CN103360297A - Preparation method for trans-3-hydroxy-L-proline - Google Patents

Abstract

The invention discloses a preparation method for trans-3-hydroxy-L-proline. The compound trans-3-hydroxy-L-proline has a structural formula as described in the specification. According to the method, industrially produced vitamin C is used as a raw material, and a multi-step mild reaction with high stereochemical selectivity is adopted for preparation of trans-3-hydroxy-L-proline. The product, i.e., trans-3-hydroxy-L-proline, has high chemical purity and optical purity. The preparation method has the advantages of simple and easily practicable process and low cost and is suitable for kg-grade production.

Description

A kind of anti--preparation method of 3-hydroxyl-L-PROLINE

Technical field

The present invention relates to the synthesis technical field of medicine intermediate, relate to more specifically a kind of anti--preparation method of 3-hydroxyl-L-PROLINE.

Background technology

Instead-and 3-hydroxyl-L-PROLINE, chemical name: (2S, 3S)-3-hydroxyl pyrrolidine-2-formic acid, its structural formula is as follows:

It is a kind of naturally occurring non-protein amino acid, and nineteen sixty-eight is separated from the hydrolysate of Mediterranean Sponge first, other 1978 separated obtaining from the hydrolysate of twig and leaf of Royal poinciana (Delonix regia) seed again; In having the structure of bioactive polypeptides matter (for example mucrorin D, tetomycin and some cyclopeptide alkaloids), some have also found the existence of anti--3-hydroxyl-L-PROLINE fragment.Instead-3-hydroxyl-L-PROLINE has been used as a kind of valuable in the asymmetric synthesis building block, for example when being carried out asymmetric synthesis, (+)-castanospermine and 3-hydroxyproline betaines all to use anti--3-hydroxyl-L-PROLINE, but natural anti--3-hydroxyl-L-PROLINE is extremely faint at the content of occurring in nature, and be not easy to separate, it is very significant therefore developing a kind of its method of a large amount of preparations of can stablizing.

At present about instead-synthetic method of 3-hydroxyl-L-PROLINE has a lot, most method relates to enzymatic reaction, perhaps relate to asymmetric reduction and make up artificially two chiral centres in the molecule, or relate to severe toxicity (will use potassium cyanide such as reductibility ground cyanogenation), also some method steps is loaded down with trivial details in addition, and used unusual expensive reagent (as: silver suboxide, ruthenium trichloride etc.), more than these methods all be unfavorable for stable prepare in large quantities high mapping pure anti--3-hydroxyl-L-PROLINE.

Summary of the invention

In order to solve the above problems, the purpose of this invention is to provide a kind of anti--synthetic method of 3-hydroxyl-L-PROLINE compound, it is starting raw material that present method adopts the vitamins C of suitability for industrialized production, reaction through the multistep mild condition, simple to operate, total cost is lower, is fit to feather weight production.

To achieve these goals, the present invention has adopted following technical scheme:

A kind of anti--3-hydroxyl-L-PROLINE compound, it has following structural formula:

Its preparation process is:

A, vitamins C is dissolved among the acetone, the add-on of acetone is 2-5 times of vitamins C weight, drip Acetyl Chloride 98Min. under the room temperature, Acetyl Chloride 98Min. and ascorbic mol ratio are 1:0.5-1, be warming up to 40 ℃-60 ℃ after adding, insulated and stirred 1-5 hour, the thin-layer chromatography detection reaction was complete, and chemical equation is as follows:

With the freezing crystallize out of reaction solution, suction filtration washs to get chemical compounds I;

B, chemical compounds I add entry, add salt of wormwood, the add-on of water is 2-5 times of chemical compounds I weight, and the mol ratio of salt of wormwood and chemical compounds I is 1:2-3, adds rear ice bath and is cooled to 0-5 ℃, slowly drip 30% hydrogen peroxide, the mol ratio of hydrogen peroxide and chemical compounds I is 1:2-3, dropwises to be warming up to room temperature reaction 8-20 hour, adds 10% sodium sulfite aqueous solution cancellation reaction, be spin-dried for solvent, the white solid washing with alcohol, suction filtration is spin-dried for ethanol; Residue is dissolved with acetonitrile, and the acetonitrile add-on is 2-5 times of chemical compounds I weight, adds iodoethane, the mol ratio of iodoethane and chemical compounds I is 1:1-2, finish and be warming up to back flow reaction 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Be spin-dried for solvent, water dissolution, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound ii;

C, compound ii add N, dinethylformamide, adding imidazoles, the DMF add-on is 2-5 times of compound ii weight, and the mol ratio of imidazoles and compound ii is 1:3-5, add rear ice bath and be cooled to 0-5 ℃, add tert-butyl diphenyl silicon chlorine, the mol ratio of tert-butyl diphenyl silicon chlorine and compound ii is 1:1-1.5, finishes stirring at room 2-5 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound III;

D, compound III add methylene dichloride, the methylene dichloride add-on is 2-4 times of compound III weight, finish and be cooled to-78 ℃, drip the di-isopropyl aluminum hydride, the mol ratio of di-isopropyl aluminum hydride and compound III is 1:2-3, dropwises insulation-78 ℃, stirs 2-4 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Drip saturated potassium sodium tartrate solution and extract the reaction of going out, have solid to separate out, the elimination solid, washed with dichloromethane, the filtrate anhydrous sodium sulfate drying is spin-dried for to get compounds Ⅳ;

E, potassium tert.-butoxide add methyltriphenylphospbromide bromide phosphorus, add toluene, the mol ratio of potassium tert.-butoxide and compounds Ⅳ is 1:4-6, and the mol ratio of methyltriphenylphospbromide bromide phosphorus and compounds Ⅳ is 3-6, and the toluene add-on is 3-5 times of compounds Ⅳ weight, finish and be warming up to return stirring 2-5 hour, the tetrahydrofuran solution that adds compounds Ⅳ, tetrahydrofuran (THF) add-on are 1-3 times of compounds Ⅳ weight, finish to continue backflow 2-3 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound V;

F, compound V add tetrahydrofuran (THF), add the borine dimethyl sulphide, the tetrahydrofuran (THF) add-on is 2-4 times of compound V weight, the mol ratio of borine dimethyl sulphide and compound V is 1:4-6, keep 0-5 ℃ of temperature to stir 10-20 minute, be warming up to room temperature reaction 2 hours, the ice bath cooling, add aqueous sodium hydroxide solution, add hydrogen peroxide, the mol ratio of sodium hydroxide and compound V is 1:1-2, the mol ratio of hydrogen peroxide and compound V is 1:5-10, finished stirring at room 1 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound VI;

G, the compound VI adds methylene dichloride, add triethylamine, the methylene dichloride add-on is 2-4 times of compound VI weight, and the mol ratio of triethylamine and compound VI is 1:2-3,0-10 ℃ of control temperature, drip Methanesulfonyl chloride, the mol ratio of Methanesulfonyl chloride and compound VI is 1:1.2-1.5, dropwises, stirring at room 2 hours, the decompression desolventizing adds DMF, add sodiumazide, the DMF add-on is 2-4 times of compound VI weight, and the mol ratio of sodiumazide and compound VI is 1:3-5, finish, be warming up to 50-80 ℃ and stirred 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound VII;

H, the compound VII adds acetic acid, add entry, the acetic acid add-on is 5-8 times of compound VII weight, the add-on of water is 0.8-1.5 times of compound VII weight, finish stirring at room 12-24 hour, the decompression desolventizing adds tetrahydrofuran (THF), adds imidazoles, the tetrahydrofuran (THF) add-on is 2-4 times of compound VII weight, the mol ratio of imidazoles and compound VII is 1:2-4, is cooled to 0-5 ℃ of stirring, adds tri-tert silicon chlorine, the mol ratio of tri-tert silicon chlorine and compound VII is 1:1.5-2, finish and be warming up to stirring at room 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound VIII;

I, compound VIII add methylene dichloride, add triethylamine, the methylene dichloride add-on is 2-4 times of compound VIII weight, the mol ratio of triethylamine and compound VIII is 1:2-3, the 0-10 ℃ of lower Methanesulfonyl chloride that drips, and the mol ratio of Methanesulfonyl chloride and compound VIII is 1:1.2-1.5, dropwise, stirring at room 2 hours, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Answer liquid to be poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound IX;

J, the compound IX adds tetrahydrofuran (THF), add triphenylphosphine, the tetrahydrofuran (THF) add-on is 2-4 times of compound IX weight, the mol ratio of triphenylphosphine and compound IX is 1:1-1.5, finish, stirring at room 8-12 hour, add the 1mol/L aqueous sodium hydroxide solution, the mol ratio of aqueous sodium hydroxide solution and compound IX is 1:0.1-0.5, finishes and is warming up to backflow, stirred 24-36 hour, be cooled to 0-10 ℃, add salt of wormwood, add chloroformic acid benzyl ester, salt of wormwood with the mol ratio of compound IX be 1:2-3, the mol ratio of chloroformic acid benzyl ester and compound IX is 1:1-1.2, finishes stirring at room 1-4 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Answer liquid to be poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound X;

K, compound X add the mixing solutions of acetic acid and water, and the ratio of acetic acid and water is 15:1～15:5, finishes stirring at room 24-48 hour, and the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

The compound XI of decompression desolventizing;

L, compound XI add acetone, add Jones reagent, and the tetrahydrofuran (THF) add-on is 2-4 times of compound XI weight, the mol ratio of Jones reagent and compound XI is 1:1.5-3, and 0-5 ℃ of ice bath cooling temperature control stirred 2-3 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Add Virahol cancellation reaction, filter, the oily matter that is spin-dried for, column chromatography for separation gets the compound XII;

M, compound XII add methylene dichloride, add trifluoroacetic acid, and the methylene dichloride add-on is 40-50 times of compound XII weight, the mol ratio of trifluoroacetic acid and compound XII is 1:3-4, finish and be warming up to back flow reaction 24-48 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

The decompression desolventizing, the oily matter that is spin-dried for, column chromatography for separation gets compounds X III;

N, compounds X III add methyl alcohol, add entry, add palladium carbon, the methyl alcohol add-on is 3-6 times of compounds X III weight, the water add-on is 1-2 times of compounds X III weight, palladium carbon add-on is 5%-10% times of compounds X III weight, finishes, and passes into hydrogen, the control hydrogen pressure is a normal atmosphere, stirred 3-5 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Filter decompression desolventizing, the compounds X IV of ethyl alcohol recrystallization.

The product that the present invention is obtained detects, and it is as follows to detect data:

¹H?NMR(D ₂O，δ：1.97-1.99(m,2H),3.41-3.47(m,1H),3.52-3.57(m,1H),4.02(s,1H),4.62(s,1H))

Compared with prior art the present invention has following advantage and beneficial effect:

It is starting raw material that the present invention adopts the vitamins C of suitability for industrialized production, directly introduces chiral source and need not to make up artificially chiral centre, and simple to operate through the reaction of multistep mild condition, total cost is lower, is fit to feather weight production.

Embodiment

The below describes the specific embodiment of the present invention in detail:

A kind of anti--3-hydroxyl-L-PROLINE compound, it has following structural formula:

Its preparation process is:

1) the 3kg vitamins C is dissolved among the 10L acetone, drips Acetyl Chloride 98Min. 670g under the room temperature, be warming up to 50 ℃ after adding and stirred 2 hours, with the freezing crystallize out of reaction solution, suction filtration washs to get chemical compounds I 2.98kg, productive rate 81%;

2) the 2kg chemical compounds I is dissolved in the 10L water, add 2.56kg salt of wormwood, add rear ice bath and be cooled to 0-5 ℃, slowly drip the hydrogen peroxide of 2L30%, dropwise and be warming up to room temperature reaction 12 hours, add 10% sodium sulfite aqueous solution, be spin-dried for solvent, the white solid washing with alcohol, suction filtration is spin-dried for ethanol; Residue is dissolved with acetonitrile, add the 1.9kg iodoethane, finish and be warming up to back flow reaction 20 hours, be spin-dried for solvent, water dissolution, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound ii 1.7kg, productive rate 90%;

3) the 5kg compound ii is dissolved among the 20L DMF, add imidazoles 4.2kg, add rear ice bath and be cooled to 0-5 ℃, add tert-butyl diphenyl silicon chlorine 7.4kg, finished stirring at room 4 hours, reaction solution is poured into water cancellation, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound III 10.8kg, productive rate 100%;

4) 547g compound III is added methylene dichloride 3L, finish and be cooled to-78 ℃, drip 1mol/L di-isopropyl aluminum hydride 2.5L, dropwise insulation-78 ℃, stirred 3 hours, drip saturated potassium sodium tartrate solution 500mL and extract the reaction of going out, have solid to separate out, suction filtration, the DCM washing, the filtrate anhydrous sodium sulfate drying is spin-dried for to get compounds Ⅳ 3.96kg, productive rate 88%;

5) potassium tert.-butoxide 370g is dissolved among the toluene 2L, add 150g methyltriphenylphospbromide bromide phosphorus, finish and be warming up to return stirring 2 hours, add the 400mL tetrahydrofuran solution of 200g compounds Ⅳ, finish and continue backflow 2-3 hour, reaction solution is poured into water cancellation, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound V 183g, productive rate 92%;

6) 800g compound V is dissolved among the tetrahydrofuran (THF) 3L, keep 0-5 ℃ of temperature, drip 303mL borine dimethyl sulphide (10mol/L), stirred 10-20 minute, be warming up to room temperature reaction 2h, the ice bath cooling adds 480mL aqueous sodium hydroxide solution (3mol/L), adds 50% hydrogen peroxide 480mL, finished stirring at room 1 hour, reaction solution is poured into water cancellation, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets compound VI 728g, productive rate 87%;

7) 500g compound VI is dissolved in the 5L methylene dichloride, adds the 450g triethylamine, 0-10 ℃ of stirring of control temperature, drip the 193g Methanesulfonyl chloride, dropwise stirring at room 2 hours, the decompression desolventizing is dissolved in the 5L DMF with residue, add the 458g sodiumazide, finish, be warming up to 50-80 ℃ and stirred 20 hours, reaction solution is poured into water cancellation, ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound VII 477g, productive rate 90%;

8) 600g compound VII is dissolved in the mixing solutions of 3L acetic acid and water (6:1) stirring at room 20 hours, decompression desolventizing, add tetrahydrofuran (THF) 3L, add the 260g imidazoles, be cooled to 0-5 ℃ of stirring, add 200g tri-tert silicon chlorine, finish and be warming up to stirring at room 20 hours, reaction solution is poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound VIII 624g, productive rate 89%;

9) 500g compound VIII is dissolved in the 5L methylene dichloride, adds the 281g triethylamine, 0-10 ℃ of stirring of control temperature, drip the 135g Methanesulfonyl chloride, dropwise, stirring at room 2 hours, reaction solution is poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, decompression desolventizing, column chromatography for separation gets compound IX 547g, productive rate 95%;

10) 500g compound IX is dissolved in the 5L tetrahydrofuran (THF), add the 320g triphenylphosphine, finish, stirring at room 6 hours adds 100mL aqueous sodium hydroxide solution (1mol/L), finish and be warming up to backflow, stirred 30 hours, and be cooled to 0-10 ℃, add 240g salt of wormwood, add the 170g chloroformic acid benzyl ester, finish, stirring at room 2 hours, reaction solution is poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, decompression desolventizing, column chromatography for separation gets compound X 433g, productive rate 85%;

11) 400g compound X is dissolved in the mixing solutions of 4L acetic acid and water (10:1), finished stirring at room 28 hours, the compound XI 311g of decompression desolventizing, productive rate 96%;

12) 520 compound XI are dissolved in 10L acetone, add Jones reagent (100g chromium trioxide, 140g sulfuric acid and 600mL water mix), 0-5 ℃ of ice bath cooling temperature control stirred 2-3 hour, added 100mL Virahol cancellation reaction, filter, the oily matter that is spin-dried for, column chromatography for separation get compound XII 481g, productive rate 90%;

13) 250g compound XII is dissolved in the methylene dichloride and trifluoroacetic acid mixing solutions 1.3L of 100:1, finishes and be warming up to back flow reaction 36 hours, the decompression desolventizing, the oily matter that is spin-dried for, column chromatography for separation gets compounds X III115g, productive rate 88%;

14) 100g compounds X III is dissolved in 1.2L first alcohol and water (3:1) mixing solutions, adds 10g10% palladium carbon, finish, displace air, logical hydrogen stirred 3-5 hour, filtered decompression desolventizing, the compounds X IV39g of ethyl alcohol recrystallization, productive rate 80%.HPLC detects purity 98%,

Claims (1)

1. anti--3-hydroxyl-L-PROLINE compound, it has following structural formula:

Its preparation process is:

A, vitamins C is dissolved among the acetone, the add-on of acetone is 2-5 times of vitamins C weight, drip Acetyl Chloride 98Min. under the room temperature, Acetyl Chloride 98Min. and ascorbic mol ratio are 1:0.5-1, be warming up to 40 ℃-60 ℃ after adding, insulated and stirred 1-5 hour, the thin-layer chromatography detection reaction was complete, and chemical equation is as follows:

With the freezing crystallize out of reaction solution, suction filtration washs to get chemical compounds I;

B, chemical compounds I add entry, add salt of wormwood, the add-on of water is 2-5 times of chemical compounds I weight, and the mol ratio of salt of wormwood and chemical compounds I is 1:2-3, adds rear ice bath and is cooled to 0-5 ℃, slowly drip 30% hydrogen peroxide, the mol ratio of hydrogen peroxide and chemical compounds I is 1:2-3, dropwises to be warming up to room temperature reaction 8-20 hour, adds 10% sodium sulfite aqueous solution cancellation reaction, be spin-dried for solvent, the white solid washing with alcohol, suction filtration is spin-dried for ethanol; Residue is dissolved with acetonitrile, and the acetonitrile add-on is 2-5 times of chemical compounds I weight, adds iodoethane, the mol ratio of iodoethane and chemical compounds I is 1:1-2, finish and be warming up to back flow reaction 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Be spin-dried for solvent, water dissolution, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets compound ii;

C, compound ii add N, dinethylformamide, adding imidazoles, the DMF add-on is 2-5 times of compound ii weight, and the mol ratio of imidazoles and compound ii is 1:3-5, add rear ice bath and be cooled to 0-5 ℃, add tert-butyl diphenyl silicon chlorine, the mol ratio of tert-butyl diphenyl silicon chlorine and compound ii is 1:1-1.5, finishes stirring at room 2-5 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound III;

D, compound III add methylene dichloride, the methylene dichloride add-on is 2-4 times of compound III weight, finish and be cooled to-78 ℃, drip the di-isopropyl aluminum hydride, the mol ratio of di-isopropyl aluminum hydride and compound III is 1:2-3, dropwises insulation-78 ℃, stirs 2-4 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Drip saturated potassium sodium tartrate solution and extract the reaction of going out, have solid to separate out, the elimination solid, washed with dichloromethane, the filtrate anhydrous sodium sulfate drying is spin-dried for to get compounds Ⅳ;

E, potassium tert.-butoxide add methyltriphenylphospbromide bromide phosphorus, add toluene, the mol ratio of potassium tert.-butoxide and compounds Ⅳ is 1:4-6, and the mol ratio of methyltriphenylphospbromide bromide phosphorus and compounds Ⅳ is 3-6, and the toluene add-on is 3-5 times of compounds Ⅳ weight, finish and be warming up to return stirring 2-5 hour, the tetrahydrofuran solution that adds compounds Ⅳ, tetrahydrofuran (THF) add-on are 1-3 times of compounds Ⅳ weight, finish to continue backflow 2-3 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound V;

F, compound V add tetrahydrofuran (THF), add the borine dimethyl sulphide, the tetrahydrofuran (THF) add-on is 2-4 times of compound V weight, the mol ratio of borine dimethyl sulphide and compound V is 1:4-6, keep 0-5 ℃ of temperature to stir 10-20 minute, be warming up to room temperature reaction 2 hours, the ice bath cooling, add aqueous sodium hydroxide solution, add hydrogen peroxide, the mol ratio of sodium hydroxide and compound V is 1:1-2, the mol ratio of hydrogen peroxide and compound V is 1:5-10, finished stirring at room 1 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound VI;

G, the compound VI adds methylene dichloride, add triethylamine, the methylene dichloride add-on is 2-4 times of compound VI weight, and the mol ratio of triethylamine and compound VI is 1:2-3,0-10 ℃ of control temperature, drip Methanesulfonyl chloride, the mol ratio of Methanesulfonyl chloride and compound VI is 1:1.2-1.5, dropwises, stirring at room 2 hours, the decompression desolventizing adds DMF, add sodiumazide, the DMF add-on is 2-4 times of compound VI weight, and the mol ratio of sodiumazide and compound VI is 1:3-5, finish, be warming up to 50-80 ℃ and stirred 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound VII;

H, the compound VII adds acetic acid, add entry, the acetic acid add-on is 5-8 times of compound VII weight, the add-on of water is 0.8-1.5 times of compound VII weight, finish stirring at room 12-24 hour, the decompression desolventizing adds tetrahydrofuran (THF), adds imidazoles, the tetrahydrofuran (THF) add-on is 2-4 times of compound VII weight, the mol ratio of imidazoles and compound VII is 1:2-4, is cooled to 0-5 ℃ of stirring, adds tri-tert silicon chlorine, the mol ratio of tri-tert silicon chlorine and compound VII is 1:1.5-2, finish and be warming up to stirring at room 12-24 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Reaction solution is poured into water cancellation, ethyl acetate extraction, and the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing gets the compound VIII;

I, compound VIII add methylene dichloride, add triethylamine, the methylene dichloride add-on is 2-4 times of compound VIII weight, the mol ratio of triethylamine and compound VIII is 1:2-3, the 0-10 ℃ of lower Methanesulfonyl chloride that drips, and the mol ratio of Methanesulfonyl chloride and compound VIII is 1:1.2-1.5, dropwise, stirring at room 2 hours, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Answer liquid to be poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound IX;

J, the compound IX adds tetrahydrofuran (THF), add triphenylphosphine, the tetrahydrofuran (THF) add-on is 2-4 times of compound IX weight, the mol ratio of triphenylphosphine and compound IX is 1:1-1.5, finish, stirring at room 8-12 hour, add the 1mol/L aqueous sodium hydroxide solution, the mol ratio of aqueous sodium hydroxide solution and compound IX is 1:0.1-0.5, finishes and is warming up to backflow, stirred 24-36 hour, be cooled to 0-10 ℃, add salt of wormwood, add chloroformic acid benzyl ester, salt of wormwood with the mol ratio of compound IX be 1:2-3, the mol ratio of chloroformic acid benzyl ester and compound IX is 1:1-1.2, finishes stirring at room 1-4 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Answer liquid to be poured into water cancellation, ethyl acetate extraction, the saturated common salt washing, anhydrous sodium sulfate drying, the decompression desolventizing, column chromatography for separation gets the compound X;

K, compound X add the mixing solutions of acetic acid and water, and the ratio of acetic acid and water is 15:1～15:5, finishes stirring at room 24-48 hour, and the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

The compound XI of decompression desolventizing;

L, compound XI add acetone, add Jones reagent, and the tetrahydrofuran (THF) add-on is 2-4 times of compound XI weight, the mol ratio of Jones reagent and compound XI is 1:1.5-3, and 0-5 ℃ of ice bath cooling temperature control stirred 2-3 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Add Virahol cancellation reaction, filter, the oily matter that is spin-dried for, column chromatography for separation gets the compound XII;

M, compound XII add methylene dichloride, add trifluoroacetic acid, and the methylene dichloride add-on is 40-50 times of compound XII weight, the mol ratio of trifluoroacetic acid and compound XII is 1:3-4, finish and be warming up to back flow reaction 24-48 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

The decompression desolventizing, the oily matter that is spin-dried for, column chromatography for separation gets compounds X III;

N, compounds X III add methyl alcohol, add entry, add palladium carbon, the methyl alcohol add-on is 3-6 times of compounds X III weight, the water add-on is 1-2 times of compounds X III weight, palladium carbon add-on is 5%-10% times of compounds X III weight, finishes, and passes into hydrogen, the control hydrogen pressure is a normal atmosphere, stirred 3-5 hour, the thin-layer chromatography detection reaction is complete, and chemical equation is as follows:

Filter decompression desolventizing, the compounds X IV of ethyl alcohol recrystallization.