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The preparation method of isosulfur blue

A kind of technology of isosulfur blue and acid blue

Active Publication Date: 2020-06-02
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

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  • The preparation method of isosulfur blue

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preparation example Construction

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

[0024] S2, after the reaction is completed, the crude isothio blue free acid is obtained;

[0025] S3. Dissolve the obtained crude isothio blue free acid in deionized water, and adjust the pH to 8-9 with saturated sodium bicarbonate aqueous solution;

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

example 1

[0030] Add acid blue (10.0g, 18.0mmol), sodium chlorite (4.9g, 54.0mmol), water (75ml), phosphoric acid into a 250mL four-necked flask equipped with a thermometer, mechanical stirring and constant pressure dropping funnel. (75ml), react in the dark at 5~10℃ for 10 hours. After the reaction, filter to obtain 10g 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), stirring for 1h;

[0031] After filtering, the filter cake was washed twice with acetone (150ml) and dried under vacuum at 40°C for 8h to obtain 5.5g of isosulfur blue.

[0032] Purity 99.6%, unknown single impurity <0.10%, 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(...

example 2

[0036] Add acid blue (10.0g, 18.0mmol), sodium chlorite (4.9g, 54.0mmol), water (75ml), and concentrate into a 250mL four-neck flask equipped with a thermometer, mechanical stirring and constant pressure dropping funnel. Sulfuric acid (75ml), react at 5~10℃ for 8 hours in the dark. After the reaction is completed, filter to obtain 10g crude isothiocyanic acid; dissolve the crude product in deionized water (30ml), adjust the pH to 8-9 with saturated sodium bicarbonate solution, and add Acetone (300ml), stirred for 1h; filtered, the filter cake was washed twice with acetone (150ml), and dried under vacuum at 40°C for 8 hours to obtain isosulfur blue 6.5g, purity 99.7%, unknown single impurities <0.10%, the yield is 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...

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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, belonging 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 control reagent for lymphatic delineation, especially as a diagnostic reagent for cancer. Isosulphur blue injection (1%) is commonly used in a mapping procedure called lymph node markers. It is an auxiliary lymphatic radiography that can visualize the lymphatic system through the injection area. It has been used frequently in breast cancer Location of the patient’s lymph node markers. At the same time, because it is cheaper and safer than the radioactive element technetium 99M sulfur colloid, the use of isosulfan blue as a guided surgical removal of cancer cells is gradually increasing. [0003] Regarding the synthesis of isosulfur blue, related patents have discl...

Claims

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Application Information

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Patent Type & Authority Patents(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