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Method for preparing isosulfan blue

A technology of isosulfide blue and acid blue, applied in the field of preparation of isosulfide blue, can solve the problems of difficult metal content, high price of silver oxide, large environmental pollution, etc., and achieves convenient large-scale production, low cost, and safety. high effect

Active Publication Date: 2018-01-12
暨明医药科技(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Regarding the synthesis of isosulfur blue, relevant patents have been disclosed, but there are certain defects. For example, U.S. Patent US8969616 and World Patent WO2008140564 disclose the synthesis method of isosulfur blue, that is, using acid blue as a starting material, oxidizing Silver is an oxidant to synthesize isosulfur blue; but the silver oxide used is expensive, and silver is a heavy metal, which has a relatively large impact on the environment; US Patent US20060224003 and Indian Patent IN-2012CH03509 use dichromate or manganese dioxide as an oxidant , but the metal content in the medicine is not easy to refine, and the impact on the environment is relatively large; US Patent US4330476 uses chloranil / NO / NO2 / air system as the oxidant, and the gas-liquid two-phase reaction, in which nitric oxide and dioxide Nitrogen, which is relatively polluting to the environment

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0023] The invention provides a preparation method of isosulfur blue, comprising the following steps, S1, under the condition of 5-10°C, adding sodium chlorite and acid blue with a molar ratio of 2.5:1.0-3.5:1.0 into the reaction bottle , and an acid solution with an equivalent concentration of 5.0N to 12.0N for reaction, and the reaction time is 6 to 10 hours. The mass ratio of the volume of the acidic solution to the acid blue is 5.0:1.0-8.0:1.0. The acidic solution is sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid. The normality of the acidic solution is preferably 6.0N-8.0N.

[0024] S2, obtain isothiocyanine free acid crude product after completion of the reaction;

[0025] S3, dissolving the prepared crude isothiocyanate free acid in deionized water, and adjusting the pH to 8-9 through saturated aqueous sodium bicarbonate solution;

[0026] S4. Recrystallize the pH-adjusted solution in S3, filter, wash, and dry to ob...

example 1

[0030] Add acid blue (10.0g, 18.0mmol), sodium chlorite (4.9g, 54.0mmol), water (75ml), phosphoric acid (75ml), react at 5~10°C in the dark for 10 hours, after the reaction is completed, filter to obtain 10g of crude isothiocyanic acid; dissolve the crude product in deionized water (30ml), adjust the pH to 8-9 with saturated sodium bicarbonate solution, add acetone (300ml), stir for 1h;

[0031] Filter, wash the filter cake twice with acetone (150ml), and dry it in vacuum at 40°C for 8h to obtain 5.5g of isosulfur blue,

[0032] The purity is 99.6%, the unknown single impurity is <0.10%, and the yield is 53%.

[0033] The infrared spectrum of the sample is completely consistent with the standard spectrum.

[0034] 1 HNMR (solvent DMSO; internal standard TMS): δ1.19-1.23(t, 12H), δ3.60-3.65(q, 8H), δ6.97-6.99(d, 4H), δ7.13(s, 1H) ), δ7.28-7.30(d, 4H), δ7.72-7.74(d, 1H), δ7.88-7.90(d, 1H) .

example 2

[0036] Add acid blue (10.0g, 18.0mmol), sodium chlorite (4.9g, 54.0mmol), water (75ml), and Sulfuric acid (75ml), react in the dark at 5~10°C for 8 hours, filter the crude product of isothiocyanic acid 10g after the reaction is completed; dissolve the crude product in deionized water (30ml), adjust the pH to 8-9 with saturated sodium bicarbonate solution, add Acetone (300ml), stirred for 1h; filtered, the filter cake was washed twice with acetone (150ml), and vacuum-dried at 40°C for 8h to obtain 6.5g of isothiocyanine, with a purity of 99.7%, an unknown simplex <0.10%, and a yield of 63%.

[0037] The infrared spectrum of the sample is completely consistent with the standard spectrum.

[0038] 1 HNMR (solvent DMSO; internal standard TMS): δ1.19-1.23(t, 12H), δ3.60-3.65(q, 8H), δ6.97-6.99(d, 4H), δ7.13(s, 1H) ), δ7.28-7.30(d, 4H), δ7.72-7.74(d, 1H), δ7.88-7.90(d, 1H) .

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Abstract

The invention provides a method for preparing isosulfan blue. The method comprises the steps: adding acid blue, sodium chlorite and an acidic solution into a reaction bottle under the condition of 5 DEG C to 10 DEG C, and carrying out a reaction for 6 to 10 hours; obtaining a free-acid crude product of the isosulfan blue after the reaction is completed, dissolving the prepared free-acid crude product of the isosulfan blue in deionized water, and adjusting the pH to 8 to 9 by a saturated sodium bicarbonate aqueous solution; and then, carrying out recrystallization, filtering, washing and drying, thereby preparing medicinal-grade isosulfan blue. According to the method, by adopting a biocatalyst-omega-transaminase, due to efficient selectivity of the enzyme, the chiral purity of the reactionis greatly improved. According to the method, the problem in the prior art that heavy metals are present in the reaction is solved; and meanwhile, the method has the advantages of simplicity in operation, high safety, good product quality, low cost and the like, thereby facilitating large-scale production.

Description

technical field [0001] The invention relates to a preparation method of isosulfur blue, which belongs to the technical field of medicinal chemistry. Background technique [0002] Isosulfur blue, also known as Purified Patent Blue Violet, is a triarylmethane dye. As an active pharmaceutical ingredient, it is mainly used as a contrast reagent for lymphatic vessel delineation, especially as a diagnostic reagent for cancer. Isothiranine injection (1%) is commonly used in a mapping procedure called lymph node labeling, an adjunct to lymphography that allows visualization of the lymphatic system by mapping the injected area, which has been used with high frequency in breast cancer Patient's lymph node marker localization. At the same time, the use of isosulfur blue as a guide for surgical removal of cancer cells is growing because it is cheaper and safer than the radioactive element technetium 99M sulfur colloid. [0003] Regarding the synthesis of isosulfur blue, relevant paten...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/32C07C309/46
Inventor 陈剑戈李斌峰顾志锋
Owner 暨明医药科技(苏州)有限公司