CN103524595A - Method for synthesizing pseudo-dipeptide Fmoc-Gly-Thr(phiMe, Me pro)-OH by utilizing new kilogram method - Google Patents

Abstract

The invention discloses a method for synthesizing pseudo-dipeptide Fmoc-Gly-Thr(phiMe, Me pro)-OH by utilizing a new kilogram method, and the method is mainly used for solving the technical problems that the original similar synthesis method has more steps, and is long in period, higher in danger of raw materials, difficult to operate, and high in cost.

Description

Feather weight novel method is synthesized the method for pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me pro)-OH

Technical field

The present invention relates to a kind of new chemical synthetic method, what be specifically related to is the method for synthetic pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me the pro)-OH of feather weight novel method.

Background technology

At present synthetic Fmoc-Gly-Thr (ψ Me, Me pro)-OH) route is as follows:

A. glycine stirs 1 hour in 8% sodium carbonate solution, then adds Fmoc-osu reaction within 2 hours, to obtain Fmoc-Gly-OH white solid;

B. by Fmoc-Gly-OH, H-Ser-OBzl.HCl and HOBt in flask, under ice bath, add DMF, after dissolving, add DIPEA activation 5min, finally add HBTU, reaction 10min recession deicing is bathed, room temperature reaction is complete to TLC detection reaction.Be extracted with ethyl acetate subsequently, 1mol/L hydrogen chloride solution, saturated sodium bicarbonate solution, saturated common salt water washing for organic phase for organic phase, anhydrous sodium sulfate drying, is spin-dried for solvent and obtains white solid, is Fmoc-Gly-Thr-OBzl;

C. by Fmoc-Gly-Thr-OBzl, DMP, PPTS in toluene, back flow reaction is complete to TLC detection reaction.Be extracted with ethyl acetate subsequently, saturated sodium bicarbonate solution, saturated common salt water washing for organic phase, anhydrous sodium sulfate drying, is spin-dried for solvent and obtains brown oil.Cross column purification and obtain yellow oil, be Fmoc-Gly-Thr (ψ Me, Me pro)-OBzl;

D. by Fmoc-Gly-Thr (ψ Me, Me pro)-OBzl in dissolve with methanol, (wherein, palladium massfraction 10%, 0.29g), passes into pressurized with hydrogen and reacts complete to TLC detection reaction to add Pd/C.Elimination Pd/C, liquid is spin-dried for the rear post of crossing, and obtains white powder, is Fmoc-Gly-Thr (ψ Me, Me pro)-OH

This process flow steps is many, and the cycle is long, and three-waste pollution is serious, and cost is high, and comprehensive benefit is poor, and middle back flow reaction is easy to cause the racemization of product, with easily dangerous larger reagent.Therefore develop the technique that low-cost and easy-to operational danger is little extremely important.

Summary of the invention

The object of the invention is to overcome the above problem that prior art exists, provide a kind of feather weight novel method to synthesize pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me pro) method of-OH, the step that solves former similar synthetic method existence is many, cycle is long, use dangerous larger raw material, be easily difficult to operation, the technical problem that cost is high.

For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the present invention is achieved through the following technical solutions:

Feather weight novel method is synthesized the method for pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me pro)-OH, comprises the following steps:

Step 1) in the sodium carbonate solution that glycine is 8% in concentration, stir 1 hour, then add Fmoc-osu reaction within 2 hours, to obtain Fmoc-Gly-OH white solid;

Step 2) Fmoc-Gly-OH, HOSU and condensing agent ECDHCl react and obtain Fmoc-Gly-Thr-OH oily matter in tetrahydrofuran (THF), and crystallization obtains pressed powder;

Step 3) Fmoc-Gly-Thr-OH obtains Fmoc-Gly-Thr (ψ Me, Me pro)-OH white powder with 2,2-dimethoxypropane reaction under reduced pressure;

Step 1,2,3 synthetic reaction formula are:

The invention has the beneficial effects as follows:

The present invention be take cheap glycine as starting raw material, does not need to process intermediate, and step is simple, it is convenient to process, and has greatly saved the raw material solvent of intermediate treatment, has reduced cost, saved in hydrogenation and needed this inflammable and explosive raw material of hydrogen, shortened the production cycle, simple to operate.

The reagent abbreviation of using in the present invention is expressed as follows:

Fmoc-osu: fluorenes methoxy carbonyl acyl succinimide

Thr: Threonine

Gly: glycine

Me: methyl

HOSU:N-N-Hydroxysuccinimide

EDCHCl:1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate

HBTU: benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

DIPEA:N, N-diisopropylethylamine

HOBt:1-hydroxybenzotriazole

PPTS: to toluene sulphur pyridinium salt

DMP:2,2-Propanal dimethyl acetal.

Embodiment

Below in conjunction with embodiment, describe the present invention in detail.

Feather weight novel method is synthesized the method for pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me pro)-OH, comprises the following steps:

Step 1) in the sodium carbonate solution that glycine is 8% in concentration, stir 1 hour, then add Fmoc-osu reaction within 2 hours, to obtain Fmoc-Gly-OH white solid;

Step 2) Fmoc-Gly-OH, HOSU and condensing agent ECDHCl react and obtain Fmoc-Gly-Thr-OH oily matter in tetrahydrofuran (THF), and crystallization obtains pressed powder;

Step 3) Fmoc-Gly-Thr-OH obtains Fmoc-Gly-Thr (ψ Me, Me pro)-OH white powder with 2,2-dimethoxypropane reaction under reduced pressure;

Step 1,2,3 synthetic reaction formula are:

Embodiment 1

Step 1) in the glass reaction still of 50 liters, 8% the sodium carbonate solution that adds 270 grams of glycine and 25 liters, stirring at room 1 hour, then be cooled to-5 ℃, by 1.275 kilograms of Fmoc-osu be dissolved in 12.5 liters 1, in 4-dioxane, solution was splashed in reactor in 1 hour, be warming up to room temperature, TCL monitoring, react 2 hours, after having reacted, with 3 liters of methyl tertiary butyl ether extractions, then separatory, water is cooled to 0 ℃, with concentrated hydrochloric acid, adjust PH to 2-3, again with 10 liters of ethyl acetate extractions, extraction liquid is with after anhydrous sodium sulfate drying, precipitation obtains 1.05 kilograms of kilogram Fmoc-Gly-OH white solids, HPLC is 95%.

Step 2) in the glass reaction still of 20 liters, add 1 kilogram of Fmoc-Gly-OH, 0.5 kilogram of HOSU and 5 liters of tetrahydrofuran (THF)s, controlling reacting liquid temperature is 25 ℃, 0.83 kilogram of EDCHCl is joined to 2.5 liters of N, in the mixed solution of dinethylformamide and 2.5 liters of tetrahydrofuran (THF)s, stir, then in 1 hour, be added drop-wise in glass reaction still, be added dropwise to complete rear stirring reaction 6 hours, TLC monitoring, after raw material reaction completes, be cooled to-5 ℃, by 269 grams of Lithium Hydroxide Monohydrates, 190 grams of Quilonum Retards and 1.2 kilograms of L-threonines are dissolved in 6 premium on currency, in 1 hour, splash in reactor, after being added dropwise to complete, be warming up to room temperature, then room temperature reaction is 1.5 hours, TLC monitoring, after having reacted, add the extraction of 3 * 1.5L ethyl acetate, extraction liquid anhydrous sodium sulfate drying, then precipitation, obtain yellow oil, add 3 liters of ethyl acetate crystallizations, obtain 1.1 kilograms of white product Fmoc-Gly-Thr-OH, HPLC purity is 97%.

Step 3) in the glass reaction still of 50 liters, 1 kilogram of Fmoc-Gly-Thr-OH is dissolved in the toluene of 10 liters, and add 3 liters of N, dinethylformamide and 20 grams of methanesulfonics, under 25-35 ℃ of condition, be decompressed under 80-30mbar, by 10 kilograms 2, 2-Propanal dimethyl acetal is dissolved in the toluene of 5 liters, then in 24 hours, add, in whole reaction process, adding toluene maintenance reaction solution volume is 13 liters, TLC monitoring, after having reacted, add 36 milliliters of triethylamines, stir 10 minutes, then add 1 premium on currency, separatory, which floor has add the sodium hydrogen carbonate solution of 5 kilogram 5%, two phase liquid is heated to 35-40 ℃, at this temperature, stir 30-45 minute, layering, organic layer uses the sodium hydrogen carbonate solution of 3 * 1.2 kilograms to extract again three times, merge water, the toluene that adds 6 liters, two-phase is heated to 35-40 ℃, it is 5.5 that sulfuric acid with 20% is adjusted PH, layering, organic layer is washed with 1 premium on currency, organic layer adds 1 premium on currency again, it is 4 that sulfuric acid with 20% is adjusted PH, layering, twice of the washing of 2 * 500 milliliters for organic layer, after precipitation, with Virahol and normal hexane recrystallization, obtain 736 grams of Fmoc-Gly-Thr (ψ Me, Me pro)-OH) white powder, HPLC=98%.

Claims (1)

1. the method for synthetic pseudo-dipeptides Fmoc-Gly-Thr (ψ Me, Me the pro)-OH of feather weight novel method, is characterized in that, comprises the following steps:

Step 1) in the sodium carbonate solution that glycine is 8% in concentration, stir 1 hour, then add Fmoc-osu reaction within 2 hours, to obtain Fmoc-Gly-OH white solid;

Step 2) Fmoc-Gly-OH, HOSU and condensing agent ECDHCl react and obtain Fmoc-Gly-Thr-OH oily matter in tetrahydrofuran (THF), and crystallization obtains pressed powder;

Step 3) Fmoc-Gly-Thr-OH obtains Fmoc-Gly-Thr (ψ Me, Me pro)-OH white powder with 2,2-dimethoxypropane reaction under reduced pressure;

Step 1,2,3 synthetic reaction formula are: