Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof
A technology of argatroban and monohydrate, which is applied in the field of directional synthesis of 21 argatroban and the preparation of crystal structure and monohydrate, which can solve the problems of low efficiency, undiscovered, complicated operation, etc.
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Examples
Embodiment 1
[0037] 1) Add 200ml chloroform and 25g (0.061mole) (2R, 4R)-1-[N G -Nitro-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride, cooled to 5°C, then added 18.5g (0.18mole) triethylamine, and added dropwise 14.7g ( 0.061mole) (3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl chloride, stirred at room temperature for 3 hours, TLC tracking reaction, to (2R,4R)-1-[ N G -Nitro-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride disappeared, the reaction was completed, washed twice with 50ml of water, dried over anhydrous magnesium sulfate, evaporated to remove solvent, column chromatography Separation gave (2R,4R)-1-[N G -Nitro-N 2 -[(3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl]-L-arginyl]-4-methyl-2-piperidinecarboxylate VI 32.5g, the yield is 92.1%;
[0038] 2) Add 100ml of ethanol and 30g (0.052mole) of intermediate VI into a 500ml four-necked reaction flask, add 100ml of 1N NaOH under stirring, stir at room temperature f...
Embodiment 2
[0042] Add 1g of 21(S) Argatroban into 150ml of distilled water, stir, and heat up to 95°C within 0.5 to 1.0 hours. At this time, all the solids are dissolved, and then cool down. 80°C, then drop to 50°C within 1 hour, then drop to 0°C within 2 hours. Placed at 0° C. for 8 hours until crystallization, then filtered, washed with water, and vacuum-dried at a temperature of 50 to 60° C. to obtain 0.65 g of 21(S) argatroban monohydrate, with a water content of 3.4% ( Karl Fischer method).
Embodiment 3
[0044] 1 g of anhydrous 21(S) argatroban VIII was recrystallized with distilled water to obtain crystal form I. X-ray diffraction of single crystal and polycrystalline powder confirmed that its absolute configuration was S body at position 21 (see Figure 2), crystal form I is an orthorhombic crystal system, P2(1)2(1)2(1) space group (space group No. 19). Unit cell parameters: a=9.372 Ȧ, b=15.503 Ȧ, c=21.735 Ȧ, α=β=γ=90°C (see Figure 3). The X-ray diffraction data of polycrystalline powder of Form I are consistent with the simulated data of single-crystal X-ray diffraction (see Figure 4, Table 1).
[0045] Table 1 Comparison of X-Diffraction Data of Single Crystal and Polycrystalline Powder of 21(S) Argatroban Form I
[0046] Single crystal diffraction simulation data
[0047] 9.94
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Abstract
Description
Claims
Application Information
- IPC
- C07D401/12; A61P7/02
- Inventors
- 宋洪海