CN103421059B - A kind of synthetic method of amrubicin - Google Patents
A kind of synthetic method of amrubicin Download PDFInfo
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- CN103421059B CN103421059B CN201210160062.XA CN201210160062A CN103421059B CN 103421059 B CN103421059 B CN 103421059B CN 201210160062 A CN201210160062 A CN 201210160062A CN 103421059 B CN103421059 B CN 103421059B
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Abstract
A synthetic method for amrubicin, with R-2-ethanoyl-2-acetylaminohydroxyphenylarsonic acid 5,8-dimethoxy-1,2; 3,4-naphthane is raw material, with the cyclization of phthalic acid anhydride acylation; with 1,3-PD and derivative protection carbonyl thereof, this protecting group is easier to slough in hydrolysis reaction.Adopt (+)-9-amino-4-demethoxylation soft red mould ketone of-9-deoxidation and 2-deoxidation-3; red-penta pyranyl-1 of 4-bis--O-ethanoyl-β-D-; 1; 1-trichlorine imido grpup acetic ester carries out nucleosides and is obtained by reacting (+)-9-amino-4-demethoxylation-9-deoxidation-7-O-(2-deoxidation-3; red-penta pyranyl of 4-bis--O-ethanoyl-β-D-) soft red mould ketone, remove ethanoyl and obtain amrubicin.This synthetic method effectively can avoid the generation of hydrolytic process isomer, and following purification steps is simple, and core reaction of guanosine significantly can reduce production cost, is suitable for industrial applications.
Description
Technical field
The present invention relates to a kind of synthetic method of amrubicin, belong to field of medicine and chemical technology.
Background technology
Cancer is the major disease of harm humans health, wherein the sickness rate of lung cancer accounts for front three, lung cancer is a kind of common pulmonary malignant tumour, in recent years along with the impact of smoking and various environmental factors, countries in the world are industrially developed country particularly, sickness rate and the case fatality rate of lung cancer rise all rapidly, die from lung cancer in the male patient of carninomatosis and rank first.Lung cancer can be divided into small cell lung cancer and nonsmall-cell lung cancer, and nonsmall-cell lung cancer can pass through operative treatment, also can pass through radiation and chemotherapy.Small cell lung cancer can only pass through chemotherapy.
Amrubicin Hydrochloride is that SUMITOMO CHEMICAL Pharmaceutical Co., Ltd develops complete synthesis anthracyclines anti-malignant tumor medicine, went on the market that (trade(brand)name: Kai De (CALSED), is approved for the treatment of nonsmall-cell lung cancer and small cell lung cancer in 2002 at Japan registration.As a kind of anthracycline drug, amrubicin is a kind of embedded type type Ⅱ topoisomerase (topoisomerase II, Topo II) inhibitor.Its mechanism of action and Zorubicin are slightly different, mainly by suppressing the activity of Topo II, finally cause the fracture of DNA and inhibition tumor cell is bred.Amrubicin does not almost have the ubiquitous cardiac toxic problem of anthracycline drug.In preclinical research work, amrubicin has just showed has better antitumour activity than traditional anthracycline drug.II clinical trial phase data show, amrubicin reaches 27.9% (wherein complete remission rate is 1.6%) to the efficient of nonsmall-cell lung cancer, efficient to small cell lung cancer, reaches 75.8% (wherein complete remission rate is 9.1%).
The synthetic method of amrubicin sees J.Org.Chem1987.52,4477-4485, and the amrubicin synthetic route that the document describes is as follows.
The method, with 5,8-dimethoxy-2-tetralin ketone starting raw material, is obtained by reacting R-2-ethanoyl-2-acetylaminohydroxyphenylarsonic acid 5 through 7 steps; 8-dimethoxy-1,2,3; 4-naphthane (compound 1); then use compound 1 and the cyclization of phthalic acid anhydride acylation, spent glycol protection carbonyl, is obtained by free radical reaction; finally hydrolysis obtains compound 5; with red-penta pyranyl bromine of 2-deoxidation-3,4-bis--O-ethanoyl-β-D-by core reaction of guanosine, be then hydrolyzed deacetylate and obtain amrubicin.In the process by this route synthesis amrubicin, find to have the following disadvantages:
(1) hydrolysis temperature is high, time is long, and (literature precedents is 80 DEG C, 30 hours), there is racemization in bibliographical information compound 5 part in hydrolytic process, the diastereomer producing compound 5 has 7-8%, not only reduce yield, and close with compound 5 character, not easily separated, can only be removed by column chromatography, complex operation, also needs a large amount of solvents;
(2) red-penta pyranyl bromine consumption of nucleosides reaction raw materials 2-deoxidation-3,4-bis--O-ethanoyl-β-D-many (3 equivalent), used catalyst trifluoro-methane sulfonic acid silver, expensive simultaneously.Produce amrubicin cost very high.
Summary of the invention
For solving the problem, the present invention develops a kind of novel synthesis preparing amrubicin on the basis of document (J.Org.Chem1987.52,4477-4485) amrubicin synthetic method, and synthetic route is as follows.
The present invention prepares the method for amrubicin through following six synthesis steps:
Step 1: reference literature; by R-2-ethanoyl-2-acetylaminohydroxyphenylarsonic acid 5; 8-dimethoxy-1,2,3; R-9-ethanoyl-9-acetylaminohydroxyphenylarsonic acid 6 is prepared in 4-naphthane (compound 1) and the cyclization of phthalic acid anhydride acylation; 11-dihydroxyl-7,8,9; 10-tetrahydrochysene-5,12-naphthacene diketone (compound 2).
Step 2: compound 2 1,3-PD and derivative protection carbonyl thereof obtain R-9-[1,1-(sub-third dioxy base) ethyl]-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8,9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 3).In the reaction of this step, the 1,3-PD used and the preferred 1,3-PD of derivative, 2，2-dimethyl-1，3-propanediol; Solvent can use varsol, as benzene,toluene,xylene, ethylbenzene.Range of reaction temperature is 80 ~ 150 DEG C, preferably 110 ~ 140 DEG C.
Step 3: compound 3 prepares R-9-acetylaminohydroxyphenylarsonic acid 9-[1,1-(sub-third dioxy base) ethyl]-4,5-dihydros-6 through free radical reaction, 13-dihydroxyl-4,14-methylene radical-2-methyl isophthalic acid 4H-anthra [3,2-f]-[1,3] oxazole alkene-7,12-diketone (compound 4).
Step 4: compound 4 is hydrolyzed the soft red mould ketone (compound 5) of preparation (+)-9-amino-4-demethoxylation-9-deoxidation.Reaction needed acid catalysis is carried out, and can use hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid.
Step 5: compound 5 and 2-deoxidation-3; red-penta pyranyl-1 of 4-bis--O-ethanoyl-β-D-; 1; 1-trichlorine imido grpup acetic ester (compound 7) carries out core reaction of guanosine preparation (+)-9-amino-4-demethoxylation-9-deoxidation-7-O-(red-penta pyranyl of 2-deoxidation-3,4-bis--O-ethanoyl-β-D-) soft red mould ketone (compound 6).
Step 6: compound 6 removes ethanoyl and prepares amrubicin.
The 1,3-PD used in above-mentioned reaction and derivative thereof, and the R in compound 3 and compound 4 represents hydrogen, methyl or ethyl.
In the present invention; with 1; the carbonyl of ammediol and derivative protection compound 2 thereof; this protecting group compares ethylene glycol protecting group can complete hydrolysis in relatively low temperature and shorter time; slough protecting group; thus avoid compound 5 overlong time and racemization in acid condition, produce diastereomer.
The preparation of compound 7 can adopt following route:
Compare with document, the carbonyl in synthetic route of the present invention adopts the protecting group more easily removed, and effectively can avoid the generation of the diastereomer of compound 5, therefore not need unnecessary purification step.Core reaction of guanosine adopts the relatively low low catalyzer trifluoromethane trifluoromethane trimethylsilyl group of price to replace expensive catalyzer silver triflate, significantly can reduce production cost, therefore be suitable for industrial applications.
The invention will be further described with comparative example by the following examples, but except following examples, the various replacement made according to ordinary skill knowledge and customary means or change, include within the scope of the invention.
Embodiment
Embodiment 1 reference literature J.Org.Chem1987.52,4477-4485 prepares compound 2
In there-necked flask; add sodium-chlor 73g; with aluminum trichloride (anhydrous) 273g; be warming up to about 130 DEG C; after being stirred to solid melting, add R-2-ethanoyl-2-acetylaminohydroxyphenylarsonic acid 5,8-dimethoxy-1; 2; 3,4-naphthane (compound 1) 20g and Tetra hydro Phthalic anhydride 20.6g, intensification 130-135 DEG C; react 1 hour; be cooled to 100-110 DEG C, add ethylene dichloride 200ml, stir; the slowly 10% oxalic acid aqueous solution 800ml that cools in advance of impouring, has toppled over rear temperature and has risen to 50-60 DEG C and stir 1 hour.Be cooled to 10-20 DEG C, stir filtration in 1 hour, filter cake washes 2 times with water, then stirs filtration in 1 hour with 2000ml water; filter cake methyl alcohol 600ml refines, and obtains R-9-ethanoyl-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8; 9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 2) 24g.
Embodiment 2 prepares compound 3
In there-necked flask, add R-9-ethanoyl-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7; 8; 9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 2) 20g; 1; ammediol 77g, dimethylbenzene 1200ml, tosic acid 1.3g; temperature rising reflux 3 hours, is gone out the moisture that reaction generates by water trap simultaneously.Then by reaction solution stirring at room temperature 1 hour, then be cooled to 0-5 DEG C and stir 2 hours, filter, after filter cake uses water and washing with alcohol successively, drying, obtains R-9-[1,1-(sub-third dioxy base) ethyl]-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8,9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 3, R=H) 20.8g.
Embodiment 3 prepares compound 3
In there-necked flask, add R-9-ethanoyl-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7; 8,9,10-tetrahydrochysene-5; 12-naphthacene diketone (compound 2) 20g; 2，2-dimethyl-1，3-propanediol 106g; dimethylbenzene 1200ml; tosic acid 1.3g, temperature rising reflux 3 hours, is gone out the moisture that reaction generates by water trap simultaneously.Then by reaction solution stirring at room temperature 1 hour, then be cooled to 0-5 DEG C and stir 2 hours, filter, after filter cake uses water and washing with alcohol successively, dry, obtain R-9-[1,1-(2, the sub-third dioxy base of 2-dimethyl) ethyl]-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8,9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 3, R=CH
3) 21.6g.
Embodiment 4 prepares compound 4
In there-necked flask, add R-9-[1, the sub-third dioxy base of 1-() ethyl]-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8,9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 3, R=H) 20g, tetracol phenixin 1600ml, N-bromo-succinimide 11.8g, Diisopropyl azodicarboxylate 1g, temperature rising reflux reacts 2 hours, add saturated sodium bicarbonate aqueous solution 200ml, sodium thiosulfate solution 200ml, is incubated 50-60 DEG C and stirs 1 hour, separate organic layer, 4 times are extracted, each 300ml with 1N aqueous hydrochloric acid.Merge sour water layer, with chloroform extraction 5 times, each 200ml, then combined chloroform, washs once with clear water 200ml, concentrated after dry, residuum 60ml isopropyl ether stirs, and filters, obtains R-9-acetylaminohydroxyphenylarsonic acid 9-[1, the sub-third dioxy base of 1-() ethyl]-4,5-dihydro-6,13-dihydroxyl-4,14-methylene radical-2-methyl isophthalic acid 4H-anthra [3,2-f]-[1,3] oxazole alkene-7,12-diketone (compound 4, R=H) 15.6g.
Embodiment 5 prepares compound 4
In there-necked flask, add R-9-[1,1-(2,2-dimethyl sub-third dioxy base) ethyl]-9-acetylaminohydroxyphenylarsonic acid 6,11-dihydroxyl-7,8,9,10-tetrahydrochysene-5,12-naphthacene diketone (compound 3, R=CH
3) 20g, tetracol phenixin 1600ml, N-bromo-succinimide 11.1g, Diisopropyl azodicarboxylate 1g, temperature rising reflux reacts 2 hours, add saturated sodium bicarbonate aqueous solution 200ml, sodium thiosulfate solution 200ml, is incubated 50-60 DEG C and stirs 1 hour, separate organic layer, 4 times are extracted, each 300ml with 1N aqueous hydrochloric acid.Merge sour water layer, with chloroform extraction 5 times, each 200ml, then combined chloroform, washs once with clear water 200ml, concentrated after dry, residuum 50ml isopropyl ether stirs, and filters, obtains R-9-acetylaminohydroxyphenylarsonic acid 9-[1, the sub-third dioxy base of 1-(2,2-dimethyl) ethyl]-4,5-dihydros-6,13-dihydroxyl-4,14-methylene radical-2-methyl isophthalic acid 4H-anthra [3,2-f]-[1,3] oxazole alkene-7,12-diketone (compounds 4, R=CH
3) 15.2g.
Embodiment 6 prepares compound 5
R-9-acetylaminohydroxyphenylarsonic acid 9-[1 is added in there-necked flask, the sub-third dioxy base of 1-() ethyl]-4, 5-dihydro-6, 13-dihydroxyl-4, 14-methylene radical-2-methyl isophthalic acid 4H-anthra [3, 2-f]-[1, 3] oxazole alkene-7, 12-diketone (compound 4, R=H) 15g, 3N aqueous sulfuric acid 1200ml, 60-70 DEG C of insulation reaction 8 hours, with sodium bicarbonate aqueous solution regulator solution pH value 7-8, with chloroform extraction water layer 4 times, each 300ml, combined chloroform layer, wash rear drying with water, concentrated after filtering, residuum isopropyl ether 60ml stirs, obtain (+)-9-amino-4-demethoxylation-9-deoxidation soft red mould ketone (compound 5) 10.1g.
Embodiment 7 prepares compound 5
R-9-acetylaminohydroxyphenylarsonic acid 9-[1,1-(2,2-dimethyl sub-third dioxy base) ethyl]-4,5-dihydros-6 are added in there-necked flask, 13-dihydroxyl-4,14-methylene radical-2-methyl isophthalic acid 4H-anthra [3,2-f]-[1,3] oxazole alkene-7,12-diketone (compounds 4, R=CH
3) 15g, 3N aqueous sulfuric acid 1200ml, 60-70 DEG C of insulation reaction 8 hours, with sodium bicarbonate aqueous solution regulator solution pH value 7-8, with chloroform extraction water layer 4 times, each 300ml, combined chloroform layer, washes rear drying with water, concentrated after filtering, residuum isopropyl ether stirs, and obtains (+)-9-amino-4-demethoxylation-9-deoxidation soft red mould ketone (compound 5) 9.6g.
Embodiment 8 prepares compound 7
1, 3, 4-tri--O-ethanoyl-2-deoxidation-β-D-ribose 10.6g is dissolved in the mixing solutions of tetrahydrofuran (THF) 70ml and methyl alcohol 30ml, less than 0 DEG C passes into dry ammonia 30 minutes, room temperature reaction half an hour, white solid is obtained by concentrated for reaction solution, residuum is dissolved with methylene dichloride, less than 0 DEG C adds Trichloroacetonitrile 21ml and DBU0.4ml, stirring at room temperature 2 hours, with 10% acetic acid,diluted solution washing, dry, concentrate and obtain melicera 2-deoxidation-3, red-penta pyranyl-1 of 4-bis--O-ethanoyl-β-D-, 1, 1-trichlorine imido grpup acetic ester (compound 7) 15.2g, purifying is not needed to be directly used in the next step.
Embodiment 9 prepares compound 6
The 2-deoxidation-3 that (+)-9-amino-4-demethoxylation soft red mould ketone (compound 5) 10g of-9-deoxidation and upper step obtain, red-penta pyranyl-1 of 4-bis--O-ethanoyl-β-D-, 1, 1-trichlorine imido grpup acetic ester (compound 7) 15.2g is dissolved in methylene dichloride 300ml, add powder 4A molecular sieve 3g, be cooled to-10 DEG C, drip Trimethylsilyl trifluoromethanesulfonate 6.4ml and anhydrous diethyl ether 60ml solution, drip off-10-20 DEG C of reactions 4 hours, add saturated sodium bicarbonate aqueous solution 100ml, after stirring, cross and filter insolubles, filtrate is washed with saturated brine, dry, filter, stir with isopropyl ether after concentrated, obtain (+)-9-amino-4-demethoxylation-9-deoxidation-7-O-(2-deoxidation-3, red-penta pyranyl of 4-bis--O-ethanoyl-β-D-) soft red mould ketone (compound 6) 13.1g.
Embodiment 10 prepares amrubicin
(+)-9-amino-4-demethoxylation-9-deoxidation-7-O-(2-deoxidation-3; red-penta pyranyl of 4-bis--O-ethanoyl-β-D-) soft red mould ketone (compound 6) 12g is dissolved in the mixed solvent of methylene dichloride 1000ml and methyl alcohol 400ml; salt of wormwood 12g is added below 0 DEG C; then 0-5 DEG C are stirred 16 hours; PH to 5-6 is regulated with 30% phosphate aqueous solution; use chloroform extraction mixed solution; merge organic layer; washing; drying, is concentrated into volume and is about 100ml after filtration, cooling; filter, obtain amrubicin 9.6g.
Claims (1)
1. a synthetic method for amrubicin, is characterized in that with compound 1 for raw material, with the cyclization of phthalic acid anhydride acylation, obtains compound 2; Then with the 1,3-PD protection carbonyl that 1,3-PD or 2 replace, structural formula:
, wherein R=hydrogen, methyl or ethyl; Obtain compound 3; Then compound 4 is obtained through free radical reaction; Then hydrolysis obtains compound 5 in acid condition; Then carry out nucleosides with compound 7 and be obtained by reacting compound 6; Then remove ethanoyl and obtain amrubicin, synthetic route is as follows:
Wherein R=hydrogen, methyl or ethyl.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4673668A (en) * | 1982-10-22 | 1987-06-16 | Sumitomo Pharmaceuticals Company | Aminonaphthacene derivatives |
| CN1489469A (en) * | 2001-01-30 | 2004-04-14 | ס����ҩ��ʽ���� | Medicine for lung cnncer |
| CN1814612A (en) * | 2005-02-02 | 2006-08-09 | 江苏豪森药业股份有限公司 | Ammonia maleate rubicin salt, and its preparing method and use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4673668A (en) * | 1982-10-22 | 1987-06-16 | Sumitomo Pharmaceuticals Company | Aminonaphthacene derivatives |
| CN1489469A (en) * | 2001-01-30 | 2004-04-14 | ס����ҩ��ʽ���� | Medicine for lung cnncer |
| CN1814612A (en) * | 2005-02-02 | 2006-08-09 | 江苏豪森药业股份有限公司 | Ammonia maleate rubicin salt, and its preparing method and use |
Non-Patent Citations (2)
| Title |
|---|
| Stereo- and regioselective glycosylation of 4-deoxy-Σ-rhodomycinone;Filip S. Ekholm，等;《Carbohydrate Research》;20110204;第346卷;第858-862页 * |
| Stereospecific Total Synhtesis of 9-Aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and Related Compounds;Kikuo Ishizumi，等;《Journal of Organic Chemistry》;19871231;第52卷(第20期);第4477-4485页 * |
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