CN102702213B - Preparation method and application of optically pure homocamptothecin intermediate - Google Patents
Preparation method and application of optically pure homocamptothecin intermediate Download PDFInfo
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- CN102702213B CN102702213B CN201210204092.6A CN201210204092A CN102702213B CN 102702213 B CN102702213 B CN 102702213B CN 201210204092 A CN201210204092 A CN 201210204092A CN 102702213 B CN102702213 B CN 102702213B
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- 0 CCOC(C=C(*)C(C=C1N2CCC1(O*)O*)=C(C*)C2=O)=O Chemical compound CCOC(C=C(*)C(C=C1N2CCC1(O*)O*)=C(C*)C2=O)=O 0.000 description 6
Abstract
The invention relates to a preparation method of synthesizing a chiral intermediate compound R-CDE loop (I) of optically pure homocamptothecin and application of the R-CDE loop (I). A chiral center exists in a chemical structure of the homocamptothecin, and researches on structure-activity relationship show that the activity of R configurational isomer is obviously higher than that of S configurational isomer, and the key to preparing the R-homocamptothecin is to obtain the optically pure intermediate R-CDE loop (I). The invention provides a method of preparing the R-CDE loop (I), and a synthesis route is shown in the specification, wherein R1 is hydrogen or linear alkyl containing C1-C5, and R2 and R3 are connected or disconnected linear or branched alkyl containing C1-C5. The invention provides the preparation method of the R-CDE loop (I), which is easy and convenient to separate, low in cost and high in yield and purity.
Description
Technical field
The present invention relates to technical field of organic chemistry, the preparation method of the chiral intermediate compound R-CDE ring (I) of the pure hCPT of synthesizing optical (being R-hCPT), it is trione compounds (R)-5-ethyl-5-hydroxyl-4,5, also [3,4-f]-indolizine-3 of 8,9-tetrahydrochysene oxa-Zhuo, 7,11 (1H).
Background technology
HCPT is the topoisomerase I inhibitor antitumor drug of new generation that development in recent years is got up, and has the advantages that activity is high, selectivity is strong and toxicity is low, successively has two hCPT analog derivative diflomotecan and elomotecan to enter clinical study.
The complete synthesis two lines that mainly contain of hCPT and derivative thereof:
1, formed through Mitsunobu reaction and intramolecular Heck reaction condensation by ring AB and ring DE:
2, formed by ring A and ring CDE process Frilander condensation:
In the chemical structure of hCPT, there is a chiral centre, structure activity study shows: R configurational isomer activity is apparently higher than S configurational isomer (O.Lavergne, et al.J Med Chem, 1998,41 (27): 5410-5419.).The key that adopts route 1 to prepare R-hCPT is to obtain optically pure intermediate R-DE ring (II), the preparation method of R-DE ring (II) has been reported, such as Lavergne etc. has reported taking Quinidine optically pure intermediate acid as resolution reagent obtains, then close ring with DCC and TMSI and obtain the synthetic method (O.Lavergne that optical purity DE encircles, et al.J Med Chem, 1998,41 (27): 5410-5419); Curran etc. build the synthetic route (D.P.Curran of optical purity DE ring by the Sharpless asymmetric Epoxidation of L-(+)-ethyl tartrate catalysis, et al.Tetrahedron, 2002,58 (32): 6329-6341); Peters etc., taking R-4-phenyl oxazolidinones as chirality assistant agent, utilize asymmetric aldol condensation reaction to obtain the method (R.Peters et al.J Org Chem, 2006,71 (20): 7583-7595.) of optical purity DE ring.But these methods exist many weak points, as used the expensive reagent such as organic palladium and organotin in committed step, AB ring builds complexity and is unfavorable for derivatize, and synthesis yield is low etc., and therefore synthetic route 1 is difficult to put into practice.
The key that adopts route 2 to prepare R-hCPT is to obtain optically pure intermediate R-CDE ring (I), and the structure of R-CDE ring (I) is as follows:
Wherein R
1for hydrogen or containing C
1～C
5straight chained alkyl.
But so far there are no about preparing the relevant report of R-CDE ring (I).
Summary of the invention
The object of this invention is to provide one and prepare the method for R-CDE ring (I), synthetic route is as follows:
Wherein, R
1for hydrogen or containing C
1～C
5straight chained alkyl, R
2and R
3for that be connected or disjunct containing C
1～C
5straight or branched alkyl.
Concrete steps are:
1, compound (III) is dissolved in to solvent and is mixed with solution, under highly basic catalysis, react and generate trans alpha, beta-unsaturated esters compound (IV) through HWE with phosphoryl triethyl acetate.
Said alkali is selected from sodium amide, potassium tert.-butoxide, sodium hydride etc., preferably sodium hydride.Said solvent is selected from one or more in the organic solvents such as methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, preferably tetrahydrofuran (THF).Temperature of reaction is-10 DEG C～35 DEG C, preferably 0 DEG C～25 DEG C.Reaction times is controlled at 12～36 hours.
2, trans alpha, beta-unsaturated esters compound (IV) is dissolved in to solvent and is mixed with solution, under nitrogen protection, selective reduction becomes vinylcarbinol compound (V).
Said reductive agent is selected from Lithium Aluminium Hydride, diisobutyl aluminium hydride, red aluminium etc., preferably diisobutyl aluminium hydride.Said solvent is selected from one or more in the organic solvents such as methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, preferably toluene.Temperature of reaction is-100 DEG C～-20 DEG C, preferably-80 DEG C～-50 DEG C.Reaction times is controlled at 2～6 hours.
3, vinylcarbinol compound (V) is dissolved in to solvent and is mixed with solution, under nitrogen protection, adopt classical Sharpless asymmetric Epoxidation method, transform and generate compound (VI).
Said solvent is selected from one or more in the organic solvents such as methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, preferably methylene dichloride.Temperature of reaction is-50 DEG C～-5 DEG C, preferably-30 DEG C～-10 DEG C.Reaction times is controlled at 6～18 hours.
4, compound (VI) is dissolved in to solvent and is mixed with solution, under nitrogen protection, the reaction of selectivity epoxy addition generates diol compound (VII).
Said reductive agent is selected from Lithium Aluminium Hydride, diisobutyl aluminium hydride, red aluminium etc., preferred red aluminium.Said solvent is selected from one or more in the organic solvents such as methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, preferably methylene dichloride.Temperature of reaction is-50 DEG C～-5 DEG C, preferably-30 DEG C～-10 DEG C.Reaction times is controlled at 6～18 hours.
5, diol compound (VII) is dissolved in to solvent and is mixed with solution, with Dai Si-Martin reagent and NaClO
2/ KH
2pO
4oxidation generates compound (VIII).
Said solvent is selected from one or more in the organic solvents such as methyl alcohol, ethanol, Virahol, the trimethyl carbinol, preferred tertiary butanols.Temperature of reaction is 0 DEG C～60 DEG C, preferably 20 DEG C～30 DEG C.Reaction times is controlled at 24～48 hours.
6, compound (VIII) is dissolved in to solvent and is mixed with solution, under acidic conditions, hydrolysis generates acid, sloughs the blocking group of ketone carbonyl simultaneously, and cyclization generates R-CDE ring (I).
The acid of said acidic conditions is selected from the mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, nitric acid, or the organic acid such as acetic acid, trifluoroacetic acid, tosic acid, Whitfield's ointment, oxalic acid, or one or more in these acid, preferably hydrochloric acid or trifluoroacetic acid.Said solvent is selected from one or more in the organic solvents such as methylene dichloride, tetrahydrofuran (THF), toluene, ether, ethanol, preferred alcohol.Temperature of reaction is 30 DEG C～100 DEG C, preferably 60 DEG C-80 DEG C.Reaction times is controlled at 4～8 hours.
Silicon ether protective group of the present invention, except tertiary butyl dimethylsilyl (TBDMS), is also applicable to the blocking group such as tri isopropyl silane base (TIPS), tert-butyl diphenyl silylation (TBDPS).
Intermediate R-CDE ring of the present invention (I) can be used for preparing R-hCPT compounds, for example, obtain optical purity hCPT compounds (X) by Friedlander condensation reaction:
Wherein R
1for hydrogen or containing C
1～C
5straight chained alkyl;
R
4, R
5, R
6, R
7can be identical or different, represent independently respectively following groups: hydrogen, halogen, low alkyl group, OR
8(R
8represent hydrogen or low alkyl group), nitro, amino, or R
5and R
6form together the chain of 3 or 4 yuan, or R
6and R
7form together the chain of 3 or 4 yuan, wherein the element of this chain is selected from CH
2, O, as methylene-dioxy or ethylenedioxy.
The invention has the advantages that: the preparation method that a high yield, highly purified R-CDE ring (I) 1, are provided; 2, reacting required reagent is all common agents, low price; 3, separate simply; 4, the present invention provides a crucial intermediate for preparing R-hCPT compounds.
Embodiment
Now the present invention is described in detail in conjunction with the embodiments.
Embodiment 1, preparation R-CDE ring (I)
1, preparation compound IV
0.50g sodium hydride is suspended in the anhydrous THF of 30mL; slowly splash into 2.84g phosphoryl triethyl acetate; there are immediately a large amount of Bubble formations; after room temperature reaction 1h; directly add 1.00g compound (III); continue reaction 24h; be cooled to 0 degree and add the cancellation of 50mL saturated ammonium chloride; suction filtration; ethyl acetate for water layer (50mL × 3) is extracted, and boils off solvent, chromatographic column column chromatography purification (sherwood oil: ethyl acetate=4: 1); obtain 1.06 grams of white solid compounds (IV), yield 90%.The m.p.96-98 DEG C of compound (IV),
1h-NMR (500MHz, DMSO-d
6) δ: 0.097 (s, 6H), 0.88 (s, 9H), 0.93 (t, 3H), 1.26 (t, 3H), 2.39 (t, 2H), 2.97 (q, 2H), 3.98 (t, 2H), 4.06-4.27 (m, 6H), 4.44 (s, 2H), 5.91 (s, 1H), 6.29 (s, 1H); HRMS:464.2475 (M+H).
2, prepare compound V
1.00g compound (IV) is dissolved in 25mL dry toluene, nitrogen replacement, be cooled to-78 DEG C with dry ice-propanone, slowly splash into 4.5mL diisobutyl aluminium hydride toluene solution, after reaction 1h, add again the diisobutyl aluminium hydride toluene solution of 4.5mL, continue after reaction 2h, at-78 DEG C, slowly splash into 20mL methyl alcohol, naturally rise to room temperature, reaction 12h, separate out jelly, suction filtration, fully wash with 20mL methylene dichloride, boil off filtrate, chromatographic column column chromatography purification (sherwood oil: ethyl acetate=4: 1) for resistates, obtain 0.83 gram of white solid compound (V), yield 91%.The m.p.163-165 DEG C of compound (V),
1h-NMR (600MHz, DMSO-d
6) δ: 0.06 (s, 6H), 0.81 (t, 3H), 0.85 (s, 9H), 2.31-2.38 (m, 4H), (3.91 t, 2H), 4.02-4.14 (m, 6H), 4.42 (s, 2H), (4.69 t, 1H), 5.52 (t, 1H), 6.10 (s, 1H); MS (ESI): 422 (M+H).
3, preparation compound VI
In 100mL three-necked bottle, add 0.1mL tetra isopropyl titanate and 15mL dry methylene chloride, nitrogen replacement, be cooled to below-20 DEG C with dry ice-tetracol phenixin, add L-(+) the diethyl tartrate dichloromethane solution of 0.07mL, after 10mins, add the peroxy tert-butyl alcohol solution of 0.95mL 5.5M, at-20 DEG C, react after 30mins, drip the dichloromethane solution that 5mL contains 0.74g compound (V), continue to react after 10h at-20 DEG C, add the aqueous tartaric acid solution of 50mL 10%, rise to room temperature 20mins, filter, filtrate is extracted with methylene dichloride (50mL × 3), boil off solvent, chromatographic column column chromatography purification (sherwood oil: ethyl acetate=2: 1) for resistates, obtain 0.58 gram of white solid compound (VI), (ee=96%), yield 75%.[α] of compound (VI)
d 20=+95.5 (c 0.09, CH
2cl
2), m.p.210-211 DEG C.
1H-NMR(500MHz，DMSO-d
6)δ：0.09(s，6H)，0.82(t，3H)，0.86(s，9H)，1.65-2.05(d?m，2H)，2.34(t，2H)，3.05(t，1H)，3.60-3.75(d?m，2H)，3.90-3.94(m，2H)，4.03-4.13(m，4H)，4.53-4.63(d?d，2H)，5.05(t，1H)，6.20(s，1H)；HRMS：438.2316(M+H)。
4, preparation compound VI I
0.50g compound (VI) is dissolved in 15mL methylene dichloride, nitrogen replacement, be cooled to-20 DEG C, add the red aluminium toluene solution of 0.77mL 70%, after 10mins, rise to 0 DEG C of reaction 12h, under ice-water bath, add the saturated sodium tartrate aqueous solutions of potassium of 50mL, stirring at room temperature is to clarification, separate organic layer, water layer uses methylene dichloride (50mL × 2) to extract again, merges organic phase, boil off solvent, chromatographic column column chromatography purification (sherwood oil: ethyl acetate=2: 1), obtain 0.45 gram of white solid compound (VII), yield 80% for resistates.[α] of compound (VII)
d 20=+86 (c 0.2, CH
2cl
2), m.p.112-113 DEG C.
1H-NMR(500MHz，DMSO-d
6)δ：0.07(s，6H)，0.69(t，3H)，0.85(s，9H)，1.73-1.95(q?m，4H)，2.32(t，2H)，3.27-3.51(dm，2H)，3.90(t，2H)，4.03-4.14(m，4H)，4.46(t，1H，)，4.76(s，2H)，5.08(s，1H)，6.47(s，1H)；MS(ESI)：440(M+H)。
5, preparation R-CDE ring (I)
0.48g compound (VII) is dissolved in 15mL methylene dichloride, adds 0.74g Dai Si-Martin reagent, after room temperature reaction 24h, add the saturated Na of 10mL
2s
2o
3the saturated NaHCO of solution and 10mL
3solution, stir after 30mins, separate organic layer, water layer uses methylene dichloride (50mL × 2) to extract again, merges organic phase, anhydrous magnesium sulfate drying, filter, boil off solvent, add the 15mL trimethyl carbinol and 3.6mL2-methyl-2-butene, stir, under room temperature, slowly splash into 15mL and contain 0.45g NaClO
2with 0.59g NaH
2pO
4the aqueous solution, after room temperature reaction 24h, boil off solvent, add 30mL water, extract by ethyl acetate (50mL × 3), water layer regulates pH=3.5 with 5% hydrochloric acid, then uses ethyl acetate (50mL × 4) to extract, and merges organic phase, wash with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, and boils off solvent and obtains compound VI II.
Compound VI II is dissolved in 15mL trifluoroacetic acid, and stirring at room temperature 12h, boils off solvent, adds 30mL methylene dichloride, uses saturated NaHCO
3solution washing, boils off solvent, chromatographic column column chromatography purification (CH for resistates
2cl
2: CH
3oH=100: 2), obtain nearly 0.24 gram of white solid R-CDE ring (I), (ee=94%), yield 80%.[α] of R-CDE ring (I)
d 20=+65.4 (c 0.6, CH
2cl
2), m.p.145-147 DEG C.
1H-NMR(DMSO，300MHz)δ：0.79(t，3H)，1.73(q，2H)，2.85(t，2H)，2.98-3.42(dd，2H)，4.09(t，2H)，5.30-5.48(dd，2H)，5.93(s，1H)，6.93(s，1H)；MS(ESI)：278(M+1)。
Embodiment 2, prepare R-hCPT compounds X with R-CDE ring (I)
0.10g o-Aminobenzaldehyde and 0.10g optical purity R-CDE ring (I) are suspended in 100mL toluene, be heated to after 100 DEG C of reaction 15mins, add 0.1g tosic acid, continue reaction 1h, cold filtration, obtain 0.07 gram of faint yellow solid compounds X, yield 50% with methyl alcohol and washing with acetone.[α] of compounds X
d 20=+55 (c 0.1, CHCl
3/ MeOH 4: 1), 300 DEG C of m.p. >.
1H-NMR(500MHz，DMSO-d
6)δ：0.87(t，，3H)，1.86(q，2H)，3.05-3.49(d?d，2H)，5.26(s，2H)，5.38-5.54(d?d，2H)，6.04(s，1H)，7.42(s，1H)，7.72(t，1H)，7.87(t，1H)，8.11-8.15(m，2H)，8.67(s，1H)；MS(ESI)：363(M+1)。
Claims (2)
1. a preparation method for optical purity hCPT intermediate R-CDE ring (I), its chemical structure is as follows:
R in formula
1for hydrogen or containing C
1～C
5straight chained alkyl,
Concrete steps are:
1) compound (III) is dissolved in to solvent and is mixed with solution, under highly basic catalysis, react and generate trans alpha, beta-unsaturated esters compound (IV) through HWE with phosphoryl triethyl acetate:
Wherein, R
1for hydrogen or containing C
1～C
5straight chained alkyl, R
2and R
3for that be connected or disjunct containing C
1～C
5straight or branched alkyl,
Said alkali is selected from sodium amide, potassium tert.-butoxide, sodium hydride, and said solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, and temperature of reaction is-10 DEG C～35 DEG C, and the reaction times is controlled at 12～36 hours;
2) trans alpha, beta-unsaturated esters compound (IV) is dissolved in to solvent and is mixed with solution, under nitrogen protection, selective reduction becomes vinylcarbinol compound (V):
Said reductive agent is selected from Lithium Aluminium Hydride, diisobutyl aluminium hydride or red aluminium, and said solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, and temperature of reaction is-100 DEG C～-20 DEG C, and the reaction times is controlled at 2～6 hours;
3) vinylcarbinol compound (V) is dissolved in to solvent and is mixed with solution, under nitrogen protection, adopt classical Sharpless asymmetric Epoxidation method, transform and generate compound (VI):
Said solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, and temperature of reaction is-50 DEG C～-5 DEG C, and the reaction times is controlled at 6～18 hours;
4) compound (VI) is dissolved in to solvent and is mixed with solution, under nitrogen protection, the reaction of selectivity epoxy addition generates diol compound (VII):
Said reductive agent is selected from Lithium Aluminium Hydride, diisobutyl aluminium hydride or red aluminium, and said solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, ether, benzene, and temperature of reaction is-50 DEG C～-5 DEG C, and the reaction times is controlled at 6～18 hours;
5) diol compound (VII) is dissolved in to solvent and is mixed with solution, with Dai Si-Martin reagent and NaClO
2/ KH
2pO
4oxidation generates compound (VIII):
Said solvent is selected from methyl alcohol, ethanol, Virahol or the trimethyl carbinol, and temperature of reaction is 0 DEG C～60 DEG C, and the reaction times is controlled at 24～48 hours;
6) compound (VIII) is dissolved in to solvent and is mixed with solution, under acidic conditions, hydrolysis generates acid, sloughs the blocking group of ketone carbonyl simultaneously, and cyclization generates R-CDE ring (I):
The acid used of said acidic conditions is selected from hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, nitric acid, or one or more in acetic acid, trifluoroacetic acid, tosic acid, Whitfield's ointment, oxalic acid, said solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, ether, ethanol, temperature of reaction is 30 DEG C～100 DEG C, and the reaction times is controlled at 4～8 hours.
2. the method for claim 1, is characterized in that R
1for containing C
1～C
5straight chained alkyl, R
2and R
3for that be connected or disjunct containing C
1～C
5straight or branched alkyl; In step 1), alkali used is sodium hydride, and said solvent is tetrahydrofuran (THF), and temperature of reaction is 0 DEG C～25 DEG C; Step 2) in reductive agent used be diisobutyl aluminium hydride, solvent for use is toluene, temperature of reaction is-80 DEG C～-50 DEG C; In step 3), solvent for use is methylene dichloride, and temperature of reaction is-30 DEG C～-10 DEG C; In step 4), reductive agent used is red aluminium, and solvent for use is methylene dichloride, and temperature of reaction is-30 DEG C～-10 DEG C; In step 5), solvent for use is the trimethyl carbinol, and temperature of reaction is 20 DEG C-30 DEG C; In step 6), acid used is hydrochloric acid or trifluoroacetic acid, and solvent for use is ethanol, and temperature of reaction is 60 DEG C-80 DEG C.
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