CN103965293A - High-purity bivalirudin and industrial preparation method thereof - Google Patents
High-purity bivalirudin and industrial preparation method thereof Download PDFInfo
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Abstract
The invention provides high-purity bivalirudin and an industrial preparation method thereof. The preparation method employs solid phase peptide synthesis technology and uses the solvent--ethyl acetate which is convenient to use and recover and has a low price as a washing agent, so reaction yield and product quality are improved, production cost is effectively reduced, and discharge of waste is reduced.
Description
Technical field
The invention belongs to a kind of high purity medical polypeptide and industrialized process for preparing thereof, special, the present invention relates to a kind of high purity Bivalirudin and industrial production process thereof.
Background technology
Bivalirudin (bivalirudin), has another name called Angiomax, molecular formula C
98h
138n
24o
33, CAS 128270-60-0, is a kind of hirudin derivative of synthetic, has the activity of Trombin inhibiting, clinical middle Chang Zuowei antithrombotics is applied in percutaneous transluminal coronary angioplasty (PCI).Bivalirudin is researched and developed by Biogen company the earliest, the exploitation listing of Hou You U.S. the Medicines company, trade(brand)name Angiomax.At present, domestic only have the vertical safe medicine company of a Shenzhen letter Bivalirudin formulation products that gone on the market, and commodity are called Tai Jianing.
Bivalirudin is comprised of 20 amino acid, its aminoacid sequence is: D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Gl u-Ile-pro-Glu-Glu-Tyr-Leu-OH, chemical name is: D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-altheine acyl-glycyl-aspartoyl-L-phenylalanyl-L-glutamy-L-glutamy-L-isoleucyl--L-prolyl-L-glutamy-L-glutamy-L-tyrosyl-L-Leu.
The industrial production of Bivalirudin bulk drug adopts the method for chemosynthesis more, concrete, can adopt the combination of liquid phase synthesizing method, solid-phase synthesis or two kinds of methods.Wherein, solid-phase synthesis is widely used because of features such as its productive rate are high, product is easily separated in the chemosynthesis of polypeptide series products.Synthesizing of Bivalirudin adopts solid-phase synthesis more at present.
The solid phase synthesis of Bivalirudin relates to a plurality of synthesis steps, all needs to use washing composition that the residual reactant washes clean in peptide resin just can be carried out to next step reaction after every single step reaction completes.Otherwise residual reactant can cause a series of side reactions, and accumulate in subsequent reactions, and then cause total yield of products to reduce, product impurity level and impurity number increase, and give follow-up thick peptide the refining difficulty of bringing.
For the selection of washing composition, the multiplex DMF of prior art or DMF coordinate methyl alcohol, methylene dichloride to walk reacted washing composition as each.Patent CN200610024611.5 has reported that use DMF is applied in Bivalirudin solid phase synthesis as washing composition; Patent CN200810008131.9 has reported that use DMF, methyl alcohol and methylene dichloride are applied in Bivalirudin solid phase synthesis as washing composition.DMF boiling point is up to 152.8 ℃, and in industrial production, recovery cost is higher, if directly discharge can cause environmental pollution; Methanol wash poor effect, cannot as washing composition, use separately, and methyl alcohol toxicity is large, easily the person is damaged, to environment; The boiling point too low (39.8 ℃) of methylene dichloride easily because of volatilization loss, is unfavorable for suitability for industrialized production, so cleaning solvent that neither be desirable when using separately or mixing use with DMF.Although in actual production, washing effect also can improve by increasing washing times, and repeatedly washing resin certainly will consume a large amount of organic solvents.So finding a kind of economy, low toxicity and efficient Bivalirudin solid phase synthesis cleaning solvent is the technical issues that need to address.
Contriver is from solving the deficiencies in the prior art, by great many of experiments, find, while adopting solid-phase synthesis to prepare Bivalirudin, use ethyl acetate can obviously improve reaction yield as resin washing composition, gained Bivalirudin has higher purity and pure peptide content.
Summary of the invention
One object of the present invention has been to provide a kind of washing composition for Bivalirudin solid phase synthesis and using method thereof, can effectively reduce Bivalirudin production cost, and the yield of gained Bivalirudin and purity are all higher than the method for prior art.
The present invention is by using the ethyl acetate of 3 ~ 6 ml/g resins to realize above-mentioned beneficial effect as the washing composition in Bivalirudin solid phase synthesis process, and washing times is 1-9 time.Described synthetic method comprises linked reaction step and deprotection steps, after linked reaction step and deprotection steps complete, use washing composition to rinse resin, avoid remaining reactant to bring in follow-up reaction, as very few in detergent amount used, may cause washing effect poor, residual reactant can be brought in follow-up reaction, and then affects reaction yield and product quality; Too much washing amount can cause waste, and increases products production cost.Described measure unit ml/g resin refers to: 1 gram of amino acid whose resin of connection of every use in each step of described solid state reaction, and corresponding step solvent for use amount is 1 ml; For example: in deprotection steps, use the ethyl acetate of 3 ~ 6 ml/g resins to refer to: 1 gram of resin for the treatment of deprotection of every use in this deprotection steps; the amount of corresponding deprotection steps washing composition ethyl acetate used is 3 ~ 6 ml; preferably, the consumption of described washing composition ethyl acetate is 4 ml/g resins.Although in theory, by repeatedly washing can more effective removal impurity, repeatedly washing certainly will increase solvent load, extends total reaction time, and then raising production cost.Contriver is by the beat all discovery of great many of experiments, in the reaction of the synthetic Bivalirudin of solid-phase polypeptide method, under the same terms, use ethyl acetate as washing composition, than using other solvents more can thoroughly wash away impurity, the detergent amount using also still less, is 1-9 time at washing times, when dosage of scour is 3 ~ 6 ml/g, use ethyl acetate particularly evident as the advantage of washing composition.Amount and the washing times of the washing composition that described every step reaction is used are separate; the washing times of described every step reaction is accumulated; concrete; for linked reaction step; the washing times of corresponding ethyl acetate is preferably 1 ~ 3 time; for deprotection steps, the washing times of corresponding ethyl acetate is for being preferably 5 ~ 9 times.
The amino acid starting material that Bivalirudin solid phase synthesis is used, its end bit amino protecting group can be protecting group common in organic chemical reactions, and as Boc, Fmoc, Moz etc., preferred, described amino protecting agent is Fmoc.
Described solid phase synthesis resin used is Leu-Wang Resin resin, charge capacity (SD) between 0.5 ~ 1 mmol/g, preferred 0.6 mmol/g.Although the resin detersive efficiency of too low charge capacity is high, reaction yield is low, and then total production cost is high; And the resin of too high charge capacity means that the peptide amount of load is high, need a large amount of cleaning solvents, during reaction, also easily because peptide chain is wound around, cause productive rate to reduce, and then reduce product quality, increase subsequent purification difficulty, total production cost raises.
Another object of the present invention has been to provide a kind of production method of Bivalirudin, the Bivalirudin solid phase synthesis that to be applicable to take ethyl acetate be washing composition, each step of the method is in conjunction with closely, and economic environmental protection, can be used in the suitability for industrialized production of Bivalirudin, described method comprises the following steps:
1), the SD of take is 0.5 ~ 1 mmol/g Leu-Wang Resin resin is raw material, uses coupling agent and activator by resin and the protected amino acid Tyr-OH of end bit amino condensation;
2), remove reaction solution, the washing of solid phase use ethyl acetate;
3), use piperidines DMF solution deprotection;
4), remove reaction solution, the washing of solid phase use ethyl acetate;
5), with reference to 1) to 4) step, by all the other 18 the protected amino acid of end bit amino according to Bivalirudin aminoacid sequence successively condensation;
6), with lytic reagent cutting Bivalirudin peptide resin, collect lytic reagent, with the thick peptide of ether sedimentation;
7), use RP-HPLC method purification of crude peptide, the dry sterling that to obtain.
In the production method of described Bivalirudin, the mixture of one or more that the coupling agent using is DCC, DIC, HBTU, TBTU, PyBOP; The activator using is one or both the mixture in HOAt, HOBt; The linked reaction solvent using is DMF; The TFA that the cracked solution of using is 95:2.5:2.5 for volume ratio, TIS, H
2o mixing solutions, usage quantity is 6-12 ml/g resin; The consumption of ether is the cracking liquid measure of 8-10 times of volume; For technical scheme of the present invention, within the scope of the rational raw material consumption and proportioning raw materials of described Bivalirudin solid-phase synthesis, use the ethyl acetate of described consumption and washing times all can realize beneficial effect as washing composition, preferably, when used coupling agent and amino acid whose ratio are at 1 ~ 1.1:1, the activator using and amino acid whose ratio are when 1 ~ 1.1:1, and washing effect is particularly evident.
In the production method of described Bivalirudin; the Deprotection reagent using is the piperidines DMF solution that percent by volume that consumption is 8-12 ml/g resin is 20%; due in actual production; for deprotection base more completely; the repeatedly operation of deprotection; and Deprotection reagent is assigned in each operation, so the consumption of described deprotecting regent refers to cumulative volume.For example, removing in same peptide resin protecting group reaction, can be that the Deprotection reagent of 10 ml/g resins is divided into two parts by usage quantity, repeats twice deprotection operation, after each deprotection operation, all uses ethyl acetate washing.
A preferred implementation of the production method of described Bivalirudin, comprises the following steps:
1), the SD of take is 0.6 mmol/g Leu-Wang Resin resin is raw material, take DIC as coupling agent, HOBt is activator, DMF is solvent, by resin and amino acid Fmoc-Tyr-OH coupling; Described coupling agent and amino acid whose mol ratio are 1.1:1, and described activator and amino acid whose mol ratio are 1.1:1;
2), remove reaction solution, solid phase is with the ethyl acetate washing of 4 ml/g resin ratio 1 time;
3), add the piperidines DMF solution deprotection that the percent by volume of 5 ml/g resins is 20%;
4), remove reaction solution, solid phase is divided 2 washings with the ethyl acetate of 4 ml/g resin ratio;
5), add the piperidines DMF that the percent by volume of 5 ml/g resins is 20% to repeat deprotection;
6), remove reaction solution, solid phase is divided 5 washings with the ethyl acetate of 4 ml/g resin ratio;
7), with reference to 1) to 6) step, take DIC as coupling agent, HOBt is activator, DMF is solvent, the amino acid that all the other 18 Fmoc are protected is according to Bivalirudin aminoacid sequence successively coupling, described coupling agent and amino acid whose mol ratio are 1.1:1, and described activator and amino acid whose mol ratio are 1.1:1;
8), with the lysate cutting Bivalirudin peptide resin of 6-12 ml/g resin, collect lysate, with the thick peptide of ether sedimentation of 8-10 times of volume cracking liquid measure;
9), with RP-HPLC method gradient elution, purify crude product, eluent w
(TFA): V
(acetonitrile): V
(water)=1:250:750 ~ 1:400:600, collects eluent, after being dried, obtains sterling.
The 3rd object of the present invention is to provide a kind of Bivalirudin product, adopts above-mentioned preparation method to make, and it has the advantages that production cost is low, purity is high, pure peptide content is high, amount of impurities is few, foreign matter content is low.
The invention provides a kind of high purity Bivalirudin and preparation method thereof, its beneficial effect is:
1, adopt ethyl acetate with low cost, that be easy to reclaim as Bivalirudin solid phase synthesis washing composition, reduced production cost, reduced discharging of waste liquid;
2, provide washing composition optimum usage quantity scope, and designed accordingly applicable ethyl acetate as the Bivalirudin solid phase synthesis process of washing composition, the method has the feature of economy, environmental protection, is applicable to Bivalirudin suitability for industrialized production;
3, provide a kind of Bivalirudin product, this product has the advantages that production cost is low, purity is high, pure peptide content is high, amount of impurities is few, foreign matter content is low.
accompanying drawing explanation
Fig. 1 is embodiment 1 gained Angiomax crude product color atlas
Fig. 2 is embodiment 1 gained Angiomax purifying product color atlas
Embodiment
Below in conjunction with concrete example, the present invention is described in further detail; but embodiments of the present invention are not subject to the restriction of following embodiment; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Embodiment 1
Adopt technical scheme of the present invention to prepare Bivalirudin
1, take 1 kg Leu-Wang Resin (SD=0.60 mmol/g) resin and be placed in the glass reactor of silanization, add 6 L DMF, resin is immersed completely, stir 30 min, suction filtration DMF.Under room temperature, by Fmoc-Tyr-OH (0.55 kg, 1.2 mol) and HOBt(0.173 kg, 1.3 mol) be dissolved in 3.3 L DMF, join in above-mentioned resin and stir, add immediately DIC(0.2 L, 1.3 mol), stirring reaction 3 ~ 4 h.Through Kaiser reagent, detect, resin presents after colourless takes reaction solution away.
2, add 4 L ethyl acetate to stir 5min, take washings away.
3, in resin, add the piperidines DMF solution that 5 L percent by volumes are 20%, stirring reaction 3-10 min, suction filtration falls reaction solution.
4, add 4 L ethyl acetate to stir 5min, take washings away, repeated washing 1 time.
5, in resin, add the piperidines DMF solution that 5 L percent by volumes are 20%, stirring reaction 20 min, suction filtration falls reaction solution.
6, add 4 L ethyl acetate to stir 5min, take washings away, repeated washing 5 times.
7, with reference to above-mentioned 1-6 step, C is held to 4-20 amino acid whose coupling successively;
Wherein 3-20 amino acid whose consumption is as follows:
Fmoc-L-Glu(OtBu)-OH： 0.51 kg，1.2mol
Fmoc-L-Glu(OtBu)-OH： 0.51 kg，1.2mol
Fmoc-L-Pro-OH： 0.404 kg，1.2mol
Fmoc-L-Ile-OH： 0.424 kg，1.2mol
Fmoc-L-Glu(OtBu)-OH： 0.51 kg，1.2mol
Fmoc-L-Glu(OtBu)-OH： 0.51 kg，1.2mol
Fmoc-L-Phe-OH： 0.464 kg，1.2mol
Fmoc-L-Asp(OtBu)-OH： 0.494 kg，1.2mol
Fmoc-Gly-OH： 0.356 kg，1.2mol
Fmoc-L-Asn(Trt)-OH： 0.716 kg，1.2mol
Fmoc-Gly-OH： 0.356 kg，1.2mol
Fmoc-Gly-OH： 0.356 kg，1.2mol
Fmoc-Gly-OH： 0.356 kg，1.2mol
Fmoc-Gly-OH： 0.356 kg，1.2mol
Fmoc-L-Pro-OH： 0.404 kg，1.2mol
Fmoc-L-Arg(Pbf)-OH： 0.776 kg，1.2mol
Fmoc-L-Pro-OH： 0.404 kg，1.2mol
Fmoc-D-Phe-OH： 0.464 kg，1.2mol
After deprotection completes and washs, vacuum drying treatment obtains 2 kg peptide resins;
8, cracking
Under room temperature, gained peptide resin is joined in batches 10 L lysate (V are housed
tFA: V
tIS: V
h2O=95:2.5:2.5), in reactor, maintain and stir 2.5 h.Suction filtration lysate, is used 3 L lysates washing resin at twice, and washings is incorporated in lysate, this lysate is splashed in approximately 120 L cold diethyl ethers and high degree of agitation, centrifuge washing.Be dried to obtain crude product 1.2 kg, through high-efficient liquid phase technique, detect, product purity 93%(spectrogram as shown in Figure 1).
9, purify
Gained crude product is adopted to RPLC gradient elution purifies and separates, take octadecylsilane chemically bonded silica as stationary phase, eluent w
(TFA): V
(acetonitrile): V
(water)=1:250:750 ~ 1:400:600, flow velocity 500 ml/min, detect wavelength 214nm.Revolve and steam the elutriant of collecting, after lyophilize, obtain Bivalirudin 0.54kg, purity 99.8%, overall yield 37%(spectrogram is as shown in Figure 2).
Comparative example 1
With reference to synthesis technique and the feed ratio of embodiment 1, change washing composition ethyl acetate wherein into DMF.Crude reaction purity 84%, after purifying, purity 99.8%, overall yield 26%.
Comparative example 2
Synthesis technique and feed ratio with reference to embodiment 1; change the washing composition ethyl acetate of the 2nd step and the 4th step wherein into DMF; the washing composition of the 6th step is changed into and uses DMF(5L * 4 time), methyl alcohol (5L * 1 time), methylene dichloride (5L * 1 time) wash successively, and the washing composition of other amino acid condensations, deprotection is also made corresponding change in the 7th step.Crude reaction purity 86%, after purifying, purity 99.8%, overall yield 28%.
in this specification sheets, the reagent name that each english abbreviation is corresponding is as follows:
Claims (10)
1. the solid phase synthesis process of a Bivalirudin; it is characterized in that described synthetic method comprises linked reaction step and deprotection steps; after linked reaction step and deprotection steps complete, the washing composition after using the ethyl acetate of 3 ~ 6 ml/g resins to complete as reaction, washing times is 1-9 time.
2. synthetic method according to claim 1, is characterized in that after described linked reaction step, and the washing times of corresponding ethyl acetate is 1 ~ 3 time; After described deprotection steps, the washing times of corresponding ethyl acetate is for being preferably 5 ~ 9 times; The consumption of described ethyl acetate is 4 ml/g resins.
3. according to the synthetic method described in claim 1-2 any one, it is characterized in that described method comprises the following steps:
1), the SD of take is 0.5 ~ 1 mmol/g Leu-Wang Resin resin is raw material, uses coupling agent and activator by resin and the protected amino acid Tyr-OH of end bit amino condensation;
2), remove reaction solution, the washing of solid phase use ethyl acetate;
3), use piperidines DMF solution deprotection;
4), remove reaction solution, the washing of solid phase use ethyl acetate;
5), with reference to 1) to 4) step, by all the other 18 the protected amino acid of end bit amino according to Bivalirudin aminoacid sequence successively condensation;
6), with lytic reagent cutting Bivalirudin peptide resin, collect lytic reagent, with the thick peptide of ether sedimentation;
7), use RP-HPLC method purification of crude peptide, the dry sterling that to obtain.
4. synthetic method according to claim 3, the mixture of one or more that it is characterized in that coupling agent that described synthetic method used is DCC, DIC, HBTU, TBTU, PyBOP, the ratio of described coupling agent is 1 ~ 1.1:1.
5. synthetic method according to claim 3, is characterized in that activator that described synthetic method used is for one or both the mixture in HOAt, HOBt, and the ratio of described activator is 1 ~ 1.1:1.
6. synthetic method according to claim 3, is characterized in that the piperidines DMF solution in described step 3) is that volume fraction is 20% piperidines DMF solution, and usage quantity is 8-12 ml/g resin.
7. synthetic method according to claim 3, the lytic reagent that it is characterized in that described step 6) is TFA, TIS, H
2the mixed solvent of O, volume ratio is 95:2.5:2.5, the consumption of described lytic reagent is 6-12 ml/g resin.
8. synthetic method according to claim 3, the volumetric usage that it is characterized in that ether in described step 6) be lytic reagent 8-10 doubly.
9. according to the synthetic method described in any one in claim 4-8, it is characterized in that described method comprises the following steps:
1), the SD of take is 0.6 mmol/g Leu-Wang Resin resin is raw material, take DIC as coupling agent, HOBt is activator, DMF is solvent, by resin and amino acid Fmoc-Tyr-OH coupling; Described coupling agent and amino acid whose mol ratio are 1.1:1, and described activator and amino acid whose mol ratio are 1.1:1;
2), remove reaction solution, solid phase is with the ethyl acetate washing of 4 ml/g resin ratio 1 time;
3), add the piperidines DMF solution deprotection that the percent by volume of 5 ml/g resins is 20%;
4), remove reaction solution, solid phase is divided 2 washings with the ethyl acetate of 4 ml/g resin ratio;
5), add the piperidines DMF that the percent by volume of 5 ml/g resins is 20% to repeat deprotection;
6), remove reaction solution, solid phase is divided 5 washings with the ethyl acetate of 4 ml/g resin ratio;
7), with reference to 1) to 6) step, take DIC as coupling agent, HOBt is activator, DMF is solvent, the amino acid that all the other 18 Fmoc are protected is according to Bivalirudin aminoacid sequence successively coupling, described coupling agent and amino acid whose mol ratio are 1.1:1, and described activator and amino acid whose mol ratio are 1.1:1;
8), with the lysate cutting Bivalirudin peptide resin of 6-12 ml/g resin, collect lysate, with the thick peptide of ether sedimentation of 8-10 times of volume cracking liquid measure;
9), with RP-HPLC method gradient elution, purify crude product, eluent w
(TFA): V
(acetonitrile): V
(water)=1:250:750 ~ 1:400:600, collects eluent, after being dried, obtains sterling.
10. a Bivalirudin product, is characterized in that adopting the synthetic method described in any one in claim 1-9 to prepare.
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| CN108383905A (en) * | 2016-12-30 | 2018-08-10 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of bivalirudin |
| CN108663439A (en) * | 2017-03-31 | 2018-10-16 | 江苏汉邦科技有限公司 | A method of using high-efficient liquid phase chromatogram purification bivalirudin |
| CN113845587A (en) * | 2021-12-01 | 2021-12-28 | 浙江湃肽生物有限公司南京分公司 | Synthetic method of bivalirudin |
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| CN102286076A (en) * | 2011-06-23 | 2011-12-21 | 成都圣诺科技发展有限公司 | Preparation method for bivalirudin |
| CN102532274A (en) * | 2012-02-13 | 2012-07-04 | 成都圣诺生物制药有限公司 | Method for preparing bivalirudin |
| CN102731624A (en) * | 2012-06-14 | 2012-10-17 | 无锡市凯利药业有限公司 | Method for synthesis of bivalirudin in solid-phase fragment approach |
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| CN102532274A (en) * | 2012-02-13 | 2012-07-04 | 成都圣诺生物制药有限公司 | Method for preparing bivalirudin |
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| CN108383905A (en) * | 2016-12-30 | 2018-08-10 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of bivalirudin |
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