CN103059054A - Synthetic method of bortezomib - Google Patents
Synthetic method of bortezomib Download PDFInfo
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Abstract
The invention relates to a synthetic method of bortezomib, and solves the problems comprising low product yield, complex operation, low cost, and unsuitableness for the industrialized production of known synthetic methods. The synthetic method comprises the following steps: carrying out a metallization reaction, a Grignard reaction and a substitution reaction of trimethyl borate, (1S,2S,3R,5S)-(+)-pinanediol and dichloromethane which are initial bulk drugs, carrying out a condensation reaction of the obtained substances and (S)-3-phenyl-2[(pyrazine-2-carbonyl)amino]propionic acid, and acidifying the obtained product to obtain bortezomib. The synthetic method of bortezomib has the advantages of cheap and easily-available raw materials, high product yield, simple operation, low cost, and suitableness for the industrialized production.
Description
Technical field:
The invention belongs to the synthetic field of medicine, relate to a kind of synthetic method of Velcade.Be specifically related to [(1R)-3-methyl-1-[[(2S)-and 1-oxygen-3-phenyl-2-[(pyrazine formyl) amino] propyl group] amino] butyl]-boric acid (Velcade, synthetic method Bortezomib).
Background technology:
At present, in the main cause of death in the whole world, cancer occupies a tiny space.According to statistics, 2008, the cancer mortality number surpassed 7,000,000, has accounted for more than 10% of all death tolls.China is less than in the time in 20 years, and cancer morbidity has risen 70%, and mortality ratio is also unprecedented soaring simultaneously.Cancer morbidity also has the trend of rejuvenation.From the statistic data that the World Health Organization provides, following cancer allows of no optimist to the consequence that the mankind bring.So the focus of research is around a kind of medicine or the method that can effectively treat cancer at present.
Multiple myeloma (multiple myeloma, MM) be a kind of of pernicious hematological system tumor, account for greatly the hematopoietic system cancer mortality ratio 10% and all tumor mortality rates 2%, be characterized in existing in the marrow continuous value-added malignant plasma cell, pernicious value-added plasmocyte produces too much monoclonicity immunoglobulin (Ig).
Research finds that the multiple myeloma cancer cells is responsive to radiotherapy chemotherapy, so adopt in early days this two kinds of methods treatments, but because advancing of disease, can cause also that to resistance reductions infected, bone necrosis etc. secondary falls ill, and finally can make patient death.
Also have other research, as utilize the eventually end differentiation of inducing tumor cell or stop to copy to treat the multiple myeloma cancer.For example: proteasome inhibitor, can be apoptosis-induced in various tumor cell strains and cancerous tumor cell, significantly strengthen the curative effect of the method inducing apoptosis of tumour cell such as some chemotherapeutics and ionization radiotherapy, and for Normocellular toxic action less.Velcade is exactly a kind of synthetic highly selective 26S borate proteasome inhibitor, and in mammalian cell, it is active that it can suppress 26S proteasome Chymotrypsin body, stops directed proteolysis, affects many signal cascades in the cell.Its normal stable state failure mechanism can cause necrocytosis.
Velcade is the new type antineoplastic medicine by the research and development of U.S. Millennium drugmaker.Chemical being called [(1R)-3-methyl-1-[[(2S)-and 1-oxygen-3-phenyl-2-[(pyrazine formyl) amino] propyl group] amino] butyl]-boric acid, molecular formula is C19H25BN4O4, relative molecular weight 384.24.Velcade finds as far back as the multiple myeloma recurrence and in the early studies in man that carries out in to the invalid patient of other therapies, studies show that it can significantly improve conditions of patients, passes through through the FDA audit, in May, 2003 official listing.The research of its action principle obtained Nobel chemistry Prize in 2004.In the same year, European approval is used for this medicine once to accept at least two kinds of therapies but invalid multiple myeloma patients.The U.S. in 2005 and European Union's approval Velcade upgrade to the two wires medication.2005, Velcade was at Discussion on Chinese Listed.Except multiple myeloma (MM), FDA (Food and Drug Adminstration) (FDA) will also ratify it in the effect of lymphoma mantle cell the end of the year 2006.Simultaneously in the treatment of other types plasmocyte disease, acute myeloid leukaemia and some solid tumor.At present, Velcade is regarded as treating the breakthrough therapy of recurrent and intractable multiple myeloma, can slow down, reverses or stop once to accept two or more therapies but failed conditions of patients continuation deterioration.
The Velcade chemical name: [(1R)-3-methyl-1-[[(2S)-and 1-oxygen-3-phenyl-2-[(pyrazine formyl) amino] propyl group] amino] butyl]-boric acid, structural formula is as follows:
The Velcade synthesis technique is announced, and main synthetic method comprises at present:
Patent WO2005097809 and patent CN1960996A disclose a kind of Velcade synthetic method, with isobutyl-boric acid, (1S, 2S, 3R, 5S)-(+)-send the alkane glycol be that bulk drug prepares Velcade, by substitution reaction, form boric acid ester, under through Zinc Chloride Anhydrous catalysis, chlorine methylene radical insertion reaction structural formula, carrying out the amido nucleophilic substitution reaction, take off trimethyl silicon basedly, obtain intermediate (aR, 3aS, 4S, 6S, 7aR)-six hydrogen-3a, 8,8-trimethylammonium-alpha-(2-methyl-propyl)-4,6-methyl-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetate or hydrochloride.The another one intermediate is take 2-pyrazine carboxylic acid and L-phenylalanine as bulk drug, get through condensation reaction, two intermediates obtain Velcade by condensation reaction, and this synthetic method condition is harsh, and yield is lower, and bulk drug isobutyl-boric acid and (1S, 2S, 3R, 5S)-(+)-send the alkane glycol expensive, reaction yield is lower, is not suitable for industrialization.
Patent CN102351890A(publication number) a kind of Velcade synthetic method is proposed, but raw material still adopts isobutyl-boric acid and (1S, 2S, 3R, 5S)-(+)-send the alkane glycol, and use Pa/C, hydrogen catalyzed reaction in the reaction, greatly increased the reaction difficulty, reaction yield is not high, and consistent with former patent synthesis technique thinking, very not obvious novelty.
The patent CN 101812026A new synthetic route of having deducted a percentage; take 3-methyl butyraldehyde and R-(+)-1-phenylethylamine as the starting raw material medicine; through condensation reaction; the addition of boron selective acid esters; the hydrogenation deprotection; with L-phenylalanine chirality condensation; obtain Velcade with 2-carboxyl-piperazine condensation; the reaction scheme design comparison is novel; but use duplex tetramethyl ethylene ketone boric acid ester in the route; the condensation reaction method that refluxes in the simultaneous reactions route; owing in the compound chiral centre is arranged; back flow reaction is not too suitable; can cause related substance or content of isomer to increase, be not suitable for suitability for industrialized production.
Summary of the invention:
The purpose of this invention is to provide low, the suitable industrialization of a kind of production cost, product yield height, the synthetic method of the Velcade that product purity is high.
The present invention is achieved in that
Velcade synthetic method of the present invention, realize by following synthesis step:
A. methylene dichloride, n-Butyl Lithium are the starting raw material medicine, through the metallization reaction deprotonation, obtain metal-salt methylene dichloride lithium,
B. methylene dichloride lithium and trimethyl borate reaction obtains chemical compounds I,
C. chemical compounds I and (1S, 2S, 3R, 5S)-(+)-send the alkane glycol to react obtain compound ii,
D. compound ii and selenium alkynide obtain the compound III by grignard reaction,
E. the compound III obtains compounds Ⅳ with two (trimethyl silicon based) Lithamide reactions,
F〉compounds Ⅳ obtains the compound V through acidifying in organic solvent,
G. compound V and compound VI (S)-3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid gets the compound VII through condensation reaction under the catalysis of basic cpd, the acidified Velcade that obtains,
H. the product Velcade through crystallization, obtains the higher Velcade trimeric form of purity in organic solvent.
In the steps A, temperature of reaction is controlled at-120～-60 ℃; It is wherein a kind of that reaction solvent is selected from tetrahydrofuran (THF), ether, toluene, methylene dichloride or methyl tertiary butyl ether, among the step B, and reaction beginning 1 hour, temperature is controlled at-120～-60 ℃; Temperature is increased to 15～30 ℃ after the stable reaction, among the step C, temperature of reaction is controlled between 15～30 ℃, chemical compounds I and (1S, 2S, 3R, 5S)-(+)-send alkane glycol feed ratio be 1 ︰ (1～1.5), among the step D, temperature of reaction is controlled under-120～-60 ℃ of conditions, catalysts just screens from following metal-salt: zinc chloride, calcium chloride or magnesium chloride, in the step e, reaction beginning 1 is little, temperature is controlled under-120～-60 ℃ of conditions, temperature is increased to 15～30 ℃ after the stable reaction, and in the step F, organic solvent screens from following solvent: methylene dichloride, tetrahydrofuran (THF), dioxane, dimethyl formamide, isopropyl ether, among the step G, compound VI (S)-3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid synthesis step is as follows:
(a) take 2-pyrazine carboxylic acid as bulk drug, obtain 2-pyrazine acyl chlorides through halogenating reaction;
(b) 2-pyrazine acyl chlorides and L-phenylalanine methyl ester hydrochloride obtains N-(2-pyrazinyl carbonyl)-L-phenylalanine methyl ester through acylation reaction;
(c) N-(2-pyrazinyl carbonyl)-L-phenylalanine methyl ester is acidified, sloughs methyl esters, obtains the compound VI.
In the steps A, temperature of reaction is controlled at-100 ℃; Reaction solvent is tetrahydrofuran (THF), among the step B, and reaction beginning 1 hour, temperature is controlled at-100 ℃; Temperature is increased to 25 ℃ after the stable reaction, and among the step C, temperature of reaction is controlled at 25 ℃; Chemical compounds I and (1S, 2S, 3R, 5S)-(+)-send alkane glycol feed ratio are 1 ︰ 1.05, and among the step D, temperature of reaction is controlled at-78 ℃; Catalysts is zinc chloride, in the step e, and reaction beginning 1 hour, temperature is-78 ℃; Temperature raises 25 ℃ after the stable reaction, and in the step F, compounds Ⅳ obtains the compound V through acidifying in organic solvent; Organic solvent is dioxane or isopropyl ether.
Halide reagent is selected from the synthesis step (a): Phosphorates phosphorus Halides or halogenation sulfoxide.
Halide reagent is selected from sulfur oxychloride or phosphorus oxychloride in the synthesis step (a).
In the synthesis step (b), the organic bases of using in the acylation reaction is selected from: triethylamine, pyridine, diethylamine, N, N-diisopropylethylamine or morpholine are wherein a kind of.
In the synthesis step (b), the organic bases of using in the acylation reaction is triethylamine.
Among the synthesis step G, compound V and compound VI obtain the Velcade crude product through the condensation reaction, condensation reagent is selected from: dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-hydroxyl-benzo-triazole (HOBT) are wherein a kind of; The organic basic catalyzer is selected from triethylamine, pyridine, diethylamine, N, and N-diisopropylethylamine or morpholine are wherein a kind of.
Among the synthesis step G, compound V and compound VI obtain the Velcade crude product through the condensation reaction, and condensation reagent selects O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU); The organic basic catalyzer is selected from triethylamine.
Among the synthesis step H, the Velcade crude product following solvent crystallization of process or purifying: one or more solvent mixtures in water, methyl alcohol, acetonitrile, ethyl acetate, acetone, the normal hexane.
The present invention proposes a kind of new route, mainly take methylene dichloride, trimethyl borate, 2-pyrazine carboxylic acid and L-phenylpropyl alcohol ammonia propylhomoserin methyl ester hydrochloride as the starting raw material medicine, avoid using expensive isobutyl-boric acid, solved the low problem of product yield in the reaction.Reaction conditions requires relatively high, mainly is to reduce temperature of reaction, avoids the appearance of isomer.The reaction scheme ratio that the present invention proposes is easier to operation, is fit to suitability for industrialized production.
Velcade synthesis technique provided by the invention has following advantage:
(1) avoids using expensive intermediate isobutyl-boric acid, adopt the very cheap intermediate trimethyl borate of price for reaction starting raw material medicine, reduce cost.
(2) step is few in the reaction, and post-reaction treatment is simple and feasible, is fit to industrialization.
(3) each step yield all reaches 80% in the reaction, and total recovery reaches more than 40%, and product purity reaches more than 99.5%.
Embodiment:
Embodiment 1:
For the synthetic route that realizes that the present invention proposes, following technical scheme is proposed
The synthetic method that the present invention proposes, realize by following reactions steps:
Synthetic route
(1) methylene dichloride and n-Butyl Lithium reacting material ratio 1 ︰ 1 are dissolved in methylene dichloride in the anhydrous tetrahydro furan, dropwise join in the reaction system under-100 ℃ of conditions, stir about 1 hour adds trimethyl borate again, restir 1 lab scale under-100 ℃ of conditions, add 1moL/L hydrochloric acid termination reaction, tell organic layer, water layer petroleum ether extraction, merging filtrate, 40 ℃ of evaporated under reduced pressure, get the oily liquids chemical compounds I, purifying does not directly drop into next step reaction.
(2) product that obtains of reaction (1) is dissolved in the methylene dichloride, adds (1S, 2S under the room temperature condition, 3R, 5S)-(+)-and send the alkane glycol, reaction was stirred 18 hours, and (ethyl acetate: sherwood oil 1:20) separation and purification obtains the colourless oil liquid compound ii to column chromatography.
(3) the oily liquids compound ii is under the anhydrous and oxygen-free condition, add zinc chloride, selenium alkynide, reaction solvent is dry isopropyl ether, reaction is 3 hours under-78 ℃ of conditions, after reaction finishes, filters, filtrate is washed with saturated ammonium chloride solution, anhydrous magnesium sulfate drying, evaporate to dryness, (ethyl acetate: sherwood oil 1:100) separation and purification obtains colourless oil liquid compound III to column chromatography.
(4) colourless oil liquid compound III is dissolved in the tetrahydrofuran (THF) (drying), and two (trimethyl silicon based) Lithamide slowly splashes into, and temperature of reaction is controlled under-78 ℃ of conditions reacted 1 hour, slowly being warming up to normal temperature spends the night, evaporated under reduced pressure solvent after reaction finishes adds sherwood oil, filters not dissolved solids, filtrate is cooled under-50 ℃ of conditions, add hydrochloric acid soln or trifluoroacetic acid solution, acidifying, reaction solution rises to normal temperature gradually, white solid washes out, and obtains white solid compound V.
(5) the compound VI mainly obtains by following route of synthesis: 2-pyrazine carboxylic acid is dissolved in methylene dichloride, adds the halogenating agent sulfur oxychloride again, and solvent evaporated obtained 2-pyrazine acyl chlorides after reaction finished; 2-pyrazine acyl chlorides is dissolved in dry methylene dichloride under anhydrous condition, the adding triethylamine is basic catalyst, add again L-phenylalanine methyl ester hydrochloride, reaction is 2 hours under-5 ℃ of conditions, saturated sodium bicarbonate washing reaction liquid, the organic layer anhydrous sodium sulfate drying filters evaporate to dryness, obtain the off-white color solid, obtain (S)-3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid (compound VI) through acidifying.
(6) compound V and compound are dissolved in the dry methylene chloride, add DIEA and TBTU, and temperature of reaction is controlled under-5 conditions, reacted 2 hours, and rose to room temperature, reaction finishes, dichloromethane layer is with 10% citric acid, saturated common salt water washing, and anhydrous sodium sulfate drying, evaporate to dryness obtain the formula VII; VII is dissolved in the acetone, uses hydrochloric acid hydrolysis, adds the pentane washing, and it is alkalescence that water layer is transferred pH, ethyl acetate extraction, and the organic layer anhydrous sodium sulfate drying, evaporated under reduced pressure obtains the white solid Velcade.
(7) the Velcade crude product obtains the higher Velcade of purity with Methanol-water (3: ︰ 1) crystallization.
Embodiment 2:
Synthesizing of midbody compound II:
Under nitrogen protection, 252mL(0. 6mol) n-Butyl Lithium splashes into anhydrous methylene chloride (42.6mL, 0.66
Mol) with 1200mL anhydrous tetrahydro furan mixing vessel in, stirred under-100 ℃ of conditions 40 minutes, in the above-mentioned reaction system of the disposable adding of 75mL trimethyl borate, react to stir under-100 ℃ of conditions and continued in 40 minutes to stir 40 minutes, reaction 120mL concentration is the cancellation of 5mol/L hydrochloric acid, progressively is warming up to room temperature, and organic layer separates, water layer extracted with diethyl ether 2 times (2 * 100mL), merge organic layer, drying, evaporate to dryness organic layer, obtain white solid chemical compounds I 93g, yield 99.3%.
Get above-mentioned crude product 53.8g, add 32.3g (1S, 2S, 3R, 5S)-(+)-send alkane glycol, be dissolved in the 100mL ether, stirring at room 18 hours, concentrated, (ethyl acetate: sherwood oil 1:20) separation and purification obtains colorless oil liquid compound ii to cross the column chromatography silica gel post, about 49.2g, yield 98.9%.
Proton nmr spectra:
1H NMR(CDCl
3, 500Hz) δ 0.85 (-CH3, s, 3H), 1.21 (-CH2, d,
J=11.2 Hz, 1H), 1.31 (-CH3, s, 3H), 1.46 (-CH3, s, 3H), 1.93-1.97 (-CH2, m, 2H), 2.13 (-CH, t,
J=5.2 Hz, 1H), 2.27-2.30 (-CH, m, 1H), 2.38-2.39 (-CH2, m, 1H), 4.47 (-CH, d,
J=8.8 Hz, 2H), 5.40 (-CH, s, 1H).
Synthesizing of midbody compound III:
Under the nitrogen protection; selenium alkynide 90mL selenium alkynide diethyl ether solution (2M) dropwise adds in midbody compound II and the 120mL diethyl ether solution; under-78 ℃ of conditions; Zinc Chloride Anhydrous 4.4g(0.0325mol) is dissolved in the 50mL ether; add fast; reaction heats up gradually; reaction overnight; reaction is filtered after finishing, and filtrate uses anhydrous slufuric acid dry with 100mL10% ammonium chloride washing, organic layer again; evaporate to dryness; cross column chromatography silica gel post (ethyl acetate: sherwood oil 1:200), obtain 11g colourless liquid sterling, yield 88.5%.
Proton nmr spectra:
1H NMR(CDCl
3, 500Hz) 0.85 (-CH3, s, 3H), 0.92 (-CH3, q,
J=6.6 Hz, 6H), 1.19 (-CH2, d,
J=11.0 Hz, 1H), 1.30 (-CH3, s, 3H), 1.42 (-CH3, s, 3H), 1.60-1.66 (-CH2, m, 1H), 1.78-1.80 (-CH2, m, 1H), 1.88-1.94 (-CH2,-CH, m, 3H), 2.09 (-CH, t
J=5.1 Hz, 1H), 2.24-2.26 (-CH, m, 1H), 2.34-2.37 (-CH2, m, 1H), 3.51-3.55 (-CH, m, 1H), 4.35-4.37 (-CH, m, 1H).
Synthesizing of midbody compound V
Under the nitrogen protection; get intermediate compound III 4.7g(0.1654moL); be dissolved in the 45mL anhydrous tetrahydro furan; two (trimethyl silicon based) Lithamide 9.5mL is dissolved in the 10mL tetrahydrofuran (THF) and dropwise adds; react under-78 ℃ of conditions, temperature of reaction progressively rises to room temperature, and reaction is spent the night; solvent evaporated; product is dissolved in the 50mL sherwood oil, filters, and filtrate adds 65mL(0.05mol under-78 ℃ of conditions) the hydrochloric acid diethyl ether solution; reaction rises to room temperature gradually; there is solid to wash out, spends the night, filter and obtain white solid; yield 65%, 3.24g.
Proton nmr spectra:
1H NMR (DMSO-
d6,500 MHz) 0.82 (-CH3, s, 3H), 0.86-0.89 (-CH3, m, 6H), 1.11-1.16 (-CH2, m, 1H), (1.25-CH3, s, 3H), 1.37 (-CH3, s, 3H), 144-1.55 (-CH2, m, 2H), 1.71-1.79 (-CH2,-CH, m, 2H), 1.86-1.88 (-CH2, m, 1H), 1.99 (-CH, t
J=5.3 Hz, 1H), 2.17-2.20 (-CH, m, 1H), 2.30-2.34 (-CH2, m, 1H), 2.70-2.75 (-CH, m, 1H), 4.41-4.44 (-CH, m, 1H), 7.45 (-NH
+3, t,
J=50.7 Hz, 3H), 8.01 (-NH
+3, s, 3H).
The midbody compound VI is synthetic to be obtained by following reaction
(1) take by weighing 115g2-pyrazine carboxylic acid, be dissolved in the 600mL toluene, measure the 132mL thionyl chloride, put in the reaction system, 80 ℃ were refluxed 3 hours, and solvent evaporated obtains the garnet solid, yield 80%, about 106.1g.
(2) above-mentioned product purifying not directly drops in next step reaction, takes by weighing 2-pyrazine acyl chlorides 88.4g, be dissolved in the 2L methylene dichloride, add triethylamine 215.6mL, splash into L-phenylalanine methyl ester hydrochloride under the condition of ice bath, reacted 2 hours, finish reaction, organic layer washs with 15% 2L sodium bicarbonate, and anhydrous magnesium sulfate 2kg is dry, evaporate to dryness, obtain product, be dissolved in 2L acetone, add under the 2mol/mL sodium hydroxide 614mL condition of ice bath and stirred 2 hours.
(3) above-mentioned reaction system, 50 ℃ of concentrating under reduced pressure boil off acetone, and water layer divides three extractions with methylene dichloride 1L, 1mol/L salt acid for adjusting pH is weakly alkaline under the condition of ice bath, have solid to wash out, water layer extracts with acetic ester, merging filtrate, dry evaporate to dryness obtains the off-white color solid, combining solid, 60 ℃ of drying under reduced pressure obtain solid 115.7g; Yield 68.8%.
Proton nmr spectra
1H NMR (acetone-d6,500 MHz) 9.22 (d, 1H, J 1.4 Hz, CH-pyrazine), (8.83 d, 1H, J 2.5 Hz, CHpyrazine), 8.63 (dd, 1H, J 2.5,1.44 Hz, CHpyrazine), (8.39 br d, 1H, NH), 7.40 –, 7.10 (m, 5H, CHPh), 5.00 (m, 1H, aCHPh), 3.34 (m, 2H, CH
2Ph).
Synthesizing of midbody compound VII
Take by weighing 33.2g midbody compound V, take by weighing again 29.8g midbody compound VI, add 38.5gTBTU, 26.45mL pyridine, add the 300mL methylene dichloride, reaction is 1 hour under-10 ℃ of conditions, then is warming up to room temperature, reacted 18 hours, reaction finishes, dichloromethane layer 250mL10% sodium bicarbonate washed twice, wash with 10% citric acid again, the dichloromethane layer anhydrous sodium sulfate drying filters the evaporate to dryness methylene dichloride, obtain the solid 51g of off-white color, yield 92%.
Proton nmr spectra
1H NMR (400 MHz, 4:1 CD3CN:D2O): δ 0.78 (m, 6H), 1.23 (m, 1H), 1.32-1.40 (m, 2H), 2.91 (m, 1H), 3.06 (m, 1H), 3.19 (m, 1H), 4.78 (m, 1H), 7.20 (m, 5H), 8.62 (s, 1H), 8.73 (s, 1H), 9.10 (s, 1H).
Velcade is synthetic:
Take by weighing intermediate VII 51g, add the 500mL dissolve with methanol, add again the 300mL normal hexane, add 20.9g isobutyl-boric acid, under the condition of ice bath, 1mol/L hydrochloric acid slowly splashes into, and stirs 3 hours, and reaction finishes to boil off a large amount of methyl alcohol, use again 200mL normal hexane washed twice, water layer is transferred about pH to 11, divides the washing water layer three times with ethyl acetate again, under the condition of ice bath, water layer uses 1moL/L salt acid for adjusting pH to slightly acidic, water layer is used dichloromethane extraction three times again, merging filtrate, saturated nacl aqueous solution washing 2 times, the dichloromethane layer anhydrous sodium sulfate drying, solvent is divided exactly in decompression, obtains the 31.2g white solid, yield 82%.
MS(m/s):1099[M+1]
+，733[2/3，M+1]
+，367[1/3，M+1]
+；
Proton nmr spectra 1H NMR (400 MHz, 4:1 CD3CN:D2O): δ 0.78 (m, 6H), 1.23 (m, 1H), 1.32-1.40 (m, 2H), 2.91 (m, 1H), 3.06 (m, 1H), 3.19 (m, 1H), 4.78 (m, 1H), 7.20 (m, 5H), 8.62 (s, 1H), 8.73 (s, 1H), 9.10 (s, 1H).
The Velcade purifying:
Take by weighing 3 Velcade crude products, be dissolved in single or mixed solvent in, stirred under the normal temperature condition 3 hours, the solid of suction filtration, drying under reduced pressure under 40 ℃ of conditions is measured its chemical purity and chiral purity.
Common solvent has: acetonitrile, methyl alcohol, different ratios Methanol-water and ethyl acetate.
Velcade chemical purity measuring method:
Measure according to high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia).Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent, and moving phase is 1% formic acid solution-acetonitrile=70:30; Flow velocity 1.0ml/min; 25 ℃ of column temperatures; The detection wavelength is 270nm.It is an amount of to get the Velcade sample, accurately weighed to volumetric flask, and (acetonitrile-water=6:3) is mixed with the need testing solution of 1mg/ml to solubilizing agent.It is an amount of to get the Velcade reference substance, accurately weighed to volumetric flask, and (acetonitrile-water=6:4) is mixed with the contrast solution of 1mg/ml to solubilizing agent.
Assay method is got need testing solution and each 20 μ l of reference substance solution, injection liquid chromatography, record color atlas.Press external standard method with calculated by peak area, and get final product.
Velcade chiral purity measuring method:
Chromatographic condition and system suitability: with Daicel OD-H chromatographic column, take normal hexane-ethanol-methyl alcohol=90:7:3 as moving phase, flow velocity is 1.0ml/min, and the detection wavelength is 270nm, and column temperature is 25 ℃.Theoretical plate number is calculated by W-13 peak should be not less than 2000.
Assay method: it is an amount of to get W-13, adds the mixed solvent dissolving of normal hexane-ethanol=90:10, is prepared into the solution that contains approximately sample 200 μ g among every 1ml, as trial-product, and accurate two district's trial-products, 20 μ l, injection liquid chromatography, record color atlas.
The following following table of result:
| Numbering | Purification solvent | HPLC (chemical purity) | The HPLC(chiral purity) |
| 1 | Methanol-water (3 ︰ 1) | 99.5% | 99.67% |
| 2 | Methanol-water (4 ︰ 1) | 99.45% | 99.53% |
| 3 | Methanol-water (5 ︰ 1) | 99.43% | 99.52% |
| 4 | Acetonitrile | 99.56% | 99.64% |
| 5 | Methyl alcohol | 99.82% | 99.91% |
| 6 | Ethyl acetate | 99.89% | 99.90% |
Claims (8)
1. Velcade synthetic method, realize by following synthesis step:
A. methylene dichloride, n-Butyl Lithium are the starting raw material medicine, through the metallization reaction deprotonation, obtain metal-salt methylene dichloride lithium,
B. methylene dichloride lithium and trimethyl borate reaction obtains chemical compounds I,
C. chemical compounds I and (1S, 2S, 3R, 5S)-(+)-send the alkane glycol to react obtain compound ii,
D. compound ii and selenium alkynide obtain the compound III by grignard reaction,
E compound III obtains compounds Ⅳ with two (trimethyl silicon based) Lithamide reactions,
F. compounds Ⅳ obtains the compound V through acidifying in organic solvent,
G.. compound V and compound VI (S)-3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid gets the compound VII through condensation reaction under the catalysis of basic cpd, the acidified Velcade that obtains,
H.. the product Velcade through crystallization, obtains the higher Velcade trimeric form of purity in organic solvent.
2. according to claims 1 described synthetic method, it is characterized in that in the steps A that temperature of reaction is controlled at-120～-60 ℃; It is wherein a kind of that reaction solvent is selected from tetrahydrofuran (THF), ether, toluene, methylene dichloride or methyl tertiary butyl ether, among the step B, and reaction beginning 1 hour, temperature is controlled at-120～-60 ℃; Temperature is increased to 15～30 ℃ after the stable reaction, among the step C, temperature of reaction is controlled between 15～30 ℃, chemical compounds I and (1S, 2S, 3R, 5S)-(+)-and to send alkane glycol feed ratio be 1 ︰ (1～1.5), among the step D, temperature of reaction is controlled under-120～-60 ℃ of conditions, in the step e, reaction beginning 1 hour, temperature is controlled under-120～-60 ℃ of conditions, and temperature is increased to 15～30 ℃ after the stable reaction, in the step F, organic solvent screens wherein a kind of from following solvent: methylene dichloride, tetrahydrofuran (THF), dioxane, dimethyl formamide, isopropyl ether, among the step G, compound VI (S)-3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid synthesis step is as follows:
(a) take 2-pyrazine carboxylic acid as bulk drug, obtain 2-pyrazine acyl chlorides through halogenating reaction;
(b) 2-pyrazine acyl chlorides and L-phenylalanine methyl ester hydrochloride obtains N-(2-pyrazinyl carbonyl)-L-phenylalanine methyl ester through acylation reaction;
(c) N-(2-pyrazinyl carbonyl)-L-phenylalanine methyl ester is acidified, sloughs methyl esters, obtains the compound VI.
3. according to claims 2 described synthetic methods, it is characterized in that in the steps A that temperature of reaction is controlled at-100 ℃; Reaction solvent is tetrahydrofuran (THF), among the step B, and reaction beginning 1 hour, temperature is controlled at-100 ℃; Temperature is increased to 25 ℃ after the stable reaction, and among the step C, temperature of reaction is controlled at 25 ℃; Chemical compounds I and (1S, 2S, 3R, 5S)-(+)-send alkane glycol feed ratio are 1 ︰ 1.05, and among the step D, temperature of reaction is controlled at-78 ℃; Catalysts is zinc chloride, in the step e, and reaction beginning 1 hour, temperature is-78 ℃; Temperature raises 25 ℃ after the stable reaction, and in the step F, compounds Ⅳ obtains the compound V through acidifying in organic solvent; Organic solvent is dioxane or isopropyl ether.
4. according to claim 2 or 3 described synthetic methods, it is characterized in that halide reagent is selected from the synthesis step (a): Phosphorates phosphorus Halides or halogenation sulfoxide.
5. according to claim 2 or 3 described synthetic methods, it is characterized in that the organic bases of using in the acylation reaction is selected from the synthesis step (b): triethylamine, pyridine, diethylamine, N, N-diisopropylethylamine or morpholine are wherein a kind of
According to claim 5, described synthetic method is characterized in that in the synthesis step (b), the organic bases of using in the acylation reaction is triethylamine.
According to claim 1 described in synthetic method, it is characterized in that among the synthesis step G, compound V and compound VI obtain the Velcade crude product through the condensation reaction, condensation reagent is selected from: dicyclohexylcarbodiimide (DCC), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-hydroxyl-benzo-triazole (HOBT) are wherein a kind of; The organic basic catalyzer is selected from triethylamine, pyridine, diethylamine, N, and N-diisopropylethylamine or morpholine are wherein a kind of.
According to claim 6 described in synthetic method, it is characterized in that among the synthesis step G that compound V and compound VI obtain the Velcade crude product through the condensation reaction, condensation reagent selects O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU); The organic basic catalyzer is selected from triethylamine.
According to claim 1 described in synthetic method, it is characterized in that among the synthesis step H that the Velcade crude product is through following solvent crystallization or purifying: one or more solvent mixtures in water, methyl alcohol, acetonitrile, ethyl acetate, acetone, the normal hexane.
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