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I-type crystallization and preparation method of l-alanine-(14-oridonin A) ester trifluoroacetate

A technology of ester trifluoroacetate, oridonin, applied in the field of type I crystallization and preparation of L-alanine-(14-oridonin) ester trifluoroacetate, can solve the problem of Problems such as poor product stability, poor fluidity, and difficulty in intravenous administration have achieved the effects of stable production process, good crystal form stability, and repeatable and controllable production process

Active Publication Date: 2017-04-12
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the oral bioavailability of oridonin is less than 5%, and the effective blood concentration cannot be reached; at the same time, oridonin is almost insoluble in water, so it is difficult to administer intravenously
Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • I-type crystallization and preparation method of l-alanine-(14-oridonin A) ester trifluoroacetate
  • I-type crystallization and preparation method of l-alanine-(14-oridonin A) ester trifluoroacetate
  • I-type crystallization and preparation method of l-alanine-(14-oridonin A) ester trifluoroacetate

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Experimental program
Comparison scheme
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Embodiment 1

[0039] Embodiment 1: Preparation of L-alanine-(14-oridonin A) ester trifluoroacetate

[0040] Step 1: Preparation of N-Boc-L-alanine-(14-oridonin A) ester

[0041] Suspend 150g (0.41mol) oridonin (II), 195g (1.04mol) Boc-L-Ala in 1.35kg dichloromethane, cool in an ice bath to 0-5°C, add 213g (1.04mol) DCC, After stirring for 0.5 h, the ice bath was removed, stirred at room temperature for 5 h, and TLC confirmed that the reaction of the raw materials was complete (dichloromethane:methanol=10:1, raw material R f = 0.4, product R f = 0.6). The reaction solution was cooled to 0° C. and stood for 2 h, filtered, and the filter cake was washed with dichloromethane (300 g×3). The organic layers were combined and concentrated to obtain a white solid. Flash silica gel column chromatography (dichloromethane:methanol=100:1~60:1; v / v), collected product fractions, concentrated to dryness under reduced pressure to obtain about 140~165g of white solid powder. Add 600g of isopropyl ether ...

Embodiment 2

[0044] Embodiment 2: Determination of the crystal form of the sample of Example 1

[0045] The solid sample X-ray powder diffraction pattern that makes in embodiment 1 sees image 3 , showing the characteristic absorption peak of the amorphous form, the DSC spectrum is shown in 4, and no melting characteristic absorption peak is seen below 300 ° C, so it is determined that the product is an amorphous solid.

Embodiment 3

[0047] Weigh 500mg of L-alanine-(14-oridonin) ester trifluoroacetate amorphous solid in a 25ml round bottom flask, add 5ml of acetone, stir to dissolve, slowly add 10ml of isopropyl ether at room temperature, Stir and crystallize for 2.5 hours, filter with suction, wash the filter cake with a small amount of acetone / isopropyl ether (V / V=1 / 2) mixed solvent and dry to obtain 370 mg of white solid, yield 74.0%. The X-ray powder diffraction pattern of this crystalline sample is shown in figure 1 . The crystallization is at about 6.85 (12.89), 8.09 (10.92), 11.30 (7.82), 13.71 (6.45), 14.08 (6.29), 14.35 (6.17), 16.40 (5.40), 17.41 (5.09), 18.19 (4.87), 18.44 (4.81), 20.12(4.41), 21.17(4.19), 23.38(3.80), 23.88(3.72), 24.42(3.64), 24.84(3.58), 25.72(3.46), 26.46(3.37), 27.22(3.27), 28.40 There are characteristic peaks at (3.14), 29.38(3.04), 31.26(2.86) and 31.79(2.81). DSC spectrum see figure 2 , with a sharp melting endothermic peak at 232.59°C, this crystal form is defined ...

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Abstract

The present invention relates to an I-type crystal of L-alanine-(14-oridonin) ester trifluoroacetate and a preparation method therefor.The preparation method comprises crystallizing a L-alanine-(14-oridonin) ester trifluoroacetate solid in any crystal form or amorphous form in a single organic solvent or a mixed organic solvent thereof to obtain the I-type crystal of the L-alanine-(14-oridonin) ester trifluoroacetate.The I-type crystal of the L-alanine-(14-oridonin) ester trifluoroacetate obtained in the present invention has a good crystal form stability and chemical stability, and uses a crystallization solvent which has a low toxicity and low residue, and can be better used in clinical treatments.

Description

technical field [0001] The invention relates to type I crystal of L-alanine-(14-oridonin A) ester trifluoroacetate and its preparation method and use. Background technique [0002] Formula (I) compound is L-alanine-(14-Oridonin A) ester trifluoroacetate, it is [0003] [0004] Taking oridonin as the mother nucleus, after transformation and modification, the obtained oridonin ester derivatives; Oridonin (Oridonin) is a kind of kaurene extracted from Oridonin Diterpenoid natural organic compounds, accounting for more than 90% of the active ingredients of Rubescens japonicus, are the main active ingredients of anti-tumor. [0005] However, the oral bioavailability of oridonin is less than 5%, and the effective blood concentration cannot be reached; at the same time, oridonin is almost insoluble in water, so it is difficult to administer intravenously. Therefore, modifying its structure, improving its water solubility and activity, and developing it into a new antitumor dr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/08A61K31/352A61P35/00A61P35/02
CPCA61K31/352C07D493/08
Inventor 孙飘扬武乖利邱振均陈永江沈灵佳
Owner JIANGSU HENGRUI MEDICINE CO LTD
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