CN106632158A - Preparation method of 7beta,10beta-dimethoxy-10-deacetylbaccatin III - Google Patents

Preparation method of 7beta,10beta-dimethoxy-10-deacetylbaccatin III Download PDF

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CN106632158A
CN106632158A CN201610921359.1A CN201610921359A CN106632158A CN 106632158 A CN106632158 A CN 106632158A CN 201610921359 A CN201610921359 A CN 201610921359A CN 106632158 A CN106632158 A CN 106632158A
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preparation
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silicon substrate
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CN106632158B (en
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明方永
黄金昆
蒲刚
阳建洪
武强
顾先涛
陈钰梅
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Jiangsu Hengrui Medicine Co Ltd
Chengdu Suncadia Pharmaceuticals Co Ltd
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Chengdu Suncadia Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a preparation method of 7beta,10beta-dimethoxy-10-deacetylbaccatin III. Particularly, the method provided by the invention takes acetylbaccatin as a raw material and comprises a series of the following steps: protecting through silicon protecting groups at a 7 site and a 13 site; selectively removing the silicon protecting group at the 7 site; directly alkylating at the 7 site and a 10 site; and finally, removing the silicon protecting group at the 13 site to prepare a taxane compound, namely the 7beta,10beta-dimethoxy-10-deacetylbaccatin III shown as a formula V. (The formula V is shown in the description.).

Description

The preparation method of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs
The application is Application No. 201310381240.6, and the applying date is August in 2013 28, entitled " 7 β, 10 The divisional application of the Chinese patent application of the preparation method of β-dimethoxy -10- deacetylate Baccatine IIIs ".
Technical field
The present invention relates to the field of chemical synthesis, more particularly to a kind of 7 β, 10 β-dimethoxy -10- deacetylate berries The preparation method of gibberellin III.
Background technology
Cabazitaxel (trade name：Jevtana it is) " to promote sexual gland to swash by the exploitation of French Sanofi-Aventis drugmaker Hormone-releasing hormone (GnRH) " acceptor inhibitor class medicine, is in metastatic hormone refractory mainly for Dinner phase patients with prostate cancer Property prostate cancer second line treatment in first and only one the medicine that significantly existence benefits is provided.And 7 β, 10 β-diformazan Oxy-1 0- deacetylates Baccatine III exactly synthesizes a key intermediate of Cabazitaxel.
7 β of CN1179116A reports, the synthetic route of 10 β-dimethoxy -10- deacetylate Baccatine IIIs is such as Shown in following scheme 1.The reaction does alkali respectively to C using sodium hydride7And C10On hydroxyl methylated, this is industrial production Bring the danger of potential blast.
Scheme 1
7 β of CN1270586A reports, the synthetic route of 10 β-dimethoxy -10- deacetylate Baccatine IIIs is such as Shown in following scheme 2.Although the reaction is disposable to C7And C10On hydroxyl methylated and yield is higher, but use Dangerous bigger hydrofining makees alkali, and the impurity of similar structures is more, not easy purification.
Scheme 2
7 β of patent CN102659721A report, the synthesis of 10 β-dimethoxy -10- deacetylate Baccatine IIIs Route is as shown in following scheme 3.Reaction Jing is protected twice and deprotected, although disposable by C7And C10Hydroxyl methylates, But make alkali using dangerous sodium hydride, and step is long, is readily incorporated impurity.
Scheme 3
Therefore provide a kind of safe, be suitable for preparing 7 β in a large number, 10 β-dimethoxy -10- deacetylate berries are red mould The method of plain III will have great importance.
The content of the invention
It is an object of the invention to overcome the weak point in said method, there is provided one kind can simply, safely prepare 7 The method of β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs.
To achieve these goals, the present invention is provided 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs Preparation method it is as described below：
1) selective protection of hydroxyl is carried out to compound shown in formula I, the compound as shown in Formula II is obtained, wherein R is (C1-10Alkyl or C6-10Aryl)3Silylation, preferred trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, the tert-butyl group two Methylsilyl, tert-butyl diphenyl silicon substrate
2) to step 1) compound as shown in Formula II for preparing carries out selective deprotection, obtains such as formula III institute The compound for showing
3) to step 2) compound as shown in formula III for preparing carries out the methylation reaction of hydroxyl, obtains such as formula Compound shown in IV
4) to step 3) compound as shown in formula IV for preparing carries out silicon substrate deprotection, obtains shown as a formula V Compound
In step 1) middle selection (C1-10Alkyl or C6-10Aryl)3Silylation may be selected its corresponding halo as protection group Thing is protection reagent, such as when using triethyl group silicon substrate (TES), t-Butyldimethylsilyl (TBS), trimethyl silicon substrate (TMS), The protection reagent for being used includes but is not limited to TESX, TBSX, TMSX, and wherein X is F, Cl, Br, I.Step 1) in reaction it is molten Agent is selected from pyridine, N,N-dimethylformamide；Reaction temperature is from 0～120 DEG C.
In a preferred embodiment of the invention, step 2) in reagent used by Deprotection selected from hydrofluoric acid pyridiniujm, Hydrofluoric acid triethylamine salt, tetrabutyl amine fluoride, hydrogen chloride, hydrogen bromide, preferred hydrofluoric acid triethylamine salt；Step 2) in Deprotection Reaction dissolvent used is selected from dichloromethane, chloroform, ethyl acetate, methyl tertiary butyl ether(MTBE), toluene, preferred dichloromethane.
In a preferred embodiment of the invention, step 3) in using iodomethane or dimethyl suflfate methylating as hydroxyl Reagent, preferred iodomethane；Step 3) in methylating for hydroxyl carry out under nitrogen protection；Reaction dissolvent in step (3) is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, 2- methyltetrahydrofurans.
In a preferred embodiment of the invention, step 3) carry out in the presence of alkali, the alkali is selected from sodium methoxide, ethanol Sodium, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropyl amido, diisopropyl amido sodium, diisopropyl amido potassium, the preferred tert-butyl alcohol Potassium.
The used solvent of reaction is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrochysene furan in step (4) Mutter, 2- methyltetrahydrofurans.
In a particularly preferred embodiment of the present invention, the invention provides a kind of 7 β, 10 β-dimethoxy- The preparation method of 10- deacetylate Baccatine IIIs, it is comprised the following steps：
Step (1)：By mass volume ratio (10- 10-deacetylate-baccaIII IIIs (i.e. 10-DAB):Pyridine=1:10～20) Reactant is weighed, 10-DAB is dissolved in pyridine.By 10-DAB：Silylation mol ratio (10-DAB:Silylation reagent=1:2 ～silylation reagent, stirring reaction 16h at a temperature of 20 DEG C 20) are added dropwise, then rise to 110 DEG C of 1.5～2h of reaction；Decompression is steamed Evaporate, after removing most of pyridine, diluted with methyl tertiary butyl ether(MTBE)；Washed with the 1mol/L watery hydrochloric acid of 0.5～3 times of reactant volume Wash reactant 1～2 time, then with the water washing reactant of 2～3 times of reactant volumes, collect organic phase, be concentrated into original volume～ 1/10, add petroleum ether, crystallization to obtain white product 1 (Formula II compound).
Step (2)：The white product 1 obtained by step (1) is taken, by mass volume ratio 1:10～100 are dissolved in organic solvent In.(white product 1 in molar ratio:Organic salt or inorganic acid=1:1～organic salt or inorganic acid 2) are added dropwise, in 20 DEG C of temperature Lower stirring reaction 16h；With the saturated sodium bicarbonate washing reaction thing of 2～3 times of reactant volumes, organic phase is collected, be concentrated into Original volume～1/10, adds petroleum ether, crystallization to obtain white product 2 (formula III compound).
Step (3)：The white product 2 obtained by step (2) is taken, by mass volume ratio (white product 2:Organic solvent:Iodine first Alkane=1:2.5:10) in being dissolved in the mixed solvent of organic solvent and iodomethane, (white product 2 in molar ratio:Alkali=1:1～ 3) alkali, 0.5～2h of stirring reaction at a temperature of 0 DEG C is added dropwise；Reaction is quenched with glacial acetic acid；Vacuum distillation, removes organic solvent And iodomethane；Chromatographic column is crossed, white product 3 (formula IV compound) is obtained.
Step (4)：The white product 3 obtained by step (3) is taken, by mass volume ratio (white product 3:Organic solvent=1: 10～20) be dissolved in organic solvent, (white product 3 in molar ratio:Tetrabutyl amine fluoride=1:1～reactant liquor 2) is added, 2～4h of stirring reaction at a temperature of 20 DEG C；Vacuum distillation, removes organic solvent；With the water and two of 2～3 times of reactant volumes The mixed solvent beating of chloromethanes, obtains 7 β, 10 β-dimethoxy -10- deacetylate Baccatine III crude products, then with four The beating of hydrogen furans obtains sterling.
The present invention has advantages below：Than existing 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs Preparation method, the present invention do not use extremely inflammable and explosive highly basic sodium hydride and hydrofining, make production more safe and reliable.
Specific embodiment
Below with reference to the instantiation present invention explained in detail, so that those skilled in the art are more fully understood The present invention.Specific embodiment is merely to illustrate technical scheme, and limits the present invention never in any form.
Embodiment 1：The conjunction of 7 β, 13 β-bis- (triethyl group silicon substrate) -10- deacetylate Baccatine IIIs (compound II) Into
10-DAB (50g, 92mmol) is dissolved in anhydrous pyridine (100ml), under nitrogen protection, 0 DEG C of addition triethyl group Chlorosilane (40ml), is warmed to room temperature reaction 16h, makes reactant mixture be warming up to 110 DEG C, is subsequently added chlorotriethyl silane (40ml) after, reacting 2 hours at about 110 DEG C, reactant mixture is dropped into room temperature, adds water (300ml) dilution, use methyl- tert fourth Base ether (100ml) is extracted, and TLC detects water layer without product.Organic layer is washed with the hydrochloric acid (100ml) of 1mol/L, water (100ml × 2) wash, sodium sulphate is dried, filter, be evaporated to original volume about 1/10, add petroleum ether (40ml) crystallization, collect white solid Body obtains 28.6g, yield：40%.
1H-NMR(400MHz；Deuterochloroform)：δ (ppm) 0.55 and 0.68 (2mts, the CH in ethyl2)；0.94 and 1.03 (2t, 9H, the CH in ethyl3)；1.08 (s, 3H, CH3)；1.17 (s, 3H, CH3)；1.58 (s, 1H, OH, 1)；1.73 (S, 3H, CH3) 1.91 and 2.57 (2mts, 1H, CH2H6)；2.04 (s, 3H, CH3)；2.12 and 2.23 (2dd, J=16 and 9,1H, CH2 14)；2.30 (s, 3H, COCH3)；3.88 (d, J=7,1H, H3)；4.16 and 4.32 (2d, J=8.5,1H, CH220)；4.27 (d, J=1,1H, OH 10)；4.40 (dd, J=11 and 7,1H, H7)；4.95 (wide d, J=10,1H, H5)；4.95 (m, 1H, H13)；5.16 (d, J=1,1H, H10)；5.60 (d, J=7,1H, H2)；7.46 (t, 2H, J=7.5, CH OCOC6H5Meta)； 7.60 (1H, t, J=7.5, CH OCOC6H5Contraposition)；8.09 (1H, d, J=7.5, CH OCOC6H5Ortho position).
Embodiment 2：The synthesis of 13 β-triethyl group silicon substrate -10- deacetylate Baccatine IIIs (compound III)
7 β, 13 β-bis- (triethyl group silicon substrate) -10- deacetylate Baccatine IIIs (10g, 13mol) are dissolved in into dichloromethane In alkane (100ml), triethylamine hydrofluoride (80ml) being added at room temperature, 16h being stirred under room temperature, TLC detection raw material reactions are complete Entirely, water (100ml × 3) washing, saturated sodium bicarbonate (100ml) washing, water (100ml) washing, sodium sulphate is added to be dried, mistake Filter, is evaporated to original volume about 1/10, adds petroleum ether (40ml) crystallization, collects white solid and obtains 6.5g, yield：76%, Content 96%.
1H-NMR(400MHz；Deuterochloroform)：δ (ppm) 0.63～0.70 (6H, m, CH2Ethyl)；0.99～1.04 (9H, T, J=8.0, CH3Ethyl)；1.09 (3H, s, CH3)；1.16 (3H, s, CH3)；1.45～1.47 (1H, d, J=7.6, OH 7)； 1.60 (1H, s, OH 1)；1.74 (3H, s, CH3)；1.79～1.86 and 2.55～2.63 (1H, 2m, CH2H6)；2.03 (3H, s, CH3)；2.09～2.16 and 2.21～2.27 (1H, 2dd, J=8.8/15.2, CH214)；2.29 (3H, s, CH3, COCH3)； 3.93～3.95 (1H, d, J=6.8, CH H3)；4.16～4.18 and 4.31～4.33 (1H, 2d, J=8.4, CH220)； 4.19～4.20 (1H, d, J=1.6, OH10)；4.24～4.29 (1H, m, CH H7)；4.93～5.00 (2H, m, CH H5 and 13)；5.23～5.24 (1H, d, J=1.6, CH H10)；5.63～5.65 (1H, d, J=7.2, CH H2)；7.46～7.50 (2H, t, J=7.8, CH OCOC6H5Meta)；7.59～7.63 (1H, t, J=7.4, CH OCOC6H5Contraposition)；8.08～8.10 (1H, d, J=7.2, CH OCOC6H5Ortho position).
Embodiment 3：13 β-the β of triethyl group silicon substrate -7,10 β-dimethoxy -10- deacetylate Baccatine III (chemical combination Thing IV) synthesis
13 β-triethyl group silicon substrate -10- deacetylate Baccatine IIIs (10g, 15.2mol) is dissolved in into tetrahydrofuran (20ml) in, add iodomethane (50ml), reaction solution is cooled into 0 DEG C, under nitrogen protection add potassium tert-butoxide (5.1mg, 45.6mmol), finish and about 1h is reacted at 0 DEG C, TLC detections raw material reaction completely, adds glacial acetic acid (2ml) that reaction is quenched, and reduces pressure Distillation, removes tetrahydrofuran and iodomethane, and with isopropyl ether (40ml) concentrate, water (20ml) washing, saturated sodium bicarbonate are dissolved (20ml) wash, water (20ml) washing, anhydrous sodium sulfate drying is filtered, and reduced pressure concentration obtains crude product, and crude product is directly used in down Step reaction.
1H-NMR(400MHz；Deuterated dimethyl sulfoxide)：δ (ppm) 0.63～0.74 (6H, m, CH2Ethyl)；1.00～1.05 (9H, t, J=8.4, CH3Ethyl)；1.15 (3H, s, CH3)；1.17 (3H, s, CH3)；1.70 (3H, s, CH3)；1.73～1.81 With 2.67～2.74 (1H, 2m, CH26)；2.06 (3H, s, CH3)；2.11～2.24 (2H, m, CH214)；2.30 (3H, s, CH3, COCH3)；3.31 (3H, s, OCH3)；3.46 (3H, s, OCH3)；3.83～3.85 (1H, d, J=6.8, CH 3)；3.90～ 3.95 (1H, dd, J=6.4/10.4, CH 7)；4.13～4.16 and 4.29～4.32 (1H, 2d, J=8.4, CH220)；4.83 (1H, s, CH 10)；4.95～5.02 (2H, m, CH 5 and 13)；5.58～5.60 (1H, d, J=7.2, CH 2)；7.45～ 7.49 (2H, t, J=8.0, CH OCOC6H5Meta)；7.58～7.62 (1H, t, J=7.2, CH OCOC6H5Contraposition)；8.08～ 8.10 (1H, d, J=7.2, CH OCOC6H5Ortho position).
Embodiment 4：The synthesis of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs (compound V)
Crude product (10g) obtained by upper step is directly dissolved in tetrahydrofuran (40ml), tetrabutyl amine fluoride (3.6g) is added. 3h is stirred at room temperature, completely, vacuum distillation removes tetrahydrofuran to TLC detections raw material reaction, adds water (20ml), dichloromethane (10ml), it is stirred overnight at room temperature.Filter, collect white solid, white solid is suspended in into backflow 2h in tetrahydrofuran (10ml), It is stored at room temperature overnight.Filter, collect white solid, vacuum drying obtains solid 6g, two step yields：70%, purity：96%.
1H-NMR(400MHz；Deuterochloroform)：δ (ppm) 0.94 (6H, s, CH3)；1.46～1.50 and 2.63～2.71 (1H, 2m, CH26)；1.52 (3H, s, CH3)；1.98 (3H, s, CH3)；2.16～2.18 (2H, m, CH214)；2.20 (3H, s, CH3, COCH3)；3.22 (3H, s, OCH3)；3.30 (3H, s, OCH3)；3.74～3.77 (1H, d, J=6.8, CH 3)；3.79～ 3.84 (1H, dd, J=6.4/10.0, CH 7)；4.01～4.06 (2H, dd, J=8.4/11.6, CH220)；4.37 (1H, s, OH 1)；4.65～4.66 (1H, m, CH 13)；4.75 (1H, s, CH 10)；4.96～4.98 (1H, d, J=9.2, CH 5)； 5.27～5.29 (1H, d, J=4.4, OH 13)；5.37～5.39 (1H, d, J=7.2, CH 2)；7.54～7.58 (2H, t, J =7.2, CH OCOC6H5Meta)；7.64～7.68 (1H, t, J=7.6, CH OCOC6H5Contraposition)；8.00～8.03 (1H, d, J =7.6, CH OCOC6H5Ortho position).
Due to according to its specific embodiment describing the present invention, some modifications and equivalent variations are for being proficient in this neck The technical staff in domain is obvious and is included within the scope of the invention.

Claims (7)

1. a kind of 7 β of method for preparing Cabazitaxel, including following preparation, 10 β-dimethoxy -10- deacetylate berries are red mould The step of plain III：
1) selective protection of hydroxyl is carried out to compound shown in formula I, the compound as shown in Formula II is obtained, wherein R is (C1-10Alkyl or C6-10Aryl)3Silylation, preferred trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl group diformazan Base silicon substrate, tert-butyl diphenyl silicon substrate
2) to step 1) compound as shown in Formula II for preparing carries out selective deprotection, obtains as shown in formula III Compound
3) to step 2) compound as shown in formula III for preparing carries out the methylation reaction of hydroxyl, obtains such as formula IV institute The compound for showing
4) to step 3) compound as shown in formula IV for preparing carries out silicon substrate deprotection, obtains chemical combination shown as a formula V Thing
2. preparation method according to claim 1, it is characterised in that step 1) in reaction dissolvent be selected from pyridine, N, N- Dimethylformamide；Reaction temperature is from 0～120 DEG C.
3. preparation method according to claim 1, it is characterised in that step 2) in reagent used by Deprotection be selected from hydrogen Fluoric acid pyridiniujm, hydrofluoric acid triethylamine salt, tetrabutyl amine fluoride, hydrogen chloride, hydrogen bromide, preferred hydrofluoric acid triethylamine salt.
4. preparation method according to claim 1, it is characterised in that step 2) in reaction dissolvent bag used by Deprotection Include dichloromethane, chloroform, ethyl acetate, methyl tertiary butyl ether(MTBE), toluene, preferred dichloromethane.
5. preparation method according to claim 1, it is characterised in that step 3) in using iodomethane or dimethyl suflfate as The methylating reagent of hydroxyl, preferred iodomethane.
6. preparation method according to claim 1, it is characterised in that step 3) in hydroxyl methylate under nitrogen protection Carry out；Reaction dissolvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, 2- methyltetrahydrofurans.
7. preparation method according to claim 1, it is characterised in that step 3) carry out in the presence of alkali, the alkali choosing From potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, caustic alcohol, lithium diisopropyl amido, diisopropyl amido sodium, two different interior base amidos Potassium, preferred potassium tert-butoxide.
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