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WO2004054975A1 - Procede de production de derives de desoxygalactonojirimycine - Google Patents

Procede de production de derives de desoxygalactonojirimycine Download PDF

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Publication number
WO2004054975A1
WO2004054975A1 PCT/GB2003/005528 GB0305528W WO2004054975A1 WO 2004054975 A1 WO2004054975 A1 WO 2004054975A1 GB 0305528 W GB0305528 W GB 0305528W WO 2004054975 A1 WO2004054975 A1 WO 2004054975A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
process according
benzyl
added
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/GB2003/005528
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English (en)
Inventor
Franz Amann
Marc Lanz
David Ian Carter Scopes
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Oxford Glycosciences UK Ltd
Original Assignee
Oxford Glycosciences UK Ltd
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Publication date
Application filed by Oxford Glycosciences UK Ltd filed Critical Oxford Glycosciences UK Ltd
Priority to AU2003295132A priority Critical patent/AU2003295132A1/en
Publication of WO2004054975A1 publication Critical patent/WO2004054975A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms

Definitions

  • This invention relates to a process for production of N-substituted- deoxygalactonojirimycin derivatives and intermediates for use in said process.
  • US 6,291,657 discloses N-alkyldeoxygalactonojirimycin derivatives, including N- butyldeoxygalactonojirimycin (NB-DGJ) and their use as inhibitors of glycolipid synthesis.
  • NB-DGJ N- butyldeoxygalactonojirimycin
  • the preparation of NB-DGJ by reaction of deoxygalactonojirimycin with butyraldehyde under a hydrogen atmosphere with a palladium black catalyst is described.
  • the process to the deoxygalactonojirimycin intermediate is not suitable for the large scale commercial preparation of NB-DGJ, for example in the quantities and purity required for use as a pharmaceutical. Therefore, improved processes for the production of NB-DGJ and other N- alkyldeoxygalactonojirimycin derivatives are required.
  • the present invention provides an improved process for the production of N-substituted- deoxygalactonojirimycin derivatives.
  • R is C 3 - ⁇ straight or branched chain alkyl, optionally substituted by C 3 - 7 cycloalkyl, and optionally interrupted by -0-, the oxygen being separated from the ring nitrogen by at least two carbon atoms; or -io alkylaryl where aryl is phenyl, optionally substituted by one or more substituents selected from F, CF 3 , OCF 3 , OR 1 , and - ⁇ straight or branched-chain alkyl; where R 1 is hydrogen, or . 6 straight or branched-chain alkyl; which process comprises reductive ring closure of a compound of formula (II):
  • Cbz is the group PhCH 2 OCO-.
  • R is preferably C 3 combat ⁇ 6 straight or branched chain alkyl, more preferably R is C 3 . 6 alkyl, in particular R is n-butyl.
  • the compound of formula (I) may be purified by methods known to those skilled in the art such as using an anion exchange resin, crystallisation and/or chromatography e.g. cation exchange chromatography. Crystallisation of the compound of formula (I) is preferably from a mixture of water and acetone.
  • butyraldehyde e.g. in an amount of 0.01 to 0.5, preferably 0.01 to 0.1 mole equivalents may be added to the reaction mixture after the reductive ring closure step.
  • the compound produced according to the process of the invention is preferably obtained with a purity of >95%, more preferably >99% w/w.
  • Protecting groups P 1 to P 4 are preferably the same.
  • Preferred protecting groups for use in the invention are benzyl or substituted benzyl, more preferably benzyl.
  • P 1 to P 4 are benzyl deprotection is preferably conducted in the presence of hydrogen gas and a catalyst such as PdCl 2 or palladium on carbon in a suitable solvent such as an alcohol, e.g. ethanol or preferably methanol.
  • a suitable solvent such as an alcohol, e.g. ethanol or preferably methanol.
  • Substituted benzyl protecting groups which may be used include p-methoxybenzyl.
  • Two adjacent P 1 to P 4 groups may be a benzylidene protecting group, e.g. P 1 and P 2 may be benzylidene.
  • the reductive ring closure of the compound of formula (II) may be conducted under any suitable reducing conditions known to those skilled in the art, for example in the presence of hydrogen gas and a catalyst such as palladium on carbon e.g. 10% palladium on carbon, in a suitable solvent such as an alcohol, e.g. ethanol or preferably methanol.
  • a catalyst such as palladium on carbon e.g. 10% palladium on carbon
  • a suitable solvent such as an alcohol, e.g. ethanol or preferably methanol.
  • the compounds of formula (II) may be produced by oxidation of a compound of formula
  • Suitable oxidising agents include trichloroisocyanuric acid in the presence of a catalyst e.g. 1,1 ',6,6'- tetramethyl piperidine-1-oxyl (TEMPO) in a suitable solvent such as sodium acetate / isopropyl acetate or sodium acetate / acetone, preferably at reduced temperature e.g. about -5 to 5°C, such as about -5 to 0°C or about 0 to 5°C.
  • TEMPO 1,1 ',6,6'- tetramethyl piperidine-1-oxyl
  • a suitable solvent such as sodium acetate / isopropyl acetate or sodium acetate / acetone, preferably at reduced temperature e.g. about -5 to 5°C, such as about -5 to 0°C or about 0 to 5°C.
  • Alternative oxidising agents include iodoxybenzoic acid in DMSO.
  • the compounds of formula (IN) may be produced by reaction of a compound of formula
  • L is a leaving group, for example chloro, in a suitable solvent e.g. isopropyl acetate or dichloromethane.
  • the compounds of formula (V) may be produced by reductive amination of the corresponding protected D-galactopyranose of formula (VII):
  • R is as defined for formula (I).
  • the reductive amination is preferably conducted in the presence of sodium cyanoborohydride. Preferably at elevated temperature, e.g. about 50°C.
  • the compounds of formulae (VI), (VII) and (VIII) are commercially available or may be prepared by methods known to those skilled in the art.
  • the compounds of formula (I) produced according to the method of the invention may be formulated as pharmaceutical compositions, e.g. for oral administration, by mixing with a pharmaceutically acceptable carrier.
  • the reactor was loaded with 2,3,4,6-tetra-O-benzyl-D-galactopyranose (540.65 g, 1.00 mol) and sodium cyanoborohydride (69.12 g, 1.1 mol) under an atmosphere of nitrogen.
  • a solution of the product from step a) (731.92 g, 1.00 mol) in methylene chloride was concentrated to about 50% of its volume at 300-750 mbar and a jacket temperature of 40-50°C.
  • Methylene chloride (950 mL) was added and the solution concentrated again to 50% of its starting volume.
  • the reactor was dried under reduced pressure and loaded with sodium acetate (164.06 g, 2.0 mol) and TEMPO (15.63 g, 0.1 mol) at 0-2°C.
  • the solution of the starting material was added after the reactor had been flooded with nitrogen.
  • Charcoal (30 g) was added to the solution of the product of step b) (729.90 g, 1.00 mol) in TBME.
  • the mixture was concentrated to a volume of about 1.5 L at 100-500 mbar and a jacket temperature of 40-50°C.
  • This mixture was diluted with methanol (2500 mL) and concentrated again to a volume of about 1.5 L.
  • the mixture was filtered and washed with methanol (1500 mL). Filtrate and washings were further diluted with methanol (5000 mL).
  • the dry and inert reactor was loaded with 10% Pd/C (e.g. Johnson Matthey type 490 paste 10%, water content ca. 60%: 73 g dry weight, 1% w/w).
  • the methanolic solution of the product of step b) was added and the mixture stirred under hydrogen (1000-1300 mbar) at 18-25°C until the consumption of hydrogen had ceased (ca. 4-10 h). After tic showed consumption of the starting material, the mixture was filtered and washed with methanol (400 mL). Filtrate and washings were concentrated to about 1.5 L at a jacket temperature of 40-60°C and 80-300 mbar. The solution was diluted with TBME (1700 mL), filtered over a plug of silica gel (750 g) and washed with TBME (2800 mL). Filtrate and washings were combined and concentrated to about 1 L at a jacket temperature of 40-60°C and 80-300 mbar.
  • the filter cake is pyrophoric and must be kept wet with water. Filtrate and washings were slowly passed through a bed of basic ion exchanger (ca. 2 L wet, hydroxide form e.g. Amberlite IRA 400). The pH of the solution had to be > 8 after leaving the column. Finally, the resin was washed with methanol (2000 mL). This solution was concentrated to about 500 to 750 mL. Charcoal (10 g) was added. The mixture was filtered (0.2 ⁇ m), concentrated to dryness and acetone (1300 mL) added. The mixture was heated to reflux and water (about 35 mL) was added until a clear solution was obtained.
  • basic ion exchanger ca. 2 L wet, hydroxide form e.g. Amberlite IRA 400
  • the reactor was loaded with 2,3,4,6-tetra-O-benzyl-D-galactopyranose (540.65 g, 1.00 mol) and sodium cyanoborohydride (69.12 g, 1.1 mol) under an atmosphere of nitrogen.
  • a solution of the product from step a) (731.92 g, 1.00 mol) in isopropyl acetate was concentrated to about 50% of its volume at 300-750 mbar and a jacket temperature of 40-50°C.
  • Isopropyl acetate 950 mL was added and the solution concentrated again to 50% of its starting volume.
  • the reactor was dried under reduced pressure and loaded with sodium acetate (164.06 g, 2.0 mol) and TEMPO (31.26 g, 0.2 mol) at -5-0°C.
  • the solution of the starting material was added after the reactor had been flooded with nitrogen.
  • a solution of trichloroisocyanuric acid (139.44 g, 0.60 mol) in isopropyl acetate (420 mL) was added slowly over at least 8 h at -5-0°C. After tic showed complete conversion, the reaction mixture was filtered and precipitate washed with isopropyl acetate (400 mL). The filtrate and washings were combined and then washed with water (2 x 600 mL) and then dried by azeotropic distillation.
  • Charcoal (30 g) was added to a solution of the product of step b) (729.90 g, 1.00 mol) in methanol (2700 mL). The mixture was stirred for 15 min and then filtered. The cake was washed with methanol (1000 mL). The mixture was concentrated to a volume of about 1.5 L at 100-500 mbar and a jacket temperature of 40-50°C. This mixture was diluted with methanol (2500 mL) and concentrated again to a volume of about 1.5 L. The mixture was filtered and washed with methanol (1500 mL). Filtrate and washings were further diluted with methanol (5000 mL). The dry and inert reactor was loaded with 10% Pd/C (e.g.

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

Abstract

L'invention concerne un procédé de production de dérivés de désoxygalactonojirimycine N-substitués comprenant une fermeture de noyau réductrice suivie d'une déprotection.
PCT/GB2003/005528 2002-12-17 2003-12-17 Procede de production de derives de desoxygalactonojirimycine Ceased WO2004054975A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003295132A AU2003295132A1 (en) 2002-12-17 2003-12-17 Process for production of deoxygalactonojirimycin derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0229476.7 2002-12-17
GB0229476A GB0229476D0 (en) 2002-12-17 2002-12-17 Novel process

Publications (1)

Publication Number Publication Date
WO2004054975A1 true WO2004054975A1 (fr) 2004-07-01

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PCT/GB2003/005528 Ceased WO2004054975A1 (fr) 2002-12-17 2003-12-17 Procede de production de derives de desoxygalactonojirimycine

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AU (1) AU2003295132A1 (fr)
GB (1) GB0229476D0 (fr)
WO (1) WO2004054975A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7528153B2 (en) 2003-10-29 2009-05-05 Genzyme Corporation Deoxynojirimycin analogues and their uses as glucosylceramidase inhibitors
WO2018220131A1 (fr) 2017-06-01 2018-12-06 Idorsia Pharmaceuticals Ltd Forme cristalline de n-butyldéoxygalactonojirimycine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4266025A (en) * 1978-12-12 1981-05-05 Bayer Aktiengesellschaft Production of N-substituted derivatives of 1-desoxy-nojirimycin
US6291657B1 (en) * 1993-05-13 2001-09-18 Monsanto Company Deoxygalactonojirimycin derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4266025A (en) * 1978-12-12 1981-05-05 Bayer Aktiengesellschaft Production of N-substituted derivatives of 1-desoxy-nojirimycin
US6291657B1 (en) * 1993-05-13 2001-09-18 Monsanto Company Deoxygalactonojirimycin derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
R BERNOTAS ET AL: "Total synthesis of (+) castanospermine and (+) deoxynojirimycin", TETRAHEDRON LETTERS, vol. 25, no. 2, 1984, pages 165 - 168, XP001180501 *
RICHARD H FURNEAUX ET AL: "Synthesis of 1,5-Dideoxy-1,5-imino-D-galactitol from L-Sorbose", TETRAHEDRON LETTERS, vol. 34, no. 22, 1993, pages 3609 - 3612, XP002275770 *
SAKAE AOYAGI ET AL: "Total synthesis of Galactosidase inhibitors (+)Galactostatin and (+)-1-deoxygalactostatin", JOURNAL OF ORGANIC CHEMISTRY, vol. 56, 1991, pages 815 - 819, XP002275771 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7528153B2 (en) 2003-10-29 2009-05-05 Genzyme Corporation Deoxynojirimycin analogues and their uses as glucosylceramidase inhibitors
WO2018220131A1 (fr) 2017-06-01 2018-12-06 Idorsia Pharmaceuticals Ltd Forme cristalline de n-butyldéoxygalactonojirimycine
KR20200011992A (ko) * 2017-06-01 2020-02-04 이도르시아 파마슈티컬스 리미티드 N-부틸데옥시갈락토노지리마이신의 결정질 형태
CN110799497A (zh) * 2017-06-01 2020-02-14 爱杜西亚药品有限公司 N-丁基脱氧半乳糖野尻霉素的结晶型
JP2020521796A (ja) * 2017-06-01 2020-07-27 イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Ｎ−ブチルデオキシガラクトノジリマイシンの結晶形
JP2021185184A (ja) * 2017-06-01 2021-12-09 イドーシア ファーマシューティカルズ リミテッドIdorsia Pharmaceuticals Ltd Ｎ−ブチルデオキシガラクトノジリマイシンの結晶形
US11306058B2 (en) 2017-06-01 2022-04-19 Idorsia Pharmaceuticals Ltd Crystalline form of N-butyldeoxygalactonojirimycin
TWI770184B (zh) * 2017-06-01 2022-07-11 瑞士商愛杜西亞製藥有限公司 N-丁基脫氧半乳糖野尻黴素(N-butyldeoxygalactonojirimycin)之結晶型
AU2018278247B2 (en) * 2017-06-01 2022-07-28 Idorsia Pharmaceuticals Ltd Crystalline form of N-butyldeoxygalactonojirimycin
US11713297B2 (en) 2017-06-01 2023-08-01 Idorsia Pharmaceuticals Ltd Crystalline form of N-butyldeoxygalactonojirimycin
JP7373529B2 (ja) 2017-06-01 2023-11-02 イドーシア ファーマシューティカルズ リミテッド Ｎ－ブチルデオキシガラクトノジリマイシンの結晶形
KR102612650B1 (ko) * 2017-06-01 2023-12-11 이도르시아 파마슈티컬스 리미티드 N-부틸데옥시갈락토노지리마이신의 결정질 형태
IL270961B1 (en) * 2017-06-01 2024-11-01 Idorsia Pharmaceuticals Ltd Crystalline form of n-butyldeoxygalactonojirimycin
IL270961B2 (en) * 2017-06-01 2025-03-01 Idorsia Pharmaceuticals Ltd Crystalline form of N-butyldeoxygalactonogirimycin

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Publication number Publication date
AU2003295132A1 (en) 2004-07-09
GB0229476D0 (en) 2003-01-22

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