CN102558263A - Doxifluridine derivative and preparation method and pharmaceutical application thereof - Google Patents
Doxifluridine derivative and preparation method and pharmaceutical application thereof Download PDFInfo
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- CN102558263A CN102558263A CN2010106198658A CN201010619865A CN102558263A CN 102558263 A CN102558263 A CN 102558263A CN 2010106198658 A CN2010106198658 A CN 2010106198658A CN 201010619865 A CN201010619865 A CN 201010619865A CN 102558263 A CN102558263 A CN 102558263A
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- 0 CC(C(*)C1*)OC1N(C=C(C(I)=N1)F)C1=O Chemical compound CC(C(*)C1*)OC1N(C=C(C(I)=N1)F)C1=O 0.000 description 4
- JFGOSGRPCNSCKQ-UHFFFAOYSA-N CCC(OC(C1)C(C)OC1N(C=C(C(N1)=S)F)C1=O)=O Chemical compound CCC(OC(C1)C(C)OC1N(C=C(C(N1)=S)F)C1=O)=O JFGOSGRPCNSCKQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a doxifluridine derivative and preparation method and pharmaceutical application thereof, particularly to a compound shown in a formula (I), and a crystal or pharmaceutical salts of the compound, wherein R1 can be =N-OR4 and the like; R2 can be hydrogen, hydroxyl and X; R3 is can be hydrogen, C2-C6 acyl group and the like; R4 can be hydrogen and the like; and X is F, Cl, Br, I and the like. The invention also relates to a preparation method of the compound. The invention further provides an anti-tumour medicine composition containing the compound, and the application of the compound in preparation of an anti-tumour medicine.
Description
Technical field
The present invention relates to have the doxifluridine analog derivative of anti-tumor activity, the invention still further relates to the preparation method and the purposes of described compound in pharmacy of this compounds.
Background technology
In decades, nucleoside medicine be widely used in clinical antitumor in, wherein fluoridize the miazines medicine and play a part important at aspect such as antitumor.5 FU 5 fluorouracil is since nineteen fifty-seven, this was synthetic, because of its selectivity and lower untoward reaction preferably is widely used in the kinds of tumors treatment.Yet the 5 FU 5 fluorouracil major part is an intravenous injection, and administration is inconvenient.For making things convenient for the patient to use, developed prodrug-the 5 '-'-Deoxy-5-fluorouridine that is fit to oral prodrug 5 FU 5 fluorouracil already.But oral 5 '-'-Deoxy-5-fluorouridine has certain intestines toxicity, and the prospect that therefore is suitable for is wideless.
Under technical field be sought after developing the prodrug of 5 FU 5 fluorouracil, this compounds itself should no cytotoxicity, but in vivo the effect of enzyme down metabolism be that 5 FU 5 fluorouracil is brought into play antitumor action.Further be that described compound also should have the good curing selectivity.
Summary of the invention
But an object of the present invention is to provide no cytotoxicity own, in vivo enzyme effect down metabolism be the doxifluridine analog derivative of 5 FU 5 fluorouracil.
Another object of the present invention provides the preparation method of said deoxidation fluorine born of the same parents uridine verivate.
A further object of the present invention provides the application of said doxifluridine analog derivative in the preparation antitumor drug.
The object of the invention realizes through following design: a kind of compound or pharmaceutically acceptable salt thereof with following formula (I):
Wherein, R
1Be selected from=N-OR
4,
R
2Be selected from hydrogen, hydroxyl and X;
R
3Be selected from hydrogen, C
2～C
6Acyl group, C
2～C
6Alkoxy acyl or
R
4Be selected from hydrogen or
R
8Be selected from hydrogen, C
2～C
16Straight or branched alkyl or straight or branched alkoxyl group, trifluoroethyl, two R
8Can be identical, can be different;
R
9Be selected from hydroxyl, C
1～C
6The straight or branched alkyl, unsubstituted phenyl, or by C
1～C
6Alkyl or C
1～C
6The substituted phenyl of alkoxyl group;
R
10Be selected from C
1～C
18Alkyl, unsubstituted phenyl, or by C
1～C
6Alkyl or C
1～C
6The substituted phenyl of alkoxyl group;
R
5Be selected from methyl, ethyl, propyl group;
R
6Be selected from C
1～C
16Dialkyl amido, or C
1～C
6Substituted diphenyl amino of alkyl or C
1～C
6The substituted piperazine of alkyl,
Perhaps R
5, R
6Can combine into ring, form substituted pyrrolidyl of N-or the substituted piperidines of N-, said substituting group is selected from C
1～C
18Alkyl;
R
7Be selected from phenyl, neighbour-or-or right-position halogenophenyl, neighbour-or-or right-position halogeno-benzyl, C
1～C
6The alkyl-substituted amino phenyl, C
1～C
6Alkyl-substituted phenyl, C
1～C
6Alkyl substituted pyrane base;
X＝F，Cl，Br，I。
The preferred compound of the present invention is as follows:
When
,
When
,
When
Another aspect of the present invention relates to the preparation method of above-mentioned doxifluridine verivate, and its route of synthesis is following:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9,, R
10Definition the same, R
11Be C
1-6Alkyl or C
6-10Or C
1～C
6Acyl group or C
1～C
6Alkoxy acyl.
Starting material compound (A) but the reference literature similar approach obtains [Chinese Journal of Pharmaceuticals such as Dong Hui, 33:108 (2002)].Set forth other step in the route of synthesis below:
1. at first compound (A) is become ester with acylating agent, obtain the compound of general formula (B).Described acylating agent is C
1-6Alkane acyl chlorides or C
1-6Alkanoic acid anhydride, C
6-10Aroyl chloride or C
6-10Aromatic acid acid anhydride, the substituted aroyl chloride of contraposition halogen or acid anhydrides, preferred acylating agent is selected from Acetyl Chloride 98Min., diacetyl oxide, propionyl chloride, propionic anhydride or Benzoyl chloride 99min..Used solvent is the single halogen or the polyhalid alkane that contain acid binding agent, aromatic hydrocarbons, acetonitrile, DMF etc. or its blended solvent, and described acid binding agent is pyridine, triethylamine, salt of wormwood or yellow soda ash.Preferred solvent is the mixed solvent of polyhalohydrocarbon and pyridine.
2. with general formula (B) compound and P
2S
5Reaction obtains general formula (C) compound.Described being reflected in the solvent carried out, and described solvent is selected from pyridine, single halogen or polyhalid alkane, THF, dioxane, benzene, acetonitrile, and preferred solvent is pyridine or dioxane.
3. with general formula (C) compound and oxammonium hydrochloride (NH
2-OHHCl) reaction obtains general formula (D) compound.Described acid binding agent is mineral alkali or organic bases, and described mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, and described organic bases is selected from pyridine, triethylamine, and preferred acid binding agent is yellow soda ash, salt of wormwood or triethylamine; Described reaction preferably is being selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, C
1-4Carry out in the solvent of aliphatic ether, preferred solvent is methyl alcohol, ethanol, acetonitrile.
4. with the reaction of general formula (D) compound with
; Then; In the presence of solvent; Carry out saponification reaction with saponifying agent, obtain general formula (H) compound.The condensing agent of reaction is selected from sodium hydride, potassium hydride KH, hydrolith, sodium tert-butoxide, potassium tert.-butoxide, n-Butyl Lithium with
, and preferred condensing agent is sodium hydride or sodium tert-butoxide; The preferred THF of reaction solvent, methylene dichloride, ether, dioxane.Described saponifying agent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.
5. with general formula (D) compound and replacement SULPHURYL CHLORIDE (F) reaction, then, in the presence of solvent, carry out obtaining general formula (I) compound after the saponification reaction with saponifying agent.With the preferred yellow soda ash of acid binding agent, salt of wormwood, pyridine, the triethylamine that replace the SULPHURYL CHLORIDE reaction; The preferred THF of solvent, methylene dichloride, ether, dioxane.Saponifying agent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.
With general formula (D) with replace chloro-formic ester (G) reaction, then in the presence of solvent with obtaining general formula (J) compound after the saponifying agent saponification.With the preferred yellow soda ash of acid binding agent, salt of wormwood, pyridine, the triethylamine that replace the SULPHURYL CHLORIDE reaction; The preferred THF of solvent, methylene dichloride, ether, dioxane.Saponification reaction reagent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.
7. obtain (K) compound with strong aqua reaction with saponifying agent after with the saponification of general formula (D) compound, under solvent and N, the disubstituted dimethylacetal of N-reacts the compound that obtains general formula (L) then.Saponifying agent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.Be selected from C with the solvent of strong aqua reaction
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol or THF.With N, the disubstituted dimethylacetal reaction solvent of N-is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether.
8. obtain (M) compound with Hydrazine Hydrate 80 reaction with saponifying agent after with the saponification of general formula (D) compound, then with C
1～C
14Alkanoic/aromatic aldehyde reaction obtains general formula (N) compound.Saponifying agent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.Be selected from C with the solvent of strong aqua reaction
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol, THF or their combination, is selected from C with the reagent of aldehyde reaction
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether.
9. with compound (A) and PROPIONYL CHLORIDE reaction, obtain (O) compound.With the preferred acetonitrile of the reaction solvent of PROPIONYL CHLORIDE, THF, dioxane.
10. with (O) compound and hydrogen reaction, obtain (P) compound.With the preferred nickel of the catalyzer of hydrogen reaction, palladium; With the preferred C of hydrogen reaction solvent
1-4Fatty Alcohol(C12-C14 and C12-C18), dioxane, THF.
11. with (P) compound and thiophosphoric anhydride (P
2S
5) reaction, obtain (Q) compound.The solvent that reacts with thiophosphoric anhydride is pyridine, single halogen or polyhalid alkane, THF, dioxane, benzene, acetonitrile, and preferred solvent is pyridine and dioxane.
10. with (Q) compound and oxammonium hydrochloride (NH2-OH.HCl) reaction, obtain (R) compound.Described acid binding agent is selected from mineral alkali sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, organic bases pyridine, triethylamine, preferred acid binding agent yellow soda ash, salt of wormwood or triethylamine; Solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, C
1-4Aliphatic ether, preferred solvent methyl alcohol, ethanol, acetonitrile.
11. with obtaining (S) compound with the strong aqua reaction after the saponification of (Q) compound, then with N, the disubstituted dimethylacetal reaction of N-obtains the compound of general formula (T).Saponifying agent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.Be selected from C with the solvent of strong aqua reaction
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol or THF.With N, the disubstituted dimethylacetal reaction solvent of N-is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether.
12. monocrystalline is cultivated operation: get the arbitrary reaction flask that places of compound (D)-(T), add absolute ethyl alcohol, 60 ℃ of following heating for dissolving, room temperature is cooled off in rearmounted 4 ℃, occurs the water white transparency monocrystalline after the week, filters washing, drying.
When needing, compound of the present invention can be prepared as the form of pharmaceutical salts according to ordinary method.Described pharmaceutical salts is its inorganic acid salt or organic acid salt: inorganic acid salt includes, but is not limited to hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate, nitrate salt; Organic acid salt include, but is not limited to acetate, PHENRAMINE MALEATE, fumarate, tartrate, SUMATRIPTAN SUCCINATE, lactic acid salt, tosilate, salicylate, oxalate.
Another aspect of the present invention relates to the pharmaceutical composition that contains general formula (I) compound (being preferably its crystalline form) or its pharmaceutical salts and pharmaceutically acceptable carrier.
Described pharmaceutically acceptable carrier can be chosen according to the practice of affiliated technical field, obtains the compsn of solid form or liquid form.
Another aspect of the present invention relates to general formula (I) compound (being preferably its crystalline form) or the application of its pharmaceutical salts in the medicine of preparation anti-tumor activity.
Described tumour comprises the cancer that esophagus, stomach, intestines, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, salt, brain or cns take place, perhaps Tiroidina cancer, white blood disease, Hokdkin disease, lymphoma or myelomatosis.
Compound of the present invention, compound crystal or its pharmaceutical salts can be avoided the intestines toxicity of 5 '-'-Deoxy-5-fluorouridine, and high in more normally organizing with the high density of its metabolism involved enzyme (dThdPase) in tumor tissues.Therefore, the medicine of processing with compound or pharmaceutically acceptable salt thereof of the present invention has again treats selectivity preferably, and such medicine can be thought very promising antitumour drug.
Description of drawings
Fig. 1 carries out the HPLC test result that pharmacokinetics is tested to compound 2 among the embodiment 51.
Fig. 2 is the Molecular Graphs and the structure cell figure of compound 37.
Fig. 3 is the Molecular Graphs and the structure cell figure of compound 38.
Fig. 4 is the Molecular Graphs and the structure cell figure of compound 43.
Fig. 5 is the Molecular Graphs and the structure cell figure of compound 15.
Embodiment
Below in conjunction with embodiment the present invention is done detailed description, but the following example should not regarded limitation of the scope of the invention as.
Preparation 5 '-deoxidation-5-fluoro-thio uridine (compound 1)
A, 2 ', 3 '-two-O-acetyl-5 '-'-Deoxy-5-fluorouridine (Formula B compound, wherein R
9Be ethanoyl)
(Chinese Journal of Pharmaceuticals such as Dong Hui, 33:108 (2002) obtains starting raw material 5 '-'-Deoxy-5-fluorouridine (compd A) to the reference literature method.Get 2g (8.1 mmole) compd A and be dissolved in the 40ml anhydrous pyridine, drip 1.8ml (18 mmole) aceticanhydride, stirred overnight at room temperature.Adding 5ml methyl alcohol then continues to stir the solution evaporate to dryness 15 minutes.Solid is dissolved in the 40ml methylene dichloride, washes with 10% sodium bicarbonate aqueous solution of 40ml, and water is used methylene dichloride 10ml * 2 extractions again.Combined dichloromethane liquid, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is used the 10ml ethyl alcohol recrystallization, gets white solid 2.4g, yield 90%, 187 to 189 ℃ of fusing points.
B, 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-thio uridine (Formula B compound, wherein R
10Be ethanoyl)
Get 2g (6.1 mmole) 2 ', 3 '-two-O-acetyl-5 '-'-Deoxy-5-fluorouridine, 1.5g (6.8 mmole) thiophosphoric anhydride joins in the 40ml anhydrous pyridine, the dissolving post-heating refluxes and to spend the night.Solution evaporate to dryness then.Resistates is dissolved in 100ml ETHYLE ACETATE, washes with the 10%HCl aqueous solution of 50ml * 2, and water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue can not purifiedly directly be used for next step reaction.
C.5 '-deoxidation-5-fluoro-sulfo-cytidine (compound 1)
Get 2g (5.8 mmole) 2 '; 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-thio uridine is dissolved in the 20ml THF; Add 10ml methyl alcohol and 6ml water then; Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 6ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 1.3g through the silicagel column purifying, yield 86.7%,
1H-NMR (DMSO-d
6) δ (ppm): 1.34 (3H, d, 4 ' CH
3), 3.71 to 3.73 (1H, d, 3 '-H), 3.86 to 3.93 (1H, d, 4 '-H), 4.05 to 4.08 (1H, d, 2 '-H), 4.94 (1H, s, OH), 5.26 (1H, s, OH), 6.22 to 6.24 (1H, d, 1 '-H), 7.56 (1H, d, CHCF).
Preparation 5 '-deoxidation-5-fluoro-N
4-oximido cytidine (compound 2)
A, 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine (general formula D compound)
Get 2g (5.8 mmole) 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-thio uridine and join in the 30ml ethanol, add 0.48g (7 mmole) oxammonium hydrochloride and 0.55g (8 mmole) salt of wormwood then, 60 ℃ are stirred 10h, evaporate to dryness.Resistates is dissolved in 100ml ETHYLE ACETATE, washes with the 10%HCl aqueous solution of 50ml * 2, and water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue can not purifiedly directly be used for next step reaction.
B, 5 '-deoxidation-5-fluoro-N
4-oximido cytidine (compound 2)
Get 2g (5.8 mmole) 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-N
4-oximido cytidine is dissolved in the 30ml THF and adds 10ml methyl alcohol and 6ml water then.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 6ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 1.2g through the silicagel column purifying, yield 79%, 180 to 182 ℃ of fusing points:
1H-NMR (DMSO-d
6) δ (ppm): 1.21 to 1.23 (3H, d, 4 ' CH
3), 3.61 to 3.64 (1H, d, 3 '-H), 3.73 to 3.77 (1H, d, 4 '-H), 3.98 to 4.01 (1H, d, 2 '-H), 5.00 (1H, s, OH), 5.22 (1H, s, OH), 5.61 to 5.64 (1H, d, 1 '-H), 7.14 (1H, d, CHCF).10.10(1H，s，NH)
Preparation 5 '-deoxidation-5-fluoro-N
4-amido cytidine (compound 3)
Get 2g (7.7 mmole) 5 '-deoxidation-5-fluoro-sulfo-cytidine, be dissolved in the 50ml methyl alcohol, be chilled to 0 ℃, slowly splash into 50% hydrazine hydrate solution of 3ml, stirring was neutralized to about pH=7 with 732 type Zeo-karbs after half hour.The elimination resin, solution evaporate to dryness, residue obtain solid 1.4g through the silicagel column purifying, yield 69.6%,
1H-NMR (DMSO-d
6) δ (ppm): 1.21 to 1.22 (3H, d, 4 '-CH
3), 3.60 to 3.63 (1H, d, 3 '-H), 3.73 to 3.77 (1H, d, 4 '-H), 3.98 to 4.01 (1H, d, 2 '-H), 5.00 (1H, s, OH), 5.22 (1H, s, OH), 5.61 to 5.64 (1H, d, 1 '-H), 7.16 (1H, d, CHCF), 10.12 (1H, s, NH)
Embodiment 4
Preparation 2 '-bromo-5 '-'-Deoxy-5-fluorouridine (compound 4)
A, 3 '-O-propionyl-2 '-bromo-5 '-'-Deoxy-5-fluorouridine (M compound)
Get 5g (20 mmole) compd A and be dissolved in the 30ml anhydrous acetonitrile, add 4.4ml (50 mmole) PROPIONYL CHLORIDE then, 60 ℃ of reacting by heating 10h.Solution evaporate to dryness then, solid is used the 100ml acetic acid ethyl dissolution, washes with 10% sodium bicarbonate aqueous solution of 50ml, and water is used ETHYLE ACETATE 30ml * 2 extractions again.Combined ethyl acetate, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is used the 20ml ethyl alcohol recrystallization, gets white solid 5.8g, yield 78.4%.
B, 2 '-bromo-5 '-'-Deoxy-5-fluorouridine (compound 4)
Get 2g (5.5 mmole) 3 '-O-propionyl-2 '-bromo-5 '-'-Deoxy-5-fluorouridine; Be dissolved in the 60ml THF; Add 50ml methyl alcohol and 12ml water then; Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 1.4g through the silicagel column purifying, yield 82%, fusing point:
1H-NMR (DMSO-d
6) δ (ppm):
1H-NMR (DMSO-d
6) δ (ppm): 0.98 to 1.02 (3H, d, 4 '-CH
3), 4.15 to 4.19 (2H, m, 2 '-H, 4 '-H), 5.22 to 5.23 (1H, d, 3 '-H), 5.85 to 5.86 (1H, d, OH), 6.22 to 6.24 (1H, d, 1 '-H), 8.33 (1H, d, CHCF).
Preparation 2 ', 5 '-dideoxy-5-floxuridine (compound 5)
A, 3 '-O-propionyl-2 ', 5 '-dideoxy-5-floxuridine (N compound)
Get 2g (4.3 mmole) 3 '-O-propionyl-2 '-bromo-5 '-'-Deoxy-5-fluorouridine and be dissolved in the 30ml anhydrous methanol, add.0.5g active nickel and 1g sodium acetate, normal temperature leads to H
2Stir 10h.Filter the solution evaporate to dryness then.Solid is with the dissolving of 50ml methylene dichloride, and with 30ml * 2 washings, water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is used ethyl alcohol recrystallization, gets white solid 1g
B, 2 ', 5 '-dideoxy-5-floxuridine (compound 5)
Get 1g (3.5 mmole) 3 '-O-propionyl-2 '-bromo-5 '-'-Deoxy-5-fluorouridine; Be dissolved in the 60ml THF; Add 50ml methyl alcohol and 12ml water then; Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 0.7g through the silicagel column purifying, yield 80%, fusing point: 157-158 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 1.24 to 1.27 (3H, d, 4 '-CH
3), 2.04 to 2.06 (1H, m, 2 '-H), 2.18 to 2.20 (1H, d, 2 '-H), 3.75 to 3.78 (1H, m, 4 '-H), 3.93 to 3.96 (1H, d, 3 '-H), 5.24 to 5.25 (1H, d, OH), 6.02 to 6.05 (1H, d, 1 '-H), 7.86 (1H, d, CHCF).
Preparation 2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine (compound 6)
A, 3 '-O-propionyl-2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine
Get 2g (4.3 mmole) 3 '-O-propionyl-2 '-bromo-5 '-'-Deoxy-5-fluorouridine, 1g (4.5 mmole) thiophosphoric anhydride joins in the 100ml anhydrous pyridine, and the dissolving post-heating refluxes and spends the night.Solution evaporate to dryness then.Resistates is dissolved in 100ml ETHYLE ACETATE, washes with the 10%HCl aqueous solution of 50ml * 2, and water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue can not purifiedly directly be used for next step reaction.
B, 2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine (compound 6)
Getting 2g (4 mmole) 3 '-O-propionyl-2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine is dissolved in the 60ml THF; Add 50ml methyl alcohol and 12ml water then; Be chilled to 0 ℃; The 2N sodium hydroxide solution that adds 12ml stirs and is neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 1g through the silicagel column purifying, yield 72%, fusing point 165-166 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 1`.02 to 1.04 (3H, d, 4 ' CH
3), 4.19 to 4.21 (2H, m, 2 '-H, 4 '-H), 5.27 to 5.29 (1H, d, 3 '-H), 5.90 to 5.92 (1H, d, OH), 6.54 to 6.56 (1H, d, 1 '-H), 7.99 (1H, d, CHCF).
Preparation 2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine (compound 7)
A, 3 '-O-propionyl-2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine (Q compound)
Get 2g (7 mmole) 3 '-O-propionyl-2 ', 5 '-dideoxy-5-floxuridine, 1.6g (7 mmole) thiophosphoric anhydride joins in the 100ml anhydrous pyridine, and the dissolving post-heating refluxes and spends the night.Solution evaporate to dryness then.Resistates is dissolved in 100ml ETHYLE ACETATE, washes with the 10%HCl aqueous solution of 50ml * 2, and water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue can not purifiedly directly be used for next step reaction.
B, 2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine (compound 7)
Get 2g (6.6 mmole) 3 '-O-propionyl-2 '; 5 '-dideoxy-5-fluorine sulfo-cytidine is dissolved in the 60ml THF; Add 50ml methyl alcohol and 12ml water then; Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 1.3g through the silicagel column purifying, yield 75%, fusing point 132-133 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 1.24 to 1.26 (3H, d, 4 '-CH
3), 2.07 to 2.13 (1H, m, 4 '-H), 2.21 to 2.26 (1H, d, 2 '-H), 3.93 to 3.97 (1H, d, 3 '-H), 5.25 to 5.26 (1H, d, OH), 5.95 to 5.98 (1H, d, 1 '-H), 7.84 (1H, d, CHCF).
Embodiment 8
Preparation 2 '-bromo-5 '-deoxidation-5-fluorine cytidine (compound 8)
Get 1g (3 mmole) 2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine, be dissolved in the 30ml methyl alcohol 60 ℃ of logical NH
3Stir 6h.Evaporate to dryness, residue obtain solid 0.82g through the silicagel column purifying, yield 82%:
1H-NMR(DMSO-d
6)δ(ppm)：0.98～1.02(3H，d，4’-CH3)，4.15～4.19(2H，m，2’-H，4’-H)，5.22～5.23(1H，d，3’-H)，5.85～5.86(1H，d，OH)，6.22～6.24(1H，d，1’-H)，8.33(1H，d，CHCF)。
Embodiment 9
Preparation 2 ', 5 '-dideoxy-5-fluorine cytidine (compound 9)
Get 1g (4 mmole) 2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine, be dissolved in the 30ml methyl alcohol 60 ℃ of logical NH
3Stir 6h.Evaporate to dryness, residue obtain solid 0.75g through the silicagel column purifying, yield 80%,
1H-NMR (DMSO-d
6) δ (ppm): 1.24～1.27 (3H, d, 4 '-CH3), 2.04～2.06 (1H, m, 2 '-H); 2.18～2.20 (1H, d, 2 '-H), 3.75～3.78 (1H, m, 4 '-H); 3.93～3.96 (1H, d, 3 '-H), 5.24～5.25 (1H, d, OH); 6.02～6.05 (1H, d, 1 '-H), 7.86 (1H, d, CHCF).
Preparation 2 '-bromo-5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine (compound 10)
Get 1g (2.7 mmole) 3 '-O-propionyl-2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine and join in the 30ml ethanol, add 0.2g (3 mmole) oxammonium hydrochloride and 0.4g (3 mmole) salt of wormwood then, 60 ℃ are stirred 10h, evaporate to dryness.Add 50ml THF, 30ml methyl alcohol and 12ml water then successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 0.63g through the silicagel column purifying, yield 72%,
1H-NMR (DMSO-d6) δ (ppm): 0.99～1.02 (3H, d, 4 '-CH3), 4.12～4.15 (2H, m, 2 '-H, 4 '-H); 5.22～5.24 (1H, d, 3 '-H), 5.86～5.87 (1H, d, OH); 6.22～6.23 (1H, d, 1 '-H), 8.35 (1H, d, CHCF).
Embodiment 11
Preparation 2 ', 5 '-dideoxy-5-fluoro-N
4-hydroxyl cytidine (compound 11)
Get 1g (3.3 mmole) 3 '-O-propionyl-2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine joins in the 30ml ethanol, adds 0.23 (3.3 mmole) oxammonium hydrochloride and 0.3 (3.3 mmole) salt of wormwood then, and 60 ℃ are stirred 10h, evaporate to dryness.Add 50ml THF, 30ml methyl alcohol and 12ml water then successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 0.57g through the silicagel column purifying, yield 79%,
1H-NMR (DMSO-d
6) δ (ppm): 1.24～1.27 (3H, d, 4 '-CH3), 2.04～2.06 (1H, m, 2 '-H); 2.18～2.20 (1H, d, 2 '-H), 3.75～3.78 (1H, m, 4 '-H); 3.93～3.96 (1H, d, 3 '-H), 5.24～5.25 (1H, d, OH); 6.02～6.05 (1H, d, 1 '-H), 7.86 (1H, d, CHCF).
Preparation 2 ', 5 '-dideoxy-5-fluoro-N
4-(2-phosphono ethyl ester methoxyl group)-cytidine (compound 12)
Get 1g (3 mmole) 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine is dissolved in the 30ml anhydrous tetrahydro furan, is chilled to 0 ℃, adds 0.1g (3 mmole) sodium hydride.Be chilled to 0 ℃.Stir and add 0.6ml (3 mmole) two ethyl phosphonic acid-methyl-p-toluenesulfonic esters after 30 minutes, continuation stirring 10h.Splash into the 2ml glacial acetic acid, evaporated under reduced pressure.Residue is dissolved in 100ml ETHYLE ACETATE, and with the washing of 50ml * 2, water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is dissolved in the 50ml THF and adds 30ml methyl alcohol and 12ml water then.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 0.88g through the silicagel column purifying, yield 72%, 97-98 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 1.22 to 1.28 (9H, m, 4 '-CH
3, OCH
2 CH 3 * 2), 3.64 to 3.65 (1H, m, 4 '-H), 3.73 to 3.77 (1H, d, 2 '-H), 4.01 to 4.10 (4 hours, m, O
CH 2 CH
3* 2), 5.02 (1H, s, OH), 5.62 (1H, s, OH), 5.64 to 5.65 (1H, d, 1 '-H), 7.32 (1H, s, CHCF), 10.57 (1H, s, NH).
Preparation 5 '-deoxidation-5-fluoro-N
4-(sulfonyloxy methyl ester group) cytidine (compound 13)
Get 1g (3 mmole) 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine is dissolved in the 30ml anhydrous tetrahydro furan, adds the 2ml pyridine, is chilled to 0 ℃, adds 0.8ml (3 mmole) Methanesulfonyl chloride.Stir evaporate to dryness after 6 hours, residue is dissolved in 100ml ETHYLE ACETATE, and with the washing of 50ml * 2, water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is dissolved in the 50ml THF and adds 30ml methyl alcohol and 12ml water then.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid 0.46g through the silicagel column purifying, yield 41%.Fusing point 175-176 ℃;
1H-NMR (DMSO-d
6) δ (ppm): 1.24 to 1.26 (3H, d, 4 ' CH
3), 3.41 (3H, s, CH
3), 3.66 to 3.68 (1H, d, 3 '-H), 3.78 to 3.82 (1H, d, 4 '-H), 4.03 to 4.06 (1H, d; 2 '-H), 5.04 to 5.06 (1H, d, OH), 5.30 to 5.32 (1H, d, OH), 5.63 to 5.65 (1H; D, 1 '-H), 7.59 (1H, d, CHCF), 11.59 (1H, s, NH).
Embodiment 14
Preparation 5 '-deoxidation-5-fluoro-N
4-(ethyl sulphonyl ester group) cytidine (compound 14)
According to the described method of embodiment 12, replace Methanesulfonyl chloride to obtain white solid yield 42%, fusing point 157-158 ℃ with ethyl chloride;
1H-NMR (DMSO-d
6) δ (ppm): 1.22 to 1.27 (6H, d, 4 '-CH
3, CH
2 CH 3 ), 3.40 to 3.45 (2H, m,
CH 2 CH
3), 3.65 to 3.69 (1H, d, 3 '-H), 3.78 to 3.80 (1H, d, 4 '-H), 4.02 to 4.07 (1H, d; 2 '-H), 5.04 to 5.06 (1H, d, OH), 5.30 to 5.31 (1H, d, OH), 5.62 to 5.65 (1H; D, 1 '-H), 7.59 (1H, d, CHCF), 11.61 (1H, s, NH).
Preparation 5 '-deoxidation-5-fluoro-N
4-(sulfonyl propyl ester group) cytidine (compound 15)
According to the described method of embodiment 12, obtain white solid yield 55% with the sulfonyl propyl chloro for Methanesulfonyl chloride, fusing point 132-133 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 0.91 to 0.93 (3H, m, CH
2CH
2 CH 3 ), 1.26 to 1.27 (6H, d, 4 '-CH
3), 1.70 to 1.77 (2H, m, CH
2 CH 2 CH
3), 3.41 to 3.47 (2H, m,
CH 2 CH
2CH
3), 3.64 to 3.69 (1H, d, 3 '-H), 3.76 to 3.81 (1H, d, 4 '-H), 4.02 to 4.07 (1H, d; 2 '-H), 5.03 to 5.05 (1H, d, OH), 5.29 to 5.31 (1H, d, OH), 5.63 to 5.65 (1H; D, 1 '-H), 7.59 (1H, d, CHCF), 11.59 (1H, s, NH).
Embodiment 16
Preparation 5 '-deoxidation-5-fluoro-N
4-(butyl sulphonyl ester group) cytidine (compound 16)
According to the described method of embodiment 12, replace Methanesulfonyl chloride to obtain white solid yield 47%, fusing point 82-83 ℃ with butyl sulfochlorides;
1H-NMR (DMSO-d
6) δ (ppm): 0.90 to 0.93 (3H, m, CH
2CH
2CH
2 CH 3 ), 1.23 to 1.25 (6H, d, 4 '-CH
3), 1.68 to 1.70 (2H, m, CH
2CH
2 CH 2 CH
3), 1.72 to 1.74 (2H, m, CH
2_
CH 2 CH
2CH
3), 3.41 to 3.43 (2H, m,
CH 2 CH
2CH
2CH
3), 3.64 to 3.67 (1H, d, 3 '-H), 3.78 to 3.81 (1H, d, 4 '-H), 4.00 to 4.05 (1H, d; 2 '-H), 5.04 to 5.06 (1H, d, OH), 5.29 to 5.31 (1H, d, OH), 5.63 to 5.65 (1H; D, 1 '-H), 7.60 (1H, d, CHCF), 11.59 (1H, s, NH).
Embodiment 17
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(tolysulfonyl ester group) cytidine (compound 17)
According to the described method of embodiment 12, replace Methanesulfonyl chloride to obtain white solid yield 53% with p-methyl benzene sulfonic chloride, fusing point 179-180 ℃,
1H-NMR (DMSO-d
6) δ (ppm): 1.21 to 1.23 (3H, m, 4 '-CH
3), 2.49 (3H, s, CH
3), 3.62 to 3.66 (1H, m, 4 '-H), 3.76 to 3.80 (1H, d, 2 '-H), 3.97 to 4.02 (1H, d, 3 '-H), 5.01 to 5.03 (1H, d, OH), 5.26 to 5.28 (1H, d, OH), 5.58 to 5.61 (1H, d, 1 '-H), 7.44 to 7.47 (2H, m,
), 7.32 (1H, s, CHCF), 7.80 to 7.83 (2H, m,
), 11.62 (1H, s, NH).
Embodiment 18
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(sec.-propyl formic acid ester group) cytidine (compound 18)
Get 1g (3 mmole) 2 ', 3 '-two-O-acetyl-5 '-deoxidation-5-fluoro-N
4-oximido cytidine is dissolved in the 30ml anhydrous tetrahydro furan, adds the 2ml pyridine, is chilled to 0 ℃, adds 1ml (3 mmole) isopropyl chlorocarbonate.Evaporate to dryness behind the stirring 6h, residue is dissolved in 100ml ETHYLE ACETATE, and with the washing of 50ml * 2, water is used the 50ml ethyl acetate extraction again.The combined ethyl acetate phase, anhydrous sodium sulfate drying filters evaporate to dryness.Residue is dissolved in the 50ml THF and adds 30ml methyl alcohol and 12ml water then.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue obtain solid yield 40% through the silicagel column purifying, fusing point 95-96 ℃;
1H-NMR (DMSO-d
6) δ (ppm): 1.018～1.065 (6H, d, CH (
CH 3 )
2 ), 1.21～1.25 (3H, d, 4 '-CH
3), 3.40～3.44 (1H, d, 3 '-H), 3.65～3.68 (1H, d, 4 '-H), 3.77～3.79 (1H, m,
CH(CH
3)
2), 4.01～4.07 (1H, d, 2 '-H), 5.04～5.06 (1H, d, OH), 5.30～5.32 (1H, d, OH), 5.63～5.65 (1H, d, 1 '-H), 7.51～7.54 (1H, d, CHCF), 11.35 (1H, s, NH).
Embodiment 19
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(butyl formic acid ester group) cytidine (compound 19)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid white solid 0.49g, yield 41%, fusing point 175-176 ℃ with butyl chlorocarbonate;
1H-NMR (DMSO-d
6) δ (ppm): 1.65～1.67 (3H, t, CH
2CH
2CH
2 CH 3 ), 1.68～1.1.69 (3H, d, 4 '-CH
3), 1.70～1.73 (4 hours, m, CH
2 CH 2 CH 2 CH
3), 3.32～3.39 (2H, m,
CH 2 CH
2CH
2CH
3), 3.64～3.69 (1H, d, 3 '-H), 3.79～3.82 (1H, d, 4 '-H), 4.04～4.07 (1H, d; 2 '-H), 5.03～5.05 (1H, d, OH), 5.29～5.31 (1H, d, OH), 5.63～5.65 (1H; D, 1 '-H), 7.57～7.59 (1H, d, CHCF), 11.59 (1H, s, NH)
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(isobutyl-formic acid ester group) cytidine (compound 20)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 45%, fusing point 84-86 ℃ with isobutyl chlorocarbonate;
1H-NMR (DMSO-d
6) δ (ppm): 0.928 (6H, d, CH (
CH 3 )
2 ), 1.23～1.25 (3H, d, 4 '-CH
3), 1.90～1.95 (1H, m,
CH(CH
3)
2), 3.67～3.69 (1H, d, 3 '-H), 3.77～3.81 (1H, d, 4 '-H), 3.94～3.96 (2H, d,
CH 2 CH) 4.01～4.07 (1H, d, 2 '-H), 5.04～5.05 (1H, d, OH), 5.29～5.31 (1H, d, OH), 5.63～5.65 (1H, d, 1 '-H), 7.52～7.54 (1H, d, CHCF), 11.39 (1H, s, NH)
Embodiment 21
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(trichlorine tertiary butyl formic acid ester group) cytidine (compound 21)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 40%, fusing point 95-96 ℃ with the chloroformic acid trichlorine tert-butyl ester;
1H-NMR (DMSO-d
6) δ (ppm): 1.24～1.28 (3H, d, 4 '-CH
3), 1.88 (6H, s, C (
CH 3 )
2 ), 3.65～3.67 (1H, d, 3 '-H), 3.78～3.81 (1H, d, 4 '-H), 4.04～4.06 (1H, d, 2 '-H), 5.04～5.06 (1H, d, OH), 5.29～5.31 (1H, d, OH), 5.63～5.66 (1H, m, 1 '-H), 7.54～7.57 (1H, d, CHCF)
Embodiment 22
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(pentylformic acid ester group) cytidine (compound 22)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 45%, fusing point 64-65 ℃ with amyl chlorocarbonate;
1H-NMR (DMSO-d
6) δ (ppm): 0.82～0.84 (3H, m, CH
2 CH 3 ), 0.87～0.89 (4 hours, m, CH
2CH
2 CH 2 CH 2 CH
3), 1.01～1.06 (3H, d, 4 '-CH
3), 1.62～1.66 (2H, m, CH
2 CH 2 CH
2CH
2CH
3), 3.40～3.44 (1H, d, 3 '-H), 3.63～3.69 (1H, d, 4 '-H), 3.75～3.79 (1H, d, 2 '-H), 4.12～4.17 (2H, d,
CH 2 CH
2), 5.04～5.06 (1H, d, OH), 5.30～5.32 (1H, d, OH), 5.62～5.64 (1H, d, 1 '-H), 7.52～7.54 (1H, d, CHCF), 11.36 (1H, s, NH)
Embodiment 23
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(isopentyl formic acid ester group) cytidine (compound 23)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 41%, fusing point 68-69 ℃ with isoamyl chlorocarbonate;
1H-NMR (DMSO-d
6) δ (ppm): 0.82～0.86 (6H, m, CH
3* 2), 1.23～1.25 (3H, d, 4 '-CH
3), 2.07～2.09 (1H, m,
CHCH
3), 3.63～3.65 (1H, d, 3 '-H), 3.67～3.68 (1H, d, 4 '-H), 3.79～3.81 (1H, d, 2 '-H), 4.03～4.05 (2H, d,
CH 2 CH) 5.03～5.05 (1H, d, OH), 5.29～5.31 (1H, d, OH), 5.63～5.65 (1H, d, 1 '-H), 7.51～7.54 (1H, d, CHCF), 11.36 (1H, s, NH).
Embodiment 24
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(decyl formic acid ester group) cytidine (compound 24)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 36%, fusing point 89-90 ℃ with chloroformic acid ester in the last of the ten Heavenly stems;
1H-NMR (DMSO-d
6) δ (ppm):
0.83～0.86(3H，t，CH
2 CH 3 )，1.23～1.28(17H，m，CH
2CH
2(
CH 7 CH 14 )CH
3，4’-CH
3)，1.56～1.63(2H，m，OCH
2 CH 2 CH
2CH
2CH
3)，3.65～3.68(1H，d，3’-H)，3.77～3.81(1H，d，4’-H)，4.01～4.05(1H，d，2’-H)，4.12～4.17(2H，d，O
CH 2 CH
2)，5.04～5.06(1H，d，OH)，5.29～5.31(1H，d，OH)，5.62～5.65(1H，d，1’-H)，7.52～7.54(1H，d，CHCF)，11.36(1H，s，NH)
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(ten dialkyl formic acid ester groups) cytidine (compound 25)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid with chloroformic acid ten dialkyls, yield 49%, fusing point 9 neighbours-91 ℃;
1H-NMR (DMSO-d
6) δ (ppm):
0.84～0.86(3H，t，CH
2 CH 3 )，1.23～1.28(21H，m，CH
2CH
2(
CH 9 CH 18 )CH
3，4’-CH
3)，1.56～1.63(2H，m，OCH
2 CH 2 CH
2CH
2CH
3)，3.65～3.6(1H，d，3’-H)，3.77～3.81(1H，d，4’-H)，4.01～4.05(1H，d，2’-H)，4.12～4.17(2H，d，O
CH 2 CH
2)，5.04～5.06(1H，d，OH)，5.29～5.31(1H，d，OH)，5.62～5.65?(1H，d，1’-H)，7.52～7.54(1H，d，CHCF)，11.36(1H，s，NH)
Embodiment 26
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(ten tetraalkyl formic acid ester groups) cytidine (compound 26)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 47%, fusing point 106-107 ℃ with chloroformic acid 14 hydrocarbon esters;
1H-NMR (DMSO-d
6) δ (ppm):
0.81～0.86(3H，t，CH
2 CH 3 ))，1.22～1.28(25H，m，CH
2CH
2(
CH 11 CH 22 )CH
3，4’-CH
3)，1.58～1.63(2H，m，OCH
2 CH 2 CH
2CH
2CH
3)，3.65～3.67(1H，d，3’-H)，3.77～3.81(1H，d，4’-H)，4.03～4.05(1H，d，2’-H)，4.12～4.16(2H，d，O
CH 2 CH
2)，5.03～5.05(1H，d，OH)，5.29～5.31(1H，d，OH)，5.62～5.65(1H，d，1’-H)，7.51～7.54(1H，d，CHCF)，11.35(1H，s，NH)
Embodiment 27
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(16 alkyl formic acid ester group) cytidine (compound 27)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 41%, fusing point 103-104 ℃ with chloroformic acid 14 hydrocarbon esters;
1H-NMR (DMSO-d
6) δ (ppm):
0.81～0.86(3H，t，CH
2 CH 3 )，1.22～1.25(29H，m，CH
2CH
2(
CH 13 CH 26 )CH
3，4’-CH
3)，1.58～1.63(2H，m，OCH
2 CH 2 CH
2CH
2CH
3)，3.65～3.68(1H，d，3’-H)，3.77～3.81(1H，d，4’-H)，4.01～4.06(1H，d，2’-H)，4.12～4.16(2H，d，O
CH 2 CH
2)，5.04～5.06(1H，d，OH)，5.29～5.31(1H，d，OH)，5.62～5.65(1H，d，1’-H)，7.51～7.54(1H，d，CHCF)，11.35(1H，s，NH)
Embodiment 28
Preparation 5 '-deoxidation-5-fluoro-N
4-O-(18 alkyl formic acid ester group) cytidine (compound 28)
According to the described method of embodiment 18, replace isopropyl chlorocarbonate to obtain white solid, yield 48%, fusing point 108-109 ℃ with chloroformic acid 18 hydrocarbon esters;
1H-NMR (DMSO-d
6) δ (ppm):
0.82～0.86(3H，t，CH
2 CH 3 )，1.22～1.25(33H，m，CH
2CH
2(
CH 15 CH 30 )CH
3，4’-CH
3)，1.59～1.61(2H，m，OCH
2 CH 2 CH
2CH
2CH
3)，3.65～3.69(1H，d，3’-H)，3.77～3.81(1H，d，4’-H)，4.03～4.05(1H，d，2’-H)，4.12～4.16(2H，d，O
CH 2 CH
2)，5.04～5.06(1H，d，OH)，5.29～5.31(1H，d，OH)，5.63～5.65(1H，d，1’-H)，7.52～7.54(1H，d，CHCF)，11.36(1H，s，NH)
Preparation 5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine (compound 29)
A, 5 '-deoxidation-5-fluoro-cytidine (compound I)
Get 5g (20 mmole) 5 '-deoxidation-5-fluoro-sulfo-cytidine and be dissolved in the 30ml methyl alcohol 60 ℃ of logical NH
3Stir 6h.Evaporate to dryness, residue obtain solid 4.8g through the silicagel column purifying, yield 90%, fusing point: 192 to 193 ℃.
B, N, the dinethylformamide dimethylacetal
The new methyl-sulfate that steams in 63g (0.5 mole) dehydration back is added 36.5g (0.5 mole) exsiccant N, in the dinethylformamide.Under agitation be heated to about 75 ℃, this temperature maintenance 3 hours, cooling is for use in icy salt solution then.27g (0.5 mole) sodium methylate is suspended in 30 to 60 ℃ the sherwood oil of 200ml, cryosel is bathed the mixed solution that cooling slowly drips the front preparation down, keeps below the temperature-5 ℃.Dropwise, continue to stir elimination polity 0.5 hour.104 to 106 ℃ of cuts are collected in the clear liquor distillation, get colourless liquid 40g, yield 65%.
C, 5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine (compound 29)
2.5g (10 moles) 5 '-deoxidation-5-fluoro-cytidine adds 40ml methyl alcohol, stirs slowly to drip 1.8ml (13 moles) N, dinethylformamide dimethylacetal down.After the stirring at room 2 hours, solid filtering is washed with ethanol and ether successively, and drying gets white solid 2.7g, yield 90%, fusing point: 204 to 205 ℃.
1H-NMR (DMSO-d
6) δ (ppm): 1.46 (3H, d, 4 '-CH
3), 3.18 and 3.0 (6H, 2s, N-CH
3), 3.90 to 3.92 (1H, m, 3 '-H), 4.18 to 4.20 (1H, m, 4 '-H), 4.27 to 4.29 (1H, d, 2 '-H), 5.80 to 5.82 (1H, d, 1 '-H), 7.88 (1H, d, CHCF), 8.56 (1H, s, N=CH).
Embodiment 30
Preparation 5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine (compound 30)
According to the described method of embodiment 17, with N, N-DEF dimethylacetal replaces N, and the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine, fusing point: 164 to 166 ℃.
1H-NMR (DMSO-d
6) δ (ppm): 1.22 (6H, 2t, CH
2 CH 3 * 2), 1.29 (2H, d, 4 '-CH
3) 3.52 to 3.59 (4 hours, m,
CH 2 CH
3* 2), 3.65 to 3.66 (1H, m, 3 '-H), 3.84 to 3.86 (1H, m, 4 '-H), 4.01 (1H, s, 2 '-H), 4.90 (1H, s, OH), 5.33 (1H, s, OH), 5.70 (1H, s, 1 '-H), 7.82 (1H, d, CHCF), 8.66 (1H, s, N=CH).
Preparation 5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine (compound 31)
According to the described method of embodiment 17, with N, N-dipropyl methane amide dimethylacetal replaces N, and the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 0.90 to 0.95 (6H, m, N-CH
2CH
2 CH 3 * 2), 1.22 to 1.26 (6H, 2t, N-CH
2 CH 2 CH
3* 2), 1.28 (2H, d, 4 ' CH
3), 3.50 to 3.54 (4 hours, m, N-
CH 2 CH
2CH
3* 2), 3.64 to 3.66 (1H, m, 3 '-H), 3.88 to 3.89 (1H, m, 4 '-H), 4.01 to 4.03 (1H, s, 2 '-H), 4.90 (1H, s, OH), 5.33 (1H, s, OH), 5.70 (1H, s, 1 '-H), 7.80 (1H, d, CHCF), 8.65 (1H, s, N=CH).
Embodiment 32
Preparation 5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine (compound 32)
According to the described method of embodiment 17, with N, N-dibutyl formamide dimethylacetal replaces N, and the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 0.87 to 0.89 (6H, m, N-CH
2CH
2CH
2 CH 3 * 2), 1.27 to 1.35 (7H, m, 4 '-CH
3And N-CH
2CH
2 CH 2 CH
3* 2), 1.49 to 1.54 (4 hours, m, N-CH
2 CH 2 CH
2CH
3* 2), 3.50 to 3.55 (1H, m, 4 '-H), 3.57 to 3.60 (4 hours, m, N-
CH 2 CH
2CH
2CH
3* 2), 3.63 to 3.65 (1H, m, 3 '-H), 3.98 to 3.99 (1H, s, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.78 (1H, d, CHCF), 8.68 (1H, s, N=CH).
Embodiment 33
Preparation 5 '-deoxidation-5-fluoro-N
4-((dibenzyl amido) methylene radical) cytidine (compound 33)
According to the described method of embodiment 17, with N, N-dibenzyl methane amide dimethylacetal replaces N, and the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-((dibenzyl amido) methylene radical) cytidine,
Embodiment 34
Preparation 5 '-deoxidation-5-fluoro-N
4-(1-(piperidyl) methylene radical) cytidine (compound 34)
According to the described method of embodiment 17, replace N with piperidyl methyl acid amides dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(1-(piperidyl) methylene radical) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 0.87～0.8 (6H, m, N-CH
2CH
2CH
2 CH 3 * 2), 1.35～1.38 (3H, d, 4 '-CH
3), 1.59～1.73 (6H, m, N-CH
2 CH 2 CH 2 CH 2 CH
2), 3.50～3.54 (2H, t, N-
CH 2 CH
2CH
2CH
2CH
2), 3.83～3.86 (2H, t, N-CH
2CH
2CH
2CH
2 CH 2 ), 3.94～3.96 (1H, m, 3 '-H), 4.15～4.18 (1H, s, 2 '-H), 4.36～4.401H, m, 4 '-H), 5.67～5.68 (1H, d, 1 '-H), 7.78 (1H, d, CHCF), 8.68 (1H, s, N=CH).
Embodiment 35
Preparation 5 '-deoxidation-5-fluoro-N
4-(1-(morpholinyl) methylene radical) cytidine (compound 35)
According to the described method of embodiment 17, replace N with morpholinyl A acid amides dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(1-(morpholinyl) methylene radical) cytidine.
1H-NMR(DMSO-d
6)δ(ppm)：1.24～1.25(3H，d，4’CH
3)，3.58～3.94(8H，m，N?
CH 2 CH 2 CH 2 CH 2 O)，3.95～3.97(1H，d，3’-H)，4.16～4.19(1H，d，4’-H)，4.39～4.42(1H，d，2’-H)，5.67～5.69(1H，d，1’-H)，7.82(1H，d，CHCF)，8.83(1H，s，N＝CH)
Embodiment 36
Preparation 5 '-deoxidation-5-fluoro-N
4-(1-(4-(4-(nitro) phenyl) piperazinyl) methylene radical) cytidine (compound 36)
According to the described method of embodiment 17, replace N with 4-(4-(nitro) phenyl) piperazinyl methane amide dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(1-(4-(4-(nitro) phenyl) piperazinyl) methylene radical) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 1.28～1.30 (3H, d, 4 ' CH
3), 3.62～3.69 (5H, m, 3 '-H with
CH 2 N
CH 2 ), 3.81～3.87 (5H, d, 4 '-H with
CH 2 N
CH 2 ), 3.99～4.04 (1H, d, 2 '-H), 5.00 (1H, s, OH), 5.33 (1H, s, OH), 5.69～5.71 (1H, d, 1 '-H), 7.06～7.10 (2H, d,
), 7..85～7.87 (1H, d, CHCF), 8.07～8.10 (2H, d,
), 8.82 (1H, s, N=CH).
Embodiment 37
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(dimethylin) ethylidene) cytidine (compound 37)
A, DMAC N,N
Get 3ml (5 mmole) diacetyl oxide, add two vitriol oils, slowly splash into 2.5ml (5 mmole) n n dimetylaniline about-5 ℃; Stirred 3 hours, and regulated about pH=7, add the 100ml ethyl acetate extraction with 10% sodium hydrogen carbonate solution; The separating ethyl acetate phase; Anhydrous sodium sulfate drying filters, and divides exactly ETHYLE ACETATE and obtains the 3.2g colourless liquid.
B, DMAC N,N dimethylacetal
According to the described method of embodiment 17, replace N with DMAC N,N, dinethylformamide obtains colourless liquid DMAC N,N dimethylacetal.
C, 5 '-deoxidation-5-fluoro-N
4-(2-(dimethylin) ethylidene) cytidine (compound 37)
According to the described method of embodiment 17, replace N with the DMAC N,N dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(2-(dimethylin) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.29 (d, 3H, 4 '-CH
3), 2.25 (s, 3H ,=CCH
3), 3.09 (s, 3H, NCH
3), 3.14 (s, 3H, NCH
3), 3.67 to 3.68 (d, 1H, 2 '-H), 3.85 to 3.87 (m, 1H, 4 '-H), 4.02 (d, 1H, 3 '-H), 5.70 to 5.72 (d, 1H, 1 '-H), 7.74 (1H, d, CHCF).
Embodiment 38
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(diethylin) ethylidene) cytidine (compound 38)
According to embodiment 25 described methods, with N, N-diethyl acetamide dimethylacetal replaces the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N
4-(2-(diethylammonium) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.18 to 1.20 (t, 3H, NCH
2 CH 3 ), 1.25 to 1.27 (t, 3H, NCH
2 CH 3 ), 1.37 to 1.38 (d, 3H, 4 '-CH
3), 2.38 (s, 3H ,=CCH
3), 3.45 to 3.48 (m, 2H,
CH 2 CH
3), 3.56 to 3.57 (m, 2H,
CH 2 CH
3), 3.91 to 3.93 (d, 1H, 2 '-H), 4.16 to 4.18 (d, 1H, 3 '-H), 4.36 to 4.38 (m, 1H, 4 '-H), 5.71 to 5.73 (d, 1H, 1 '-H), 7.72 (1H, d, CHCF).
Embodiment 39
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(dipropyl amido) ethylidene) cytidine (compound 39)
According to embodiment 25 described methods, with N, N-Valpromide dimethylacetal replaces the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N
4-(2-(dipropyl) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.97 to 1.00 (m, 6H, NCH
2CH
2 CH 3 * 2), 1.35 to 1.37 (d, 3H, 4 '-CH
3), 1.67 to 1.69 (m, 4 hours, NCH
2 CH 2 CH
3* 2), 3.31 to 3.33 (m, 4 hours, N
CH 2 CH
2CH
3* 2), 3.54 (s, 3H ,=CCH
3), 3.95 to 3.97 (d, 1H, 2 '-H), 4.16 to 4.18 (d, 1H, 3 '-H), 4.41 to 4.43 (m, 1H, 4 '-H), 6.03 to 6.05 (d, 1H, 1 '-H), 7.78 (1H, d, CHCF).
Embodiment 40
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(dibutyl amino) ethylidene) cytidine (compound 40)
According to embodiment 25 described methods, with N, N-dibutyl acetamide dimethylacetal replaces the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N
4-(2-(dibutyl) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.95 to 1.01 (m, 6H, N CH
2CH
2CH
2 CH 3 * 2), 1.38 to 1.39 (d, 3H, 4 '-CH
3), 1.61 to 1.64 (m, 8H, N CH
2 CH 2 CH 2 CH
3* 2), 2.42 (s, 3H ,=CCH
3), 3.37 to 3.38 (t, 2H, N
CH 2 CH
2CH
2CH
3), 3.59 to 3.61 (t, 2H, N
CH 2 CH
2CH
2CH
3), 3.97 to 3.99 (d, 1H, 2 '-H), 4.21 to 4.22 (d, 1H, 3 '-H), 4.42 to 4.44 (m, 1H, 4 '-H), 5.71 to 5.72 (d, 1H, 1 '-H), 7.71 (1H, d, CHCF).
Embodiment 41
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(diisopropylamino) ethylidene) cytidine (compound 41)
According to embodiment 25 described methods, with N, N-di-isopropyl ethanamide dimethylacetal replaces the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N
4-(2-(di-isopropyl) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.27 to 1.29 (t, 6H, NCH (
CH 3 )
2), 1.35 to 1.37 (d, 3H, 4 '-CH
3), 1.46 to 1.48 (t, 6H, NCH (
CH 3 )
2), 2.38 (s, 3H ,=CCH
3), 3.74 to 3.76 (m, 1H, N
CH(CH
3)
2), 3.85 to 3.87 (m, 1H, N
CH(CH
3)
2), 3.94 to 3.96 (d, 1H, 2 '-H), 4.17 to 4.19 (d, 1H, 3 '-H), 4.37 to 4.39 (m, 1H, 4 '-H), 5.66 to 5.68 (d, 1H, 1 '-H), 7.64 (1H, d, CHCF).
Embodiment 42
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(Pyrrolidine base) ethylidene) cytidine (compound 42)
According to embodiment 25 described methods, replace the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N with Pyrrolidine yl acetamide dimethylacetal
4-(2-Pyrrolidine base) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.35 to 1.37 (d, 3H, 4 '-CH
3), 1.96 to 1.99 (m, 4 hours, NCH
2 CH 2 CH 2 CH
2), 2.39 (s, 3H ,=CCH
3), 3.54 to 3.56 (t, 2H, N
CH 2 CH
2CH
2CH
2), 3.64 to 3.66 (t, 2H, NCH
2CH
2CH
2 CH 2 ), 3.93 to 3.95 (d, 1H, 2 '-H), 4.17 to 4.19 (d, 1H, 3 '-H), 4.35 to 4.37 (m, 1H, 4 '-H), 5.68 to 5.70 (d, 1H, 1 '-H), 7.67 (1H, d, CHCF).
Embodiment 43
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(piperidyl) ethylidene) cytidine (compound 43)
According to embodiment 25 described methods, replace the DMAC N,N dimethylacetal to obtain white solid 5 '-deoxidation-5-fluoro-N with piperidyl ethanamide dimethylacetal
4-(2-piperidyl) ethylidene) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.36 to 1.38 (d, 3H, CH
3), 1.67 to 1.70 (m, 6H, NCH
2 CH 2 CH 2 CH 2 CH
2), 2.38 (s, 3H ,=CCH
3), 3.52 to 3.54 (t, 2H, N
CH 2 CH
2CH
2CH
2CH
2), 3.82 to 3.84 (t, 2H, NCH
2CH
2CH
2CH
2 CH 2 ), 3.92 to 3.94 (d, 1H, 2 '-H), 4.15 to 4.16 (d, 1H, 3 '-H), 4.36 to 4.38 (m, 1H, 4 '-H), 5.67 to 5.69 (d, 1H, 1 '-H), 7.66 (1H, d, CHCF).
Embodiment 44
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine (compound 44)
According to the described method of embodiment 17, replace N with N-crassitude dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 1.28 (3H, d, 4 '-CH
3), 1.97 to 2.04 (2H, m), 3.01 to 3.05 (5H, m), 3.50 to 3.54 (2H, m); 3.66 to 3.70 (1H, m, 3 '-H), 3.83 to 3.87 (1H, s, 4 '-H), 4.01 to 4.05 (1H; M, 2 '-H), 4.88 (1H, d, OH), 5.18 (1H, d; OH), 5.70 to 5.71 (1H, d, 1 '-H), 7.71 (1H, d, CHCF).
Embodiment 45
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(1-octyl group) pyrrolidylidene) cytidine (compound 45)
According to the described method of embodiment 17, replace N with N-octyl group tetramethyleneimine dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(2-(1-octyl group) pyrrolidylidene) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 0.86 to 0.88 (3H, d, CH
2CH
2CH
2CH
2CH
2 CH 3 ), 1.28 to 1.33 (m, 10H,
CH 2 CH 2 CH 2 CH 2 CH 2 CH
3), 1.34 to 1.36 (3H, d, 4 '-CH
3), 3.27 to 3.29 (t, 2H, J=10Hz, N
CH 2 CH
2CH
2CH
2CH
2), 3.54 to 3.56 (t, 2H, NCH
2), 3.57 to 3.59 (t, 2H, CH
2), 3.66 to 3.70 (1H, m, 3 '-H), 3.97 to 3.99 (d, 1H, 2 '-H), 4.16 to 4.18 (d, 1H, 3 '-H), 4.41 to 4.43 (m, 1H, 4 '-H), 5.65 to 5.67 (d, 1H, 1 '-H), 7.71 (1H, d, CHCF).
Embodiment 46
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine (compound 46)
According to the described method of embodiment 17, replace N with N-methyl piperidine dimethylacetal, the dinethylformamide dimethylacetal obtains white solid 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine,
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (3H, d, 4 '-CH
3), 1.97 to 2.14 (4 hours, m), 3.05 to 3.08 (5H, m), 3.52 to 3.56 (2H, m); 3.68 to 3.70 (1H, m, 3 '-H), 3.85 to 3.88 (1H, s, 4 '-H), 4.02 to 4.05 (1H; M, 2 '-H), 4.86 (1H, d, OH), 5.16 (1H, d; OH), 5.70 to 5.71 (1H, d, 1 '-H), 7.73 (1H, d, CHCF).
Embodiment 47
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-pyrans imido grpup) cytidine (compound 47)
Get 1g (4 mmole) 5 '-deoxidation-5-fluoro-N
4-amido cytidine is dissolved in the 30ml anhydrous methanol, adds 2ml (4 mmole) furfural, 60 ℃ of heated and stirred 6h, and solvent evaporated, residue obtains solid 0.42g through the silicagel column purifying, yield 32%, fusing point 208-209 ℃;
1H-NMR (DMSO-d
6) δ (ppm): 1.13 to 1.18 (3H, d, 4 '-CH
3), 3.66 to 3.69 (1H, m, 4 '-H), 3.79 to 3.81 (1H, d, 2 '-H), 4.00 to 4.07 (1H, m, 4 '-H), 5.01 to 5.04 (1H, d, OH), 5.29 to 5.33 (1H, d, OH), 5.67
To 5.71 (1H, d, 1 '-H); 6.60 to 6.63 (1H, d,
); 7.23 to 7.25 (1H, d,
); 7.56 (1H, d, CHCF); 7.87 to 7.89 (1H; D,
), 10.42 (1H; S, NH).
Embodiment 48
Preparation 5 '-deoxidation-5-fluoro-N
4-(1-(3, the 5-dimethoxy) phenyl imido) cytidine (compound 48)
According to the described method of embodiment 36, with 3, the 5-dimethoxy benzaldehyde replaces furfural to obtain white solid 0.41g, yield 32%, fusing point 208-209 ℃;
1H-NMR (DMSO-d
6) δ (ppm): 1.25 to 1.27 (3H, d, 4 '-CH
3), 3.68 to 3.71 (1H, m, 4 '-H), 3.79 (6H, s, OCHCH
3* 2), 3.80 to 3.81 (1H, d, 2 '-H), 4.08 to 4.10 (1H, m, 4 '-H), 5.03 to 5.05 (1H, d, OH), 5.29 to 5.30 (1H, d, OH), 5.69 to 5.72 (1H, d, 1 '-H), 6.55 to 6.57 (1H, t,
), 7.22 to 7.23 (1H, d,
), 7.54 to 7.56 (1H, d, CHCF), 8.36 (1H, s,
), 10.96 (1H, s, NH).
Embodiment 49
Preparation 5 '-deoxidation-5-fluoro-N
4-(1-(4-(N, N-dimethyl-) phenyl imido) cytidine (compound 49)
According to the described method of embodiment 36, replace furfural to obtain solid, yield 36%, fusing point 184-185 ℃ with 4-(N, N-dimethyl-) phenyl aldehyde;
1H-NMR (DMSO-d
6) δ (ppm): 1.24 to 1.27 (3H, d, 4 ' CH
3), 2.98 (6H, s, N (CH
3)
2), 3.40 to 3.44 (1H, m, 4 '-H), 3.65 to 3.71 (1H, d, 2 '-H), 4.05 to 4.08 (1H, m, 4 '-H), 5.02 to 5.04 (1H, d, OH), 5.28 to 5.30 (1H, d, OH), 5.68 to 5.71 (1H, d, 1 '-H), 6.69 to 6.72 (1H, t,
), 7.44 to 7.47 (1H, d, CHCF), 7.81 to 7.84 (1H, s,
), 10.66 (1H, s, NH).
Embodiment 50
Monocrystalline is cultivated
1. monocrystalline is cultivated operation
Get compound 37100mg in 10ml single port bottle, add the 5ml absolute ethyl alcohol, 60 ℃ of following heating for dissolving are observed in the rearmounted 4 ℃ of refrigerators of room temperature cooling, occur the water white transparency monocrystalline after the week.
The method that all target compounds are cultivated monocrystalline according to compound 37 is carried out the monocrystalline cultivation.
2. monocrystalline collection of illustrative plates and data
(1) the monocrystalline data and the collection of illustrative plates of compound 37
Empirical formula C
13H
19F N
4O
4
Molecular weight 314.32
Temperature 293 (2) K
Wavelength 0.71073A
Crystal system, space group iris, P2 (1) 2 (1) 2 (1)
Unit cell dimension a=5.860 (5) A α=90 °
b＝12.766(11)A β＝90°
c＝19.974(17)A γ＝90°
Volume 1494 (2) A
3
Z, the density 4 of calculating, 1.397mg/m
3
Uptake factor 0.113mm
-1
F(000) 664
Crystallographic dimension 0.12x 0.06x 0.05mm
1.89 to 25.00 ° of the θ scopes of data acquisition
Limit index-6＜=h＜=6 ,-15＜=k＜=15 ,-12＜=1＜=23
Convergence reflex/unique reflection 6157/2621 [R (int)=0.1400]
The degree fully of θ=25.00 100.0%
Absorption correction is from the semiempirical of equivalent
Minimum and maximum transmission 0.9944 and 0.9866
Method of refining F
2On the complete matrix least square
Data/constraint/parameter 2621/0/199
F
2On goodness of fit 0.607
Final R index [I＞2 ∑s (I)] R1=0.0479, wR2=0.0518
R index (all data) R1=0.1624, wR2=0.0638
Absolute structure parameter-1.7 (17)
Maximum difference peak and hole 0.151 and-0.159e.A-3
(2) the monocrystalline data and the collection of illustrative plates of compound 38
Empirical formula C
15H
23F N
4O
4
Molecular weight 342.37
Temperature 293 (2) K
Wavelength 0.71073A
Crystal system, space group oblique crystal, P2 (1)
Unit cell dimension a=6.017 (3) A α=90 °
b＝12.877(7)A?β＝91.619(7)°
c＝11.168(6)A?γ＝90°
Volume 865.0 (8) A
3
Z, the density 2 of calculating, 1.314mg/m
3
Uptake factor 0.103mm
-1
F(000) 364
Crystallographic dimension 0.12x 0.10x 0.08mm
θ scope 1.82 to 26.01 degree of data acquisition.
Limit index-7＜=h＜=7 ,-12＜=k＜=15 ,-13＜=1＜=10
The reflection 3904/2553 of set/uniqueness [R (int)=0.0489]
The degree fully of θ=26.01 99.3%
Absorption correction is from the semiempirical of equivalent
Minimum and maximum transmission 0.9918 and 0.9877
Method of refining F
2On the complete matrix least square
Data/constraint/parameter 2553/2/221
F
2On goodness of fit 1.035
Final R index [I＞2 ∑s (I)] R1=0.0485, wR2=0.1240
R index (all data) R1=0.0533, wR2=0.1281
Absolute structure parameter 0.7 (12)
Maximum difference peak and hole 0.209 and-0.292e.A-3
(3) the monocrystalline data and the collection of illustrative plates of compound 43
Empirical formula C
16H
23F N
4O
4
Molecular weight 354.38
Temperature 293 (2) K
Wavelength 0.71073A
Crystal system, space group iris, P2 (1) 2 (1) 2 (1)
Unit cell dimension a=8.642 (8) A=90 °
b＝11.453(11)A β＝90°
c＝17.611(16)A γ＝90°
Volume 1743 (3) A
3
Z, the density 4 of calculating, 1.350Mg/m
3
Uptake factor 0.105mm
-1
F(000) 752
Crystallographic dimension 0.10x 0.08x 0.05mm
2.12 to 26.00 ° of the θ scopes of data acquisition
Limit index-10＜=h＜=8 ,-14＜=k＜=9 ,-21＜=1＜=21
The reflection 7908/3425 of set/uniqueness [R (int)=0.0417]
The degree fully of θ=26.00 99.9%
Absorption correction is from the semiempirical of equivalent
Minimum and maximum transmission 0.9948 and 0.9896
Method of refining F
2On the complete matrix least square
Data/constraint/parameter 3425/1/230
F
2On goodness of fit 0.800
Final R index [I＞2 ∑s (I)] R1=0.0340, wR2=0.0545
R index (all data) R1=0.0659, wR2=0.0593
Absolute structure parameter 0.4 (8)
Maximum difference peak and hole 0.104 and-0.119e.A
-3
(4) the monocrystalline data and the collection of illustrative plates of compound 15
Empirical formula C
12H
19F N
3O
7.50S
Molecular weight 376.36
Temperature 293 (2) K
Wavelength 0.71073A
Crystal system, space group oblique crystal, P2 (1)
Unit cell dimension a=11.156 (5) A α=90 °
b＝11.684(5)A β＝94.809(6)°
c＝12.653(5)A γ＝90°
Volume 1643.6 (12) A
3
Z, the density 4 of calculating, 1.521Mg/m
3
Uptake factor 0.252mm
-1
F(000) 788
Crystallographic dimension 0.25x 0.20x 0.20mm
1.62 to 26.01 ° of the θ scopes of data acquisition
Limit index-13＜=h＜=13 ,-13＜=k＜=14 ,-10＜=1＜=15
The reflection 7458/6101 of set/uniqueness [R (int)=0.1037]
The degree fully of θ=26.01 99.4%
Absorption correction is from the semiempirical of equivalent
Minimum and maximum transmission 0.9513 and 0.9397
Method of refining F
2On the complete matrix least square
Data/constraint/parameter 6101/6/476
Goodness of fit on F^2 0.971
Final R index [I＞2 ∑s (I)] R1=0.0725, wR2=0.1789
R index (all data) R1=0.0855, wR2=0.1876
Absolute structure parameter-0.07 (10)
Optical extinction coefficient 0.0001 (15)
Maximum difference peak and hole 0.357 and-0.462e.A-3
Embodiment 51
The anti tumor activity in vitro testing experiment
TP: adopt mtt assay to carry out the anti tumor activity in vitro test.
Test cell strain: lung carcinoma cell (A549), liver cancer cell (QGY), cervical cancer cell (hela).
Positive control drug: 5 FU 5 fluorouracil (5-Fu)
1. cell cultures
Subject cell is at 5%CO
2, under 37 ℃ of conditions,, test used cell and all be in logarithmic phase with the DMEM solution that the contains 10% calf serum cultivation of going down to posterity.
2. soup preparation:
Receive the reagent thing to be made into 10g/L solution with DMSO respectively;-20 ℃ of preservations before the experiment, are put room temperature with the soup taking-up and are melted; And becoming the soup sample of 80 μ g/ml, 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml respectively with the dissolving of the DMEM nutrient solution of 10% calf serum, 4 ℃ of refrigerators are preserved.
3.MTT method is surveyed each sample anti-tumor activity:
1) cell in vegetative period of taking the logarithm with the DMEM nutrient solution that contains 10% calf serum, is processed single cell suspension 1 * 10
5Individual/ml, this suspension is added in 96 orifice plates, every hole adds 100 μ L.
2) in 37 ℃ of incubators, cultivate after 24 hours, draw supernatant, what add each concentration respectively receives the reagent thing, establishes two multiple holes, continues to cultivate 24 hours.
3) draw supernatant, add 20 μ L MTT solution (5 μ g/ml), continue to cultivate after 4 hours, draw supernatant, add the DMSO of 100L, fully light absorption value (OD value) is measured in the dissolving back at the 570nm place, and calculates its inhibiting rate by following formula.
Inhibiting rate (%)=(control wells OD value-experimental port OD value)/control wells OD value * 100% IC
50Value is calculated by SPSS software.
Compound anti tumor activity in vitro test result
Annotate: the no result of-expression, IC
50The expression half-inhibition concentration.
Embodiment 52
Inside and outside anti-tumor activity testing experiment
Irritate the influence of 45 pairs of human colon carcinoma nude mices of stomach compound transplanted tumor through this experimental observation.Animal-origin, article belong to, and plant system: 5～6 age in week male BALB/c nu/nu nude mouse, the SPF level is provided by west, Shanghai pul-Bi Kai laboratory animal ltd.Sex: male.Body weight: 20～22g.
TP:
The foundation of the subcutaneous plantation knurl of colorectal carcinoma animal model
1. animal is selected: 5～6 age in week male BALB/c nu/nu nude mouse, body weight 20～22g, SPF level.
2. cell is selected: CCL188 HCT116
3. animal divides into groups: negative control group, positive drug capecitabine group (350mg/kg), experimental drug compounds-45 group (high dose group 700mg/kg, low dose group 350mg/kg)
4. the subcutaneous plantation knurl of colorectal carcinoma mouse model: the suspension 100 μ l injection nude mice that will contain 2 * 106 tumour cells is the limb oxter nearby, become knurl after, separate the knurl cells in vivo, be inoculated into new nude mice, carry out interior generation and cultivate.Selected for the 3rd generation became the knurl mouse, carry out the research of drug influence.
5. medication and knurl are resurveyed and decided: mice with tumor is pressed the uniformly distributing of knurl body size in model group (negative control group; Give zero(ppm) water), positive controls (giving capecitabine), compound 45 high dose group (700mg/kg), compound 45 low dose group (350mg/kg); Continuous gastric infusion; 5 days was 1 course of treatment, drug withdrawal 2 days, continuous 2 courses of treatment.After the last administration the 16th hour, after nude mice is weighed, strip tumour, weigh.
Tumour inhibiting rate %=(1-treatment group knurl weight/negative control group knurl is heavy) * 100%
Experiment is divided into groups and dose form
Administration number of times: continuous gastric infusion, 5 days was 1 course of treatment, drug withdrawal 2 days, amounts to 10 times continuous 2 courses of treatment
Observation index and observing time: take by weighing nude mice body weight, knurl heavily
Data and statistical analysis: experimental data is represented with
; Carry out variance analysis with SPSS 10.0 softwares, do test of significance.
Test-results:
Negative control zero(ppm) water group nude mice tumour heavily is 1.138 ± 0.631g; Compound 45 dose groups 350mg/kg are 68.4% to tumor control rate; Positive control drug capecitabine (350mg/kg) is 76.9% to tumor control rate; Knurl heavily is merely 0.263 ± 0.125g, compares with negative control, and difference has significance meaning (P＜0.01).See table 1.
The influence of table 1 pair transplanting human colon carcinoma (HCT116) tumor bearing nude mice tumor weight (x ± SD)
Compare * P＜0.01 with negative control group
Conclusion: the restraining effect of irritating 45 pairs of transplanting of stomach compound human colon carcinoma (HCT116) tumor bearing nude mice tumour is suitable with positive control drug card times he guest.
Embodiment 53
Pharmacokinetics is tentatively tested
Test animal: rat
HPLC condition: moving phase: methanol=10/90, C18 post, flow velocity 1ml/ minute, column temperature=20 ℃.
1. plasma sample pre-treatment
Venous samples can places 2.0ml plastic centrifuge tube (adding anticoagulant heparin), 3000 rev/mins of centrifugal 5 minutes separated plasmas.Get blood plasma 100 μ l and place the little centrifuge tube of 1.5ml plastics, add 500 μ l albumen precipitation reagent (methyl alcohol), one fen half of vortex mixed in 12000 rev/mins of high speed centrifugations 15 minutes, is drawn supernatant, and 40 ℃ of logical nitrogen of water-baths volatilize.Residue is got 100 μ l sample introductions with moving phase 200 μ l dissolving.
2. experimentation on animals
Get compound 220mg and be dissolved in the 5ml saline water, with the injection of 30mg/Kg dosage rat tail vein, before administration and after the administration, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2h, 3h, 4 hours, the 6h time point was got blood, pressed the plasma sample treating processes and handled.
3. experimentation on animals
Get compound 4520mg and be dissolved in the 5ml saline water, with the injection of 30mg/Kg dosage rat tail vein, before administration and after the administration, 15 minutes; 30 minutes, 45 minutes, 60 minutes, 2 hours; 3 hours, 4 hours, time point was got blood in 6 hours, pressed the plasma sample treating processes and handled.
3. experimental result
Referring to Fig. 1; The RT of compound 2 is 8.764 minutes; The RT of 5-DFUR (the doxifluridine analog derivative of 5 FU 5 fluorouracil) is 7.654 minutes; Can find out 30 minutes after administration, compound 2 metabolism go out 5-DFUR, in the time of 6 hours compound 2 and 5-DFUR basically all metabolism finish.
Claims (10)
1. compound or pharmaceutically acceptable salt thereof with following formula (I):
Wherein, R
1Be selected from=N-OR
4,
R
2Be selected from hydrogen, hydroxyl and X;
R
3Be selected from hydrogen, C
2～C
6Acyl group, C
2～C
6Alkoxy acyl or
R
4Be selected from hydrogen or
R
8Be selected from hydrogen, C
2～C
16Straight or branched alkyl or straight or branched alkoxyl group, trifluoroethyl, two R
8Can be identical, can be different;
R
9Be selected from hydroxyl, C
1～C
6The straight or branched alkyl, unsubstituted phenyl, or by C
1～C
6Alkyl or C
1～C
6The substituted phenyl of alkoxyl group;
R
10Be selected from C
1～C
18Alkyl, unsubstituted phenyl, or by C
1～C
6Alkyl or C
1～C
6The substituted phenyl of alkoxyl group;
R
5Be selected from methyl, ethyl, propyl group;
R
6Be selected from C
1～C
16Dialkyl amido, or C
1～C
6Substituted diphenyl amino of alkyl or C
1～C
6The substituted piperazine of alkyl,
Perhaps R
5, R
6Can combine into ring, form substituted pyrrolidyl of N-or the substituted piperidines of N-, said substituting group is selected from C
1～C
18Alkyl;
R
7Be selected from phenyl, neighbour-or-or right-position halogenophenyl, neighbour-or-or right-position halogeno-benzyl, C
1～C
6The alkyl-substituted amino phenyl, C
1～C
6Alkyl-substituted phenyl, C
1～C
6Alkyl substituted pyrane base;
X＝F，Cl，Br，I，
Wherein, described compound is preferably crystalline form;
2. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, described compound is selected from:
5 '-deoxidation-5-fluoro-thio uridine;
5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine;
2 '-bromo-5 '-'-Deoxy-5-fluorouridine;
2 ', 5 '-dideoxy-5-floxuridine;
2 '-bromo-5 '-deoxidation-5-fluorine sulfo-cytidine;
2 ', 5 '-dideoxy-5-fluorine sulfo-cytidine;
2 '-bromo-5 '-deoxidation-5-fluorine cytidine;
2 ', 5 '-dideoxy-5-fluorine cytidine;
2 '-bromo-5 '-deoxidation-5-fluoro-N
4-hydroxyl cytidine;
2 ', 5 '-dideoxy-5-fluoro-N
4-hydroxyl cytidine;
5 '-deoxidation-5-fluoro-N
4-(sulfonyloxy methyl ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-(ethyl sulphonyl ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-(sulfonyl propyl ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-(butyl sulphonyl ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-(tolysulfonyl ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(sec.-propyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(butyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(isobutyl-formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(trichlorine tertiary butyl carbamate base) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(pentylformic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(isopentyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(decyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(ten dialkyl formic acid ester groups) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(ten tetraalkyl formic acid ester groups) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(16 alkyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-O-(18 alkyl formic acid ester group) cytidine;
5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine:
5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((dibenzyl amido) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-(1-(piperidyl) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-(1-(morpholinyl) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-(1-(4-(4-(nitro) phenyl) piperazinyl) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(dimethylin) ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(diethylin) ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(dipropyl amido) ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(dibutyl amino) ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(diisopropylamino) ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-Pyrrolidine base ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-piperidyl ethylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(1-octyl group) pyrrolidylidene) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-pyrans imido grpup) cytidine;
5 '-deoxidation-5-fluoro-N
4-(1-(3, the 5-dimethoxy) phenyl imido) cytidine; Or
5 '-deoxidation-5-fluoro-N
4-(1-(4-(N, N-dimethyl-) pyrans imido grpup) cytidine.
3. the preparation method of compound as claimed in claim 1 (preferably its crystalline form) or its pharmaceutical salts, described method comprises:
(1) makes compound (B) and P
2S
5React, obtain the compound of general formula (C):
(2) compound (C) that step (1) is obtained reacts with oxammonium hydrochloride, obtains the compound of general formula (D):
Then
(3) compound (D) that step (2) is obtained reacts in the presence of condensing agent with
or
; Carry out saponification reaction with saponifying agent then, obtain general formula (H), general formula (I) and general formula (J) compound respectively:
Perhaps
(4) compound (C) that with saponifying agent step (1) is obtained carries out after the saponification reaction and NH
3Reaction obtains compound (K), and then with
Reaction obtains general formula (L) compound:
(5) compound (D) that with saponifying agent step (2) is obtained carries out obtaining compound (M) with the Hydrazine Hydrate 80 reaction after the saponification reaction, and then and C
1～C
14Alkanoic/aromatic aldehyde reaction obtains general formula (N) compound:
perhaps
(6) make compound (A) reaction, obtain (O) compound with
:
(7) compound (O) and the H that step (6) are obtained
2Reaction obtains compound (P):
(8) make compound (P) and P
2S
5Reaction obtains general formula (Q) compound:
(9) compound (Q) that step (8) is obtained reacts with NH2-OH.HCl, obtains the compound of general formula (R):
perhaps
(10) with saponifying agent compound (P) is carried out after the saponification reaction and NH
3Reaction obtains compound (S), and then with
Reaction obtains general formula (T) compound:
Wherein said R
1-R
10Definition and claim 1 in identical, R
11Be C
1-6Alkyl or C
6-10Or C
1～C
6Acyl group or C
1～C
6Alkoxy acyl; Described method also randomly comprises the following steps (11) and (12):
(11) compound that said step (1)-(10) arbitrary step obtains is converted into its pharmaceutical salts; Perhaps
(12) the arbitrary compound that obtains in step (1)-(10) is converted into its crystal.
4. preparation method as claimed in claim 3, wherein, described saponifying agent is selected from mineral alkali, C
1-4Sodium alkoxide or ammoniacal liquor; Described saponification reaction is carried out in solvent, and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), water, THF or its combination.
5. preparation method as claimed in claim 4, wherein said mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash or salt of wormwood, described C
1-4Sodium alkoxide is selected from sodium methylate or sodium ethylate; Described C
1-4Fatty Alcohol(C12-C14 and C12-C18) is selected from methyl alcohol, ethanol, propyl alcohol or Virahol.
6. preparation method as claimed in claim 4, wherein step (1) and P
2S
5Be reflected in the solvent that is selected from pyridine, single halogen or polyhalid alkane, THF, dioxane, benzene, acetonitrile and carry out, described solvent is pyridine or dioxane; Step (2) is reflected to be selected from the solvent that contains acid binding agent with oxammonium hydrochloride carries out; Described acid binding agent is selected from mineral alkali and organic bases; Described mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood and sodium hydrogencarbonate; Described organic bases is selected from the organic bases of pyridine, triethylamine, and described acid binding agent is selected from yellow soda ash, salt of wormwood or triethylamine;
Described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, C
1-4Aliphatic ether, preferred solvent is selected from methyl alcohol, ethanol, acetonitrile;
The condensing agent of step (3) reaction with
is selected from sodium hydride, potassium hydride KH, hydrolith, sodium tert-butoxide, potassium tert.-butoxide, n-Butyl Lithium, and preferred condensing agent is sodium hydride or sodium tert-butoxide; Described solvent is selected from THF, methylene dichloride, ether, dioxane; Be reflected in the solvent that contains acid binding agent with SULPHURYL CHLORIDE in the step (3) and carry out, the preferred yellow soda ash of described acid binding agent, salt of wormwood, pyridine, triethylamine, described solvent is selected from THF, methylene dichloride, ether, dioxane; Step (3) is carried out with being reflected in the solvent that contains acid binding agent of
, and described acid binding agent is selected from yellow soda ash, salt of wormwood, pyridine, triethylamine; Described solvent is selected from THF, methylene dichloride, ether, dioxane;
Step (4) and NH
3Be reflected in the solvent and carry out, described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol or THF;
With N, the two substituted dimethyl aldolizations of N-carry out in solvent in the step (4), and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether;
Step (5) is reflected in the solvent with Hydrazine Hydrate 80 carries out, and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol or THF;
Step (5) is carried out in solvent with aldehyde reaction, and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether;
Step (6) is reflected in the solvent with PROPIONYL CHLORIDE carries out, and described solvent is selected from acetonitrile, THF, dioxane;
Step (7) and H
2Be reflected in the solvent, catalyzer carries out under existing, described catalyzer is nickel, palladium; Solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), dioxane, THF;
Step (8) and P
2S
5Be reflected in the solvent and carry out, described solvent is selected from pyridine, single halogen or polyhalid alkane, THF, dioxane, benzene, acetonitrile, and preferred solvent is pyridine or dioxane;
Step (9) is reflected in containing the solvent of acid binding agent with oxammonium hydrochloride carries out; Described acid binding agent is selected from mineral alkali or organic bases; Described mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate; Described organic bases is selected from pyridine, triethylamine, and preferred acid binding agent is selected from yellow soda ash, salt of wormwood or triethylamine; Described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, C
1-4Aliphatic ether, preferred solvent is methyl alcohol, ethanol, acetonitrile;
Step (10) and NH
3The solvent of reaction is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, dioxane, preferred solvent is methyl alcohol or THF; With N, the two substituted dimethyl aldolizations of N-carry out in solvent in the step (10), and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether.
7. method as claimed in claim 3, wherein, step (11) is carried out in solvent, and described solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), acetonitrile, THF, C
1-4Aliphatic ether, preferred solvent methyl alcohol, ethanol, acetonitrile; Described pharmaceutical salts is selected from its inorganic acid salt and organic acid salt: described inorganic acid salt is selected from hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate, nitrate salt; Described organic acid salt be selected from acetate, PHENRAMINE MALEATE, fumarate, tartrate, SUMATRIPTAN SUCCINATE, lactic acid salt, tosilate, salicylate, oxalate;
Said step (12) comprises monocrystalline cultivation operation: gets the arbitrary compound that obtains in step (1)-(10) and places reaction flask, add absolute ethyl alcohol, and 40 ℃～60 ℃ heating for dissolving, room temperature cooling back is left standstill in 0 ℃～10 ℃ and is obtained monocrystalline.
8. anti-tumor composition, it comprises claim 1 or 2 described compounds (being preferably its crystalline form) or its pharmaceutical salts, and pharmaceutically acceptable carrier.
9. according to claim 1 or claim 2 compound (being preferably its crystalline form) or its pharmaceutical salts application in the preparation antitumor drug.
10. application as claimed in claim 9; Wherein, Described tumour is selected from the cancer that esophagus, stomach, intestines, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, salt, brain or cns take place, perhaps Tiroidina cancer, white blood disease, Hokdkin disease, lymphoma or myelomatosis.
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| CN102690309A (en) * | 2011-03-25 | 2012-09-26 | 中国人民解放军第二军医大学 | Floxuridine compound and preparation method and application thereof |
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| CN104530164A (en) * | 2014-12-31 | 2015-04-22 | 辰欣药业股份有限公司 | Synthesis technology for capecitabine |
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| CN113293203A (en) * | 2021-04-09 | 2021-08-24 | 西安交通大学 | RNA 4-mercaptouracil specific labeling method and application thereof |
| CN116217644A (en) * | 2023-04-24 | 2023-06-06 | 南京颐媛生物医学研究院有限公司 | Anti-coronavirus ribonucleoside compound, and preparation method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690309A (en) * | 2011-03-25 | 2012-09-26 | 中国人民解放军第二军医大学 | Floxuridine compound and preparation method and application thereof |
| CN103539702A (en) * | 2012-07-12 | 2014-01-29 | 陕西师范大学 | Novel preparation method of N'-aryl-N, N-dimethyl formamidine |
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| CN104530164A (en) * | 2014-12-31 | 2015-04-22 | 辰欣药业股份有限公司 | Synthesis technology for capecitabine |
| CN113293203A (en) * | 2021-04-09 | 2021-08-24 | 西安交通大学 | RNA 4-mercaptouracil specific labeling method and application thereof |
| CN116217644A (en) * | 2023-04-24 | 2023-06-06 | 南京颐媛生物医学研究院有限公司 | Anti-coronavirus ribonucleoside compound, and preparation method and application thereof |
| CN116217644B (en) * | 2023-04-24 | 2023-08-08 | 南京颐媛生物医学研究院有限公司 | Anti-coronavirus ribonucleoside compound, and preparation method and application thereof |
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