CN104231008B - The Regioselective synthesis of nucleoside medicine 5 ' bit amino acid esters - Google Patents

The Regioselective synthesis of nucleoside medicine 5 ' bit amino acid esters Download PDF

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CN104231008B
CN104231008B CN201310227397.3A CN201310227397A CN104231008B CN 104231008 B CN104231008 B CN 104231008B CN 201310227397 A CN201310227397 A CN 201310227397A CN 104231008 B CN104231008 B CN 104231008B
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许佑君
刘家安
梁爽
曾琴
冯德日
王妍妍
辛海龙
何仲贵
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Shenyang Pharmaceutical University
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Abstract

The present invention relates to the Regioselective synthesis of nucleoside medicine 5' bit amino acid esters as shown in formula I for the architectural feature and its pharmaceutically acceptable salt.Wherein Base, R, R2, R3As description definition, the method is by using triaryl methyl (Ar3C) optionally protect nucleoside medicine 5' position hydroxyl; then utilize allyloxycarbonyl (allyloxycarbonyl; AOC remaining all avtive spot in nucleoside medicine base portion and sugared structure division) are protected; acid lower selectively removing triaryl methyl again; and then the amino acid condensation with Boc protection, the 5' position in nucleoside medicine molecule optionally become ester; and then palladium chtalyst removing AOC, removes Boc under acid condition and becomes corresponding salt.The method of the present invention has high income, and products therefrom is easily isolated purification, more suitable for the advantage of industrialized production.

Description

The Regioselective synthesis of nucleoside medicine 5 '-bit amino acid esters
Technical field
The invention belongs to pharmaceutical technology field, it is related to the ucleosides using triaryl methyl and allyloxycarbonyl Preservation tactics The Regioselective synthesis of medicine 5'- bit amino acid esters.
Background technology
Nucleoside medicine clinic is widely used in antiviral and antitumor etc., and this kind of medicine is former using bioisostere Reason, during DNA is synthesized, the structure of the metabolite such as required purine, pyrimidine is made trickle change and is obtained, i.e. antimetabolitases.It is administered it Afterwards, activate through intracellular triphosphoric acid process, intracellular three phosphorus are made by the relevant enzyme suppressing purine biosynthesis or pyrimidine nucleotide Interference cell duplication, the synthesis of competitive inhibition DNA in the synthesis imbalance of soda acid base Deoxydization nucleotide, incorporation DNA or RNA macromole Relevant enzyme etc. three class Main Function, the metabolism of specificity RNA, stop division and the breeding of cell, ultimately result in tumor thin Born of the same parents' death or suppressing virus replication.But because most nucleoside medicine polarity are big, membrane permeability is poor, metabolic stability is low former Because so that the oral administration biaavailability of such medicine is relatively low.For problem in this respect, the focus of research is using having spy at present Determine the aminoacid of space structure or parent drug modified by oligopeptide, make peptide transporter (The Peptide Transporter1, PepT1) targeting prodrug, to improve the transhipment of its film, and then improves its oral administration biaavailability.Become Such prodrug of work(listing has：Valaciclovir (Valaciclovir), valganciclovir (Valganciclovir), its oral life Thing availability brings up to 55% and 61% by original 10%～20% and 6% respectively.
He Zhonggui et al. (Molecular Pharmaceutics, 2009,6 (1), 315～325) utilizes benzyl chloroformate (carbobenzyloxy chloride, Cbz-Cl) selective protection cytosine arabinoside (cytarabine, Arainosylcytosine, ara-C) 4- bit amino, the aminoacid then protected with tertiary fourth oxygen formoxyl (Boc) is in carbonyl diurethane It is condensed into ester under imidazoles (CDI) catalysis, recycle palladium carbon (Pd/C) catalytic hydrogenation to slough the Cbz blocking group of 4- bit amino, Last removing Boc hydrochloric acid salt in acid condition, have synthesized a series of cytosine arabinoside 5'- amino acids esters derivative (CN101250209).But in this route, first, protect reaction selectivity during 4- bit amino poor using Cbz, produce more By-product, must be isolated and purified by column chromatography, operation inconvenience, and yield is relatively low；Secondly, with Boc protected amino acid acyl Chemical conversion ester when, in cytosine arabinoside molecule sugar three hydroxyls reaction selectivity poor, by-product is more, except generate required for Outside the monoesters of 5'- position, also the position isomer 3'- position monoesters of similar quantity generates simultaneously, both Rf value bases on silica gel plate This is consistent, and common silica gel chromatography is difficult to be isolated, and can only obtain a small amount of sample by preparation liquid phase separation, thus cannot expire The preparation of foot a large amount of samples needed for furtheing investigate, is more not suitable for industrialized production (as shown in Scheme1).
Gallop, M.A. et al. (WO2004041203) utilize trim,ethylchlorosilane (trimethyl chlorosilane, TMSCl) protection gemcitabine (gemcitabine) 4- bit amino and 3', 5'- position hydroxyl, then utilize 1- (allyloxy carbon oxygen Base) -1H- benzotriazole (allyl1-benzotriazolyl carbonate, AOC-OBt) optionally protects its 4- position ammonia Base, then the aminoacid of selectively removing TMS and Boc protection in acid condition is in 4-dimethylaminopyridine (4- Dimethylaminopyridine, DMAP), dicyclohexylcarbodiimide (dicyclohexylcarbodiimide, DCC) make With under be condensed into ester, then palladium chtalyst removing allyloxycarbonyl, finally acid lower remove Boc hydrochloric acid salt, having synthesized one is Row gemcitabine 5'- amino acids esters derivative.Similar to the synthetic route of the cytosine arabinoside amino-acid ester of Sun Yongbing etc., its Also exist during being condensed into ester and be difficult to control to the selectively producing thus effectively stoping 3'- position isomer of 5'- position monoesters Generate, not only yield is low and extremely difficult isolates and purifies it is impossible to meet the preparation (as shown in Scheme2) of a large amount of samples.
The selective problems occurring when Scheme2. through Gallop method synthesizing gemcitabine 5'- bit amino acid esters
In sum, the synthetic route of this kind of nucleoside medicine 5'- amino acid ester prodrugs of report, due to dividing to nucleoside Multiple not electing property of hydroxyl protections of sugar in son, while producing 5'- bit amino acid esters when becoming ester reaction, also with appreciable amount 3'- position position isomer it is difficult to isolate and purify, be not suitable for industrialized production.Therefore, for this kind of nucleoside medicine 5'- ammonia The selective synthesizing achievement of base acid esters seems very necessary.
Content of the invention
The technical problem to be solved is to provide a kind of regioselectivity of nucleoside medicine 5'- bit amino acid esters Synthetic method.
The present invention is achieved through the following technical solutions：
Using triaryl methyl (Ar3C-) optionally protect nucleoside medicine 5'- position hydroxyl, then utilize allyl oxygen carbonyl Remaining all active sites in nucleoside medicine base portion and sugared structure division protected by base (allyloxycarbonyl, AOC) Point, more acid lower selectively removing triaryl methyl, so the amino acid condensation with Boc protection, in nucleoside medicine molecule 5'- position optionally become ester, then palladium chtalyst removing AOC, removing Boc become corresponding salt under acid condition.
Concrete reactions steps are as follows：
(1) formula VII becomes ether that formula VI is obtained with triaryl methyl reagent；
(2) formula VI and the condensation of allyloxycarbonyl reagent are obtained formula V；
(3) triarylmethyl protecting group group in selectively removing 5'- position is obtained formula IV to formula V in acid condition；
(4) a-amino acid that formula IV is protected with corresponding Boc is condensed into ester and general formula III is obtained；
(5) general formula III removes all of AOC protection group under homogeneous palladium catalytic condition and formula II is obtained；
(6) formula II removes all of AOC protection group under homogeneous palladium catalytic condition and formula I is obtained.
Wherein：
Formula I～VII structural formula is respectively：
Wherein, base Base part be natural pyrimidine base base class, purine base base class or their structural modification base Class, the corresponding base nucleosides of base Base are cytosine arabinoside (Cytarabine), gemcitabine (Gemcitabine), arabinose gland Glycosides (Vidarabine), PSI 6130, agent clofarabine (Clofarabine), Thiarabine, triciribine (Triciribine)；X is carbon atom, oxygen or sulphur atom；R2Or R3For hydrogen atom, hydroxyl, halogen atom, azido, methyl or Trifluoromethyl, and existed with the arbitrary configuration in R- type or S- type, R2Or R3Can also be double halogen atoms such as double fluorine atom, fluorine chlorine Atom or the combination in any for above two atom or atomic group；RCH (the NH of 5'- position2) COO- ester bond part aminoacid Come from various natural or engineered a-amino acid RCH (NH2) COOH, wherein aminoacid is glycine, alanine, figured silk fabrics ammonia Acid, leucine, isoleucine, Phenylalanine, proline, Gamma Amino Butyric Acid, and existed with L-type, D- type or racemate form.
According to this method for selective synthesis, obtain 5'- bit amino acid esters and its pharmaceutical salts of base nucleosides, preferably PSI- 6130 5'- bit amino acid esters dihydrochloride.
In step (1), described triaryl methyl reagent is trityl chloride (Triphenylmethyl Chloride, TrCl), trifluoromethanesulfonic acid three benzene methyl (Triphenylmethyl triflate TrOTf), two (to methoxy benzene Base) phenyl methyl chlorine (4,4'-Dimethoxytrityl Chloride, DMTr-Cl), three p-methoxyphenyl methyl chlorides (4,4', 4''-trimethoxytrityl Chloride, TMTr-Cl), preferably trityl chloride (Triphenylmethyl chloride,TrCl)；Reaction dissolvent is pyridine, dichloromethane, dichloroethanes, chloroform, benzene,toluene,xylene, chlorobenzene, tetrahydrochysene Furan, 2- methyltetrahydrofuran, 1,2- dimethoxy-ethane, DMF, N,N-dimethylacetamide, or above-mentioned The various combination of solvent；Reaction organic base used is pyridine, dimethylamino naphthyridine, triethylamine, diisopropyl ethyl amine, N, N- Dimethylaniline, or inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide；This reaction Temperature is -20 °C～solvent reflux temperature；Response time is different regarding concrete substrate difference.
In step (2), described allyloxycarbonyl reagent is 1- allyloxycarbonyl tetrazolium (1- (Allyloxycarbonyl) tetrazole, AOC-Tet), 1- (allyloxy carbon epoxide) -1H- benzotriazole (allyl1- Benzotriazolyl carbonate, AOC-OBt), allyl chlorocarbonate (allyl chloroformate, AOC-Cl), excellent Select allyl chlorocarbonate (allyl chloroformate, AOC-Cl)；Reaction dissolvent be dichloromethane, dichloroethanes, chloroform, Benzene,toluene,xylene, chlorobenzene, oxolane, 2- methyltetrahydrofuran, 1,2- dimethoxy-ethane, N, N- dimethyl formyl Amine, N,N-dimethylacetamide, or the various combination of above-mentioned solvent；Reaction organic base used is dimethylamino naphthyridine, three second Amine, diisopropyl ethyl amine, DMA, pyridine, or inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, bicarbonate Potassium, sodium hydroxide, potassium hydroxide；This reaction temperature is -20 °C～solvent reflux temperature；Response time is regarding concrete substrate difference Different.
In step (3), described acid is hydrogen chloride, formic acid, glacial acetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid, and described acid is preferably Hydrogen chloride；The solvent that this reaction is selected is selected from the alcohols of 1～6 carbon such as methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, different The various combination of butanol, the tert-butyl alcohol or these solvents, or ethereal solvent for example ether, methyl tertiary butyl ether(MTBE), Di Iso Propyl Ether, Oxolane, 2- methyltetrahydrofuran, the various combination of 1,2- dimethoxy-ethane, Isosorbide-5-Nitrae-dioxane or these solvents, or Person's esters solvent such as methyl acetate, ethyl acetate, butyl acetate, or be water, or the various combination of above-mentioned solvent；This reaction temperature Spend for -20 °C～solvent reflux temperature；Response time is different regarding concrete substrate difference.
In step (4), described reaction condensing agent is selected from N, N'- dicyclohexylcarbodiimide (DCC), 1- ethyl -3- (3- Dimethylamine propyl) carbodiimide hydrochloride (EDCI), carbonyl dimidazoles (CDI), 2- (7- azo BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), 2- (7- azo BTA)-tetramethylurea hexafluorophosphoric acid ester (HBTU), 1- Hydroxyl -7- azo BTA (HOAt), I-hydroxybenzotriazole (HOBt), the preferred EDCI of described condensing agent；Catalyst selects From DMAP (DMAP), pyridine, triethylamine, diisopropylethylamine；This reaction dissolvent is selected from dichloromethane, two chloroethenes Alkane, chloroform, benzene,toluene,xylene, chlorobenzene, oxolane, 2- methyltetrahydrofuran, 1,2- dimethoxy-ethane, 1,4- dioxy Six rings, DMF, N,N-dimethylacetamide, or the various combination of above-mentioned solvent；This reaction temperature is at -20 °C Carry out under～solvent reflux temperature, preferably 0～45 °C；Response time is different regarding concrete substrate difference.
In step (5), available palladium catalyst is tetrakis triphenylphosphine palladium [Pd (PPh3)4], Palladous chloride. (PdCl2), vinegar Sour palladium [Pd (OAc)2], three (dibenzalacetone) two palladium [Pd2(dba)3·CHCl3], described palladium catalyst preferably four (triphen Base phosphine) palladium；For increasing the stability of palladium catalyst, above-mentioned catalyst is combined coordination with organophosphine ligand；This reaction is selected Neutrality or faintly acid nucleopilic reagent be 1,1-Dimethyl-3,5-diketocyclohexane (Dimedone), 1,3- dimethyl barbituric acid (NDMBA), formic acid, acetic acid, Mixture [ammonium formate (the HCOO of primary amine, secondary amine and formic acid or carbonic acid-NH4 +), formic acid positive fourth ammonium (HCOOH/n-BuNH2), formic acid Diethyl ammonium (HCOOH/Et2NH), carbonic acid diethyl ammonium [(Et2NH2 +)2CO3 2-], bicarbonate diethyl ammonium (Et2NH2 +HCO3 -)], described The preferred formic acid of nucleopilic reagent positive fourth ammonium (HCOOH/n-BuNH2)；The available solvent of this reaction is selected from dichloromethane, 1,2- dichloro Ethane, chloroform, ether, methyl tertiary butyl ether(MTBE), Di Iso Propyl Ether, oxolane, 2- methyltetrahydrofuran, 1,2- dimethoxy second The various combination of alkane, Isosorbide-5-Nitrae-dioxane or above-mentioned solvent, the preferred oxolane of described solvent；This reaction temperature be -20 °C～ Solvent reflux temperature, preferably 0～45 °C.
The reaction equation of step (6) is：
For clarity, when Base is for cytosine arabinoside, formula I～corresponding structure of VII is respectively I1～VII1, specifically As follows.
The method of the present invention has high income, and products therefrom is easily isolated purification, more suitable for the advantage of industrialized production.
Specific embodiment
The following example that is embodied as is for more completely the present invention being described, being not meant to limit by any way as power The scope of the present invention defined in profit requirement.
Embodiment 1:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method one
Step 1：Under argon protection, cold water cooling, trityl chloride 256.5g (0.92mol) is added slowly to cytosine arabinoside (VII1) 194.6g (0.80mol) and anhydrous pyridine 1500mL mixed liquor in, notes being sufficiently stirred for reaction by mechanical agitation System, controls charging rate so that the material of addition is gradually dispersed or dissolved in system.Finish, after continuing stirring 2h, more slowly It is warming up to 30 °C and continues to react 20h, TLC detection reaction finishes.
The pyridine that concentrating under reduced pressure is tried one's best in recovery reaction system, then add dehydrated alcohol 300mL fully to divide in residue Scattered content.This mixture is slowly inclined to frozen water 5.0L, quick stirring ice solution, separate out white solid.
Sucking filtration, washing, it is dried, obtain faint yellow crude product 480.5g.By crude product with ethyl acetate 1000mL recrystallization, sucking filtration, White solid is gradually separated out after filtrate cooling.Stand overnight, sucking filtration, be dried, obtain white solid (VI1) 462.2g, yield 95.2%, m.p.210～213 °C.
1H NMR(d6-DMSO)δ3.15(m,2H,5’-CH2),3.81(m,1H,4'-CH2),3.84(m,1H,2'-CH), 3.88(m,1H,3'-CH),5.32(d,1H,3'-OH),5.41(d,H,2'-OH),5.55(d,1H,J=7.4Hz,5-CH), 6.05(d,1H,1'-H),7.00(s,2H,4-NH2),7.30(m,15H,Ph3),7.42(d,1H,J=7.4Hz,6-CH);
ESI-MS(m/z):486.2[M+H]+,508.3[M+Na]+,524.2[M+K]+.
Step 2：Under argon protection, the DME500mL solution of allyl chlorocarbonate 211.4mL (2.0mol) is slowly added dropwise To compound VI1In 242.8g (0.5mol), sodium hydroxide 100.0g (2.5mol) and anhydrous DME1000mL mixed liquor, process In need Quick mechanical to stir and control interior temperature in -5～0 °C, about need 3.0h completion of dropping.Slowly reaction system is risen to room Temperature simultaneously continues stirring reaction 4.0h, and TLC detection reaction finishes.
Sucking filtration, concentrating under reduced pressure mother solution.Residue is successively with ethyl acetate 600mL and cold water 400mL dispersed with stirring, standing point Layer.Divide and take organic layer, water layer is extracted with ethyl acetate (300mL × 2), merge organic layer, saturated aqueous common salt (500mL × 2) is washed, Anhydrous sodium sulfate drying.Filter, filtrate reduced in volume is extremely dry, more abundant drying under reduced pressure, obtain off-white powder (V1)297.0g.Slightly The mixing solvent recrystallization through ethyl acetate and petroleum ether for the product, obtains white solid 169.6g, yield 73.1%, m.p.155～158 ° C.
1H NMR(d6-DMSO)δ3.35(m,2H,5'-CH2),4.25(q,1H,4'-CH),4.48(t,2H,CH2-CH- CH2),4.60(t,4H,CH2-CH-CH2), 5.21 (m, 1H, 2'-CH), 5.19～5.37 (m, 6H, CH2-CH-CH2),5.44(m, 1H,3'-CH),5.80(m,3H,CHCH2),6.23(d,1H,1'-CH),6.93(d,1H,J=7.5Hz,5-CH),7.30(m, 15H,Ph3),7.91(d,1H,J=7.5Hz,6-CH),10.84(s,1H,4-NH);
ESI-MS(m/z):738.3[M+H]+,760.3[M+Na]+,776.3[M+K]+.
Step 3：0～5 °C, argon protection under, by compound V1About 147.5g (0.20mol) adds to hydrogen chloride ethyl acetate In solution (2.0mol/L) 500mL, note stirring while adding.Carry out with reaction, gradually separate out white solid, TLC detection is aobvious Show that about 2.0h reaction terminates.
Sucking filtration, ethyl acetate is washed, drying under reduced pressure, obtains white solid 75.4g.Add frozen water 500mL in mother solution, with saturation Na2CO3Solution adjusts pH7, stands after being sufficiently stirred for, and divides and takes organic layer, and water layer is extracted with ethyl acetate 200mL again.Merge organic Layer, saturated aqueous common salt (200mL × 2) is washed, anhydrous sodium sulfate drying.Filter, be evaporated to appearance muddiness, and be stirred overnight, Separate out white solid, sucking filtration, drying under reduced pressure again, obtain 23.7g.Gained solid (IV twice1) add up total recovery：89.4%, M.p.69～73 °C.
1H NMR(d6-DMSO)δ3.68(d,2H,5'-CH2),4.14(d,1H,4'-CH),4.50(t,2H,CH2-CH- CH2),4.64(t,4H,CH2-CH-CH2), 5.21 (m, 1H, 2 '-CH), 5.15～5.42 (m, 6H, CH2-CH-CH2),5.32(s, 1H,5'-OH)5.45(m,1H,3'-CH),5.90(m,3H,CHCH2),6.23(d,1H,1'-CH),7.06(d,1H,J= 7.5Hz,5-CH),8.18(d,1H,J=7.5Hz,6-CH),10.84(s,1H,4-NH);
ESI-MS(m/z):496.2[M+H]+,518.2[M+Na]+,534.2[M+K]+.
Step 4：Under ice-water bath, argon protection, EDCI41.3g (0.20mol) is added slowly to compound IV149.5g (0.10mol), Boc protection L-Valine 26.1g (0.12mol), DMAP1.2g (0.01mol) and anhydrous methylene chloride 300mL Mixed liquor in, note control charging rate and control reaction interior temperature be less than 10 °C.Finish, slowly reaction system is risen to Room temperature, continues reaction about 2.0h, and TLC detection reaction finishes.
Add frozen water 300mL, be sufficiently stirred for rear stratification, divide and take organic layer, water layer is with dichloromethane (150mL × 2) Extraction, merges organic layer, successively with 1.0mol/L hydrochloric acid solution (150mL × 2), saturated sodium carbonate solution (200mL), saturation food Saline (200mL) is washed, anhydrous sodium sulfate drying.Filter, filtrate reduced in volume, to dry, drying under reduced pressure, obtains white solid (III1) 64.0g, yield 92.1%, m.p.149～151 °C.
1H NMR(d6-DMSO)δ0.83(d,6H,(CH3)2CH),1.35(s,9H,(CH3)3C),1.98(t,1H,CH (CH3)2),3.86(t,1H,CH(CH3)2), 4.28～4.38 (d, 2H, 5'-CH2),4.41(d,1H,4'-CH),4.48(t,2H, CH2-CH-CH2),4.61(t,4H,CH2-CH-CH2), 5.12 (m, 1H, 2'-CH), 5.19～5.36 (m, 6H, CH2-CH-CH2), 5.42(t,1H,3’-CH),5.80(m,3H,CHCH2),6.26(d,1H,1'-CH),7.07(d,1H,J=7.5Hz,5-CH), 7.15(d,1H,NH-CH),7.98(d,1H,J=7.5Hz,6-CH),10.83(s,1H,4-NH);
ESI-MS(m/z):693.1[M+H]+.
Step 5：Under argon protection, when -50 °C about, tetrakis triphenylphosphine palladium 1.15g (5.0mol%) is added to chemical combination Thing III113.89g (0.02mol), anhydrous formic acid 4.49mL (0.12mol), n-butylamine 11.70mL (0.12mol) and anhydrous four In hydrogen furan 200mL mixed liquor.Finish, argon is repeatedly replaced with the air in exclusion system by reduced vacuum, then slowly It is warmed to room temperature reaction, react after TLC detection display stirring reaction 4.0h and terminate.
Concentrating under reduced pressure reactant liquor, residue is successively with dichloromethane 100mL and cold water 100mL dispersed with stirring, stratification. Divide and take organic layer, water layer is extracted with dichloromethane (40mL × 2), merge organic layer.With 1.0mol/L hydrochloric acid solution (80mL × 2) By product back extraction to water layer.Water layer is sufficiently stirred for ethyl acetate (100mL), adjusts standing point after pH7 with saturated sodium carbonate solution Layer, divides and takes organic layer, with ethyl acetate 100mL aqueous layer extracted.Merge organic layer, saturated aqueous common salt (200mL × 2) is washed, anhydrous Sodium sulfate is dried.Filter, filtrate reduced in volume, to dry, obtains pale solid 7.20g.Crude product, through oxolane recrystallization, obtains white Color solid (II1) 6.50g, yield 73.9%, m.p.168～172 °C.
1H NMR(d6-DMSO)δ0.84(d,6H,(CH3)2CH),1.34(s,9H,(CH3)3C),1.97(m,1H,CH (CH3)2), 3.85(m,2H,5'-CH2),3,91(m,1H,2'-CH),3.94(m,1H,CH-NH),4.13(q,1H,3'-CH), 4.35(q,1H,4'-CH),5.55(t,2H,2'-OH,3'-OH),5.60(d,1H,J=7.5Hz,5-CH),6.05(d,1H,1'- CH),6.98(d,2H,4-NH2),7.11(d,1H,NH-CH),7.42(d,1H,J=7.5Hz,6-CH);
13C NMR(d6-DMSO)δ18.78(CH3-CH),19.38(CH3-CH),28.68((CH3)3-C),30.14(CH- CH3),59.83(CH-NH),64.72(C-5'),74.64(C-3'),77.20(C-2'),78.71(C-(CH3)3),82.37(C- 4'),86.91(C-5),92.92(C-1'),143.23(C-6),155.54(C-2),156.23(CONH),166.08(C-4), 172.47(COO);
ESI-MS(m/z):443.3[M+H]+,465.3[M+Na]+,481.2[M+K]+.
Step 6：Under argon protection, when 0～5 °C, by compound II122.1g (0.05mol) adds to hydrogen chloride ethyl acetate In solution (2.0mol/L) 100mL, note stirring while adding.Finish, slowly reaction system be warmed to room temperature, with react into OK, gradually separate out white solid.About 4.0h reaction finishes.
Sucking filtration, ethyl acetate is washed, drying under reduced pressure, obtains white solid (I1a) 19.2g, purity 98.65%, m.p.225～228 ° C, yield 92.5%.
1H NMR(d6-DMSO)δ0.94(q,6H,(CH3)2CH)),2.16(m,1H,CH(CH3)2),3.87(s,1H, CHNH),3.97(m,2H,5'-CH2),4.05(m,1H,2'-CH)4.31(q,1H,3'-CH),4.50(q,1H,4'-CH), 5.83(s,2H,2'-OH,3'-OH),6.01(d,1H,1'-CH),6.12(d,1H,J=7.5Hz,5-CH),7.79(d,1H,J= 7.5Hz,6-CH),8.56(s,2H,4-NH2),8.63(d,2H,NH2-CH);
13C NMR(d6-DMSO)δ17.92(CH3-CH),17.98(CH3-CH),29.82(CH-CH3),57.84(CH- NH),65.44(C-5'),74.44(C-3'),76.41(C-2'),83.61(C-4'),87.67(C-5),93.17(C-1'), 146.23(C-6),147.07(C-2),160.03(C-4),169.13(COO);
ESI-MS(m/z):343.3[M+H]+,365.3[M+Na]+,381.3[M+K]+.
Embodiment 2:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method two
EDCI is replaced with CDI, carries out the reaction of step 4 in embodiment 1, yield is 88.3%.According to the step in embodiment 1 Suddenly carry out remaining each step reaction prepare compound I1a, purity 98.78%.Six steps add up yield 36.2%.
Embodiment 3:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method three
EDCI is replaced with DCC, carries out the reaction of step 4 in embodiment 1, yield is 93.4%.According to the step in embodiment 1 Suddenly carry out remaining each step reaction prepare compound I1a, purity 98.56%.Six steps add up yield 37.6%.
Embodiment 4:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method four
With PdCl2Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out the anti-of step 5 in embodiment 1 Should, yield is 70.1%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11a, purity 98.40%.Six The accumulative yield 35.2% of step.
Embodiment 5:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method five
With Pd (OAc)2Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out step 5 in embodiment 1 Reaction, yield be 66.9%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11a, purity 98.73%.Six steps add up yield 32.8%.
Embodiment 6:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method six
With Pd2(dba)3·CHCl3Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out embodiment 1 The reaction of middle step 5, yield is 63.8%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11a, pure Degree 98.36%.Six steps add up yield 32.4%.
Embodiment 7:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method seven
HCOOH/n-BuNH is replaced with Dimedone2, carry out the reaction of step 5 in embodiment 1, yield is 68.2%.According to Step in embodiment 1 carries out remaining each step reaction prepare compound I1a, purity 98.69%.Six steps add up yield 32.6%.
Embodiment 8:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method eight
HCOOH/n-BuNH is replaced with NDMBA2, carry out the reaction of step 5 in embodiment 1, yield is 67.2%.According to reality Apply the step in example 1 and carry out remaining each step reaction prepare compound I1a, purity 98.47%.Six steps add up yield 31.5%.
Embodiment 9:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-phonetic Piperidinyl] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method nine
With HCOOH/Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 66.7%.Press Carry out remaining each step reaction prepare compound I according to the step in embodiment 11a, purity 98.77%.Six steps add up yield 33.9%.
Embodiment 10:S-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Valine ester, I1a) preparation method Ten
With HCOOH/Et3N replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 67.4%.Press Carry out remaining each step reaction prepare compound I according to the step in embodiment 11a, purity 98.68%.Six steps add up yield 34.2%.
Embodiment 11:R-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-Val ester, I1b) preparation method One
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 1, yield is 92.2%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11b, obtain white solid 10.4g, purity 99.02%, m.p.212～215 °C.Six steps add up yield 35.2%.
1H NMR(d6-DMSO)δ0.95(q,6H,(CH3)2CH)),2.16(m,1H,CH(CH3)2),3.86(s,1H, CHNH),4.00(m,2H,5'-CH2),4.07(m,1H,2'-CH),4.35(q,1H,3'-CH),4.40(q,1H,4'-CH), 5.86(s,2H,2'-OH,3'-OH),6.00(d,1H,1'-CH),6.17(d,1H,J=7.8Hz,5-CH),7.79(d,1H,J= 7.8Hz,6-CH),8.62(s,2H,4-NH2),8.71(d,2H,NH2-CH);
13C NMR(d6-DMSO)δ18.02(CH3-CH),18.86(CH3-CH),29.85(CH-CH3),57.74(CH- NH),65.62(C-5'),74.61(C-3'),76.51(C-2'),83.20(C-4'),87.82(C-5),93.35(C-1'), 146.40(C-6),147.39(C-2),160.00(C-4),169.22(COO);
ESI-MS(m/z):343.3[M+H]+,365.3[M+Na]+,381.3[M+K]+.
Embodiment 12:R-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-Val ester, I1b) preparation method Two
Replace Boc protection L-Valine, DCC to replace EDCI with Boc protection D-Val, carry out step 4 in embodiment 1 Reaction, yield is 90.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11b, purity 98.86%. Six steps add up yield 34.8%.
Embodiment 13:R-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-Val ester, I1b) preparation method Three
Replace Boc protection L-Valine, HATU to replace EDCI with Boc protection D-Val, carry out step 4 in embodiment 1 Reaction, yield be 88.4%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11b, purity 98.25%.Six steps add up yield 32.2%.
Embodiment 14:R-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-Val ester, I1b) preparation method Four
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 1.And with PdCl2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 1, yield For 69.5%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11b, purity 98.10%.Six steps add up to receive Rate 33.0%.
Embodiment 15:R-2- amino -3 Methylbutanoic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-Val ester, I1b) preparation method Five
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 1.And with HCOO NH4 +Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 68.2%.According in embodiment 1 Step carry out remaining each step reaction prepare compound I1b, purity 98.68%.Six steps add up yield 34.2%.
Embodiment 16:S-2- alanine 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Alanine ester, I1c) preparation method one
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 1, yield is 90.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11c, obtain white solid 8.9g, purity 98.93%, m.p.203～207 °C.Six steps add up yield 37.6%.
1H NMR(d6-DMSO)δ1.39(d,3H,CH3-CH),3.96(s,1H,CHNH),4.05(m,2H,5'-CH2), 4.11(m,1H,2'-CH),4.32(q,1H,3'-CH),4.43(q,1H,4'-CH),5.81(s,2H,2'-OH,3'-OH), 6.00(d,1H,1'-CH),6.13(d,1H,J=7.6Hz,5-CH),7.77(d,1H,J=7.6Hz,6-CH),8.55(s,2H,4- NH2),8.60(d,2H,NH2-CH);
13C NMR(d6-DMSO)δ16.15(CH3-CH),48.38(CH-CH3),65.50(C-5'),74.66(C-3'), 76.44(C-2'),83.18(C-4'),87.55(C-5),93.34(C-1'),146.26(C-6),147.58(C-2),160.15 (C-4),170.36(COO);
ESI-MS(m/z):315.3[M+H]+,337.2[M+Na]+,353.2[M+K]+.
Embodiment 17:S-2- alanine 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Alanine ester, I1c) preparation method two
Replace Boc protection L-Valine, CDI to replace EDCI with Boc protection L-Alanine, carry out step 4 in embodiment 1 Reaction, yield is 85.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11c, purity 98.59%. Six steps add up yield 36.4%.
Embodiment 18:S-2- alanine 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Alanine ester, I1c) preparation method three
Replace Boc protection L-Valine, HBTU to replace EDCI with Boc protection L-Alanine, carry out step 4 in embodiment 1 Reaction, yield be 89.0%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11c, purity 98.23%.Six steps add up yield 31.6%.
Embodiment 19:S-2- alanine 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Alanine ester, I1c) preparation method four
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 1.And with Pd (OAc)2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 1, yield For 68.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11c, purity 98.55%.Six steps add up to receive Rate 32.9%.
Embodiment 20:S-2- alanine 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Alanine ester, I1c) preparation method five
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 1.And with (Et2NH2 +)2CO3 2Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 69.3%.According to enforcement Step in example 1 carries out remaining each step reaction prepare compound I1c, purity 98.22%.Six steps add up yield 34.1%.
Embodiment 21:S-2- amino -4- methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Leu ester, I1d) preparation method One
Boc protection L-Valine is replaced with Boc protection L-Leu, carries out the reaction of step 4 in embodiment 1, yield is 92.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11d, obtain white solid 9.7g, purity 98.52%, m.p.203～207 °C.Six steps add up yield 35.4%.
1H NMR(d6-DMSO)δ0.86(q,6H,(CH3)2CH)),1.64(t,2H,CH2),1,75(m,1H,CH (CH3)2),3.92(s,1H,CHNH),4.00(m,2H,5'-CH2),4.06(m,1H,2'-CH),4.31(q,1H,3'-CH), 4.43(q,1H,4'-CH),5.86(s,2H,2'-OH,3'-OH),5.99(d,1H,1'-CH),6.17(d,1H,J=7.8Hz,5- CH),7.79(d,1H,J=7.8Hz,6-CH),8.66(s,2H,4-NH2),8.75(d,2H,NH2-CH);
13C NMR(d6-DMSO)δ22.44(CH3-CH2),22.67(CH3-CH2),24.22(CH-(CH3)2),40.24 (CH2-CHNH2),51.10(CH-NH),65.52(C-5'),74.57(C-3'),76.48(C-2'),83.36(C-4'),87.74 (C-5),93.24(C-1’),146.29(C-6),147.21(C-2),160.03(C-4),170.19(COO);
ESI-MS(m/z):357.3[M+H]+,379.2[M+Na]+,395.2[M+K]+.
Embodiment 22:S-2- amino -4- methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Leu ester, I1d) preparation method Two
Replace Boc protection L-Valine, HATU to replace EDCI with Boc protection L-Leu, carry out step 4 in embodiment 1 Reaction, yield be 87.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11d, purity 98.56%.Six steps add up yield 34.1%.
Embodiment 23:S-2- amino -4- methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Leu ester, I1d) preparation method Three
Replace Boc protection L-Valine, HOAt to replace EDCI with Boc protection L-Leu, carry out step 4 in embodiment 1 Reaction, yield be 85.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11d, purity 98.78%.Six steps add up yield 31.9%.
Embodiment 24:S-2- amino -4- methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Leu ester, I1d) preparation method Four
Boc protection L-Valine is replaced with Boc protection L-Leu, carries out the reaction of step 4 in embodiment 1.And with Pd2 (dba)3·CHCl3Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the anti-of step 5 in embodiment 1 Should, yield is 69.1%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11d, purity 98.63%.Six The accumulative yield 32.6% of step.
Embodiment 25:S-2- amino -4- methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Leu ester, I1d) preparation side Method five
Boc protection L-Valine is replaced with Boc protection L-Leu, carries out the reaction of step 4 in embodiment 1.And with Et2NH2 +HCO3Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 66.3%.According in embodiment 1 Step carry out remaining each step reaction prepare compound I1d, purity 98.67%.Six steps add up yield 34.9%.
Embodiment 26:S-2- amino -3 methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Isoleucine ester, I1e) preparation side Method one
Boc protection L-Valine is replaced with Boc protection L-Isoleucine, carries out the reaction of step 4 in embodiment 1, yield For 90.8%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11e, obtain white solid 8.8g, purity 99.01%, m.p.216～218 °C.Six steps add up yield 34.3%.
1H NMR(d6-DMSO)δ0.87(q,6H,CH3CH2,CH3CH),1.25(t,1H,CH2CH3),1.43(t,1H, CH2CH3),1.92(m,1H,CH3CH),3.91(s,1H,CHNH),4.00(m,2H,5'-CH2),4.07(m,1H,2'-CH), 4.29(q,1H,3'-CH),4.51(q,1H,4'-CH),5.80(s,1H,3'-OH),5.84(s,1H,2'-OH),6.01(d, 1H,1'-CH),6.10(d,1H,J=7.8Hz,5-CH),7.75(d,1H,J=7.8Hz,6-CH),8.60(s,2H,4-NH2), 8.60(s,2H,NH2-CH);
13C NMR(d6-DMSO)δ12.00(CH3-CH2),14.67(CH3-CH),25.84(CH2-CH3),36.38(CH- CH3),56.54(CH-NH),65.42(C-5'),74.45(C-3'),76.45(C-2'),83.62(C-4'),87.90(C-5), 93.15(C-1'),146.15(C-6),147.14(C-2),160.06(C-4),169.02(COO);
ESI-MS(m/z):357.3[M+H]+,379.2[M+Na]+,395.2[M+K]+.
Embodiment 27:S-2- amino -3 methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Isoleucine ester, I1e) preparation side Method two
Replace Boc protection L-Valine, HBTU to replace EDCI with Boc protection L-Isoleucine, carry out step in embodiment 1 4 reaction, yield is 86.1%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11e, purity 98.91%.Six steps add up yield 33.5%.
Embodiment 28:S-2- amino -3 methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Isoleucine ester, I1e) preparation side Method three
Replace Boc protection L-Valine, HOBt to replace EDCI with Boc protection L-Isoleucine, carry out step in embodiment 1 4 reaction, yield is 87.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11e, purity 98.46%.Six steps add up yield 32.9%.
Embodiment 29:S-2- amino -3 methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Isoleucine ester, I1e) preparation side Method four
Boc protection L-Valine is replaced with Boc protection L-Isoleucine, carries out the reaction of step 4 in embodiment 1.And with Dimedone replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 65.7%.According in embodiment 1 Step carry out remaining each step reaction prepare compound I1e, purity 98.38%.Six steps add up yield 30.9%.
Embodiment 30:S-2- amino -3 methylvaleric acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-Isoleucine ester, I1e) preparation side Method five
Boc protection L-Valine is replaced with Boc protection L-Isoleucine, carries out the reaction of step 4 in embodiment 1.And with HCOOH/Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 70.1%.According to embodiment 1 In step carry out remaining each step reaction prepare compound I1e, purity 98.28%.Six steps add up yield 32.6%.
Embodiment 31:S-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-phenylalanine ester, I1f) preparation side Method one
Boc protection L-Valine is replaced with Boc protection L- benzenpropanoic acid, carries out the reaction of step 4 in embodiment 1, yield is 92.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11f, obtain white solid 8.2g, purity 98.67%, m.p.200～203 °C.Six steps add up yield 38.7%.
1H NMR(d6-DMSO)δ3.13(q,2H,CH2Ph),3.92(s,1H,CHNH),3.99(m,2H,5'-CH2), 4.14(m,1H,2'-CH),4.28(q,1H,3'-CH),4.31(q,1H,4'-CH),5.82(s,2H,3'-OH,2'-OH), 5.99(d,1H,1'-CH),6.14(d,1H,J=7.8Hz,5-CH),7.26(m,5H,Ph),7.74(d,1H,J=7.8Hz,6- CH),8.68(s,2H,4-NH2),8.68(s,2H,NH2-CH);
13C NMR(d6-DMSO)δ36.22(CH-Ph),53.85(CH-NH),65.58(C-5'),74.59(C-3'), 76.44(C-2'),83.22(C-4'),87.70(C-5),93.30(C-1'),127.71,129.03,129.96,135.20 (Ph-CH),146.31(C-6),147.24(C-2),160.02(C-4),169.22(COO);
ESI-MS(m/z):391.3[M+H]+,413.3[M+Na]+.
Embodiment 32:S-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-phenylalanine ester, I1f) preparation side Method two
Replace Boc protection L-Valine, HATU to replace EDCI with Boc protection L-phenylalanine, carry out step in embodiment 1 4 reaction, yield is 86.9%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11f, purity 98.61%.Six steps add up yield 32.5%.
Embodiment 33:S-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-phenylalanine ester, I1f) preparation side Method three
Boc protection L-Valine is replaced with Boc protection L-phenylalanine, carries out the reaction of step 4 in embodiment 1.And with Et3N/HCOOH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 68.2%.According in embodiment 1 Step carry out remaining each step reaction prepare compound I1f, purity 98.53%.Six steps add up yield 34.0%.
Embodiment 34:S-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position L-phenylalanine ester, I1f) preparation side Method four
Boc protection L-Valine is replaced with Boc protection L-phenylalanine, carries out the reaction of step 4 in embodiment 1.And with NDMBA replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 64.7%.According to the step in embodiment 1 Suddenly carry out remaining each step reaction prepare compound I1f, purity 98.47%.Six steps add up yield 34.7%.
Embodiment 35:R-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-phenylalanine ester, I1g) preparation side Method one
Boc protection L-Valine is replaced with Boc protection D-phenylalanine, carries out the reaction of step 4 in embodiment 1, yield For 91.2%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11g, obtain white solid 8.2g, purity 98.49%, m.p.209～211 °C.Six steps add up yield 37.6%.
1H NMR(d6-DMSO)δ3.14(m,2H,CH2Ph),3.90(s,1H,CHNH),3.95(m,2H,5'-CH2), 4.15(m,1H,2'-CH),4.22(q,1H,3'-CH),4.35(q,1H,4'-CH),5.74(s,1H,3'-OH),5.80(s, 1H,2'-OH),5.98(d,1H,1'-CH),6.09(d,1H,J=7.8Hz,5-CH),7.25(m,5H,Ph),7.72(d,1H,J= 7.8Hz,6-CH),8.56(s,2H,4-NH2),8.72(s,2H,NH2-CH);
13C NMR(d6-DMSO)δ36.34(CH-Ph),53.81(CH-NH),65.63(C-5'),74.59(C-3'), 76.49(C-2'),82.94(C-4'),87.65(C-5),93.36(C-1'),127.74,129.07,129.90,135.14 (Ph-CH),146.09(C-6),148.31(C-2),160.75(C-4),169.32(COO);
ESI-MS(m/z):391.3[M+H]+,413.3[M+Na]+,429.2[M+K]+.
Embodiment 36:R-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-phenylalanine ester, I1g) preparation side Method two
Replace Boc protection L-Valine, HOAt to replace EDCI with Boc protection D-phenylalanine, carry out step in embodiment 1 4 reaction, yield is 87.1%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11g, purity 98.36%.Six steps add up yield 34.6%.
Embodiment 37:R-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-phenylalanine ester, I1g) preparation side Method three
Boc protection L-Valine is replaced with Boc protection D-phenylalanine, carries out the reaction of step 4 in embodiment 1.And with PdCl2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 1, yield For 64.7%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 11g, purity 98.69%.Six steps add up to receive Rate 33.6%.
Embodiment 38:R-2- amino -3- phenylpropionic acid 2- (2R, 3S, 4S, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -3,4- dihydroxytetrahydrofandn base } methyl ester hydrochloride (cytosine arabinoside 5'- position D-phenylalanine ester, I1g) preparation side Method four
Boc protection L-Valine is replaced with Boc protection D-phenylalanine, carries out the reaction of step 4 in embodiment 1.And with HCOOH/Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 69.9%.According to embodiment 1 In step carry out remaining each step reaction prepare compound I1g, purity 98.62%.Six steps add up yield 34.7%.
Embodiment 39:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method one
Step 1：Under argon protection, cold water cooling, trityl chloride 10.70g (38.37mmol) is added slowly to hydrochloric acid lucky His shore (VII of west2) 10.00g (33.37mmol) and anhydrous pyridine 100mL mixed liquor in, note being sufficiently stirred for reaction system, Charging rate is controlled so that the material of addition is gradually dispersed or dissolved in system.Finish, after continuing stirring 2h, then be to slowly warm up to 30 °C and continue react 20h, TLC detection reaction finish.
The pyridine that concentrating under reduced pressure is tried one's best in recovery reaction system, then add dehydrated alcohol 20mL fully dispersed in residue Content.This mixture is slowly inclined to frozen water 500mL, quick stirring ice solution, separate out white solid.
Sucking filtration, washing, it is dried, obtain faint yellow crude product 16.50g.By crude product with ethyl acetate 40mL recrystallization, sucking filtration, filter White solid is gradually separated out after liquid cooling.Stand overnight, sucking filtration, be dried, obtain white solid (VI2) 15.39g, yield 91.2%. M.p.267～269 °C
1H NMR(d6-DMSO)δ3.28(d,2H,5'-CH2),3.98(m,1H,3'-CH),4.28(q,1H,4'-CH), 5.63(d,1H,J=7.5Hz,5-CH),6.17(s,1H,3'-OH),6.33(d,1H,1'-H),7.21(s,2H,4-NH2), 7.37(m,15H,Ph3),7.62(d,1H,J=7.5Hz,6-CH);
ESI-MS(m/z):506.2[M+H]+,528.2[M+Na]+,544.2[M+K]+.
Step 2：Under argon protection, the dichloromethane 20mL solution of allyl chlorocarbonate 3.91mL (37.86mmol) is delayed Slowly drop to compound VI28.70g (17.21mmol), sodium hydroxide 2.38g (60.23mmol) and anhydrous methylene chloride 50mL In mixed liquor, during need quickly to stir and control interior temperature in -5～0 °C, about need 0.5h completion of dropping.Slowly by reactant System is warmed to room temperature and continues stirring reaction 4.0h, and TLC detection reaction finishes.
Add frozen water 80mL, be sufficiently stirred for rear stratification, divide and take organic layer, water layer is extracted with dichloromethane (40mL × 2) Take, merge organic layer, washed with saturated aqueous common salt (150mL × 2), anhydrous sodium sulfate drying.Filter, filtrate reduced in volume is extremely dry, Abundant drying under reduced pressure, obtains pale yellow waxy solid 11.32g again.The mixing solvent recrystallization through ethyl acetate and petroleum ether for the crude product, Obtain white solid (V2) 10.35g, yield 89.3%.M.p.140～142 °C.
1H NMR(d6-DMSO)δ3.42(m,2H,5'-CH2),4.40(q,1H,4'-CH),4.67(m,4H,CH2-CH- CH2), 5.23～5.38 (m, 4H, CH2-CH-CH2),5.42(m,1H,3'-CH),5.92(m,2H,CHCH2),6.30(m,1H, 1’-CH),7.04(d,1H,J=7.6Hz,5-CH),7.31(m,15H,Ph3),8.01(d,1H,J=7.6Hz,6-CH),11.04 (s,1H,4-NH);
ESI-MS(m/z):674.4[M+H]+,696.4[M+Na]+,712.3[M+K]+,672.2[M-H]-.
Step 3：0～5 °C, argon protection under, by compound V2It is molten that 6.76g (0.01mol) adds to hydrogen chloride ethyl acetate In liquid (2.0mol/L) 50mL, note stirring while adding.Carry out with reaction, gradually separate out white solid, TLC detects about 2.0h Reaction terminates.
Sucking filtration, ethyl acetate is washed, drying under reduced pressure, obtains white solid 2.95g.Add frozen water 20mL in mother solution, with saturation Na2CO3Solution adjusts pH7, stands after being sufficiently stirred for, and divides and takes organic layer, and water layer is extracted with ethyl acetate 50mL again.Merge organic layer, Saturated aqueous common salt (100mL × 2) is washed, anhydrous sodium sulfate drying.Filter, be evaporated to appearance muddiness, and be stirred overnight, again Separate out white solid, sucking filtration, drying under reduced pressure, obtain 0.88g.Gained solid (IV twice2) add up total recovery：88.6%.m.p.155 ～156 °C.
1H NMR(d6-DMSO)δ3.70(m,2H,5'-CH2),4.24(q,1H,4'-CH),4.62(m,4H,CH2-CH- CH2),5.19(s,1H,5'-OH),5.27(m,4H,CH2-CH-CH2),5.36(m,1H,3'-CH),5.91(m,2H,CHCH2), 6.26(t,1H,1'-CH),7.08(d,1H,J=7.6Hz,5-CH),8.12(d,1H,J=7.6Hz,6-CH),10.96(s,1H, 4-NH);
ESI-MS(m/z):432.1[M+H]+,454.1[M+Na]+,430.0[M-H]-.
Step 4：Under ice-water bath, argon protection, EDCI3.56g (18.55mmol) is added slowly to compound IV24.00g (9.27mmol), Boc protection L-Valine 2.22g (10.2mmol), DMAP0.12g (1.00mmol) and anhydrous methylene chloride In the mixed liquor of 40mL, note controlling charging rate and controlling reaction interior temperature to be less than 10 °C.Finish, slowly by reaction system It is warmed to room temperature, continues reaction about 2.0h, TLC detection reaction finishes.
Add frozen water 40mL, be sufficiently stirred for rear stratification, divide and take organic layer, water layer is extracted with dichloromethane (15mL × 2) Take, merge organic layer, successively with 1.0mol/L hydrochloric acid solution (50mL × 2), saturated sodium carbonate solution (50mL), saturated aqueous common salt (50mL) wash, anhydrous sodium sulfate drying.Filter, filtrate reduced in volume, to dry, drying under reduced pressure, obtains white solid (III2) 5.17g, Yield 88.4%.M.p.136～138 °C.
1H NMR(d6-DMSO)δ0.83(d,6H,(CH3)2CH),1.33(s,9H,(CH3)3C),1.96(t,1H,CH (CH3)2),3.82(t,1H,CH-NH),4.34(q,1H,4'-CH),4.50(d,2H,5'-CH2),4.63(q,4H,CH2-CH- CH2),5.25(m,4H,CH2-CH-CH2),5.36(t,1H,3'-CH),5.90(m,2H,CHCH2),6.31(t,1H,1'-CH), 7.14(d,1H,NH-CH),7.25(d,1H,J=8.0Hz,5-CH),8.00(d,1H,J=8.0Hz,6-CH),11.00(s,1H, 4-NH);
ESI-MS(m/z):631.2[M+H]+,653.2[M+Na]+,669.2[M+K]+.
Step 5：Under argon protection, when -50 °C about, tetrakis triphenylphosphine palladium 0.28g (5.0mol%) is added to chemical combination Thing III23.00g (4.76mmol), anhydrous formic acid 1.07mL (28.54mmol), n-butylamine 2.78mL (28.54mmol) and anhydrous In oxolane 60mL mixed liquor.Finish, argon is repeatedly replaced with the air in exclusion system by reduced vacuum, then slowly It is warmed to room temperature reaction, react after TLC detection display stirring reaction 6.0h and terminate.
Concentrating under reduced pressure reactant liquor, residue is successively with dichloromethane 40mL and cold water 50mL dispersed with stirring, stratification.Point Take organic layer, water layer is extracted with dichloromethane (30mL × 2), merge organic layer.Will with 1.0mol/L hydrochloric acid solution (50mL × 2) Product back extraction is to water layer.Water layer is sufficiently stirred for ethyl acetate (80mL), adjusts stratification after pH7 with saturated sodium carbonate solution, Divide and take organic layer, with ethyl acetate 80mL aqueous layer extracted.Merge organic layer, saturated aqueous common salt (150mL × 2) is washed, anhydrous slufuric acid Sodium is dried.Filter, filtrate reduced in volume, to dry, obtains pale solid 1.68g.Crude product, through oxolane recrystallization, obtains white solid Body (II2) 1.55g, yield 70.4%.M.p.151～153 °C.
1H NMR(d6-DMSO)δδ0.83(q,6H,(CH3)2CH),1.33(s,9H,(CH3)3C),1.96(m,1H,CH (CH3)2),3.82(t,1H,CH-NH),3.98(m,1H,3'-CH),4.20(m,1H,4'-CH),4.31(q,2H,5'-CH2), 5.76(d,1H,J=7.6Hz,5-CH),6.13(t,1H,1'-CH),6.42(d,1H,3'-OH),7.24(d,1H,NH-CH), 7.38(d,2H,4-NH2),7.47(d,1H,J=7.6Hz,6-CH);
ESI-MS(m/z):463.2[M+H]+,485.1[M+Na]+,501.1[M+K]+.
Step 6：Under argon protection, when 0～5 °C, by compound II21.55g (3.35mmol) adds to chlorination hydroacetic acid second In ester solution (2.0mol/L) 20mL, note stirring while adding.Finish, slowly reaction system be warmed to room temperature, with react into OK, gradually separate out white solid.About 4.0h reaction finishes.
Sucking filtration, ethyl acetate is washed, drying under reduced pressure, obtains white solid (I2a) 1.34g, purity 98.75%, m.p.230～232 ° C.Yield 91.8%.
1H NMR(d6-DMSO)δ0.93(q,6H,(CH3)2CH)),2.15(m,1H,CH(CH3)2),3.91(m,1H, CHNH2),4.13(m,1H,3'-CH),4.27(q,1H,4'-CH),4.46(q,2H,5'-CH2),6.12(t,1H,1'-CH), 6.19(d,1H,J=7.6Hz,5-CH),7.88(d,1H,J=7.6Hz,6-CH),8.60(s,2H,4-NH2),8.69(s,2H, NH2-CH);
ESI-MS(m/z):363.1[M+H]+,385.1[M+Na]+,401.1[M+K]+.
Embodiment 40:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method two
EDCI is replaced with CDI, carries out the reaction of step 4 in embodiment 39, yield is 89.6%.According in embodiment 39 Step carries out remaining each step reaction prepare compound I2a, purity 98.90%.Six steps add up yield 32.1%.
Embodiment 41:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method three
EDCI is replaced with DCC, carries out the reaction of step 4 in embodiment 39, yield is 91.3%.According in embodiment 39 Step carries out remaining each step reaction prepare compound I2a, purity 98.60%.Six steps add up yield 31.5%.
Embodiment 42:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method four
With PdCl2Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out step 5 in embodiment 39 Reaction, yield is 67.2%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, purity 98.42%. Six steps add up yield 31.0%.
Embodiment 43:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method five
With Pd (OAc)2Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out step 5 in embodiment 39 Reaction, yield be 66.8%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, purity 98.51%.Six steps add up yield 32.9%.
Embodiment 44:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method six
With Pd2(dba)3·CHCl3Replace Pd (PPh3)4, and add part PPh in reaction system3, carry out embodiment 39 The reaction of middle step 5, yield is 62.8%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, pure Degree 98.28%.Six steps add up yield 31.8%.
Embodiment 45:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method seven
HCOOH/n-BuNH is replaced with Dimedone2, carry out the reaction of step 5 in embodiment 39, yield is 64.9%.Press Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, purity 98.44%.Six steps add up yield 32.8%.
Embodiment 46:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method eight
HCOOH/n-BuNH is replaced with NDMBA2, carry out the reaction of step 5 in embodiment 39, yield is 65.9%.According to reality Apply the step in example 39 and carry out remaining each step reaction prepare compound I2a, purity 98.34%.Six steps add up yield 33.1%.
Embodiment 47:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method nine
With HCOOH/Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 68.6%. Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, purity 98.72%.Six steps add up yield 33.5%.
Embodiment 48:S-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Valine ester, I2a) preparation side Method ten
With HCOOH/Et3N replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 69.1%.Press Carry out remaining each step reaction prepare compound I according to the step in embodiment 392a, purity 98.92%.Six steps add up yield 32.2%.
Embodiment 49:R-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-Val ester, I2b) preparation side Method one
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 39, yield is 92.0%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392b, obtain white solid 1.52g, purity 98.71%, m.p.226～228 °C.Six steps add up yield 33.2%.
1H NMR(d6-DMSO)δ0.94(d,6H,(CH3)2CH)),2.16(m,1H,CH(CH3)2),3.92(s,1H, CHNH),4.10(m,1H,3'-CH),4.32(q,1H,4'-CH),4.47(m,2H,5'-CH2),6.13(t,1H,1'-CH), 6.18(d,1H,J=7.8Hz,5-CH),7.90(d,1H,J=7.8Hz,6-CH),8.58(s,2H,4-NH2),8.73(d,2H, NH2-CH);
ESI-MS(m/z):363.1[M+H]+,385.1[M+Na]+.
Embodiment 50:R-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-Val ester, I2b) preparation side Method two
Replace Boc protection L-Valine, DCC to replace EDCI with Boc protection D-Val, carry out step 4 in embodiment 39 Reaction, yield be 92.2%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392b, purity 98.65%.Six steps add up yield 35.2%.
Embodiment 51:R-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-Val ester, I2b) preparation side Method three
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 39.And with PdCl2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 39, yield For 66.9%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392b, purity 98.37%.Six steps add up Yield 34.0%.
Embodiment 52:R-2- amino -3 Methylbutanoic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-Val ester, I2b) preparation side Method four
Boc protection L-Valine is replaced with Boc protection D-Val, carries out the reaction of step 4 in embodiment 39.And with HCOO NH4 +Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 62.1%.According to embodiment 39 In step carry out remaining each step reaction prepare compound I2b, purity 98.62%.Six steps add up yield 32.4%.
Embodiment 53:S-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position L-Alanine ester, I2c) preparation method one
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 39, yield is 90.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392c, obtain white solid 1.15g, purity 98.50%, m.p.237～239 °C.Six steps add up yield 32.1%.
1H NMR(d6-DMSO)δ1.38(d,3H,CH3-CH),3.86(q,1H,CHNH),4.10(m,1H,3'-CH), 4.32(q,1H,4'-CH),4.47(m,2H,5'-CH2),6.13(t,1H,1'-CH),6.18(d,1H,J=7.6Hz,5-CH), 7.90(d,1H,J=7.6Hz,6-CH),8.58(s,2H,4-NH2),8.73(d,2H,NH2-CH);
ESI-MS(m/z):335.0[M+H]+,357.0[M+Na]+,372.9[M+K]+.
Embodiment 54:S-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position L-Alanine ester, I2c) preparation method two
Replace Boc protection L-Valine, CDI to replace EDCI with Boc protection L-Alanine, carry out step 4 in embodiment 39 Reaction, yield be 89.5%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392c, purity 98.85%.Six steps add up yield 36.7%.
Embodiment 55:S-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position L-Alanine ester, I2c) preparation method three
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 39.And with Pd (OAc)2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 39, receive Rate is 68.4%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392c, purity 98.70%.Six steps are tired out Rate of collecting 34.9%.
Embodiment 56:S-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position L-Alanine ester, I2c) preparation method four
Boc protection L-Valine is replaced with Boc protection L-Alanine, carries out the reaction of step 4 in embodiment 39.And with Et2NH2 +HCO3Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 68.1%.According to embodiment 39 In step carry out remaining each step reaction prepare compound I2c, purity 98.67%.Six steps add up yield 33.3%.
Embodiment 57:R-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position D-alanine ester, I2d) preparation method one
Boc protection L-Valine is replaced with Boc protection D-alanine, carries out the reaction of step 4 in embodiment 39, yield is 90.8%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392d, obtain white solid 1.22g, purity 98.42%, m.p.241～243 °C.Six steps add up yield 33.6%.
1H NMR(d6-DMSO)δ1.39(d,3H,CH3-CH),3.98(q,1H,CHNH2),4.12(m,1H,3'-CH), 4.34(q,1H,4'-CH),4.46(m,2H,5'-CH2),6.11(t,1H,1'-CH),6.20(d,1H,J=7.8Hz,5-CH), 7.99(d,1H,J=7.8Hz,6-CH),8.59(s,2H,4-NH2),8.77(s,2H,NH2-CH);
ESI-MS(m/z):335.1[M+H]+,357.1[M+Na]+,332.9[M-H]-,378.9[M+HCOO]-.
Embodiment 58:R-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position D-alanine ester, I2d) preparation method two
Replace Boc protection L-Valine, HATU to replace EDCI with Boc protection D-alanine, carry out step 4 in embodiment 39 Reaction, yield be 85.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392d, purity 98.69%.Six steps add up yield 33.9%.
Embodiment 59:R-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position D-alanine ester, I2d) preparation method three
Boc protection L-Valine is replaced with Boc protection D-alanine, carries out the reaction of step 4 in embodiment 39.And with Pd2(dba)3·CHCl3Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out step 5 in embodiment 39 Reaction, yield be 67.2%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392d, purity 98.64%.Six steps add up yield 33.7%.
Embodiment 60:R-2- alanine 2- (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4, The fluoro- 3- hydroxyl tetrahydrofuran base of 4- bis- } methyl ester hydrochloride (gemcitabine 5'- position D-alanine ester, I2d) preparation method four
Boc protection L-Valine is replaced with Boc protection D-alanine, carries out the reaction of step 4 in embodiment 39.And with (Et2NH2 +)2CO3 2Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 62.4%.According to enforcement Step in example 39 carries out remaining each step reaction prepare compound I2d, purity 98.51%.Six steps add up yield 32.0%.
Embodiment 61:S-2- amino -4- methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Leu ester, I2e) preparation side Method one
Boc protection L-Valine is replaced with Boc protection L-Leu, carries out the reaction of step 4 in embodiment 39, yield is 89.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392e, obtain white solid 1.18g, purity 98.89%, m.p.194～196 °C.Six steps add up yield 31.1%.
1H NMR(d6-DMSO)δ0.84(d,6H,(CH3)2CH)),1.62(t,2H,CH2),1,72(m,1H,CH (CH3)2),3.98(q,1H,CHNH2),4.11(m,1H,3'-CH),4.29(q,1H,4'-CH),4.46(m,2H,5'-CH2), 6.11(t,1H,1'-CH),6.18(d,1H,J=7.9Hz,5-CH),7.87(d,1H,J=7.9Hz,6-CH),8.59(s,2H,4- NH2),8.67(s,2H,NH2-CH);
ESI-MS(m/z):377.0[M+H]+,399.0[M+Na]+,415.0[M+K]+.
Embodiment 62:S-2- amino -4- methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Leu ester, I2e) preparation side Method two
Replace Boc protection L-Valine, HBTU to replace EDCI with Boc protection L-Leu, carry out step 4 in embodiment 39 Reaction, yield be 87.4%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392e, purity 98.29%.Six steps add up yield 32.7%.
Embodiment 63:S-2- amino -4- methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Leu ester, I2e) preparation side Method three
Boc protection L-Valine is replaced with Boc protection L-Leu, carries out the reaction of step 4 in embodiment 39.And with HCOOH/Et3N replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 65.0%.According to embodiment 39 In step carry out remaining each step reaction prepare compound I2e, purity 98.30%.Six steps add up yield 32.0%.
Embodiment 64:S-2- amino -3 methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Isoleucine ester, I2f) preparation Method one
Boc protection L-Valine is replaced with Boc protection L-Isoleucine, carries out the reaction of step 4 in embodiment 39, yield For 88.1%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392f, obtain white solid 1.02g, purity 98.46%, m.p.208～210 °C.Six steps add up yield 31.6%.
1H NMR(d6-DMSO)δ0.81(m,6H,CH3CH2,CH3CH),1.21(m,1H,CH2CH3),1.91(m,1H, CH3CH),3.94(q,1H,CHNH2),4.09(m,1H,3'-CH),4.26(q,1H,4'-CH),4.43(m,2H,5'-CH2), 6.10(t,1H,1'-CH),6.18(d,1H,J=7.7Hz,5-CH),7.84(d,1H,J=7.7Hz,6-CH),8.69(s,2H,4- NH2),8.69(s,2H,NH2-CH);
ESI-MS(m/z):377.1[M+H]+,399.1[M+Na]+.
Embodiment 65:S-2- amino -3 methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Isoleucine ester, I2f) preparation Method two
Replace Boc protection L-Valine, HOAt to replace EDCI with Boc protection L-Isoleucine, carry out step in embodiment 39 Rapid 4 reaction, yield is 82.9%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392f, purity 98.16%.Six steps add up yield 30.8%.
Embodiment 66:S-2- amino -3 methylvaleric acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-Isoleucine ester, I2f) preparation Method three
Boc protection L-Valine is replaced with Boc protection L-Isoleucine, carries out the reaction of step 4 in embodiment 39.And with HCOOH/Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 63.8%.According to embodiment Step in 39 carries out remaining each step reaction prepare compound I2f, purity 98.48%.Six steps add up yield 32.7%.
Embodiment 67:S-2- amino -3- phenylpropionic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-phenylalanine ester, I2g) preparation Method one
Boc protection L-Valine is replaced with Boc protection L-phenylalanine, carries out the reaction of step 4 in embodiment 39, yield For 90.4%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392g, obtain white solid 1.17g, purity 98.43%, m.p.242～244 °C.Six steps add up yield 33.4%.
1H NMR(d6-DMSO)δ3.12(q,2H,CH2Ph),4.01(m,1H,CHNH),4.09(m,1H,3'-CH),4.32 (m,2H,5'-CH2),4.44(q,1H,4'-CH),6.07(t,1H,1'-CH),6.20(d,1H,J=7.8Hz,5-CH),7.24 (m,5H,Ph),7.78(d,1H,J=7.8Hz,6-CH),8.68(s,2H,4-NH2),8.68(s,2H,NH2-CH);
ESI-MS(m/z):411.0[M+H]+,433.0[M+Na]+,449.0[M+K]+.
Embodiment 68:S-2- amino -3- phenylpropionic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position L-phenylalanine ester, I2g) preparation Method two
Replace Boc protection L-Valine, HOBt to replace EDCI with Boc protection L-phenylalanine, carry out step in embodiment 39 Rapid 4 reaction, yield is 82.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392g, purity 98.15%.Six steps add up yield 32.1%.
Embodiment 69:R-2- amino -3- phenylpropionic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-phenylalanine ester, I2h) preparation Method one
Boc protection L-Valine is replaced with Boc protection D-phenylalanine, carries out the reaction of step 4 in embodiment 39, yield For 89.9%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392h, obtain white solid 1.04g, purity 98.92%, m.p.233～235 °C.Six steps add up yield 34.9%.
1H NMR(d6-DMSO)δ3.12(q,2H,CH2Ph),3.91(m,1H,CHNH),4.23(m,1H,3'-CH),4.31 (m,2H,5'-CH2),4.37(q,1H,4'-CH),6.07(t,1H,1'-CH),6.14(d,1H,J=7.8Hz,5-CH),7.25 (m,5H,Ph),7.82(d,1H,J=7.8Hz,6-CH),8.66(s,2H,4-NH2),8.66(s,2H,NH2-CH);
ESI-MS(m/z):411.1[M+H]+,433.1[M+Na]+,449.0[M+K]+.
Embodiment 70:R-2- amino -3- phenylpropionic acid 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine Base] the fluoro- 3- hydroxyl tetrahydrofuran base of -4,4- two } methyl ester hydrochloride (gemcitabine 5'- position D-phenylalanine ester, I2h) preparation Method two
Boc protection L-Valine is replaced with Boc protection D-phenylalanine, carries out the reaction of step 4 in embodiment 39.And with NDMBA replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 62.9%.According in embodiment 39 Step carries out remaining each step reaction prepare compound I2h, purity 98.28%.Six steps add up yield 32.7%.
Embodiment 71:2- glycine 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4,4- Two fluoro- 3- hydroxyl tetrahydrofuran bases } methyl ester hydrochloride (gemcitabine 5'- position glycinate, I2i) preparation method one
Boc protection L-Valine is replaced with Boc protection glycine, carries out the reaction of step 4 in embodiment 39, yield is 82.6%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 392i, obtain white solid 1.13g, purity 98.08%, m.p.202～204 °C.Six steps add up yield 30.8%.
1H NMR(d6-DMSO)δ3.98(m,1H,3'-CH),4.09(m,2H,CH2NH2),4.29(q,1H,4'-CH), 4.48(m,2H,5'-CH2),6.11(t,1H,1'-CH),6.24(d,1H,J=7.9Hz,5-CH),7.90(d,1H,J=7.9Hz, 6-CH),8.50(s,2H,4-NH2),8.85(s,2H,NH2-CH);
ESI-MS(m/z):321.0[M+H]+,343.0[M+Na]+.
Embodiment 72:2- glycine 2- { (2R, 3R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4,4- Two fluoro- 3- hydroxyl tetrahydrofuran bases } methyl ester hydrochloride (gemcitabine 5'- position glycinate, I2i) preparation method two
Boc protection L-Valine is replaced with Boc protection glycine, carries out the reaction of step 4 in embodiment 39.And with Dimedone replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 39, yield is 63.2%.According to embodiment 39 In step carry out remaining each step reaction prepare compound I2i, purity 98.23%.Six steps add up yield 31.0%.
Embodiment 73:S-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxyl
4.45(q,2H,5'-CH),6.16(t,1H,1'-CH),6.58(d,1H,J=7.9Hz,5-CH),7.94(d,1H,J=7.9Hz, 6-CH),8.56(s,2H,4-NH2),8.82(s,2H,NH2-CH);
ESI-MS(m/z):359.2[M+H]+,381.2[M+Na]+,397.1[M+K]+.
Embodiment 74:S-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Valine ester, I3a) Preparation method two
Cytosine arabinoside is replaced with PSI 6130, and EDCI is replaced with CDI, carry out the reaction of step 4 in embodiment 1, yield For 86.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 13a, purity 98.48%.Six steps add up to receive Rate 31.1%.
Embodiment 75:S-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Valine ester, I3a) Preparation method three
Cytosine arabinoside is replaced with PSI 6130, and with PdCl2Replace Pd (PPh3)4, add part in reaction system simultaneously PPh3, carry out the reaction of step 5 in embodiment 1, yield is 66.3%.Carry out remaining each step reaction according to the step in embodiment 1 Prepare compound I3a, purity 98.36%.Six steps add up yield 30.2%.
Embodiment 76:S-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Valine ester, I3a) Preparation method four
Cytosine arabinoside is replaced with PSI 6130, and HCOOH/n-BuNH is replaced with Dimedone2, carry out step in embodiment 1 Rapid 5 reaction, yield is 67.0%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 13a, purity 98.23%.Six steps add up yield 31.8%.
Embodiment 77:R-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-Val ester, I3b) Preparation method one
Cytosine arabinoside is replaced with PSI 6130, and replaces Boc protection L-Valine, DCC to replace with Boc protection D-Val EDCI, carries out the reaction of step 4 in embodiment 1, and yield is 92.0%.Carry out remaining each step reaction according to the step in embodiment 1 Prepare compound I3b, purity 98.81%.Six steps add up yield 31.1%.
1H NMR(d6-DMSO)δ0.95(d,6H,(CH3)2CH)),1.32(d,3H,CH3CF),2.13(m,1H,CH (CH3)2),3.94(s,1H,CHNH),4.12(m,1H,3'-CH),4.31(q,1H,4'-CH),4.48(m,2H,5'-CH2), 6.15(t,1H,1'-CH),6.20(d,1H,J=7.8Hz,5-CH),7.87(d,1H,J=7.8Hz,6-CH),8.56(s,2H,4- NH2),8.70(d,2H,NH2-CH);
ESI-MS(m/z):359.1[M+H]+,381.1[M+Na]+.
Embodiment 78:R-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-Val ester, I3b) Preparation method three
Cytosine arabinoside, Boc protection D-Val is replaced to replace Boc protection L-Valine with PSI 6130, and with Pd (OAc)2Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the reaction of step 5 in embodiment 1, yield For 68.3%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 13b, purity 98.63%.Six steps add up to receive Rate 30.9%.
Embodiment 79:R-2- amino -3 Methylbutanoic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-Val ester, I3b) Preparation method four
Cytosine arabinoside, Boc protection D-Val is replaced to replace Boc protection L-Valine with PSI 6130, and with NDMBA Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 63.9%.Enter according to the step in embodiment 1 Remaining each step reaction prepare compound I of row3b, purity 98.52%.Six steps add up yield 31.7%.
Embodiment 80:S-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Alanine ester, I3c) preparation method One
Cytosine arabinoside, Boc protection L-Alanine is replaced to replace Boc protection L-Valine with PSI 6130, via embodiment 1 Similar preparation method, can prepare compound I3c, purity 98.43%.Six steps add up yield 31.8%.
1H NMR(d6- DMSO) δ 1.32～1.38 (d, d, 6H, CH3-CH,CH3CF),3.84(q,1H,CHNH),4.08 (m,1H,3'-CH),4.30(q,1H,4'-CH),4.45(m,2H,5'-CH2),6.15(t,1H,1'-CH),6.20(d,1H,J= 7.7Hz,5-CH),7.80(d,1H,J=7.7Hz,6-CH),8.60(s,2H,4-NH2),8.75(d,2H,NH2-CH);
ESI-MS(m/z):331.0[M+H]+,353.0[M+Na]+,368.9[M+K]+.
Embodiment 81:S-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Alanine ester, I3c) preparation method Two
Cytosine arabinoside is replaced with PSI 6130, and Boc protection L-Valine, HATU generation are replaced with Boc protection L-Alanine For EDCI, carry out the reaction of step 4 in embodiment 1, yield is 83.8%.Carry out remaining each step according to the step in embodiment 1 anti- Answer prepare compound I3c, purity 98.41%.Six steps add up yield 32.9%.
Embodiment 82:S-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Alanine ester, I3c) preparation method Three
Cytosine arabinoside, Boc protection L-Alanine is replaced to replace Boc protection L-Valine with PSI 6130, and with HCOO-NH4 +Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 67.0%.Enter according to the step in embodiment 1 Remaining each step reaction prepare compound I of row3c, purity 98.49%.Six steps add up yield 32.1%.
Embodiment 83:R-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-alanine ester, I3d) preparation method One
Cytosine arabinoside is replaced with PSI 6130, Boc protection D-alanine replaces Boc protection L-Valine, via embodiment 1 Similar preparation method, can prepare compound I3d, purity 98.10%.Six steps add up yield 32.6%.
1H NMR(d6- DMSO) δ 1.35～1.40 (d, d, 6H, CH3-CH,CH3CF),3.85(q,1H,CHNH),4.10 (m,1H,3'-CH),4.28(q,1H,4'-CH),4.42(m,2H,5'-CH2),6.12(t,1H,1'-CH),6.22(d,1H,J= 7.9Hz,5-CH),7.78(d,1H,J=7.9Hz,6-CH),8.56(s,2H,4-NH2),8.69(d,2H,NH2-CH);
ESI-MS(m/z):331.1[M+H]+,353.1[M+Na]+.
Embodiment 84:R-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-alanine ester, I3d) preparation method Two
Cytosine arabinoside, Boc protection D-Val is replaced to replace Boc protection L-Valine with PSI 6130, and with Pd2 (dba)3·CHCl3Replace Pd (PPh3)4, add part PPh in reaction system simultaneously3, carry out the anti-of step 5 in embodiment 1 Should, yield is 66.7%.Carry out remaining each step reaction prepare compound I according to the step in embodiment 13d, purity 98.56%.Six The accumulative yield 31.8% of step.
Embodiment 85:R-2- alanine 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] - 4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-alanine ester, I3d) preparation method Three
Cytosine arabinoside, Boc protection D-alanine is replaced to replace Boc protection L-Valine with PSI 6130, and with HCOOH/ Et2NH replaces HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 65.3%.According to the step in embodiment 1 Suddenly carry out remaining each step reaction prepare compound I3d, purity 98.62%.Six steps add up yield 32.8%.
Embodiment 86:S-2- amino -4- methylvaleric acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Leu ester, I3e) Preparation method one
Cytosine arabinoside is replaced with PSI 6130, Boc protection L-Leu replaces Boc protection L-Valine, via embodiment 1 Similar preparation method, can prepare compound I3e, purity 99.04%.Six steps add up yield 34.3%.
1H NMR(d6-DMSO)δ0.85(d,6H,(CH3)2CH)),1.33(d,3H,CH3CF),1.64(t,2H,CH2 (CH)2),1,73(m,1H,CH(CH3)2),3.96(q,1H,CHNH2),4.10(m,1H,3'-CH),4.28(q,1H,4'-CH), 4.44(m,2H,5’-CH2),6.13(t,1H,1'-CH),6.20(d,1H,J=8.0Hz,5-CH),7.88(d,1H,J=8.0Hz, 6-CH),8.60(s,2H,4-NH2),8.72(s,2H,NH2-CH);
ESI-MS(m/z):373.0[M+H]+,395.0[M+Na]+,411.0[M+K]+.
Embodiment 87:S-2- amino -4- methylvaleric acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Leu ester, I3e) Preparation method two
Cytosine arabinoside is replaced with PSI 6130, and Boc protection L-Valine, HBTU generation are replaced with Boc protection L-Leu For EDCI, carry out the reaction of step 4 in embodiment 1, yield is 80.5%.Carry out remaining each step according to the step in embodiment 1 anti- Answer prepare compound I3e, purity 98.67%.Six steps add up yield 33.0%.
Embodiment 88:S-2- amino -3 methylvaleric acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Isoleucine ester, I3f) Preparation method one
Cytosine arabinoside is replaced with PSI 6130, Boc protection L-Isoleucine replaces Boc protection L-Valine, via enforcement The similar preparation method of example 1, can prepare compound I3f, purity 98.87%.Six steps add up yield 33.2%.
1H NMR(d6-DMSO)δ0.82(m,6H,CH3CH2,CH3CH),1.20(m,1H,CH2CH3),1.33(d,3H, CH3CF),1.90(m,1H,CH3CH),3.95(q,1H,CHNH2),4.10(m,1H,3'-CH),4.25(q,1H,4'-CH), 4.46(m,2H,5’-CH2),6.12(t,1H,1'-CH),6.20(d,1H,J=7.8Hz,5-CH),7.85(d,1H,J=7.8Hz, 6-CH),8.68(s,2H,4-NH2),8.69(s,2H,NH2-CH);
ESI-MS(m/z):373.1[M+H]+,395.1[M+Na]+.
Embodiment 89:S-2- amino -3 methylvaleric acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-Isoleucine ester, I3f) Preparation method two
Cytosine arabinoside, Boc protection L-Isoleucine is replaced to replace Boc protection L-Valine with PSI 6130, and with (Et2NH2 +)2CO3 2-Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 61.6%.According to embodiment Step in 1 carries out remaining each step reaction prepare compound I3f, purity 98.32%.Six steps add up yield 31.1%.
Embodiment 90:S-2- amino -3- phenylpropionic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-phenylalanine ester, I3g) Preparation method one
Cytosine arabinoside is replaced with PSI 6130, Boc protection L-phenylalanine replaces Boc protection L-Valine, via enforcement The similar preparation method of example 1, can prepare compound I3g, purity 98.79%.Six steps add up yield 35.2%.
1H NMR(d6-DMSO)δ1.35(d,3H,CH3CF),3.15(q,2H,CH2Ph),4.00(m,1H,CHNH),4.10 (m,1H,3'-CH),4.33(m,2H,5’-CH2),4.45(q,1H,4'-CH),6.08(t,1H,1'-CH),6.18(d,1H,J= 7.9Hz,5-CH),7.25(m,5H,Ph),7.87(d,1H,J=7.9Hz,6-CH),8.70(s,2H,4-NH2),8.70(s,2H, NH2-CH);
ESI-MS(m/z):407.1[M+H]+,429.1[M+Na]+,445.0[M+K]+.
Embodiment 91:S-2- amino -3- phenylpropionic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position L-phenylalanine ester, I3g) Preparation method two
Cytosine arabinoside is replaced with PSI 6130, and Boc protection L-Valine, HOAt are replaced with Boc protection L-phenylalanine Replace EDCI, carry out the reaction of step 4 in embodiment 1, yield is 82.0%.Carry out remaining according to the step in embodiment 1 respectively to walk Reaction prepare compound I3g, purity 98.50%.Six steps add up yield 31.5%.
Embodiment 92:R-2- amino -3- phenylpropionic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-phenylalanine ester, I3h) Preparation method one
Cytosine arabinoside is replaced with PSI 6130, Boc protection D-phenylalanine replaces Boc protection L-Valine, via enforcement The similar preparation method of example 1, can prepare compound I3h, purity 98.29%.Six steps add up yield 34.8%.
1H NMR(d6-DMSO)δ1.32(d,3H,CH3CF),3.13(q,2H,CH2Ph),4.03(m,1H,CHNH),4.12 (m,1H,3'-CH),4.30(m,2H,5’-CH2),4.41(q,1H,4'-CH),6.10(t,1H,1'-CH),6.21(d,1H,J= 7.8Hz,5-CH),7.22(m,5H,Ph),7.85(d,1H,J=7.8Hz,6-CH),8.67(s,2H,4-NH2),8.67(s,2H, NH2-CH);
ESI-MS(m/z):407.0[M+H]+,429.0[M+Na]+.
Embodiment 93:R-2- amino -3- phenylpropionic acid 2- (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H) - Pyrimidine radicals] -4- fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position D-phenylalanine ester, I3h) Preparation method two
Cytosine arabinoside, Boc protection D-phenylalanine is replaced to replace Boc protection L-Valine with PSI 6130, and with Et2NH2 +HCO3 -Replace HCOOH/n-BuNH2, carry out the reaction of step 5 in embodiment 1, yield is 64.8%.According to the step in embodiment 1 Suddenly carry out remaining each step reaction prepare compound I3h, purity 98.54%.Six steps add up yield 32.9%.
Embodiment 94:2- glycine 2- { (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position glycinate, I3i) preparation method one
Cytosine arabinoside is replaced with PSI 6130, Boc protection glycine replaces Boc protection L-Valine, via embodiment 1 Similar preparation method, can prepare compound I3i, purity 98.06%.Six steps add up yield 30.2%.
1H NMR(d6-DMSO)δ1.34(d,3H,CH3CF),4.00(m,1H,3'-CH),4.10(m,2H,CH2NH2), 4.30(q,1H,4'-CH),4.46(m,2H,5’-CH2),6.14(t,1H,1'-CH),6.26(d,1H,J=7.7Hz,5-CH), 7.89(d,1H,J=7.7Hz,6-CH),8.57(s,2H,4-NH2),8.82(s,2H,NH2-CH);
ESI-MS(m/z):317.0[M+H]+,339.0[M+Na]+.
Embodiment 95:2- glycine 2- { (2R, 3R, 4R, 5R) -5- [4- amino -2- oxo -1 (1H)-pyrimidine radicals] -4- Fluoro- 3- hydroxy-4-methyl tetrahydrofuran base } methyl ester hydrochloride (PSI 61305'- position glycinate, I3i) preparation method two
Cytosine arabinoside is replaced with PSI 6130, and replaces Boc protection L-Valine, HOBt to replace with Boc protection glycine EDCI, carries out the reaction of step 4 in embodiment 1, and yield is 62.3%.Carry out remaining each step reaction according to the step in embodiment 1 Prepare compound I3i, purity 98.36%.Six steps add up yield 30.7%.

Claims (14)

1. the Regioselective synthesis of nucleoside medicine 5'- bit amino acid esters are it is characterised in that selected using triaryl methyl Protect to selecting property nucleoside medicine 5'- position hydroxyl, then utilize allyloxycarbonyl protection nucleoside medicine base portion and sugar knot Structure partly in avtive spot, more acid lower selectively removing triaryl methyl, so the amino acid condensation with Boc protection, 5'- position in nucleoside medicine molecule optionally becomes ester, then palladium chtalyst removing allyloxycarbonyl, under acid condition Removing Boc simultaneously becomes corresponding salt, comprises the following steps that：
(1) formula VII becomes ether that formula VI is obtained with triaryl methyl reagent；
(2) formula VI and the condensation of allyloxycarbonyl reagent are obtained formula V；
(3) triarylmethyl protecting group group in selectively removing 5'- position is obtained formula IV to formula V in acid condition；
(4) a-amino acid that formula IV is protected with corresponding Boc is condensed into ester and general formula III is obtained；
(5) general formula III removes all of AOC protection group under homogeneous palladium catalytic condition and formula II is obtained；
(6) formula II under acid condition, conventional method removing Boc and be obtained the corresponding salt of formula I；
Wherein：
Formula I～VII structural formula is respectively：
Wherein, base Base part be natural pyrimidine base base class, purine base base class or their structural modification base class；X For carbon atom, oxygen or sulphur atom；R in Formula VII, VI, I, II2Or R3For hydroxyl, and deposited with the arbitrary configuration in R- type or S- type In the R in Formula V-III2Or R3Hydroxyl for allyloxycarbonyl protection；RCH (the NH of 5'- position2) COO- ester bond part aminoacid Come from various natural or engineered a-amino acid RCH (NH2) COOH, wherein aminoacid is glycine, alanine, figured silk fabrics ammonia Acid, leucine, isoleucine, Phenylalanine, proline, Gamma Amino Butyric Acid, and existed with L-type, D- type or racemate form.
2. synthetic method according to claim 1 it is characterised in that obtain base nucleosides 5'- bit amino acid esters and its Pharmaceutical salts.
3. synthetic method according to claim 2 is it is characterised in that described salt deoxygenates -2'- fluoro- 2'-C- first for 2'- The 5'- bit amino acid esters dihydrochloride of base cytidine.
4. synthetic method according to claim 1 is it is characterised in that in step (1), described triaryl methyl reagent For trityl chloride, trifluoromethanesulfonic acid three benzene methyl, two (p-methoxyphenyl) phenyl methyl chlorine, three p-methoxyphenyl methyl chlorides.
5. synthetic method according to claim 1 is it is characterised in that step (1) or (2) are carried out, instead in the basic conditions Alkali that should be used is organic base or inorganic base, and described organic base is pyridine, dimethylamino naphthyridine, triethylamine, diisopropyl second Base amine or DMA, inorganic base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or hydroxide Potassium.
6. synthetic method according to claim 1 is it is characterised in that reaction dissolvent in step (1), (2), (4) or (5) For pyridine, dichloromethane, dichloroethanes, chloroform, ether, benzene,toluene,xylene, chlorobenzene, methyl tertiary butyl ether(MTBE), diisopropyl Ether, oxolane, 2- methyltetrahydrofuran, 1,2- dimethoxy-ethane, 1,4- dioxane, N,N-dimethylformamide, N, N- dimethyl acetylamide, or the various combination of above-mentioned solvent, reaction temperature is -20 DEG C～solvent reflux temperature.
7. synthetic method according to claim 1 is it is characterised in that in step (2), described allyloxycarbonyl reagent For 1- allyloxycarbonyl tetrazolium, 1- (allyloxy carbon epoxide) -1H- benzotriazole, allyl chlorocarbonate.
8. synthetic method according to claim 1 is it is characterised in that in step (2), described allyloxycarbonyl reagent For allyl chlorocarbonate.
9. synthetic method according to claim 1 is it is characterised in that in step (3), the acid in described acid condition is chlorine Change hydrogen, formic acid, glacial acetic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid；This reaction select solvent be selected from 1～6 carbon alcohols solvent, Ethereal solvent or esters solvent, described alcohols solvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, uncle Butanol or the various combination of these solvents；Described ethereal solvent is selected from ether, methyl tertiary butyl ether(MTBE), Di Iso Propyl Ether, tetrahydrochysene Furan, 2- methyltetrahydrofuran, the various combination of 1,2- dimethoxy-ethane, 1,4- dioxane or these solvents；Described Esters solvent is selected from methyl acetate, ethyl acetate, butyl acetate, or is water, or the various combination of above-mentioned solvent, reaction temperature For -20 DEG C～solvent reflux temperature.
10. synthetic method according to claim 1 is it is characterised in that in step (4), the condensing agent of reaction is N, N'- bis- Carbodicyclo hexylimide, 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride, carbonyl dimidazoles, 2- (7- azo benzo Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 2- (7- azo BTA)-tetramethylurea hexafluorophosphoric acid ester, 1- hydroxyl -7- azo BTA, I-hydroxybenzotriazole；Catalyst is DMAP, pyridine, triethylamine or two Wopropyl ethyl amine.
11. synthetic methods according to claim 1 it is characterised in that in step (4), the condensing agent of reaction be 1- ethyl- 3- (3- dimethylamine propyl) carbodiimide hydrochloride.
12. according to claim 1 synthetic method it is characterised in that palladium catalyst in step (5) is four (triphenylphosphines) Palladium, Palladous chloride., palladium, three (dibenzalacetone) two palladium.
13. synthetic methods according to claim 1 are it is characterised in that the catalyst of reaction is combined with organophosphine ligand Coordination, from neutral or faintly acid nucleopilic reagent, selected from 1,1-Dimethyl-3,5-diketocyclohexane, 1,3- dimethyl barbituric acid, formic acid, acetic acid, primary amine, secondary Amine and the mixture of formic acid or carbonic acid.
14. synthetic methods according to claim 13 are it is characterised in that described nucleopilic reagent is selected from ammonium formate, formic acid Positive fourth ammonium, formic acid diethyl ammonium, carbonic acid diethyl ammonium, bicarbonate diethyl ammonium.
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