CN105367627A - Method for preparing terlipressin - Google Patents

Method for preparing terlipressin Download PDF

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Publication number
CN105367627A
CN105367627A CN201410434586.2A CN201410434586A CN105367627A CN 105367627 A CN105367627 A CN 105367627A CN 201410434586 A CN201410434586 A CN 201410434586A CN 105367627 A CN105367627 A CN 105367627A
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gly
trt
fmoc
terlipressin
resin
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陈阿娜
刘标
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Anhui Polytechnic University
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Anhui Polytechnic University
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    • 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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Abstract

The invention relates to a method for preparing terlipressin, and belongs to the technical field of polypeptide synthesis. The method comprises the steps that terlipressin peptide resin is synthesized through a fragment condensation method, 3-12 fragments are synthesized through a solid phase method, 1-2 fragments are connected to 3-12 solid phase amino-acid resin, full-peptide resin is obtained, and the terlipressin is obtained after cracking and cyclizing. Due to the fact that Boc-Gly-Cly-OH is adopted as a raw material, lack of glycine impurities is reduced, the operation step of removing glycine protection groups at an N terminal is omitted, product purity is improved, and the total cost is obviously reduced.

Description

A kind of preparation method of terlipressin
Technical field
The present invention relates to peptide synthesis technology field, especially the preparation method of terlipressin.
Background technology
Terlipressin, English Terlipressin by name, molecular formula is: C 52h 74n 16o 15s 2, to be 1227.4 structural formulas be molecular weight, structural formula:
Terlipressin is clinical is used for the treatment of serious acute esophageal varices bleeding, serious acute stomach, duodenal ulcer and hemorrhage, acute erosive gastritis or hemorrhagic gastritis, pancreas, courage and intestines assisting therapy repeatly and the assisting therapy of diabetic ketoacidosis, terlipressin, non-activity own, in vivo through aminopeptidase effect, after sloughing 3 glycine residues of N-terminal, be converted into activated Schweine-Vasopressin lentamente, be used for the treatment of the acute Esophageal varix bleeding that Cirrhotic Portal Hypertension causes, a kind ofly treat the hemorrhage medicine of Acute Venous varicose safely and effectively.
Preparation report about terlipressin is little, is mainly concerned with solid phase synthesis and Partial Liquid Phase synthetic method.
Liquid phase synthesizing method is should be mentioned that in Czechoslovakia patent CZP281589, with Boc-Gly-chloromethyl resin for starting raw material, Boc-Lys (Tos) is connected successively by terlipressin sequence, Boc-Pro, Boc-Cys (Bzl), Boc-Asn, Boc-Gln, Boc-Phe, Boc-Tyr (Z), Boc-Cys (Bzl), Boc-Gly, Boc-Gly, Boc-Gly, again through ammonia solution, sodium solution, the series reaction such as oxidation obtain terlipressin, it is low that this method connects peptide efficiency, be only 75%, process time is long, and technique serious three wastes, be unfavorable for scale operation.
Solid-phase synthesis is should be mentioned that in Chinese patent CN1865282B; with RinkAmide resin for starting raw material; successively the amino acid that Fmoc protects is connected on solid phase carrier by terlipressin peptide sequence; then add and cut peptide reagent and carry out cutting peptide; add ether sedimentation; obtain reduced form crude product; it is blowing air oxidation under the condition of 7.5-10.0 at pH; obtain oxidized form crude product; C18 (or C8) post is finally adopted to carry out separation and purification; obtain terlipressin, this method, in preparation process, easily produces des-Gly 1terlipressin impurity (terlipressin of a disappearance glycine), has a strong impact on whole process recovery ratio; The oxidising process time is long, easily Fragmentation phenomenon occurs.
Fragment condensation is should be mentioned that in Chinese patent CN102408471A, liquid phase synthesis 1-3 fragment, again this fragment is connected on the fragment 4-12-resin of solid phase synthesis, obtain terlipressin peptide resin, the thick peptide of terlipressin is obtained through cutting, oxidation, finally adopt C18 column separating purification to obtain target product, this method, in preparation process, easily produces des-Gly 1, Gly 2, Gly 3terlipressin impurity (missing N-terminal three glycine), and 1-3 segment condense difficulty is large, cost is high, easily forms the impurity of disappearance glycine and many glycine.
Summary of the invention
The present invention is directed to deficiency, propose a kind of preparation method of terlipressin, quality product and yield high.
In order to realize foregoing invention object, the invention provides following technical scheme: a kind of preparation method of terlipressin, comprising:
Step 1: adopt solid-phase synthesis synthesis 3-12 terlipressin fragment, obtain intermediate , Fmoc-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin;
Step 2: Boc-Gly-Gly-OH is connected to intermediate on, obtain intermediate : Boc-Gly-Gly-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin;
Step 3: intermediate cracking, cyclisation obtain the thick peptide of terlipressin:
Step 4: thick peptide obtains terlipressin sterling through separation and purification.
According to preferred embodiments of the present invention, in step 1 and 2, adopt solid-phase synthesis, first according to the peptide sequence of terlipressin, N is held to hold by C, successively Fmoc-Gly-OH, Fmoc-Lys (Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys (Trt)-OH, Fmoc-Asn (Trt)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys (Trt)-OH, Fmoc-Gly-OH are connected on solid-phase resin, obtain intermediate ; Again Boc-Gly-Gly-OH fragment is connected to and sloughs blocking group X 1intermediate on, obtain intermediate .Wherein solid-phase resin is RinkAmide resin, RinkAmide-MBHA resin, RinkAmide-BHA resin, RinkAmide-AM resin or Sieber resin; Deprotecting regent is DBU/ piperidines/DMF solution, and wherein DBU accounts for 0.5% ~ 15%, and piperidines accounts for 0.5% ~ 20%, is dissolved in DMF; Coupling condensation reagent uses TBTU or HOBt or HBTU, and activating reagent uses DIC or DIEA.Intermediate synthesis comprise the following steps:
(1) intermediate preparation:
Resin activated: RinkAmide resin is fully swelling, wash, drain, add deprotecting regent DBU/ hexahydropyridine/DMF solution, deresinate blocking group, wash away free group with DMF, obtain the resin of activation; Wherein, resin substitution degree is 0.4 ~ 1.2mmol/g;
The preparation of Fmoc-Gly-resin: take appropriate Fmoc-Gly-OH, HOBt and be dissolved in DMF, add DIC activation, soak time is 3 ~ 15min, amino acid solution after activation is added in resin, react 1.5 ~ 4.0h at 25 ~ 35 DEG C, ninhydrin detects resin transparent, reaction terminating; The group that the removing of DMF washing resin is free, adds diacetyl oxide/pyridine/DMF mixing solutions, closes the group that 1h, DMF washing removing is free, drain and obtain Fmoc-Gly-resin at 20 ~ 35 DEG C; Wherein, the feed ratio of Fmoc-Gly-OH, HOBt, DIC is 1.2 ~ 6.0 times of resin, and the feed ratio of diacetyl oxide, pyridine is 2 ~ 20 times of resin;
Intermediate preparation (extension of peptide chain): in Fmoc-Gly-resin, add deprotecting regent DBU/ hexahydropyridine/DMF solution; remove Fmoc blocking group; DMF fully washs the free group of removing; successively Fmoc-Lys (Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys (Trt)-OH, Fmoc-Asn (Trt)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys (Trt)-OH, Fmoc-Gly-OH are connected on Fmoc-Gly-resin according to the peptide sequence of terlipressin, obtain intermediate , amino acid, HOBt, DIC feed ratio are 1.2 ~ 6.0 times, and temperature of reaction is 25 ~ 35 DEG C, and the reaction times is 1.5 ~ 4.0h, until react completely, it is transparent that triketohydrindene hydrate detects resin.
(2) intermediate preparation: at intermediate in add deprotecting regent DBU/ hexahydropyridine/DMF solution; remove Fmoc blocking group; DMF fully washs the free group of removing; add Boc-Gly-Gly-OH/HOBt/DIC activation solution; 1.5 ~ 4.0h is reacted at 25 ~ 35 DEG C; until react completely, the feed ratio of amino acid, HOBt, DIC is 1.2 ~ 6.0 times.
(3) intermediate cracking, cyclisation:
Lytic reagent uses mixing acid reagent, and mixing acid reagent is TFA, water and other capture agent mixture, and capture agent selects at least one in EDT, MPS, phenol, and TFA ratio is 80% ~ 85%, and capture agent ratio is 10% ~ 15%, and all the other are water.Pyrolysis time is 1 ~ 4h, cracking temperature 15 ~ 35 DEG C, and lytic reagent consumption needs 4 ~ 20ml lytic reagent by every gram of peptide resin.Lysate washed with diethylether, precipitation, centrifugal, after getting precipitation ether repetitive scrubbing 4 ~ 8 times, dryly obtain linear terlipressin crude product.
Dissolved by thick for linear terlipressin peptide, use weak ammonia adjustment pH value of solution to 7.5 ~ 10.0, with the cyclisation of the oxidising agent such as hydrogen peroxide or iodine, reaction 1 ~ 3h, until cyclisation terminates, adjustment pH value of solution, to acid, obtains the thick peptide of terlipressin.
(4) separation and purification
Thick for terlipressin peptide solution is used filtering with microporous membrane, get the upper C18 post of filtrate, gradient elution, wherein flow phase system selects 0.1% aqueous acetic acid-acetonitrile solution, determined wavelength is selected between 210 ~ 280nm, get purity be more than 99% sample be terlipressin refined liquid.
As seen from the above technical solution, present method adopts fragment condensation synthesis terlipressin, solid phase synthesis 3-12 fragment, then Boc-Gly-Gly-OH is connected in solid phase fragment, often step connects peptide yield >=99%, peptide resin obtains the thick peptide of terlipressin through cracking, cyclisation, it is 77% that thick peptide prepares yield, obtains smart peptide by purifying, and purity is more than 99%, yield is 92%, process overall yields more than 70%.
Compared with prior art, solid phase synthesis 3-12 fragment of the present invention, using DBU/ hexahydropyridine/DMF solution as deprotecting regent, reduces the generation of disappearance peptide impurity; Directly be connected in 3-12 fragment with Boc-Gly-Gly-OH fragment, reduce des-Gly 1and des-Gly 1, Gly 2, Gly 3the generation of impurity, Boc-Gly-Gly-OH cost well below Boc-Gly-Gly-Gly-OH, and does not contain the influential impurity of product synthesis technique quality, and total cost and quality product all have a clear superiority in.
Embodiment
Described herein, term " amido protecting group " indication part is protection amino-moiety, prevents amino participation from reacting, and to reaction itself without unacceptable disadvantageous effect.Fmoc, Boc etc. are amido protecting group.Term " carboxy protective group " indication segment bounds protection carboxy moiety, prevents carboxyl from participating in reaction, and to the unacceptable disadvantageous effect of the thing of reaction own.
Described herein, Fmoc is 9-fluorenylmethyloxycarbonyl, and Boc is tertbutyloxycarbonyl, the tBu tertiary butyl, Trt is trityl group, and DMF is N, N-dimethyl imide, TBTU is O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, HOBt is 1-hydroxy benzo triazole, DIC is DIC, EDT is 1，2-ethandithiol, and MPS is mercaptoethanol.
Describe the present invention below in conjunction with specific embodiment, the description of this part is only exemplary and explanatory, should not have any restriction to protection scope of the present invention.
embodiment 1: the synthesis of Fmoc-Gly-RinkAmide resin
In reaction column, add 20 grams of RinkAmide resins (1.00mmol/g), add DMF swelling 30 minutes; Swelling complete after, be the DBU/ hexahydropyridine/DMF solution deprotection twice of 2/10/88 by ratio, be respectively 5min and 8min, then wash six times with DMF.By Fmoc-Gly-OH (17.8g, 60mmol), HOBt (8.2g, 60mmo1) and DIC (7.6g, 60mmol) is added in above-mentioned reaction column after dissolving with appropriate DMF, reacts 120min under room temperature.Reaction completes, and vacuum pumps reaction solution, washes six times with DMF, obtains Fmoc-Gly-RinkAmide resin.
embodiment 2:
The synthesis of Fmoc-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-RinkAmide resin
Get the Fmoc-Gly-RinkAmide resin prepared in above-described embodiment 1, add by ratio be 2/10/88 DBU/ hexahydropyridine/DMF solution deprotection twice, be respectively 5min and 8min, then wash six times with DMF.Add in above-mentioned reaction column after Fmoc-Lys (Boc)-OH (28.1g, 60mmol), HOBt (8.2g, 60mmo1) and DIC (7.6g, 60mmol) are dissolved with appropriate DMF, under room temperature, react 120min.Reaction completes, and vacuum pumps reaction solution, washes six times with DMF, obtains Fmoc-Lys (Boc)-Gly-RinkAmide resin.
With method successively by Fmoc-Pro-OH, Fmoc-Cys (Trt)-OH, Fmoc-Asn (Trt)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys (Trt)-OH, Fmoc-Gly-OH is connected on Fmoc-Lys (Boc)-Gly-RinkAmide resin, obtain Fmoc-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-RinkAmide resin, wherein, amino acid, HOBt, the feed ratio of DIC is resin substitution degree three times.
embodiment 3:
The synthesis of Boc-Gly-Gly-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin
Get the intermediate prepared in above-described embodiment 2
Fmoc-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-RinkAmide resin; add by ratio be 2/10/88 DBU/ hexahydropyridine/DMF solution deprotection twice; be respectively 5min and 8min, then wash six times with DMF.By Boc-Gly-Gly-OH (14.0g, 60mmol), HOBt (8.2g, 60mmo1) and DIC (7.6g, 60mmol) adds in above-mentioned reaction column after dissolving with appropriate DMF, reacts 120min under room temperature.Reaction completes, vacuum pumps reaction solution, six times are washed with DMF, three times are shunk again with methyl alcohol, vacuum-drying, to constant weight, obtains Boc-Gly-Gly-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin.
embodiment 4: the preparation of linear terlipressin
The full peptide resin Boc-Gly-Gly-Gly-Cys (Trt) of terlipressin in Example 3-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin, join in lytic reagent [TFA/MPS/EDT/ water=85: 5: 5:5 (V/V)] (10ml lytic reagent/gram resin), uniform stirring reaction 2h, cross and filter resin, get filtrate and add ether (filtrate/ether volume ratio is 1:6) precipitation, centrifuging and taking precipitation uses washed with diethylether 5 times repeatedly, drain and obtain the thick peptide 25.7g of linear terlipressin.
embodiment 5: the preparation of the thick peptide of terlipressin
The linear terlipressin crude product pure water that Example 4 obtains dissolves and makes the solution of about 2mg/ml, stir the hydrogen peroxide of lower dropping 10%, stirring reaction 90minEllman reagent detects adjusts pH to 2.5 without adding TFA after sulfydryl reaction, obtain the thick peptide solution of terlipressin, detecting terlipressin purity is 97.2%, containing object peptide 18.9g.
embodiment 6: the purifying of the thick peptide of terlipressin
The terlipressin solution that Example 5 obtains, reverse phase liquid chromatography is adopted to carry out purifying after filtering, the C18 reverse-phase chromatographic column of 80mm*250mm, determined wavelength is set as 230nm, and flow phase system is 0.1% aqueous acetic acid-acetonitrile solution, gradient elution, the object that purity is 99% is collected in segmentation, and measure terlipressin object peptide 17.4g, total recovery is 71%, after boiling off acetonitrile, lyophilize obtains terlipressin product.
The purity that HPLC measures terlipressin product is 99.5%, and moisture content is 3.5%, and acetic acid content is 7.6%, object peptide content 100.5%, mass spectrometric detection MS=1228 (M +), process overall yields is 71%.
Below be only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (5)

1. a preparation method for terlipressin, comprises the steps:
Step 1: obtain intermediate :
Fmoc-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin
Step 2: obtain intermediate :
Boc-Gly-Gly-Gly-Cys (Trt)-Tyr (tBu)-Phe-Gln (Trt)-Asn (Trt)-Cys (Trt)-Pro-Lys (Boc)-Gly-resin
Step 3: intermediate cracking, cyclisation obtain the thick peptide of terlipressin:
Step 4: thick peptide obtains terlipressin sterling through separation and purification.
2. the preparation method of terlipressin according to claim 1, it is characterized in that: described step 1 and 2 adopts solid-phase synthesis, first according to the peptide sequence of terlipressin, N is held to hold by C, successively Fmoc-Gly-OH, Fmoc-Lys (Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys (Trt)-OH, Fmoc-Asn (Trt)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Phe-OH, Fmoc-Tyr (tBu)-OH, Fmoc-Cys (Trt)-OH, Fmoc-Gly-OH are connected on solid-phase resin, obtain intermediate ; Again Boc-Gly-Gly-OH fragment is connected to the intermediate sloughing blocking group Boc on, obtain intermediate .
3. the preparation method of terlipressin according to claim 2, is characterized in that: described solid-phase resin is RinkAmide resin, RinkAmide-MBHA resin, RinkAmide-BHA resin; Deprotecting regent is DBU/ piperidines/DMF solution, and wherein DBU accounts for 0.5% ~ 15%, and piperidines accounts for 0.5% ~ 20%, is dissolved in DMF; Coupling condensation reagent uses TBTU or HOBt or HBTU, and activating reagent uses DIC or DIEA.
4. the preparation method of terlipressin according to claim 1, it is characterized in that: in described step 3, lytic reagent uses mixing acid reagent, mixing acid reagent is TFA, water and other capture agent mixture, capture agent selects at least one in EDT, MPS, phenol, TFA ratio is 80% ~ 85%, and capture agent ratio is 10% ~ 15%, and all the other are water.
5. the preparation method of terlipressin according to claim 1, is characterized in that: in described step 4, and cyclization process weak base regulates cyclisation liquid pH to 7.2 ~ 10.0, adds the cyclisation of the oxidising agent such as hydrogen peroxide or iodine, and reaction 1 ~ 3h, obtains the thick peptide of terlipressin.
CN201410434586.2A 2014-08-29 2014-08-29 Method for preparing terlipressin Pending CN105367627A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107778353A (en) * 2016-08-25 2018-03-09 成都圣诺生物制药有限公司 A kind of method for synthesizing terlipressin
WO2019127919A1 (en) * 2017-12-29 2019-07-04 深圳翰宇药业股份有限公司 Carrier compound for liquid phase synthesis of polypeptide, preparation method therefor and use thereof
CN114685613A (en) * 2020-12-28 2022-07-01 深圳翰宇药业股份有限公司 Preparation method of terlipressin impurity Q

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Publication number Priority date Publication date Assignee Title
CN101693738A (en) * 2009-10-29 2010-04-14 深圳市翰宇药业有限公司 Method for synthesizing terlipressin by solid-phase oxidization and cyclization
CN102408471A (en) * 2011-06-23 2012-04-11 成都圣诺科技发展有限公司 Preparation method of Terlipressin
CN102731625A (en) * 2012-06-27 2012-10-17 深圳翰宇药业股份有限公司 Method for purifying terli
CN103254295A (en) * 2013-05-31 2013-08-21 青岛国大生物制药股份有限公司 Preparation method of terlipressin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101693738A (en) * 2009-10-29 2010-04-14 深圳市翰宇药业有限公司 Method for synthesizing terlipressin by solid-phase oxidization and cyclization
CN102408471A (en) * 2011-06-23 2012-04-11 成都圣诺科技发展有限公司 Preparation method of Terlipressin
CN102731625A (en) * 2012-06-27 2012-10-17 深圳翰宇药业股份有限公司 Method for purifying terli
CN103254295A (en) * 2013-05-31 2013-08-21 青岛国大生物制药股份有限公司 Preparation method of terlipressin

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107778353A (en) * 2016-08-25 2018-03-09 成都圣诺生物制药有限公司 A kind of method for synthesizing terlipressin
CN107778353B (en) * 2016-08-25 2021-04-20 成都圣诺生物制药有限公司 Method for synthesizing terlipressin
WO2019127919A1 (en) * 2017-12-29 2019-07-04 深圳翰宇药业股份有限公司 Carrier compound for liquid phase synthesis of polypeptide, preparation method therefor and use thereof
CN109988056A (en) * 2017-12-29 2019-07-09 深圳翰宇药业股份有限公司 A kind of compound and its preparation method and application for peptide synthesis in liquid phase carrier
CN114685613A (en) * 2020-12-28 2022-07-01 深圳翰宇药业股份有限公司 Preparation method of terlipressin impurity Q

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Application publication date: 20160302