CN106397542A - Method for preparing triptorelin acetate through specific microwave synthesis - Google Patents
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Abstract
The invention discloses a method for preparing triptorelin acetate through specific microwave synthesis. The method includes the following operation steps that firstly, Rink Amide-AM Resin amino resin which is obtained after swelling, deprotection and washing and has the substitution degree of 0.3-0.5 mmol/g serves as an initiative resin carrier and sequentially reacts with an activated protected amino acid solution in a constant-temperature oscillator to obtain triptorelin precursor peptide I-amino resin; secondly, a triptorelin precursor peptide I-amino resin solution is deprotected and washed to obtain solid particles, the solid particles are used for a cutting reaction, and a triptorelin crude peptide II is obtained through sediment; thirdly, the triptorelin crude peptide II is purified, a C4 filler preparation column is used, the A phase, which is 0.1% acetic acid/water and the B phase, namely 0.1% acetic acid/acetonitrile serve as a mobile phase, separation and extraction of polypeptides are conducted according to the elution gradient process of B.Cone/%:5-70,0-60 min, and pure polypeptides are obtained. The purification technology is used, product purity reaches 99%, the yield is 50% or above, the production period is shortened, and mass production is facilitated.
Description
Technical field
The invention belongs to polypeptide drugs synthesis preparation method technical field is and in particular to the synthetically prepared acetic acid of specificity microwave
The method of triptorelin.
Background technology
Chinese name：Triptorelin acetate, English name：Triptorelin Acetate
Structural formula：Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2 HAC, molecular formula：
C64H82N18O13, molecular weight：1311.46.
Triptorelin acetate is a kind of luteinizing hormone releasing hormone analog of synthetic, on the basis of natural LHRH,
Using D-Trp, the Gly on LHRH peptide chain the 6th is replaced, produce a kind of stronger synthesis of biologic activity effect and promote gonad and swash
The homologue of hormone-releasing hormone, the improvement of its structure enhances the affinity of it and pituitary receptors and slows down the passivation of target tissue
Effect, and compared to natural LHRH, possess longer Half-life in vivo and higher biological stability.Clinically lead
It is used for treating hysteromyoma, children genuine sexual precosity, womb endometrium ectopia, can be used for body in the treatment of infertility
Outer fertilization-embryo transfer process.
At present, the method for synthesizing and purifying with regard to triptorelin acetate is reported seldom both at home and abroad, the following is four with regard to synthesis
The Patent of purification process；
A kind of purification process of triptorelin is disclosed in patent CN201410743707.1：Qu Pu is prepared using solid phase
First peptide fragment sequences of Rayleigh full guard, liquid phase is prepared the second peptide fragment sequences of the full guard of triptorelin and is removed its ammonia
Cardinal extremity protection group；In liquid phase, it is stripped of the second peptide fragment sequences and first peptide fragment sequences of the full guard of aminoterminal protection group
Obtain the triptorelin of full guard；The Side chain protective group sloughing the triptorelin of full guard obtains the thick peptide of triptorelin, liquid-phase pure
Change is changed salt and is obtained triptorelin acetate, and it is to prepare triptorelin using the method for solid liquid phase binding fragment condensation；
Shortcoming：Need in building-up process to cut through multiple, synthesis cycle is long, complex process.
Disclose the purification process of another kind of triptorelin in patent CN200710044419.7：Closed using solid-phase synthesis
Become triptorelin, the method according to solid phase synthesis is sequentially connected the aminoacid with blocking group, obtain protection ten peptide resins, its
Between slough Fmoc- blocking group successively, synchronously carry out de- side chain protecting group and cut peptide, obtain crude product, crude product prepares post through C18
Isolate and purify, after lyophilizing, prepared triptorelin fine work；
Shortcoming：The triptorelin total recovery obtaining only 25% about.
Disclose a kind of purification process of triptorelin patent CN201310013712.2 is another, be by song to be purified
Puri woods is dissolved with solvent and filters to get filtrate, and gained filtrate is loaded on ion exchange column, with mobile phase eluting and make song
Puri woods changes into its salt, collects main peak effluent；Gained effluent is loaded on silicagel column, uses mobile phase eluting, collect
Main peak eluent, removes solvent, obtains final product；
Shortcoming：Purification process is complicated, and purification time length, production cost are high, are unfavorable for large-scale production；
Disclose a kind of purification process of triptorelin in patent CN201310074154.0 again：First with containing organic solvent
Aqueous dissolution sample, with octadecylsilane chemically bonded silica as fixing phase, with the buffer salt of phosphoric acid or sulphuric acid for A phase, second
Nitrile is B phase, carries out gradient elution；Then, using Reversed phase HPLC method, with octadecylsilane chemically bonded silica as fixing phase, will
Triptorelin phosphate changes into acetate, lyophilizing obtains triptorelin acetate；
Shortcoming:The total recovery of triptorelin is only 30% about.
Content of the invention
It is an object of the invention to provide the synthetically prepared acetic acid Qu Purui that a kind of purification yield is high, process is simple, the time is short
The method of woods, realizes particular by below scheme：
The method of the synthetically prepared triptorelin acetate of specificity microwave, operating procedure is as follows：
Step one：With swelling, deprotection and the substitution value after washing is the Rink Amide-AM of 0.3～0.5mmol/g
Resin amino resins are initial resin carrier, react with the protected amino acid solution of activation successively, pass through in isothermal vibration device
The condensation reaction of solid-phase synthesis accesses corresponding protected amino acid, obtains triptorelin precursor peptide I-amino resins；
Step 2：Triptorelin precursor peptide I-amino resin solution is carried out by deprotection and washs, obtains solid particle；Should
Solid particle is used for carrying out cleavage reaction, after sedimentation, obtains the thick peptide of triptorelin II；
Step 3：To triptorelin, thick peptide II carries out purification, and purification prepares post from C4 filler, with A phase：0.1% acetic acid/
Water, B phase：0.1% acetic acid or acetonitrile are mobile phase, and with B.Cone/% (5 → 70), the Gradient program of 0 → 60min carries out polypeptide
Separating-purifying, obtain triptorelin acetate.
The setting-up point of described solid-phase synthesis is 20-40 DEG C, and the activator that condensation reaction is used is DIC, contracting
Mixture is HOBT.
After amino acid condensation reaction, then carry out the synthetic reaction of 10-20 second with microwave, improve condensation efficiency.
The swelling solvent of amino resins is DCM, soaks more than 2 hours.
Protected amino acid is put in centrifuge tube with HOBT successively, and adds DMF reagent, obtain mixing test solution；To mixing
Deca DIC in test solution solution, completely, dissolving obtains the protected amino acid solution of described activation for mixing；
Deprotection described in the step one and step 2 operation washed is as follows：
(1), after draining solution, volume is added to be 20% piperidines of reactor volume 1/3-1/2 and the mixed solution of DMF,
The reactor that will be equipped with mixed solution is placed on the decolorization swinging table that rotating speed is 30r/min, after shaking 20min, solution is drained；
(2) add the DMF solution that volume is reactor volume 1/3-1/2 in the reactor after solution to draining again, and will react again
Device is placed on decolorization swinging table, after shaking 60s-90s, solution is drained；(3) operation of repetition (2) three times.
The reaction reagent of the cleavage reaction described in step 2 is the mixed liquor of TFA, TIS and H2O.
Described cleavage reaction is to carry out under the conditions of the shaking of 20r/min, and the response time is 38-42min.
Solution containing the thick peptide of triptorelin II after cleavage reaction is carried out with the anhydrous ether solution of -20 DEG C of low temperature pre-coolings
Centrifugal sedimentation, obtains the thick peptide II of emulsion state.
Described protected amino acid is：Fmoc-Gly-OH、Fmoc-Pro-OH、Fmoc-Arg(pbf)-OH、Fmoc-Leu-
OH、Fmoc-D-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Trp(Boc)-OH、
Fmoc-His(Trt)-OH、Fmoc-Pyr-OH.
The Advantageous Effects of the present invention：
(1) pass through reduction mobility pH value in the present invention and improve ion pairing ability, be conducive to purification and improve purity,
And optimize purification gradient, shorten purification time, save the use of purification mobile phase, reduce production cost；With second
Acid replaces trifluoroacetic acid to adjust mobile phase PH, it is to avoid contain trifluoroacetic acid in final products, reduces product toxicity, simplifies work
Skill flow process.
(2) present invention utilize Fmoc solid phase synthesis principle, develop solid phase synthesis technique, using common be easy to get, low cost
Reagent condensation reaction, and using distinctive purifying process condition so that triptorelin crude yield up to more than 80%, it is pure
Product yield reaches 50%, substantially increases the yield of triptorelin；The present invention is simple to operate, and synthesis cycle is short, low production cost,
By-product is few, and product yield is high, beneficial to industrialized production.
(3) present invention improves heterogeneous phenomenon, break sequence due to synthetically produced using the peculiar energy of microwave technology
Secondary structure, thus improve the biological activity of polypeptide it is achieved that the production technology purpose of high activity, high yield.
(4) present invention carries out the purification of the thick peptide of triptorelin using purifying process, and product purity reaches 99%, product yield
Reach more than 50%, substantially reduce the production cycle while ensureing yield, reduce production cost, be conducive to giving birth in a large number
Produce, there is good market application foreground.
Specific embodiment
For the ease of it will be appreciated by those skilled in the art that the present invention is further illustrated with reference to specific embodiment.
Embodiment 1:The method of the synthetically prepared triptorelin acetate of specificity microwave, operating procedure is as follows：
(1)：The preparation of the desired amino resin of initial resin carrier
By the Rink Amide-AM Resin amino resins 0.1g for 0.38mmol/g for the substitution value, from opening add to
In Peptide systhesis reactor, take DCM reagent to add to reactor, so that resin is completely submerged in DCM solvent, abundant with solvent
Contact, swelling 2h；
After amino resin solution is drained, add 20% piperidines and the DMF mixed solution of 1/3 reactor volume, be placed in
On the decolorization swinging table of 30r/min, then deprotection solution drained by shaking reaction 20min with vacuum pump；Add 1/3 reactor
The DMF solution of volume, is placed in shaking 1min on decolorization swinging table, is drained solution with vacuum pump, adds DMF solution washing tree again
Fat, repetitive operation 2 times；Using 1,2,3-indantrione monohydrate color developing detection, qualified after obtain desired amino resin；
(2)：The preparation of protected amino acid
Protected amino acid is put in centrifuge tube with HOBT successively, and adds DMF reagent, obtain mixing test solution；To mixing
Deca DIC in test solution solution, completely, dissolving obtains the protected amino acid solution activating for mixing；
Protected amino acid is：
Fmoc-Gly-OH、Fmoc-Pro-OH、Fmoc-Arg(pbf)-OH、Fmoc-Leu-OH、Fmoc-D-Trp(Boc)-
OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Trp(Boc)-OH、Fmoc-His(Trt)-OH、Fmoc-
Pyr-OH；
, weigh 22mg Fmoc-Gly-OH and 12mg HOBT in centrifuge tube taking Fmoc-Gly-OH as a example, plus 2ml DMF
Dissolved, then added 10ul DIC in solution with dropper, mix homogeneously is obtained the protected amino acid solution activating；
(3)：The synthesis of triptorelin resin I
Above-mentioned protected amino acid solution is sequentially added in the reactor equipped with desired amino resin drained, protects ammonia
The inventory of base acid by 2 times of throwings amino resins molal quantity, activator is DIC, and condensing agent is HOBT；Reactor is placed in 30
DEG C isothermal vibration device in react 10min, using microwave be condensed 15s.Using above-mentioned same method, it is sequentially ingressed into the 2-10 ammonia
The corresponding Fmoc- protected amino acid of base acid, that is, obtain triptorelin precursor peptide I-amino resins；
Triptorelin precursor peptide I-amino resins are：
Fmoc-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-Trp(Boc)-Leu-Arg(pbf)-Pro-
Gly- amino resins.
(4)：The synthesis of the thick peptide of triptorelin II
After triptorelin precursor peptide I-amino resin solution is drained, add 20% piperidines and the DMF of 1/2 reactor volume
Mixed solution, is placed in shaking reaction 20min on the decolorization swinging table of 30r/min, is then drained solution with vacuum pump；Add 1/
The DMF solution of 2 reactor volumes, is placed in shaking 1min on decolorization swinging table, is drained solution with vacuum pump, adds DMF molten again
Liquid washs triptorelin precursor peptide I-amino resins, repetitive operation three times.
Resin solution vacuum pump in reactor is drained to graininess, configures 10ml cutting reagent：9.5ml TFA+
0.25ml TIS+0.25ml H2O, is added in reactor, cleavage reaction 40min under the sway condition of 20r/min；
After cleavage reaction, the absolute ether of -20 DEG C of low temperature pre-coolings, centrifugal sedimentation three times are selected in the sedimentation of polypeptide, obtain breast
Gluey thick peptide sample；
Weigh after crude product lyophilizing, obtain powdered samples 32mg, the amount according to crude product and synthesis measure actual substitution value
(SD=0.3mmol/g) theoretical amount calculating, calculates crude yield and reaches 82.3%, than the prior art only yield of 50-60%
Have and significantly increase exponentially.
(5)：The purification of the thick peptide of triptorelin II
Dissolve triptorelin crude product II with the mixed solution of 20% acetonitrile and water, inverted high performance liquid chromatography purification obtains
To triptorelin polypeptide, purification condition is：Post prepared by C4 filler, and mobile phase is A phase：0.1% acetic acid/water, B phase：0.1% second
Acid/acetonitrile, flow velocity 9ml/min, Detection wavelength 210nm, prepare Gradient program
Collect sample peak solution, weigh after lyophilizing sample be 21.4mg, through analytical calculation, triptorelin purity reaches
99.2%, its sterling yield reaches 53.6%.
Embodiment 2:
(1)：The preparation of the desired amino resin of initial resin carrier
By the Rink Amide-AM Resin amino resins 2g for 0.45mmol/g for the substitution value, add at most from opening
In peptide symthesis reactor, take DCM reagent to add to reactor, so that resin is completely submerged in DCM solvent, fully connect with solvent
Touch, swelling 8h；
After amino resin solution is drained, add 20% piperidines and the DMF mixed solution of 1/2 reactor volume, be placed in
On the decolorization swinging table of 30r/min, then deprotection solution drained by shaking reaction 20min with vacuum pump；Add 1/2 reactor
The DMF solution of volume, is placed in shaking 90s on decolorization swinging table, is drained solution with vacuum pump, adds DMF solution washing tree again
Fat, repetitive operation 2 times, using 1,2,3-indantrione monohydrate color developing detection, qualified after obtain desired amino resin；
(2)：The preparation of protected amino acid
Protected amino acid is put in centrifuge tube with HOBT successively, and adds DMF reagent, obtain mixing test solution；To mixing
Deca DIC in test solution solution, completely, dissolving obtains the protected amino acid solution activating for mixing；
Protected amino acid is：
Fmoc-Gly-OH、Fmoc-Pro-OH、Fmoc-Arg(pbf)-OH、Fmoc-Leu-OH、Fmoc-D-Trp(Boc)-
OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Trp(Boc)-OH、Fmoc-His(Trt)-OH、Fmoc-
Pyr-OH；
, weigh 500mg Fmoc-Gly-OH and 250mg HOBT in centrifuge tube taking Fmoc-Gly-OH as a example, plus 12ml
DMF is dissolved, then adds 200ul DIC in solution with dropper, and mix homogeneously obtains the protected amino acid solution activating；
(3)：The synthesis of triptorelin resin I
Above-mentioned protected amino acid solution is added separately in the reactor equipped with desired amino resin drained successively, protects
The inventory of shield aminoacid by 2 times of throwings amino resins molal quantity, activator is DIC, and condensing agent is HOBT；Reactor is put
React 45min in 30 DEG C of isothermal vibration device, be condensed 20s using microwave.Using above-mentioned same method, it is sequentially ingressed into 2-10
The corresponding Fmoc- protected amino acid of individual aminoacid, that is, obtain triptorelin precursor peptide I-amino resins；
Triptorelin precursor peptide I-amino resins are：
Fmoc-His(Trt)-Trp(Boc)-Ser(tbu)-Tyr(tbu)-D-Trp(Boc)-Leu-Arg(pbf)-Pro-
Gly- amino resins.
(4)：The synthesis of the thick peptide of triptorelin II
After triptorelin precursor peptide I-amino resin solution is drained, add 20% piperidines and the DMF of 1/2 reactor volume
Mixed solution, is placed in shaking reaction 20min on the decolorization swinging table of 30r/min, is then drained solution with vacuum pump；Add 1/
The DMF solution of 2 reactor volumes, is placed in shaking 90s on decolorization swinging table, is drained solution with vacuum pump, adds DMF solution again
Washing triptorelin precursor peptide I-amino resins, repetitive operation three times.
Resin vacuum pump in reactor is drained to graininess, configures 100ml cutting reagent：95mlTFA+2.5ml
TIS+2.5ml H2O, is added in reactor, cleavage reaction 40min under the sway condition of 20r/min；The sedimentation choosing of polypeptide
With the absolute ether of -20 DEG C of low temperature pre-coolings, centrifugal sedimentation three times, obtain the thick peptide sample of emulsion state；
Weigh after crude product lyophilizing, obtain powdered samples 746mg, the amount according to crude product and synthesis measure actual substitution value
(SD=0.36mmol/g) theoretical amount calculating, calculates crude yield and reaches 81.3%, than the prior art only yield of 50-60%
Have and significantly increase exponentially.
(5)：The purification of the thick peptide of triptorelin II
Dissolve triptorelin crude product II with the mixed solution of 20% acetonitrile and water, inverted high performance liquid chromatography purification obtains
To triptorelin polypeptide, purification condition is：Post prepared by C4 filler, and mobile phase is A phase：0.1% acetic acid/water, B phase：0.1% second
Acid/acetonitrile, flow velocity 9ml/min, Detection wavelength 210nm, prepare Gradient program
Collect sample peak solution, weigh after lyophilizing sample be 441.5mg, through analytical calculation, triptorelin purity reaches
99.1%, its sterling yield reaches 53.1%.
Present invention employs solid phase synthesis technique, using common be easy to get, the reagent condensation reaction of low cost, and using peculiar
Purifying process condition so that triptorelin crude yield up to more than 80%, its sterling yield reaches 50%, synthesis cycle
Short, low production cost, by-product are few, high income, beneficial to industrialized production.
Embodiment 1 starts at the 1-10 corresponding guarantor of aminoacid with protected amino acid used in embodiment 2 from resin
Shield aminoacid and molecular weight are as shown in table 1 below；
Table 1
Used in embodiment 1 and embodiment 2, the implication of english abbreviation is as shown in table 2 below.
Table 2
Above content is only citing made for the present invention and illustrates, affiliated those skilled in the art are to being retouched
The specific embodiment stated is made various modifications or supplements or substituted using similar mode, without departing from invention or super
More scope defined in the claims, all should belong to protection scope of the present invention.
Claims (10)
1. the synthetically prepared triptorelin acetate of specificity microwave method it is characterised in that：Operating procedure is as follows：
Step one：With swelling, deprotection and the substitution value after washing is the RinkAmide-AM Resin of 0.3～0.5mmol/g
Amino resins are initial resin carrier, react in isothermal vibration device with the protected amino acid solution of activation successively, by solid phase
The condensation reaction of synthetic method accesses corresponding protected amino acid, obtains triptorelin precursor peptide I-amino resins；
Step 2：Triptorelin precursor peptide I-amino resin solution is carried out by deprotection and washs, obtains solid particle；This solid
Granule is used for carrying out cleavage reaction, after sedimentation, obtains the thick peptide of triptorelin II；
Step 3：To triptorelin, thick peptide II carries out purification, and purification prepares post from C4 filler, with A phase：0.1% acetic acid/water, B
Phase：0.1% acetic acid/acetonitrile is mobile phase, with gradient as B.Cone/%：The program of 5 → 70,0 → 60min carries out polypeptide
Separating-purifying, obtain triptorelin acetate.
2. the synthetically prepared triptorelin acetate of specificity microwave according to claim 1 method it is characterised in that：Described
The setting-up point of solid-phase synthesis is 20-40 DEG C, and the activator that condensation reaction is used is DIC, and condensing agent is HOBT.
3. the synthetically prepared triptorelin acetate of specificity microwave according to claim 2 method it is characterised in that：In ammonia
After base acid condensation reaction, then carry out the synthetic reaction of 10-20s with microwave, improve condensation efficiency.
4. the synthetically prepared triptorelin acetate of specificity microwave according to claim 1 method it is characterised in that：Amino
The swelling solvent of resin is DCM, soaks more than 2 hours.
5. the synthetically prepared triptorelin acetate of specificity microwave according to claim 1 method it is characterised in that：To protect
Shield aminoacid is put in centrifuge tube with HOBT successively, and adds DMF reagent, obtains mixing test solution；Drip in mixing test solution solution
Plus DIC, completely, dissolving obtains the protected amino acid solution of described activation for mixing；Wherein, HOBT is as the condensation of condensation reaction
Agent, DIC is as the activator of condensation reaction.
6. the synthetically prepared triptorelin acetate of specificity microwave according to claim 1 method it is characterised in that：Step
One and step 2 described in deprotection and the operation washed is as follows：
(1), after solution being drained, add volume to be 20% piperidines of reactor volume 1/3-1/2 and the mixed solution of DMF, will fill
The reactor having mixed solution is placed on the decolorization swinging table that rotating speed is 30r/min, after shaking 20min, solution is drained；(2) again
Add, to draining, the DMF solution that volume is reactor volume 1/3-1/2 in reactor after solution, and again reactor is placed in
On decolorization swinging table, after shaking 60s-90s, solution is drained；(3) operation of repetition (2) three times.
7. the synthetically prepared triptorelin acetate of specificity microwave according to claim 1 method it is characterised in that：Step
The reaction reagent of the cleavage reaction described in two is the mixed liquor of TFA, TIS and H2O.
8. the synthetically prepared triptorelin acetate of specificity microwave according to claim 7 method it is characterised in that：Described
Cleavage reaction is to carry out under the conditions of the shaking of 20r/min, and the response time is 38-42min.
9. the method according to the described synthetically prepared triptorelin acetate of specificity microwave arbitrary in claim 1,7,8, it is special
Levy and be：Solution containing the thick peptide of triptorelin II after cleavage reaction is carried out with the anhydrous ether solution of -20 DEG C of low temperature pre-coolings
Centrifugal sedimentation, obtains the thick peptide II of emulsion state.
10. according to claim 1 or 5 the synthetically prepared triptorelin acetate of specificity microwave method it is characterised in that：
Described protected amino acid is：Fmoc-Gly-OH、Fmoc-Pro-OH、Fmoc-Arg(pbf)-OH、Fmoc-Leu-OH、Fmoc-
D-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Trp(Boc)-OH、Fmoc-His
(Trt)-OH、Fmoc-Pyr-OH.
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Cited By (3)
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| CN114685616A (en) * | 2020-12-31 | 2022-07-01 | 哈尔滨三联药业股份有限公司 | Synthetic method of triptorelin acetate |
| CN116375790A (en) * | 2023-06-05 | 2023-07-04 | 厦门胜泽泰医药科技有限公司 | Microfluidic chip solid-phase peptide synthesis method and device |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114685615A (en) * | 2020-12-31 | 2022-07-01 | 哈尔滨三联药业股份有限公司 | Purification method of triptorelin acetate polypeptide crude product |
| CN114685616A (en) * | 2020-12-31 | 2022-07-01 | 哈尔滨三联药业股份有限公司 | Synthetic method of triptorelin acetate |
| CN114685616B (en) * | 2020-12-31 | 2024-03-29 | 哈尔滨三联药业股份有限公司 | Synthesis method of triptorelin acetate |
| CN116375790A (en) * | 2023-06-05 | 2023-07-04 | 厦门胜泽泰医药科技有限公司 | Microfluidic chip solid-phase peptide synthesis method and device |
| CN116375790B (en) * | 2023-06-05 | 2023-08-18 | 厦门胜泽泰医药科技有限公司 | Microfluidic chip solid-phase peptide synthesis method and device |
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Application publication date: 20170215 |