CN107200757A - A kind of bridged ring fluoroester and its preparation method and application - Google Patents

A kind of bridged ring fluoroester and its preparation method and application Download PDF

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CN107200757A
CN107200757A CN201710530491.4A CN201710530491A CN107200757A CN 107200757 A CN107200757 A CN 107200757A CN 201710530491 A CN201710530491 A CN 201710530491A CN 107200757 A CN107200757 A CN 107200757A
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李大峰
陈平
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Shanghai Hongbo Zhiyuan Pharmaceutical Ltd By Share Ltd
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

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Abstract

The invention discloses a kind of brand-new bridged ring fluoroester (1R, 4R, 5R, 6R) formic acid esters (structural formula is as shown in such as V) of 6 fluorine, 6 methyl 2,7 dioxy-bicyclo [2.2.1] heptyl 5 and preparation method thereof and synthesized with the compound V PSI 6130 so that synthesize Suo Feibuwei purposes application.Its structure is as follows：

Description

A kind of bridged ring fluoroester and its preparation method and application
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of bridged ring fluoroester and preparation method thereof, Yi Jili With the application of bridged ring fluoro Lipase absobed PSI-6130 and then synthesis Suo Feibuwei medicines.
Background technology
Suo Feibuwei (Sofosbuvir, PSI-7977), entitled (S) -2- (((S)-(((2R, 3R, 4R, the 5R) -5- of chemistry ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methoxyl group) phosphorus Acylated phenoxy group) amino) isopropyl propionate.The medicine is a kind of new oral treatment chronic hepatitis C that Gilead companies of the U.S. develop Medicine, belong to a new generation nucleoside polymerase NS5B inhibitor.Suo Feibuwei is on December 6th, 2013 by state of U.S. food medicine Product Surveillance Authority (FDA) approval is in U.S.'s listing, and Europe drug administration on January 16th, 2014 (EMA) approval is each in European Union State lists, and is that the first interferon that need not combine just can safely and effectively treat the medicine of main hepatitis hypotype.
PSI-6130 be synthesize Suo Feibuwei main intermediate, and synthesize PSI-6130 routes largely using (2R)- 2- deoxidations -2- fluoro- 2- methyl Ds-erythro form pentonic acids-gamma lactone (compound 1) is raw material.
Existing many documents and patent the more commonly used in compound 1, industrial production are to synthesize in the prior art The method reported in WO2008045419 and J.Org.Chem.2009,74,6819-6824.Using chiral glyceraldehyde as raw material, warp The reaction of seven steps obtains compound 1, then obtains intermediate PSI-6130 through the reaction of five steps, specifically reacts as shown in Scheme1：
But, this method route is tediously long, cumbersome, and yield is relatively low, and last handling process produces a large amount of waste water, gives up solid, ring Packing pressure is very big.
Vorbr ü ggen methods are also commonly used for the synthesis of nucleosides, J.Org.Chem.2002, and 67,3996-4013 report use Vorbr ü ggen methods carry out synthetic nucleosides after improvement.With 1,6- anhydrousugars, [marked as 4 in Scheme 2, the preparation of anhydrousugar is joined Examine (J.Org.Chem.2013,78,10088-10105), (Helvetica Chimica Acta, 86 (3), 633-643； 2003)、(Eur.J.Org.Chem.2014,2053–2069)、(J.Org.Chem.1998,53,3473-3479)、 (Carbohydrate Research 309 (1998) 281 ± 286), (Eur.J.Org.Chem.2013,1963-1972)] and Synthetic nucleosides of the base under Louis acid catalysis, high income and selectivity is good, but be also only limitted to anhydrousugar 2 have big position Resistance and in the presence of can carrying out the group of ortho position participation.If 2 without anhydrousugar without big steric hindrances and can be with The group for carrying out ortho position participation is present, and selectivity is just poor, sees document Eur.J.Org.Chem.2013,1963-1972.Tool Precursor reactant is as shown in Scheme 2.
The content of the invention
For above-mentioned deficiency of the prior art, the technical problem to be solved in the present invention is to provide a kind of bridged ring fluoroester Fluoro- 6- methyl -2,7- dioxy-bicyclos [2.2.1] heptyl -5- formic acid esters (structural formula is as shown in such as V) of (1R, 4R, 5R, 6R) -6- and Its preparation method and PSI-6130 is synthesized with compound V and then the application of Suo Feibuwei medicines can be synthesized.
Its structural formula is as follows：
A kind of bridged ring fluoroester is provided one of to achieve these goals, and the bridged ring fluoroester is (1R, 4R, 5R, 6R) -6- Fluoro- 6- methyl -2,7- dioxy-bicyclo [2.2.1] heptyl -5- formic acid esters, its structure corresponds to logical formula (V), wherein R include phenyl, Methyl, substituted-phenyl etc.：
The second object of the present invention is to provide a kind of preparation method of above-mentioned bridged ring fluoroester, and this method includes：
Use the compound of formula (I)：
By：Sour cyclisation, upper leaving group, reduction, cyclization four-step reaction formed formula (V) ring fluoro lactone (1R, 4R, 5R, 6R) fluoro- 6- methyl -2,7- dioxy-bicyclos [2.2.1] heptyl -5- formic acid ester compounds of -6-：
It is preferred that, in the sour cyclisation step, Deprotection and it is cyclized in acid condition using the compound of formula (I) Form the compound of formula (II)：
Wherein, the acid condition is：Acid is any one in HCl, HOAc, TFA, is dissolved in solvent：MeCN、 EtOH、THF、DCM、H2Any one in O, toluene；And reaction temperature control is -50 DEG C to 90 DEG C.
It is preferred that, in the upper leaving group step, carried out in a solvent with reaction reagent using the compound of formula (II) Upper leaving group reacts and forms the compound of formula (III)：
Wherein, X includes Cl, Br, I, NO as leaving group2, TosO, MsO, CF3SO3、PhSO3, o-methyl-benzene sulphonyl Base, a Methyl benzenesulfonyl base, naphthalene sulfonyl base etc., the reaction dissolvent is times in MeCN, EtOH, THF, DCM, toluene, pyridine Meaning is a kind of；Reaction temperature is -50 DEG C to 90 DEG C
It is preferred that, in the reduction step, gone back using the compound and reducing agent of formula (III) in reaction dissolvent Original is reacted and forms the compound of formula (IV)：
Wherein, the reducing agent is DIBAL-H, Red-Al, LiAlH (OBu-t)3In any one, it is described reaction it is molten Agent is any one in THF, MTBE, DCM, toluene, and the reaction temperature is -50 DEG C to 90 DEG C.
It is preferred that, in the cyclization step, ring closure reaction is carried out simultaneously in the basic conditions using the compound of formula (IV) Form the compound of formula (V)：
Wherein, the alkalescence condition is：Alkali is DBU, NH3.H2O、Et3Any one in N, DIPEA, is dissolved in solvent： Any one in THF, DCM, toluene, acetonitrile, the reaction temperature is -50 DEG C to 90 DEG C.
It is a kind of application of above-mentioned bridged ring fluoroester that the third object of the present invention, which is provided, and the bridged ring fluoroester is used to synthesize Formula is used as intermediate to prepare Suo Feibuwei medicines for the compound PSI -6130, PSI-6130 of (VII).
The fourth object of the present invention is to provide a kind of preparation method using above-mentioned bridged ring fluoro Lipase absobed PSI-6130, should Method includes：
The use of the compound of logical formula (V) is the fluoro- 6- methyl -2,7- dioxy-bicyclos of ring fluoroester (1R, 4R, 5R, 6R) -6- [2.2.1] heptyl -5- formic acid esters passes through：Into the PSI-6130 compounds of glycosides, deprotection base two-step reaction formation formula (VII)：
It is preferred that, in the step into glycosides, the uracil or cytimidine protected using the compound of formula (V) with TMS Glycosidation is carried out in the reaction dissolvent that lewis acid is present and forms the compound of formula (VI)：
Wherein Y is OH or NHBz groups；
When Y is OH groups, the compound that formula is (VI -1) is formed：
When Y is NHBz groups, the compound of formula (VI -2) is formed：
Wherein, the lewis acid is TMSOTf, SnCl4、TiCl4、BF3·Et2Any one in O, the reaction is molten Agent is DCM, Cl-Ph, ClCH2CH2Cl, MeCN, toluene, CF3-Ph、CF3- Ph/MeCN mixed liquors, CH3Appointing in COOiPr, THF Meaning is a kind of, and the reaction temperature is -50 DEG C to 90 DEG C.
It is preferred that, in the deprotection base step, entered using formula for the compound of (VI -1) in alkaline reaction solvent Row Deprotection reaction sloughs blocking group and forms the compound PSI -6130 that formula is (VII)：
Wherein, reaction dissolvent is MeOH, EtOH, H2Any one in O, THF, DCM, toluene, the reaction temperature for- 50 DEG C to 90 DEG C；
It is preferred that, in the deprotection base step, use compound first in acid condition NHBz of the formula for (VI-2) Become to deprotect base in the basic conditions after OH and slough Bz groups and obtain compound PSI -6130 of the reaction expression into (VI),
Wherein reaction dissolvent is MeOH, EtOH, H2Any one in O, THF, DCM, toluene, the reaction temperature for- 50 DEG C to 90 DEG C.
In summary, road is specifically reacted the invention provides a kind of brand-new intermediate come the method for synthesizing PSI-6130 Line is as shown in Scheme 3：
The synthetic route of this method is brief, and spatial configuration is selectively excellent and controllable, course of reaction without using heavy metal, Hypertoxic raw material, the three wastes of generation are few, environment-friendly, with obvious economic benefit, are adapted to industrialized production.
Compared with prior art, the present invention has following clear advantage：
1. the three wastes that synthetic method is produced in the present invention are few, a large amount of waste water are not produced, environmental protection pressure is small.
2. the present invention is easy to operate, it is adapted to industrialized production.
3. route of the present invention it is novel there is provided brand-new midbody compound V related chemistry reaction can be used for preparing it is a variety of Chiral cyclic ester.
Embodiment
The invention will now be further described with reference to specific embodiments, but these embodiments be only it is exemplary, it is not right The scope of the present invention constitutes any limitation.Those skilled in the art, which should be understood that, is not departing from the present invention On the premise of principle, some improvements and modifications can also be made, these improvements and modifications also should be regarded as protection scope of the present invention.
Embodiment 1：Compound II preparation
Compound I (40g, 113mmol, 1eq are prepared with reference to patent document CN101023094A) is dissolved in MeCN at room temperature (200ml, 5V) and H2In O (14ml, 0.3V), lower addition TFA (22.5ml, 2.65eq) is stirred at room temperature, 90 degree, reaction are heated to After 3h, it is spin-dried for removing acetonitrile, EA extracting and demixings, organic phase is washed with NaCl, Na2SO4Dry, residue mixes sample column chromatography and obtains 26g Compound as white solid II, yield 86%.
Compound II hydrogen spectrum：
1H-NMR(400MHz,CDCl3):δ 8.14-8.05 (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).
Embodiment 2：Compound III preparation
Compound II (18.3g, 68.23mmol) is dissolved in dry Py (54ml, 3V), 0 degree is cooled to, is added portionwise Not higher than 5 degree of temperature in TosCl (19.5g, 103mmol, 1.5eq), control.Finish and 24h is stirred at room temperature.TLC reactions are finished, Demineralizing acid pyridiniujm is filtered, residue is added water, is extracted twice with EA, and organic phase is washed with NaCl (sat), anhydrous sodium sulfate is done It is dry, it is spin-dried for, post purifying (PE:EA=10:1) 17g compound as white solid III (yield 75%) and 2.65g chloro production is obtained Thing (chloro-product also can use obtains V with the operation of III identicals)
1H-NMR(400MHz,CDCl3):δ 8.07-8.02 (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).
Compound III hydrogen spectrum：
Embodiment 3：Compound IV preparation
Compound III (17g, 40.25mmol) is dissolved in dry THF (85ml) under nitrogen protection, be then cooled to- 20 degree, LiAlH (OBu-t) is slowly added dropwise3(60.4ml, 60.4mmol, 1.5eq), and control interior temperature must not be higher than -15 degree, drop Stirred at this temperature after adding 3 hours.TLC reactions are finished, and are quenched with saturation HCl (125ml, 1M), diatomite drainage, rear to use (850ml*2 times) extraction of EA, merges organic phase, organic phase is washed with NaCl (sat), and anhydrous sodium sulfate drying is spin-dried for, post purifying Obtain 12.8g compound IV, white solid (β:α=1:0.4), yield：75%.
Compound IV hydrogen spectrum：
1H-NMR(400MHz,CDCl3):δ 8.06 (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).
Embodiment 4：Compound V preparation
Compound IV (5g, 11.8mmol) is dissolved in acetonitrile (25mL) at room temperature, addition DBU (3.6g, 23.6mmol).Add and reacted 5 hours in room temperature, TLC raw materials disappear.Rotation removes acetonitrile, adds NH4Cl (sat) is quenched, acetic acid Ethyl ester is extracted.Organic phase is washed with NaCl (sat), Na2SO4Dry, be spin-dried for, residue mixes column chromatography (PE after sample:EA=2:1) Obtain 2.1g compound V, white solid, yield：70%.
Compound V hydrogen spectrum：
1H-NMR(400MHz,CDCl3):δ 8.14-8.06 (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).
Embodiment 5：PSI-6130 preparation
Uracil (3.5g, 32mmol) is dissolved in HMDS (20mL) under nitrogen protection, (NH is added4)2SO4(80mg)。 Finish to solution to become in 150 degree of reactions and clarify.Rotation removes HMDS, and the urine that residue vacuum drying 1h obtains compound TMS protections is phonetic Pyridine；
Nitrogen protection under the TMS uracils protected are dissolved in dry MeCN (10ml), after by TMSOTf (7.12g, 32mmol) it is added dropwise, finishes stirring to reaction solution and become after clarification, then by compound V (1g, 4mmol) MeCN (2ml) solution It is added dropwise in reaction solution above, finishes and 10h is stirred under 40 degree, TLC compounds V is finished, and is quenched with frozen water, diatomite is helped Filter, (30ml*2 times) washing filter cake of DCM, layering, organic phase is washed with NaCl (sat), and anhydrous sodium sulfate drying is spin-dried for crude product straight Connect for next step；
Crude product VI-1 is dissolved in MeOH (10ml), and NH is added afterwards3MeOH solution (10ml, wherein NH3Concentration is 11M), room Temperature stirring 16h.Raw material disappears, and is spin-dried for solvent, mixes sample column chromatography (DCM:MeOH=20:1) 833mg white solids, two steps are obtained Yield：50% (α:β=1:3).
Influence (see the table below) of the reaction dissolvent to selectivity：
Compound VI-1- β hydrogen spectrum：
1H-NMR(400MHz,CD3OD):δ 8.07 (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).
Compound VI-1- α hydrogen spectrum：
1H-NMR(400MHz,CD3OD):δ 8.17 (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).
PSI-6130 hydrogen spectrum：
1H-NMR(400MHz,DMSO-d6):δ 11.53-11.41 (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).
Embodiment 6：PSI-6130 preparation
By N-4 benzoylcytosines (6.9g, 32mmol), (NH under nitrogen protection4)2SO4(100mg), HMDS (30mL) It is dissolved in chlorobenzene, is heated to backflow and is clarified until becoming to reaction solution.Rotation removes solvent, obtains the compound TMS protections of slurry Cytimidine；
Nitrogen protection under the TMS cytimidines protected are dissolved in dry MeCN (10ml), after by TMSOTf (7.12g, 32mmol) it is added dropwise, finishes stirring 5min or so reaction solutions and become after clarification, then by compound V (1g, 4mmol) MeCN (2ml) solution is added dropwise in reaction solution above, finishes and 10h is stirred under 40 degree, and TLC compounds V is finished, and is quenched with frozen water Go out, diatomite drainage, (30ml*2 times) washing filter cake of DCM, layering, organic phase is washed with NaCl (sat), and anhydrous sodium sulfate is done It is dry, it is spin-dried for crude product and is directly used in next step；
Crude product VI-2 is added in HOAc (10mL) solution at room temperature, and heating reflux reaction 20h, TLC detection raw material disappears, rotation Dry solvent, forms crude product VI-1 and is directly used in next step；
Crude product VI-1 is dissolved in MeOH (10ml), and NH is added afterwards3MeOH solution (10ml, wherein NH3Concentration is 11M), room Temperature stirring 16h.Raw material disappears, and is spin-dried for solvent, mixes sample column chromatography (DCM:MeOH=20:1) 780mg white solids, three steps are obtained Yield：40% (α:β=1:2).
Influence (see the table below) of the reaction dissolvent to selectivity：
Solvent α/β selectivity Total recovery
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%
Compound VI-2- β hydrogen spectrum：
1H-NMR(400MHz,CD3OD):δ 8.75 (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).
Compound VI-2- α hydrogen spectrum：
1H-NMR(400MHz,CD3OD):δ 8.22 (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).
PSI-6130 hydrogen spectrum：
1H-NMR(400MHz,DMSO-d6):δ 11.53-11.41 (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 part preferred embodiment of the present invention is above are only, the present invention is not limited in the content of embodiment.For ability For technical staff in domain, can there are various change and change in the concept of technical solution of the present invention, that is made appoints What changes and changed, within the scope of the present invention.

Claims (10)

1. a kind of bridged ring fluoroester, it is characterised in that：The bridged ring fluoroester is the fluoro- 6- methyl -2,7- of (1R, 4R, 5R, 6R) -6- Dioxy-bicyclo [2.2.1] heptyl -5- formic acid esters, its structure corresponds to logical formula (V), wherein R1Including phenyl, methyl, substituted benzene Base：
2. a kind of preparation method of bridged ring fluoroester as claimed in claim 1, it is characterised in that this method includes：Use formula (I) compound：
By：Sour cyclisation, upper leaving group, reduction, cyclization four-step reaction formed formula (V) ring fluoroester (1R, 4R, 5R, 6R) fluoro- 6- methyl -2,7- dioxy-bicyclos [2.2.1] heptyl -5- formic acid ester compounds of -6-：
3. preparation method according to claim 2, it is characterised in that in the sour cyclisation step, use the change of formula (I) Compound Deprotection and is cyclized in acid condition, and the compound of formula (II) is made：
Wherein, the acid condition is：Acid is any one in HCl, HOAc, TFA, is dissolved in solvent：MeCN、EtOH、 THF、DCM、H2Any one in O, toluene；And reaction temperature control is -50 DEG C to 90 DEG C.
4. preparation method according to claim 2, it is characterised in that in the upper leaving group step, use formula (II) Compound and reaction reagent carry out leaving group reaction in a solvent, the compound of formula (III) is made：
Wherein, X includes Cl, Br, I, NO as leaving group2, TosO, MsO, CF3SO3、PhSO3, o-methyl-benzene sulfonyl, a first Base benzenesulfonyl, naphthalene sulfonyl base etc., the reaction dissolvent is any one in MeCN, EtOH, THF, DCM, toluene, pyridine； Reaction temperature is -50 DEG C to 90 DEG C.
5. preparation method according to claim 2, it is characterised in that in the reduction step, uses the change of formula (III) Compound carries out reduction reaction with reducing agent in reaction dissolvent, and the compound of formula (IV) is made：
Wherein, the reducing agent is DIBAL-H, Red-Al, LiAlH (OBu-t)3In any one, the reaction dissolvent is Any one in THF, MTBE, DCM, toluene；Reaction temperature is -50 DEG C to 90 DEG C.
6. preparation method according to claim 2, it is characterised in that in the cyclization step, use the change of formula (IV) Compound carries out ring closure reaction in the basic conditions, and the compound of formula (V) is made：
Wherein, the alkalescence condition is：Alkali is DBU, NH3·H2O、Et3Any one in N, DIPEA, is dissolved in solvent： Any one in THF, DCM, toluene, acetonitrile；Reaction temperature is -50 DEG C to 90 DEG C.
7. a kind of application of bridged ring fluoroester as claimed in claim 1, it is characterised in that：The bridged ring fluoroester is used to synthesize logical Formula is the compound PSI -6130 of (VII)：
PSI-6130 is used as intermediate to prepare Suo Feibuwei medicines.
8. a kind of utilization bridged ring fluoro Lipase absobed PSI-6130 preparation method, it is characterised in that this method includes：
The use of the compound of logical formula (V) is the fluoro- 6- methyl -2,7- dioxy-bicyclos of ring fluoroester (1R, 4R, 5R, 6R) -6- [2.2.1] heptyl -5- formic acid esters passes through：Into glycosides, the compound PSI -6130 of deprotection base two-step reaction formation formula (VII)：
9. synthesis PSI-6130 according to claim 8 preparation method, it is characterised in that in the step into glycosides, make Carried out into the compound and the TMS uracils protected or cytimidine of formula (V) in the reaction dissolvent that lewis acid is present Glycosides reacts and forms the compound of formula (VI)：
Wherein Y is OH or NHBz groups；
When Y is OH groups, the compound that formula is (VI -1) is formed：
When Y is NHBz groups, the compound of formula (VI -2) is formed：
Wherein, the lewis acid is TMSOTf, SnCl4、TiCl4、BF3·Et2Any one in O, the reaction dissolvent is DCM、Cl-Ph、ClCH2CH2Cl, MeCN, toluene, CF3-Ph、CF3- Ph/MeCN mixed liquors, CH3It is any one in COOiPr, THF Kind；Reaction temperature is -50 DEG C to 90 DEG C.
10. synthesis PSI-6130 according to claim 8 preparation method, it is characterised in that the deprotection base step In：
Deprotection reaction is carried out in the basic conditions using formula for the compound of (VI -1) to slough blocking group and formed logical Formula is the compound PSI -6130 of (VII)：
Wherein, reaction dissolvent is MeOH, EtOH, H2Any one in O, THF, DCM, toluene, the reaction temperature is -50 DEG C To 90 DEG C；
Become OH groups for the first NHBz groups in acid condition of compound of (VI-2) using formula, then go in the basic conditions Protection group sloughs blocking group and obtains compound PSI -6130 that reaction expression is (VII),
Wherein reaction dissolvent is MeOH, EtOH, H2Any one in O, THF, DCM, toluene, the reaction temperature is -50 DEG C and arrived 90℃。
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