CN102002004A - Taltirelin intermediate and synchronizing method of taltirelin - Google Patents
Taltirelin intermediate and synchronizing method of taltirelin Download PDFInfo
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- CN102002004A CN102002004A CN 201010509468 CN201010509468A CN102002004A CN 102002004 A CN102002004 A CN 102002004A CN 201010509468 CN201010509468 CN 201010509468 CN 201010509468 A CN201010509468 A CN 201010509468A CN 102002004 A CN102002004 A CN 102002004A
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- taltirelin
- hydrogenated methyl
- benzyl ester
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Abstract
The invention discloses a taltirelin intermediate and a synchronizing method of taltirelin. The taltirelin intermediate is 3-methyl hydroorotic acid and L-histidine-L-proline amide. The invention discloses a synchronizing method of the 3-methyl hydroorotic acid, which mainly comprises the steps of: reacting L-Asn with ethyl chloroformate, and then obtaining hydroorotic acid under the action of sodium ethoxide; reacting with benzyl bromide; reacting with methyl iodide under the action of NaH to obtain 3-methyl benzyl hydroorotic; and hydrogenating to obtain 3-methyl hydroorotic acid. The invention also discloses a synchronizing method of the L-histidine-L-proline amide and a synchronizing method of taltirelin. The invention provides a more appropriate path, the taltirelin is synchronized by using a liquid phase process, the reaction raw materials are easy to obtain, the reaction condition is mild and the operation is simple.
Description
[technical field]
The present invention relates to the synthetic method of a peptide species intermediate and polypeptide, relate in particular to the synthetic method of Taltirelin intermediate and Taltirelin.
[background technology]
The contained Taltirelin of this product (English name: Taltirelin), with the similar of TRH.The difference of it and TRH mainly is to have replaced original Pyrrolidonecarboxylic acid with 3-hydrogenated methyl breast hydracid.After these structural modifications, make its excitation to CNS stronger 10～100 times than TRH, acting duration is about 8 times than TRH.The internal secretion effect of this product than TRH a little less than, but more stable than TRH in vivo.In addition, this product to the effect of thyroliberin be TRH 1/6～1/11, thyrotropin can suppress this product and TRH potential internal secretion effect.
Describe in open source literature and the patent at present Taltirelin the synthesis technique complicated operation, higher to equipment requirements, be unfavorable for that industrial production, using value are not high.
[summary of the invention]
The present invention proposes a more suitable route, use the synthetic Taltirelin of liquid phase method, reaction raw materials is easy to get, and reaction conditions gentleness, simple to operate.
The objective of the invention is, the 3-hydrogenated methyl vitamin B13 synthetic method of one of a kind of Taltirelin intermediate is provided, the method includes the steps of:
1) L-Asn and Vinyl chloroformate reaction gets N
α-ethoxycarbonyl l-asparagine;
2) with N
α-ethoxycarbonyl l-asparagine gets hydrogenation breast hydracid under the effect of sodium ethylate;
3) hydrogenation breast hydracid and cylite react hydroorotic acid benzyl ester;
4) hydroorotic acid benzyl ester and methyl iodide get 3-hydrogenated methyl whey acid benzyl ester under the effect of NaH;
5) 3-hydrogenated methyl vitamin B13 benzyl ester hydrogenation is got 3-hydrogenated methyl vitamin B13.
Step 1) L-Asn and Vinyl chloroformate can be chosen under the catalyzer condition and react, and L-Asn is 1 with the amount ratio of Vinyl chloroformate: 2-3, L-Asn is 1 with the amount ratio of catalyzer: 2-3, catalyzer can be Et
3N.Reacted 2-4 hour, with dilute hydrochloric acid with the pH regulator of mixed solution to 1.5-3, preferred pH=2 use ethyl acetate extraction, organic phase usefulness saturated common salt water washing three times, be spin-dried for after the drying white solid.
Step 2) but the sodium ethylate alcohol sodium solution also can be that metal Na is put into ethanolic soln.N
α-ethoxycarbonyl l-asparagine in alcohol sodium solution back flow reaction 3-4 hour spins off ethanol, the residue water dissolution, and dilute hydrochloric acid is acidified to pH1.5-3, and preferred pH=2 uses ethyl acetate extraction then, and organic phase washes twice with water, dry concentrating.The gained solid obtains white solid with ethyl acetate-normal hexane recrystallization.
Step 3) hydrogenation breast hydracid and cylite reaction can get hydroorotic acid benzyl ester under the condition of catalyzer, catalyzer can be Et
3N; Can be with Et
3N and cylite add in the DMF suspension of hydroorotic acid, hydroorotic acid: Et
3N: cylite=1: 2-3: 2-3 (amount ratio).Stirring at normal temperature two days is poured reaction solution in the frozen water into, with methyl alcohol (MeOH) recrystallization, obtains clear crystal behind the solid drying that filtration obtains.
Prior art adopts the method for vacuum concentration to remove DMF, and is time-consuming and handle unclean; The present invention pours DMF solution in the frozen water into, promptly can obtain product by filtering, and has simplified treating processes, has saved manpower and equipment cost, and simultaneously, this treatment process also makes the yield of product bring up to more than 80% from 61% of prior art.
Step 4) hydroorotic acid benzyl ester and methyl iodide get 3-hydrogenated methyl whey acid benzyl ester under the effect of NaH;
NaH is added in the mixed solution of methyl iodide and hydroorotic acid benzyl ester hydroorotic acid benzyl ester: NaH: methyl iodide=1: 1-1.5: 4-6 (amount ratio), the concentration of NaH is 60%-80%, preferred 70%.Reaction is 3-5 hour under the stirring at normal temperature, and reaction solution is poured in the frozen water, filter, and drying, the gained solid washs with ethyl acetate, obtains white solid.
This step is poured reaction soln in the frozen water into, simplifies treating processes, has improved production efficiency.
Step 5) gets 3-hydrogenated methyl vitamin B13 with 3-hydrogenated methyl vitamin B13 benzyl ester hydrogenation, this step can be carried out under the following conditions: add 10%Pd-C in the ethanolic soln of 3-hydrogenated methyl whey acid benzyl ester, 3-hydrogenated methyl whey acid benzyl ester: Pd-C=5-15: 1, preferred 10: 1 (amount ratio).Hydrogenation 16 hours filters Pd-C, and filtrate is spin-dried for, and gained solid recrystallizing methanol obtains white solid.
This step can greatly improve yield, adopts this step yield to bring up to 90% from 70% of prior art.
3-hydrogenated methyl vitamin B13 synthetic method can adopt following route to further specify:
1) be initial feed by L-Asn-OH, and chemical compounds I (suc as formula I) reaction, compound ii (suc as formula II) obtained;
2) with compound ii and sodium ethylate reaction, with obtaining compound III (suc as formula III) behind the hcl acidifying;
3) with compound III and cylite reaction, obtain compound IV (suc as formula IV);
4) compound IV and methyl iodide, NaH are reacted, obtain compound V (suc as formula V);
5) benzyl is removed in the hydrogenation of compound V, obtained compound VI (suc as formula VI);
Another object of the present invention provides the synthetic method of the L-Histidine-L-proline(Pro) acid amides of one of Taltirelin intermediate, and the method includes the steps of:
1) L-Boc-His (Trt)-OH and L-Pro-NH2 react L-Boc-His (Trt)-L-Pro-NH2;
2) L-Boc-His (Trt)-L-Pro-NH2 gets L-His-L-Pro-NH2 under the cracking agent effect.
Wherein: step 1) L-Boc-His (Trt)-OH and L-Pro-NH2 react L-Boc-His (Trt)-L-Pro-NH2; This reaction can be carried out under the following conditions: with L-Boc-His (Trt)-OH, L-Pro-NH2 and DCC are dissolved among the 150-250ml DCM, L-Boc-His (Trt)-OH: L-Pro-NH2: DCC=1: 1: 1 (amount ratio).Stirring at normal temperature reaction 2--4 hour is filtered, and filtrate is spin-dried for the back with the EA-PE recrystallization, obtains the 6.6g white solid.This step is not high to the selectivity of condensing agent, adopts general condensing agent to get final product, as DCC, and EDC etc.
Step 2) L-Boc-His (Trt)-L-Pro-NH2 gets L-His-L-Pro-NH2 under the cracking agent effect, and described cracking agent is TFA.
Prior art is to adopt Z-His-OH and H-Pro-OH condensation to the synthetic of H-His-Pro-NH2; make Z-His-Pro-NH2 after the ammonification; obtain H-His-Pro-NH2.2HBr with the HBr/HOAc deprotection again; because the side chain of Z-His-OH is protection not; need to adopt relatively mild method to prevent that side chain from reacting; so need to adopt azide method, the complicated and bad control of reaction process.The present invention can directly carry out condensation with general condensing agent (as DCC, EDC etc.) because selected raw material is reasonable, and reaction system is simple and processing is convenient, can carry out scale operation.
Last purpose of the present invention is, the synthetic method of Taltirelin is provided, and the method includes the steps of:
4) be prepared into 3-hydrogenated methyl vitamin B13 by the synthetic method that the present invention put down in writing;
5) be prepared into L-His-L-Pro-NH2 by the synthetic method that the present invention put down in writing;
6) with 3-hydrogenated methyl vitamin B13 and L-His-L-Pro-NH2 reaction, filter, filtrate is spin-dried for, be dissolved in water, filtrate is regulated pH to 8 with the saturated aqueous solution of NaHCO3, and filtrate is spin-dried for, and uses the dissolve with methanol sample, filters solid and is spin-dried for, and promptly gets Taltirelin.
Wherein step 6) joins DCC in the DMF solution of 3-hydrogenated methyl vitamin B13 and HOSu, wherein, and DCC: 3-hydrogenated methyl vitamin B13: HOSu=1-1.5: 1-1.5: 1-1.5 (amount ratio).0 ℃ was reacted 1-2 hour.Add His-Pro-NH again
2And Et
3N, His-Pro-NH
2: Et
3N=1: 2-3 (amount ratio).After the reaction, filter, be dissolved in water after filtrate is spin-dried for, filtrate is used NaHCO
3Saturated aqueous solution regulate pH to 7.5-9, preferred pH=8.Be spin-dried for the back and use the dissolve with methanol sample, filter solid and be spin-dried for and promptly obtain target product.
In the method for prior art, thick product need carry out post with the MIC GEL CHP-20P (Mitsubishi) of cost costliness to be separated, and production cost is higher.The present invention adopts simple adjustment PH and filtration treatment can obtain highly purified product, has saved great amount of cost.
The Taltirelin synthetic method can adopt following route to further specify:
Step 3) obtains the pressed powder of compound VII (suc as formula VII) with compound VI and L-His-L-Pro-OH condensation;
Total concrete reactions steps:
Wherein:
DCM representative: methylene dichloride
TFA representative: trifluoroacetic acid
DCC representative: dicyclohexylcarbodiimide
EDC representative: ethylene dichloride
DMF representative: dimethyl formamide
HOSu representative: N-hydroxy-succinamide
BzlBr representative: cylite
Net3 representative: triethylamine
MeI representative: methyl iodide
L-His-L-Pro-NH
2: L-Histidine-L-proline(Pro) acid amides
EA-PE representative: ethyl acetate-phosphatidylethanolamine
The Pd-C representative: palladium carbon, promptly the metal nanoparticle of palladium or oxide particle load on the carbon, and carbon can be carbon nanotube (CNT) or carbon film, also can be materials such as gac.Being used for catalysis reacts accordingly.
Technology of the present invention has characteristics such as operation is simple, reaction conditions is gentle, aftertreatment is easy, has considerable economical and practical value.
[embodiment]
The preparation of embodiment 1, hydrogenation breast hydracid
1, with L-Asn.H
2O (15.013g, 100mmol) and Et
3N (23.274g, 230mmol) (200ml) soluble in water drips Vinyl chloroformate (24.962g while stirring under the normal temperature, 230mmol), drip follow-up continuous reaction fully two hours, with the pH regulator to 2 of dilute hydrochloric acid with mixed solution, use ethyl acetate extraction, organic phase is spin-dried for after the drying with saturated common salt water washing three times, obtains the 16.334g white solid, yield: 80%, purity: 96%, MS:204,227.
2, with N
α-ethoxycarbonyl l-asparagine (16.334g, 80mmol) join metal Na (3.68g, in ethanolic soln 160mmol), back flow reaction 4 hours, spin off ethanol, the residue water dissolution, dilute hydrochloric acid is acidified to pH=2, use ethyl acetate extraction then, organic phase washes twice with water, dry concentrating.The gained solid obtains the 9.36g white solid with ethyl acetate-normal hexane recrystallization.Yield: 74%, purity: 95%, MS:159,182.
The preparation of embodiment 2,3-hydrogenated methyl vitamin B13
1, with Et
3N (25.298g, 250mmol) and cylite (34.206g, 200mmol) add hydroorotic acid (15.811g, in DMF suspension 100mmol), stirring at normal temperature two days.Reaction solution is poured in a large amount of frozen water, used the MeOH recrystallization behind the solid drying that filtration obtains, obtain the 20.6g clear crystal.Yield: 83%, purity: 98%, MS:248,271.
2, (2.02g, (43.31g, 310mmol) (15.3g in mixed solution 62mmol), reacted 4 hours under the stirring at normal temperature, and thin-layer chromatography shows that raw material reaction is complete with hydroorotic acid benzyl ester 62mmol) to add MeI with 70%NaH.Reaction solution is poured in the frozen water, filtered, drying, gained solid ethyl acetate washed twice obtains the 8.52g white solid.Yield: 53%, purity: 97.5%, MS:262,285.
3,3-hydrogenated methyl whey acid benzyl ester (8.52g, add in ethanolic soln 32.5mmol) 10%Pd-C (852mg, 3.25mmol), hydrogenation 16 hours filters palladium carbon, filtrate is spin-dried for, gained solid recrystallizing methanol obtains the 4.98g white solid.Yield: 89%, purity: 98%, MS:172,195.
Embodiment 3, L-His-L-Pro-NH
2Preparation
1, with L-Boc-His (Trt)-OH (9.952g, 20mmol), L-Pro-NH
2(2.283g, 20mmol) and DCC (4.326g 21mmol) is dissolved among the DCM (200ml), stirring at normal temperature reaction 2 hours, thin-layer chromatography shows and reacts completely.Filter solid, filtrate is spin-dried for the back with the EA-PE recrystallization, obtains the 6.6g white solid. yield: and 55.6%, purity 91%, MS:594.
2, with L-Boc-His (Trt)-L-Pro-NH
2(6.6g 11mmol) joins in the 66ml TFA solution, and stirring reaction is one hour under the condition of ice bath, and thin-layer chromatography shows that raw material reaction is complete.Reaction solution is poured in the anhydrous diethyl ether of 10 times of amounts, centrifugal, anhydrous diethyl ether washes twice, and vacuum-drying obtains the 4.32g white solid.Yield: 82%, MS:251.
The preparation of embodiment 4, Taltirelin
1, with DCC (1.4g, 6.6mmol) join 3-hydrogenated methyl vitamin B13 (1.03g, 6.0mmol) and HOSu (760mg, in DMF solution 6.6mmol), 0 ℃ the reaction 1.5 hours.Add His-Pro-NH again
2.2TFA (3.16g, 6.6mmol) and Et
3(1.4g, 14mmol), mixed solution reacted 24 hours under 10 ℃ of conditions N.Filter dicyclohexylurea (DCU) (DCU), be dissolved in water after filtrate is spin-dried for, continue to filter, filtrate is used NaHCO
3Saturated aqueous solution regulate pH to 8, be spin-dried for the back and use the dissolve with methanol sample, filter solid and be spin-dried for and promptly obtain the 1.6g target product.Yield: 68%, purity: 95%, MS:406.
2, the 1 1.6g product that obtains is dissolved with little water, refrigeration is placed, and filters and collects the solid of separating out, and obtains 1.6g strip crystal, yield: 85%.
To sum up embodiment the present invention proposes a more suitable route, uses the synthetic Taltirelin of liquid phase method, and reaction raw materials is easy to get, and reaction conditions gentleness, simple to operate.
Above content be in conjunction with concrete preferred implementation to further describing that the present invention did, can not assert that concrete enforcement of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (7)
1. the synthetic method of a 3-hydrogenated methyl vitamin B13 is characterized in that, comprises following steps:
1) L-Asn and Vinyl chloroformate reaction gets N α-ethoxycarbonyl l-asparagine;
2) N α-ethoxycarbonyl l-asparagine is got hydrogenation breast hydracid under the effect of sodium ethylate;
3) hydrogenation breast hydracid and cylite react hydroorotic acid benzyl ester;
4) hydroorotic acid benzyl ester and methyl iodide get 3-hydrogenated methyl whey acid benzyl ester under the effect of NaH;
5) 3-hydrogenated methyl vitamin B13 benzyl ester hydrogenation is got 3-hydrogenated methyl vitamin B13.
2. the method for claim 1 is characterized in that: L-Asn and Vinyl chloroformate reaction, get N α-ethoxycarbonyl l-asparagine in the catalyzer condition, and catalyzer is a triethylamine.
3. the method for claim 1 is characterized in that: step 3) hydrogenation breast hydracid and cylite reaction, and obtain reaction solution after reaction finishes and pour in the frozen water, filtration obtains solid.
4. method as claimed in claim 2 is characterized in that: step 3) hydrogenation breast hydracid and cylite reaction, and obtain reaction solution after reaction finishes and pour in the frozen water, filtration obtains solid.
5. as any described method of claim 1-4, it is characterized in that: step 5) 3-hydrogenated methyl vitamin B13 benzyl ester hydrogenation, be in ethanolic soln, under the catalytic condition of 10%Pd-C, to carry out, 3-hydrogenated methyl whey acid benzyl ester and Pd-C amount ratio=5-15: 1.
6. the synthetic method of L-Histidine-L-proline(Pro) acid amides is characterized in that, comprises following steps:
1) L-Boc-His (Trt)-OH and L-Pro-NH2 react L-Boc-His (Trt)-L-Pro-NH2;
2) L-Boc-His (Trt)-L-Pro-NH2 gets L-His-L-Pro-NH2 under the cracking agent effect.
7. the synthetic method of a Taltirelin is characterized in that, comprises following steps:
1) synthetic method by claim 1 is prepared into 3-hydrogenated methyl vitamin B13;
2) be prepared into L-His-L-Pro-NH2 by claim 5 or 6 described synthetic methods;
3) with 3-hydrogenated methyl vitamin B13 and L-His-L-Pro-NH2 reaction, filter, filtrate is spin-dried for, be dissolved in water, filtrate is regulated pH to 8 with the saturated aqueous solution of NaHCO3, and filtrate is spin-dried for, and uses the dissolve with methanol sample, filters solid and is spin-dried for, and promptly gets Taltirelin.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588862A (en) * | 2012-08-13 | 2014-02-19 | 苏州中科天马肽工程中心有限公司 | Synthesis and crystal form-transforming method of taltirelin |
| CN104530186A (en) * | 2015-01-04 | 2015-04-22 | 上海吉尔多肽有限公司 | Method for separating and purifying taltirelin |
| CN104725470A (en) * | 2013-12-18 | 2015-06-24 | 重庆莱美药业股份有限公司 | New taltirelin crystal form, preparation method and applications thereof |
| CN105254573A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Preparing method for taltirelin and midbody of taltirelin |
| CN105949280A (en) * | 2016-05-26 | 2016-09-21 | 吉尔生化（上海）有限公司 | Preparation method of Taltirelin and intermediate thereof |
| CN113493488A (en) * | 2020-04-07 | 2021-10-12 | 成都简则医药技术有限公司 | Synthetic method of taltirelin |
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| CN85105655A (en) * | 1984-07-10 | 1987-01-28 | 田辺制药株式会社 | Process for preparing novel derivatives of 1-methyl-4, 5-dihydroorotic acid and pharmaceutical compositions thereof |
| JPH04273898A (en) * | 1991-02-26 | 1992-09-30 | Tanabe Seiyaku Co Ltd | Production of histidylprolineamide derivative |
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2010
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| CN85105655A (en) * | 1984-07-10 | 1987-01-28 | 田辺制药株式会社 | Process for preparing novel derivatives of 1-methyl-4, 5-dihydroorotic acid and pharmaceutical compositions thereof |
| JPH04273898A (en) * | 1991-02-26 | 1992-09-30 | Tanabe Seiyaku Co Ltd | Production of histidylprolineamide derivative |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588862A (en) * | 2012-08-13 | 2014-02-19 | 苏州中科天马肽工程中心有限公司 | Synthesis and crystal form-transforming method of taltirelin |
| CN104725470A (en) * | 2013-12-18 | 2015-06-24 | 重庆莱美药业股份有限公司 | New taltirelin crystal form, preparation method and applications thereof |
| CN104725470B (en) * | 2013-12-18 | 2020-03-27 | 重庆莱美药业股份有限公司 | Novel taltirelin crystal form and preparation method and application thereof |
| CN104530186A (en) * | 2015-01-04 | 2015-04-22 | 上海吉尔多肽有限公司 | Method for separating and purifying taltirelin |
| CN105254573A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Preparing method for taltirelin and midbody of taltirelin |
| CN105254573B (en) * | 2015-11-17 | 2018-01-23 | 重庆莱美隆宇药业有限公司 | A kind of preparation method of Taltirelin and its intermediate |
| CN105949280A (en) * | 2016-05-26 | 2016-09-21 | 吉尔生化（上海）有限公司 | Preparation method of Taltirelin and intermediate thereof |
| CN113493488A (en) * | 2020-04-07 | 2021-10-12 | 成都简则医药技术有限公司 | Synthetic method of taltirelin |
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Application publication date: 20110406 |