WO2006031179A1 - Processus de preparation de phtalimide - Google Patents

Processus de preparation de phtalimide Download PDF

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Publication number
WO2006031179A1
WO2006031179A1 PCT/SE2005/001315 SE2005001315W WO2006031179A1 WO 2006031179 A1 WO2006031179 A1 WO 2006031179A1 SE 2005001315 W SE2005001315 W SE 2005001315W WO 2006031179 A1 WO2006031179 A1 WO 2006031179A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
phtalimide
dione
isoindole
acetyl
Prior art date
Application number
PCT/SE2005/001315
Other languages
English (en)
Inventor
Ann-Sofie Krig
Mats Thelin
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2006031179A1 publication Critical patent/WO2006031179A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention is directed to a new process for the synthesis of (S)-glycidyl phtalimide as well as to new intermediates in the process.
  • a further method to synthesise (S)-glycidyl phtalimide is described in WO 99/24393 and comprises the steps of reacting (S)-epichlorohydrin with phtalimide in DMF and subsequently reacting the product of said reaction step with tBuONa in ethanol.
  • One object of the present invention was to develop a process for the production of (S)- glycidyl phtalimide that is more suitable for large-scale production.
  • the present invention is directed to a new process for the production of (S)-glycidyl phthalimide in high purity and with retained stereochemistry.
  • the process according to the present invention comprises the steps of: a) Reacting (R)-3-Chloro-l,2-propanediol and a phthalimide salt b) Reacting the product of step a) with trimethylorthoacetate and an essentially water- free acid c) Reacting the product of step b) with acetyl halogenide d) Reacting the product of step c) in a basic ester hydrolysis.
  • the present invention is also directed to the intermediates (S)-2-(2-Methoxy-2-methyl- [l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione, (S)-2-(2-Acetoxy-3-bromo-propyl)- isoindole-l,3-dione, (S)-2-(2-Acetoxy-3-chloro-propyl)-isoindole-l,3-dione and (S)-2-(2- Acetoxy-3-iodo-propyl)-isoindole-l,3-dione.
  • the process according to the present invention comprises the steps of: a) Reacting (R)-3-Chloro-l,2-propanediol and a phthalimide salt b) Reacting the product of step a) with trimethylorthoacetate and a water-free acid c) Reacting the product of step b) with acetyl halogenide d) Reacting the product of step c) in a basic ester hydrolysis.
  • the reaction in step a) takes place in an alcohol solvent such as methanol or polyethylene glycol.
  • the reaction is carried out at from 6O 0 C to 80°C for 5 hours to 20 hours.
  • the phtalimide salt is potassium phtalimide or sodium phtalimide.
  • 1.0 to 1.4 equivalents of phtalimide salt is used.
  • 1.1 to 1.3 equivalents of phtalimide salt is used.
  • 1.2 equivalents of phtalimide salt is used.
  • step b) is carried out in an aprotic solvent, such as methylene chloride or acetonitrile.
  • the reaction is carried out at from 0°C to room temperature for 1 hour to 6 hours.
  • the essentially water-free acid may be trifluoroacetic acid (TFA), methanesulfonic acid, p-toluene sulfonic acid or pyridinium p- toluenesulfonate (PPTS).
  • the essentially water-free acid is trifluoroacetic acid.
  • the wording "essentially water-free" means that the acid used in the process according to the present invention may contain up to 2% water.
  • step c) is carried out in an aprotic solvent, such as toluene, methylene chloride or acetonitrile.
  • the acetyl halogenide is selected from acetyl chloride, acetyl iodide or acetyl bromide. In one embodiment, the acetyl halogenide is acetyl bromide.
  • the reaction is carried at from O 0 C to room temperature for 1 hour to 4 hours.
  • step d) is carried out in a polar solvent, such as methanol, tetrahydrofuran (THF) or dioxane.
  • a polar solvent such as methanol, tetrahydrofuran (THF) or dioxane.
  • the basic ester hydrolysis can be performed using a base such as potassium carbonate (K 2 CO 3 ), sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide (tBuONa) or potassium tert- butoxide (tBuOK).
  • the base potassium carbonate (K 2 CO 3 ) is used.
  • the reaction is carried out at from O 0 C to room temperature for 1 hour to 4 hours.
  • Step b) (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione
  • the crude (S)-2-(2,3-Dihydroxy-propyl)-isoindole-l,3-dione from step a) was suspended in toluene (50 mL) followed by addition of trimethylorthoacetate (1.5 eq, 8.5 mL, 66.5 mmoles) and trifluoroacetic acid (0.2 eq, 0.67 mL, 8.9 mmoles).
  • Step c) (S)-2-(2-Acetoxy-3-bromo-propyl)-isoindole-l,3-dione
  • the crude (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione from step b) was dissolved in toluene (50 mL) and the mixture was cooled to 0°C before the addition of acetyl bromide (1.3 eq, 4.3 mL, 57.6 mmoles). After 1 h of reaction at ambient temperature and inert atmosphere, the mixture was concentrated at reduced pressure at 40 0 C.

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

Abstract

La présente invention concerne un nouveau processus de synthèse de (S) -glycidyl phthalimide et de nouveaux intermédiaires de ce processus. Le processus consiste à faire réagir un (R)-3-chloro-1,2-propanediol et un sel de phtalimide, et à faire réagir le produit avec le triméthylorthoacétate ainsi qu'un acide sensiblement exempt d'eau. On fait ensuite réagir le produit avec un halogénure d'acétyle et l'on effectue l'hydrolyse d'ester basique.
PCT/SE2005/001315 2004-09-13 2005-09-12 Processus de preparation de phtalimide WO2006031179A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0402200-0 2004-09-13
SE0402200A SE0402200D0 (sv) 2004-09-13 2004-09-13 New process II

Publications (1)

Publication Number Publication Date
WO2006031179A1 true WO2006031179A1 (fr) 2006-03-23

Family

ID=33157527

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2005/001315 WO2006031179A1 (fr) 2004-09-13 2005-09-12 Processus de preparation de phtalimide

Country Status (2)

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SE (1) SE0402200D0 (fr)
WO (1) WO2006031179A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145698A (zh) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 一种利伐沙班中间体的制备方法及利伐沙班的新合成方法
CN104569213A (zh) * 2015-01-23 2015-04-29 江苏正大清江制药有限公司 高效液相色谱法测定(s)-(+)-n-(2,3-乙氧基丙基)邻苯二甲酰亚胺含量的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244901A (en) * 1991-06-27 1993-09-14 Synthelabo 4-pyrimidinecarboxamide derivatives, their preparation and their application in therapy
WO1999024393A1 (fr) * 1997-11-07 1999-05-20 Pharmacia & Upjohn Company Procede de production d'oxazolidinones
EP1403267A1 (fr) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Procédé de préparation de glycidylphthalimide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244901A (en) * 1991-06-27 1993-09-14 Synthelabo 4-pyrimidinecarboxamide derivatives, their preparation and their application in therapy
WO1999024393A1 (fr) * 1997-11-07 1999-05-20 Pharmacia & Upjohn Company Procede de production d'oxazolidinones
EP1403267A1 (fr) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Procédé de préparation de glycidylphthalimide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOLB H.C. AND SHARPLESS K.B.: "A Simplified Procedure for the Stereospecific Transformation of 1,2-Diols into Epoxides", TETRAHEDRON, vol. 48, 1992, pages 10515 - 10530, XP002993847 *
KOLB H.C. ET AL: "Catalytic Asymmetric Dihydroxylation", CHEM. REV., vol. 94, 1994, pages 2483 - 2547, XP002248191 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145698A (zh) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 一种利伐沙班中间体的制备方法及利伐沙班的新合成方法
CN104569213A (zh) * 2015-01-23 2015-04-29 江苏正大清江制药有限公司 高效液相色谱法测定(s)-(+)-n-(2,3-乙氧基丙基)邻苯二甲酰亚胺含量的方法

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Publication number Publication date
SE0402200D0 (sv) 2004-09-13

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