CN101880287B - Intermediate compounds for thiophane nucleoside analogues and preparation method thereof - Google Patents
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Abstract
The invention discloses intermediate compounds expressed as a general formula 1 for synthesizing thiophane nucleoside analogues and a preparation method thereof. In the general formula, Ac represents acetyl. The intermediate compounds can be used for synthesizing new thiophane nucleoside analogues. The thiophane nucleoside compounds or pharmaceutically acceptable salts, solvates, optical isomers or polymorphic substances thereof have good anti-tumor effect.
Description
Technical field
The present invention relates to one type of midbody compound, be specifically related to midbody compound that is used for synthetic one type of new THTP nucleoside analog and preparation method thereof.
Background technology
Malignant tumour is a kind of common disease of serious threat human health, although do not find the medicine of radical cure tumour so far as yet, anticancer chemotherapy has been obtained sizable progress in decades, and antitumor drug emerges in an endless stream.Nucleoside compound is exactly one type of important antineoplastic chemotherapy medicine wherein.
The ucleosides antitumor drug comprises the verivate of various purine and pyrimidine nucleoside.This compounds is as metabolic antagonist; Produce CDCC from three aspects: 1) nucleoside compound biochemical reaction as pseudo-substrate; The relevant enzyme that suppresses the Nucleotide de novo synthesis is disturbed triphosphoric acid dezyribonucleoside nucleic acid (dNTPs) storehouse, thereby suppresses duplicating of DNA; 2) nucleoside compound mixes DNA and RNA.Interrupt the extension of DNA and RNA chain; 3) suppress nucleic acid synthetic relevant enzyme,, thereby suppress synthesizing and reparation of nucleic acid molecule like archaeal dna polymerase and nucleic acid reductase enzyme etc.
At present; The antitumor nucleoside medicine that has gone on the market has a carat Qu Bin, capecitabine etc.; They all are the purine or the pyrimidine nucleoside compounds of furyl glycosyl; And sulphur atom is as the isostere of Sauerstoffatom, the purine of deutero-tetrahydro-thienyl or pyrimidine nucleoside compounds and the research aspect antitumor drug thereof therefrom, and bibliographical information is less.
Summary of the invention
Therefore; The technical problem that the present invention will solve is exactly long to the reaction scheme of the synthetic existence of present THTP nucleoside compound; Cost is high, and deficiencies such as condition harshness provide midbody compound of a kind of synthetic one type of new THTP nucleoside analog and preparation method thereof.
Among the present invention, the compound of general formula 1 is the new synthetic compound of the present invention, is the midbody compound that is used for tetrahydrobiopterin synthesis thiophene nucleoside analog,
In the above-mentioned general formula, Ac represents ethanoyl.
The present invention also provides the preparation method of the midbody compound shown in the described general formula 1; Comprise the steps: the compound shown in the general formula 16 in non-protonic solvent; Wherein toluene is preferred solvent; React under Diisopropyl azodicarboxylate catalysis with tributyl tin hydrogen, form the compound shown in the general formula 1
In the above-mentioned general formula, Ac represents ethanoyl.In this reaction, molar ratio is a compound 16: tributyl tin hydrogen: Diisopropyl azodicarboxylate=1: 1: 0.05-1: 1.5: 0.05; Temperature of reaction be preferable be 60 ℃～110 ℃, preferred 110 ℃.
Compound shown in the described general formula 16 can be made by following method: the compound shown in the general formula 15 in toluene, done catalyzer and Iod R with triphenylphosphine,, forms the compound shown in the general formula 16 to introduce iodine in the 5-position,
In the above-mentioned general formula, Ac represents ethanoyl.In this reaction, what temperature of reaction was preferable is 60～110 ℃, preferred 110 ℃; Molar ratio is a compound 15: iodine: triphenylphosphine: imidazoles=1: 2: 2.5: 3.
The preparation method of the compound shown in the described general formula 15 comprises the steps: the compound shown in the general formula 14 in THF, with the tetrabutyl ammonium fluoride reaction, can remove tertiary butyl dimethyl-is silica-based.
In the above-mentioned general formula, Ac represents ethanoyl; TBDMS represents tertiary butyl dimethyl-silica-based.In this reaction, what temperature of reaction was preferable is 10～60 ℃, preferred 25 ℃; Molar ratio is a compound 14: tertiary butyl ammonium fluoride=1: 1-1: 1.2.
The preparation method of the compound shown in the described general formula 14 comprises the steps: the compound shown in the general formula 13 is heated in aceticanhydride, can form the compound shown in the general formula 14,
In the above-mentioned general formula, Ac represents ethanoyl; TBDMS represents tertiary butyl dimethyl-silica-based.The preferred temperature of the reaction of this reaction is 100 ℃.
The preparation method of the compound shown in the described general formula 13 comprises the steps: the compound shown in the general formula 12 in methylene dichloride, to be oxidized to compound 13 with metachloroperbenzoic acid.
In the above-mentioned general formula, TBDMS represents tertiary butyl dimethyl-silica-based.-78～-10 ℃ is preferred temperature, and is more preferably-78～-50 ℃; Molar ratio is a compound 12: metachloroperbenzoic acid=1: 1.
The preparation method of the compound shown in the described general formula 12 comprises the steps: the compound shown in the general formula 11 at N, in the dinethylformamide, with the hydrated sodium sulfide reaction, forms the compound shown in the general formula 12.
In the above-mentioned general formula, TBDMS represents tertiary butyl dimethyl-silica-based; Ms represents methylsulfonyl.Temperature of reaction is 80～120 ℃, and preferred temperature is 100 ℃; Molar ratio is a compound 11: hydrated sodium sulfide=1: 1-1: 1.2.
The compound of general formula 11 is known compounds, and general formula 12～16 and 1 compound are the neoteric new compounds of the present invention.Starting compound that other do not do to specify or reagent, all commercially available getting.
Among the present invention, making the reaction raw materials of special instruction or the consumption of solvent is this area conventional amount used.
Than prior art.Beneficial effect of the present invention is following: above-mentioned midbody compound of the present invention can be used for synthetic one type of new THTP nucleoside analog.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Alleged among the present invention " room temperature " is meant that temperature is 15～35 ℃.
Among the embodiment, the fusing point of compound is measured with the capillary melting point determination appearance, and TM is not proofreaied and correct;
1HNMR is interior mark by Varian AM-400 type nmr determination with TMS, and chemical shift is represented with δ (ppm); Mass spectrum is measured with Q-TOF type mass spectrograph; Specific rotatory power is measured by Perkin Elmer P-341 polarimeter.
The column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces (thin-layer chromatography H type), HSGF 254 types that thin layer chromatography board is produced for Yantai Zhifu experiment chemical plant.
Embodiment 1: (2S, 3S, 4R)-and 2-tertiary butyl diformazan silica methyl-3,4-O-isopropylidene-THTP (compound 12)
Compound 11 (32.1g 0.07mol) is dissolved in the DMSO 99.8MIN. of 700mL, at room temperature add hydrated sodium sulfide (20g, 0.08mol), 100 ℃ of mechanical stirring, TLC monitors to raw material and disappears.After reducing to room temperature, reaction system is poured in the frozen water, stirs after 5 minutes, with ether extraction 5 times (200mL/ time).Merge organic layer,, organic layer is concentrated after with anhydrous magnesium sulfate drying, get the yellow oil bullion with washing organic layer 3 times (200mL/ time).This bullion through column chromatography purification (petrol ether/ethyl acetate 20/1), is got yellow oil 13.8g yield 65%.
[α]
D 20=194 ° of C=1.0, methyl alcohol.
MS?m/z：305(M
++1).
1HNMR(CDCl
3)δ(ppm)：0.89(s，9H)；0.08(s，6H)；1.29(s，3H)；1.41(s，3H)；2.86(t?J＝2.0；J＝1.6，2H)；3.32～3.37(m，1H)；3.78(dd，J＝7.2；J＝10.0，1H)；4.03(dd，J＝7.6；J＝10.4，1H)；4.69～4.72(m，1H)；4.84～4.87(m，1H)。
Embodiment 2: (2S, 3S, 4R)-and 1-oxo-2-tertiary butyl diformazan silica methyl-3,4-O-isopropylidene-THTP (compound 13)
(7.4g 24.3mmol) is dissolved in the 150mL methylene dichloride compound 12.(50mL 24.5mmol), reacts after 1 hour the dichloromethane solution of the metachloroperbenzoic acid of dropping 0.49mol/L, rises to room temperature, adds saturated sodium bicarbonate aqueous solution, stirs 5 minutes under-78 ℃.Static layering with dichloromethane extraction three times (30mL/ time), merges organic layer with water layer, washes organic layer with saturated common salt.Anhydrous magnesium sulfate drying gets white solid after concentrating.Through column chromatography purification (petrol ether/ethyl acetate 3/1), get the 3.97g white solid, yield 51%.
[α]
D 20=153 ° of C=1.0, methyl alcohol.
MS?m/z：343(M
++23).
1HNMR(CDCl
3)δ(ppm)：0.93(s，9H)；0.12(S，6H)；1.30(S，3H)；1.49(S，3H)；2.85(dd，J＝6.0；J＝13.6；1H)；3.12～3.17(m，1H)；3.64(dd，J＝1.6；J＝13.6；1H)
Embodiment 3: (2S, 3S, 4R)-and 1-oxo-2-tertiary butyl diformazan silica methyl-3,4-O-isopropylidene-THTP (compound 13)
(7.4g 24.3mmol) is dissolved in the 150mL methylene dichloride compound 12.Dripping down 0.49mol/L at-10 ℃ adds the dichloromethane solution of metachloroperbenzoic acid (50mL 24.5mmol), react and rises to room temperature after 1 hour, and the adding saturated sodium bicarbonate aqueous solution stirred 5 minutes.Static layering with dichloromethane extraction water layer three times (30mL/ time), is washed organic layer with saturated common salt behind the merging organic layer.Anhydrous magnesium sulfate drying gets white solid after the filtering and concentrating.Through column chromatography purification (petrol ether/ethyl acetate 3/1), get white solid, yield 48%.
[α]
D 20=153 ° of C=1.0, methyl alcohol.
MS?m/z：343(M
++23).
1HNMR(CDCl
3)δ(ppm)：0.93(s，9H)；0.12(S，6H)；1.30(S，3H)；1.49(S，3H)；2.85(dd，J＝6.0；J＝13.6；1H)；3.12～3.17(m，1H)；3.64(dd，J＝1.6；J＝13.6；1H)
Embodiment 4: (3R, 4S, 5S)-and the 2-acetoxy-3,4-O-isopropylidene-5-tertiary butyl diformazan silica methyl-THTP (compound 14)
(2.89g 9mmol) was dissolved in the aceticanhydride of 10mL, 100 ℃ of following heated and stirred 3 hours with compound 13.Remove aceticanhydride under reduced pressure, with 10ml acetic acid ethyl dissolution residue, respectively with saturated sodium bicarbonate aqueous solution and saturated common salt washing organic layer.Anhydrous magnesium sulfate drying, after concentrating oily matter 3.10g (bullion of compound 14), bullion can get the non-corresponding isomer of compound 14 through column chromatography for separation (petrol ether/ethyl acetate 3/1).Bullion can not purifiedly directly be cast single step reaction.
Compound 14a
MS?m/z：422(M
++23).
1HNMR(CDCl
3)δ(ppm)：0.83(s，9H)；0.00(S，6H)1.22(S，3H)；1.40(S，3H)；1.97(S，3H)；3.68～3.72(m，1H)；3.74～3.78(m，1H)；3.93～3.97(m，1H)；4.71～4.73(m，1H)；4.79～4.81(m，1H)；5.88(S，1H)。
Compound 14b
MS?m/z：422(M
++23).
1HNMR(CDCl
3)δ(ppm)：0.90(s，9H)；0.07(S，6H)；1.33(S，3H)；1.54(S，3H)；2.10(S，3H)；3.71～3.76(m，1H)；3.52～3.58(m，1H)；4.07～4.11(m，1H)；4.83(t，J＝5.6；J＝6.0；1H)；4.92(t，J＝6.4；J＝6.4；1H)；5.98(d，J＝6.4；1H)。
Embodiment 5: (3R, 4S, 5S)-and the 2-acetoxy-3,4-O-isopropylidene-5-methylol-THTP (compound 15)
(10g 27.6mmol) at room temperature is dissolved in the THF of 100mL, adds tetrabutyl ammonium fluoride, and 10 ℃ were stirred 3 hours down with the bullion of compound 14.Remove solvent under reduced pressure, with 30mL acetic acid ethyl dissolution residue, the washing organic layer.Anhydrous magnesium sulfate drying, after the filtering and concentrating the bullion 5g of compound 15.Behind the purifying mixture of isomers, bullion also not purifying directly cast single step reaction.
MS?m/z：271(M
++23).
1HNMR(CDCl
3)δ(ppm)：1.32(s，3H)；1.37(S，1H)；1.504(S，3H)；1.57(S，1H)；2.06(S，3H)；2.12(s，1H)；3.60(b，1H)；3.60～3.64(m，0.3H)；3.72(b，0.3H)；3.81～3.85(m，1H)；3.96～3.97(m，2.2H)；4.06～4.11(m，0.3H)；4.82(d，J＝6.0；1H)；4.87～4.90(m，0.3H)；4.96～4.99(m；1H)；5.08～5.11(m，0.3H)。5.98(s，0.3)；5.99(s，1H)
Embodiment 6: (3R, 4S, 5S)-and the 2-acetoxy-3,4-O-isopropylidene-5-methylol-THTP (compound 15)
(10g 27.6mmol) at room temperature is dissolved in the THF of 100mL, adds tetrabutyl ammonium fluoride, and 60 ℃ were stirred 1 hour down with the bullion of compound 14.Remove solvent under reduced pressure, residue is used the 30mL acetic acid ethyl dissolution, the washing organic layer.Anhydrous magnesium sulfate drying, after concentrating the bullion 4.8g of compound 15.This bullion not purifying is directly cast single step reaction.
Embodiment 7: (3R, 4S, 5R)-and the 2-acetoxy-3,4-O-isopropylidene-5-iodomethyl-THTP (compound 16)
The bullion (5g) of compound 15 is dissolved in the 100mL toluene, at room temperature add respectively triphenylphosphine (13.2g, 50.5mmol), imidazoles (4.12g, 60.6mmol) and iodine (10g, 40.4mmol).Stir back 60 ℃ and reacted 1 hour, add saturated sodium bicarbonate aqueous solution and stirred static layering 5 minutes; Water layer merges organic layer with ethyl acetate extraction three times (30mL/ time), washes with 10% sodium thiosulfate solution; Anhydrous magnesium sulfate drying; Filter the back and concentrate, residue gets yellow oil 3.82g (compound 16) through column chromatography purification (petrol ether/ethyl acetate 15/1), three step yields 38%.
[α]
D 15=-179.2 ° of C=1.0, methyl alcohol.
MS?m/z：381(M
++23).
1HNMR(CDCl
3)δ(ppm)：1.33(S，3H)；1.50(S，3H)；2.05(S，3H)；3.29～3.33(m，1H)；3.46(t，J＝10.0；J＝9.6；1H)；3.95～3.97(m，1H)；?4.84～4.89(m，2H)；6.00(S，1H)。
Embodiment 8: (3R, 4S, 5R)-and the 2-acetoxy-3,4-O-isopropylidene-5-iodomethyl-THTP (compound 16)
The bullion (5g) of compound 15 is dissolved in the 100mL toluene, add respectively at ambient temperature triphenylphosphine (13.2g, 50.5mmol), imidazoles (4.12g, 60.6mmol) and iodine (10g, 40.4mmol).Be warming up to backflow after stirring, after 20 minutes, add saturated sodium bicarbonate aqueous solution and stirred 5 minutes; Static layering, water layer merge organic layer with ethyl acetate extraction three times (30mL/ time); Sodium thiosulfate solution with 10% is washed organic layer, and anhydrous magnesium sulfate drying filters the back and concentrates; Residue is carried out column chromatography purification (petrol ether/ethyl acetate 15/1) get yellow oil 4.05g (compound 16), two step yields 41%.
[α]
D 15=-179.2 ° of C=1.0, methyl alcohol.
MS?m/z：381(M
++23).
1HNMR(CDCl
3)δ(ppm)：1.33(S，3H)；1.50(S，3H)；2.05(S，3H)；3.29～3.33(m，1H)；3.46(t，J＝10.0；J＝9.6；1H)；3.95～3.97(m，1H)；4.84～4.89(m，2H)；6.00(S，1H)。
Embodiment 9: (3R, 4S, 5S)-and the 2-acetoxy-3,4-O-isopropylidene-5-methyl-THTP (compound 1)
With compound 16 (6.2g; 17.3mmol) be dissolved in the toluene, add tri-n-butyl tin hydrogen (0.72mL respectively; 26.0mmol) and Diisopropyl azodicarboxylate (1.42g; 8.65mmol).110 ℃ were stirred 20 minutes, removed solvent under reduced pressure, and residue is dissolved in ETHYLE ACETATE; The washing organic layer is used anhydrous magnesium sulfate drying, filters; Get yellow oil after concentrating, column chromatography (petrol ether/ethyl acetate 10/1) purifying gets 2.67g faint yellow solid compound 1, and yield is 67%
[α]
D 13=-212.6 ° of C=1.0, methyl alcohol, mp:44～46 ℃.
MS?m/z：255(M
++23).
1HNMR(CDCl
3)δ(ppm)：1.32(S，3H)；1.50(S，3H)；1.38(d，J＝6.8；3H)；2.05(S，3H)；3.69～3.72(m，1H)；4.70～4.73(m，1H)；4.77～4.78(m，1H)；5.94(S，1H)。
Embodiment 10: (3R, 4S, 5S)-and the 2-acetoxy-3,4-O-isopropylidene-5-methyl-THTP (compound 1)
With compound 16 (6.2g; 17.3mmol) be dissolved in the toluene, add tri-n-butyl tin hydrogen (0.72mL respectively; 26.0mmol) and Diisopropyl azodicarboxylate (1.42g; 8.65mmol).60 ℃ were stirred 1 hour, removed solvent under reduced pressure, and residue is dissolved in the ETHYLE ACETATE; The washing organic layer, anhydrous magnesium sulfate drying filters; Get yellow oil after concentrating, column chromatography (petrol ether/ethyl acetate 10/1) purifying gets 2.67g faint yellow solid compound 1, and yield is 58%
[α]
D 13=-212.6 ° of C=1.0, methyl alcohol, mp:44～46 ℃.
MS?m/z：255(M
++23).
1HNMR(CDCl
3)δ(ppm)：1.32(S，3H)；1.50(S，3H)；1.38(d，J＝6.8；3H)；2.05(S，3H)；3.69～3.72(m，1H)；4.70～4.73(m，1H)；4.77～4.78(m，1H)；5.94(S，1H)。
Embodiment 11: THTP nucleoside analog 2-chloro-6-cyclohexylamino-9-[(2R, 3R, 4S; 5S)-3; 4-dihydroxyl-5-methyl-THTP-2-yl] purine (A7) and 2-chloro-6-cyclohexylamino-9-[(2S, 3R, 4S; 5S)-3,4-dihydroxyl-5-methyl-THTP-2-yl] preparation of purine (A ' 7)
With compound 1 (3g, 12.9mmol) with compound 2,6-dichloropurine (6.11g; 32.3mmol) and exsiccant acetonitrile (30ml) place the 100ml three-necked bottle, nitrogen protection drips the dichloromethane solution (15.5ml of 1mmol/L tin tetrachloride under ice bath; 15.5mmol), stirred overnight at room temperature.Under ice bath, with reaction solution impouring methylene dichloride and saturated NaHCO
3In the mixed solution of the aqueous solution, stirring 5min, static layering, water layer merges organic layer with dichloromethane extraction three times (10ml/ time), the washing organic layer, anhydrous magnesium sulfate drying filters, and concentrates, and gets yellow oil.This yellow oil is dissolved in the 15mL THF, drips hexahydroaniline, stirs and remove solvent under reduced pressure after 6 hours, the aqueous formic acid 5mL of residue and 85% is placed the 10mL reaction flask at 20 ℃, 0 ℃ of stirring down, TLC monitoring reaction to raw material disappears.Remove solvent under reduced pressure, residue can obtain white solid compound 2-chloro-6-cyclohexylamino-9-[(2R respectively through column chromatography purification; 3R, 4S, 5S)-3; 4-dihydroxyl-5-methyl-THTP-2-yl] purine (A7) and 2-chloro-6-cyclohexylamino-9-[(2S, 3R, 4S; 5S)-3,4-dihydroxyl-5-methyl-THTP-2-yl] purine (A ' 7).
A7: [α]
D 13=-85.6 ° of C=1.0, methyl alcohol, mp:127 ℃ (dec); Yield 57% A ' 7: [α]
D 13=-24 ° of C=1.0, methyl alcohol, mp:125 ℃ (dec); Yield 22%
The nuclear-magnetism of compd A 7 and A ' 7 and mass spectrum
Further specify beneficial effect of the present invention through effect embodiment below.
Effect embodiment
The anti tumor activity in vitro test-results of The compounds of this invention A7 and A ' 7 is following:
1. TP: adopt mtt assay to measure compd A 7 and A ' 7 inhibiting rate and half-inhibition concentration (IC to being tried tumour cell when concentration is 100 μ g/ml
50), measure.
Mtt assay: it is 4～5 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of MK-2 in the dissolving back.
2. tried tumour cell: human breast cancer cell MDA-MB-435, human colon cancer cell LOVO and human leukemia cell CEM.
3. positive control drug is 5 FU 5 fluorouracil and CldAdo.
7 pairs of three kinds of tumour cells of compd A 7 and A ' inhibiting rate and IC to being tried tumour cell when concentration is 100 μ g/ml
50During value is listed in the table below.Visible by table, compound of the present invention has good activity to human leukemia cell CEM.
The in-vitro multiplication restraining effect of compd A 7 and 7 pairs of human body tumour cells of A '
Claims (6)
1. the midbody compound that is used for tetrahydrobiopterin synthesis thiophene nucleoside compound shown in general formula 1,
In the above-mentioned general formula, Ac represents ethanoyl.
2. the preparation method of the midbody compound shown in the general formula 1 as claimed in claim 1; It is characterized in that; Comprise the steps: the midbody compound shown in the general formula 16 in non-protonic solvent; React under Diisopropyl azodicarboxylate catalysis with tri-n-butyl tin hydrogen, form the midbody compound shown in the general formula 1
In the above-mentioned general formula, Ac represents ethanoyl.
3. preparation method as claimed in claim 2 is characterized in that described non-protonic solvent is selected from toluene.
4. preparation method as claimed in claim 2 is characterized in that, described temperature of reaction is 60～110 ℃.
5. preparation method as claimed in claim 2 is characterized in that, described compound 16 is made by following method: with the compound shown in the general formula 15 in toluene; Do catalyzer and Iod R with triphenylphosphine; To introduce iodo in the 5-position, form the compound shown in the general formula 16
In the above-mentioned general formula, Ac represents ethanoyl.
6. preparation method as claimed in claim 5 is characterized in that, the temperature of reaction of preparation compound 16 is 60～110 ℃.
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