WO2014019166A1 - Procédé de production industrielle pour composé borane de haute activité - Google Patents

Procédé de production industrielle pour composé borane de haute activité Download PDF

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Publication number
WO2014019166A1
WO2014019166A1 PCT/CN2012/079499 CN2012079499W WO2014019166A1 WO 2014019166 A1 WO2014019166 A1 WO 2014019166A1 CN 2012079499 W CN2012079499 W CN 2012079499W WO 2014019166 A1 WO2014019166 A1 WO 2014019166A1
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WIPO (PCT)
Prior art keywords
borane
ether
solution
solvent
complex
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PCT/CN2012/079499
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English (en)
Chinese (zh)
Inventor
魏彦君
于向达
赵欢
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上海威智医药科技有限公司
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Priority to PCT/CN2012/079499 priority Critical patent/WO2014019166A1/fr
Publication of WO2014019166A1 publication Critical patent/WO2014019166A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • the present invention relates to a process for the preparation of a borane compound, and more particularly to an industrial process for producing a highly active borane compound.
  • Highly active borane compounds are those having a strong reducing ability, including borane complexes such as an alkane tetrahydrofuran complex, a borane dimethyl sulfide complex, a borane t-butylamine complex, Borane N,N-diethylaniline complex, borane trimethylamine complex, borane pyridine complex, borane amine complex, borane triethylamine complex, etc.; additionally, high activity boron
  • the alkane compound also includes higher borane compounds such as trialkylboron, catechol borane, pinacol borane, 9-BBN alkane, diisopinazinylborane, diisopinyl chloroboron.
  • Alkane (DPC), etc. wherein the trialkyl boron includes: triethylboron, dipropylboron, tributylboron, and these compounds can spontaneously ignite or even explode when exposed to air.
  • Highly active borane compounds have high chemical activity and toxicity, and their stability is poor. They can spontaneously ignite when exposed to air. They may cause burning when exposed to fire, heat, friction and impact. If they are exposed to high heat, they may cause violent decomposition and cause containers. A rupture or explosion accident; reacting with water and water vapor, releasing hydrogen that is explosive and igniting.
  • Highly active borane compounds are highly toxic to humans and can strongly irritate mucous membranes, upper respiratory tract, eyes and skin. After inhalation, it can be caused by paralysis of the throat and bronchi, inflammation, edema, chemical pneumonia and pulmonary edema.
  • a laboratory scale synthesis method for preparing a tetrahydrofuran solution of a diborane tetrahydrofuran solution and a borane dimethyl sulfide complex is provided in U.S. Patent No. 3,634,277 and U.S. Patent No. 4,320,027, which are incorporated herein by reference. The reaction was carried out to synthesize a borane tetrahydrofuran solution.
  • Chinese patent 200410084444. 4 reports a new method for preparing a solution of borane tetrahydrofuran complex, in which a low-cost potassium borohydride and lithium chloride are firstly reacted in tetrahydrofuran to obtain lithium borohydride, lithium borohydride. Further, it is reacted with a boron trifluoride diethyl ether complex to obtain diborane. The diborane is immediately combined with tetrahydrofuran in the reaction system to form a borane tetrahydrofuran complex, and then the solid waste is removed by filtration.
  • the existing technology lacks a treatment method for synthesizing high-activity borane compound solid waste, which is very active, spontaneously ignites or even explodes when exposed to air or moisture, and is toxic.
  • the technical problem to be solved by the present invention is to provide an industrial production method of a highly active borane compound.
  • the method solves the problem of treating toxic, flammable and explosive wastes generated during the production of highly active borane compounds, and the industrialization method is a safe, environmentally friendly, low-cost method for synthesizing highly active borane compounds.
  • an industrial production method of a borane compound (highly active borane compound) of the present invention wherein the borane compound comprises: a borane complex or a higher borane compound
  • the industrial production includes the steps of: (1) in an ether solvent, boron trifluoride ether is reacted with a borohydride to form a borane (gas) and a reaction waste;
  • the ortho-dihydroxy compound comprises: catechol or pinacol;
  • the olefin compound comprises: a linear olefin of C2 ⁇ 4, 1, 5-cyclooctadiene, a terpene, wherein the terpene comprises: (+) - ⁇ Terpene, (-)- ⁇ -decene;
  • the preferred borane compound solution comprises: a catechol borane solution, a pinacol borane solution, a trialkylboron solution, a 9-fluorene borane solution, a diisopinazinylborane solution or a diisosyllium group. Further preparing a solution of diisopinolylchloroborane in a borane solution;
  • a quenching agent is added to the reaction waste of the step (1) to form a treatment liquid to remove borane.
  • the method further comprises the steps of: (4) filtering or centrifuging the treatment liquid formed in the step (3) to recover an ether solvent to remove residual quencher, borate and borate.
  • ether means any chemical structure having one oxygen atom bonded to two carbon atoms.
  • "Ether solvent” means present in liquid form at the temperatures required by the process.
  • the ether solvent suitable for the process disclosed in the present invention includes those ether solvents which do not dissolve or slightly dissolve borane, and include, for example, one of a linear ether, a cyclic ether or a mixture thereof; wherein the linear ether includes: diethyl ether, One or more of methyl tert-butyl ether, diisopropyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether; cyclic ethers include: tetrahydrofuran, 1, 4-dioxane One or two of the rings.
  • the ratio of the volume of the ether solvent to the number of moles of the borohydride is 0. 2 ⁇ 2. 0L : lmol o
  • the borohydride refers to those borohydrides which can react with boron trifluoride or its complex boron trifluoride diethyl ether to produce borane, including: lithium borohydride, sodium borohydride or One or more of potassium borohydride, preferably sodium borohydride. ⁇ 8.
  • the reaction temperature is -5 to 35 ° C, and the reaction time varies depending on the scale of the reaction, and is usually 1. 5 to 30 hours.
  • the first solvent comprises: tetrahydrofuran, dimethyl sulfide, t-butylamine, N,N-diethylaniline, trimethylamine, pyridine, ammonia or triethylamine;
  • the borane complex comprises: borane tetrahydrofuran a complex, a borane dimethyl sulfide complex, a borane t-butylamine complex, a borane N,N-diethylaniline complex, a borane trimethylamine complex, a borane pyridine complex, Borane amine complex or borane triethylamine complex.
  • the second solvent comprises: tetrahydrofuran or dimethyl sulfide;
  • the reaction temperature is -20 to 30 ° C, and the molar ratio of catechol to borane is 0.95 to 1. 2: 1; when the pinacol is added, the reaction temperature is - 20 ⁇ 30°C, the molar ratio of pinacol to borane is 0. 95 ⁇ 1. 2: 1; when adding C2 ⁇ 4 linear olefin (such as ethylene, propylene), depending on the reactivity of the olefin, the reaction Temperature can be 00.
  • the ratio of the molar ratio of linear olefin to borane is 3. 0 ⁇ 6. 0 : 1 ;
  • reaction temperature is 60 to 100 ° C, and the molar ratio of 5-cyclooctadiene to borane is 0 ⁇ 95 ⁇ 1 ⁇ 2:1;
  • the reaction temperature is -20 to 30 ° C, and the molar ratio of the terpene to the borane is 2. 1 to 2. 5: 1, wherein the terpene is preferably ⁇ -pinene.
  • the solvent of the higher borane compound is removed by distillation to obtain a higher borane compound, such as a catechol borane solution, a pinacol borane solution, a trialkylboron solution, 9- ⁇ .
  • a borane solution or a diisossonylborane solution is used to remove the solvent by distillation to obtain catechol borane, pinacol borane, trialkylboron, 9-decaneborane or diisopinylboron.
  • a hydrogen chloride gas may be introduced, wherein the hydrogen chloride is added in the following amounts: hydrogen chloride and diisopinazinylborane
  • the molar ratio of the solution is 0. 95 ⁇ 1.
  • 02: 1 a solution of diisopinyl chloroborane is obtained, and the solution of the diisopinyl chloroborane can also be removed by distillation to obtain diisosyllium. Chloroborane.
  • the diisopinocampheylchloroborane can be dissolved in a heptane or hexane solution according to commercial requirements to obtain a solution of diisopinolylchloroborane heptane or hexane.
  • the reaction waste contains residual borane, which can be understood by those skilled in the art.
  • Borane especially diborane in gaseous state, is an extremely flammable, explosive and toxic gas. If it is directly treated by filtration, it will cause great harm to the operator's body, and it is prone to spontaneous combustion or even explosion. There is a huge security risk. Even if the filter press can be protected by an inert gas, the final mother liquor treatment is extremely risky and cumbersome to operate.
  • the reaction mother liquid should be sufficiently reacted with the quencher before contact with air to remove the highly active borane and then subjected to subsequent operations to solve the above technical problems.
  • the quencher is an alcohol or ketone solvent, including: acetone or one to five carbon (C1 ⁇ C5) alcohol solvents, including: acetone, methanol, ethanol, isopropanol, n-propanol, n-butanol, One or more of sec-butanol, tert-butanol, and pentanol can achieve the effect of quenching the active borane to borate.
  • the molar ratio of the quencher to the borohydride is preferably 0.05 to 1. 5: 1, to ensure that the active borane has been completely converted into a borate analog, and then spontaneously ignited with air or moisture, no longer on the human body. Produces large toxic side effects.
  • the invention solves the problem that the borane production waste is toxic, flammable and explosive by adding a quenching agent, and can realize the recycling of the solvent.
  • the filtration method is preferably a water-repellent filtration; the method for recovering the ether solvent is distillation; wherein, the end point of the distillation is acetone or the alcohol solvent content is less than 0.5%, and the ether solvent is recycled and utilized. 05% ⁇ The ether content of the solvent is more than 96%, water content of 0. 05% or less.
  • Catechol borane, pinacol borane, trialkyl boron, 9-BBN borane, diisopinyl borane, diisopinyl chloroborane, etc. are very common in organic synthesis and drug synthesis. A wide range of applications.
  • Borane dimethyl sulfide and borane tetrahydrofuran complexes are synthetic catechol borane, pinacol borane, trialkyl boron, 9-BBN borane, diisopinyl borane, diisosyllium Chloroborane
  • the raw material, and in the present invention, the borane gas produced can be directly reacted with catechol, pinacol, C2 ⁇ 4 linear olefin, 1, 5-cyclooctadiene, terpene raw material without synthesis, and synthesized.
  • the invention synthesizes a highly active borane compound by adopting a basic raw material, and solves the problem of toxic, flammable and explosive of borane production waste by adding a quenching agent, and can realize solvent recycling and reduction.
  • the production cost of the above-mentioned advanced high-activity borane compound solves the toxic and side effects of the production waste of the product, eliminates the safety hazard in the actual industrial production, and solves the environmental protection problem.
  • the preparation method of catechol borane, pinacol borane, trialkyl boron, 9-BBN borane, diisoxanthyl borane, diisopinyl chloroborane is also simple and convenient. .
  • the present invention is suitable for industrialized large-scale production, and solves the technical problem that the high-activity borane compound (including: borane complex and high-grade borane compound) is dangerous and toxic, difficult to handle, and has simple operation and low cost. , production safety, environmental protection and other advantages.
  • the high-activity borane compound including: borane complex and high-grade borane compound
  • a borohydride was added to a nitrogen-protected 200 liter glass-lined reactor, an ether solvent was added, and a gas tube was connected to another 100 liter reactor.
  • the 100 liter reactor was maintained at an internal temperature of -20 to 35 °C. 5 ⁇ 6 ⁇ After the addition of the mixture was continued to 0. 5 ⁇ 6 0 ⁇ , until the reaction is complete (reaction time varies depending on the scale of the reaction, usually 1. 5 ⁇ 30 hours), close the ventilation catheter.
  • a ketone or alcohol solvent is added to the 200 liter autoclave to remove residual high activity borane until no more gas is generated, stirring is continued for 2 to 4 hours, discharging, filtration or centrifugation to obtain a mixed solvent.
  • the mixed solvent recovers the ether solvent by distillation.
  • the 100 liter reactor was a solution of the borane complex product. The recovered ether solvent can be recycled throughout the reaction.
  • borane is continuously reacted with catechol, pinacol, C2 ⁇ 4 linear olefin, 1,5-cyclooctadiene, ⁇ -pinene in a solvent to obtain a higher borane compound.
  • the solution of the product is subjected to a corresponding treatment (e.g., distillation, etc.) to obtain a higher borane compound.
  • the borane reaction waste in a 100 liter reaction vessel while stirring, slowly adding 3 kg of ethanol through a dropping tank, stirring until gas is no longer generated, stirring is continued for 3.0 hours, and water is filtered to obtain an organic solvent 100.
  • l containing ethanol, ether, triethyl borate and ethylene glycol dimethyl ether.
  • the organic solvent is distilled under normal pressure, and the solvent is recovered.
  • the recovery requirement is 97% of ethylene glycol dimethyl ether (measured by gas chromatography), and the ethanol content is 0.5% (measured by gas chromatography), and the water content is 0. 05% (determined by Karl Fischer method).
  • the 200 liter autoclave was stirred once every 4 hours, stirred once for 15 minutes, and after standing still for 15 hours, tetrahydrofuran was removed by filtration to obtain diisopinylborane. 5 ⁇ 1
  • the molar ratio of hydrogen chloride to borane complex is 0. 95 ⁇ 1
  • the molar ratio of hydrogen chloride to borane is 0. 95 ⁇ 1 02: 1, until the reaction system is clarified, a tetrahydrofuran solution containing diisopinyl chloroborane can be obtained, and distilled under reduced pressure to obtain diisossonyl chloroborane in a content of 97% (conventional Titration method).
  • the borane reaction waste in a 100 liter reaction vessel while stirring, slowly adding 3 kg of ethanol through a dropping tank, stirring until gas is no longer generated, stirring is continued for 3.0 hours, and water is filtered to obtain an organic solvent 100.
  • l containing ethanol, ether, triethyl borate and diethylene glycol dimethyl ether.
  • the organic solvent is distilled under normal pressure, and the solvent is recovered.
  • the recovery requirement is 97% of diethylene glycol dimethyl ether (measured by gas chromatography), and the ethanol content is 0.5% (determined by gas chromatography), and the water content is 0. 05% (determined by Karl Fischer method).
  • the method of synthesizing the higher borane compound is carried out as follows:
  • borane is continuously reacted with ethylene in a tetrahydrofuran solvent at an internal temperature of -5 to 20 ° C for 5 hours to obtain a triethylboron solution, which is distilled to obtain triethylboron. It is 97% (determined by gas chromatography).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

L'invention porte sur un procédé de production industrielle pour un composé borane de haute activité, comprenant : 1) la réaction d'éther de diéthyle et de trifluorure de bore avec un borohydrure dans un solvant éther, pour former du borane et un rejet de réacteur ; 2) la dissolution du borane dans un premier solvant, pour former un complexe de borane disponible pour une utilisation commerciale ; ou après dissolution du borane dans un second solvant, l'ajout d'un composé hydroxyle ou d'un composé oléfine pour réaction, pour former une solution de composé borane supérieur ; et 3) l'ajout d'un agent d'extinction au rejet de réacteur de l'étape 1), pour former une solution de traitement. La présente invention est applicable à une production en masse industrialisée, permet de résoudre le problème technique consistant en ce que le rejet de production du composé borane de haute activité est toxique et dangereux et, par conséquent, difficile à traiter, et elle a également un fonctionnement simple, de faibles coûts, une production sans danger et est respectueuse de l'environnement.
PCT/CN2012/079499 2012-08-01 2012-08-01 Procédé de production industrielle pour composé borane de haute activité WO2014019166A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108059579A (zh) * 2017-10-23 2018-05-22 上海福乐医药科技有限公司 一种含稳定剂的硼烷试剂组合溶液、其制备方法及用途
CN108456220A (zh) * 2018-02-11 2018-08-28 乐山师范学院 一种制备氯代二(五氟苯基)硼烷的方法
US20220234990A1 (en) * 2015-07-24 2022-07-28 Celgene Corporation Methods of synthesis of (1r,2r,5r)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein

Citations (4)

* Cited by examiner, † Cited by third party
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CN85100257A (zh) * 1985-04-01 1986-08-06 武汉大学 基本硼氢化试剂甲硼烷甲硫醚配合物的简便合成方法
US5292946A (en) * 1990-09-24 1994-03-08 Merck & Co., Inc. In-situ preparation of diisopinocamphenyl chloroborane
US5567849A (en) * 1995-05-09 1996-10-22 Aldrich Chemical Company, Inc. Borane-sulfide hydroboration agents
WO2007030721A2 (fr) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Procedes pour preparer (3r,4s)-4-((4-benzyloxy)phenyle)-1-(4-fluorophenyle)-3-((s)-3-(4-fluorophenyle)-3-hydroxypropyle)-2-azetidinone, un intermediaire pour la synthese de l'ezetimibe

Patent Citations (4)

* Cited by examiner, † Cited by third party
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CN85100257A (zh) * 1985-04-01 1986-08-06 武汉大学 基本硼氢化试剂甲硼烷甲硫醚配合物的简便合成方法
US5292946A (en) * 1990-09-24 1994-03-08 Merck & Co., Inc. In-situ preparation of diisopinocamphenyl chloroborane
US5567849A (en) * 1995-05-09 1996-10-22 Aldrich Chemical Company, Inc. Borane-sulfide hydroboration agents
WO2007030721A2 (fr) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Procedes pour preparer (3r,4s)-4-((4-benzyloxy)phenyle)-1-(4-fluorophenyle)-3-((s)-3-(4-fluorophenyle)-3-hydroxypropyle)-2-azetidinone, un intermediaire pour la synthese de l'ezetimibe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BROWN, H.C. ET AL.: "Hydroboration. 45. New, Convenient Preparations of Representative Borane Reagents Utilizing Borane-Methyl Sulfide", J. ORG. CHEM., vol. 2, no. 8, 1977, pages 1392 - 1398 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220234990A1 (en) * 2015-07-24 2022-07-28 Celgene Corporation Methods of synthesis of (1r,2r,5r)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein
US11780801B2 (en) * 2015-07-24 2023-10-10 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein
CN108059579A (zh) * 2017-10-23 2018-05-22 上海福乐医药科技有限公司 一种含稳定剂的硼烷试剂组合溶液、其制备方法及用途
CN108456220A (zh) * 2018-02-11 2018-08-28 乐山师范学院 一种制备氯代二(五氟苯基)硼烷的方法

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