ZA200306223B - Method of synthesizing camptotecin-relating compounds. - Google Patents
Method of synthesizing camptotecin-relating compounds. Download PDFInfo
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- ZA200306223B ZA200306223B ZA200306223A ZA200306223A ZA200306223B ZA 200306223 B ZA200306223 B ZA 200306223B ZA 200306223 A ZA200306223 A ZA 200306223A ZA 200306223 A ZA200306223 A ZA 200306223A ZA 200306223 B ZA200306223 B ZA 200306223B
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- 150000001875 compounds Chemical class 0.000 title claims description 127
- 238000000034 method Methods 0.000 title claims description 50
- 230000002194 synthesizing effect Effects 0.000 title description 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 150000002576 ketones Chemical class 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000004795 grignard reagents Chemical class 0.000 claims description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- HHCZNCHGYNRIBP-UHFFFAOYSA-N 1-(2-amino-5-hydroxyphenyl)propan-1-one Chemical compound CCC(=O)C1=CC(O)=CC=C1N HHCZNCHGYNRIBP-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003810 Jones reagent Substances 0.000 claims description 4
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical group [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000005574 benzylation reaction Methods 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- 238000006192 iodination reaction Methods 0.000 claims 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 239000012670 alkaline solution Substances 0.000 claims 2
- 239000007795 chemical reaction product Substances 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000007788 liquid Substances 0.000 claims 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 229910052762 osmium Inorganic materials 0.000 claims 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- 238000000746 purification Methods 0.000 claims 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims 2
- WCASXYBKJHWFMY-NSCUHMNNSA-N 2-Buten-1-ol Chemical compound C\C=C\CO WCASXYBKJHWFMY-NSCUHMNNSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims 1
- IVZHSVBWLCIEQE-UHFFFAOYSA-L FC(C(=O)[O-])(F)F.[Ag+].[I+].FC(C(=O)[O-])(F)F Chemical group FC(C(=O)[O-])(F)F.[Ag+].[I+].FC(C(=O)[O-])(F)F IVZHSVBWLCIEQE-UHFFFAOYSA-L 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 1
- KOLFEOGHVLYIHV-UHFFFAOYSA-N acetonitrile 2-propan-2-yloxypropane hydrate Chemical compound O.CC#N.CC(C)OC(C)C KOLFEOGHVLYIHV-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 229910002091 carbon monoxide Inorganic materials 0.000 claims 1
- 230000017858 demethylation Effects 0.000 claims 1
- 238000010520 demethylation reaction Methods 0.000 claims 1
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical group [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 230000022244 formylation Effects 0.000 claims 1
- 238000006170 formylation reaction Methods 0.000 claims 1
- WCASXYBKJHWFMY-UHFFFAOYSA-N gamma-methylallyl alcohol Natural products CC=CCO WCASXYBKJHWFMY-UHFFFAOYSA-N 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 230000026045 iodination Effects 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 238000003475 lamination Methods 0.000 claims 1
- 239000010410 layer Substances 0.000 claims 1
- 239000012044 organic layer Substances 0.000 claims 1
- 239000003444 phase transfer catalyst Substances 0.000 claims 1
- BPAZVIWQBHZKSY-UHFFFAOYSA-M sodium;1-chloropyrrolidine-2,5-dione;iodide Chemical compound [Na+].[I-].ClN1C(=O)CCC1=O BPAZVIWQBHZKSY-UHFFFAOYSA-M 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 229940127093 camptothecin Drugs 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 4
- 238000006257 total synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 3
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- USJPEEICWDPCCR-UHFFFAOYSA-N (6-methoxypyridin-2-yl)-trimethylsilane Chemical compound COC1=CC=CC([Si](C)(C)C)=N1 USJPEEICWDPCCR-UHFFFAOYSA-N 0.000 description 2
- NQKIFRSZGVLWSK-UHFFFAOYSA-N 4-iodo-2-methoxy-6-trimethylsilylpyridine-3-carbaldehyde Chemical compound COC1=NC([Si](C)(C)C)=CC(I)=C1C=O NQKIFRSZGVLWSK-UHFFFAOYSA-N 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- -1 aryl isonitrile Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 1
- YEMFHJFNJPXYOE-UHFFFAOYSA-N 3-iodo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1I YEMFHJFNJPXYOE-UHFFFAOYSA-N 0.000 description 1
- XLYPHUGUKGMURE-UHFFFAOYSA-N 5-hydroxy-2-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C(C=O)=C1 XLYPHUGUKGMURE-UHFFFAOYSA-N 0.000 description 1
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001620634 Roger Species 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- CTPKSRZFJSJGML-UHFFFAOYSA-N sulfiram Chemical compound CCN(CC)C(=S)SC(=S)N(CC)CC CTPKSRZFJSJGML-UHFFFAOYSA-N 0.000 description 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 description 1
Description
® @
Tr 2003/63,y
SPECIFICATION
Method of synthesizing camptothecin-relating compounds
The present invention relates to a process for synthesizing camptothecin related compound(s). More particularly, the invention relates to a process for preparing intermediates related to the synthesis of camptothecin analogs having an anti-tumor activity and use of said intermediates, and relates to a total synthesis of camptothecin analogs.
Background Art } Camptothecin (hereinafter described as CPT) isolated from the bark, root, fruit, leaf and the like of Camtotheca acuminata of Chinese origin is a pentacyclic alkaloid and is known to show the anti~tumor activityby inhibitionof a nucleic acid synthesis.
In the meantime, as to a camptothecin derivative the induction of diarrhea and the like as a side effect are reported (Gann to Kagaku Ryohou 17, p115-120, 1990), leaving a problem to cause disorder for the gastrointestinal tract, and therefore, various kinds of derivatives have been examined to reduce the toxicity, to increase the effect, and so on.
Thus, the inventors already reported 7-~ethyl~10-[4-(1- piperidino)-l-piperidino]carbonyloxycamptothecin:hydrochlor ide trihydrate (hereinafter described as CPT-11), the water soluble semisynthetic derivative of CPT, as a compound which is reduce in toxicity compared to CPT, and it is at present widely used as the anti-tumor agent (general name; irinotecan hydrochloride).
Camptothecin analogs such as CPT-11 can be derived by a chemical modification of CPT obtained from natural materials. 1 al
However, owing to an extremely low amount of CPT obtained from natural materials such as Camtotheca acuminata which is the starting material, it is anticipated that according to an increased demand of CPT~11 which is a useful derivative and the like, a sufficient supply of CPT becomes difficult notwithstanding a measure for the starting material supply such as afforestation. Althoughthetotal synthesis is also examined, it is the present situation that it has not yet been into practical use.
As a process by total synthesis is known the method of Shen,
W. etal. represented by thebelow reaction schemevia Friedlinder reaction of the aminopropiophenone and the tricyclic ketone (J.
Org. Chem. 1993, 58, 611-617 "Concise Total Syntheses of } dl~-Camptothecin and Related Anticancer Drugs.", though there are problems that the steps are tedious, the yields are not sufficient and only the racememate is synthesized. [o] ood 00, 2 on
NH, ° N © Me0.C Et * MoO 0 bi! Her. 140°C HO ax, Et 0 ——p N 2) 0p, CuCl, N
DMF, gh 0 83% Ho
Et ©
In the meantime, although Curran, D. P. et al. carried out a total synthesis by the method using a cascade radical cyclization of the aryl isonitrile and the iodopyridone represented by the below reaction scheme (Chem. Eur. J. 1998, 4, 67-83 "A General Synthetic Approach to the (20S) -Camptothecin
Family of Antitumor Agents by a Regiocontrolled Cascade Radical
Cyclization of Aryl Isonitriles."), problems are pointed out in which the yield of the cyclization reaction is not sufficient and deprotection of the protective group is necessary after cyclization.
MeO,
MeO Mes Sn 0 47 %HBr pa —=4 N ———> N38 + N nc Et o Jenzene 10°C wo’ hv, 70°C 0 90%
Et 57%
Jo
Pi Mes S
Bg ON g { wx 0 ya ) ———> SN-38B-11
Y 0 + Bi benzene 0 NC % © sealed tube
Ho Et hv, a0. oh 31%
Additionally, although the above Curran, D. P. et al. synthesized 4-iodo-2-methoxy-6-trimethylsilylpyridine-3- carbaldehyde, an intermediate in the synthesis of the tricyclic ketone part of CPT analogs, according to the below scheme,
OMe go OMe
TY Ta '
Z rs Mo nab G0 > — x 78C 400 30°C 78C~0C a th cy ih ™5 I 0%
Josien, H; Ko, S-8; Bom D; Quran, D.P. Gham Ar. J. 1988,4, Na 1, 67. this method is highly dangerous due to the necessity to use t-Buli easily flammable ina large amount industrially, and the reaction at -78°C as a reaction temperature is required, making it impossible to enlarge the batch size. Further, owing to the necessity of a complicated temperature control in the total reaction system it was not an industrially practical reaction system.
It is an object of the invention to provide efficiently . CPT, which is a starting material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and camptothecin analogs such as 7-ethyl-10-hydroxycamptothecin, which is a key intermediate of the irinotecan hydrochloride synthesis, by a practical total synthesis. Particularly, it is an object of the invention to synthesize an intermediate corresponding to the AB-ring part of camptothecin skeleton and an intermediate corresponding to the CDE-ring part respectively, and further to synthesize camptothecin analogs using these intermediates.
Mode for Carrying Out the Invention
In view of these circumstances the inventors made an extensive research, and consequently as to the AB-ring part, made Compound (a) (5-hydroxy-2-nitrobenzaldehyde):
H CHO
(a)
NO, a starting material, and found a means to provide CPT and its derivatives stably by an efficient preparation of 2'-amino-5'-hydroxypropiophenone corresponding to the AB~-ring part of CPT skeleton, and as to the CDE-ring part starting from
Compound (k) (2-methoxy-6-trimethylsilylpyridine (MTP)):
Me 0 w
TMS
(wherein TMS represents a trimethylsilyl group, and Me represents a methyl group.)
found a means to provide CPT and its derivatives stably by an efficient preparation of a tricyclic ketone corresponding to the CDE-ring part of CPT skeleton, and established a total synthetic process for CPT analogs by an appropriate combination of these means without using natural materials, finishing the invention.
Namely, the invention relates to a process for preparing 2'-amino-5‘-hydroxypropiophenone corresponding to the AB-ring of CPT skeleton according to the route;
OH
H CHO Ri CHO R
ROGER ¢ Gi ¢ Og
NO, NO, NO, (a) (b) (c) 0 0]
R ~
COC 6 (d) (e) (wherein R represents a protective group.), and relates to a total synthetic process of CPT analogs by the appropriate combination of a process for the tricyclic ketone corresponding to the CDE-ring part of CPT skeleton comprising particularly synthesis of 3-formyl-4-iodo-2-methoxy-6- trimethylsilylpyridine (Compound (1)) from 2-methoxy-6- trimethylsilylpyridine (Compound (k)) or 3-hydroxymethyl-4- iodo-2-methoxy-6-~trimethylsilylpyridine (Compound (v)) by improving and optimizing a process according to the synthetic route;
Me o Me Me Me ‘a v CHO rd rd 0 — Xm J — XC ™s ms” TN ™sT YN ms FY ™S ® 0 (m) o
Me ° e e z =z Zz N” — FX — £1 — joe! — wo ALL ™S “Er oH ™S ho” ee® Ho” "Et° o WoTUE (0) 12] 0] 4] 0 [0] [0]
H Lo)
IPS SC IEE Ss SCREEN eS §!
P xX x y .
Ho” Et® Boo I Tho et o Ho” Et® ° ® ® ® (wherein TMS is a trimethylsilyl group, Me is a methyl group,
Et is an ethyl group, Pr is a propyl group, and “Bu is a t-butyl group.), established on the basis of Curran route (Josien, H,;
Ko, S. B.; Bom, D.: Curran, D. P. Chem. Eur. J. 1998, 4 67-83) and Pharmacia & Upjohn route (hereinafter described as P&U route;
Heneger, K. E.; Ashford, S, W.; Baughman, T. A.; Sih, J. C.;
Gu, R. L. J. Org. Chem. 1997, 62, 6588-6597.) which are synthetic routes currently known. Further, since Compound (v) is a byproduct arising in the process to synthesize 3-(2-~ butenyloxymethyl)~4-iodo-2-methoxy-6-trimethylsilylpyridine (Compound (m)), in the above synthetic route Compound (1) is described in the downstream.
Particularly, the invention relates to a process for preparing 2’-amino-5‘-hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):
H CHO
(a)
NO,
. ® @®
Compound (b):
R CHO
NO; is produced; and from Compound (b) Compound (c):
OH
R
(c)
NO. is produced; and from Compound (c) Compound (d):
[0]
R
(d)
NO; is produced; and from Compound (d) Compound (e): 0
H
(e)
NH, ’ is produced; wherein R is a protective group which can be deprotected by a catalytic reduction.
Also, the invention relates to the above process, wherein the protective group which can be deprotected by a catalytic reduction is a benzyl group.
Further, the invention relates to the above process, wherein it contains one or more steps selected from the group consisting of
(1) a step to obtain Compound (b) mixing Compound (a), a benzylation reagent and a base, and stirring said mixture in solvent under reflux; (2) a step to obtain Compound (c) by dropping Grignard reagent to Compound (b) under an inert gas atmosphere; (3) a step to obtain Compound (d) mixing Compound (c) and an oxidizing agent and stirring the mixture; (4) a step to obtain Compound (e) by a catalytic reduction of
Compound (d).
Further, the invention relates to the above process wherein in the step (1) the solvent is dimethylformamide.
The invention also relates to the above process wherein in the step (2) the Grignard reagent is vinyl magnesium bromide.
Further, the invention relates to the above process wherein in the step (3) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-(2,2,6,6~tetramethylpiperidine~1-oxyl)- sodium hypochlorite.
Also, the invention relates to compound represented by formula (c’):
OH
Bn Z (e¢’)
NO, (wherein Bn is a benzyl group.).
Further, the invention relates to compound represented by formula (d’): 0
RS Of (d") (wherein Bn is a benzyl group.).
® ®
Also, the invention is a process for preparing 2'-amino-5’-~-hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):
H CHO
XX (a)
NO,
Compound (c’’):
OH
HO =
NO;
BN is produced; and from Compound (c’’) Compound (d’’): 0
HO =
NO; is produced; and from Compound (d’‘) Compound (e):
Oo
H
(eo)
NH, is produced.
Further, the inventionrelates to the above process, wherein it contains one or more steps selected from the group consisting of (1) a step to obtain Compound (c’’) by dropping Grignard reagent to Compound (a) under an inert gas atmosphere; (2) a step to obtain Compound (d‘‘) mixing the Compound (c’’) and an oxidizing agent and stirring the mixture; and 9 y
(3) a step to obtain Compound (e) by a catalytic reduction of
Compound (d’'’).
The invention also relates to the above process wherein in the step (1) the Grignard reagent is vinyl magnesium bromide.
Further, the invention relates to the above process wherein in the step (2) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-sodium hypochlorite.
The invention also relates to use of 2’~-amino-5‘-hydroxypropiophenone, which is obtained by the above process, to the preparation of camptothecin analogs.
Further, the invention relates to a process for preparing camptothecin analogs, comprising reaction of 2’ ~amino-5‘~hydroxypropiophenone obtained by the above process and a tricyclic ketone.
The invention also is a process for preparing the tricyclic ketone to synthesize camptothecinanalogs, wherein from Compound (k):
Me d
Ll ow
TMS
(whereinTMS isatrimethylsilyl group, andMe is amethyl group. ), or Compound (Vv):
Me 4 OH (v)
J
TMS l (wherein TMS is a trimethylsilyl group, and Me is amethyl group.) 10 rr
Compound (1):
Me
CHO
: (1)
TMS
(wherein TMS is a trimethylsilyl group, and Me is amethyl group.) is produced; and from Compound (1) Compound (m):
Cd (m)
TMS I
(wherein TMS is a trimethylsilyl group, and Me is amethyl group.) is produced; and from Compound (m) Compound (n):
Me (n)
T™S
Et (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.) is produced; and from Compound (n) Compound (0):
J
7 (0)
TMS oo"
Et OH (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.)
Claims (37)
- . PN ® CLAIMS l. A process for preparing 2’'-amino-5'- hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a): H CHO XX (a) NO, Compound (b): R CHO is produced; and from Compound (b) Compound (c): OH R (e) NO; is produced; and from Compound (c) Compound (d): O R (d) NO; is produced; and from Compound (d) Compound (e): lo] H (e) NH,is produced; wherein R is a protective group which can be deprotected by a catalytic reduction.
- 2. A process according to claim 1, wherein the protective group which can be deprotected by a catalytic reduction is a benzyl group.
- 3. A process according to claim 1 or 2, wherein it contains one or more steps selected from the group consisting of (1) a step to obtain Compound (b) mixing Compound (a), a benzylation reagent and a base, and stirring said mixture in solvent under reflux: (2) a step to obtain Compound (c) by dropping Grignard reagent to Compound (b) under an inert gas atmosphere; (3) a step to obtain Compound (d) mixing Compound (c) and an oxidizing agent and stirring the mixture; and (4) a step to obtain Compound (e) by a catalytic reduction of - Compound (d).
- 4. A process according to claim 3, wherein in the step (1) the solvent is dimethylformamide.
- 5. A process according to claim 3, wherein in the step (2) the Grignard reagent is vinyl magnesium bromide.
- 6. A process according to claim 3, wherein in the step (3) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-sodium hypochlorite.
- 7. Compound represented by formula (c’): 79 AMENDED SHEETOH B (ec) NO, (wherein Bn is a benzyl group.).
- 8. Compound represented by formula (d'): [0 B (d") NO, (wherein Bn is a benzyl group.).
- 9. A process for preparing 2'-amino-5‘- hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a): H CHO (a) NO, Compound (c‘’): OH HO _ (c"’) NO, is produced; and from Compound (c’’) Compound (d’’): 0 HO = (d"") NO, is produced; and from Compound (d’’) Compound (e):H (eo) NH, is produced.
- 10. A process according to claim 9, wherein it contains one or more steps selected from the group consisting of (1) a step to obtain Compound (c’’) by dropping Grignard reagent to Compound (a) under an inert gas atmosphers; (2) a step to obtain Compound (d'’) mixing Compound (c¢’‘) and an oxidizing agent and stirring the mixture; and (3) a step to obtain Compound (e) by a catalytic reduction of Compound (d'’).
- 11. A process according to claim 10, wherein in the step (1) the Grignard reagent is vinyl magnesium bromide. :
- 12. A process according to claim 11, wherein in the step (2) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-sodium hypochlorite.
- 13. Use of 2’-amino-5’-hydroxypropiophenone, which is obtained by the process according to any one of claims 1-6 and 9-12, to the preparation of camptothecin analogs.
- 14. A process for preparing camptothecin analogs, comprising reaction of 2°‘-amino-5‘-hydroxypropiophenone, obtained by the process according to any one of claims 1-6 and 9-12, and a tricyclic ketone.
- 15. A process for preparing the tricyclic ketone to 81 AMENDED SHEET synthesize camptothecin analogs, wherein from Compound (k): fe) Iw TMS (wherein TMS is a trimethylsilyl group, and Me is amethyl group. ), or Compound (Vv): Me OH (v) TMS I(wherein TMS isatrimethylsilyl group, and Me is amethyl group.), Compound (1): Me CHO l : (1) TMS (wherein TMS is a trimethylsilyl group, and Me is amethyl group.) is produced; and from Compound (1) Compound (m): dd (m) T™S (wherein TMS is a trimethylsilyl group, and Me is amethyl group.) is produced; and from Compound (m) Compound (n):Me (n) T™S Et (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.) is produced; and from Compound (n) Compound (0): L 7 (0) TMS oot x Et OH (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.) is produced; and from Compound (0) Compound (p): Me “1 (p) ™s 0 ’ HO" “Et (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.) is produced; and from Compound (p) Compound (q): Me d . I (q) p8 [0] HO" "Et (wherein Me is a methyl group, and Et is an ethyl group.) is produced; and from Compound (gq) Compound (r):Me [J ° (r) \ HO Et oO (wherein Me is a methyl group, Et is an ethyl group, and Pr is a propyl group.) is produced; and from Compound (r) Compound (8):H. P ° (s) HO” “Et 0 (wherein Et is an ethyl group, and Pr is a propyl group.) is produced; and from Compound (s) Compound (t): 0 BuO (©) HO Ho” gt (wherein Et is an ethyl group, and tBu is a t-butyl group.) is produced; and from Compound (t) Compound (h): 0 N ™ 0 0 HO" "Et (wherein Et is an ethyl group.) is produced, wherein it contains one or more steps selected from the group consisting of; (1) asteptoobtainCompound (1) mixing Compound (k), alithiating agent, a formylation reagent and an iodination reagent; (2) a step to obtain Compound (m) mixing Compound (1), crotyl alcohol, triethylsilane and an acid, and reacting said mixture without use of solvent; (3) astep toobtain Compound (1) mixing Compound (Vv), a byproduct in the step(2), with an oxidizing agent and a base; (4) astep to obtain Compound (n) mixing Compound (m),a palladium catalyst, a base and a phase-transfer catalyst, and refluxing said mixture in solvent; (5) a step to obtain Compound (0) mixing Compound (n), an osmium catalyst, aco-oxidizing agent, abaseand an asymmetric reagent; (6) a step to obtain Compound (p) mixing Compound (0), a base and iodine, and refluxing said mixture in an alcohol-water mix liquid; (7) a step to obtain Compound (gq) mixing Compound (p) and a desilylation-iodination reagent; (8) astep toobtain Compound (r) mixing Compound (q), a palladium catalyst and a base, and reacting said mixture in l-propanol under a carbon monoxide gas atmosphere; (9) a step to obtain Compound (s) mixing Compound (r) and a demethylation reagent, and reacting said mixture at room temperature; (10) a step to obtain Compound (t) reacting Compound (s) under the presence of t-butyl acrylate and a base.
- 16. A process according to claim 15, wherein in the step (1) the lithiating agent is n-butyl lithium.
- 17. A process according to claim 15 or 16, wherein in the step (1) the reaction temperature is the constant temperature of -30 to -40°C.
- 18. A process according to claim 15, wherein in the step (3) the oxidizing agent is TEMPO-sodium hypochlorite.® ®
- 19. A process according to claim 15, wherein in the step (4) the base is potassium carbonate or diisopropylethylamine.
- 20. A process according to claim 15 or 19, wherein in the step (4) the solvent is tetrahydrofuran, or a diisopropyl ether- acetnitrile-water mix liquid.
- 21. A process according to claim 15, wherein in the step (5) the osmium catalyst is potassium osmate(VI).
- 22. A process according to claim 15, wherein in step (6) the iodine against Compound (0) is in 4 equivalent.
- 23. A process according to claim 15, wherein in the step (7) the desilylation-iodination reagent is iodine-silver trifluoroacetate or N-chlorosuccinimide-sodium iodide.
- 24. A process according to claim 15 or 23, wherein Compound (gq) is purified chemically by purification steps consisting of; - a step to add the reaction product obtained by the step to produce Compound (q) from Compound (p) to an aqueous alkaline solution and to stir; -astep to add anorganic solvent and to stir, followed by removal of the organic layer; and - a step to make the aqueous layer acidic and to extract with an organic solvent.
- 25. A process according to claim 24, wherein the aqueous alkaline solution is an aqueous sodium hydoxide solution.
- 26. A process according to claim 24, wherein the organic solvent is chloroform.a ®
- 27. Aprocess according to claim 15 or 23, wherein Compound (q) is purified optically by purification steps consisting of; ~- a step to dissolve the reaction product obtained by the step to produce Compound (gq) from Compound (p) in a high polarity solvent, followed by lamination of a low polarity solvent; and ~asteptofilteraprecipitatewhich is followed by concentration of the filtrate to dryness under reduced pressure.
- 28. A process according to claim 27, wherein the high polarity solvent is chloroform.
- 29. Aprocessaccordingtoclaim27, whereinthelowpolarity solvent is n-hexane.
- 30. A process according to claim 15, wherein in the step (10) the base is potassium carbonate.
- 31. Use of the tricyclic ketone obtained by the process according to any one of claims 15-30 to the preparation of camptothecin analogs.
- 32. Aprocess for preparing camptothecin analogs, wherein thetricyclic ketone, which is obtained by the process according to any one of claims 15-30, is reacted with 2’'-amino-5’'-hydroxypropiophenone.
- 33. A process according to claim 32, wherein the 2’-amino-5'-hydroxypropiophenone is 2’'-amino-5’'-hydroxypropiophenone obtained by the process according to any one of claims 1-6 and 9-12.
- 34. A process according to any one of claims 14, 32 and 33, wherein the tricyclic ketone and 2’'-amino- 5’ -hydroxypropiophenone are mixed, and said mixture is reacted under an inert gas atmosphere.
- 35. A process according to claim 1, 9, 14, 15 or 32 substantially as herein described and exemplified. :
- 36. A compound according to claim 7 or 8, : substantially as herein described and exemplified.
- 37. Use according to claim 13 or 31, substantially as herein described and exemplified. 88 AMENDED SHEET
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001045430 | 2001-02-21 |
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| ZA200306223B true ZA200306223B (en) | 2004-06-03 |
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| US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
| SG104284A1 (en) * | 1996-10-30 | 2004-06-21 | Tanabe Seiyaku Co | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
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| CN101337900B (en) | 2013-12-18 |
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