CN108484467A - A kind of preparation method of Oseltamivir acetylethyleneimine intermediate - Google Patents

Abstract

The invention discloses a kind of preparation methods of Oseltamivir (Oseltamivir) acetylethyleneimine intermediate compound I (attached drawing 1).The method is raw material with shikimic acid epoxides II, Oseltamivir acetylethyleneimine intermediate compound I is made through six chemical synthesis steps (attached drawing 2), yield is 44~61%.The present invention includes following six chemical synthesis step：(1) 3 open loops of epoxide II and pass through " one kettle way " three step cascade reaction formed 3,4 aziridine cpds III；(2) 33 open loops of amylalcohol selectivity attack obtain compounds Ⅳ；(3) 4 removing allyls obtain compound V；(4) 4 bit amino acetylations obtain compound VI；(5) 5 hydroxyl Mesylations obtain compound VII；5 cyclizations of (6) 4 acetylamino attacks obtain Oseltamivir acetylethyleneimine intermediate compound I.

Description

A kind of preparation method of Oseltamivir acetylethyleneimine intermediate

Technical field

The invention belongs to drug chemical technology fields, are related to the preparation method of drug, and in particular to a kind of Oseltamivir second The preparation method of acyl aziridine intermediate.

Technical background

The chemical full name of Oseltamivir phosphate (Oseltamivir phosphate) is 4- acetylaminohydroxyphenylarsonic acid 5- amino -3- (1- ethylpropoxies) -1- cyclohexene -1- carboxylic acid, ethyl ester phosphate is a kind of active drug of prevention bird flu.For a long time, The outburst of bird flu brings very grave disaster to the mankind., exactly Gilead companies and Switzerland Roche (Roche) company in 1999 Department of the phosphoric acid Austria (trade name of joint research and development exploitation：Tamiflu) listing, so that the bird flu of disaster human society is under control, is anti- Influenza is controlled, Oseltamivir phosphate also becomes the strategic reserves drug of many countries.

Oseltamivir phosphate be a kind of neuraminidase inhibitor (referring to:Nature.1993,363,418； WO91/ 16320；J.Med.Chem.1998,41,2451；J.Am.Chem.Soc.1997,119,681), but up to the present, have The method of the only Roche one for the production that industrial value can be paid, it is single to be not sufficient to cope with from the point of view of the production capacity of Oseltamivir phosphate The whole world problem (referring to：Angew.Chem.Int.Ed.2006,45, 7330).Gilead companies and Roche (Roche) company The method of cooperative development discloses one kind using naturally occurring shikimic acid and chinic acid as starting material, is selected by the solid of ketal The reduction of selecting property introduces 1- ethylpropoxies lawsuit and can roll into a ball, and nitrogen-containing functional group is introduced with nitrine reagent, allyl amine or tert-butylamine, The stereoselectivity ring-opening reaction of aziridine and etc. realize Oseltamivir phosphate industrialized production (referring to： Org.Process Res. Dev.1999,3,266；Org.Process Res.Dev.2004,8,86； J.Am.Chem.Soc.1997,119, 681；J.Org.Chem.1998,63,4545；Angew.Chem.Int.Ed.2006, 45,7330； US5763483/1998；WO99/55664；US5886213/1999；WO98/07685；EP1059283/ 2000), but its synthesis technology there are many problems：Inflammable and explosive chemicals nitrine must be used in the synthesis technology of the method Sodium, although production can carry out in explosion-proof workshop, there is security risks always, also easily lead to production process yield Lowly；The very strong trifluoromethanesulfonic acid of corrosivity (price is also costly) is used in the synthesis technology of the method, corrodes the pair generated Product not only brings difficulty to purifies and separates work, but also is bound to cause the extraneoas loss of product, influences the receipts of production process Rate.

In recent years, some patents of invention disclose with shikimic acid, pyridine, chiral amino compound, aldehyde and nitro compds, 1, 3- butadiene and ethyl ethyl propiolate, D-Glucose or D- xyloses, cis-1,4-butylene glycol, L-cysteine etc. are Beginning Material synthesis Oseltamivir phosphate or in which mesosome method (referring to： CN101351438A；CN101475573A； CN101538221A；CN101735140A； CN101801914A；CN102046592A；CN102127003A； CN102180821A； CN102464596A；CN103402973A；CN103833570A；CN104447451A； CN105330558A；CN105439884A；US2011021762A1；US2011040120A1； US2014243537A1； US2016222029A1).And the method for these presently disclosed synthesis Oseltamivir phosphates is still difficult to overcome using dangerous easy Fire explosive reagent, using expensive reagent, synthetic route length, low yield, severe reaction conditions, unfriendly environment the shortcomings of, cause It is difficult to industrialized production Oseltamivir phosphate.And have outburst when influenza is equal in the world at present, to influenza can be successfully managed The demand of Tamiflu be growing on and on, therefore insider it is expected that relevant scientific worker gives Improvement, provides one kind The preparation method of safer, easy, inexpensive, efficient Oseltamivir phosphate, to meet the whole mankind to prevention bird flu drug war The needs slightly laid in.

Invention content

The present invention provides a kind of preparation method of Oseltamivir acetylethyleneimine intermediate, it compared with prior art, Have the advantages that safe, easy, inexpensive, efficient, and raw material sources are abundant that (the raw materials used in the present invention is the epoxy compound of shikimic acid Object II can largely be prepared according to the literature method that this group has delivered by shikimic acid, referring to：Eur.J.Org.Chem.2013, 6389), it is easy to be produced on a large scale, increases the production capacity of Tamiflu, so as to meets the whole mankind to prevention bird flu drug war The needs slightly laid in.

To achieve the purpose of the present invention, using following technological means：

A kind of preparation method (see Fig. 2) of Oseltamivir phosphate acetylethyleneimine intermediate (see Fig. 1), including：With thick grass The epoxides of acid is raw material, carries out open loop to epoxy with allyl amine, and three step one kettle ways form 3 under alkaline condition, 4- aziridine, 3- amylalcohols introduce side chain to aziridine open loop in 3- selectivity, 4- allyls are sloughed under palladium chtalyst simultaneously Will be acetylated, then by cyclization obtains target product under highly basic effect after 5- hydroxyl Mesylations.

The body implementation steps of the present invention are described as follows：

1, compound ii forms epoxy, 3- allyl amidos to three step one of epoxy addition through allyl amine open loop, 4,5- Pot legal system obtains 3,4- allyl aziridine -5- hydroxyl ethyl shikimates, hereinafter referred to as compound III.

It is first that the allyl amine of 2~3 times of compound ii molar equivalents is soluble in water, compound ii is then dissolved in ethyl alcohol In, it is configured to 10~15% uniform solution, is then added in allyl amine solution, it is small to be heated to 55~85 DEG C of reactions 4~6 When, compound ii is converted into compound III.The volume ratio of second alcohol and water is 1/20~20/1, preferred alcohol/water=1/2, reaction Preferably 75 DEG C of temperature.After reaction, it the ethyl acetate of liquor capacities such as is added thereto, is sufficiently stirred, again with few after liquid separation It measures ethyl acetate and washs water layer two to three times, merge organic layer and drying, then carry out removing solvent ethyl acetate under reduced pressure, obtain one Kind yellow liquid, that is, compound III, yield are 88~92%.This step product can be refined for reacting in next step.

2,3- amylalcohols carry out compound III at 3- selective opening and 3- (1- ethylpropoxies) -4- allylamines are made Base -5- hydroxyl ethyl shikimates, hereinafter referred to as compounds Ⅳ.

First step 1 gained compound III is dissolved in 3- amylalcohols, is configured to the solution of compound III a concentration of 15~25%, The lewis acid of 1.0~2.0 times of compound III molar equivalents, preferably 1.5 times of equivalent boron trifluoride ether are added at room temperature (BF₃·OEt₂), reaction solution is then heated to 60~85 DEG C, preferably 70 DEG C, 3~6 hours compound IIIs of reaction convert completely For compounds Ⅳ.Reaction solution is cooled to room temperature, the ethyl acetate and water of 3~4 times of liquor capacities is separately added into thereto, stirs It mixes, and potash solid is added, pH is adjusted to 8~10, liquid separation simultaneously washs water layer 1~2 with a small amount of ethyl acetate, merges organic layer And it is dry, solvent, which is evaporated off, can obtain the yellow oily crude product of compounds Ⅳ, and for reacting in next step after further refining, yield is up to 85 ~90%.

3, compounds Ⅳ passes through the removing allyl under palladium chtalyst effect and 3- (1- ethylpropoxies) -4- amino -5- hydroxyls is made Base ethyl shikimate, hereinafter referred to as compound V.

First the compounds Ⅳ of gained in step 2 is dissolved in be configured in polar solvent 4~6% uniform solution, solvent is excellent It selects ethyl alcohol, is added the cation capturing agent 1 of 1.1~1.5 times of molar equivalents, 3- dimethyl barbituric acids (NDMBA), preferably 1.1 The triphenylphosphine of equivalent, the palladium and 0.02~0.08 times of molar equivalent that add 0.005~0.02 molar equivalent is urged Change, preferably 0.01 times of equivalents acetic acid palladium and 0.04 times of equivalent triphenylphosphine are protected with nitrogen or argon gas, reacted at 25~40 DEG C 2~3 hours complete removing allyls, preferably 35 DEG C.Ethyl alcohol is evaporated off under the conditions of room temperature or low-grade fever, is added thereto in equal volume Ethyl acetate and 5%wt K₂CO₃Aqueous solution stirs, and liquid separation simultaneously washs water layer 2~3 times with a small amount of ethyl acetate, merges organic layer And it is dry, solvent, which is evaporated off, can obtain V crude product of faint yellow compound, and yield can be directly used for reacting in next step up to 87~93%.

4, by acetylated obtained 3- (1- the ethylpropoxies) -4- acetylaminohydroxyphenylarsonic acid 5- hydroxyl shikimic acids of compound V Ethyl ester, hereinafter referred to as compound VI.

Step 3 gained compound V is dissolved in be configured in ethyl acetate 8~10% uniform solution, and be added etc. bodies 1.2 times of molar equivalents are slowly added dropwise as acid binding agent in the potassium carbonate of long-pending water, preferably 1.5 times molar equivalents under condition of ice bath Acetic anhydride, reaction in 10~30 minutes terminate, and liquid separation simultaneously washs water layer 1~2 time with a small amount of ethyl acetate, merge organic layer and do Dry, solvent evaporated can obtain faint yellow solid i.e. compound VI, and yield is up to 90~95%.It can be directly used for reacting in next step.

5,3- (1- ethylpropoxies) -4- acetylaminohydroxyphenylarsonic acid 5- mesyloxy thick grass is made through Mesylation in compound VI Acetoacetic ester, hereinafter referred to as compound VII.

First step 4 gained compound VI is dissolved in ethyl acetate or dichloromethane, be configured to a concentration of 4~6% it is equal The triethylamine of 1.5~2.0 times of VI molar equivalents of compound, preferably 1.5 times are first added at 0 DEG C, adds 0.05 for one solution The catalyst DMAP of~0.1 times of VI molar equivalent of compound, preferably 0.1 times are then added dropwise 1.25 times at 0 DEG C (in ice bath) The methane sulfonyl chloride of VI molar equivalent of compound constantly has white solid precipitation to generate, and the duration is added dropwise up to 0.5 hour left side The right side after being added dropwise, is further continued for reaction 0~0.5 hour, and compound VI is converted into compound VII.After reaction into solution The 5%wt K of the liquor capacities such as addition₂CO₃Aqueous solution is sufficiently stirred, and is washed again with a small amount of ethyl acetate or dichloromethane after liquid separation Water layer one is washed to twice, merges organic layer and drying, then carry out removing solvent ethyl acetate or dichloromethane under reduced pressure, obtains one kind Yellow solid, that is, compound VII, yield reaches 90~94%.It can further refine for reacting in next step.

6,3- (1- ethylpropoxies) -4,5- acetylethyleneimine ethyl shikimates are made through cyclization in compound VII, i.e., department difficult to understand His Wei acetylethyleneimine intermediate compound I.

By in step 5 gained compound VII be dissolved in be configured in polar solvent 4~6% uniform solution, polar solvent It is preferred that tetrahydrofuran, the highly basic for being slowly added to 2 times of molar equivalents at room temperature is reacted, the hydrogen that highly basic preferred content is 60% Change sodium, 1~2 hour compound VII of reaction is fully converted to Oseltamivir intermediate compound I.Tetrahydrofuran is evaporated off at room temperature, is added Isometric ethyl acetate and water is extracted, and a small amount of ethyl acetate washing water layer is used in combination 1~2 time, merges organic layer and drying, Solvent, which is evaporated off, can obtain yellow liquid, and yield is 84~89%.The Oseltamivir acetyl nitrogen of colorless liquid can be obtained by further refining Third pyridine intermediate compound I, thus intermediate can be made according to literature method Oseltamivir phosphate (referring to：Tetrahedron: Asymmetry 2013,24,638；RSC Adv.2014, 4,11417；).

Description of the drawings

Oseltamivir intermediate structure I and synthetic route are respectively referring to Figure of description Fig. 1 and Fig. 2.

Specific implementation mode

With reference to the embodiment content that the present invention is furture elucidated, but embodiment does not influence protection scope of the present invention：

Embodiment 1

The preparation of 3,4- allyl aziridine -5- hydroxyls ethyl shikimate, that is, compound III：

It takes 66mL water and 33mL absolute ethyl alcohols to be added in 250mL single-necked flasks, allyl amine is added thereto (3.226g, 57.3mmol) then changes 3, the 4- allyl aziridine -5- hydroxyl ethyl shikimates of gained in embodiment 4 It closes object II (5.003g, 19.1mmol) to be added thereto, is heated to 75 DEG C of stirrings and is down to room temperature after reacting 5 hours, add thereto Enter 100mL ethyl acetate to be extracted, water layer is washed twice with 50mL ethyl acetate respectively, merges organic layer and with anhydrous sulphur Sour magnesium drying, filters out magnesium sulfate solid, removes ethyl acetate and part ethyl alcohol under reduced pressure, obtain weak yellow liquid i.e. compound III (3.947g, 17.7mmol), yield 93%.Column chromatography purifying again is used for Structural Identification.

Compound III is detected with Nuclear Magnetic Resonance, as a result as follows：

¹H NMR(CDCl₃) δ=1.27 (t, J=7.1Hz, 3H), 2.05 (t, J=7.4Hz, 1H), 2.12-2.38 (m, 4H), 2.73 (m, 2H), 2.89-2.98 (m, 1H) 3.02-3.10 (m, 1H), 4.17 (q, J=7.4Hz, 2H), 4.48 (s, 1H),5.08-5.24(m,2H),5.81-5.94(m,1H),7.24-7.30(m,1H).¹³C NMR (CDCl₃) δ=166.72, 136.51,134.44,127.72,116.77,62.53,61.75,60.65,46.52,34.88, 29.99,14.20.

Embodiment 2

The preparation of 3- (1- ethylpropoxies) -4- allyl amido -5- hydroxyoxalates ethyl ester, that is, compounds Ⅳ：

It will be placed in 250mL single-necked flasks in 1 gained compound III (6.004g, 26.9mmol) of embodiment, be first added 30mL3- amylalcohols dissolve, and boron trifluoride ether (5.735g, 40.4mmol) is added thereto at room temperature, are heated to 70 DEG C of reactions 3 Hour, reaction solution is cooled to room temperature by TLC monitoring raw materials after completely disappearing, and is separately added into 100mL ethyl acetate and water thereto Stirring, and potash solid is added, pH is adjusted to 10 or so, liquid separation is used in combination ethyl acetate washing water layer twice (2 × 50mL), is closed And ethyl acetate and drying, ethyl acetate is evaporated off and 3- amylalcohols obtain yellow liquid i.e. compounds Ⅳ (7.526g, 24.2mmol), Yield is up to 90%.Column chromatography purifying again is used for Structural Identification.

Compounds Ⅳ is detected with Nuclear Magnetic Resonance, as a result as follows：

1H NMR(CDCl₃) δ=0.80-0.96 (m, 6H), 1.25 (t, J=7.1Hz, 3H), 1.38-1.63 (m, 4H), 2.20-2.32(m,1H),2.36-3.13(m,4H),3.30-3.40(m,2H),3.47(dd,J₁=13.9Hz； J₂=5.8Hz, 1H), 3.59-3.69 (m, 1H), 3.91-3.99 (m, 1H), 4.16 (q, J=7.1Hz, 2H), 5.01-5.11 (m, 1H), 5.11-5.23(m,1H),5.80-5.94(m,1H),6.74-6.84(m,1H).13C NMR(CDCl₃) δ=166.49, 136.81,136.62,128.94,116.05,80.57,75.69,67.54,62.62, 60.79,50.29,32.37,26.24, 25.43,14.16,9.53,9.37.

Embodiment 3

The preparation of 3- (1- ethylpropoxies) -4- amino -5- hydroxyls ethyl shikimate, that is, compound V：

The compounds Ⅳ (5.003g, 16.1mmol) of gained in embodiment 2 is placed in 250mL single-necked flasks, is added 100mL ethyl alcohol dissolves, and 1,3- dimethyl barbituric acids (2.761g, 17.7mmol) are added at room temperature, palladium is then added (36mg, 0.16mmol) and triphenylphosphine (168mg, 0.64mmol) is heated to 35 DEG C of reactions and is reacted for 2 hours with nitrogen protection Terminate.Then ethyl alcohol is evaporated off at 30 DEG C or so, 100mL ethyl acetate and 5%wt wet chemicals, extraction is respectively added thereto Liquid separation simultaneously washs water layer (2 × 50mL) twice with ethyl acetate, and after combined ethyl acetate is dried with anhydrous magnesium sulfate, acetic acid is evaporated off Ethyl ester obtains yellow liquid i.e. compound V (4.065g, 15.0mmol), and yield is up to 93%.Column chromatography purifying again is reflected for structure It is fixed.

Compound V is detected with Nuclear Magnetic Resonance, as a result as follows：

¹H NMR(CDCl₃) δ=0.82-0.96 (m, 6H), 1.25 (t, J=7.1Hz, 3H), 1.38-1.64 (m, 4H), 2.12-2.25(m,1H),2.68-2.84(m,2H),2.92-3.20(m,3H),3.28-3.38(m,1H), 3.53-3.65(m, 1H), 3.75-3.84 (m, 1H), 4.16 (q, J=7.1Hz, 2H), 6.70-6.77 (m, 1H)¹³C NMR(CDCl₃) δ= 166.40,137.05,129.06,80.96,78.16,68.88,60.80,58.13, 32.87,26.40,25.62,14.16, 9.72,9.40.

Embodiment 4

The preparation of 3- (1- ethylpropoxies) -4- acetylaminohydroxyphenylarsonic acid 5- mesyloxies ethyl shikimate, that is, compound VI：

Compound V (4.001g, 14.8mmol) is placed in 100mL single-necked flasks, 40mL and 40mL water is added, then add Enter potash solid (3.063g, 22.2mmol), ice bath stirring, then acetic anhydride (1.815g, 17.8mmol) is slowly added dropwise, 10 points Clock or so is added dropwise, and TLC is monitored after reaction, extracts liquid separation, and ethyl acetate washing water layer is used in combination twice (2 × 20mL), Merge organic layer and dried with anhydrous magnesium sulfate, filters off magnesium sulfate, remove ethyl acetate under reduced pressure and obtain faint yellow solid i.e. chemical combination Object VI (4.413g, 14.1mmol), yield is up to 95%.Column chromatography purifying again is used for Structural Identification.

Compound VI is detected with Nuclear Magnetic Resonance, as a result as follows：

¹H NMR(CDCl₃) δ=0.90 (t, J=7.1Hz, 6H), 1.30 (t, J=7.1Hz, 3H), 1.41-1.61 (m, 4H),2.04(s,3H),2.29-2.44(m,1H),2.72-2.87(m,1H),3.31-3.44(m,1H), 3.75-3.86(m, 1H), 3.91-4.03 (m, 1H), 4.00-4.18 (m, 2H), 4.22 (q, J=7.1Hz, 2H), 5.99 (d, J=7.0Hz, 1H), 6.70-6.85(m,1H).¹³C NMR(CDCl₃) δ=172.11,166.26,136.91,129.07,81.90,74.97, 67.87,60.91,57.35,32.92,26.19,25.64,23.48,14.15, 9.52,9.22.

Embodiment 5

The preparation of 3- (1- ethylpropoxies) -4- acetylaminohydroxyphenylarsonic acid 5- mesyloxies ethyl shikimate, that is, compound VII：

Compound VI (4.003g, 12.8mmol) is placed in 250mL single-necked flasks, 80mL ethyl acetate, ice are added Bath stirring, is added MsCl (2.189g, 19.2mmol) and DMAP (0.156g, 1.3 mmol), then by Et₃N(2.586g, 25.6mmol) slowly drop is in reaction solution, time for adding 0.5h, and the reaction was continued 0.5h adds 80mL 5%wt K₂CO₃Water Solution stirs, and extracts liquid separation, and ethyl acetate washing water layer is used in combination twice (2 × 40mL), it is dry with anhydrous magnesium sulfate to merge organic layer It is dry, magnesium sulfate is filtered off, ethyl acetate is removed under reduced pressure and obtains yellow solid i.e. compound VII (4.809g, 12.3mmol), yield 96%.Column chromatography purifying again is used for Structural Identification.

Compound VII is detected with Nuclear Magnetic Resonance, as a result as follows：

¹H NMR(CDCl₃) δ=0.81-0.97 (m, 6H), 1.30 (t, J=7.1Hz, 3H), 1.42-1.59 (m, 4H), 2.03(s,3H),2.50-2.63(m,1H),3.05(s,3H),3.07(dd,J₁=16.8Hz；J₂=5.6Hz, 1H), 3.29- 3.39(m,1H),3.88(dd,J₁=19.4Hz；J₂=8.7Hz, 1H), 4.22 (q, J=7.1Hz, 2H), 4.40 (d, J= 8.6Hz, 1H), 4.99-5.11 (m, 1H), 6.02 (d, J=8.1Hz, 1H), 6.75-6.84 (m, 1H)¹³C NMR(CDCl₃)δ =171.14,165.47,138.06,127.21,82.46,75.89,74.42,61.20,55.4 8,38.58,31.55, 26.23,25.66,23.54,14.20,9.55,9.26

Embodiment 6

3- (1- ethylpropoxies) -4,5- acetylethyleneimines ethyl shikimate, that is, Oseltamivir acetylethyleneimine intermediate compound I Preparation：

Compound VII (2.00g, 5.1mmol) is placed in 100mL single-necked flasks, 60mL tetrahydrofurans, water-bath are added Stirring is slowly added to 60%NaH (0.816g, 20.4mmol), is terminated with TLC detection reactions after reacting 1h, tetrahydrochysene furan is evaporated off It mutters, 40mL ethyl acetate and water extraction is added, it is primary that organic layer with a small amount of ethyl acetate (20mL) washs water layer.Gained organic layer Anhydrous magnesium sulfate is dried, and is filtered off magnesium sulfate, is removed ethyl acetate under reduced pressure and obtain pale yellow oil i.e. Oseltamivir intermediate compound I (1.43g, 4.84mmol), yield is up to 89%.Column chromatography purifying again is used for Structural Identification.

Oseltamivir acetylethyleneimine intermediate compound I is detected with Nuclear Magnetic Resonance, as a result as follows：

¹H NMR(CDCl₃) δ=0.91 (t, J=7.4Hz, 3H), 0.96 (t, J=7.4Hz, 3H), 1.29 (t, J= 7.1Hz,3H),1.46-1.64(m,4H),2.14(s,3H),2.56-2.70(m,1H),2.85-3.02(m,3H), 3.37- 3.49 (m, 1H), 4.21 (q, J=7.1Hz, 2H), 4.33-4.42 (m, 1H), 6.83 (s, 1H)¹³C NMR (CDCl₃) δ= 182.55,166.46,133.04,127.72,82.41,68.50,60.87,37.11,34.76,26.62, 26.56,23.78, 23.44,14.15,9.89,9.44。

Claims (6)

1. a kind of preparation method of Oseltamivir phosphate acetylethyleneimine intermediate, the method are to be with the epoxides of shikimic acid Raw material, it is characterised in that the method includes chemical synthesis step following six：

(1) in polar solvent system, allylamine stirring is first added at room temperature, then epoxide II is added to mixed liquor In, it is warming up to 55~85 DEG C of reactions and obtains 3,4- allyl aziridine -5- hydroxyl ethyl shikimates in 4~6 hours, be labeled as chemical combination Object III；

(2) it will be dissolved in 3- amylalcohols by the compound III obtained by step (1), the Louis of 1.0~2.0 times of molar equivalents be added Acid catalysis, then reaction system was warming up to 60~85 DEG C of reactions at 3~6 hours, 3- (1- ethylpropoxies) -4- allyls amido - 5- hydroxyl ethyl shikimates are labeled as compounds Ⅳ；

(3) it will be dissolved in polar solvent by the compounds Ⅳ obtained by step (2), with 1, the 3- diformazans of 1.1~1.5 molar equivalents Base barbiturates (NDMBA) is cation capturing agent, in the palladium of 0.005~0.02 times of molar equivalent and 0.02~0.08 times It under the catalytic action of the triphenylphosphine of molar equivalent, is reacted 2~3 hours at 25~40 DEG C, removes allyl, obtain 3- (1- second Base propoxyl group) -4- amino -5- hydroxyl ethyl shikimates, it is labeled as compound V；

(4) using ethyl acetate and water two-phase as solvent, using the inorganic base of 1.2~2 times of molar equivalents as acid binding agent,

10~30 minutes hours will be reacted at 0~10 DEG C with acetic anhydride by the compound V obtained by step (3), 3- (1- are made Ethylpropoxy) -4- acetylaminohydroxyphenylarsonic acid 5- hydroxyl ethyl shikimates, it is labeled as compound VI；

(5) it will be dissolved in ethyl acetate or dichloromethane by the compound VI obtained by step (4), is first being added 1.5~2.0 times moles The triethylamine of equivalent adds the 4-dimethylaminopyridine (DMAP) of catalytic amount, and 1.1~1.5 times moles are added dropwise at 0~10 DEG C Equivalent mesyl chloride reacts 0.5~1 hour obtained 3- (1- ethylpropoxies) -4- acetylaminohydroxyphenylarsonic acid 5- mesyloxy shikimic acid Ethyl ester is labeled as compound VII；

(6) it will be dissolved in polar solvent by the compound VII obtained by step (5), at 10~25 DEG C, 4- pulled out with highly basic 5- removing mesyloxies of active proton and attack on acetylamino, are made 3- (1- ethylpropoxies) -4,5- acetyl nitrogen Third pyridine ethyl shikimate is labeled as finished product I.

2. preparation method as described in claim 1, it is characterised in that polar solvent used is DMF, DMSO, third in step (1) One kind in ketone, methanol, second alcohol and water, or the mixed solvent that is made of water and alcohol, the mixing ratio of mixed solvent be water/alcohol= One kind in 20/1~1/20.

3. preparation method as described in claim 1, it is characterised in that described lewis acid is zinc chloride, chlorine in step (2) Change one kind in tin, aluminium chloride, iron chloride, copper chloride, zinc bromide, magnesium bromide, copper bromide and boron trifluoride ether.

4. preparation method as described in claim 1, it is characterised in that in step (3) described polar solvent be tetrahydrofuran, One kind in ethyl alcohol, methanol.

5. preparation method as described in claim 1, it is characterised in that described inorganic base is sodium bicarbonate, carbon in step (4) One kind in sour sodium, potassium carbonate, sodium hydroxide, potassium hydroxide.

6. preparation method as described in claim 1, it is characterised in that in step (6) described polar solvent be tetrahydrofuran, Or tetrahydrofuran and toluene, the mixed solvent of dichloromethane, described highly basic are potassium tert-butoxide, sodium tert-butoxide, butyl lithium, hydrogenation One kind in sodium, hydrofining, sodium methoxide.