CN101074230A - Production of 2-amino-6-fluorine-9-(4-hydroxy-3-methylol-butyl) purine and its intermediate - Google Patents
Production of 2-amino-6-fluorine-9-(4-hydroxy-3-methylol-butyl) purine and its intermediate Download PDFInfo
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Abstract
Production of antiviral medicine 2-amino-6-fluorine-9-(4-hydroxy-3-methylol-butyl) purine nucleoside ammonia chloride salt and its intermediate is carried out by reacting 2-amino-6-fluorine-9-(4-hydroxy-3-methylol-butyl) purine with trimethylamine alcohol solution in organic solvent to obtain nucleoside ammonia chloride salt, and reacting with anhydrous potassium fluoride at 20-60 degree to obtain final product. It substitutes anhydrous trimethylamine with trimethylamine alcohol solution, has gentle reactive condition and short reactive time, it's stable and has no reactive by-products.
Description
Technical field
The present invention relates to antiviral, particularly the preparation method of the purine nucleoside compounds 2-amino of anti-herpes simplex virus-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine and intermediate nucleosides chlorination ammonium salt thereof.
Background technology
In recent years, along with people deepen continuously to the research synthetic and biological assessment of purine nucleoside and analogue thereof, find that this compounds has antitumor and antiviral activity clinically.By structure of modification to nucleoside analog, produce a series of tangible antiviral activity nucleoside analogs that have, become the important component part of antiviral class drug research.Simultaneously, chemical compound lot has physiologically active because of contain fluorine atoms, and in its compound that induces one, certain variation will take place for its physico-chemical property and physiologically active.Thereby the medicine that fluorochemicals is stronger as biological activity, selectivity is higher is widely used.Nucleoside analog 9-(4-hydroxyl-3-methylol-butyl) guanine (be Penciclovir, structural formula is as shown in the formula shown in 6) is a kind of effective as selective inhibitor of simplexvirus class, is mainly used in the serious herpesvirus infection of treatment clinically.Penciclovir is carried out structural modification at present, synthesized the 9-[(4-fluorine)-3-hydroxymethyl butyl] guanine (is FHBG, structural formula is as shown in the formula shown in 7), 8-fluoro-9-(4-hydroxyl-3-hydroxymethyl butyl) guanine (is 8-Fluoropenciclovir, structural formula is as shown in the formula shown in 8) fluorochemicals, obtain fine drug effect.By structure and the active research to a kind of simplexvirus proteinoid HSV1-TK (herpes simplex virus 1-Thymine deoxyriboside kinase protein), purine C-6 position may be and HSV1-TK bonded reactive site.(Kim, D-K such as Kim; Lee, N; Kim, H-T; Im, G.-J; Kim, K-H.Bioorganic﹠amp; Medicinal Chemistry, 1999,7,565.) the introducing fluorine atom has synthesized 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine (6-Fluoropenciclovir on purine C-6 position, structural formula is as shown in the formula shown in 1), and it has been carried out esterification, obtain the Penciclovir prodrug that purine C-6 replaces with fluorine, and obtain certain drug effect.
The synthetic route of disclosed formula 1 compound is in the document:
But raw materials used formula 3 compounds are not conventional reagent in the first step in the said synthesis route, be difficult for buying, and because Trimethylamine 99 (TMA) boiling point lower (2～3 ℃), generally need be in application of sample under the cryogenic condensation and reaction, synthesis condition is relatively harsher, and the reaction times reaches 5 days simultaneously; And second step, according to literature method, the reaction side reaction product is many down at 80 ℃, and experiment is difficult to be repeated; So influenced its widespread use.
Summary of the invention
The objective of the invention is to overcome the defective of above-mentioned prior art, a kind of intermediate of synthesis type 1 compound be provided---the preparation method of formula 4 compound nucleosides chlorination ammonium salts.
Preparation method of the present invention comprises by formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine and Trimethylamine 99 ethanolic soln and to react in the N-dimethylformamide mixed solvent at tetrahydrofuran (THF) and N.
Preferably; described reaction may further comprise the steps: formula 3 compounds are dissolved in tetrahydrofuran (THF) and N; in the N-dimethylformamide mixed solvent; place-20～0 ℃ of salt ice-water baths; logical nitrogen protections etc. are anhydrous, under the oxygen free condition, get the Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction; slowly rise to room temperature, reaction is spent the night.TLC follows the tracks of and reacts to the complete back of raw material primitive reaction stopped reaction, filters, and is dry under vacuum with the anhydrous diethyl ether washing, obtains white solid formula 4 compounds.
Wherein, tetrahydrofuran (THF) and N in the above-mentioned mixed solvent, the volume ratio of N-dimethylformamide is preferably 2～5: 1, more preferably 3～4: 1.
And for easy, the Trimethylamine 99 ethanolic soln adopts the commercially available prod among the present invention, and wherein Trimethylamine 99 and alcoholic acid volume ratio are 1: 2.
The said room temperature of the present invention is generally 10～25 ℃.
Formula 3 compounds can be sloughed two ethanoyl reactions through hydrolysis by the raw material formula 2 compound 2-amino that are easy to get-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine and make.
Said hydrolysis reaction comprises formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine is dissolved in THF, adds K
2CO
3Place 0～20 ℃ of following stirring reaction, TLC follows the tracks of and reacts complete to the raw material primitive reaction.Stopped reaction, rotary evaporation is removed reaction solvent, gets faint yellow solid, uses washing with alcohol, separates through silicagel column, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 3 compounds.
Preferably, add methyl alcohol and water mixed solution in above-mentioned system, two ethanoyl are sloughed in hydrolysis, preserve the chlorine atom on 6 simultaneously, can obtain formula 3 compounds of high yield; The volume ratio of this first alcohol and water is preferably 1: 1.
Another object of the present invention provides the preparation method of a kind of formula 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine.
Described preparation method comprises the steps:
1. by above-mentioned intermediates preparation preparation formula 4 compound nucleosides chlorination ammonium salts;
2. formula 4 compounds are dissolved in N, the N-dimethylformamide adds anhydrous potassium fluoride, places 20～60 ℃ to carry out stirring reaction.TLC follows the tracks of and reacts complete to the raw material primitive reaction.After reaction finishes, filter, rotary evaporation is removed partial solvent, separates through silicagel column, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 1 compound.
Its preferable synthetic route is:
Made in the step of formula 4 compounds by formula 3 compounds above-mentioned, the present invention replaces Trimethylamine Anhydrous with the Trimethylamine 99 ethanolic soln, has avoided the severe condition of cryogenic condensation, and the reaction times also shortens (common one day just can) greatly.
And in the step of formula 4 compounds accepted way of doing sth 1 compound, the inventor finds that temperature of reaction is bigger to this reaction influence, and when temperature of reaction was lower than 60 ℃, nucleosides chlorination ammonium salt was stable, with a fluorination reagent reaction production 1 compound; But when temperature of reaction during greater than 60 ℃, then this nucleosides chlorination ammonium salt can decompose, and generates by product.
As seen, preparation method of the present invention has simplified processing condition, and is easy to operate, particular requirements such as no high temperature, high pressure, and common response equipment can be finished, and purifying products adopts methods such as filtration, post separation, and simple, product purity is higher.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Synthesizing of embodiment 1 formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine
(358mg 1mmol), is dissolved in 12ml THF to modus ponens 2 compounds, adds 10ml K
2CO
3(150mg, 1mmol) methyl alcohol and water mixed solution (MeOH/H
2O volume ratio=1: 1), place 0 ℃ of following stirring reaction, TLC follows the tracks of (developping agent: 10% ethanol/dichloromethane) react complete to the raw material primitive reaction.Stopped reaction, rotary evaporation is removed reaction solvent, gets faint yellow solid, uses the 25ml washing with alcohol, again with a spot of THF dissolving.Separate through silicagel column (10% ethanol/dichloromethane is made leacheate), collect R
fValue is 0.36 component, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 3 compounds, yield 78.4%.
Synthesizing of embodiment 2～3 formulas 3 compounds
Temperature of reaction is respectively 15 ℃ and 20 ℃, and is surplus with embodiment 1, obtains white solid formula 3 compounds, and yield is respectively 70.8%, 64.5%.
Synthesizing of embodiment 4 formulas 4 compound nucleosides chlorination ammonium salts
(813mg 3mmol) is dissolved in 40ml mixed solvent (THF/DMF volume ratio=3: 1) and places 0 ℃ of ice-water bath modus ponens 3 compounds, logical nitrogen protection.Get 9ml Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction.Reaction slowly rises to room temperature, and reaction is spent the night, and the adularescent solid generates.TLC follows the tracks of (developping agent: 10% ethanol/methylene) react complete to the raw material primitive reaction.Stopped reaction filters, and is dry under vacuum with anhydrous diethyl ether (10ml * 2) washing, obtains white solid formula 4 compounds, yield 90.5%.
Synthesizing of embodiment 5 formulas 4 compound nucleosides chlorination ammonium salts
(813mg 3mmol) is dissolved in 40ml mixed solvent (THF/DMF volume ratio=4: 1) and places-20 ℃ of salt ice-water baths modus ponens 3 compounds, logical nitrogen protection.Get 12ml Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction.Reaction slowly rises to room temperature, and reaction is spent the night, and the adularescent solid generates.Surplus with embodiment 4, obtain white solid formula 4 compounds, yield 86.8%.
Synthesizing of embodiment 6 formulas 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
(165mg 0.5mmol) is dissolved in 5ml DMF to modus ponens 4 compounds, and (240mg 5mmol), places 60 ℃ of stirring reactions, and TLC follows the tracks of (developping agent: 10% ethanol/methylene) react complete to the raw material primitive reaction to add anhydrous K F.After reaction finishes, filter, rotary evaporation is removed partial solvent, separates through silicagel column (leacheate is 10% methanol/dichloromethane solution), collects R
fValue is 0.45 component, and rotary evaporation removes and desolvates, and vacuum-drying obtains white solid formula 1 compound, yield 87.3%.
Synthesizing of embodiment 7～8 formulas 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
Temperature of reaction is respectively 20 ℃, 40 ℃, and is surplus with embodiment 6, obtains formula 1 compound, and yield is respectively 70.8,72.6%.
Raw material among this preparation method: formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine is Changzhou Kangli Pharmaceutical Co., Ltd's product; Anhydrous tetrahydro furan (THF), N, N-dimethylformamide (DMF, extra dry) is purchased the chemical reagents corporation in Acros; Anhydrous potassium fluoride, 33% Trimethylamine 99 (TMA) ethanolic soln are purchased in traditional Chinese medicines chemical reagents corporation; Other reagent is analytical pure and purchases in traditional Chinese medicines chemical reagents corporation, the not purified direct use of all reagent.
The physico-chemical property and the spectroscopic data of final product of the present invention and main intermediate are as follows:
Formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine
M.p.141.6～142.0 ℃; UV-vis (EtOH) λ max:223nm, 248nm and 310nm; IR (KBr) V:3320,3200,2930,1610,1570,1380,1060cm-1;
1H-NMR (DMSO-d
6) δ: 8.15 (s, 1H, C
8H), 6.90-6.80 (s, 2H, NH
2), 4.55-4.50 (m, 2H, OH), 4.05-4.15 (t, 2H, NCH
2, J=7.3Hz), 3.30-3.50 (m, 4H, OCH
2), 1.70-1.80 (m, 2H, CH
2CH), 1.40-1.50 (m, 1H, CH
2CH); MS m/z (%): 271 (M
+, 72), 240 (57), 170 (100).
Formula 4 compound nucleosides chlorination ammonium salts
m.p.168.1～170.5℃；UV-vis(EtOH)λmax：225nm，245nm，320nm；IR(KBr)V：3310，2920，1630，1570，1480，1320，1040cm-1；
1H-NMR(D
2O)δ：8.40(s，1H，C
8H)，4.20-4.30(t，2H，NCH
2，J＝7.42Hz)，3.70(s，9H，CNH
3)，3.55-3.65(m，4H，OCH
2)，1.85-1.90(m，2H，CH
2CH)，1.65-1.60(m，1H，CH
2CH；MSm/z(％)：280(M-CH
3Cl，92)，249(100)，191(80)。
Formula 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine
m.p.173.5～175.4℃；UV(EtOH)λmax：306nm；IR(KBr)V：3320，3310，2930，1660，1570，1410，1220，1030，783，625cm-1；
1H-NMR(DMSO-d
6)δ：8.10(s，1H，C
8H)，6.85(s，2H，NH
2)，4.50-4.60(m，2H，OH)，4.15-4.05(t，2H，4′H-CH
2，J＝7.42)，3.45-3.30(m，4H，OCH
2)，1.80-1.70(m，2H，CH
2CH)，1.50-1.35(m，1H，CH
2CH)；
19F-NMR(DMSO-d
6)δ：-74.12(s，1F)；MS?m/z(％)：255(M
+，26)，224(27)，153(100)。
Claims (7)
1, a kind of preparation method of the nucleosides of compound as shown in Equation 4 chlorination ammonium salt, it comprises that formula 3 compound 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine and Trimethylamine 99 ethanolic soln are at organic solvent
In react.
2, preparation method as claimed in claim 1 is characterized in that described reaction may further comprise the steps: formula 3 compounds are dissolved in tetrahydrofuran (THF) and N, in the N-dimethylformamide mixed solvent, place-20～0 ℃ of salt ice-water baths, logical nitrogen protection; Get the Trimethylamine 99 ethanolic soln and dropwise add above-mentioned system, stirring reaction slowly rises to room temperature, and reaction is spent the night.
3, preparation method as claimed in claim 2 is characterized in that tetrahydrofuran (THF) and N in this mixed solvent, and the volume ratio of N-dimethylformamide is 2～5: 1.
4, preparation method as claimed in claim 2, wherein Trimethylamine 99 and alcoholic acid volume ratio are 1: 2 to it is characterized in that using Trimethylamine 99 ethanolic soln stable under the normal temperature.
5, preparation method as claimed in claim 1 is characterized in that these formula 3 compounds slough two by formula 2 compound 2-amino-6-chloro-9-(4-acetoxy-3-acetyl-o-methyl butyl) purine through hydrolysis
The ethanoyl reaction makes.
6, preparation method as claimed in claim 5, it is characterized in that described hydrolysis sloughs the reaction of two ethanoyl and may further comprise the steps: formula 2 compounds are dissolved in anhydrous tetrahydro furan, place under 0～20 ℃, the methyl alcohol and the water mixed solution that add salt of wormwood react.
7, the preparation method of a kind of formula 1 compound 2-amino-6-fluoro-9-(4-hydroxyl-3-methylol-butyl) purine, it comprises the steps:
1. as each described preparation method's preparation formula 4 compound nucleosides chlorination ammonium salts of claim 1～6;
2. formula 4 compounds are dissolved in N, the N-dimethylformamide adds anhydrous potassium fluoride, places 20～60 ℃ to carry out stirring reaction.
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