CN107200757B - Bridged fluorinated ester and preparation method and application thereof - Google Patents
Bridged fluorinated ester and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a brand new bridged fluorinated ester (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxy bicyclo [2.2.1]]Heptyl-5-formate (the structural formula is shown as V), a preparation method thereof and application of the compound V in synthesizing PSI-6130 and further synthesizing Sofosbuvir. The structure is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to bridged cyclic fluoro ester, a preparation method thereof, and application of the bridged cyclic fluoro ester in synthesizing PSI-6130 and further synthesizing Sofosbuvir.
Background
Sofosbuvir (Sofosbuvir, PSI-7977), chemically (S) -2- (((S) - (((2R,3R,4R,5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphorylated phenoxy) amino) isopropyl propionate. The medicine is a novel oral medicine for treating chronic hepatitis C, which is developed by Gilead company in the United states and belongs to a new generation of nucleoside polymerase NS5B inhibitor. Sofosbuvir is approved by the Food and Drug Administration (FDA) of the United states to be marketed in 2013, 12 and 6, and approved by the European drug administration (EMA) in 2014, 1 and 16, to be marketed in countries of European Union, and is the first drug for safely and effectively treating the main hepatitis C subtype without combining interferon.
PSI-6130 is the main intermediate for synthesizing Sofosbuvir, and most of the synthetic routes of PSI-6130 adopt (2R) -2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid-gamma-lactone (compound 1) as raw material.
There are many documents and patents in the prior art for the synthesis of compound 1, and the methods reported in WO2008045419 and j. org. chem.2009,74,6819-6824 are more commonly used in industrial production. Taking chiral glyceraldehyde as a raw material, carrying out seven-step reaction to obtain a compound 1, and carrying out five-step reaction to obtain an intermediate PSI-6130, wherein the specific reaction is shown as Scheme 1:
however, the method has the disadvantages of long route, complex operation, low yield, large amount of waste water generated in the post-treatment process, solid waste and great environmental protection pressure.
The method of Vorbr ü ggen is also commonly used for the synthesis of nucleosides, and the improved method of Vorbr ü ggen 4013 is reported for the synthesis of nucleosides by the improved method of Vorbr ü ggen.1, 6-anhydro sugar [ Scheme 2, labeled 4, anhydro sugar preparation reference (J. Org. chem.2013,78, 10088-.
Disclosure of Invention
Aiming at the defects in the prior art, the technical problem to be solved by the invention is to provide bridged fluorinated ester (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxybicyclo [2.2.1] heptyl-5-formic ether (the structural formula is shown as V), a preparation method thereof and application of the compound V in synthesizing PSI-6130 and further synthesizing Sofosbuvir medicaments.
The structural formula is as follows:
to achieve one of the above objects, there is provided a bridged fluorinated ester which is (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxabicyclo [2.2.1] heptyl-5-carboxylate and has a structure corresponding to general formula (V), wherein R includes phenyl, methyl, substituted phenyl, and the like:
another object of the present invention is to provide a method for preparing the bridged fluorinated ester, which comprises:
use of a compound of formula (I):
comprises the following steps: acid cyclization, leaving group addition, reduction and ring closure four-step reaction to form the cyclic fluoro lactone (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxy bicyclo [2.2.1] heptyl-5-formic ester compound with the general formula (V):
preferably, in the acid cyclisation step, a compound of formula (i) is used to deprotect and cyclise under acidic conditions to form a compound of formula (ii):
wherein the acidic conditions are: the acid is any one of HCl, HOAc and TFA, and is dissolved in a solvent: MeCN, EtOH, THF, DCM, H2O or toluene; and the reaction temperature was controlled to-50 ℃ to 90 ℃.
Preferably, in the step of adding a leaving group, a compound of the general formula (II) is used to react with a reagent in a solvent to form a compound of the general formula (III):
wherein X as a leaving group comprises Cl, Br, I, NO2、TosO、MsO，CF3SO3、PhSO3O-methylbenzenesulfonyl, m-methylbenzenesulfonyl, naphthalenesulfonyl and the like, wherein the reaction solvent is any one of MeCN, EtOH, THF, DCM, toluene and pyridine; the reaction temperature is-50 ℃ to 90 DEG C
Preferably, in the reducing step, the compound of the general formula (iii) is subjected to a reduction reaction with a reducing agent in a reaction solvent to form a compound of the general formula (iv):
wherein the reducing agent is DIBAL-H, Red-Al, LiAlH (OBu-t)3The reaction solvent is any one of THF, MTBE, DCM and toluene, and the reaction temperature is-50 ℃ to 90 ℃.
Preferably, in the ring closing step, a ring closing reaction is performed by using a compound of the general formula (iv) under basic conditions to form a compound of the general formula (v):
wherein the alkaline conditions are as follows: the base is DBU or NH3.H2O、Et3N, DIPEAAny one, dissolved in a solvent: THF, DCM, toluene and acetonitrile, wherein the reaction temperature is-50 ℃ to 90 ℃.
The third object of the present invention is the use of the above bridged fluoroesters for the synthesis of the compound of formula (VII), PSI-6130 being used as an intermediate for the preparation of Sofosbuvir drugs.
The fourth purpose of the invention is to provide a preparation method for synthesizing PSI-6130 by utilizing the bridged fluorinated ester, which comprises the following steps:
the use of a compound of formula (V), namely cyclic fluoro ester (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxabicyclo [2.2.1] heptyl-5-carboxylate, is via: forming glucoside and removing protecting group to form PSI-6130 compound with general formula (VII):
preferably, in the glycoside forming step, a compound of the general formula (V) and TMS protected uracil or cytosine are subjected to a glycoside forming reaction in a reaction solvent in the presence of a Lewis acid to form a compound of the general formula (VI):
wherein Y is OH or NHBz group;
when Y is an OH group, a compound of formula (VI-1) is formed:
when Y is a NHBz group, a compound of formula (VI-2) is formed:
wherein the Lewis acid is TMSOTf or SnCl4、TiCl4、BF3·Et2Any one of OThe reaction solvent is DCM, Cl-Ph and ClCH2CH2Cl, MeCN, toluene, CF3-Ph、CF3-Ph/MeCN mixture, CH3COOiPr or THF, wherein the reaction temperature is-50 ℃ to 90 ℃.
Preferably, in the deprotection step, a deprotection reaction is carried out in a basic reaction solvent using a compound of formula (VI-1) to remove the protecting group and form a compound of formula (VII) PSI-6130:
wherein the reaction solvent is MeOH, EtOH and H2Any one of O, THF, DCM and toluene, wherein the reaction temperature is-50 ℃ to 90 ℃;
preferably, in the step of removing the protecting group, the compound of formula (VI-2) is firstly used to change NHBz into OH under acidic condition, and then the protecting group is removed under basic condition to obtain the compound PSI-6130 of formula (VI),
wherein the reaction solvent is MeOH, EtOH, H2O, THF, DCM and toluene, and the reaction temperature is-50 ℃ to 90 ℃.
In conclusion, the invention provides a brand new method for synthesizing PSI-6130 by using an intermediate, and the specific reaction route is shown in Scheme 3:
the method has the advantages of short synthetic route, excellent and controllable stereo configuration selectivity, no use of heavy metal and highly toxic raw materials in the reaction process, less three wastes generation, environmental friendliness, obvious economic benefit and suitability for industrial mass production.
Compared with the prior art, the invention has the following obvious advantages:
1. the synthetic method of the invention produces less three wastes, does not produce a large amount of waste water and has small environmental protection pressure.
2. The method is simple and convenient to operate and suitable for industrial mass production.
3. The invention has novel route, and the related chemical reaction of the provided brand new intermediate compound V can be used for preparing various chiral cyclic esters.
Detailed Description
The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes and modifications may be made without departing from the principles of the invention and these changes and modifications are to be considered within the scope of the invention.
Example 1: preparation of Compound II
Compound I (40g, 113mmol, 1eq, prepared according to patent document CN 101023094A) was dissolved in MeCN (200ml, 5V) and H at room temperature2O (14ml, 0.3V), TFA (22.5ml, 2.65eq) was added to the mixture under stirring at room temperature, the mixture was heated to 90 ℃ and reacted for 3 hours, then acetonitrile was removed by spin-drying, the separated layers were extracted with EA, the organic phase was washed with NaCl and Na2SO4Drying, and subjecting the residue to column chromatography to give 26g of compound II as a white solid with a yield of 86%.
Hydrogen spectrum of compound II:
1H-NMR(400MHz,CDCl3):δ8.14-8.05(m,2H),7.64(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),5.53(dd,J＝16.7,6.7Hz,1H),4.74-4.65(m,1H),4.10(dd,J＝13.2,2.3Hz,1H),3.86(dd,J＝13.2,2.9Hz,1H),2.49(br,1H),1.75(d,J＝23.6Hz,3H)。
example 2: preparation of Compound III
Compound II (18.3g, 68.23mmol) was dissolved in dry Py (54ml, 3V), cooled to 0 deg.C, and TosCl (19.5g, 103mmol, 1.5eq) was added portionwise with internal temperature controlled at not higher than 5 deg.C. After the addition, the mixture was stirred at room temperature for 24 hours. After completion of the TLC reaction, pyridine hydrochloride was removed by filtration, the residue was extracted twice with EA and the organic phase was washed with NaCl (sat), dried over anhydrous sodium sulfate, spin-dried and column-purified (PE: EA: 10:1) to obtain 17g of a white solid compound III (yield 75%) and 2.65g of a chlorinated product (the chlorinated product was also obtained in the same manner as in III to obtain V)
1H-NMR(400MHz,CDCl3):δ8.07-8.02(m,2H),7.80(d,2H),7.64(t,J＝7.5Hz,1H),7.49(t,J＝7.8Hz,2H),7.34(d,J＝8.1Hz,2H),5.38(dd,J＝15.8,6.7Hz,1H),4.80-4.74(m,1H),4.42(dd,J＝11.7,2.6Hz,1H),4.30(dd,J＝11.7,3.7Hz,1H),2.43(s,3H),1.71(d,J＝23.6Hz,3H)。
Hydrogen spectrum of compound III:
example 3: preparation of Compound IV
Compound III (17g, 40.25mmol) was dissolved in dry THF (85ml) under nitrogen, then cooled to-20 ℃ and LiAlH (OBu-t) was slowly added dropwise3(60.4ml, 60.4mmol, 1.5eq) with internal temperature controlled not to be higher than-15 ℃ and stirred at this temperature for 3 hours after the end of the addition, TLC reaction was quenched with saturated HCl (125ml, 1M), filtered with celite, extracted with EA (850ml 2 times), the organic phases were combined, washed with nacl (sat), dried over anhydrous sodium sulfate, spun dry, and column purified to give 12.8g of compound IV as a white solid (β: α ═ 1:0.4) in 75% yield.
Hydrogen spectrum of compound IV:
1H-NMR(400MHz,CDCl3):δ8.06(d,2H),7.79(d,J＝8.2Hz,2H),7.62(d,J＝7.4Hz,1H),7.48(d,J＝7.7Hz,2H),7.31(d,J＝8.2Hz,2H),5.40(dd,J＝22.9,7.7Hz,1H),5.28(d,J＝14.0Hz,1H),4.46(dd,J＝11.0,2.9Hz,1H),4.38(ddd,J＝8.0,5.4,3.0Hz,1H),4.23(dd,J＝11.0,5.4Hz,1H),3.33(s,3H),1.51(d,J＝22.6Hz,3H)。
example 4: preparation of Compound V
Compound IV (5g,11.8mmol) was dissolved in acetonitrile (25mL) at room temperature and DBU (3.6g,23.6mmol) was added. After completion of the addition, the TLC starting material disappeared after 5 hours of reaction at room temperature. Removing acetonitrile by rotation, adding NH4Cl (sat) quench and ethyl acetate extract. The organic phase is washed with NaCl (sat), Na2SO4Drying, spin-drying, sample-dressing of the residue and column chromatography (PE: EA ═ 2:1) gave 2.1g of compound V, a white solid, yield: 70 percent.
Hydrogen spectrum of compound V:
1H-NMR(400MHz,CDCl3):δ8.14-8.06(m,2H),7.59(t,J＝7.4Hz,1H),7.46(t,J＝7.7Hz,2H),5.40(d,J＝1.0Hz,1H),4.90(t,J＝2.8Hz,1H),4.83(d,J＝3.0Hz,1H),3.68-3.55(m,2H),1.68(d,J＝22.3Hz,3H)。
example 5: preparation of PSI-6130
Uracil (3.5g,32mmol) was dissolved in HMDS (20mL) under Nitrogen and (NH) was added4)2SO4(80 mg). After the addition, the reaction was carried out at 150 ℃ until the solution became clear. Removing HMDS in a rotating mode, and drying the residue in vacuum for 1h to obtain compound TMS protected uracil;
dissolving TMS protected uracil in dry MeCN (10ml) under the protection of nitrogen, dropwise adding TMSOTf (7.12g,32mmol), stirring until the reaction solution becomes clear, dropwise adding MeCN (2ml) solution of compound V (1g,4mmol) into the reaction solution, stirring for 10h at 40 ℃ after adding, quenching with ice water after TLC compound V is finished, filtering with diatomite, washing filter cake with DCM (30ml for 2 times), demixing, washing the organic phase with NaCl (sat), drying with anhydrous sodium sulfate, and spin-drying the crude product for the next step;
the crude VI-1 was dissolved in MeOH (10ml) and NH added3In MeOH (10ml, NH-in)3Concentration 11M), stirred at rt for 16h, the starting material disappeared, the solvent dried and column chromatographed with stirring (DCM: MeOH ═ 20:1) to give 833mg of a white solid in 50% yield over two steps (α: β ═ 1: 3).
Effect of reaction solvent on selectivity (see table below):
hydrogen spectrum of Compound VI-1- β:
1H-NMR(400MHz,CD3OD):δ8.07(dd,J＝8.4,1.3Hz,2H),7.72(dd,J＝8.2,3.0Hz,1H),7.65(m,1H),7.51(t,J＝7.8Hz,1H),6.34(d,J＝19.0Hz,1H),5.74(m,2H),4.61–4.52(m,1H),3.89(dd,J＝12.6,2.6Hz,1H),3.72(d,J＝3.6Hz,1H),1.53(d,J＝22.4Hz,3H)。
hydrogen spectrum of Compound VI-1- α:
1H-NMR(400MHz,CD3OD):δ8.17(d,J＝8.1Hz,1H),8.07(d,J＝7.1Hz,2H),7.71–7.62(m,1H),7.51(dd,J＝10.7,4.8Hz,2H),6.23(d,J＝18.7Hz,1H),5.77(d,J＝8.1Hz,1H),5.57(dd,J＝21.5,9.2Hz,1H),4.35(dd,J＝9.1,0.9Hz,1H),4.00(dd,J＝12.9,2.1Hz,1H),3.75(dd,J＝12.9,2.6Hz,1H),1.42(d,J＝22.5Hz,3H)。
hydrogen spectrum of PSI-6130:
1H-NMR(400MHz,DMSO-d6):δ11.53-11.41(br,1H),7.97(d,J＝8.1Hz,1H),5.99(d,J＝18.9Hz,1H),5.67(dd,J＝7.2,5.1Hz,2H),5.30(s,1H),3.83(m,3H),3.67-3.58(m,1H),1.28(s),1.25(d,J＝22.5Hz,3H)。
example 6: preparation of PSI-6130
N-4 benzoylcytosine (6.9g,32mmol), (NH)4)2SO4(100mg), HMDS (30mL) was dissolved in chlorobenzene and heated to reflux until the reaction solution became clear. Removing the solvent by spinning to obtain a slurry-like compound TMS-protected cytosine;
dissolving TMS protected cytosine in dry MeCN (10ml) under the protection of nitrogen, dropwise adding TMSOTf (7.12g,32mmol), stirring for about 5min after adding, then dropwise adding a MeCN (2ml) solution of a compound V (1g,4mmol) into the reaction solution, stirring for 10h at 40 ℃ after adding, quenching with ice water after TLC compound V is finished, filtering with diatomite, washing a filter cake with DCM (30ml for 2 times), demixing, washing an organic phase with NaCl (sat), drying with anhydrous sodium sulfate, and spin-drying a crude product for the next step;
adding the crude product VI-2 into HOAc (10mL) solution at room temperature, heating and refluxing for 20h, detecting by TLC that the raw material disappears, and spin-drying the solvent to form a crude product VI-1 which is directly used in the next step;
the crude VI-1 was dissolved in MeOH (10ml) and NH added3In MeOH (10ml, NH-in)3Concentration 11M), stirred at rt for 16h, the starting material disappeared, the solvent was spun dry and column chromatography (DCM: MeOH ═ 20:1) afforded 780mg white solid in three steps of yield: 40% (α: β ═ 1: 2).
Effect of reaction solvent on selectivity (see table below):
| solvent(s) | α/β selectivity | Overall yield of |
| DCM | 55:45 | 61.5％ |
| MeCN | 24:48 | 40％ |
| ClCH2CH2Cl | 44:36 | 73.3％ |
| Cl-Ph | 53:24 | 45％ |
| CH3-Ph | 55:15 | 21.1％ |
| CF3-Ph | 53:23 | 22.6％ |
Hydrogen spectrum of Compound VI-2- β:
1H-NMR(400MHz,CD3OD):δ8.75(d,J＝7.4Hz,1H),8.09(d,J＝7.3Hz,2H),7.99(d,J＝7.5Hz,2H),7.75-7.62(m,3H),7.54(dd,J＝17.4,7.9Hz,4H),6.41(d,J＝18.1Hz,1H),5.64(dd,J＝21.6,9.3Hz,1H),4.44(d,J＝9.3Hz,1H),4.08(dd,J＝13.0,1.7Hz,1H),3.81(dd,J＝12.9,2.2Hz,1H),1.42(d,J＝22.5Hz,3H)。
hydrogen spectrum of Compound VI-2- α:
1H-NMR(400MHz,CD3OD):δ8.22(dd,J＝7.6,2.6Hz,1H),8.13-8.04(m,2H),8.03-7.96(m,2H),7.72-7.62(m,3H),7.59-7.42(m,4H),6.54(d,J＝17.8Hz,1H),5.79(dd,J＝21.2,8.4Hz,1H),4.66(d,J＝8.5Hz,1H),3.94(dd,J＝12.6,2.6Hz,1H),3.75(dd,J＝12.6,3.6Hz,1H),1.63(d,J＝22.5Hz,3H)。
hydrogen spectrum of PSI-6130:
1H-NMR(400MHz,DMSO-d6):δ11.53-11.41(br,1H),7.97(d,J＝8.1Hz,1H),5.99(d,J＝18.9Hz,1H),5.67(dd,J＝7.2,5.1Hz,2H),5.30(s,1H),3.83(m,3H),3.67-3.58(m,1H),1.28(s),1.25(d,J＝22.5Hz,3H)。
the above description is only a part of the preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made within the spirit of the invention, and any changes and modifications made are within the scope of the invention.
Claims (6)
1. A bridged fluorinated ester characterized by: the bridged fluorinated ester is (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxy bicyclo [ 2.2.1%]Heptyl-5-carboxylate, the structure of which corresponds to formula (V), wherein R1Phenyl, methyl:
2. a process for the preparation of a bridged fluorinated ester of claim 1, comprising: use of a compound of formula (I):
comprises the following steps: acid cyclization, leaving group addition, reduction and ring closure four-step reaction to form the cyclic fluoro ester (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxybicyclo [2.2.1] heptyl-5-formate compound of the general formula (V):
in the acid cyclization step, a compound of the general formula (I) is used for removing a protecting group and cyclizing under an acidic condition to prepare a compound of the general formula (II):
wherein the acidic conditions are: the acid is any one of HCl, HOAc and TFA, and is dissolved in a solvent: MeCN, EtOH, THF, DCM, H2O or toluene; and the reaction temperature is controlled to be-50 ℃ to 90 ℃;
in the leaving group adding step, a leaving group adding reaction is carried out in a solvent by using a compound of a general formula (II) and a reaction reagent to prepare a compound of a general formula (III):
wherein X is Cl, Br, I, NO as leaving group2、TosO、MsO，CF3SO3、PhSO3The reaction solvent is any one of MeCN, EtOH, THF, DCM, toluene and pyridine; the reaction temperature is-50 ℃ to 90 ℃;
in the reduction step, a compound of the general formula (III) and a reducing agent are subjected to reduction reaction in a reaction solvent to prepare a compound of the general formula (IV):
wherein the reducing agent is DIBAL-H, Red-Al, LiAlH (OBu-t)3The reaction solvent is any one of THF, MTBE, DCM and toluene; the reaction temperature is-50 ℃ to 90 ℃;
in the ring closing step, a ring closing reaction is carried out by using a compound of a general formula (IV) under an alkaline condition to prepare a compound of a general formula (V):
wherein the alkaline conditions are as follows: the base is DBU or NH3·H2O、Et3N, DIPEA, dissolved in a solvent: any one of THF, DCM, toluene and acetonitrile; the reaction temperature is-50 ℃ to 90 ℃.
3. Use of a bridged fluorinated ester according to claim 1, wherein: the bridged fluorinated ester is used for synthesizing a compound PSI-6130 with the general formula (VII):
PSI-6130 was used as an intermediate to prepare sofosbuvir drugs.
4. A preparation method for synthesizing PSI-6130 by utilizing bridged cyclic fluoro ester is characterized by comprising the following steps:
the use of a compound of formula (V), namely cyclic fluoro ester (1R,4R,5R,6R) -6-fluoro-6-methyl-2, 7-dioxabicyclo [2.2.1] heptyl-5-carboxylate, is via: forming glucoside and removing protecting group to form a compound PSI-6130 with a general formula (VII):
5. the method of claim 4, wherein the step of forming glycosides comprises reacting the compound of formula (v) with TMS-protected uracil or a compound of formula (v-1) in the presence of a lewis acid in a reaction solvent to form the compound of formula (vi):
wherein Y is OH or NHBz group;
when Y is an OH group, a compound of formula (VI-1) is formed:
when Y is a NHBz group, a compound of formula (VI-2) is formed:
wherein the Lewis acid is TMSOTf or SnCl4、TiCl4、BF3·Et2O, wherein the reaction solvent is DCM, Cl-Ph or ClCH2CH2Cl, MeCN, toluene, CF3-Ph、CF3-Ph/MeCN mixture, CH3COOiPr or THF; the reaction temperature is-50 ℃ to 90 ℃.
6. The method of claim 4, wherein the deprotecting step comprises:
deprotecting the group using a compound of formula (VI-1) under basic conditions to form a compound of formula (VII) PSI-6130:
wherein the reaction solvent is MeOH, EtOH and H2Any one of O, THF, DCM and toluene, wherein the reaction temperature is-50 ℃ to 90 ℃;
the compound with the general formula (VI-2) is firstly used for changing NHBz group into OH group under acidic condition, then protecting group is removed under alkaline condition to obtain the compound PSI-6130 with the reaction general formula (VII),
wherein the reaction solvent for removing the protecting group under the alkaline condition is MeOH, EtOH, H2O, THF, DCM and toluene, and the reaction temperature is-50 ℃ to 90 ℃.
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| CN101023094A (en) * | 2004-07-21 | 2007-08-22 | 法莫赛特股份有限公司 | Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives |
| CN104327138A (en) * | 2014-10-21 | 2015-02-04 | 齐鲁制药有限公司 | Preparation method of PSI-7977 intermediate compound |
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| CN101437524B (en) * | 2004-09-14 | 2012-01-11 | 法莫赛特股份有限公司 | Preparation of 2' ifluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
| AU2005328519B2 (en) * | 2005-03-04 | 2012-03-01 | Fresenius Kabi Oncology Limited | Intermediate and process for preparing of beta- anomer enriched 21deoxy, 21 ,21-difluoro-D-ribofuranosyl nucleosides |
| WO2006095359A1 (en) * | 2005-03-10 | 2006-09-14 | Sms Pharmaceuticals Limited | Synthesis of 2-deoxy-2, 2-di fluoro-d-ribo furanose-3, 5 di(4-methy/4-nitro-chloro)benzoate and its conversion to gemcitabine hydrochloride thereof |
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| CN101023094A (en) * | 2004-07-21 | 2007-08-22 | 法莫赛特股份有限公司 | Preparation of alkyl-substituted 2-deoxy-2-fluoro-d-ribofuranosyl pyrimidines and purines and their derivatives |
| CN104327138A (en) * | 2014-10-21 | 2015-02-04 | 齐鲁制药有限公司 | Preparation method of PSI-7977 intermediate compound |
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