CN107629078A - A kind of bortezomib and its synthetic method - Google Patents
A kind of bortezomib and its synthetic method Download PDFInfo
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Abstract
The invention discloses a kind of bortezomib and its synthetic method, the key step of the synthetic method includes：Condensation, debenzylation, condensation, oxidation deprotection, purifying.The synthetic method of bortezomib provided by the invention, pass through reasonably optimizing raw material proportioning, properly increase reaction temperature, screen high performance-price ratio formula, finally improve the purity and yield of bortezomib, high purity 99.7%, high income have very important realistic meaning up to 67.0%, for the industrialized production of bortezomib.
Description
Technical field
The present invention relates to the field of chemical synthesis, relates generally to a kind of bortezomib and its synthetic method.
Background technology
Bortezomib, chemical name：[(1R) -3- methyl isophthalic acids-[[(2S) -1- oxygen -3- phenyl -2- [(pyrazine formyl) amino]
Propyl group] amino] butyl]-boric acid, outer literary fame (or) common name：Bortezomib.
Bortezomib (Bortezomib) is a kind of dipeptides ylboronic acid compound, is ground by Millennium drugmakers of the U.S.
The new type antineoplastic medicine of hair, and in acquisition May 19 in 2003 FDA approval, with Velcade trade name list marketings, for note
Agent is penetrated, is mainly used in treating recurrent and Refractory Multiple Myeloma.Recent study confirms that bortezomib is as protease
Body inhibitor, can be apoptosis-induced in various tumor cell strains and cancerous tumor cell, significantly increases some chemotherapeutics and ionization
The effect of the methods of radiotherapy inducing apoptosis of tumour cell, and it is relatively small for the toxic action of normal cell.
Find that in existing synthetic method, the condensing agent cost in condensation reaction is higher and is difficult to remove through retrieval；Together
When bortezomib be to be got by multistep reaction chemical synthesis, product unstable chemcial property, containing be easy to oxidation group,
Side reaction easily occurs during reaction, so as to introduce other impurity；The presence of chiral radicals causes the mistake that product synthesizes
Difficulty increase, the presence of isomer impurities, makes optical purity of products relatively low, generally existing preparation process is answered in the prior art in journey
Miscellaneous, the problems such as yield is low, the more purity of product impurity do not reach quality standard.
Patent CN1960996A discloses a kind of Synthetic method of bortezomib, with isobutaneboronic acid, (1S, 2S, 3R, 5S)-
(+)-send alkane glycol to prepare bortezomib for bulk drug, by substitution reaction, borate is formed, is catalyzed by anhydrous zinc chloride
Under, chlorine methylene intercalation reaction structural formula, amido nucleophilic substitution is being carried out, trimethyl silicon substrate is being taken off, obtains intermediate.In addition
One intermediate obtains using 2- pyrazine carboxylic acids and L-phenylalanine as bulk drug by condensation reaction, and two intermediates pass through contracting
Close reaction and obtain bortezomib, the synthetic method condition is harsh, and yield is than relatively low, and bulk drug is expensive, is not suitable for industry
Change.
Patent CN 101812026A disclose a kind of Synthetic method of bortezomib, with 3- methylbutyraldehyds and R- (+) -1- benzene
Ethamine is initiation material medicine, is deprotected by condensation reaction, the addition of boron selective acid esters, hydrogenation, with the chiral contracting of L-phenylalanine
Close, obtain bortezomib with 2- carboxyls-piperazine condensation, duplex pinacol borate, while condensation reaction are used in reaction scheme
With the method for backflow, due to having chiral centre in compound, relevant material or content of isomer increase can be caused, be not suitable for industry
Metaplasia is produced.
Therefore it provides it is a kind of it is environment-friendly, technological operation is simple, cost is low, product purity is high, the bortezomib of high income
Preparation method, there is very important realistic meaning for the industrialized production of bortezomib medicine.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of bortezomib and its synthetic method, pass through reasonably optimizing
Raw material proportioning, reaction temperature is properly increased, screen high performance-price ratio formula, finally improve the purity and yield of bortezomib, it is pure
Degree up to 99.7%, high income has very important realistic meaning up to 67.0%, for the industrialized production of bortezomib.
In a first aspect, the present invention provides a kind of synthetic method of bortezomib, comprise the following steps：
(1) it is 1 by mol ratio under the protection of inert gas:(1.5-2.5):(2-5):Double (R) -1- ammonia of (3-8)
Base -3- methyl butyl boric acid pinane diols ester hydrochloride, 2 (S) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N- methyl
Quinoline is added in ether solvent, is catalyzed through acid binding agent, is reacted in alkaline environment, generation compound II；
(2) it is 1 by mol ratio:The compound II and Pd/C of (2-4) are in H2Debenzylation is carried out in environment, obtains chemical combination
Thing III；
(3) it is 1 by mol ratio under inert gas shielding:(4-6):(3.5-4):Compound III, the pyrrole of (2.5-3.5)
Piperazine -2- carboxylic acids, organic amine and condensing agent carry out condensation reaction after mixing, and obtain compound IV；
(4) it is 1 by mol ratio:The compound IV of (6-8) is added in ether solvent with oxidant and is carried out aoxidizing instead after mixing
Should, compound I, i.e. bortezomib are obtained after reagent purification.
Inventor has found, if total recovery can be not only greatly reduced by adding excessive reaction raw materials, can also produce it is more in
Between product, therefore, the present invention pass through lot of experiments, draw said ratio, the yield of reaction and purity is reached metastable
Higher level.If exceeding the framework of the present definition, purity and yield substantially reduce, and cause the bad shadow such as the waste of reaction raw materials
Ring.
Preferably, step (1) described mol ratio is 1:(1.5-2):(2-4.5):(3-7.5), such as can be 1:2:3:
6、1:1.5:2:3、1:2:4.5:7.5 or 1:1.5:3:6, preferably 1:2:3:6.
Preferably, inert gas described in step (1) and (3) is nitrogen and/or argon gas, preferably nitrogen.
Preferably, the aldehydes solvent described in step (1) and (4) includes tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethyl formyl
In amine or dimethyl acetamide any one or at least two mixture, such as can be tetrahydrofuran and dimethyl sulfoxide (DMSO)
Combination, the combination of dimethyl sulfoxide (DMSO) and dimethylformamide, the combination of dimethylformamide and dimethyl acetamide or tetrahydrochysene
The combination of furans and dimethyl acetamide, preferably tetrahydrofuran.
Preferably, the addition of ether solvent is to add 4L per in mol reactants.
Preferably, acid binding agent described in step (1) includes DIPEA and/or triethylamine.
Preferably, the pH of step (1) described alkaline environment is 9.5-11.5, for example, can be 9.5,9.8,10,10.5,
11st, 11.2 or 11.5, preferably 10.
Preferably, the time of step (1) described reaction is 1-3h, for example, can be 1h, 1.5h, 2h, 2.5h, 2.8h or
3h, preferably 2h.
Preferably, the temperature of step (1) described reaction is 40-60 DEG C, for example, can be 40 DEG C, 42 DEG C, 44 DEG C, 46 DEG C,
48 DEG C, 50 DEG C, 55 DEG C, 58 DEG C or 60 DEG C, preferably 55 DEG C.
Preferably, step (2) the compound II and Pd/C mol ratio is 1:(2-3.5), such as can be 1:2、1:
2.5、1:2.8、1:3 or 1:3.5, preferably 1:3, Pd/C molal quantity is in terms of Pd.
Preferably, the temperature of step (2) described reaction is 60-80 DEG C, for example, can be 60 DEG C, 65 DEG C, 68 DEG C, 70 DEG C,
75 DEG C, 78 DEG C or 80 DEG C, preferably 68 DEG C.
Preferably, the pressure of step (2) described reaction is 2-8atm, for example, can be 2atm, 3atm, 4atm, 5atm,
6atm, 7atm or 8atm, preferably 6atm.
Preferably, the time of step (2) described reaction is 1-2.5h, such as can be 1h, 1.5h, 2h, 2.2h or 2.5h,
Preferably 2h.
Preferably, step (3) described mol ratio is 1:(4-5):(3.5-3.8):(2.5-3), such as can be 1:4:
3.5:2.5、1:5:3.8:3 or 1:4.5:3.6:2.8, preferably 1:5:3.8:3.
Preferably, organic amine described in step (3) includes triethylamine or/and DIPEA.
Preferably, condensing agent described in step (3) includes 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Or/and I-hydroxybenzotriazole.
Preferably, the temperature of step (3) described reaction is 35-45 DEG C, for example, can be 35 DEG C, 36 DEG C, 38 DEG C, 40 DEG C,
42 DEG C, 44 DEG C or 45 DEG C, preferably 38 DEG C.
Preferably, the time of step (3) described reaction is 2-3h, for example, can be 2h, 2.2h, 2.4h, 2.5h, 2.7h or
3h, preferably 2.5h.
Preferably, step (4) described mol ratio is 1:(6-7.5), such as can be 1:6、1:6.2、1:6.4、1:6.8、
1:7、1:7.3 or 1:7.5, preferably 1:7.
Preferably, step (4) described oxidant is any of sodium metaperiodate, potassium metaperiodate, periodic acid or at least two
The mixture of kind, such as can be the mixture or height of the mixture of sodium metaperiodate and potassium metaperiodate, potassium metaperiodate and periodic acid
The mixture of sodium iodate and periodic acid, preferably sodium metaperiodate.
Preferably, the temperature of step (4) described reaction is 65-75 DEG C, for example, can be 65 DEG C, 66 DEG C, 68 DEG C, 70 DEG C,
72 DEG C or 75 DEG C, preferably 68 DEG C.
Preferably, step (4) described purified reagent is through acetone and/or toluene.
Preferably, the time of step (4) described reaction is 3-5h, for example, can be 3h, 3.2h, 3.4h, 3.6h, 4h,
4.2h, 4.6h, 4.8h or 5h, preferably 4h.
Preferably, the described method comprises the following steps：
(1) it is 1 by mol ratio under the protection of nitrogen and/or argon gas:(1.5-2.5)：(2-5)：Double (R) of (3-8)-
1- amino -3- methyl butyl boric acid pinane diols ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N- first
Base morpholine is added in ether solvent, is catalyzed through acid binding agent DIPEA and/or triethylamine, is 40-60 DEG C in temperature,
PH is that reaction 1-3h is carried out in 9.5-11.5 environment, generation compound II；
Described aldehydes solvent is included in tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide
One or more kinds of mixtures, the addition of ether solvent are to add 4L per in mol reactants；
(2) it is 1 by mol ratio:The compound II and Pd/C of (2-4) are in H2Debenzylation, the temperature of reaction are carried out in environment
Spend for 60-80 DEG C, the pressure of reaction is 2-8atm, and the time of reaction is 1-2.5h, obtains compound III；
(3) it is 1 by mol ratio under inert gas shielding:(4-6):(3.5-4):Compound III, the pyrrole of (2.5-3.5)
Piperazine -2- carboxylic acids, organic amine and condensing agent carry out condensation reaction after mixing, the temperature of reaction is 35-45 DEG C, and the time of reaction is 2-
3h, obtain compound IV；The organic amine includes triethylamine or/and N, N- diisopropylethylamine；The condensing agent includes 1- second
Base-(3- dimethylaminopropyls) carbodiimide hydrochloride or/and I-hydroxybenzotriazole；
(4) it is 1 by mol ratio:6-8 compound IV is added in ether solvent with oxidant and is carried out oxidation reaction after mixing,
The temperature of reaction is 65-75 DEG C, and the time of reaction is 3-5h, obtains compound I after purification through acetone and/or toluene, i.e., boron is for assistant
Rice；
The oxidant is sodium metaperiodate, potassium metaperiodate, any of periodic acid or at least two mixture, described
Aldehydes solvent include one or both of tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide with
On mixture, the addition of ether solvent is to add 4L per in mol reactants.
Second aspect, the present invention provide bortezomib prepared by a kind of synthetic method according to first aspect.
Compared with prior art, beneficial effects of the present invention are：
Synthetic method provided by the invention properly increases reaction temperature, screens high sexual valence by reasonably optimizing raw material proportioning
Than formula, finally reactions steps are simplified, reaction cost reduces, and reaction reagent low-toxicity green is environment-friendly, technological operation letter
It is single, the purity and yield of bortezomib are improved, high purity 99.7%, high income is up to 67.0%, for the work of bortezomib
The production of industry metaplasia has very important realistic meaning.
Embodiment
Further to illustrate the technological means and its effect of the invention taken, below in conjunction with being preferable to carry out for the present invention
Example further illustrates technical scheme, but the present invention is not limited in scope of embodiments.
Embodiment 1
(1) it is 1 by mol ratio under the protection of nitrogen:2:4.5:7.5 double (R) -1- amino -3- methyl butyl boric acid
Pinane diol ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add ether solvent tetrahydrochysene
In furans, addition is to add 4L per in mol reactants, is catalyzed through acid binding agent DIPEA, is 55 DEG C in temperature,
PH is that reaction 2h is carried out in 10 environment, generation compound II；
(2) it is 1 by mol ratio:3 compound II and Pd/C is in H2Debenzylation is carried out in environment, the temperature of reaction is
68 DEG C, the pressure of reaction is 6atm, and the time of reaction is 2h, obtains compound III；
(3) it is 1 by mol ratio under the protection of nitrogen:5:3.8:3 compound III, pyrazine -2- carboxylic acids, triethylamine and
Condensing agent 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride carries out condensation reaction after mixing, and the temperature of reaction is
38 DEG C, the time of reaction is 2.5h, obtains compound IV；
(4) it is 1 by mol ratio:7 compound IV is added in tetrahydrofuran with oxidizing agent sodium periodate and is carried out oxygen after mixing
Change reaction, the temperature of reaction is 68 DEG C, and the time of reaction is 4h, and compound I, i.e. bortezomib are obtained after purification through toluene.
Embodiment 2
(1) it is 1 by mol ratio under the protection of argon gas:1.5:2:3 double (R) -1- amino -3- methyl butyl boric acid pinanes
Alkane glycol ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add ether solvent dimethyl
In sulfoxide, addition is to add 4L per in mol reactants, is catalyzed through acid binding agent triethylamine, is 40 DEG C in temperature, pH is 9.5
Reaction 1h, generation compound II are carried out in environment；
(2) it is 1 by mol ratio:2 compound II and Pd/C is in H2Debenzylation is carried out in environment, the temperature of reaction is
60 DEG C, the pressure of reaction is 2atm, and the time of reaction is 1h, obtains compound III；
(3) it is 1 by mol ratio under argon gas protection:4:3.5:2.5 compound III, pyrazine -2- carboxylic acids, N, N- bis- are different
Propylethylamine and condensing agent I-hydroxybenzotriazole carry out condensation reaction after mixing, the temperature of reaction is 35 DEG C, the time of reaction
For 2h, compound IV is obtained；
(4) it is 1 by mol ratio:6 compound IV is added in dimethylformamide with oxidant periodic acid and carried out after mixing
Oxidation reaction, the temperature of reaction is 65 DEG C, and the time of reaction is 3h, and compound I, i.e. bortezomib are obtained after purification through acetone.
Embodiment 3
(1) it is 1 by mol ratio under the protection of nitrogen:2.5:5:8 double (R) -1- amino -3- methyl butyl boric acid pinanes
Alkane glycol ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add dimethylformamide
In, addition is to add 4L per in mol reactants, is catalyzed through acid binding agent DIPEA, is 60 DEG C in temperature, pH is
Reaction 3h, generation compound II are carried out in 11.5 environment；
Described aldehydes solvent include one or both of tetrahydrofuran, dimethyl sulfoxide (DMSO) or dimethyl acetamide with
On mixture, ether solvent；
(2) it is 1 by mol ratio:4 compound II and Pd/C is in H2Debenzylation is carried out in environment, the temperature of reaction is
80 DEG C, the pressure of reaction is 8atm, and the time of reaction is 2.5h, obtains compound III；
(3) it is 1 by mol ratio under argon gas protection:6:4:3.5 compound III, pyrazine -2- carboxylic acids, triethylamine and contracting
Mixture I-hydroxybenzotriazole carries out condensation reaction after mixing, the temperature of reaction is 45 DEG C, and the time of reaction is 3h, obtains chemical combination
Thing IV；
(4) it is 1 by mol ratio:8 compound IV is added in dimethylformamide with periodic acid and is carried out aoxidizing instead after mixing
Should, the temperature of reaction is 75 DEG C, and the time of reaction is 5h, and compound I, i.e. bortezomib are obtained after purification through toluene.
Embodiment 4
(1) it is 1 by mol ratio under the protection of argon gas:2:4.5:7.5 double (R) -1- amino -3- methyl butyl boric acid
Pinane diol ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add ether solvent diformazan
In yl acetamide, the addition of ether solvent is to add 4L per in mol reactants, is catalyzed through acid binding agent triethylamine, is in temperature
48 DEG C, pH is that reaction 1.5h is carried out in 11 environment, generation compound II；
(2) it is 1 by mol ratio:3.5 compound II and Pd/C is in H2Debenzylation, the temperature of reaction are carried out in environment
For 70 DEG C, the pressure of reaction is 5atm, and the time of reaction is 1.8h, obtains compound III；
(3) it is 1 by mol ratio under the protection of nitrogen:3.5:3.7:2.7 compound III, pyrazine -2- carboxylic acids, N, N-
Diisopropylethylamine and condensing agent 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride after mixing be condensed instead
Should, the temperature of reaction is 37 DEG C, and the time of reaction is 2.7h, obtains compound IV；
(4) it is 1 by mol ratio:6.7 compound IV is added in dimethyl acetamide with sodium metaperiodate and is carried out oxygen after mixing
Change reaction, the temperature of reaction is 66 DEG C, and the time of reaction is 3.9h, and compound I, i.e. bortezomib are obtained after purification through toluene.
Embodiment 5
(1) it is 1 by mol ratio under the protection of argon gas:2.2：3.2：(4.2 double (R) -1- amino -3- methyl butyl boron
Sour pinane diol ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add ether solvent four
In hydrogen furans, the addition of ether solvent is to add 4L per in mol reactants, is catalyzed through acid binding agent DIPEA,
It it is 42 DEG C in temperature, pH is that reaction 1.2h is carried out in 9.9 environment, generation compound II；
(2) it is 1 by mol ratio:2.3 compound II and Pd/C is in H2Debenzylation, the temperature of reaction are carried out in environment
For 63 DEG C, the pressure of reaction is 4.6atm, and the time of reaction is 2.3h, obtains compound III；
(3) it is 1 by mol ratio under the protection of argon gas:4.3:3.8:2.6 compound III, pyrazine -2- carboxylic acids, N, N-
Diisopropylethylamine and condensing agent 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride after mixing be condensed instead
Should, the temperature of reaction is 44 DEG C, and the time of reaction is 2.4h, obtains compound IV；
(4) it is 1 by mol ratio:6.6 compound IV is added in ether solvent tetrahydrofuran with periodic acid and carried out after mixing
Oxidation reaction, the temperature of reaction is 73 DEG C, and the time of reaction is 3.3h, and compound I, i.e. bortezomib are obtained after purification through acetone.
Comparative example 1
Compared with Example 1, except the mol ratio of step (1) is changed to 1:1:1:Outside 1, other conditions are same as Example 1.
Comparative example 2
Compared with Example 1, except the mol ratio of step (1) is changed to 1:3:6:Outside 10, other conditions and the phase of embodiment 1
Together.
Comparative example 3
Compared with Example 1, except the mol ratio of step (2) is changed to 1:Outside 1, other conditions are same as Example 1.
Comparative example 4
Compared with Example 1, except the mol ratio of step (2) is changed to 1:Outside 6, other conditions are same as Example 1.
Comparative example 5
Compared with Example 1, except the mol ratio of step (3) is changed to 1:1:1:Outside 1, other conditions are same as Example 1.
Comparative example 6
Compared with Example 1, except the mol ratio of step (3) is changed to 1:7:7:Outside 5, other conditions are same as Example 1.
Comparative example 7
Compared with Example 1, except the mol ratio of step (4) is changed to 1:Outside 1, other conditions are same as Example 1.
Comparative example 8
Compared with Example 1, except the mol ratio of step (4) is changed to 1:Outside 10, other conditions are same as Example 1.
Comparative example 9
Compared with Example 1, except reaction temperature declines 10 DEG C, the reaction time extends outside 1h, and other conditions are with implementing
Example 1 is identical.
Comparative example 10
Compared with Example 1, except reaction temperature rises 10 DEG C, reaction reagent shortens outside 1h, and other conditions are with implementing
Example 1 is identical.
Bortezomib chemical purity assay method：
Determine according to high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia 2010 edition), be bonded with octadecylsilane
Silica gel is filler, and mobile phase is 1% formic acid solution；Flow velocity 1.0ml/min；25 DEG C of column temperature；Detection wavelength is 270nm.
Take bortezomib sample appropriate, accurately weighed into volumetric flask, solubilizer (acetonitrile：Water=6:3) it is configured to 1mg/
Ml need testing solution.Take bortezomib reference substance appropriate, accurately weighed into volumetric flask, solubilizer (acetonitrile：Water=6:4) match somebody with somebody
1mg/ml contrast solution is made.Need testing solution and each 20 μ l of reference substance solution are taken, injects liquid chromatograph, records chromatogram
Figure.By external standard method with calculated by peak area, produce, as a result as shown in table 1.
Overall yield of reaction refers to the number of the product of output by chemically reacting, and theoretical yield refers to perfectly balanced
In reaction can output maximum product volume, but actual production is often less than theoretical yield., can be with to embody reaction efficiency
Total recovery is calculated using following formula：Total recovery %=(actual production/theoretical yield) × 100%.According to above formula,
The total recovery of embodiment and comparative example is calculated, as a result as shown in table 1.
Table 1
Analyzed from table 1, the embodiment 1-5 institutes of raw material proportioning and reaction condition in scope provided by the present invention
The purity of the sample of synthesis is held in more than 99%, up to 99.7%, and sample yield liquid is more than 65%, embodiment
1 is optimal case, and yield is up to 67%.And after comparative example 1-8 raw material proportioning over range, comparative example 9-10 reaction bar
After part over range, sample yield and purity decline to a great extent.
In summary, synthetic method provided by the invention passes through lot of experiments, reasonably optimizing raw material proportioning, properly increases anti-
Temperature is answered, high performance-price ratio formula is screened, finally reactions steps is simplified, reaction cost reduces, reaction reagent low-toxicity green, ring
Border is friendly, and technological operation is simple, improves the purity and yield of bortezomib, the yield of reaction and purity is reached relatively stable
Higher level, high purity 99.7%, high income up to 67.0%, for bortezomib industrialized production have it is extremely important
Realistic meaning, if exceeding the framework of the present definition, purity and yield substantially reduce, and cause the waste of reaction raw materials etc. bad
Influence.
Applicant states that the present invention illustrates the method detailed of the present invention, but not office of the invention by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implemented.Art
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, selection of concrete mode etc., within the scope of all falling within protection scope of the present invention and disclosing.
Claims (10)
1. a kind of synthetic method of bortezomib, it is characterised in that comprise the following steps：
(1) it is 1 by mol ratio under the protection of inert gas:(1.5-2.5):(2-5):Double (R) -1- amino -3- of (3-8)
Methyl butyl boric acid pinane diol ester hydrochloride, 2 (S) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N-methylmorpholine add
In ether solvent, it is catalyzed through acid binding agent, is reacted in alkaline environment, generation compound II；
(2) it is 1 by mol ratio:The compound II and Pd/C of (2-4) are in H2Debenzylation is carried out in environment, obtains compound
III；
(3) it is 1 by mol ratio under inert gas shielding:(4-6):(3.5-4):The compound III of (2.5-3.5), pyrazine-
2- carboxylic acids, organic amine and condensing agent carry out condensation reaction after mixing, and obtain compound IV；
(4) it is 1 by mol ratio:The compound IV of (6-8) is added in ether solvent with oxidant and is carried out oxidation reaction after mixing, is passed through
Compound I, i.e. bortezomib are obtained after reagent purification.
2. according to the method for claim 1, it is characterised in that step (1) described mol ratio is 1:(1.5-2):(2-
4.5):(3-7.5), preferably 1:2:3:6.
3. method according to claim 1 or 2, it is characterised in that inert gas described in step (1) and (3) is nitrogen
And/or argon gas, preferably nitrogen.
4. according to the method any one of claim 1-3, it is characterised in that the aldehydes described in step (1) and (4) is molten
Agent includes any one or at least two in tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide
Mixture, preferably tetrahydrofuran；
Preferably, the addition of ether solvent is to add 4L per in mol reactants.
5. according to the method any one of claim 1-4, it is characterised in that acid binding agent includes N described in step (1),
N- diisopropylethylamine and/or triethylamine；
Preferably, the pH of step (1) described alkaline environment is 9.5-11.5, preferably 10；
Preferably, the time of step (1) described reaction is 1-3h, preferably 2h；
Preferably, the temperature of step (1) described reaction is 40-60 DEG C, preferably 55 DEG C.
6. according to the method any one of claim 1-5, it is characterised in that step (2) the compound II and Pd/C
Mol ratio be 1:(2-3.5), preferably 1:3；
Preferably, the temperature of step (2) described reaction is 60-80 DEG C, preferably 68 DEG C；
Preferably, the pressure of step (2) described reaction is 2-8atm, preferably 6atm；
Preferably, the time of step (2) described reaction is 1-2.5h, preferably 2h.
7. according to the method any one of claim 1-6, it is characterised in that step (3) described mol ratio is 1:(4-
5):(3.5-3.8):(2.5-3), preferably 1:5:3.8:3；
Preferably, organic amine described in step (3) includes triethylamine or/and DIPEA；
Preferably, condensing agent described in step (3) include 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride or/
And I-hydroxybenzotriazole；
Preferably, the temperature of step (3) described reaction is 35-45 DEG C, preferably 38 DEG C；
Preferably, the time of step (3) described reaction is 2-3h, preferably 2.5h.
8. according to the method any one of claim 1-7, it is characterised in that step (4) described mol ratio is 1:(6-
7.5), preferably 1:7；
Preferably, the temperature of step (4) described reaction is 65-75 DEG C, preferably 68 DEG C；
Preferably, step (4) described purified reagent is through acetone and/or toluene；
Preferably, step (4) described oxidant is any of sodium metaperiodate, potassium metaperiodate, periodic acid or at least two
Composition, preferably sodium metaperiodate；
Preferably, the time of step (4) described reaction is 3-5h, preferably 4h.
9. such as the synthetic method any one of claim 1-8, it is characterised in that the described method comprises the following steps：
(1) it is 1 by mol ratio under the protection of nitrogen and/or argon gas:(1.5-2.5)：(2-5)：Double (R) -1- ammonia of (3-8)
Base -3- methyl butyl boric acid pinane diols ester hydrochloride, 2 (s) benzyl amino -3- phenylpropionic acids, isobutyryl chloride and N- methyl
Quinoline is added in ether solvent, is catalyzed through acid binding agent DIPEA and/or triethylamine, is 40-60 DEG C in temperature, pH is
Reaction 1-3h, generation compound II are carried out in 9.5-11.5 environment；
Described aldehydes solvent includes one kind in tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide
Or two or more mixtures, the addition of ether solvent are to add 4L per in mol reactants；
(2) it is 1 by mol ratio:The compound II and Pd/C of (2-4) are in H2Debenzylation is carried out in environment, the temperature of reaction is
60-80 DEG C, the pressure of reaction is 2-8atm, and the time of reaction is 1-2.5h, obtains compound III；
(3) it is 1 by mol ratio under inert gas shielding:(4-6):(3.5-4):The compound III of (2.5-3.5), pyrazine-
2- carboxylic acids, organic amine and condensing agent carry out condensation reaction after mixing, the temperature of reaction is 35-45 DEG C, and the time of reaction is 2-3h,
Obtain compound IV；The organic amine includes triethylamine or/and N, N- diisopropylethylamine；The condensing agent include 1- ethyls-
(3- dimethylaminopropyls) carbodiimide hydrochloride or/and I-hydroxybenzotriazole；
(4) it is 1 by mol ratio:6-8 compound IV is added in ether solvent with oxidant and is carried out oxidation reaction after mixing, is reacted
Temperature be 65-75 DEG C, the time of reaction be 3-5h, and compound I, i.e. bortezomib are obtained after purification through acetone and/or toluene；
Described aldehydes solvent includes one kind in tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide
Or two or more mixtures, the addition of ether solvent are to add 4L per in mol reactants, the oxidant is periodic acid
Any of sodium, potassium metaperiodate, periodic acid or at least two composition.
A kind of 10. bortezomib prepared according to any one of claim 1-9 synthetic method.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011098963A1 (en) * | 2010-02-09 | 2011-08-18 | Ranbaxy Laboratories Limited | Process for the preparation of bortezomib |
| CN102351890A (en) * | 2011-09-30 | 2012-02-15 | 重庆泰濠制药有限公司 | Method for synthesizing bortezomib |
-
2017
- 2017-10-30 CN CN201711038542.8A patent/CN107629078A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011098963A1 (en) * | 2010-02-09 | 2011-08-18 | Ranbaxy Laboratories Limited | Process for the preparation of bortezomib |
| CN102351890A (en) * | 2011-09-30 | 2012-02-15 | 重庆泰濠制药有限公司 | Method for synthesizing bortezomib |
Non-Patent Citations (1)
| Title |
|---|
| 杨冲生 等: "硼替佐米中间体的合成及工艺优化", 《云南化工》 * |
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