened, but all of the di-tert-butyl-ester groups of the compound represented by the chemical formula 1 may be hydrolyzed.
  • the hydrolysis reaction may be performed at a temperature range of about 0°C to about 40°C, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction is performed at a temperature of about 0°C to about 40°C, about 0°C to about 37°C, about 0°C to about 34°C, about 0°C to about 31°C, about 0°C to about 28°C, about 3°C to about 40°C, about 3°C to about 37°C, about 3°C to about 34°C, about 3°C to about 31°C, about 3°C to about 28°C, about 6°C to about 40°C, about 6°C to about 37°C, about 6°C to about 34°C, about 6°C to about 31°C, about 6°C to about 28°C, about 9°C to about 40°C, about 9°C to about 37°C, about 9°C to about 34°C, about 9°C to about 31°C, about
  • the hydrolysis reaction may be preferably performed at about 25° C.
  • the hydrolysis reaction may be performed for about 12 hours to about 36 hours, but may not be limited thereto. In one embodiment of the present invention, the hydrolysis reaction is carried out for about 12 hours to about 36 hours, about 12 hours to about 34 hours, about 12 hours to about 32 hours, about 12 hours to about 30 hours, about 12 hours to about 28 hours, about 12 hours to about 26 hours, about 14 hours to about 36 hours, about 14 hours to about 34 hours, about 14 hours to about 32 hours, about 14 hours to about 30 hours, about 14 hours to about 28 hours, about 14 hours to about 26 hours, about 16 hours to about 36 hours, about 16 hours to about 34 hours, about 16 hours to about 32 hours, about 16 hours to about 30 hours, about 16 hours to about 28 hours, about 16 hours to about 26 hours, about 18 hours to about 36 hours, about It can be performed for about 18 hours to about 34 hours, about 18 hours to about 32 hours, about 18 hours to about 30 hours, about 18 hours to about 28 hours, about 18 hours to about 26 hours, about 20 hours to about 36 hours, about
  • the hydrolysis reaction when using about 0.5 equivalents of the catalyst, may be performed for about 12 hours to about 36 hours. In one embodiment of the present invention, when using about 0.5 equivalents of the catalyst, the hydrolysis reaction may be preferably performed for about 24 hours. In one embodiment of the present invention, when using about 1 equivalent of the catalyst, the hydrolysis reaction may be preferably performed for about 12 hours.
  • it may be performed under solution conditions including a solvent, but may not be limited thereto.
  • the solvent may be at least one selected from a hydrochloric organic solvent, an aliphatic hydrocarbon solvent, and an aromatic hydrocarbon solvent.
  • the hydrochloric organic solvent may be at least one selected from carbon tetrachloride, chloroform, dichloromethane, and dichloroethane.
  • the aliphatic hydrocarbon organic solvent may be at least one selected from n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the aromatic hydrocarbon solvent may be at least one selected from benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, and n-amylnaphthalene.
  • the solvent may be at least one selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, n-amylnaphthalene, n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the toluene may be substituted or unsubstituted and may be selected from toluene, fluorotoluene, 1,2-difluorotoluene, 1,3-difluorotoluene, 1,4-difluorotoluene, trifluorotoluene, 1,2,4-trifluorotoluene, chlorotoluene, 1,2-dichlorotoluene, 1,3-dichlorotoluene, 1,4-dichlorotoluene, 1,2,4-trichlorotoluene, iodotoluene, 1,2-diiodotoluene, 1,3-diiodotoluene, 1,4-diiodotoluene, or 1,2,4-triiodotoluene.
  • n-hexane may be substituted or unsubstituted and may be selected from n-hexane, 1-chlorohexane, 1-bromohexane, 1-iodohexane, 1,6-dichlorohexane, 1,6-dibromohexane, 1,6-diiodohexane, and 1-hydroxyhexane.
  • the solvent may be at least one selected from dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. In one embodiment of the present invention, it may be preferable that the solvent is dichloromethane or chloroform.
  • it may further include, but is not limited to, performing a crystallization process after the hydrolysis reaction.
  • the solvent used in the crystallization process may be at least one selected from an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, and an alcohol solvent.
  • the aliphatic hydrocarbon solvent used in the crystallization process may be at least one selected from n-pentane, iso-pentane, n-hexane, iso-hexane, n-heptane, iso-heptane, 2,2,4-trimethylpentane, n-octane, iso-octane, cyclohexane, and methylcyclohexane.
  • the aromatic hydrocarbon solvent used in the crystallization process may be at least one selected from benzene, toluene, xylene, mesitylene, ethylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, iso-propylbenzene, diethylbenzene, iso-butylbenzene, triethylbenzene, di-iso-propylbenzene, and n-amylnaphthalene.
  • the alcohol solvent used in the crystallization process may be at least one selected from methanol, ethanol, iso-propyl alcohol, butanol, and octanol.
  • the solvent used in the crystallization process may be n-heptane.
  • the present invention may further include, but is not limited to, performing a concentration process and a filtration process after the hydrolysis reaction.
  • the mono-tert-butyl-esterified saturated hydrocarbon can be obtained as a solid compound using a conventional separation method.
  • the hydrolysis reaction is a reaction in which no impurities are generated, a mono-tert-butyl esterified saturated hydrocarbon can be easily separated and obtained.
  • the purity of the mono-tert-butyl esterified saturated hydrocarbon obtained by the cyclic production method of the mono-tert-butyl esterified saturated hydrocarbon may be about 90% or more, about 95% or more, about 98% or more, or about 99% or more.
  • the cyclic production method of the mono-tert-butyl esterified saturated hydrocarbon can be applied to a commercial process.
  • the cumulative crystallization yield of the mono-tert-butyl esterified saturated hydrocarbon obtained by the cyclical production method of the mono-tert-butyl esterified saturated hydrocarbon may be about 40% or more, about 50% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, or about 90% or more.
  • the conversion rate represents the HPLC area at the end of the reaction.
  • Example 1-1 Dichloromethane (dichloromethane) 48 99.5
  • Comparative Example 1-1 N,N-Dimethylformaldehyde (N,N-dimethylformaldehyde) 0 -
  • Comparative Example 1-2 Tetrahydrofuran (tetrahydrofuran) 0 - Comparative Example 1-3 Acetone (acetone) 0 - Comparative Example 1-4 Ethyl acetate (ethyl acetate) 0 -
  • Comparative Examples 1-1 to 1-4 were unsuitable as reaction solvents because hydrolysis into octadecanedioic acid-mono-tert-butyl ester did not occur.
  • Examples 1-1 and 1-2 showed a high conversion rate of about 40% or more compared to Comparative Examples 1-1 to 1-4, and it was confirmed that products with a purity of about 99% or more were obtained, thereby confirming their suitability as solvents.
  • the respective conversion rates were 39% and 26%, which were lower values than Examples 1-1 and 1-2.
  • chloride-based organic solvents aromatic hydrocarbon-based solvents, and aliphatic hydrocarbon-based solvents are suitable as solvents for hydrolysis reactions, while ketone-based solvents, amide-based solvents, ester-based solvents, and ether-based solvents are unsuitable.
  • the yield represents the actual mass% of octadecanedioic acid-mono-tert-butyl-ester obtained through the post-treatment process after the reaction is completed.
  • Examples 2-2, 2-3, and 2-4 showed relatively fast reactions compared to Example 2-1; however, in Example 2-3, the solution discolored during the reaction, and the product obtained was not decolorized. Examples 2-2 and 2-4 had relatively fast reaction rates, and if the analysis time during the reaction is long, a lot of by-products are generated, so the process risk is high compared to Example 2-1.
  • the conversion rate, yield, and purity of the product obtained in Example 2-1 were 48%, 45%, and 99.5%, respectively, confirming that the zinc bromide of Example 2-1 was the most suitable catalyst for the hydrolysis reaction.
  • ZnBr 2 was used in amounts of 0.2 mmol, 0.5 mmol, and 1.0 mmol, respectively, and the reaction was carried out for 12 hours, 24 hours, and 36 hours, respectively, for each amount of ZnBr 2 .
  • the reaction temperature was 25°C, and 3.1 mL of dichloromethane was used as a solvent.
  • the obtained octadecanedioic acid-mono-tert-butyl ester was analyzed by HPLC to measure the conversion rate and purity, which are shown in Table 3 below:
  • Example 3-1 0.5 12 34 99.4 30
  • Example 3-2 0.5 24 48 99.5 45
  • Example 3-3 0.5 36 35 92.5 28
  • Example 3-4 1.0 12 27 91.0 22
  • Comparative Example 3-1 0.2 12 12 95.0% or more 10
  • Comparative Example 3-2 0.2 24 17 95.0% or more 13
  • Comparative Example 3-3 0.2 36 20 95.0% or more 15
  • Examples 3-1 to 3-4 all showed a purity of 90% or higher, and among these, Example 3-2 showed the best hydrolysis activity with a conversion rate of 48% and a purity of 99.5%, whereas Comparative Examples 3-1 to 3-5 showed very low conversion rates of 20% or less. Accordingly, it was experimentally confirmed that the appropriate amount and reaction time of ZnBr 2 used in the hydrolysis reaction were 0.5 equivalents and 24 hours, respectively.
  • the HPLC analysis result showed that the ratio of the starting material (di-tert-butyl-octadecanedioate) of the hydrolysis reaction and the target product (octadecanedioic acid-mono-tert-butyl ester) in the filtrate was measured to be 95:5.
  • the mass of the filtrate was measured to be 55 g, and accordingly, the mass of the starting material contained in the filtrate was confirmed to be 52.3 g (0.123 mol).
  • Example 5-1 The hydrolysis reaction was performed on the filtrate of Example 5-1 in the same manner as in Example 4-3 to additionally obtain the target product (Example 5-2).
  • the hydrolysis reaction was performed in the same manner on the filtrate of Example 5-2 (Example 5-3), and the hydrolysis reaction was performed in the same manner on the filtrate of Example 5-3 (Example 5-4).
  • a recovery process of repeatedly performing the same hydrolysis reaction on the filtrate generated after each hydrolysis reaction was performed, and a total of four recovery processes were performed on the filtrate of Example 4-3.
  • the yields and purities of Example 4-3 and Examples 5-1 to 5-4 are as shown in Table 5 below:
  • Example 6-1 16-(tert-butoxy)-16-oxohexadecanoic acid (CAS No. 843666-27-3) 89 99.3% to 99.9% D 1.25(m, 20 H); 1.44(s, 8 H); 1.59(m, 4H), 2.27(m, 4H)
  • Example 6-2 13 17-(tert-butoxy)-17-oxoheptadecanoic acid (CAS No.

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Abstract

La présente demande concerne un procédé de préparation d'un hydrocarbure saturé estérifié de mono-tert-butyle, et un procédé de préparation cyclique associé. Le procédé de préparation d'un hydrocarbure saturé estérifié de mono-tert-butyle, selon des modes de réalisation de la présente demande, comprend des procédés qui sont plus faciles que ceux d'un procédé classique et peuvent être mis en œuvre dans des conditions modérées. Contrairement à un procédé classique, le procédé de préparation d'un hydrocarbure saturé estérifié de mono-tert-butyle, selon des modes de réalisation de la présente demande ne génère pas d'impuretés, et permet ainsi d'isoler et d'obtenir facilement un hydrocarbure saturé estérifié de mono-tert-butyle.
PCT/KR2024/005933 2023-05-10 2024-05-02 Procédé de préparation d'hydrocarbure saturé estérifié de mono-tert-butyle, et procédé de préparation cyclique associé Pending WO2024232593A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110306551A1 (en) * 2009-02-19 2011-12-15 Novo Nordisk A/S Modification of Factor VIII
CN113061086A (zh) * 2020-01-02 2021-07-02 南京药石科技股份有限公司 一种长链脂肪二羧酸单叔丁酯的制备方法
CN113773200A (zh) * 2021-09-14 2021-12-10 郑州猫眼农业科技有限公司 戊二酸单叔丁酯的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110306551A1 (en) * 2009-02-19 2011-12-15 Novo Nordisk A/S Modification of Factor VIII
CN113061086A (zh) * 2020-01-02 2021-07-02 南京药石科技股份有限公司 一种长链脂肪二羧酸单叔丁酯的制备方法
CN113773200A (zh) * 2021-09-14 2021-12-10 郑州猫眼农业科技有限公司 戊二酸单叔丁酯的制备方法

Non-Patent Citations (2)

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Title
KAUL RAMESH, BROUILLETTE YANN, SAJJADI ZOHREH, HANSFORD KARL A., LUBELL WILLIAM D.: "Selective tert -Butyl Ester Deprotection in the Presence of Acid Labile Protecting Groups with Use of ZnBr 2", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, UNITED STATES, vol. 69, no. 18, 1 September 2004 (2004-09-01), United States, pages 6131 - 6133, XP093235837, ISSN: 0022-3263, DOI: 10.1021/jo0491206 *
WU, Y.-Q. LIMBURG, D.C. WILKINSON, D.E. VAAL, M.J. HAMILTON, G.S.: "A mild deprotection procedure for tert-butyl esters and tert-butyl ethers using ZnBr"2 in methylene chloride", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 41, no. 16, 1 April 2000 (2000-04-01), AMSTERDAM, NL, pages 2847 - 2849, XP004195685, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)00300-2 *

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