WO2009004350A1 - Procédé de préparation du bortézomib et intermédiaires utilisés dans sa préparation - Google Patents

Procédé de préparation du bortézomib et intermédiaires utilisés dans sa préparation Download PDF

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Publication number
WO2009004350A1
WO2009004350A1 PCT/GB2008/002302 GB2008002302W WO2009004350A1 WO 2009004350 A1 WO2009004350 A1 WO 2009004350A1 GB 2008002302 W GB2008002302 W GB 2008002302W WO 2009004350 A1 WO2009004350 A1 WO 2009004350A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
acid
lithium
bortezomib
Prior art date
Application number
PCT/GB2008/002302
Other languages
English (en)
Inventor
Michal Janca
Petr Dobrovolny
Original Assignee
Pliva Hrvatska D.O.O.
Bucks, Teresa Anne
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pliva Hrvatska D.O.O., Bucks, Teresa Anne filed Critical Pliva Hrvatska D.O.O.
Publication of WO2009004350A1 publication Critical patent/WO2009004350A1/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
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention relates generally to the synthesis of boronic acid and ester compounds.
  • it relates to the preparation of bortezomib and intermediates for the preparation of bortezomib.
  • Bortezomib also known as N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine boronic acid, is a biologically active compound having the following structure.
  • Bortezomib is an N-acylated dipeptide analog of phenylalanyl-leucine in which
  • B(OH) 2 replaces the C-terminal carboxylic acid.
  • bortezomib acts to inhibit proteasome and has been clinically approved for use in treating mantle cell lymphoma and multiple myeloma. Bortezomib has been previously prepared as disclosed in U.S. Patent Publication 2005/020047 ('047 application).
  • FIGURE 1 shows a process for preparation of bortezomib as described herein.
  • Figure I shows a synthetic route to bortezomib from a compound of formula I using methods of the invention. Briefly, the known boronic acid ester having formula I is halogenated by exposure to a lithium amide base, dichloromethane, and a Lewis acid in THF to give a compound of formula II.
  • the latter compound is converted to the silyl amine (formula III) using a salt of hexamethyldisilazane and then to the ammonium salt (formula IV) upon exposure to a suitable acid.
  • a salt of the N-pyrazinyl-phenylalanine (formula V) is then coupled to the compound of formula IV without the use of any additional base to give the boronate ester of formula VI.
  • the pinanediol ester group is removed under acidic conditions to give the boronic acid, bortezomib (formula VII).
  • the product obtained from the present method improves not only the yield and purity of the compound of formula II, but also the yield and purities of the final product, bortezomib, compared to the use of other solvents (such as tert-butyldimethylether) or lower percentages of THF.
  • the invention provides methods for preparing a compound of formula II comprising exposing a compound of formula I
  • the solvent comprises about 95.5 % tetrahydrofuran and about 4.5% dichloromethane by volume.
  • the compound of formula II was prepared in 91-95% yield and contained only 3-5% starting material.
  • the method used in the '047 application provided the compound of formula II in only 77-85% yield and contained 10-15% starting material.
  • lithium amide bases for such reactions include, but are not limited to, lithium diisopropyl amide, lithium diethylamide, and lithium dimethylamide. Typical concentrations of the lithium amide base used in the present reaction may range from about 0.5 M to about 2 M.
  • suitable Lewis acids for use in the present reaction include transition metal halide such as, but not limited to, ZnCl 2 , ZnBr 2 , FeBr 3 , FeCl 3 , or a mixture of any two or more thereof.
  • the present transformation may be carried out a temperature ranging from about -70 °C to about 10 0 C.
  • the present halogenation is carried out, at least initially, at a temperature ranging from about -70 0 C to about -60 0 C.
  • the present methods of synthesizing bortezomib may further include exposing the compound of formula II to the salt of a silylamine such as, e.g., lithium hexamethyldisilazane, sodium hexamethyldisilazane, or potassium hexamethyldisilazane, under conditions suitable to provide a compound of formula III
  • a silylamine such as, e.g., lithium hexamethyldisilazane, sodium hexamethyldisilazane, or potassium hexamethyldisilazane
  • Suitable conditions for the formation of the compound of formula III include carrying out the reaction in a solvent comprising tetrahydrofuran or a mixture of tetrahydrofuran and methylcyclohexane. Formation of the silylamine may be carried out at temperatures ranging from -60°C to 30°C or from -30°C to 30°C. In some embodiments, the temperature ranges from -20 0 C to about 25 0 C.
  • the compound of formula III was obtained in 89-93% yield and containing 0.6-0.8% of an isomer of the compound of formula III. In contrast, preparation of the compound of formula III according to the method disclosed in the '047 patent resulted in only 75-80% yield and contained 8-10% of the second isomer.
  • Methods of preparing bortezomib may further include contacting the compound of formula III with a suitable acid to provide a compound of formula IV
  • Suitable acids for desilylation of silylamines are known in the art and include those strong enough to remove the silyl groups without substantially degrading the reactant (formula III) or product (formula IV).
  • suitable acids include but are not limited to C 1-10 alkanoic acids such as formic and acetic acids, C 2-10 perhaloalkanoic acids such as trifluoroacetic acid and trichloroacetic acid, HCl, HBr, or C 1-6 sulfonic acids such as methanesulfonic acid and triflic acid.
  • trifluoroacetic acid is used.
  • Formation of the compound of formula IV may be carried out at temperatures ranging from about -30°C to about 25°C over the course of 0.5 to 2.5 hours.
  • the purity of the compound of formula IV produced by present methods was 99.8% or greater with only 0.04-0.1% of a second isomer of the compound produced.
  • the process disclosed in the '047 application yielded a purity of only 87-94% and a content of 5-6% of a second isomer of the compound of formula IV.
  • bortezomib is a convergent synthesis in which the ammonium compound of formula IV is coupled to a phenylalanine derivative of formula V.
  • the latter compound may be readily made using standard techniques.
  • a suitably C- protected derivative of phenylalanine e.g. the phenylalanine methyl ester may be coupled to pyrazine carboxylic acid using any standard technique for the formation of amide bonds, particularly those used in peptide synthesis.
  • the resulting ester of N-(pyrazine-2-ylcarbonyl)-L- phenylalanine may be hydrolyzed to give the corresponding salt (formula V), which may be used for coupling with the compound of formula IV.
  • Methods of hydrolysis are well known in the art and typically include exposing an ester to a solution of metal hydroxide in water, alcohol, or mixtures of water and various alcohols or other organic solvents.
  • the present methods may further include contacting a compound of formula V
  • Z is a lithium, sodium, potassium, rubidium, calcium, or magnesium cation
  • the coupling may be effected with any suitable agent for amide bond formation such as coupling agents used for peptide synthesis.
  • suitable agent for amide bond formation such as coupling agents used for peptide synthesis.
  • Such coupling agents include but are not limited to TBTU, DIP, DCC, EDC, HBTU, HCTU, TCTU 5 HATU, PyBOP, and PyABOP.
  • Use of the compound of formula V, i.e., a salt of the carboxylic acid advantageously avoids the use of an organic amine as a base and provides superior yields to known methods of forming the compound of formula VI.
  • the present methods of synthesis of bortezomib may include exposing a compound of formula VI to a sufficient amount of acid to produce a compound of formula VII or its cyclic anhydride
  • HCl, HBr, or combinations of HCl and/or HBr with a boronic acid such as 2- methylpropylboronic acid may be used.
  • the reaction is conducted in the presence of a non-polar solvent in which pinanediol is soluble but the product boronic acid is not.
  • Step 2 (IS)-(S) -Pinanediol l-chloro-3-methylbutane-l-boronate
  • reaction mixture was warmed up to -45 °C and stirred at this temperature for 30 minutes.
  • the mixture was further warmed to 10°C over a period of 90 minutes.
  • 10% H 2 SO4 33.0 ml was added and mixture warmed up to 25 0 C.
  • tert-Buthylmethyl ether (36.0 ml) was added and mixture was transferred to separatory funnel.
  • the jacketed (250 ml) flask was washed with 20.0 ml of water and layers were separated.
  • the organic layer was extracted with 90.0 ml H 2 O; 90.0 ml H 2 O + 0.5ml 10% H 2 SO 4 , 90.0 ml H 2 O + 1.5ml 10% H 2 SO 4 ; 90.0 ml +1.5ml 10% H 2 SO 4 ; 90.0 ml 10% NaCl.
  • Step 3 (1R ⁇ )-(S * )-Pinanediol 1 bis(trimethylsilyl ' )amino-3-butane-l-boronate
  • the mixture was warmed up to -15°C and stirred for 65 minutes. The mixture was further warmed up to 25°C over a period of 25 minutes. The resulting mixture was transferred to a 250 ml flask and the jacketed (250 ml) flask was washed 2 x 5 ml hexane + 30 ml hexane and the resultant solution was concentrated to dryness under vacuum at 50 0 C. 10 ml of hexane was used for the preparation of a suspension of 0.78 g CELITE which was transferred to a filtration apparatus with a PTFE filter (45 ⁇ m). The product was dissolved in 30 ml of hexane and filtered through CELITE.
  • Step 5 Recrystallization of (lR " )-(SVPinanediol-l-ammoniumtrifluoroacetate-3-methylbutane- 1-boronate
  • the mixture was then cooled down to -5°C and stirred for 150 minutes. From - 5 0 C the mixture was warmed to 20°C and filtered. The jacketed flask was washed with 2 x 27.8 ml of isopropylether, filtered, and the filter cake was washed with 27.8 ml of isopropylether. The title product was dried in vacuo at 45 0 C to provide white woolly crystals (4.0 g, yield 74.4 %, under analytical evaluation).
  • Step 1 Methylester ofN-(pyrazin-2-yl-carbonyl)-L-phenylalanine
  • Step 2 N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine sodium salt
  • Step 1 (IR)-(S)- Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenylalanine-L-leucine boronate
  • N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine sodium salt (1.8 g) and TBTU (2.2 g) were suspended in dichloromethane (115 ml ) in a beaker. The suspension was charged to a jacketed flask and the beaker was washed with dichloromethane (115 ml). The suspension was cooled to 0°C and stirred for 30 minutes.
  • the mixture was extracted with 2 x 230 ml H 2 O, 2 x 230 ml 1% H 3 PO 4, 1 x 230 ml and 1 x 195 ml 2% K 2 CO 3, 2 x 230 ml 10% NaCl , 2 x 230 ml H 2 O.
  • the organic layer was transferred to a 500 ml flask and dried over Na 2 SO 4 (26.5 g) which was subsequently filtered off and washed with 100 ml dichloromethane.

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

Abstract

L'invention concerne des procédés de préparation du bortézomib et des intermédiaires utilisés dans sa préparation. Lesdits procédés fournissent de façon inattendue des rendements et des puretés élevés, notamment des puretés optiques pour le bortézomib et des intermédiaires pour sa préparation.
PCT/GB2008/002302 2007-07-03 2008-07-02 Procédé de préparation du bortézomib et intermédiaires utilisés dans sa préparation WO2009004350A1 (fr)

Applications Claiming Priority (2)

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US94783807P 2007-07-03 2007-07-03
US60/947,838 2007-07-03

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WO2009004350A1 true WO2009004350A1 (fr) 2009-01-08

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2185159A2 (fr) * 2007-09-12 2010-05-19 Dr. Reddy's Laboratories, Ltd. Bortézomib et procédé de production de celui-ci
CN101812026A (zh) * 2010-04-12 2010-08-25 孙江涛 一种硼替佐米的合成方法
CN101899062A (zh) * 2009-05-26 2010-12-01 上海威智医药科技有限公司 α-手性硼酸及硼酸酯的合成工艺
WO2010146172A2 (fr) 2009-06-19 2010-12-23 Lek Pharmaceuticals D.D. NOUVELLE TECHNIQUE DE SYNTHÈSE POUR LA PRÉPARATION DE DÉRIVÉS D'ACIDE α-AMINOBORONIQUE PAR L'INTERMÉDIAIRE D'ALK-1-YNES SUBSTITUÉES
EP2270019A1 (fr) 2009-06-19 2011-01-05 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation d'esters boronique alpha-aminé
EP2280016A1 (fr) 2009-07-27 2011-02-02 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation d'esters boroniques aminés via des Alk-1-ynes substitués
WO2011098963A1 (fr) 2010-02-09 2011-08-18 Ranbaxy Laboratories Limited Procédé de préparation de bortézomib
EP2377868A1 (fr) * 2004-03-30 2011-10-19 Millennium Pharmaceuticals, Inc. Synthèse de Bortezomib
WO2012048745A1 (fr) 2010-10-14 2012-04-19 Synthon Bv Procédé pour la fabrication de bortézomib et intermédiaires pour le procédé
CN102675415A (zh) * 2012-05-11 2012-09-19 武汉人福医药集团股份有限公司 制备硼替佐米的方法
CN103012551A (zh) * 2012-12-14 2013-04-03 江苏奥赛康药业股份有限公司 一种高纯度硼替佐米的合成方法及其中间体
CN103044468A (zh) * 2012-11-28 2013-04-17 深圳万乐药业有限公司 N-(2-吡嗪羰基)-l-苯丙氨酸-l-亮氨酸硼酸的制备方法
CN103204867A (zh) * 2012-01-14 2013-07-17 成都爱群科技有限公司 手性氨基硼酸酯及制备方法与其在硼替佐米合成中的应用
US8497374B2 (en) 2011-05-12 2013-07-30 Scinopharm Taiwan, Ltd. Process for preparing and purifying bortezomib
WO2014170628A1 (fr) 2013-04-16 2014-10-23 Cipla Limited Procédé pour la préparation d'ester de mannitol du bortézomib
CN104387409A (zh) * 2012-05-11 2015-03-04 人福医药集团股份公司 催化剂及其应用
KR20150066724A (ko) * 2013-12-09 2015-06-17 주식회사 경보제약 보르테조밉의 제조방법 및 그의 신규 중간체
US9505787B2 (en) 2012-09-11 2016-11-29 Cipla Limited Process for preparing of bortezomib
WO2018150386A1 (fr) 2017-02-17 2018-08-23 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation d'esters d'acide boronique
CN117820347A (zh) * 2024-03-06 2024-04-05 深圳智微通科技有限公司 一种连续流合成硼替佐米的方法

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US4525309A (en) * 1983-03-15 1985-06-25 Washington State University Research Foundation, Inc. Lewis acid catalysis of the homologation of boronic esters with haloalkylmetal reagents
WO2005097809A2 (fr) * 2004-03-30 2005-10-20 Millennium Pharmaceuticals, Inc. Synthese d'ester borique et de composes acides

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US4525309A (en) * 1983-03-15 1985-06-25 Washington State University Research Foundation, Inc. Lewis acid catalysis of the homologation of boronic esters with haloalkylmetal reagents
WO2005097809A2 (fr) * 2004-03-30 2005-10-20 Millennium Pharmaceuticals, Inc. Synthese d'ester borique et de composes acides
US20050240047A1 (en) * 2004-03-30 2005-10-27 Millennium Pharmaceuticals, Inc. Synthesis of boronic ester and acid compounds

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2377868A1 (fr) * 2004-03-30 2011-10-19 Millennium Pharmaceuticals, Inc. Synthèse de Bortezomib
EP2185159A2 (fr) * 2007-09-12 2010-05-19 Dr. Reddy's Laboratories, Ltd. Bortézomib et procédé de production de celui-ci
EP2185159A4 (fr) * 2007-09-12 2012-02-08 Reddys Lab Ltd Dr Bortézomib et procédé de production de celui-ci
CN101899062A (zh) * 2009-05-26 2010-12-01 上海威智医药科技有限公司 α-手性硼酸及硼酸酯的合成工艺
US9315525B2 (en) 2009-06-19 2016-04-19 Lek Pharmaceuticals D.D. Synthetic route for the preparation of α-amino boronic acid derivatives via substituted alk-1-ynes
WO2010146172A2 (fr) 2009-06-19 2010-12-23 Lek Pharmaceuticals D.D. NOUVELLE TECHNIQUE DE SYNTHÈSE POUR LA PRÉPARATION DE DÉRIVÉS D'ACIDE α-AMINOBORONIQUE PAR L'INTERMÉDIAIRE D'ALK-1-YNES SUBSTITUÉES
EP2270019A1 (fr) 2009-06-19 2011-01-05 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation d'esters boronique alpha-aminé
WO2010146172A3 (fr) * 2009-06-19 2012-02-23 Lek Pharmaceuticals D.D. NOUVELLE TECHNIQUE DE SYNTHÈSE POUR LA PRÉPARATION DE DÉRIVÉS D'ACIDE α-AMINOBORONIQUE PAR L'INTERMÉDIAIRE D'ALK-1-YNES SUBSTITUÉES
US8785674B2 (en) 2009-06-19 2014-07-22 Lek Pharmaceuticals D.D. Process for hydrogenation of halogenoalkenes without dehalogenation
EP2280016A1 (fr) 2009-07-27 2011-02-02 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation d'esters boroniques aminés via des Alk-1-ynes substitués
WO2011098963A1 (fr) 2010-02-09 2011-08-18 Ranbaxy Laboratories Limited Procédé de préparation de bortézomib
CN101812026B (zh) * 2010-04-12 2013-08-28 亚邦医药股份有限公司 一种硼替佐米的合成方法
CN101812026A (zh) * 2010-04-12 2010-08-25 孙江涛 一种硼替佐米的合成方法
WO2012048745A1 (fr) 2010-10-14 2012-04-19 Synthon Bv Procédé pour la fabrication de bortézomib et intermédiaires pour le procédé
US8884009B2 (en) 2010-10-14 2014-11-11 Synthon Bv Process for making bortezomib and intermediates for the process
US8497374B2 (en) 2011-05-12 2013-07-30 Scinopharm Taiwan, Ltd. Process for preparing and purifying bortezomib
CN103204867A (zh) * 2012-01-14 2013-07-17 成都爱群科技有限公司 手性氨基硼酸酯及制备方法与其在硼替佐米合成中的应用
CN104387409A (zh) * 2012-05-11 2015-03-04 人福医药集团股份公司 催化剂及其应用
CN102675415A (zh) * 2012-05-11 2012-09-19 武汉人福医药集团股份有限公司 制备硼替佐米的方法
CN104387409B (zh) * 2012-05-11 2017-09-29 人福医药集团股份公司 催化剂及其应用
US9505787B2 (en) 2012-09-11 2016-11-29 Cipla Limited Process for preparing of bortezomib
CN103044468A (zh) * 2012-11-28 2013-04-17 深圳万乐药业有限公司 N-(2-吡嗪羰基)-l-苯丙氨酸-l-亮氨酸硼酸的制备方法
CN103012551A (zh) * 2012-12-14 2013-04-03 江苏奥赛康药业股份有限公司 一种高纯度硼替佐米的合成方法及其中间体
US10023611B2 (en) 2013-04-16 2018-07-17 Cipla Limited Process for the preparation of bortezomib mannitol ester
WO2014170628A1 (fr) 2013-04-16 2014-10-23 Cipla Limited Procédé pour la préparation d'ester de mannitol du bortézomib
KR101691353B1 (ko) 2013-12-09 2016-12-30 주식회사 경보제약 보르테조밉의 제조방법 및 그의 신규 중간체
KR20150066724A (ko) * 2013-12-09 2015-06-17 주식회사 경보제약 보르테조밉의 제조방법 및 그의 신규 중간체
AU2018221670B2 (en) * 2017-02-17 2021-02-04 Fresenius Kabi Oncology Ltd. An improved process for the preparation of boronic acid esters
WO2018150386A1 (fr) 2017-02-17 2018-08-23 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation d'esters d'acide boronique
CN110312727A (zh) * 2017-02-17 2019-10-08 费森尤斯卡比肿瘤学有限公司 一种改进的制备硼酸酯的方法
JP2020507615A (ja) * 2017-02-17 2020-03-12 フレゼニウス・カビ・オンコロジー・リミテッド ボロン酸エステルの調製のための改良プロセス
US11667654B2 (en) 2017-02-17 2023-06-06 Fresenius Kabi Oncology Ltd. Process for the preparation of boronic acid esters
CN117820347A (zh) * 2024-03-06 2024-04-05 深圳智微通科技有限公司 一种连续流合成硼替佐米的方法

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