[go: up one dir, main page]

WO2006031179A1 - Process for preparation of phtalimide - Google Patents

Process for preparation of phtalimide Download PDF

Info

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
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
Application number
PCT/SE2005/001315
Other languages
French (fr)
Inventor
Ann-Sofie Krig
Mats Thelin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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.

Landscapes

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

Abstract

The present invention is directed to a novel process for the synthesis of (S) -glycidyl phthalimide and to novel intermediates in the process. The process comprises, reacting a (R) -3 -Chloro-1,2-propanediol and phtalimide salt. Then reacting the product with trimethylorthoacetate and an essentially water free acid. Then reacting the product with acetyl halogenide and do a basic ester hydrolysis.

Description

PROCESS FOR PREPARATION OF PHTALIMIDE
Field of the invention
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.
Background of the invention
Stereoselective conversion of diols into epoxides has been described in KoIb; Sharpless, Tetrahedron 1992, 48, 10515-30.
A method to synthesize (S)-glycidyl phthalimide has been disclosed in Gutcait et al, Tetrahedron Asymmetiy, 1996, 7, 1641-48. In this method, (S)-Glycidyl phthalimide is synthesised in one step in about 80 % yield during Mitsunobu conditions. This method is not suitable for large-scale synthesis due to the use of the very hazardous reagent DEAD and the necessity to remove the reagents by chromatography after completed reaction.
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. Outline of the invention
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 process according to the invention is further illustrated below:
Figure imgf000003_0001
(R)-3-Chloro-1 ,2- (S)-2-(2,3-Dihydroxy-propyl)- (S)-2-(2-Methoxy-2-methyl-[1 ,3]dioxolane- propanediol isoindole-1 ,3-dione 4-ylmethyl)-isoindoIe-1 ,3-dione
Figure imgf000003_0002
(S)-2-(2-Acetoxy-3-bromo-propyI)- (S)-2-Oxiranylmethyl~ isoindole-1 ,3-dione (X = Br) isoindole-1 ,3-dione
(S)-2-(2-Acetoxy-3-iodo-propyI)- isoindole-1 ,3-dione (X= I)
(S)-2-(2-Acetoxy-3-chIoro-propyl)- isoindole-1 ,3-dione (X = Cl)
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. Methods of preparation
General procedure for the "one-pot" synthesis of (S)-Glycidyl phthalimide:
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.
In one embodiment of the present invention, the reaction in step a) takes place in an alcohol solvent such as methanol or polyethylene glycol. The reaction is carried out at from 6O0C to 80°C for 5 hours to 20 hours. In one embodiment of the present invention, the phtalimide salt is potassium phtalimide or sodium phtalimide. In one embodiment, 1.0 to 1.4 equivalents of phtalimide salt is used. In a further embodiment, 1.1 to 1.3 equivalents of phtalimide salt is used. In yet a further embodiment, 1.2 equivalents of phtalimide salt is used.
In one embodiment of the invention, 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). In one embodiment, 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.
In one embodiment of the present invention, 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 O0C to room temperature for 1 hour to 4 hours.
In one embodiment of the present invention, step d) is carried out in a polar solvent, such as methanol, tetrahydrofuran (THF) or dioxane. The basic ester hydrolysis can be performed using a base such as potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide (tBuONa) or potassium tert- butoxide (tBuOK). In one embodiment, the base potassium carbonate (K2CO3) is used. The reaction is carried out at from O0C to room temperature for 1 hour to 4 hours.
Examples
Procedure for the "one-pot" synthesis of (S)-Glycidyl phthalimide:
Step a) (S)-2-(2,3-Dihydroxy-propyl)-isoindole-l,3-dione
(R)-3-Chloro-l,2-propanediol (1.0 eq, 5.0 g, 44.3 mmoles) and potassium phthalimide (1.2 eq, 10.0 g, 53.2 mmoles) was heated to reflux in ethanol (50 mL) for 24 h in an inert atmosphere. The resulting slurry was cooled to 40°C and the solvent was evaporated at reduced pressure.
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). After 1.5 h of reaction at ambient temperature and inert atmosphere, the mixture was filtered (to remove excess phthalimide and KCl) and concentrated at reduced pressure at 40°C (to remove methanol that is formed in the reaction). 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 400C.
Step d) (S)-2-Oxiranylmethyl-isoindole-l,3-dione
The crude (S)-2-(2-Acetoxy-3-bromo-propyl)-isoindole-l,3-dione from step c) was dissolved in methanol (80 mL). Potassium carbonate was added in portions during cooling. After 1 h of reaction at 00C in inert atmosphere, the mixture was quenched with ammonium chloride (25 mL, saturated aqueous solution). Extraction with ethyl acetate (2 x 50 mL) was performed after the addition of water (30 mL). The combined organic layers were dried with sodium sulphate and concentrated at reduced pressure at 40°C. The crude product was dissolved in methanol (60 mL) at 60°C. A clear filtration was performed and the solution was cooled to ambient temperature whereupon the product crystallized. The crystals were filtered off after 18 h and dried at reduced pressure at 400C for 3 days. This gave 4.84 g of the product (S)-2-Oxiranylmethyl-isoindole-l,3-dione (54 % overall yield from (R)-3-chloro-l,2-propanediol) with a LC-purity of 100 %.
Synthesis and isolation of new compounds including NMR-data
Figure imgf000006_0001
(S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione
Figure imgf000007_0001
(S)-2-(2-Acetoxy-3 -bromo-propyl)-isoindole- 1 ,3 -dione
Figure imgf000007_0002
(S)-2-(2-Acetoxy-3-Iodo-propyl)-isoindole-l,3-dione
Preparation of (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-yImethyl)-isoindole-l,3- dione R-3-Chloro-l,2-propanediol (5.0 g, 44.8 mmoles) and potassium phthalimide (1.2 eq, 10.1 g, 53.7 mmoles) were heated to reflux in ethanol (25 mL) for 17 h. The mixture was concentrated and the formed (S)-2-(2,3-Dihydroxy-propyl)-isoindole- 1,3 -dione was purified by silica chromatography using EtOAc as eluent. After concentration, toluene (25 mL) and triethylorthoacetate (1.5 eq, 8.6 mL, 67.2 mmoles) were added and to the resulting slurry trifluoroacetic acid (0.01 eq, 0.3 mL, 0.4 mmoles) was added slowly at room temperature. After 2 h of reaction, the mixture was concentrated to give 7.6 g (61 % yield) of (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione as a mixture of diastereomers. 1H-NMR (400 MHz, CDCl3): δ 7.85 (m, 2H), 7.73 (m, 2H), 4.65-4.45 (m, IH), 4.23-4.13 (m, IH), 4.1-3.68 (m, 3H), 3.32-3.24 (2s, 3H), 1.57-1.51 (2s, 3H)
13C-NMR (400 MHz, CDCl3): δ 168.1, 134.2, 131.9, 123.5, 122.5, 122.3, 73.9, 73.7, 67.9, 67.6, 50.1, 49.9, 40.7, 40.6, 21.7, 21.5 MS: m/z = 246 (M-OCH3), M+H not stable
Preparation of (S)-2-(2-Acetoxy-3-bromo-propyI)-isoindole-l,3-dione (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4-ylmethyl)-isoindole-l,3-dione (2.03 g, 7.32 mmoles) was dissolved in toluene (10 mL) and the mixture was cooled to O0C before acetyl bromide (1.3 eq, 0.72 mL, 9.52 mmoles) was added slowly. After 2 h of reaction the solution was concentrated and the crude (S)-2-(2-Acetoxy-3-bromo-propyl)-isoindole-l,3-
5 dione was dissolved in MeOH (10 mL). The mixture was cooled to O0C whereupon (S)-2- (2-Acetoxy-3-bromo-propyl)-isoindole-l,3-dione precipitated. The white solid was dried at 4O0C at reduced pressure to give 1.94 g (81 % yield) of (S)-2~(2-Acetoxy-3-bromo- propyl)-isoindole- 1 ,3-dione. 1H-NMR (400 MHz, CDCl3): δ 7.87 (m, 2H), 7.75 (m, 2H), 5.32 (m, IH), 4.01 (d, J = 5.03 o Hz, 2H), 3.59 (dd, J = 11.18, 4.65 Hz, IH), 3.47 (dd, J = 11.18, 6.57 Hz, IH), 2.06 (s, 3H) 13C-NMR (400 MHz5 CDCl3): δ 170.2, 168.0, 134.2, 131.8, 123.5, 70.7, 39.7, 31.1, 20.9 MS: m/z = 326 (M+l), 343 (M+NH/)
Preparation of ((S)-2-(2-Acetoxy-3-Iodo-propyI)-isoindole-l,3-dione) s (S)-2-(2-Acetoxy-3-bromo-propyl)-isoindole-l,3-dione (1.07 g, 3.28 mmoles), NaI (0.75 g, 4.92 mmoles) and methyl isobutylketone (10 mL) were heated to reflux for 18 h. The mixture was concentrated and purified by silica chromatography using a solution of toluene:EtOAc, 1:1, as eluent. After concentration the product was dissolved in methanol (5 mL) and after cooling to 00C orange needle-formed crystals precipitated. The crystals o were dried at 40°C at reduced pressure to give 0.96 g (78 % yield) of ((S)-2-(2-Acetoxy-3- Iodo-propyl)-isoindole- 1 ,3-dione) .
1H-NMR (400 MHz, CDCl3): δ 7.87 (m, 2H), 7.75 (m, 2H), 5.15 (m, IH), 4.00 (d, J= 4.95 Hz, 2H), 3.41 (dd, J = 10.92, 4.75 Hz, IH), 3.27 (dd, J= 10.92, 7.11 Hz, IH), 2.05 (s, 3H). 13C-NMR (400 MHz, CDCl3): δ 170.2, 168.0, 134.2, 131.8, 123.5, 71.0, 40.7, 20.8, 3.5 5 MS: m/z = 374 (M+H), 391 (M+NILt4).

Claims

Claims
1. A process for the preparation of S-glycidyl phtalimide comprising the steps of a) Reacting (R)-3 -Chloro- 1 ,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; and d) Reacting the product of step c) in a basic ester hydrolysis.
2. A process according to claim 1, wherein the water-free acid in step b) is selected from trifluoroacetic acid, methanesulfonic acid, p-toluene sulfonic acid and pyridinium p-toluenesulfonate.
3. A process according to claim 2, wherein the water-free acid in step b) is trifluoroacetic acid.
4. A process according to any one of claims 1-3 wherein the acetyl halogenide in step c) is selected from acetyl chloride, acetyl iodide and acetyl bromide.
5. A process according to claim 4, wherein the acetyl halogenide in step c) is acetyl bromide.
6. A process according to any one of claims 1-5, wherein the basic ester hydrolysis in step d) is performed using a base selected from potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide (tBuONa) and potassium tert-butoxide (tBuOK).
7. A process according to claim 6, wherein the basic ester hydrolysis in step d) is performed using potassium carbonate (K2CO3).
8. A process according to any one of claims 1-7, wherein the phtalimide salt in step a) is potassium phtalimide.
9. A process according to any one of claims 1-8, wherein from 1.0 to 1.4 equivalents of phtalimide salt is used in step a).
10. A process according to claim 9, wherein from 1.1 to 1.3 equivalents of phtalimide salt is used in step a).
11. A process according to claims 10, wherein 1.2 equivalents of phtalimide salt is used in step a).
12. A compound selected from (S)-2-(2-Methoxy-2-methyl-[l,3]dioxolane-4- ylmethyl)-isoindole- 1 ,3-dione, (S)-2-(2-Acetoxy-3-Iodo-propyl)-isoindole- 1,3- dione and (S)-2-(2-Acetoxy-3-bromo-propyl)-isoindole-l,3-dione.
PCT/SE2005/001315 2004-09-13 2005-09-12 Process for preparation of phtalimide Ceased WO2006031179A1 (en)

Applications Claiming Priority (2)

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

Publications (1)

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

Family

ID=33157527

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2005/001315 Ceased WO2006031179A1 (en) 2004-09-13 2005-09-12 Process for preparation of phtalimide

Country Status (2)

Country Link
SE (1) SE0402200D0 (en)
WO (1) WO2006031179A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145698A (en) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 Preparation method of Rivaroxaban midbody and novel synthetic method of Rivaroxaban
CN104569213A (en) * 2015-01-23 2015-04-29 江苏正大清江制药有限公司 Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography

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 (en) * 1997-11-07 1999-05-20 Pharmacia & Upjohn Company Process to produce oxazolidinones
EP1403267A1 (en) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Process for preparing 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 (en) * 1997-11-07 1999-05-20 Pharmacia & Upjohn Company Process to produce oxazolidinones
EP1403267A1 (en) * 2002-09-25 2004-03-31 Daiso Co., Ltd. Process for preparing 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 (en) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 Preparation method of Rivaroxaban midbody and novel synthetic method of Rivaroxaban
CN104569213A (en) * 2015-01-23 2015-04-29 江苏正大清江制药有限公司 Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography

Also Published As

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

Similar Documents

Publication Publication Date Title
CA1340549C (en) Method of preparing sphingosine derivatives
DE69327567T2 (en) Process for the preparation of alanylglutamine
US20030212292A1 (en) Shortened synthesis of 3,3-diarylpropylamine derivatives
CN116621792A (en) A method for preparing N-n-butyl-1,2-benzisothiazolin-3-one-1-oxide
US6417403B1 (en) Process for preparing chiral (s)-2,3-disubstituted-1-propylamine derivatives
WO2006031179A1 (en) Process for preparation of phtalimide
Adamo et al. An Improved Resolution Of 2-Methyl Piperidine And Its Use in The Synthesis Of Homochiral Trans-2, 6-Dialkyl Piperidines
JP5301676B2 (en) Process for producing (3S, 4S) -4-((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone and novel intermediate used therefor
KR0125155B1 (en) Phthalimide compounds and method of producing same
US20080221340A1 (en) Process for the Production of Nebivolol
KR100203457B1 (en) Method for preparing turbina pin
US4346042A (en) Preparation of epihalohydrin enantiomers
KR100332703B1 (en) Method for preparing (S) -3,4-epoxybutyrate having optical activity
CN117088830B (en) Synthesis method of 2-amino-2- (furan-3-yl) acetic acid compound
EP0273316A2 (en) Stereoconvergent process for preparing optically active carboxylic acids
US4786744A (en) Method for opening the gem dicyano epoxides and the formation of compounds therefrom
CN111662293B (en) A kind of preparation method of zeatin
KR0162703B1 (en) Process for preparing sufentanil(n-4-methoxymethyl)-1-[2-(thienyl)ethyl]-4-piperidinyl-n-phenylpropanamide)having potent analgesic and anaesthetic properties and its n-arylalkyl-4-piperidone intermediates
JP2000063321A (en) Production of long-chain beta-hydroxycarboxylic acid of high optical purity
KR101087631B1 (en) Method of preparing spin gosin
JP3283959B2 (en) D-biotin intermediate and method for producing the same
KR100311949B1 (en) Process for the preparation of 1-[(cyclopent-3-en-1-yl)methyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione
KR790001648B1 (en) Process for the preparation of trimethoxy benzyl piperazino ethanol deriyatives
CN120757489A (en) Preparation method of key intermediate of anamorelin
DK161318B (en) PROCEDURE FOR THE PREPARATION OF 4-ACETYL-2- (ALKYL OR ARALKYL) IMIDAZOLES AND 2-CHLOR-1,1-DIALCOXY-3 BUTANONS USED AS INTERMEDIATES

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase