CN116063451B - Synthetic method of capelin - Google Patents

Synthetic method of capelin Download PDF

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CN116063451B
CN116063451B CN202211697497.8A CN202211697497A CN116063451B CN 116063451 B CN116063451 B CN 116063451B CN 202211697497 A CN202211697497 A CN 202211697497A CN 116063451 B CN116063451 B CN 116063451B
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fmoc
peptide
capecitabine
ser
synthesizing
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CN116063451A (en
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王芮
王宜龙
玄其存
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Sinopep Allsino Biopharmaceutical Co ltd
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Sinopep Allsino Biopharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

The invention relates to a synthesis method of capelin, belonging to the technical field of polypeptide synthesis. The method adopts special amino acid Fmoc-Ile- (propargyl) Gly-OH for 15, 16-position amino acids; the amino acid at the 5,6 positions adopts Boc-Ser (Fmoc-Ser) -OH; and coupling the rest amino acids from the carbon end to the nitrogen end sequentially according to the peptide sequence, synthesizing the full-protection capecitabine peptide by solid phase, and obtaining the capecitabine peptide line peptide after cleavage. Dissolving with pure water, adding PbCl 2 Further cleavage of propargyl, adjustment of pH to alkaline, oxidation of Pb to form disulfide bond, and obtaining capelin. The method improves the purity of the crude peptide, greatly reduces the labor cost and the purification cost, and is beneficial to industrialized amplified production.

Description

Synthetic method of capelin
Technical Field
The invention relates to the field of polypeptide medicine synthesis, in particular to a method for synthesizing a medicine suitable for treating acute heart failure (including chronic heart failure and severe) diseases.
Background
Capelin peptide sequence:
H-Ser 1 -Leu 2 -Arg 3 -Arg 4 -Ser 5 -Ser 6 -Cys 7 -Phe 8 -Gly 9 -Gly 10 -Arg 11 -Met 12 –Asp 13 -Arg 14 -Ile 15 -Gly 16 -Ala 17 -Gln 18 -Ser 19 -Gly 20 -Leu 21 -Gly 22 -Cys 23 -Asn 24 -Ser 25 -Phe 26 -Arg 27 -Tyr 28 -OH
the indication for capelin is acute heart failure (including exacerbation of chronic heart failure). The pharmacological effect of the carperitide is to stimulate myocardial extension, synthesize by particles in the ventricle, then act on vascular smooth muscle and kidney tissues through the whole body of the coronary artery distribution, and regulate blood pressure and in vivo electrolyte balance. The carperitide is a circulation regulating hormone composed of 28 amino acids and has the functions of vasodilation and diuresis. The vasodilation by capelin is achieved by binding to the ANP (atrial natriuretic peptide) receptor of vascular smooth muscle and by increasing the guanylate cyclase activity, suggesting that cardiac preload can be reduced.
Current methods for the synthesis of capecitabine fall into two broad categories: firstly, gene recombination, and secondly, liquid phase or solid phase synthesis by adopting a Boc route. ZL200510012425.5 discloses a method for producing the capelin by adopting a gene recombination technology, CN102382188 reports a method for preparing the capelin by coupling one by adopting a solid-phase Fmoc route, CA1245635A1 reports that the capelin is obtained by adopting a Boc route for solid-phase synthesis and finally steps such as HF resin cutting, liquid-phase oxidation, HPLC (high-pressure liquid chromatography) purification and the like, CA1245637A1 reports that the capelin is produced by adopting a gene recombination technology, and other patent documents such as EP0440311A1, JP3004169A, US4673732A and the like are all the capelin produced by adopting a gene recombination technology or the capelin is obtained by adopting a Boc route for solid-phase or liquid-phase synthesis. Adopts the gene recombination technology, has complex operation, large investment, low medicine purity and higher technical barriers. The use of liquid or solid phase synthesis by the Boc route requires the use of HF and the use of large amounts of TFA, which results in serious environmental pollution. Meanwhile, the liquid phase method has the defects of long operation period, complicated operation and the like, and is not beneficial to large-scale industrial production.
Disclosure of Invention
The invention aims to solve the problems of more impurities, low purity and yield, high cost, complicated operation steps, excessive waste liquid and adverse industrial production in the existing synthesis process and provides an optimized synthesis method of the capecitabine.
The technical scheme for realizing the aim of the invention is as follows:
a method for synthesizing capelin, which is characterized by comprising the following steps:
(1) The propargyl Fmoc-Ile- (propargyl) Gly-OH is introduced into amino acids 15-16 of the capelin sequence; amino acids 5-6 of the carperitide sequence were Boc-Ser (Fmoc-Ser) -OH;
(2) Sequentially synthesizing amino acids at other sites of the carperitide sequence in solid phase, synthesizing fully-protected carperitide, performing cleavage precipitation, dissolving, and adding PbCl 2 Removing propargyl, regulating pH, and cyclizing to obtain the carperitide.
The further preferable technical scheme of the synthesis method of the carperitide is that in the step (2), the condensing agent used for synthesizing each amino acid is one or more of DIC/HOBt, HBTU/HOBt/DIEA, pyBop/HOBt/DIEA.
According to the synthesis method of the capelin, a further preferable technical scheme is that in the step (2), one or more of DCM, DMF, NMP, DMSO reaction solvents are used.
According to the synthesis method of the capelin, a further preferable technical scheme is that in the step (2), the Fmoc removal reagent is a v/v20% piperidine/DMF solution.
The further preferable technical scheme of the synthesis method of the carperitide is that in the step (2), the adopted cracking reagent is as follows: TFA: TA: EDT: anisole=90:5:3:2.
The further preferable technical scheme of the synthesis method of the capecitabine peptide is that in the step (2), the cyclization method is as follows: dissolving and adding PbCl 2 The pH is adjusted to be alkaline, and disulfide bonds are formed by oxidation.
The further preferable technical scheme of the synthesis method of the carperitide is that in the step (2), the carperitide is dissolved until the concentration is 2g/L.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the capecitabine adopts special protected amino acid: fmoc-Ile- (propargyl) Gly-OH, boc-Ser (Fmoc-Ser) -OH. The propargyl is introduced to improve the ductility of peptide chains, overcome the problem of difficult peptide sequence linkage, and greatly improve the yield of crude peptide; pH is regulated to be weak alkaline by PbCl 2 The propargyl is removed, and simultaneously, disulfide bond oxidation can be carried out, so that the synthesis steps are greatly simplified by a one-pot method, the labor cost and the purification cost are reduced, and the industrial scale-up production is facilitated.
Drawings
FIG. 1 is a chromatogram of a crude peptide obtained in example 1 of the present invention;
FIG. 2 is a chromatogram of a crude peptide obtained in example 2 of the present invention;
FIG. 3 is a chromatogram of a crude peptide obtained in example 3 of the present invention.
Detailed Description
The invention is described in detail below with reference to the drawings and the specific embodiments.
Example 1:
preparation of Capellitide peptide resins (sequential Synthesis)
Wang Resin 30.00g (sub=0.42 mmol/g) was weighed into a solid phase reactor and 200 mM DCM swollen Resin was added for 0.5h. The solvent was drained and washed 3 times with DMF. 16.0g Fmoc-Tyr (tBu) -OH, DIC, DMAP, DMF was added and coupled for 3h, after which the solvent was removed and washed three times. Adding Ac 2 O-pyridine end capping, the degree of substitution was determined to be 0.33mmol/g.
30g of Fmoc-Tyr (tBu) -Wang Resin (sub=0.33 mmol/g) was weighed and added to 200 mM DTMF for swelling for 1h. The solvent was removed and a 200mLv/v20% piperidine/DMF solution was added to deprotect the reaction for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The indene test result is positive. Fmoc-Arg (Pbf) -OH 21.41g, HOBt4.82g, DIC5.5mL,200 mM LDMF solution was weighed, ice-bath activated for 10 minutes, and the activation temperature was not more than 10 ℃. And adding the activated solution into a reactor, reacting for 1h, and draining after the indene detection result is negative. DMF was added and washed 3 times with 200mL each.
The above steps were repeated with the amino acid sequences Fmoc-Tyr (tBu) -OH, fmoc-Arg (Pbf) -OH, fmoc-Phe-OH, fmoc-Ser (tBu) -OH, fmoc-Asn (Trt) -OH, fmoc-Cys (Trt) -OH, fmoc-Gly-OH, fmoc-Leu-OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gln (Trt) -OH, fmoc-Ala-OH, fmoc-Gly-OH, fmoc-Ile-OH, fmoc-Arg (Pbf) -OH, fmoc-Asp (OtBu) -OH, fmoc-Met-OH, fmoc-Arg (Pbf) -OH, fmoc-Gly-OH, fmoc-Phe-OH, fmoc-Cys (Trt) -OH, fmoc-Ser (tBu) -OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gly-OH. After the coupling, 250mL of DMF was added for 3 times, followed by deprotection by addition of 200mLv/v20% piperidine/DMF solution for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The DCM and MeOH were alternately washed 3 times each with 400mL each, and the indene test was positive. And (5) drying in vacuum to obtain the carperitide peptide resin.
Cracking:
500mL of cleavage reagent is prepared, wherein the cleavage reagent is TFA: EDT: anisole=90:5:3:2, the full-protection peptide is added under the ice bath condition, the reaction is continued for 2 hours at room temperature, and anhydrous isopropyl ether is added for precipitation after the reaction is finished. The precipitate was centrifuged 4 times, washed with 3000mL of isopropyl ether each. The product obtained after drying was 35.65g of capecitabine peptide.
Cyclization:
19L of purified water was added to the cyclization tank, 38.60g of linear peptide was weighed, added to the cyclization tank and stirred uniformly at a concentration of about 2g/L.
Slowly dripping an iodoethanol solution for cyclization; thiol detection was performed with Ellmans reagent and the negative reaction was completed. Dropping ascorbic acid until the crude peptide solution is colorless, and standing for 1 hour; filtering with 0.45um microporous membrane, collecting filtrate, and sampling and detecting. The crude peptide is quantified by 20.50g of a reference substance, the total yield is 40.50%, and the purity is 41.97%; the chromatogram of the crude peptide is shown in FIG. 1.
Example 2:
preparation of Capelii peptide resin (Boc-Ser (Fmoc-Ser) -OH)
Wang Resin 30.00g (sub=0.42 mmol/g) was weighed into a solid phase reactor and 200 mM DCM swollen Resin was added for 0.5h. The solvent was drained and washed 3 times with DMF. 16.0g Fmoc-Tyr (tBu) -OH, DIC, DMAP, DMF was added and coupled for 3h, after which the solvent was removed and washed three times. Adding Ac 2 O-pyridine end capping, the degree of substitution was determined to be 0.33mmol/g.
30g of Fmoc-Tyr (tBu) -Wang Resin (sub=0.33 mmol/g) was weighed and added to 200 mM DTMF for swelling for 1h. The solvent was removed and a 200mLv/v20% piperidine/DMF solution was added to deprotect the reaction for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The indene test result is positive. Fmoc-Arg (Pbf) -OH 21.41g,HOBt4.82g,DIC5.5mL,200mL DMF solution is weighed, and the solution is activated for 10 minutes in an ice bath, wherein the activation temperature is not more than 10 ℃. And adding the activated solution into a reactor, reacting for 1h, and draining after the indene detection result is negative. DMF was added and washed 3 times with 200mL each.
The above steps were repeated with the amino acid sequences Fmoc-Tyr (tBu) -OH, fmoc-Arg (Pbf) -OH, fmoc-Phe-OH, fmoc-Ser (tBu) -OH, fmoc-Asn (Trt) -OH, fmoc-Cys (Trt) -OH, fmoc-Gly-OH, fmoc-Leu-OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gln (Trt) -OH, fmoc-Ala-OH, fmoc-Gly-OH, fmoc-Ile-OH, fmoc-Arg (Pbf) -OH, fmoc-Asp (OtBu) -OH, fmoc-Met-OH, fmoc-Arg (Pbf) -OH, fmoc-Gly-OH, fmoc-Phe-OH, fmoc-Cys (Trt) -OH, boc-Ser (tBu) -OH, fmoc-Gly-OH, fmoc-Phe-OH, fmoc-Cys (Trt) -OH, fmoc-Ser (Tbf) -OH, fmoc-Arg (Pbf) -OH). After the coupling, 250mL of DMF was added for 3 times, followed by deprotection by addition of 200mLv/v20% piperidine/DMF solution for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The DCM and MeOH were alternately washed 3 times each with 400mL each, and the indene test was positive. And (5) drying in vacuum to obtain the carperitide peptide resin.
Cracking:
500mL of cleavage reagent is prepared, wherein the cleavage reagent is TFA: EDT: anisole=90:5:3:2, the full-protection peptide is added under the ice bath condition, the reaction is continued for 2 hours at room temperature, and anhydrous isopropyl ether is added for precipitation after the reaction is finished. The precipitate was centrifuged 4 times, washed with 3000mL of isopropyl ether each. The product obtained after drying was namely 37.65g of capelin peptide.
Cyclization:
19L of purified water was added to the cyclization tank, 38.60g of linear peptide was weighed, added to the cyclization tank and stirred uniformly at a concentration of about 2g/L.
Slowly dripping an iodoethanol solution for cyclization; thiol detection was performed with Ellmans reagent and the negative reaction was completed. Dropping ascorbic acid until the crude peptide solution is colorless, and standing for 1 hour; filtering with 0.45um microporous membrane, collecting filtrate, and sampling and detecting. The crude peptide was quantified by the control to 23.50g, overall yield 53.70% and purity 49.80%. The chromatogram of the crude peptide is shown in FIG. 2.
Example 3:
preparation of Capelip peptide resin (Fmoc-Ile- (propargyl) Gly-OH, boc-Ser (Fmoc-Ser) -OH)
Wang Resin 30.00g (sub=0.42 mmol/g) was weighed into a solid phase reactor and 200 mM DCM swollen Resin was added for 0.5h. The solvent was drained and washed 3 times with DMF. 16.0g Fmoc-Tyr (tBu) -OH, DIC, DMAP, DMF was added and coupled for 3h, after which the solvent was removed and washed three times. Adding Ac 2 O-pyridine end capping, the degree of substitution was determined to be 0.33mmol/g.
30g of Fmoc-Tyr (tBu) -Wang Resin (sub=0.33 mmol/g) was weighed and added to 200 mM DTMF for swelling for 1h. The solvent was removed and a 200mLv/v20% piperidine/DMF solution was added to deprotect the reaction for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The indene test result is positive. Fmoc-Arg (Pbf) -OH 21.41g,HOBt4.82g,DIC5.5mL,200mL DMF solution is weighed, and the solution is activated for 10 minutes in an ice bath, wherein the activation temperature is not more than 10 ℃. And adding the activated solution into a reactor, reacting for 1h, and draining after the indene detection result is negative. DMF was added and washed 3 times with 200mL each.
The above steps were repeated with the amino acid sequences Fmoc-Tyr (tBu) -OH, fmoc-Arg (Pbf) -OH, fmoc-Phe-OH, fmoc-Ser (tBu) -OH, fmoc-Asn (Trt) -OH, fmoc-Cys (Trt) -OH, fmoc-Gly-OH, fmoc-Leu-OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gln (Trt) -OH, fmoc-Ala-OH, fmoc-Ile- (propargyl) Gly-OH, fmoc-Arg (Pbf) -OH, fmoc-Asp (OtBu) -OH, fmoc-Met-OH, fmoc-Arg (Pbf) -OH, fmoc-Gly-OH, fmoc-Phe-OH, fmoc-Cys (Trt) -OH, boc-Ser (tBu) -OH, fmoc-Ser (Fmoc-OH). After the coupling, 250mL of DMF was added for 3 times, followed by deprotection by addition of 200mLv/v20% piperidine/DMF solution for 15+15min. The mixture was drained and washed 6 times with 250mL of DMF. The DCM and MeOH were alternately washed 3 times each with 400mL each, and the indene test was positive. And (5) drying in vacuum to obtain the carperitide peptide resin.
Cracking:
500mL of cleavage reagent is prepared, wherein the cleavage reagent is TFA: EDT: anisole=90:5:3:2, the full-protection peptide is added under the ice bath condition, the reaction is continued for 2 hours at room temperature, and anhydrous isopropyl ether is added for precipitation after the reaction is finished. The precipitate was centrifuged 4 times, washed with 3000mL of isopropyl ether each. The product obtained after drying was namely 38.65g of capelin peptide.
Cyclization:
19L of purified water was added to the cyclization tank, 38.60g of linear peptide was weighed, added to the cyclization tank and stirred uniformly at a concentration of about 2g/L.
Adding PbCl 2 Removing propargyl, adjusting pH to be alkaline, and oxidizing to form disulfide bonds; thiol detection was performed with Ellmans reagent and the negative reaction was completed. Standing for 1 hour; filtering with 0.45um microporous membrane, collecting filtrate, and sampling and detecting. The crude peptide is quantified by 29.50g through a reference substance, the total yield is 67.50%, and the purity is 76.09%; the chromatogram of the crude peptide is shown in FIG. 3.

Claims (6)

1. A method for synthesizing capecitabine, comprising the steps of: solid phase synthesis of fully protected capecitabine, cleavage precipitation, dissolution, and addition of PbCl 2 Removing propargyl, regulating pH, and cyclizing to obtain the capecitabine; in the solid-phase synthesis of the full-protection carperitide, fmoc-Ile- (propargyl) Gly-OH is adopted in amino acids 15-16 of the carperitide sequence for coupling reaction, and Boc-Ser (Fmoc-Ser) -OH is adopted in amino acids 5-6 of the carperitide sequence for coupling reactionAmino acids at other sites of the peptide are synthesized sequentially.
2. The method of claim 1, wherein the condensing agent used for synthesizing each amino acid is one of DIC/HOBt, HBTU/HOBt/DIEA, pyBop/HOBt/DIEA.
3. The method of claim 1, wherein the reaction solvent for synthesizing the fully protected capecitabine is one of DCM, DMF, NMP, DMSO.
4. The method for synthesizing capecitabine according to claim 1, wherein the cleavage reagent used in the step is: TFA: TA: EDT: anisole=90:5:3:2.
5. The method for synthesizing capecitabine according to claim 1, wherein in the step, the cyclization method is as follows: dissolving and adding PbCl 2 The pH is adjusted to be alkaline, and disulfide bonds are formed by oxidation.
6. The method of claim 5, wherein the step comprises dissolving the carperitide to a concentration of 2g/L.
CN202211697497.8A 2022-12-28 2022-12-28 Synthetic method of capelin Active CN116063451B (en)

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