CN85103835A - Improving one's methods of preparation 4-demethoxy-daunorubicin - Google Patents
Improving one's methods of preparation 4-demethoxy-daunorubicin Download PDFInfo
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- CN85103835A CN85103835A CN198585103835A CN85103835A CN85103835A CN 85103835 A CN85103835 A CN 85103835A CN 198585103835 A CN198585103835 A CN 198585103835A CN 85103835 A CN85103835 A CN 85103835A CN 85103835 A CN85103835 A CN 85103835A
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- demethoxy
- daunorubicin
- following formula
- optically active
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Abstract
Introduced a kind of the improving one's methods of preparation 4-demethoxy-daunorubicin hydrochloride (formula (I)).The initial substance that present method is used
Be optically active 4-demethoxy-daunomycin ketone; in a kind of suitable organic solvent and in the presence of the silver triflate; make the same N of this optically active material; the 1-chlorine road Nuo Shi amine of O-trifluoroacetyl group protection carries out condensation reaction; obtain N; the glucosides of the a-end group isomery of O-trifluoroacetyl group protection; at first remove an one protecting group with methyl alcohol; carry out gentle alkaline hydrolysis with rare aqueous sodium hydroxide solution then; obtain the free glycoside alkali of (I), at last its isolated in form with corresponding hydrochloride is come out.
Description
The present invention relates to improving one's methods of synthetic 4-demethoxy-daunorubicin (formula I).
This compound is a kind of useful antineoplastic compound, at United States Patent (USP) 4,046,878(1977 September 6) in narrated and required patent right.
At that time, this compound was by racemic 4-demethoxy-daunomycin ketone and 2,3,6-three deoxidations-3-trifluoroacetamido-4-O-trifluoroacetyl group-α-L-lysol-own pyrans glycosyl muriate condensation prepared.
This condensation reaction is according to known Buddhist nun's Ke Gus-Nore (Koenigs-Knorr) synthesis step, in the suitable anhydrous organic solvent and carry out in the presence of red precipitate, mercuric bromide and molecular sieve as dewatering agent.Yet, under these conditions, obtaining a kind of complex mixture of glycoside compounds, it contains by α-or the glucosides of β-end group isomery, has to chromatography they be separated.
In addition, because adopting racemic 4-demethoxy-daunomycin ketone is starting raw material, isolated every kind of α-or the glucosides glycoside of β-end group isomery be still its aglycone and partly have natural 7S: (-) of 9S configuration-Dao Nuoshi amino (+)-4-demethoxy-daunomycin ketone and its aglycone partly have non-natural 7R: the non-enantiomer mixture of (-) of 9R configuration-Dao Nuoshi amino (-)-4-demethoxy-daunomycin ketone.
Separate this very similar diastereomer isomer, need through a long-time and pretty troublesome operation steps, this has seriously influenced the overall yield of needed final product.
Adopt to require improving one's methods of the power of giving a patent among the application, the original shortcoming of all that all can be eliminated, thereby can obtain the pure 4-demethoxy-daunorubicin of high yield.
The raw material that present method is used is the 4-demethoxy-daunomycin ketone (English Patent the 1st, 500, No. 421) of optically active, and it has natural 7S: the 9S configuration.Make it in suitable organic solvent (as chloroform or methylene dichloride), and under the condition that soluble silver salt and molecular sieve as dewatering agent exist, follow the 1-fontanel derivative of road Nuo Shi amine to carry out condensation with protecting group.
Used silver salt trifluoro-methane sulfonic acid silver (AgSO
3CF
3) solubility in organic solvent, condensation reaction can be carried out in homogeneous phase, thereby avoided the well-known complicacy [people such as Ge Zewuerfu of Buddhist nun Ke Gus in the presence of the compound of insoluble silver or mercury-Nore reaction, " applied chemistry " (Gunther Wuiff et al.Ang.Chem.Int.Ed.(West Germany) 13,157(1974))].
This condensation reaction can be finished at short notice, obtains the glucosides that protecting group is arranged of high yield.And amazing and very importantly: this reaction is stereospecific, promptly only forms α end group isomer in reaction, like this, does not just need the end group isomer is carried out the chromatographic separation of trouble.Following examples explanation the present invention.
Example 1
N-TFA-4-demethoxy-daunorubicin
4-demethoxy-daunomycin the ketone (British Patent No. 1,500,421) of 1 gram optically active is dissolved in 100 milliliters contains 1.2 gram 1-chloro-N, in the anhydrous methylene chloride of 0-trifluoroacetyl road Nuo Shi amine.Solution is in the presence of 10 mol sieves (4
Merck) with being dissolved in the gram of 0.86 in 40 milliliters of ether AgSO
3CF
3Handle.Place after 20 minutes the saturated NaHCO of reaction mixture under the room temperature
3The solution neutralization.Isolate organic phase, boil off organic solvent under the vacuum.The glucosides that has protecting group on relevant N on its glycosyloxy ring that generates, the O atom was handled 30 minutes with 200 ml methanol at 50 ℃.
After boiling off organic solvent, obtain the thick product of 1.4 grams.This thick product with after the chloroform recrystallization, is obtained the pure N-TFA base-4-demethoxy-daunorubicin of 1.3 grams.Fusing point: 155～157 ℃; [α]
20 D=+188 ° (C=0.1 diox).
Example 2
4-demethoxy-daunorubicin hydrochloride (I)
To get 0.6 gram by the N-TFA base-4-demethoxy-daunorubicin that makes described in the example 1 and be dissolved in 5 milliliters of acetone, solution is with 40 milliliters of 0.1NNaOH solution-treated.Place under the room temperature after 30 minutes, regulate the pH value to 8 of this solution, use chloroform multiple extraction then with hydrochloric acid.Each time chloroform extracted solution is merged, and drying also is concentrated to small volume, and the absolute methanol solution with hydrogenchloride is acidified to PH3.5 with it then.In wherein adding excessive ether, obtain the pure 4-demethoxy-daunorubicin hydrochloride of 0.35 gram.Fusing point: 183～185 ℃ [α]
20 D=+205 ° (C=0.1 methyl alcohol).
Claims (1)
1, the 4-demethoxy-daunorubicin hydrochloride of a kind of following formula of preparation (I):
Improve one's methods, it is characterized in that and will be dissolved in the 7S that has of following formula II in the anhydrous methylene chloride: the 4-demethoxy-daunomycin ketone of the optically active of 9S configuration:
In the presence of silver triflate and molecular sieve, in the 1-chloro-N of room temperature with following formula III, O-trifluoroacetyl group road Nuo Shi amine:
React, obtain the N of following formula IV, the 4-demethoxy-daunorubicin of O-trifluoroacetyl group protection:
Earlier compound (IV) is removed first protecting group with methyl alcohol; obtain the derivative of N-TFA base protection; remove second protecting group with dilute sodium hydroxide aqueous solution then; obtain the needed 4-demethoxy-daunorubicin (I) that exists with the free glycoside alkali form, at last its isolated in form with corresponding hydrochloride is come out.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN198585103835A CN85103835A (en) | 1985-05-13 | 1985-05-13 | Improving one's methods of preparation 4-demethoxy-daunorubicin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN198585103835A CN85103835A (en) | 1985-05-13 | 1985-05-13 | Improving one's methods of preparation 4-demethoxy-daunorubicin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN85103835A true CN85103835A (en) | 1986-11-12 |
Family
ID=4793468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN198585103835A Pending CN85103835A (en) | 1985-05-13 | 1985-05-13 | Improving one's methods of preparation 4-demethoxy-daunorubicin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN85103835A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019057165A1 (en) * | 2017-09-22 | 2019-03-28 | 南京正大天晴制药有限公司 | Crystal form of idarubicin hydrochloride monohydrate |
-
1985
- 1985-05-13 CN CN198585103835A patent/CN85103835A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019057165A1 (en) * | 2017-09-22 | 2019-03-28 | 南京正大天晴制药有限公司 | Crystal form of idarubicin hydrochloride monohydrate |
| CN111094313A (en) * | 2017-09-22 | 2020-05-01 | 南京正大天晴制药有限公司 | Crystalline form of idarubicin hydrochloride monohydrate |
| CN111094313B (en) * | 2017-09-22 | 2022-07-05 | 南京正大天晴制药有限公司 | Crystalline form of idarubicin hydrochloride monohydrate |
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