CN109836404A - Intermediate of epirubicin hydrochloride compound - Google Patents
Intermediate of epirubicin hydrochloride compound Download PDFInfo
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- CN109836404A CN109836404A CN201711186718.4A CN201711186718A CN109836404A CN 109836404 A CN109836404 A CN 109836404A CN 201711186718 A CN201711186718 A CN 201711186718A CN 109836404 A CN109836404 A CN 109836404A
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Abstract
The present invention provides a kind of new intermediate of epirubicin hydrochloride compound.The yield and purity of epirubicin hydrochloride can be significantly improved using the intermediate, and reaction condition is mild；The use of bromine or bromo-derivative is avoided, it is environmental-friendly.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of intermediate of epirubicin hydrochloride compound.
Background technique
Epirubicin hydrochloride also known as Farmorubine Hydrochloride belong to Anthraquinones antibiotic, chemical name: (8S, 10S) -10-
[(3 '-amino -2 ', 3 ', 6 '-three deoxidation-alpha-L- arabopyranose bases)-O-] -6,8,11- trihydroxy -8- hydroxyl acetyl
Base -1- methoxyl group -7,8,9,10- tetrahydro aphthacene -5,12- dione hydrochlorides, structural formula are as follows:
Epirubicin hydrochloride is by Pfizer's exploitation for treating the anthracene nucleus antineoplastic antibiosis of breast cancer, lung cancer, liver cancer
Element lists for 1984 in Europe, lists in the U.S. within 1999.In treatment leukaemia, lymthoma and various solid tumors (including cream
Gland cancer, non-small cell tumour, cervix cancer and head and neck cancer) in have a wide range of applications.Its mechanism of action is to be directly embedded into DNA
Between core alkali pair, transcription is interfered, the formation of mRNA is prevented, to inhibit the synthesis of DNA and RNA.In addition, Epi-ADM pair
Type Ⅱ topoisomerase also has inhibiting effect.It is effective to a variety of transplanted tumors for a cell cycle nonspecific agent (CCNSA).With Ah
Mycin is compared, and curative effect is equal or slightly higher, but smaller to the toxicity of heart.
Epirubicin hydrochloride can be fermented or semi-synthetic obtained.CN102154192A discloses a kind of vacation for producing Epi-ADM
Pseudomonas, it is lower by the resulting Epi-ADM fermentation unit of this method, do not have industrialization meaning also at present.It is semi-synthetic
It is to obtain epirubicin hydrochloride as raw material chemical synthesis to ferment obtained daunorubicin hydrochloride or doxorubicin hydrochloride.
Need to overturn the hydroxyl of the upper 4 '-position of sugar using daunorubicin hydrochloride as the method for Material synthesis epirubicin hydrochloride at present
With in 14- introducing hydroxyls, synthetic route reported in the literature is as follows:
WO2006096665A is disclosed said synthesis route (1), and 21 react with trifluoacetic anhydride and make hydroxyl and amino three on sugar
Only make ester hydrolysis obtain 22,22 after fluoroacetylation under sodium bicarbonate effect to go into the well in dimethyl sulfoxide (DMSO) and oxalyl chloride effect
Swern aoxidize 23,23 after sodium triacetoxy borohydride restores sodium hydroxide effect under deamination protect table is soft red
Mycin (24), the first bromo in 24 position 14- hydrolyze again, and the reaction of 2 steps introduces hydroxyl and obtains 1 epirubicin hydrochloride.Totally seven steps are anti-for the route
It answers, total recovery 26%.This method step is shorter but Swern oxidation reaction needs to carry out in a low temperature of being lower than -60 DEG C, energy consumption
Height, it is industrial relatively difficult to achieve；And Pummerer translocation reaction forms intermediate alcoxyl sulfonium salt and breaks to form impurity, in subsequent step
It is difficult to remove in rapid.
US5945518A is disclosed said synthesis route (2), and 21 react with trifluoacetic anhydride and make hydroxyl and amino trifluoro on sugar
So that ester hydrolysis is obtained 22,22 after acetylation under sodium bicarbonate effect activates hydroxyl at ester with trifluoromethanesulfonic acid anhydride reactant
Afterwards with N, O- bis- trimethyl silane yl acetamides (BSA) reaction protection hydroxyls obtain 27,27 reacted with triethylamine isobutyrate after
Desiliconization is protected under potassium fluoride effect, under sodium hydroxide effect in desugar hydroxyl protecting group, the protecting group of amino in desugar
The first bromo in the position 14- for obtaining 24,24 hydrochlorides hydrolyzes again, and the reaction of 2 steps introduces hydroxyl and obtains 1 epirubicin hydrochloride, and totally eight steps are reacted,
Total recovery 30%.
Two above reaction route has bromo-reaction, causes certain pollution to environment, and the preparation of above-mentioned route
The yield of epirubicin hydrochloride is lower, therefore it is necessary to provide a kind of reaction condition mild, environmentally friendly and in high yield
The method for preparing epirubicin hydrochloride.
Summary of the invention
In view of the deficiencies in the prior art, the purpose of the present invention is to provide a kind of new intermediate of epirubicin hydrochloride chemical combination
Object.The yield and purity of epirubicin hydrochloride can be significantly improved using the intermediate.Specific technical solution of the present invention is as follows:
A kind of intermediate of epirubicin hydrochloride compound, structural formula are as follows:
The intermediate the preparation method is as follows: using daunorubicin hydrochloride generate intermediate I, generated by intermediate I
Intermediate II, then intermediate II is aoxidized and generates intermediate III.Reaction route is as follows:
Preferably, the step of intermediate I being prepared with daunorubicin hydrochloride are as follows: under organic solvent, nitrogen protection, hydrochloric acid table
Soft to use pure water after reaction than star and trifluoroacetic acid anhydride reactant, concentration organic phase obtains intermediate I.
Preferably, the step of intermediate II being prepared by intermediate I are as follows: intermediate I and triethyl group silicon substrate triflate
It is reacted in pyridine, methanol and pure water is added, adjust pH7~8, the reaction was continued at room temperature, and organic phase is collected in liquid separation after reaction,
Saturated sodium-chloride water solution washing, collects and organic phase is concentrated and obtain intermediate II.
Preferably, the step of intermediate III being prepared by intermediate II are as follows: intermediate II is dissolved in toluene and pyridine, is added
Oxidant is reacted, and is washed after reaction with saturated sodium-chloride water solution, collects and organic phase is concentrated and obtain intermediate III.
Wherein, the step of intermediate III being prepared by intermediate II, use lead tetraacetate and Bronsted acid composite oxidant as
Oxidant, the Bronsted acid are preferably alchlor or titanium tetrachloride.
A method of epirubicin hydrochloride being prepared using intermediate III, reaction route is as follows:
Preferably, the step of intermediate IV being prepared by intermediate III are as follows: by intermediate III, methanol, methylene chloride investment is anti-
It answers in bottle, under nitrogen protection, cooling instills the ethanol solution of sodium borohydride, acetone is added after reaction, hydrochloric acid tune pH is extremely
4.0, organic phase, pure water are collected in liquid separation, and concentration organic phase obtains intermediate IV.
Preferably, the step of intermediate V being prepared by intermediate IV are as follows: intermediate IV is dissolved in chloroform, add potassium fluoride and
Acetic acid triethylamine, reacts at room temperature, liquid separation and collects organic phase after reaction, and pure water, anhydrous sodium sulfate are dry, concentration
Intermediate V is obtained to doing, crossing silicagel column.
Preferably, the step of epirubicin hydrochloride being prepared by intermediate V are as follows: intermediate V is suspended in pure water, is cooled down
To 0~4 DEG C, sodium hydroxide solution insulation reaction, hydrochloric acid tune pH to 5.0 are instilled, methylene chloride washs, and dichloro is added in water phase
Methane and methanol, sodium hydroxide tune pH to 8.2, liquid separation simultaneously collect organic phase, are concentrated under reduced pressure；Normal propyl alcohol is added, after mixing
0.1mol/L ethanol solution of hydrogen chloride is added, continues to be concentrated, n-hexane crystallization is added, filters dry epirubicin hydrochloride.
In the prior art, the oxidants such as dimethyl sulfoxide can just obtain epirubicin hydrochloride after generally requiring bromo-reaction.
The present invention replaces dimethyl sulfoxide as oxidant using lead tetraacetate and Bronsted acid as composite oxidant, by intermediate II
14- methyl oxidations, are not required to bromo and addition Bronsted acid all improves a lot to reaction rate and reaction yield, meanwhile, it avoids
Pummerer translocation reaction forms intermediate alcoxyl sulfonium salt and breaks to form impurity in Swern oxidation reaction.The reaction route energy
Consume low, reaction condition is mild；The use of bromine or bromo-derivative is avoided, it is environmental-friendly.Gained salt according to the technical solution of the present invention
The total recovery of sour epirubicin is more than 60%, is much higher than the prior art；Products obtained therefrom HPLC purity is higher than 99.6%, and list is miscellaneous to be less than
0.2%.
Specific embodiment
The content of patent in order to better understand the present invention further illustrates the present invention below by specific embodiment
Technical solution, but these embodiments are not intended to limit the present invention.The yield is molar yield.
The synthesis of 1 intermediate I of embodiment
630ml methylene chloride is put into reaction flask, 7.50g daunorubicin hydrochloride is cooled to -2~2 under nitrogen protection
DEG C, 13.9ml trifluoroacetic anhydride is instilled at this temperature, and insulation reaction 1h is washed twice with pure water 200mlx2, and organic phase is concentrated
Obtain intermediate I, yield 100%, HPLC purity 97.6%.
The synthesis of 2 intermediate II of embodiment
Into reaction flask put into 870ml methylene chloride, 8.76g intermediate I, at room temperature be added 10.2ml pyridine and
25.5ml triethyl group silicon substrate triflate reacts 4h at room temperature, 170ml methanol and 200ml pure water is added, with 5% carbonic acid
Hydrogen sodium water solution tune pH to 7.5 reacts 2h at room temperature, collects organic phase after liquid separation, with saturated sodium-chloride water solution 200mlx2
It washes twice, collects and organic phase is concentrated and obtain intermediate II, yield 90.0%, HPLC purity 98.2%.
The synthesis of 3 intermediate III of embodiment
11.6g intermediate II is dissolved in 1160ml toluene and 11.0ml pyridine, 3.27g lead tetraacetate and 0.16g is added
Alchlor is washed twice in 30 DEG C of insulation reaction 12h with saturated sodium-chloride water solution 200mlx2, collects and organic phase is concentrated
Obtain intermediate III, yield 86.0%, HPLC purity 97.8%.
The synthesis of 4 intermediate III of embodiment
11.6g intermediate II is dissolved in 1160ml toluene and 11.0ml pyridine, 3.27g lead tetraacetate and 0.12g is added
Titanium tetrachloride is washed twice in 30 DEG C of insulation reaction 12h with saturated sodium-chloride water solution 200mlx2, collects and organic phase is concentrated
Obtain intermediate III, yield 89.4%, HPLC purity 98.2%.
The synthesis of 5 intermediate IV of embodiment
By 10.41g intermediate III, 355ml methanol, 170ml methylene chloride is put into reaction flask, is cooled down under nitrogen protection
To -2~2 DEG C, about 15min instills solution of the 0.115g sodium borohydride in 71ml dehydrated alcohol, insulation reaction at this temperature
5.0ml acetone is added after 20min to be collected organic phase with 0.1mol/L hydrochloric acid solution tune pH to 4.0 after liquid separation, used pure water
200mlx2 is washed twice, and concentration organic phase obtains intermediate IV, yield 90.1%, HPLC purity 97.3%.
The synthesis of 6 intermediate V of embodiment
9.39g intermediate IV is dissolved in 939ml chloroform, 93.9ml48% potassium fluoride solution and 2g vinegar triethylenetetraminehexaacetic acid is added
Amine reacts 25h at room temperature, and liquid separation simultaneously collects organic phase, washs x2 twice with pure water 200ml, and anhydrous sodium sulfate is dry, is concentrated into
It did silicagel column (mobile phase is methylene chloride: acetone=95:5) and obtains intermediate V, yield 92.0%, HPLC purity 96.9%.
The synthesis of 7 epirubicin hydrochloride of embodiment
5.69g intermediate V is suspended in 260ml pure water, is cooled to 0~4 DEG C, instills 3.5% hydrogen at this temperature
Sodium hydroxide solution 45ml, insulation reaction 45min wash two with methylene chloride 100ml x2 with 1mol/L hydrochloric acid tune pH to 5.0
It is secondary, 780ml methylene chloride and 50ml methanol are added into water phase, with 0.1mol/L sodium hydroxide solution tune pH to 8.2, liquid separation is simultaneously
Organic phase is collected, 10ml is concentrated under reduced pressure into, 30ml normal propyl alcohol is added, 0.1ml0.1mol/L hydrogen chloride second is added after mixing
Alcoholic solution continues to be concentrated into 10ml, filters dry finished product epirubicin hydrochloride；Yield 96.0%, HPLC purity
99.6%, largest single impurity is less than 0.18%.
The synthesis of 1 intermediate III of comparative example
11.6g intermediate II is dissolved in 1160ml toluene and 11.0ml pyridine, 3.27g lead tetraacetate is added, at 30 DEG C
Insulation reaction 12h is washed twice with saturated sodium-chloride water solution 200mlx2, collects and organic phase is concentrated and obtain intermediate III, yield
42.1%, HPLC purity 76.3%.
The synthesis of 2 intermediate III of comparative example
11.6g intermediate II is dissolved in 1160ml toluene and 11.0ml pyridine, 3.27g lead tetraacetate and 0.09g is added
Boron trifluoride is washed twice in 30 DEG C of insulation reaction 12h with saturated sodium-chloride water solution 200mlx2, collects and organic phase is concentrated
Obtain intermediate III, yield 56.2%, HPLC purity 92.3%.
III compound of intermediate is analyzed with 1H-NMR and MS mass spectrum:
H-NMR (DMSO-d6) δ 0.90~0.94 (27H, m, CH3CH2), 1.23 (3H, d, CH3-6 '), 1.43~1.48
(18H, m, CH3CH2), 1.75~2.12 (4H, m, CH2-2 '+CH2-8), 2.85 (3H, S, COCH3), 3.06 (2H, brs,
CH2-10), 3.62(3H,S,OCH3),4.22(1H,q,CH-5’),4.38(1H,t,CH-3’),5.03(1H,brs,CH-
1 '), 5.06 (2H, S, COCH2O), 5.20 ((1H, t, CH-7), 7.78~8.08 (2H, brs, NH3), 7.93~8.18 (3H,
m,Ar)。
MS(ESI):1023.2338(m+h+)。
Claims (9)
1. a kind of intermediate of epirubicin hydrochloride compound is shown in formula III, structural formula is as follows:
2. a kind of preparation method of midbody compound described in claim 1, which comprises the steps of: utilize
Daunorubicin hydrochloride generates intermediate I, generates intermediate II by intermediate I, then intermediate II is aoxidized and generates intermediate III.
3. preparation method according to claim 2, which is characterized in that the step of preparing intermediate I with daunorubicin hydrochloride are as follows:
Under organic solvent, nitrogen protection, epirubicin hydrochloride and trifluoroacetic acid anhydride reactant use pure water, concentration after reaction
Organic phase obtains intermediate I.
4. preparation method according to claim 2, which is characterized in that the step of preparing intermediate II by intermediate I are as follows: intermediate
Body I reacts in pyridine with triethyl group silicon substrate triflate, and methanol and pure water is added, and adjusts pH7~8, continues at room temperature anti-
It answers, organic phase is collected in liquid separation after reaction, and saturated sodium-chloride water solution washing collects and organic phase is concentrated and obtains intermediate II.
5. preparation method according to claim 2, which is characterized in that the step of preparing intermediate III by intermediate II are as follows: will
Intermediate II is dissolved in toluene and pyridine, and oxidant reaction is added, is washed after reaction with saturated sodium-chloride water solution, is collected
And organic phase is concentrated and obtains intermediate III.
6. preparation method according to claim 5, which is characterized in that the oxidant is that lead tetraacetate and Bronsted acid form
Composite oxidant.
7. preparation method according to claim 6, which is characterized in that the Bronsted acid is alchlor or titanium tetrachloride.
8. any one preparation method according to claim 1~7, which is characterized in that synthetic route is as follows:
9. midbody compound described in claim 1 is preparing the purposes in epirubicin hydrochloride.
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| CN201711186718.4A CN109836404B (en) | 2017-11-24 | 2017-11-24 | Epirubicin hydrochloride intermediate compound |
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| CN201711186718.4A CN109836404B (en) | 2017-11-24 | 2017-11-24 | Epirubicin hydrochloride intermediate compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574267A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound III |
| CN115785168A (en) * | 2022-08-22 | 2023-03-14 | 浙江亚瑟医药有限公司 | Method for preparing 4-demethoxydaunorubicin hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006096665A1 (en) * | 2005-03-07 | 2006-09-14 | Solux Corporation | Epimerization of 4'-c bond and modification of 14-ch3-(co)-fragment in anthracyclin antibiotics |
| JP2007261976A (en) * | 2006-03-28 | 2007-10-11 | Meiji Seika Kaisha Ltd | Method for producing antineoplastic anthracycline-based antibiotic |
| CN106749447A (en) * | 2017-01-10 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of intermediate of epirubicin hydrochloride compound |
-
2017
- 2017-11-24 CN CN201711186718.4A patent/CN109836404B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006096665A1 (en) * | 2005-03-07 | 2006-09-14 | Solux Corporation | Epimerization of 4'-c bond and modification of 14-ch3-(co)-fragment in anthracyclin antibiotics |
| JP2007261976A (en) * | 2006-03-28 | 2007-10-11 | Meiji Seika Kaisha Ltd | Method for producing antineoplastic anthracycline-based antibiotic |
| CN106749447A (en) * | 2017-01-10 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of intermediate of epirubicin hydrochloride compound |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574267A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound III |
| CN115785168A (en) * | 2022-08-22 | 2023-03-14 | 浙江亚瑟医药有限公司 | Method for preparing 4-demethoxydaunorubicin hydrochloride |
| CN115785168B (en) * | 2022-08-22 | 2023-11-07 | 浙江亚瑟医药有限公司 | Method for preparing 4-demethoxydaunorubicin hydrochloride |
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