Preparation method of biliverdin or derivatives thereof

The technology of a derivative and biliverdin is applied in the field of preparation of biliverdin or a derivative thereof, and can solve the problems of many reaction steps of dimethyl dipropionate, unsuitable for industrialized production, low yield of biliverdin, and the like, Achieve the effect of low cost, easy purification and simple process

Active Publication Date: 2021-04-09
POSEIDON PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Preparation of biliverdin by synthetic method is an important and effective way to solve biliverdin and bilirubin, so far, only a small amount of reports about biliverdin synthetic method (K.M.Smith, R.K.Pandey, Tetrahedron, 1984,40 , 1749~1754; E.D.Sturrock, J.R.Bullb, R.E.Kirsch, J.Labelled Compd.Rad., 1994, 263~274), which is 3,3'-(3,18-dichloroethyl-2,7, 13,17-tetramethyl-1,19-dioxo-1,19,22,24-tetrahydro-21H-8,12-porphyrinyl)-dimethyl propionate as raw material, in strong base Under neutral conditions, hydrogen chloride is removed to obtain biliverdin dimethyl ester, but this method has many reaction steps for synthesizing dimethyl dipropionate, low yield and high cost
Its dehydrochlorination under strong alkaline conditions generates biliverdin dimethyl ester with a molar ratio of about 1:1, the product of 3-position and 18-position ring formation, and the yield of biliverdin is low, only 20%. In addition, biliverdin Chlorophyll dimethyl ester, 3-position and 18-position cyclic products need to be separated by chromatography, which is not suitable for industrial production

Method used

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  • Preparation method of biliverdin or derivatives thereof
  • Preparation method of biliverdin or derivatives thereof
  • Preparation method of biliverdin or derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Weigh 0.92 grams of compound 3,3'-(3,18-bis(2-p-toluenesulfinylethyl)-2,7,13,17-tetramethyl-1,19-dioxo-1, 19,22,24-tetrahydro-21H-8,12-porphyrinyl)-dimethyl dipropionate (compound shown in formula 3), add 40 ml of xylene to dissolve, heat up to 135 ° C, keep stirring and react 2 Hours, the temperature was lowered, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 0.50 g of blue-green solid, which was biliverdin diester (compound shown in formula 7), and the yield was 63%. 1 H NMR (400MHz, CDCl 3 ): δ1.89(s, 3H), 2.10(s, 3H), 2.13(s, 3H), 2.20(s, 3H), 2.56(t, J=8.1Hz, 4H), 2.95(t, J= 8.1Hz, 4H), 3.69(s, 6H), 5.46(d, J=12.0Hz, 1H), 5.66(dd, J=12.0, 4.0Hz, 1H), 5.68(dd, J=16.0, 4.0Hz, 1H),6.02(s,1H),6.08(s,1H),6.14(dd,J=16.0,4.0Hz,1H),6.51(dd,J=16.0,12.0Hz,1H),6.64(dd,J =16.0,12.0Hz,1H),6.81(s,1H);ESI-Mass:633.20[M+Na] + .

[0034] The reaction formula is as follows:

[0035]

Embodiment 2

[0037]Weigh 0.92 grams of compound 3,3'-(3-vinyl-18-(2-p-toluenesulfinylethyl)-2,7,13,17-tetramethyl-1,19-dioxo- 1,19,22,24-tetrahydro-21H-8,12-porphyrinyl)-dimethyl dipropionate (compound shown in formula 4) as raw material, add 40 ml of DMF to dissolve, heat up to 130 ° C, keep warm The reaction was stirred for 2 hours, the temperature was lowered, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a blue-green solid, which was biliverdin diester (compound shown in formula 7), and the yield was 60%.

[0038] The reaction formula is as follows:

[0039]

Embodiment 3

[0041] Weigh 0.92 grams of compound 3,3'-(3,18-bis(2-p-toluenesulfinylethyl)-2,7,13,17-tetramethyl-1,19-dioxo-1, 19,22,24-tetrahydro-21H-8,12-porphyrinyl)-dimethyl dipropionate (compound shown in formula 3), add 40 ml of nitrobenzene to dissolve, heat up to 150°C, keep warm and stir for reaction After 2 hours, the temperature was lowered, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 0.50 g of blue-green solid, which was biliverdin diester (compound shown in formula 7), and the yield was 61%. 1 H NMR (400MHz, CDCl 3 ): δ1.89(s, 3H), 2.10(s, 3H), 2.13(s, 3H), 2.20(s, 3H), 2.56(t, J=8.1Hz, 4H), 2.95(t, J= 8.1Hz, 4H), 3.69(s, 6H), 5.46(d, J=12.0Hz, 1H), 5.66(dd, J=12.0, 4.0Hz, 1H), 5.68(dd, J=16.0, 4.0Hz, 1H),6.02(s,1H),6.08(s,1H),6.14(dd,J=16.0,4.0Hz,1H),6.51(dd,J=16.0,12.0Hz,1H),6.64(dd,J =16.0,12.0Hz,1H),6.81(s,1H);ESI-Mass:633.20[M+Na] + .

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Abstract

The present invention provides a method for preparing biliverdin or a derivative thereof, the biliverdin or the derivative is prepared from a compound represented by formula 2. The picture in the specification represents a single bond or a double bond, the pictures at the positions shown as A and B are respectively and independently selected from one of the single bond and the double bond, when the picture represents a single bond, R1 or R2 connected with the single bond is selected from one of p-toluenesulfonyl, p-toluenesulfinyl, benzenesulfonyl and benzenesulfinyl, and when the picture represents a double bond, R1 or R2 connected with the double bond is hydrogen. The preparation method of the biliverdin or the biliverdin derivative is simple in process, does not need a column chromatography method, is high in yield and low in cost, and is suitable for industrial production; and moreover, by-products generated in synthesis of biliverdin dimethyl ester or biliverdin are reduced, and the purity of the product is improved.

Description

technical field [0001] The patent of the present invention belongs to the field of drug synthesis, and more specifically, the present invention relates to a preparation method of biliverdin or its derivatives. Background technique [0002] Biliverdin (biliverdin) is a tetrapyrrole ring substance (its structure is shown in formula 8) obtained by hydrolysis of heme by heme oxygenase (hemeoxygenase-1, HO-1). Named for its dark green color. Biliverdin is not only an intermediate metabolite in the circulatory system of heme metabolism, but also initiates physiological effects such as anti-inflammation and immune regulation, such as improving liver function, reducing alanine aminotransferase, and alleviating ischemia-reperfusion caused by liver transplantation Injury, inhibition of vascular remodeling in neovascular intima formation, and inhibition of bovine diarrhea virus replication. Therefore, biliverdin has great potential for clinical drug use. [0003] In addition, biliru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/44
CPCC07D207/44B01J31/0204B01J31/0235C07D403/14
Inventor 陈发普石聿新陈发凯
Owner POSEIDON PHARM CO LTD
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