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Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives

A technology of enantiomers and alkyl groups, applied in medical preparations containing active ingredients, pharmaceutical formulations, organic chemistry, etc., can solve the problems of expensive chiral stationary phases, high equipment and time costs

Inactive Publication Date: 2013-07-17
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These chromatographic methods are very costly in terms of equipment and time, are limited to small quantities, and use large amounts of solvent
Additionally, chiral stationary phases are very expensive

Method used

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  • Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives
  • Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives
  • Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Preparation of 2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid

[0198] step 1

[0199] A solution of 2-anilino-pyrimidine (71 g, 415 mmol; prepared according to T. Matsukawa et al., Yakugaku Zasshi 1951, 71, 933) and lithium tert-butoxide (14 g, 175 mmol) in tetrahydrofuran (170 ml) was cooled to -5°C . At this temperature 2-[bis(tert-butoxycarbonyl)]amino-prop-2-enoic acid methyl ester (100 g, 332 mmol; according to K. El Abdioui et al., Bull. Soc. Chim. Belg. 1997, 106, 425) in tetrahydrofuran (70 ml), the mixture was further stirred at -5°C for 4 hours and then warmed to room temperature (RT).

[0200] step 2

[0201] The reaction mixture obtained in step 1 was mixed with 23% sodium hydroxide solution (290 g, 1.6 mol) and heated under reflux for 7 hours. Tetrahydrofuran was distilled off, and the reaction solution was cooled to room temperature and extracted with methyl tert-butyl ether (400 ml). The aqueous phase was diluted with isopr...

Embodiment 2

[0204] Preparation of (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid (S)-1-phenylethyl-ammonium

[0205] step 1

[0206]2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid (120 g, 335 mmol) as prepared in Example 1 was dissolved in n-butyl acetate (1000 ml) at 50° C. The suspension in (S)-phenylethyl-amine (38.5 g, 318 mmol; 99.7% chemical purity, 99.3% ee (enantiomeric excess); BASF) was mixed and the mixture was further stirred at this temperature Cool to room temperature after 2 hours. The precipitated solid was filtered off with suction and dried to give a beige crystalline crude product (83.9 g), which was used directly in Step 2.

[0207] step 2

[0208] The crude product (83.9 g) obtained in step 1 was heated in ethyl acetate (590 ml) under reflux for 2 hours and then cooled to 5°C. The solid was filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid ...

Embodiment 3

[0211] Preparation of (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid

[0212] (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid (S)-1-phenylethyl-ammonium (37.2g, 77.5mmol, 99.5 A suspension of %de) in aqueous isopropanol (50% strength, 90ml) was mixed with 1N sulfuric acid (97ml, 48.5mmol) and stirred at room temperature for 1 hour. The solid was filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propionic acid (26.5 g, 95%, >99.9%ee).

[0213] C 18 h 22 N 4 o 4 , M=358.40g / mol; MS (ESI): m / z=359 ((M+1) + , 100%); 1 H-NMR (400MHz, DMSO-d 6 ): δ=12.60(bs, 1H), 8.36(d, J=4.8Hz, 2H), 7.42-7.36(m, 2H), 7.30-7.21(m, 3H), 7.05(t, J=8.3Hz, 1H), 6.76(t, J=4.8Hz, 1H), 4.48-4.30(m, 2H), 4.12-4.01(m, 1H), 1.31(s, 9H)ppm; HPLC (column: Chiralpak AD-H, 250x4.6mm, n-heptane+0.1%TFA: ethanol+0.1%TFA95:5, 1ml / min, 254nm): retention time [min]=19.1(S), 21.4(R).

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Abstract

The invention relates to a process for the preparation of the enantiomeric forms of 2,3-diaminopropionic acid derivatives of formula (I), wherein R1, R2 and R3 are defined as in the claims, by racemate resolution. The separation of the racemate into its enantiomers takes place through formation of diastereomeric salts upon addition of an enantiomerically pure auxiliary, and subsequent separation by fractional crystallization.

Description

technical field [0001] The present invention relates to a process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives of formula I by resolution of the racemic compounds. Separation of the racemic compound into its enantiomers is carried out by addition of an enantiomerically pure auxiliary to form diastereoisomeric salts and subsequent separation by fractional crystallization. Compounds of formula I are suitable intermediates for the preparation of IkB kinase inhibitors as described eg in WO01 / 30774A1, WO2004 / 022553A1 and US2007 / 0142417A1. [0002] Background technique [0003] Enantiomerically pure 2,3-diaminopropionic acid derivatives are known as building blocks for the synthesis of active pharmaceutical ingredients, including IkB kinase inhibitors (see WO2004 / 022553A1 and US2007 / 0142417A1). Since these building blocks have hitherto been produced only in isolated cases by asymmetric synthesis, enantiomerically pure compounds are usually...

Claims

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Application Information

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IPC IPC(8): C07D213/74C07D239/42
CPCC07D239/42C07D213/74C07D213/73A61K31/505
Inventor C-D.格拉夫J.里克-扎普
Owner SANOFI SA
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