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Contents / Journal of Chinese Pharmaceutical Sciences 21 (2012)
http://www.jcps.ac.cn
Short communications pp 468–471
Direct chiral separation of azelnidipine by HPLC with Pirkletype column Xiaoxia Ye, Xu Xu * 9.167 10.834 NO 2 (CH 3 ) 2 CHOOC
COO
Sample: azelnidipine Chiral Column: OA2500 Mobile Phase: hexane–ethanol (60:40, v/v)
N
H 3 C N NH 2
2.5 5.0 7.5 10.0 t (min)
12.5 15.0
pp 472–476
A new synthesis route of cabazitaxel Guoning Zhang, Weishuo Fang * HO
O OH 10
HO
O
O OH
O
O
O O
NH
7
H HO OBz OAc
O
HO
10Deacetylbaccatin III
H HO OBz OAc
O
HO
5
H HO OBz OAc
O O
Boc
O
O
Ph O HO
6
H HO OBz OAc
O
Cabazitaxel 1a
2
A new and efficient route for the synthesis of cabazitaxel from 10deacetylbaccatin III, in 20% yield for six steps, was developed. The key reaction of 7OH methylation of 5 was carried out in the presence of proton sponge and trimethyloxonium tetrafluoroborate in 66% yield.
pp 477–482
Acute toxicity and genotoxicity evaluation of hyperoside extracted from Abelmoschus manihot (L.) Medic Guo Ai, Zhengming Huang * , Dewen Wang, Haiting Zhang OH OH HO
Acute toxicity study: the LD 50 was >5000 mg/kg in BALB/c mice
O O OH O
Ames test: negative
OH OH
O
Chromosome aberration test: negative Micronucleus test: negative
OH HO
Abelmoschus manihot (L.) Medic Hyperoside (Hyperin)
Special subject Establishment of an internationally recognized platform for the communication of pharmaceutical researches supported by the National New Drug Innovation Programs
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Heqing Huang * , Jian Han, Jingjing Zhang In the new situation, Journal of Chinese Pharmaceutical Sciences (JCPS) plays a critical role in the communication of new discoveries in pharmaceutical researches. To fulfill the roles as an internationally recognized platform, the JCPS editorial office will take advantage of its English language specialty, emphasize quality and digital access, and promote the advancement of the journal.
Others The 8 th International Symposium for Chinese Medicinal Chemists and the 9 th IUPAC international Symposium on Biomolecular Chemistry were held in Beijing
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Call for Papers: A Special Issue of Medicinal Chemistry and Biomolecular Chemistry
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General information and subscription
Cover 3
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Journal of Chinese Pharmaceutical Sciences
http://www.jcps.ac.cn
Short communication
A new synthesis route of cabazitaxel Guoning Zhang, Weishuo Fang * State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract: A new route for the synthesis of cabazitaxel (Javanta ® ) starting with 10deacetylbaccatin III was developed. In this new procedure, a mild condition for the methylation of 7OH was applied, thus the epimerization of 7βOH under basic conditions was reduced. The total yield of this 6step synthesis is 20%. Keywords: Cabazitaxel; 7OH Methylation CLC number: R916.42
Document code: A
Article ID: 1003–1057(2012)5–472–05
1. Introduction
RO Boc
Cabazitaxel (1a, Fig. 1) is a semisynthetic taxane ap proved by the US Food and Drug Administration (FDA) in June 2010 [1] for the treatment of metastatic refractory prostate cancer. Prostate cancer is the most common malignancy in men and the third leading cause of death in the western countries. It is estimated that 240 890 new patients are diagnosed in the United States, and about 33 720 of them die from this disease in 2011 [2] . Before the approval of cabazitaxel, docetaxel (1b, Fig. 1) is one of limited options for castrationresistant prostate cancer (CRPC) patients. Cabazitaxel is a potent tubulinbinding taxane and poor substrate of Pglycoprotein (Pgp), an ATPdependent drug efflux pump [3] . Docetaxel is a good substrate of Pgp, thus suffering from Pgp overexpression mediated drug resistance [4–6] . Clinical studies showed that cabazitaxel remains active in docetaxelresistant tumors [7] . Thus, cabazitaxel is an important new treatment option for the docetaxel refractory metastatic CRPC. Although cabazitaxel is a very important second line treatment for the metastatic CRPC, there are still limited reports on the synthesis of 1a (Table 1). In 2002, Aventis reported the first synthetic route of Received date: 20120509. Foundation items: NSFC (Grant No. 30930108) and MOST (Grant No. 2009YZHLCH03). * Corresponding author. Tel.: 861063165229; Email:
[email protected] doi:10.5246/jcps.2012.05.062
O OR
NH O
Ph HO
O
R = CH3 R = H
O H HO OBz OAc
1a 1b
Figure 1. Structrues of cabazitaxel and docetaxel
cabazitaxel starting from 10deacetylbaccatin III (10DAB, 2) [8] . The synthesis consisted of 6 steps with a total yield of 4.9%. In 2011, Sun et al. reported the synthesis of 1a by methylating the 7 and 10OH in 10DAB simultaneously to furnish 7,10dimethyl 10DAB, which was then coupled with a protected (3R,4S)βlactam followed by deprotection of the 2′OH, the total yield is 17.8% for 3 steps [9] . In 2012, Zhang et al. reported a new route for the synthesis of 1a, starting from 9, which is an intermediate in the synthesis of docetaxel (1b), with a yield of 82% for 3 steps [10] . The two hydroxyls at position 7 and 10 in compound 9 was released by removing of the Troc using acetic acid and zinc powder in 95% yield, and then the two hydroxyls was methylated by CH3I and NaH simultaneously in 92% yield. At last the pro tection group on the side chain was removed using TsOH to afford cabazitaxel in 94% yield. However the staring material 9 is an intermediate in the synthesis of docetaxel. In our synthesis of cabazitaxel, we found that the 7βOH methylation of either 2 or 5 is inefficient in the presence of strong base. We have tried to optimize the reactions with different methylating reagents such
G. N. Zhang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 472–476
Table 1. Reported syntheses of cabazitaxel Group Aventis Sun et al. Zhang et al. a b
Starting material 2 2 9
Steps Yield 6 4.9% 3 17.8% a –42.4% b 3 82.2%
Reference [8] [9] [10]
Using NaH/CH3I for the 7,10diOH methylation; Using KH/CH3I for the 7,10diOH methylation.
TrocO
O OTroc
O O
Boc N
H HO OBz OAc
O
MeO
O
9
as methyl iodide or dimethyl sulfate, in combination with sodium hydride or potassium hydride as the base, in the solvent of N,Ndimethyl formamide or tetrahydrofuran, but most of the starting materials decomposed and the main product is 7αOH isomers. A previous report also revealed that the 7βOH in paclitaxel can be converted to αOH through a retro aldol reaction in the presence of a strong base [11] . However, in all the reported syntheses of 1, a strong base such as sodium hydride or potassium hydride was used for the methylation of 7βOH. There is still a need to develop a more efficient synthesis of cabazitaxel (1a) under mild condition. In this paper, we reported a new route for the synthesis of cabazitaxel, in which the methylation of 7OH of taxane was carried out with a more active alkylating reagent, trimethyloxonium tetrafluoroborate, in the presence of a weak organic base proton sponge.
2. Results and discussion The synthesis started with 10DAB (2), which can be extracted from yew tree needles in large quantities. There are four hydroxyls in 10DAB, and the order of acetylation for the three secondary hydroxyl groups is C7>C10>>C13 [12,13] . In the beginning, we attempted to methylate the hydroxyls at position C7 and C10 simultaneously, but obtained the target product 7,10dimethyl10deacetylbaccatin III (6) only in 7% yield. We have also tried with different
473
methylating reagents such as methyl iodide and dimethyl sulfate, in combination with sodium hydride or potassium hydride as the base, in the solvent of N,Ndimethyl formamide or tetrahydrofuran. The target product was afforded in only about 10% yield under the best situation, which is much less than the patented procedure [9] by Zhang et al., in which 10DAB can be converted into 7,10bisMe10DAB directly in 24%. Considering the easy epimerization of 7βOH in the presence of a strong base, we first protected the 7βOH of 2 with trimethyl chlorosilane to afford 3, which can be methylated with MeI and NaH in DMF to furnish 10methoxy7Otriethylsilyl ether (4) in 91% yield. After the desilylation of 4, 10methoxy 10DAB (5) was obtained in 89% yield. The stabilization of the 7epiOH by the 13α hydroxyl group in taxane makes the epimerization of 7βOH dominant, and thus the methylation of 7OH generally occurs in poor yields in the presence of a strong base. To overcome the competitive epimerization during the methylation of 7OH in 5, a more active methylating reagent, trimethyloxonium tetrafluoroborate in combination with a weak organic base, proton sponge, were used to afford 7,10bis OMe10DAB (6) in 66% yield. Compound 6 was then coupled with the protected enantiomeric (3R, 4S)βlactam (7) to afford 2′OTEScabazitaxel (8), which can be converted to cabazitaxel (1a) through 2′desilylation (Scheme 1). In conclusion, we have developed a new synthesis route of cabazitaxel from 10DAB, a commercially available natural taxane, in 20% yield for six steps. In this new route, the key transformation, 7OH methylation, was conducted under a mild condition to avoid C7OH epimerization.
3. Experimental section 3.1. General methods Pyridine was dried by boiling with KOH prior to distillation and stored over 4 Å molecular sieves. Dichloromethane was freshly distilled from CaH2 before use. THF was freshly distilled from Na before use. DMF was dried over 4 Å molecular sieves and
G. N. Zhang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 472–476
474
HO
O OH 10
HO
HO
7
O O
Si
O
HO
H HO OBz OAc 10Deacetylbaccatin III
Si
O
b
a O
O O
c
O
H HO OBz OAc
O OH
HO
H HO OBz OAc
3
O
HO
H HO OBz OAc
4
O
5
2 SETO O
O O
O
d HO
H HO OBz OAc
O
N O O 7 e
O
O O
O
Boc
O O
Boc NH
O
H HO OBz OAc
Si O
6
NH
f
O
Ph
O
O
Ph
8
O HO
H HO OBz OAc
O
Cabazitaxel 1a
Scheme 1. Synthesis of cabazitaxel. a. TESCl, Pyr., RT (82%); b. NaH, CH3I, DMF (91%); c. HF, Pyr., CH3CN (89%); d. Proton sponge, Trimethyloxonium Tetrafluoroborate, DCM (66%); e. LiHMDS, THF (60%); f. HF, Pyr., CH3CN (77%).
distilled at reduced pressure. The CH3I was also newly distilled before use. All other reagents were reagent grade quality and were used without further purifi cation. Column chromatography was performed with silicagel H. 1 H and 13 C NMR spectra were recorded with Varian Mecury300 or Varian Mecury400 spectrometer with TMS as the internal standard. 3.2. 7,10BisOMe10DAB (6) Method A The mixture of 10DAB 2 (20 mg) and NaH (80% dispersion in mineral oil, 5.5 mg, 5 eq.) was cooled to 0 °C for 5 min under the atmosphere of Ar. THF (0.25 mL) and CH3I (80 μL, 30 eq.) was added and the solution was stirred for 4 h at this temperature. The mixture was extracted with aq. NH4Cl (sat.) and EtOAc, washed with saline and dried over Na2SO4. The organic solvent was removed under vacuum and the residue was purified on silica gel column to afford the product of 7,10bisOMe 10DAB (1.5 mg, 7%). Method B The mixture of 10OMe10DAB (42 mg), proton sponge (48 mg, 3 eq.), trimethyloxonium tetrafluoroborate (22 mg, 2 eq.) and powdered molecular sieve (40mg) was stirred for 24 h at RT, and another portion of proton sponge (48 mg, 3 eq.) and trimethyloxonium tetrafluoroborate (22 mg, 2 eq.) was added. The mixture was stirred at RT for another 18 h and extracted with EtOAc and saline. After workup and purification 28 mg of 7, 10bis OMe10DAB 6 (66%) was obtained and 9 mg of
the 10OMe10DAB 5 (21%) was recovered. 1 H NMR (CDCl3, 300 MHz) δ: 8.11 (d, 2H, J 7.8 Hz), 7.59 (m, 1H), 7.47 (m, 1H), 5.60 (d, 1H, J 6.9 Hz), 5.02 (d, 1H, J 9.9 Hz), 4.90 (m, 1H), 4.84 (s, 1H), 4.32 (d, 1H, J 8.1 Hz), 4.17 (d, 1H, J 8.1 Hz), 3.91 (m, 2H), 3.46 (s, 3H), 3.31 (s, 3H), 2.71 (m, 1H), 2.35 (m, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.70 (s, 3H), 1.61 (b s, 1H), 1.17 (s, 3H), 1.11 (s, 3H). ESIMS: 573.2 [M+H] + . The 1 H NMR data is consistent with that of CN102285947. 3.3. 7TES10DAB (3) To a solution of 10DAB 2 (81 mg) in anhydrous pyridine (7 mL), triethylsilyl chloride (0.5 mL, 20 eq.) was added under an argon atmosphere at RT. The mixture was stirred for 17 h at RT and 15 mL of saturated saline solution was added. The mixture was extracted with EtOAc (3×15 mL) and dried over Na 2SO4 for 4 h. The solvent was removed under vacuum and the residue was purified on silica gel column. 7TES10DAB 3 (80 mg, 82%) was afforded as a pale yellow solid after purification. 1 H NMR (CDCl3, 300 MHz) δ: 8.12 (d, 2H, J 8.1 Hz), 7.60 (m, 1H), 7.47 (m, 1H), 5.60 (d, 1H, J 6.9 Hz), 5.17 (s, 1H), 4.97 (d, 1H, J 9.0 Hz), 4.90 (m, 1H), 4.44 (m, 1H), 4.33 (d, 1H, J 8.1 Hz), 4.18 (d, 1H, J 8.1 Hz), 3.96 (d, 1H, J 7.2 Hz), 2.53 (m, 1H), 2.28 (s, 3H), 2.25 (m, 1H), 2.08 (s, 3H), 2.02 (m, 1H), 1.90 (m, 3H), 1.73 (s, 3H), 1.25 (s, 9H), 1.08 (s, 6H), 0.82–0.96 (m, 10H), 0.48–0.63 (m, 6H).
G. N. Zhang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 472–476
3.4. 7TES10OMe10DAB (4) To a solution of 7TESDAB 3 (80 mg, 1 eq.) and NaH (80% dispersion in mineral oil, 5.5 mg, 1.3 eq.) in DMF (0.45 mL), CH3I (0.50 mL) was added at 0 °C. The mixture was stirred for 7 h at this tem perature and NH4Cl (sat. aq. 30 mL) was added. The mixture was extracted with EtOAc (3×15 mL) and dried over Na2SO4 for 4 h. The solvent was removed under vacuum and the residue was purified on silica gel column. After work up, 7TES10OMe10DAB 4 (75 mg, 91%) was obtained. 1 H NMR (CDCl3, 300 MHz) δ: 8.12 (d, 2H, J 7.8 Hz), 7.60 (m, 1H), 7.47 (m, 1H), 5.60 (d, 1H, J 6.9 Hz), 4.91 (s, 1H), 4.88–4.97 (m, 2H), 4.44 (m,1H), 4.31 (d, 1H, J 8.7 Hz), 4.16 (d, 1H, J 8.7 Hz), 3.90 (d, 1H, J 6.9 Hz), 3.41 (s, 3H), 2.49 (m,1H), 2.28 (s, 3H), 2.25 (m, 1H), 2.10 (s, 3H), 1.92 (m, 1H), 1.68 (s, 3H), 1.17 (s, 3H), 1.07 (s, 3H), 0.85–0.99 (m, 11H), 0.51–0.61 (m, 6H). ESIMS: 695.4 [M+Na] + . 3.5. 10OMe10DAB (5) To a solution of 7TES10OMe10DAB 4 (75 mg) in acetonitrile (1.0 mL), Pyr (0.72 mL, 80 eq.) and HF (0.26 mL, 40 eq.) were added. The mixture was stirred for 20 h at RT and sat. NaHCO3 (aq. 15 mL) was added and extracted with EtOAc (3×15 mL) dried over Na2SO4 for 4 h. The solvent was removed under vacuum and the residue was purified on silica gel column. After workup and purification 56 mg of 10OMe10DAB 5 (89%) was obtained. 1 H NMR (CDCl3, 400 MHz) δ: 8.11 (d, 2H, J 7.6 Hz), 7.60 (m, 1H), 7.47 (m, 1H), 5.64 (d, 1H, J 7.2 Hz), 4.97–4.99 (m, 2H), 4.90 (m, 1H), 4.30 (m, 2H), 3.95 (d, 1H, J 7.2 Hz), 3.45 (s, 3H), 2.61 (m, 1H), 2.28 (s, 3H), 2.08 (s, 3H), 1.83 (m, 1H), 1.70 (m, 1H), 1.68 (s, 3H), 1.16 (s, 3H), 1.08 (s, 3H), 0.94–0.99 (m, 2H). ESIMS: 581.3 [M+Na] + . 3.6. 2′TEScabazitaxel (8) The mixture of 7,10bisOMe10DAB 6 (23 mg) and (3R,4S)βlactam 7 (38 mg, 2.5 eq.) was dissolved in THF (1.5 mL). The solvent was cooled to –40 °C for 5 min and lithium hexamethyldisilazide (1 M in THF, 80 μL, 2 eq. ) was added dropwise. The solution was stirred for 2 h at this temperature and then
475
EtOAc (20 mL) was added and washed (20 mL) with saline. After workup and purification on the silica gel column 2′TEScabazitaxel 8 (23 mg, 60 %) was afforded as a white solid. 1 H NMR (CDCl3, 400 MHz) δ: 8.12 (d, 2H, J 7.6 Hz), 7.61 (m, 1H), 7.50 (m, 2H), 7.26–7.40 (m, 5H), 6.32 (t, 1H, J 8.8 Hz), 5.67 (d, 1H, J 7.2 Hz), 5.49 (br d, 1H, J 9.6 Hz), 5.28 (br s, 1H), 5.02 (d, 1H, J 9.6 Hz), 4. 81 (s, 1H), 4. 55 (br s, 1H), 4.33 (d, 1H, J 8.8 Hz), 4.20 (d, 1H, J 8.8 Hz), 3.86–3.92 (m, 2H), 3.46 (s, 3H), 3.31 (s, 3H), 2.70 (m, 1H), 2.53 (s, 3H), 2.22– 2.45 (m, 2H), 1.96 (s, 3H), 1.84 (m, 2H), 1.72 (s, 3H), 1.33 (s, 9H), 1.25 (s, 6H), 1.21 (s, 3H), 0.73–0.89 (m, 10H), 0.31–0.48 (m, 6H). ESIMS: 950.5 [M+H] + , 972.5 [M+Na] + . 3.7. Cabazitaxel (1a) To a solution of 2′TEScabazitaxel 8 (22 mg) in acetonitrile (0.4 mL), Pyr (155 μL, 80 eq.) and HF (56 μL, 40 eq.) were added. The mixture was stirred for 8 h at RT. After workup and purification 15 mg of cabazitaxel 1a (77%) was afforded as a white solid. 1 H NMR (400 MHz, CDC13) δ: 8.10 (d, 2H, J 7.7 Hz), 7.62 (m, 1H), 7.50 (m, 2H), 7.33–7.40 (m, 5H), 6.21 (t, 1H, J 8.7 Hz), 5.62 (d, 1H, J 6.7 Hz), 5.43 (d, 1H, J 8.9 Hz), 5.28 (br s, 1H), 4.97 (d, 1H, J 9.2 Hz), 4.80 (s, 1H), 4.63 (br s, 1H), 4.31 (d, 1H, J 8.6 Hz), 4.18 (d, 1H, J 8.6 Hz), 4.11 (m, 1H), 3.82 (m, 1H), 3.80 (d, 1H, J 6.8 Hz), 3.45 (s, 3H), 3.30 (s, 3H), 2.70 (m, 1H), 2.36 (s, 3H), 2.27 (m, 2H), 2.04 (s, 3H), 1.88 (s, 3H), 1.79 (m, 2H), 1.72 (s, 3H), 1.35 (s, 9H), 1.26 (m, 3H), 1.22 (s, 3H), 1.21 (s, 3H). 13 C NMR (100 MHz, CDC13) δ: 205.04, 172.85, 170.55, 167.09, 155.45, 138.79, 138.53, 135.76, 133.75, 130.26, 128.93, 128.76, 128.17, 126.96, 84.22, 82.77, 81.89, 80.88, 80.43, 80.36, 78.86, 76.67, 74.67, 73.82, 72.67, 57.46, 57.15, 57.04, 56.25, 47.52, 43.43, 35.37, 32.25, 28.34, 26.96, 22.80, 20.80, 14.40, 10.47. ESIMS: 836.4 [M+H] + , 853.4 [M+NH4] + . The 1 H NMR data are consistent with that of cabazitaxel [9] .
Acknowledgements We acknowledge the support of NSFC (Grant No. 30930108) and MOST (Grant No. 2009YZHLCH03).
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一种合成卡巴他赛的新方法 张国宁, 方唯硕* 中国医学科学院 北京协和医学院 药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050 摘要: 本文报道了一种以10去乙酰基巴卡丁III为起始原料合成卡巴他赛的新方法。 路线中使用了温和的条件对 底物7羟基进行甲醚化, 从而避免了7β羟基在强碱性条件下的差向异构化。该路线共6步, 总收率为20%。 关键词: 卡巴他赛; 7羟基甲基化