CN115057833A - Synthetic route and intermediate compound of anticancer drug cabazitaxel - Google Patents
Synthetic route and intermediate compound of anticancer drug cabazitaxel Download PDFInfo
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Abstract
The invention discloses a synthesis route and an intermediate compound of an anticancer drug cabazitaxel, which comprise the following steps: mixing 9-dihydro-13-acetyl baccatin III, tetrabutylammonium iodide and sodium methoxide for reaction, adding water to react with dichloromethane, collecting dichloromethane part, and purifying to obtain 9-dihydro-10-deacetyl-13-acetyl baccatin III solid; adding tetrabutylammonium iodide and dimethyl carbonate, adding water and dichloromethane, terminating the reaction, collecting the organic phase, and purifying to obtain 9-dihydro-7,10-dimethoxy-13-acetyl baccatin III solid; adding Daisy-martin oxidant, purifying to obtain 7,10-dimethoxy-13-acetyl baccatin III; dissolving in ethanol, adding hydrazine hydrate, standing and crystallizing to obtain 7,10-dimethoxy baccatin III solid; adding DMAP and DCC, stirring at room temperature until the reaction is complete, quenching the reaction mixture, concentrating and purifying the organic phase, adding p-TsOH, stirring, concentrating the organic phase, and purifying by reversed-phase column chromatography to obtain the cabazitaxel with the purity of more than 99.5 percent.
Description
Technical Field
The invention relates to compound synthesis, in particular to a new synthesis path and an intermediate compound of an anticancer drug carbateside.
Background
Carbartrace is a drug in the class of gonadotropin releasing hormone (GnRH) receptor inhibitors, mainly for advanced prostate cancer patients, and is the first and only one of the second-line treatments for metastatic hormone refractory prostate cancer that provides significant survival benefits. The American food and drug administration approves the treatment of advanced prostate cancer, and the medicament for treating advanced and anti-hormone type prostate cancer is preferred when the common advanced prostate cancer medicament docetaxel is ineffective or even aggravated clinically.
Patents CN102532065B, CN102675256A, CN103242267B, US5847170, US2007293687a1, EP0817779, EP0817780, FR2732340, US5889043, US6372780, US6387946, WO9630355, WO9630356, etc. describe process routes for synthesizing cabazitaxel from 10-deacetylbaccatin III (10-DAB), and these process routes all have the disadvantages of complex process, low total yield or harsh reaction conditions, and are difficult to produce on an industrial scale; meanwhile, 10-DAB is derived from Taxus baccata and has limited resources, so that the raw material source of the carbateside is urgently needed to be enlarged and the synthesis process of the carbateside is urgently needed to be optimized.
Disclosure of Invention
In view of the defects of the prior art and the limitation of raw material sources, the invention synthesizes the carbarty race by using the 9-dihydro-13-acetyl baccatin III (9-DHAB) extracted and separated from Canadian sequoia as the starting material, and provides a synthetic route and an intermediate compound of the anticancer drug carbarty race.
The technical scheme adopted by the invention is as follows: a synthetic route and intermediate compounds for the anticancer drug cabazitaxel, comprising:
a compound having the structure shown in formula one:
wherein R is 1 Is a hydrogen atom or a suitable hydroxyl protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
Preferably, wherein the suitable hydroxy protecting group is selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ether, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
Preferably, wherein the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and p-phenylsulfonyl.
Preferably, R 1 Is methyl.
Preferably, R 2 Is methyl.
Preferably, R 3 Is an acetyl group.
The invention also provides a compound having a structure represented by formula two:
wherein R is 1 Is a hydrogen atom or a suitable hydroxy protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
In a preferred embodiment of the invention, suitable hydroxy protecting groups are selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ether, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
In a preferred embodiment of the invention, the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and p-phenylsulfonyl.
Preferably, R 1 Is methyl.
Preferably, R 2 Is methyl.
Preferably, R 3 Is an acetyl group.
The invention also provides a compound having a structure represented by formula three:
the invention also provides a process for preparing a compound of formula III, comprising the steps of: reacting an oxidant with a compound having a formula represented by formula IV,
wherein R is 1 Is a hydrogen atom or a suitable hydroxy protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
In a preferred embodiment of the invention, suitable hydroxy protecting groups are selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ether, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
In a preferred embodiment of the invention, the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and p-phenylsulfonyl.
Preferably, R 1 Is methyl.
Preferably, R 2 Is methyl.
Preferably, R 3 Is an acetyl group.
In a preferred embodiment of the invention, the oxidant is selected from Dess-Martin oxidant (Dess-Martin periodinane), corin oxidant (Colin's reagent), Swern oxidant (Swern's reagent), John's oxidant (John's reagent), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO) 2 ) And tetra-n-propylAmmonium Perruthenate (TPAP).
The invention also provides a preparation process for converting 9-dihydro-13-acetyl baccatin III (9-DHAB) into taxane derivatives, which comprises the following steps: removing the acetyl group at the 10-position of 9-dihydro-13-acetyl baccatin III and oxidizing the hydroxyl group at the 9-position.
In a preferred embodiment of the present invention, the oxidizing step comprises adding the following oxidizing agents: Dess-Martin oxidizer (Dess-Martin periodinane), Colin oxidizer (Colin's reagent), Swern's reagent, John's reagent, pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO's reagent), chromium oxide (cr), and mixtures thereof 2 ) And tetra-n-propylperoxyruthenate (TPAP).
The invention also provides a synthetic route of carbateside, which is characterized by comprising the following steps:
(a) the method comprises the following steps Removing the acetyl group at the 10-position of 9-dihydro-13-acetyl baccatin III to obtain 9-dihydro-10-deacetyl-13-acetyl baccatin III;
(b) the method comprises the following steps Protecting the 7-, 10-hydroxy group of 9-dihydro-10-deacetyl-13-acetylbaccatin III with a suitable protecting group to obtain a protected intermediate;
(c) the method comprises the following steps The hydroxyl group at the 9-position of the protected intermediate is oxidized with a suitable oxidizing agent.
In a preferred embodiment of the invention, the protecting groups include: benzyl radical, C 1 -C 25 Substituted benzyl, benzyl formate, C 1 -C 25 Substituted benzyl formate, phenylsulfonyl, C 1 -C 25 Substituted benzenesulfonyl, methyl, methoxymethyl, C 1 -C 25 Alkyl radical, C 1 -C 25 Substituted alkyl, benzoyl, C 1 -C 25 Substituted benzoyl, C 1 -C 25 Trialkylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methyldiphenylsilyl, benzyloxycarbonyl, C 1 -C 25 The silicon ether is selected from silicon ether,C 1 -C 25 esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonate ester.
In a preferred embodiment of the present invention, the oxidizing agent comprises: Dess-Martin oxidizer (Dess-Martin period), corin oxidizer (Colin's reagent), Swern oxidizer (Swern's reagent), John oxidizer (John's reagent), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO) 2 ) And ammonium tetra-n-propylperruthenate (TPAP).
In a preferred embodiment of the present invention, the process further comprises the step of removing the acetyl group at the 13-position of the intermediate 7, 10-dimethoxy-10-deacetyl-13-acetylbaccatin III.
In a preferred embodiment of the invention, removal of the 13-acetyl group is accomplished by the use of strong bases, including n-butyllithium, methyllithium, red aluminum, sodium borohydride, and hydrazine hydrate.
In a preferred embodiment of the invention, further comprising the step of adding a suitable side chain to the 13-position of 7, 10-dimethoxy-10-deacetylbaccatin III, and optionally deprotection to obtain the desired compound.
In a preferred embodiment of the invention, the selective deprotection is the removal of the p-methoxybenzoyl protecting group from the side chain.
In a preferred embodiment of the invention, selective deprotection is accomplished using p-toluenesulfonic acid.
In a preferred embodiment of the invention, the side chain comprises (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4' -methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid, (2R,4S,5R) -3-tert-butoxycarbonyl-2-dimethyl-4-phenyl-1, 3-oxazolidine-5-carboxylic acid, (3R,4S) -3- (1-ethoxyethyl) -4-phenyl-N-tert-butoxycarbonyl-2-azetidinone, (2R, 3S) -N-tert-butoxycarbonyl-O- (1-ethoxyethyl) -3-phenylisoserine.
The invention solves the defects in the background technology, and has the following beneficial effects:
(1) the invention overcomes the defects of complex reaction, high reagent toxicity, low product yield, high purification difficulty, high production cost and the like of the prior process conditions;
(2) the invention uses 9-dihydro-13-acetyl baccatin III as the starting material for synthesis, enlarges the source of the raw materials for synthesizing the carbartrace and simplifies the process;
(3) the invention eliminates high-toxicity and high-pollution chemicals used in the traditional carbateside synthesis process, creatively uses a synthetic reagent with low toxicity or no toxicity and more environmental protection;
(4) the purity of the product obtained by the method is higher and can reach more than 99.5 percent.
Drawings
FIG. 1 is a key intermediate of a preferred embodiment of the present invention;
fig. 2 is a composite path diagram of a preferred embodiment of the present invention.
Detailed Description
Reference throughout this specification to "one embodiment," "one embodiment," or "another embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least some embodiments, but not necessarily all embodiments, and all other embodiments obtained by those skilled in the art without inventive faculty are within the scope of the invention.
The synthetic route to carbateside, comprising the following steps:
dissolving 9-dihydro-13-acetylbaccatin III (9-dihydro-13-acetylbaccatin III,9-DHAB) in methanol, mixing with tetrabutylammonium iodide and sodium methoxide for reaction, adding water and dichloromethane for terminating the reaction, collecting dichloromethane part, and purifying to obtain 9-dihydro-10-deacetyl-13-acetylbaccatin III (9-dihydro-10-deacetyl-13-acetylbaccatin III, IM1) solid; dissolving IM1 in THF, adding tetrabutylammonium iodide and dimethyl carbonate, dripping into mineral oil solution of sodium cyanide, adding water and dichloromethane after the reaction is finished, stopping the reaction, collecting an organic phase, and purifying to obtain a solid of 9-dihydro-7,10-dimethoxy-13-acetylbaccatin III (9-dihydro-7,10-dimethoxy-13-acetylbaccatin III, IM 2); adding Dess-Martin oxidant (Dess-Martin periodinane) into the dichloromethane solution containing IM2, and purifying by silica gel column chromatography after the reaction to obtain 7,10-dimethoxy-13-acetyl baccatin III (7,10-dimethoxy-13-acetylbaccatin III, IM 3); dissolving IM3 in ethanol, adding hydrazine hydrate, reacting overnight at room temperature, and standing for crystallization to obtain 7,10-dimethoxy baccatin III (7,10-dimethoxy baccatin III, IM4) solid; DMAP and DCC were added to an anhydrous toluene solution containing (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4 ' -methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid { (2R,4S,5R) -3-tert-butoxycarbyl-2- (4 ' -methoxyphenyl) -4-phenyl-1, 3-oxozolidine-5-carboxylic acid, docetaxel side chain } and IM4, stirred at room temperature until the reaction was complete, followed by quenching the reaction mixture and concentrating and purifying the organic phase to give {7, 10-dimethoxybaccatin III-13- (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4 ' -methoxyphenyl) -4-phenyl-1, 3-oxazolidine-5-carboxylate, IM5 }; adding p-TsOH into the methanol solution of IM5, stirring, quenching the reaction mixture with brine after the reaction is completed, concentrating the organic phase, and purifying by reversed-phase column chromatography to obtain the cabazitaxel with the purity of more than 99.5%.
The first embodiment is as follows:
preparation of the key intermediate 10-deacetyl-9-dihydro-13-acetylbaccatin III (IM1) (formula five):
50 g (79.3mmol) of 9-dihydro-13-acetylbaccatin III (9-DHAB) are dissolved in 700ml of methanol (CH) 3 OH) and after complete dissolution of 9-DHAB, 5.9 g of tetrabutylammonium iodide (Bu) were added 4 NI, 15.9mmol,0.2 equiv), stirred and the temperature was reduced to 0 ℃, followed by the addition of sodium methoxide (CH) in one portion 3 ONa,8.6g, 158.6mmol, 2-fold equivalent), continue stirring and slowly warm to room temperature, continue the reaction at this temperature for about 1.5 hours until TLC check shows 9-DHAB is completely reacted, add 300ml water and 500 Dichloromethane (DCM) to the reaction and continue stirring for 20 minutes, stop stirring, and stand for 2 hours. Filter elementThe white precipitated solid was washed with 100ml of water, the filtrate was allowed to stand for separation, the organic phase was washed with 100ml of water and then concentrated under reduced pressure to about 50ml, and the concentrate was left to crystallize. The white crystals were filtered off and washed with 100ml of purified water. The secondary white crystalline solids were combined and dried to give IM1 as a white solid (40 g, IM1, 87% yield) 1 H-NMR(CDCl 3 )δ8.11(d,2H),7.62(t,lH),7.49(t,2H),6.21(t,lH),5.78(d,lH),4.96(d,lH),4.93(d,lH),4.89(d,1H),4.40(dd,lH),4.35(d,lH),4.32(d,lH),4.20(d,lH),3.51(d,OH),3.24(d,OH),3.08(d,lH),2.56(ddd,lH),2.30(s,3H),2.25-2.0(m,2H),2.21(s,3H),1.96(dd,lH),1.87(d,3H),1.85(dd,1H),1.73(s,3H),1.62(s,3H),1.33(s,3H)ppm。
Example two:
preparation of 7, 10-dimethoxy-10-deacetyl-9-dihydro-13-acetylbaccatin III (IM2) (formula VI):
the compound 10-deacetyl-9-dihydro-13-acetylbaccatin III (IM1,135mmol,79g) was dissolved in 700ml of anhydrous Tetrahydrofuran (THF), cooled to-60 ℃ and then a catalytic amount of tetrabutylammonium iodide (Bu4NI, 10g, 27mmol), dimethyl carbonate [ (CH3O)2CO, 62g,695mmol,5equiv]After stirring for about 10 minutes, a solution of sodium cyanide (NaH,13g,540mmol,4equiv) in mineral oil was then added dropwise, stirring was continued for one hour at low temperature and then the temperature was slowly raised to 0 ℃ and maintained until the completion of the TLC check reaction. The reaction vessel was charged with a mixed solution of 500ml of purified water and 500ml of methylene chloride, stirred for 5 minutes, and then allowed to stand for separation. The collected organic phase was then washed with 1000ml of saturated aqueous sodium chloride solution, the organic phase was then concentrated to dryness under reduced pressure, the residue was dissolved in a small amount of acetone and then separated and purified on a column of reverse phase polystyrene/divinylbenzene polymeric material resin, and the fraction containing IM2 was collected and concentrated to give white IM2 as a solid (68.5 g, yield 63%). 1 H-NMR：δ8.05(d,2H),7.60(t,lH),7.45(t,2H),6.18(t,lH),5.75(d,lH),4.96(d,lH),4.85(d,lH),4.79(d,1H),4.40(dd,lH),4.35(d,lH),4.30(d,lH),4.12(d,lH),3.41(s,3H，OMe),3.24(s,3H，OMe),3.08(d,lH),2.67(ddd,lH),2.30(s,3H),2.25-2.0(m,2H),2.21(s,3H),1.96(dd,lH),1.78(d,3H),1.85(dd,1H),1.73(s,3H),1.65(s,3H),1.17(s,3H)ppm。
Example three:
preparation of 7, 10-dimethoxy-10-deacetyl-13-acetylbaccatin III (IM3) (formula seven):
to a stirred solution of 7, 10-dimethoxy-10-deacetyl-9-dihydro-13-acetylbaccatin III (IM2,25g, 20mmol) in methylene chloride was added Dess-Martin oxidant (24g,50mmol), the mixture was stirred at room temperature overnight, after TLC check showed completion of the reaction, water was added to quench the reaction, and the organic phase was washed twice with purified water and then dehydrated with anhydrous sodium sulfate. The organic phase is concentrated to dryness in vacuo and the residue is purified by flash chromatography to give 7, 10-dimethoxy-10-deacetyl-13-acetylbaccatin III (IM3, 22.5g, 91% yield). 1 H-NMR(400MHz，CDCl 3 )：δ8.10(d,2H),7.60(t,lH),7.45(t,2H),6.23(t,1H)5.75(d,lH),4.96(d,lH),4.93(s,lH),4.86(t,1H),4.40(d,lH),4.35(d,1H),4.19(d,lH),3.90(dd,lH),3.85(d,1H),3.45(S,3H,OMe),3.28(S,3H,OMe),2.56(ddd,lH),2.30(s,3H),2.25-2.0(m,2H),2.21(s,3H),1.96(dd,lH),1.85(dd,1H),2.04(s,3H)，1.65(s,3H),1.20(s,3H),1.05(s,3H)ppm。
Example four:
preparation of 7, 10-dimethoxy-10-deacetylbaccatin III (IM4) (formula VIII):
40g of 7, 10-dimethoxy-10-deacetyl-13-acetylbaccatin III (IM3, 48.5mmol) are dissolved in 1.7L of 95% ethanol and stirred, 235ml of 85% hydrazine hydrate are added to the above stirred solution, the mixture is stirred at room temperature overnight, and the next day when a TLC check shows that all starting materials have been consumed, 3L of purified water are added to the mixed solution and stirring is continued for one hour, and then the mixture is left to stand for crystallization. The white solid was filtered, and the filter cake was washed with 100ml of purified water and dried at 50C in a vacuum oven to give 34g of 7, 10-dimethoxy-10-deacetylbaccatin III (IM4) as a white solid with a yield of 89%.
1 H-NMR(400MHz，CDCl 3 )：δ8.05(d,2H),7.56(t,lH),7.45(t,2H),5.56(d,lH),4.96(d,lH),4.83(s,lH),4.80(t,1H),4.30(d,lH),4.12(d,lH),3.90(dd,lH),3.85(d,1H),3.45(S,3H,OMe),3.28(S,3H,OMe),2.56(ddd,lH),2.30(s,3H),2.25-2.0(m,2H),2.05(s,3H),1.96(dd,lH),1.85(dd,1H),1.65(s,3H),1.18(s,3H),1.03(s,3H)ppm。
Example five:
preparation of 7, 10-dimethoxy-10-deacetylbaccatin III-13-tert-butoxycarbonyl-2- (4' -methoxyphenyl) -4-phenyl-1, 3-oxazolidine-5-carboxylate (IM5) (formula nine):
DMAP (0.6 equiv.) and DCC (3 equiv.) are added to a stirring solution of (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4' -methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid (docetaxel side chain) (20g, 0.3 mol.) and IM4(20.0g, 0.15 mol.) in dry toluene. This mixture was stirred at room temperature for 2 hours. When TLC showed complete disappearance of starting material, the reaction mixture was quenched with water. The organic phase was collected, washed with water and brine, and then with anhydrous sodium sulfate (Na) 2 SO 4 ) Drying, filtering, and vacuum concentrating the filtrate. The residue was purified by silica gel column chromatography to give IM5(21g, yield 90%). 1 H-NMR(400MHz，CDCl 3 )：δ7.96(d,2H),7.58(t,1H),7.43(t,2H),7.25-7.40(m,7H),6.88(d,2H),6.33(s,1H),6.07(t,1H),5.53(d,1H),5.36(m,1H),4.85(bd,1H),4.67(s,1H),4.53(d,1H),4.16(d,1H),4.06(d,1H),3.76(s,3H),3.73(m,1H),3.64(d,1H),3.35(s,3H),3.22(s,3H),2.60(m,1H),2.15(dd,1H),2.14(s,3H),2.02(dd,1H),1.78(s,3H),1.65-1.85(m,1H),1.63(s,3H),1.17(s,3H),1.10(s,3H),1.02(s,9H)ppm。
Example six:
preparation of Cabazitaxel (Cabazitaxel) (formula 10):
to a solution of IM5(5.0g, 5.5mmol) in methanol (50ml) was added p-TsOH (1g, 6mmol) and the mixture was stirred at room temperature for 3 h. When TLC showed disappearance of the starting material, NaHCO was used 3 (0.5g) the reaction mixture was quenched, then concentrated in vacuo, and the residue was purified by column chromatography to give Cabazitaxel (Cabazitaxel, IM6,2.8g, yield 78.0%). 1 H-NMR(400MHz，CDCl 3 )：δ8.10(d,2H),7.65(t,1H),7.52(t,2H),7.30-7.50(m,5H),6.24(t,1H),5.65(d,1H),5.47(d,1H),4.65(mt,1H),4.33(d,1H),4.20(d,1H),3.88(dd,1H),3.85(d,1H),3.48(mt,1H),3.48(s,3H),3.35(s,3H),2.70(m,1H),2.39(s,3H),2.31(m,2H),1.91(s,3H),1.82(mt,1H),1.75(s,3H),1.70(s,1H),1.39(s,9H),1.25(s,3H),1.23(s,3H)ppm。
In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (32)
1. A compound having the structure shown in formula one:
wherein R is 1 Is a hydrogen atom or a suitable hydroxy protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
2. The compound of claim 1, wherein: wherein suitable hydroxy protecting groups are selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ether, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
3. The compound of claim 1, wherein: wherein the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and a phenylsulfonyl group.
4. The novel synthetic route of the anticancer drug cabazitaxel as claimed in claim 1, wherein: wherein R is 1 Is a methyl group.
5. The novel synthetic route for the anticancer drug cabazitaxel as claimed in claim 1, wherein: wherein R is 2 Is methyl.
6. The novel synthetic route of the anticancer drug cabazitaxel as claimed in claim 1, wherein: wherein R is 3 Is an acetyl group.
7. A compound having the structure shown in formula two:
wherein R is 1 Is a hydrogen atom or a suitable hydroxy protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
8. The compound of claim 7, wherein: wherein suitable hydroxy protecting groups are selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ether, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
9. The compound of claim 7, wherein: wherein the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and a phenylsulfonyl group.
10. The compound of claim 7, wherein: wherein R is 1 Is methyl.
11. The compound of claim 7, wherein: wherein R is 2 Is methyl.
12. The compound of claim 7, wherein: wherein R is 3 Is an acetyl group.
13. A compound having the structure shown in formula three:
14. a process for preparing a compound of formula iii, comprising the steps of: reacting an oxidant with a compound having a formula represented by formula IV,
wherein R is 1 Is a hydrogen atom or a suitable hydroxy protecting group;
R 2 is a hydrogen atom or a suitable hydroxy protecting group;
R 3 is a hydrogen atom or a suitable hydroxyl protecting group.
15. The compound of claim 13, wherein: wherein suitable hydroxy protecting groups are selected from C 1 -C 25 Ethers, C 1 -C 25 Substituted methyl ethers, C 1 -C 25 Substituted ethyl ethers, C 1 -C 25 Acyl radical, C 1 -C 25 Haloacyl radical, C 1 -C 25 Benzyl ethers，C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonic acid ester.
16. The process of claim 14, wherein: wherein the suitable hydroxy protecting group is selected from the group consisting of methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2,2, 2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methylbenzyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl, allylsulfonyl, methylsulfonyl, and a phenylsulfonyl group.
17. The process of claim 14, wherein: wherein R is 1 Is methyl.
18. The process of claim 14, wherein: wherein R is 2 Is methyl.
19. The process of claim 14, wherein: wherein R is 3 Is an acetyl group.
20. The process of claim 14, wherein: wherein the oxidant is selected from Dess-Martin oxidant (Dess-Martin periodinane), corin's oxidant (Colin's reagent), Swern's oxidant (Swern's reagent), John's oxidant (John's reagent), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO) 2 ) And ammonium tetra-n-propylperruthenate (TPAP).
21. The preparation process of converting 9-dihydro-13-acetyl baccatin III (9-DHAB) into taxane derivative includes the following steps: removing the acetyl group at the 10-position of 9-dihydro-13-acetyl baccatin III and oxidizing the hydroxyl group at the 9-position.
22. The process of claim 21, wherein: the oxidation step comprises the addition of the following oxidizing agents: Dess-Martin oxidizer (Dess-Martin period), corin oxidizer (Colin's reagent), Swern oxidizer (Swern's reagent), John oxidizer (John's reagent), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO) 2 ) And tetra-n-propylperoxyruthenate (TPAP).
23. The synthetic route for carbateside, characterized in that it comprises the following steps:
(a) the method comprises the following steps Removing the acetyl group at the 10-position of 9-dihydro-13-acetyl baccatin III to obtain 9-dihydro-10-deacetyl-13-acetyl baccatin III;
(b) the method comprises the following steps Protecting the 7-, 10-hydroxyl group of 9-dihydro-10-deacetyl-13-acetylbaccatin III with a suitable protecting group to obtain a protected intermediate;
(c) the method comprises the following steps The hydroxyl group at the 9-position of the protected intermediate is oxidized with a suitable oxidizing agent.
24. The synthetic pathway of claim 23, wherein the protecting group comprises: benzyl radical, C 1 -C 25 Substituted benzyl, benzyl formate, C 1 -C 25 Substituted benzyl formate, phenylsulfonyl, C 1 -C 25 Substituted benzenesulfonyl, methyl, methoxymethyl, C 1 -C 25 Alkyl radical, C 1 -C 25 Substituted alkyl, benzoyl, C 1 -C 25 Substituted benzoyl, C 1 -C 25 Trialkylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylmethoxysilyl, tert-butyldimethylsilylButyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, methyldiphenylsilyl, benzyloxycarbonyl, C 1 -C 25 Silyl ethers, C 1 -C 25 Esters, C 1 -C 25 Carbonic esters, C 1 -C 25 A sulfonate ester.
25. The synthetic pathway of claim 23 wherein the oxidizing agent comprises: Dess-Martin oxidizer (Dess-Martin period), corin oxidizer (Colin's reagent), Swern oxidizer (Swern's reagent), John oxidizer (John's reagent), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), chromium dioxide (CrO) 2 ) And ammonium tetra-n-propylperruthenate (TPAP).
26. The synthetic route as claimed in claim 23 further comprising the step of removing the acetyl group at the 13-position of the intermediate 7, 10-dimethoxy-10-deacetyl-13-acetylbaccatin III.
27. The synthetic route of claim 26 wherein the removal of the acetyl group at the 13-position is accomplished by the use of strong bases including n-butyllithium, methyllithium, red aluminum, sodium borohydride, and hydrazine hydrate.
28. The synthetic route of claim 26 further comprising the step of adding a suitable side chain to the 13-position of 7, 10-dimethoxy-10-deacetylbaccatin III and selective deprotection to obtain the desired compound.
29. The synthetic route of claim 28, wherein the selective deprotection is removal of the p-methoxybenzoyl protecting group from the side chain.
30. The synthetic route of claim 29 wherein selective deprotection is accomplished using p-toluenesulfonic acid.
31. The synthetic route of claim 28, wherein the side chain comprises (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4' -methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid, (2R,4S,5R) -3-tert-butoxycarbonyl-2-dimethyl-4-phenyl-1, 3-oxazolidine-5-carboxylic acid, (3R,4S) -3- (1-ethoxyethyl) -4-phenyl-N-tert-butoxycarbonyl-2-azetidinone, (2R, 3S) -N-tert-butoxycarbonyl-O- (1-ethoxyethyl) -3-phenylisoserine.
32. The taxane derivative of claim 21 which is cabazitaxel.
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