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CN103897028A - Synthesis method of bortezomib - Google Patents

Synthesis method of bortezomib Download PDF

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Publication number
CN103897028A
CN103897028A CN201410134931.0A CN201410134931A CN103897028A CN 103897028 A CN103897028 A CN 103897028A CN 201410134931 A CN201410134931 A CN 201410134931A CN 103897028 A CN103897028 A CN 103897028A
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李合亭
万阳
张斌
冀学芳
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Yiteng Pharmaceutical (taizhou) Co Ltd
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Yiteng Pharmaceutical (taizhou) Co Ltd
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Abstract

The invention discloses a synthesis method of a bortezomib. The synthesis method comprises the following steps: performing esterification, chlorination, ammonia substitution and deprotection reactions on (1S, 2S, 3R,5S)-(+)-2,3-pinanediol and an isobutylboronic acid as starting raw materials to obtain a trifluoroacetate, next, carrying out a reaction of the trifluoroacetate and Boc-L-phenylalanine, amino deprotection and condensation with pyrazine-2-carboxylic acid, and finally, removing a protecting group to obtain [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarboxyl)amino]proyl]amino]butyl]boric acid. The synthesis method has the advantages of easily available raw materials, low price, mild reaction conditions, low requirements for production equipment, simplicity in operations and relatively low production cost. In the entire process, no heavy metal compound joins in the reactions, and tremendously high chemical purity of 99.5% and high yield of 82% can be obtained by use of simple treatment such as crystallization in stead of column chromatography. The bortezomib can be used as a raw material with tremendously high optical purity and yield, and is applicable to industrial production.

Description

A kind of synthetic method of Velcade
Technical field
The present invention relates to a kind of preparation method of cancer therapy drug, be specifically related to a kind of synthetic method of Velcade.
Background technology
Velcade, chemical name: [(1R)-3-methyl isophthalic acid-[[(2S)-1-oxygen-3-phenyl-2-[(pyrazine formyl) amino] propyl group] amino] butyl]-boric acid, outer literary fame or general by name: Bortezomib, translated name Velcade; Commodity are by name: Velcade, trade(brand)name translated name is: Wan Ke, molecular formula: C 19h 25bN 4o 4.Velcade is a kind of two skin ylboronic acid compounds, as a kind of new and effective single-minded proteinase inhibitor, be to be researched and developed by Millennium Pharmaceuticals company of the U.S. the earliest, and the approval that obtains FDA May 19 in 2003 is with the list marketing of Velcade trade(brand)name, is injection.Go on the market successively in Britain, Switzerland, Iceland, Australia, Malaysia and the country such as Chinese subsequently, be mainly used in treating recurrent and Refractory Multiple Myeloma.Along with a large amount of medical workers' continuous research is found, Velcade not only has good curative effect at treatment recurrent and Refractory Multiple Myeloma, and research also shows that it all demonstrates and have cytotoxicity multiple other human tumor cells.Show in American-European clinical application, it is for the treatment of other solid tumors, for example have obvious curative effects in treatments such as treatment lymphoma, uterine neck knurl, hepatocellular carcinoma, acute leukemia and myelodysplastic syndromes, therefore Velcade is becoming the important drugs of oncotherapy.Current existing research data has shown that Velcade has shown positive effect in the targeted therapy of hemopathy tumour as a kind of proteasome inhibitor, it is applied to the treatment research of other solid tumor, also will point out a new anticancer road for us.
At home in existing synthetic method, great majority use palladium carbon hydrogenation catalyst method of reducing in the time of deprotection, or use heavy metal catalyst synthetic, in medicine, inevitably produce heavy-metal residual and extremely difficulty remove.And the pharmacopeia of China's latest edition is to heavy-metal residual, for example, palladium content limit value requires extremely strict (requiring < 1ppm), therefore we to develop a cost lower, working condition gentleness, and the route of the synthetic Velcade of heavy metal free participation, have very heavy meaning.
Velcade molecular structure is as follows:
The production technique of the domestic Velcade of having reported has following several:
1, CN 101812026 A patent routes are:
Figure 2014101349310100002DEST_PATH_IMAGE002
This patent is taking 3-methyl butyraldehyde and R-(+)-1-phenylethylamine as starting raw material; by the condensation of chiral reagent R-1-phenylethylamine, the addition of boron selective acid esters, hydrogenation, twice condensation, finally obtain Velcade (Bortezomib) by isobutyl-boric acid deprotection.Although this synthetic method is raw materials used simple and easy to get, raw materials cost is lower, or uses the catalyzer such as organic titanium, inorganic caesium, organic Inorganic Copper and palladium metal in synthetic.The characteristics such as that organic titanium catalyzer has is inflammable, facile hydrolysis and toxicity, inorganic metal catalyzer has increased the risk that in bulk drug, heavy metal content exceeds standard greatly, particularly use palladium carbon catalytic hydrogenating reduction, palladium charcoal not only expensive but also current palladium as I metalloid, in requirement bulk drug, palladium content must not be higher than 1ppm, this is difficult to reach in reality is produced, and pressurized with hydrogen hydrogenation, exists very large combustion explosion hidden danger simultaneously; On the other hand in process of production, repeatedly use column chromatography purification, not only cause the increase of production cost, and the waste liquid, waste gas and the solid silicone that produce also can cause certain pollution to environment.In a word, the use of numerous catalyzer, repeatedly the purifying mode of column chromatography, no matter from production cost, is still all unsuitable for suitability for industrialized production from the viewpoint of this routes such as environment protection.
2, CN 102659919 A patent routes are:
Figure 2014101349310100002DEST_PATH_IMAGE003
This patent is optimized production technique on the basis of patent CN101812026.Adopt isovaleric aldehyde as raw material, use the sub-sulfonephthalein amine of the chirality R-tertiary butyl replace R-1-phenylethylamine as chiral shift reagent by condensation, nucleophilic addition(Adn), hydrolysis, condensation and under the effect of isobutyl-boric acid ester deprotection obtain Velcade.With respect to patent CN101812026, this technique can obtain the compound of pure single configuration, the bulk drug quality finally having ensured.Walk around palladium charcoal catalytic hydrogenating reduction step, produce cost greatly.Although pass through process modification; product yield and purity are all improved; or but this route use equally organic titanium, inorganic caesium, organic Inorganic Copper and etc. catalyzer, Multiple through then out reaches the purity requirement of product to column chromatography method, be generally also unsuitable for large-scale production.
3, CN 102351890 A patent routes are:
This patent, taking the salt of R-1-amino-3-methyl-boron-dihydroxide pinane diol ester as raw material is through condensation, debenzylation, condensation, oxidation deprotection, obtains Velcade after solvent purification.The method reactions steps is few, reaction conditions is gentle, has improved the purity of Velcade; Slough pinine glycol by change coupling reagent and final step oxidation, reduced production cost, be conducive to suitability for industrialized production.But in coupling one step is produced, need to obtain qualified product by column chromatography purification; When debenzylation, need to use palladium carbon and hydrogen.Column chromatography and palladium charcoal catalytic hydrogenation are all unsuitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art part, a kind of method that can suitability for industrialized production Velcade is provided, the method is simple, processing is convenient, with low cost and environmental friendliness, technical problem to be solved is to optimize synthesis technique, is operated and can be produced to steady and continuous the bulk drug Velcade conforming to quality requirements completely by simple industrial.
Technical solution problem of the present invention adopts following technical scheme: the synthetic method of Velcade of the present invention is taking isobutyl-boric acid as starting raw material; pinine glycol is that chiral reagent forms boric acid ester through condensation; afterwards by the insertion reaction of chloromethyl; amino nucleophilic substitution reaction, then take off trimethyl silicon based blocking group and obtain important intermediate.This intermediate passes through amino acid condensation again, tertbutyloxycarbonyl deprotection, and amino acid condensation, by the synthetic Velcade that obtains of the steps such as isobutyl-boric acid hydrolysis.
The synthetic method of a kind of Velcade of the Velcade the present invention relates to, according to the following steps preparation:
1), with isobutyl-boric acid and (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol is starting raw material, and at room temperature molar equivalent is than 1:1 ~ 3, and reaction solvent is hydro carbons or the ether solvents such as hexanaphthene, methyl ether, ether and isopropyl ether; Stirring reaction, obtains the isobutyl-boric acid ester product that compound 1 pinine glycol is protected, and the structure of described compound 1 as shown in Equation 1;
Figure 2014101349310100002DEST_PATH_IMAGE005
Formula 1
2), compound 1 with diisopropylamino lithium (LDA) molar equivalent than being 1:1 ~ 2, with the mol ratio of Zinc Chloride Anhydrous be 1:1 ~ 4, in organic solvent solution, generate product compound 2 by rearrangement reaction, the structure of described compound 2 as shown in Equation 2;
Formula 2
3), compound 2 and hexamethyl silicon amido lithium (LiHMDS, 1N tetrahydrofuran solution)) or hexamethyl silicon sodium amide (NaHMDS, 1N tetrahydrofuran solution) molar equivalent than for 1:1 ~ 3, obtain compound 3 through amino substitution reaction, the structure of described compound 3 as shown in Equation 3;
Figure 2014101349310100002DEST_PATH_IMAGE007
Formula 3
4), compound 3 is dissolved in organic solvent, or by trifluoroacetic acid hydrogenchloride deprotection in organic solvent, generate compound 4, the structure of described compound 4 is as shown in Equation 4;
Figure 2014101349310100002DEST_PATH_IMAGE008
Formula 4
5), compound 4 by with the condensation of Boc-L-phenylalanine, obtain compound 5, condensing agent is wherein one or several such as TBTU, EDCI, HOBt, HATU and PyBOP, organic bases is that the one such as triethylamine, diisopropylethylamine or mixing are used, and the structure of described compound 5 as shown in Equation 5;
Figure DEST_PATH_IMAGE009
Formula 5
6), compound 5 is dissolved in organic solvent, or in the organic solution of trifluoroacetic acid hydrogenchloride deprotection, obtain compound 6, the structure of described compound 6 as shown in Equation 6;
Figure 2014101349310100002DEST_PATH_IMAGE010
Formula 6
7), compound 6 obtains compound 7 with 2-pyrazine carboxylic acid by amino acid condensation, condensing agent is wherein one or several such as TBTU, EDCI, HOBt, HATU and PyBOP, organic bases is that the one such as triethylamine, diisopropylethylamine or mixing are used, and the structure of described compound 7 as shown in Equation 7;
Figure DEST_PATH_IMAGE011
Formula 7
8), compound 7 is sloughed pinine glycol protecting group by isobutyl-boric acid; utilize one or mixed solvent in the organic solvents such as ethyl acetate, methylene dichloride, isopropyl ether, methyl tertiary butyl ether normal hexane to obtain the finished product Velcade by recrystallization; be compound 8, the structure of described compound 8 as shown in Equation 8.
Formula 8
Velcade preparation process of the present invention is specific as follows.
Figure DEST_PATH_IMAGE013
Adopt after such scheme, beneficial effect is: the synthetic method of Velcade provided by the invention, be raw materials usedly easy to get, cheap, and reaction conditions gentleness, less demanding to production unit, simple to operate, production cost is lower.Avoid the use of palladium metal and other metal catalysts, make whole process not have heavy metal compound to participate in reaction, just can obtain very high chemical purity 99.5% and yield 82% by the simple process such as crystallization instead of column chromatography.All very high bulk drugs of optical purity and yield.Meet new edition pharmacopeia to heavy-metal residual limit value, obtain all very high and environmental friendliness of bulk drug chemical purity and optical purity, be applicable to very much carrying out suitability for industrialized production.
Embodiment
Embodiment 1.
1. the preparation of intermediate 2
Under anhydrous condition, isobutyl-boric acid 102g, pinine glycol 170g are dissolved in 1000 ml normal hexanes, under room temperature, stir 15 hours.Concentrating under reduced pressure, except desolventizing, obtains faint yellow oily matter intermediate 2(256g), yield is greater than 100%;
NMR（DMSO-d 6）: δ=4.27(1H, dd); 2.30(1H, m); 2.18(1H, m); 1.95(1H, t); 1.86(1H, m); 1.79(1H); 1.69(1H, m); 1.31(3H, s); 1.26(3H, s); 1.02(1H, d); 0.9(3H, d); 0.81(3H, s); 0.69(2H, m)。
2. the preparation of intermediate 3
Under nitrogen protection, intermediate 2 is taken to 23.6 g, add 200 mL THF dissolve after be transferred in 1L reaction flask, add the DCM of 23.6 mL.Cool to-80 degree, drip the tetrahydrofuran solution of LDA(2N) 50 mL solution, after dripping off, subzero 80 degree reaction half hours.(41 THF solution g), dripped and finish, subzero 60 ~ 80 degree reaction one hour to keep temperature to drip zinc chloride.Return to 10 DEG C of left and right, add 10% the sulfuric acid preparing, stir 20 minutes.Leave standstill separatory.Water extracts at twice with 250 mL isopropyl ethers, merges organic phase, saturated aqueous common salt, water washing for organic phase.The dry decolouring of organic phase is spent the night, and decompression is spin-dried for solvent at 50 DEG C, obtains safran oily matter intermediate 3 (32 g) yield > 100%.
3. the preparation of intermediate 4
Intermediate 3 is taken to 28.4 g and add the anhydrous THF of 300 mL to dissolve, stir and obtain light yellow transparent solution.Be cooled to-80 DEG C, drip two (trimethyl silicon based) Lithamide (LiHMDS, the tetrahydrofuran solution of 1N), 200 mL, drip and finish.Be cooled to-60 DEG C, stirring reaction 1h, heats up naturally, and concentrating under reduced pressure is except desolventizing.In resistates, add 2.8 L isopropyl ethers, stir, separate out solid.Pad diatomite suction filtration filtrate is spin-dried for solvent and obtains oily matter intermediate 4(44 g), and yield is greater than 100%.
4. the preparation of intermediate 5
Take intermediate 4 40.9 g, after using the anhydrous THF of 200 mL to dissolve, join in 1 L reaction flask, stir.Get 50 g trifluoroacetic acids in constant pressure funnel, stand-by.After nitrogen replacement, protect, be cooled to-20 DEG C.Drip trifluoroacetic acid, drip and finish, nitrogen protection, reacts 2h at-25 DEG C.Suction filtration, filter cake obtains off-white color filter cake with 100 mL isopropyl ether drip washing, after vacuum-drying 4h, weigh to obtain intermediate 5 (23.8 trifluoroacetates g), yield 58.2%
1H-NMR(DMSO-d 6): δ=7.76(3H, b); 4.43(1H, dd); 2.81(1H, m) 2.35(1H, m); 2.21(1H, m); 2.01(1H, t); 1.88(1H, m); 1.74(1H, m); 1.72(1H); 1.48(2H, m); 1.37(3H, s); 1.26(3H,s); 1.10(1H,d); 0.87(6H, d); 0.83(3H, s)。
5. the preparation of intermediate 6
By DCM(50 mL) join in 100 mL there-necked flasks, under stirring, add intermediate 5, (15 g), Boc-L-phenylalanine (10.5g), and (6 g) for HOBt.Ice-water bath is cooled to below 5 degree, and (15.2 g), and temperature remains on below 5 degree to start to drip triethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, respectively with 1% phosphoric acid, 2% salt of wormwood, 10% sodium-chlor washing, then with 150 mL washings, be dried, concentrating under reduced pressure obtains oily matter intermediate 6 (11.1 g, yield 55%).
6. prepared by intermediate 7
Take ethyl acetate solution 600 mL of intermediate 6 (51.2g), 2N HCl are added in reaction flask, stirring at room temperature 6h, TLC shows that raw material reaction is complete.Reaction solution is obtained to white solid at 40 DEG C of concentrating under reduced pressure.In resistates, add 200 mL ethyl acetate, under 600 mL normal heptane room temperatures, pull an oar and spend the night.Obtain white solid intermediate 7 (30.1g, yield 67.1%).
7. the preparation of intermediate 8.
By DCM(500ml) join in 1L there-necked flask, under stirring, add intermediate 7, (44.9 g), 2-pyrazine carboxylic acid (13.6 g), TBTU(35.7g).Ice-water bath is cooled to below 5 degree, and (41.3 g), and temperature remains on below 5 degree to start to drip diisopropylethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, wash with 1% phosphoric acid, 2% salt of wormwood and 10% sodium-chlor respectively, finally wash with water again, dry concentrated, obtain oily matter intermediate 8(55g, yield 106.2%).
8. the preparation of Velcade.
Take intermediate 8, (51.8 g) add methyl alcohol (300 mL), normal hexane (500 mL), and (17.3 g), under room temperature, stirs after 5 hours, and TLC detection reaction is complete for 1N hydrochloric acid (230 mL) and isobutyl-boric acid.Concentration of reaction solution, adds water, and with 3000 mL n-hexane extractions.Water regulates pH to alkalescence with 2N sodium hydroxide, with methylene dichloride 800 mL extractions.Water adds after 400 mL methylene dichloride, to acid, separates methylene dichloride phase with 1N salt acid for adjusting pH, and with 500 mL dichloromethane extractions, combined dichloromethane phase, is dried.Filter, receive dry solvent and obtain crude product Velcade, crude product obtains Velcade (27.8 g, yield 72.5%) after ethyl acetate and isopropyl ether 4:1 recrystallization. 1H-NMR(400MHz (CD 3OD) : 0.77 (m, 6H) , 1.21 (m,1H), 1.32-1.40 (m, 2H)，2.93 (m, 1H)，3.11 (m, 1 H)，3.22 (m,1 H)，4. 86 (m, 1H)，7. 23 (m，5H)，8.65 (s, 1H),8.78 (s, 1H)，9. 13 (s, 1H)，0.77 (m, 6H)。
Embodiment 2.
1. the preparation of intermediate 2
Under anhydrous condition, isobutyl-boric acid 102g, pinine glycol 187g are dissolved in 1000 mL methyl ethers, under room temperature, stir 8 hours.After reaction finishes, reaction solution concentrating under reduced pressure, except desolventizing, obtains faint yellow oily matter intermediate 2(238g), yield is greater than 100%.
2. the preparation of intermediate 3
Under nitrogen protection, intermediate 2(23.6 g), is dissolved in 200 mL THF, adds the DCM of 23.6 mL.Cool to-80 degree, drip the tetrahydrofuran solution of LDA(2N) 100 mL solution, drip and finish, subzero 80 degree reaction half hours.(41 THF solution g), drip and finish, and subzero 60-80 degree reaction one hour, return to about 10 DEG C reactions to keep this temperature to drip zinc chloride.Add 10% the sulfuric acid preparing, stir 20 minutes.Leave standstill separatory, water extracts at twice with 250 mL isopropyl ethers, merges organic phase, saturated aqueous common salt, water washing for organic phase.The dry decolouring of organic phase is spent the night, and decompression is spin-dried for solvent at 50 DEG C, obtain safran oily matter intermediate 3 (32 g) yield be greater than 100%.
3. the preparation of intermediate 4
Intermediate 3 28.4 g are dissolved in to the anhydrous THF of 300 mL, stir and obtain light yellow transparent solution.Be cooled to-80 DEG C, drip two (trimethyl silicon based) sodium amide (NaHMDS, 1N tetrahydrofuran solution)) 200 mL, drip and finish.Be cooled to-60 DEG C, stirring reaction 1h, heats up naturally, and concentrating under reduced pressure is except desolventizing.In resistates, add 2.8 L isopropyl ethers, stir, separate out solid.Pad diatomite suction filtration, filtrate concentrated oily matter intermediate 4(33 g), yield is 80.7%.
4. the preparation of intermediate 5
By intermediate 4 40.9 g, be dissolved in 100 mL isopropyl ethers.After nitrogen replacement, protect, be cooled to-20 DEG C.Drip THF solution 200 mL of 2N hydrogenchloride, after dripping off, room temperature reaction 2h under nitrogen protection.Suction filtration, filter cake obtains off-white color filter cake with 100 mL isopropyl ether drip washing, after vacuum-drying 4h, weigh the hydrochloride of intermediate 5 (15 g), yield 39.6%.
5. the preparation of intermediate 6
By DCM(50 mL) join in 100 mL there-necked flasks, under stirring, add intermediate 5, (15 g), and (10.5 g), and (6 g), and (8.5 g) for EDC for HOBt for Boc-L-phenylalanine.Under condition of ice bath, (16.3 g), and temperature remains on below 25 degree to drip diisopropylethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, respectively with 1% phosphoric acid, 2% salt of wormwood and the washing of 10 % sodium-chlor, then with 150 mL washings, dry, obtain oily matter intermediate 6 (14 g, yield 69.3%).
6. the preparation of intermediate 7
Take by intermediate 6 (51.2 g) and dichloromethane solution 600 mL of 2N HCl add in reaction flask, stirring at room temperature 6h, TLC shows that raw material reaction is complete.Reaction solution is obtained to white solid at 40 DEG C of concentrating under reduced pressure.In resistates, add 200 mL ethyl acetate, under 600 mL normal heptane room temperatures, pull an oar 12 hours, obtain white solid intermediate 7 (25.1g, yield 55.9%).
7. the preparation of intermediate 8
Take intermediate 7(44.9 and g) be dissolved in 500 mL methyl chloride, (14.8 g) and EDC (28.75) g, and (24.45 g), drips wherein after being chilled to 0 DEG C for HOBT to add pyrazine-2-carboxylic acid n, N-diisopropylethylamine (DIPEA; 19.4 g); drip to finish to stir and within 0. 5 hours, be warming up to room temperature, under nitrogen protection, stir 12 hours, reacted in rear and added 300 mL purified water; layering; dichloromethane extraction twice for water, organic phase is respectively with saturated sodium bicarbonate solution washing and saturated sodium-chloride washing, anhydrous sodium sulfate drying; filtering and concentrating obtains intermediate 8(18.8 g, yield 36.3%).
8. the preparation of Velcade
By intermediate 8(51.8 g) and isobutyl-boric acid (46.5 g) add in 500 mL flasks, and add 150 mL methyl alcohol as solvent, be cooled to 0 DEG C, slowly add lN hydrochloric acid soln 130mL adjust pH 5-6, be warming up to 50 DEG C, stirring reaction 20h, after finishing, reaction is cooled to room temperature, separatory, water extracted with diethyl ether three times, merge organic phase, wash organic phase with saturated sodium carbonate solution, after separatory, organic phase anhydrous magnesium sulfate drying, revolve and steam except desolventizing, methylene dichloride and anhydrous diethyl ether 2:1 recrystallization for crude product, obtain white solid and be target product 25.3 g, yield 65.9%.
Embodiment 3.
1. the preparation of intermediate 2
Under anhydrous water condition, isobutyl-boric acid 102 g, pinine glycol 187 g are dissolved in 1000 ml ether, under room temperature, stir 10 hours.After reaction finishes, reaction solution concentrating under reduced pressure, except desolventizing, obtains faint yellow oily matter intermediate 2(237g), yield > 100%.
2. the preparation of intermediate 3
Under nitrogen protection, intermediate 2 is taken (23.6 g), add 200 mL THF dissolve after be transferred in 1L reaction flask, add the methylene dichloride of 23.6 mL.Cool to-80 degree, drip lithium diisopropylamine (2N tetrahydrofuran solution) 70 mL solution, drip and finish, subzero 80 degree reaction half hours.(53 THF solution g), drip and finish, and subzero 60 ~ 80 degree reaction one hour, return to about 10 DEG C reactions, add 10% the sulfuric acid preparing, and stir 20 minutes to keep temperature to drip zinc chloride.Leave standstill separatory, water extracts at twice with 250 mL isopropyl ethers, merges organic phase, saturated aqueous common salt, water washing for organic phase.The dry decolouring of organic phase is spent the night, and decompression is spin-dried for solvent at 50 DEG C, obtain safran oily matter intermediate 3 (33 g) yield be greater than 100%.
3. the preparation of intermediate 4
Intermediate 3 is taken to (28.4 g) add the anhydrous THF of 300 mL to dissolve, and stir and obtain light yellow transparent solution.Be cooled to-80 DEG C, drip two (trimethyl silicon based) sodium amide (NaHMDS, 1N tetrahydrofuran solution), 100 mL, drip and finish, be cooled to-60 DEG C, stirring reaction 1h, heats up naturally, and concentrating under reduced pressure is except desolventizing.In resistates, add 2.8 L isopropyl ethers, stir, separate out solid.Pad diatomite suction filtration, filtrate is spin-dried for solvent and obtains oily matter intermediate 4(33 g), and yield is 80.7%.
4. the preparation of intermediate 5
Intermediate 4 is taken to 40.9 g(0.1 mol), use the anhydrous THF of 100 mL to dissolve.After nitrogen replacement, protect, be cooled to-20 DEG C.Drip THF solution 200 mL of 2N hydrogenchloride, drip and finish, under nitrogen protection, react 2h at-25 DEG C.Suction filtration, filter cake obtains off-white color filter cake with 100 mL isopropyl ether drip washing, and intermediate 5 (15.4 hydrochlorides g), yield 51.2 % weigh after vacuum-drying 4h to obtain.
5. the preparation of intermediate 6
By DCM(50 mL) join in 100 mL there-necked flasks, under stirring, add intermediate 5(15 g), (10.5 g), and (14 g) for TBTU for Boc-L-phenylalanine.Ice-water bath cooling, temperature is down to below 5 degree, and (15.2 g), and temperature remains on below 5 degree to start to drip triethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, after washing with 1% phosphoric acid, 2% salt of wormwood and 10% sodium-chlor respectively, then with 150 mL washings, be dried the concentrated oily matter intermediate 6 (18.3 g, yield 91%) that obtains.
6. the preparation of intermediate 7
Take intermediate 6 51.2g (0.1mol), 10% trifluoracetic acid dichloromethane solution 600 mL are added in reaction flask, stirring at room temperature 6h, TLC shows that raw material reaction is complete.Reaction solution is obtained to white solid at 40 DEG C of concentrating under reduced pressure.In resistates, add ethyl acetate 200 mL, under normal heptane 600 mL room temperatures, pull an oar 12 hours, obtain white solid intermediate 7 (38.2 g, yield 70%).
7. the preparation of intermediate 8
By DCM(500ml) join in 1L there-necked flask, under stirring, add intermediate 7, (44.9 g), and (27.2 g), and TBTU(35.7 is g) for 2-pyrazine carboxylic acid.Ice-water bath is cooled to below 5 degree, and (41.3 g), and temperature remains on below 5 degree to start to drip diisopropylethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, after washing with 1% phosphoric acid, 2% salt of wormwood and 10% sodium-chlor respectively, then wash with water, dry concentrated obtain oily matter intermediate 8(46.1 g, yield 89%).
8. the preparation of Velcade
By intermediate 8, (51.8 g), and (40.4 g) and 1N hydrochloric acid 150 mL for isobutyl-boric acid, drop into 1000 mL there-necked flasks, add methyl alcohol (600 mL) to heat up, back flow reaction 6 hours, then cool to room temperature, layering.Water layer normal hexane extraction 3 times.After organic layer drying is concentrated, with the NaOH solution washing of 2N, then use dichloromethane extraction.Crude product after ethyl acetate and isopropyl ether ether mixed solvent 4:1 are refining 18.8 grams of qualified product, yield 49%, purity detecting 99.1%. 1H-NMR(400MHz (CD 3OD) : 0.76 (m, 6H) , 1.21 (m, 1H), 1.31-1.39 (m, 2H)，2.93 (m, 1H)，3.11 (m, 1 H)，3.22 (m,1 H)，4. 86 (m, 1H)，7. 24 (m，5H)，8.65 (s, 1H), 8.78 (s, 1H)，9. 13 (s, 1H)，0.77 (m, 6H)。
Embodiment 4
1. the preparation of intermediate 2
Under anhydrous condition, isobutyl-boric acid 102 g, pinine glycol 425 g are dissolved in 1000 mL isopropyl ethers, under room temperature, stir 20 hours.After reaction finishes, reaction solution concentrating under reduced pressure, except desolventizing, obtains faint yellow oily matter intermediate 2(320 g), and yield is greater than 100%.
2. the preparation of intermediate 3
Under nitrogen protection, intermediate 2(23.6 g) is dissolved in 200 mL THF, then adds the DCM of 23.6 mL.Cool to-80 degree, drip LDA(2N tetrahydrofuran solution) solution 50 mL, drip and finish, subzero 80 degree reaction half hours.(53 THF solution g), drip and finish, and subzero 60 ~ 80 degree reaction one hour, return to about 10 DEG C reactions, add 10% the sulfuric acid preparing, and stir 20 minutes to keep this temperature to drip zinc chloride.Leave standstill separatory, water extracts at twice with 250 mL isopropyl ethers, merges organic phase, saturated aqueous common salt, water washing for organic phase.The dry decolouring of organic phase is spent the night, at 50 DEG C concentrating under reduced pressure except desolventizing, obtain safran oily matter intermediate 3(32 g) yield be greater than 100%.
1. the preparation of intermediate 4
Intermediate 3 is taken to (28.4 g) add the anhydrous THF of 300ml to dissolve, and stir and obtain light yellow transparent solution.Be cooled to-80 DEG C, drip two (trimethyl silicon based) sodium amide (LiHMDS, the tetrahydrofuran solution of 1N) solution 100 mL, drip and finish.Be cooled to-60 DEG C, stirring reaction 1h, heats up naturally, and concentrating under reduced pressure is except desolventizing.In resistates, add 2.8 L isopropyl ethers, stir, separate out solid.Suction filtration, filtrate be spin-dried for solvent concentrated oily matter intermediate 4(28 g), yield is 75%.
2. the preparation of intermediate 5
Intermediate 4 is taken to (40.9 g), uses the anhydrous THF of 100 mL to dissolve.After nitrogen replacement, protect, be cooled to-20 DEG C.Drip THF hydrogen chloride solution 100 ml of 2N, drip and finish, under nitrogen protection, react 2h at-25 DEG C.Suction filtration, filter cake obtains off-white color filter cake with 100 mL isopropyl ether drip washing, the hydrochloride of intermediate 5 (15g) of weighing after vacuum-drying 4h to obtain, yield 39.6%.
5. the preparation of intermediate 6
By DCM(50 mL) join in 100 mL there-necked flasks, under stirring, add intermediate 5(15 g), (10.5 g), and (14 g) for TBTU for Boc-L-phenylalanine.Ice-water bath cooling, temperature is down to below 5 degree, and (16.3 g), and temperature remains on below 5 degree to start to drip diisopropylethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, after washing with 1% phosphoric acid, 2% salt of wormwood and 10% sodium-chlor respectively, then wash with water, the dry concentrated oily matter intermediate 6 (21 g, yield 103.4%, is greater than 100%) that obtains.
6. the preparation of intermediate 7
Take by intermediate 6 (51.2 g) He 20% trifluoracetic acid dichloromethane solution 600 mL add in reaction flask, stirring at room temperature 6h, TLC show raw material reaction complete.Reaction solution is obtained to white solid at 40 DEG C of concentrating under reduced pressure.Pull an oar 12 hours to adding under 200 mL ethyl acetate and 600 mL normal heptane room temperatures in resistates, obtain white solid intermediate 7 (39.5 g, yield 75%).
7. the preparation of intermediate 8
By DCM(500 mL) join in 1L there-necked flask, under stirring, add intermediate 7(44.9 g), (13.6 g), and TBTU(71.4 is g) for 2-pyrazine carboxylic acid.Ice-water bath is cooled to below 5 degree, and (41.3 g), and temperature remains on below 5 degree to start to drip diisopropylethylamine.Stir after one hour, TLC detection reaction is complete.Be spin-dried for solvent, add ethyl acetate 200 mL, after washing with 1% phosphoric acid, 2% salt of wormwood and 10% sodium-chlor respectively, then wash with water, the dry concentrated oily matter intermediate 8 (48.2 g, yield 93%) that obtains.
8. the preparation of Velcade
Take intermediate 8, (51.8 g) add methyl alcohol (300 mL), hexanaphthene (500 mL), and (34.6 g), under room temperature, stirs after 10 hours, and TLC detection reaction is complete for 1N hydrochloric acid (230 mL) and isobutyl-boric acid.Separatory, and with 3000 mL hexanaphthene extractions, to alkalescence, use methylene dichloride 1000 mL extractions with sodium hydroxide adjusting pH.Water adds after 400 mL methylene dichloride, is adjusted to pH extremely acid with hydrochloric acid, separates methylene dichloride phase, and with 500 mL dichloromethane extractions, merges organic phase, dry, filters, and concentrates and obtains crude product Velcade.Crude product after ethyl acetate and methyl tertiary butyl ether mixed solvent 4:1 making beating is refining qualified product Velcade (31.5 g, yield 82%), purity detecting reaches 99.5%. 1H-NMR(400MHz (CD 3OD) : 0.77 (m, 6H) , 1.21 (m,1H), 1.32-1.40 (m, 2H)，2.93 (m, 1H)，3.11 (m, 1 H)，3.22 (m,1 H)，4. 86 (m, 1H)，7. 23 (m，5H)，8.65 (s, 1H),8.78 (s, 1H)，9. 13 (s, 1H)，0.77 (m, 6H)。

Claims (3)

1. a synthetic method for Velcade, is characterized in that, synthetic as follows:
The first step: taking isobutyl-boric acid as starting raw material, obtain compound 1 with pinine glycol protection condensation;
Second step: compound 1 highly basic is taken hydrogen by force, then rearrangement reaction obtains compound 2;
The 3rd step: compound 2 obtains compound 3 with hexamethyl silicon amine alkane;
The 4th step: compound 3 removes trimethyl silicon based, generates salt compound 4;
The 5th step: compound 4 obtains compound 5 with the condensation of Boc-L-phenylalanine;
The 6th step: compound 5 is sloughed Boc protecting group and obtained compound 6;
The 7th step: compound 6 obtains compound 7 with the condensation of pyrazine-2-carboxylic acid;
The 8th step: compound 7, under the effect of isobutyl-boric acid, is sloughed pinine glycol protecting group, obtains the finished product Velcade, i.e. compound 8.
2. synthetic method according to claim 1, is characterized in that, according to the following steps preparation:
1), with isobutyl-boric acid and (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol is starting raw material, and at room temperature molar equivalent is than 1:1 ~ 3, and reaction solvent is hydro carbons or the ether solvents such as hexanaphthene, methyl ether, ether and isopropyl ether; Stirring reaction, obtains the isobutyl-boric acid ester product that compound 1 pinine glycol is protected, and the structure of described compound 1 as shown in Equation 1;
Figure 2014101349310100001DEST_PATH_IMAGE001
Formula 1
2), compound 1 with diisopropylamino lithium (LDA) molar equivalent than being 1:1 ~ 2, with the mol ratio of Zinc Chloride Anhydrous be 1:1 ~ 4, in organic solvent solution, generate product compound 2 by rearrangement reaction, the structure of described compound 2 as shown in Equation 2;
Figure 816982DEST_PATH_IMAGE002
Formula 2
3), compound 2 and hexamethyl silicon amido lithium (LiHMDS, 1N tetrahydrofuran solution)) or hexamethyl silicon sodium amide (NaHMDS, 1N tetrahydrofuran solution) molar equivalent than for 1:1 ~ 3, obtain compound 3 through amino substitution reaction, the structure of described compound 3 as shown in Equation 3;
Figure 2014101349310100001DEST_PATH_IMAGE003
Formula 3
4), compound 3 is dissolved in organic solvent, or by trifluoroacetic acid hydrogenchloride deprotection in organic solvent, generate compound 4, the structure of described compound 4 is as shown in Equation 4;
Figure 734123DEST_PATH_IMAGE004
Formula 4
5), compound 4 by with the condensation of Boc-L-phenylalanine, obtain compound 5, condensing agent is wherein one or several such as TBTU, EDCI, HOBt, HATU and PyBOP, organic bases is that the one such as triethylamine, diisopropylethylamine or mixing are used, and the structure of described compound 5 as shown in Equation 5;
Figure 2014101349310100001DEST_PATH_IMAGE005
Formula 5
6), compound 5 is dissolved in organic solvent, or in the organic solution of trifluoroacetic acid hydrogenchloride deprotection, obtain compound 6, the structure of described compound 6 as shown in Equation 6;
Figure 451543DEST_PATH_IMAGE006
Formula 6
7), compound 6 obtains compound 7 with 2-pyrazine carboxylic acid by amino acid condensation, condensing agent is wherein one or several such as TBTU, EDCI, HOBt, HATU and PyBOP, organic bases is that the one such as triethylamine, diisopropylethylamine or mixing are used, and the structure of described compound 7 as shown in Equation 7;
Figure 2014101349310100001DEST_PATH_IMAGE007
Formula 7
8), compound 7 is sloughed pinine glycol protecting group by isobutyl-boric acid; utilize one or mixed solvent in the organic solvents such as ethyl acetate, methylene dichloride, isopropyl ether, methyl tertiary butyl ether normal hexane to obtain the finished product Velcade by recrystallization; be compound 8, the structure of described compound 8 as shown in Equation 8;
Figure 784436DEST_PATH_IMAGE008
Formula 8.
3. synthetic method according to claim 1, is characterized in that, the approximately 12 hours stirring reaction time in step a.
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