CN101724018B - 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof - Google Patents

2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof Download PDF

Info

Publication number
CN101724018B
CN101724018B CN2009102132574A CN200910213257A CN101724018B CN 101724018 B CN101724018 B CN 101724018B CN 2009102132574 A CN2009102132574 A CN 2009102132574A CN 200910213257 A CN200910213257 A CN 200910213257A CN 101724018 B CN101724018 B CN 101724018B
Authority
CN
China
Prior art keywords
glycyl
amidomalonic acid
ester
compound
amidomalonic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2009102132574A
Other languages
Chinese (zh)
Other versions
CN101724018A (en
Inventor
赵俊
宗在伟
伏世建
杨建楠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Aosaikang Pharmaceutical Co Ltd
Abeona Therapeutics Inc
Original Assignee
Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Aosaikang Pharmaceutical Co Ltd filed Critical Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority to CN2009102132574A priority Critical patent/CN101724018B/en
Publication of CN101724018A publication Critical patent/CN101724018A/en
Application granted granted Critical
Publication of CN101724018B publication Critical patent/CN101724018B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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

Abstract

The invention relates to 2-(2-methacrylamide triglycyl) aminomalonate ester (I) with a structural formula as below as well as a preparation method and application thereof. The 2-(2-methacrylamide triglycyl) aminomalonate ester (I) can be applied to preparing an aminomalonate platinum complex Prolindac; the preparation method has short synthesis steps, simple and convenient operation, good product quality, high yield and easy industrialized production; and wherein R is equal to (C1 to C5) alkyl.

Description

2-(2-methacryloyl amido three glycyl) amidomalonic acid ester and preparation method thereof, application
Technical field
What the present invention relates to is a kind of 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds, and the method, the application that prepare 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds.
Background technology
Amino malonate platinum complex compound Prolindac (claims again: be that a kind of novel cyclohexanediamine closes the platinum tumor-targeting drug AP5346), by U.S. ACCESS Pharmaceutical Co., Ltd. (Access Pharmaceuticals, Inc.) research and development; Amino malonate platinum complex compound Prolindac (AP5346) is the compound of being researched and developed for the sense organ neurotoxicity in the dosage range that solves oxaliplatin, amino malonate platinum complex compound Prolindac (AP5346) has finished the II phase clinical study of ovarian cancer in Europe at present, obtains satisfied clinical study result.
Amino malonate platinum complex compound Prolindac (AP5346) chemical structural formula is as follows:
Figure G2009102132574D00011
The synthetic bibliographical information of amino malonate platinum complex compound Prolindac (AP5346) is less, patent US7166733, WO2005079396, CN200710130242 and Bioconjug Chem.2006Sep-Oct; 17 (5): 1270-9. all discloses following preparation process, and reaction formula is expressed as follows:
Figure G2009102132574D00021
Figure G2009102132574D00031
Wherein:
Raw material 1 chemical name is: Rocryl 410, following abbreviation: HPMA;
Raw material 2 chemical names are: 2-methacryloyl amido glycyl glycine p-nitrophenyl ester, following abbreviation: MA-GG-ONp;
The intermediate A chemical name is: polymethyl acrylic acid hydroxypropyl ester group glycyl glycine p-nitrophenyl ester, following abbreviation: poly (HPMA)-GG-ONp; Its molecular weight is about: 22 kilodaltons;
The intermediate B chemical name is: polymethyl acrylic acid hydroxypropyl ester group-three glycyl-amidomalonic acid diethyl ester, following abbreviation: poly (HPMA)-GGG-Ama-diEt, research and development code name: AP5195.
Above-mentioned amino malonate platinum complex compound Prolindac synthetic method is loaded down with trivial details, especially need pass through three-step reaction from raw material Rocryl 410 (HPMA) preparation target product amino malonate platinum complex compound Prolindac, cause total recovery low, the cost height is not easy to suitability for industrialized production.
Summary of the invention
The objective of the invention is at above-mentioned weak point; a kind of 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds has been synthesized in design; only need two-step reaction by raw material Rocryl 410 (HPMA) and 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds prepared in reaction amino malonate platinum complex compound Prolindac medicine; synthesis step is short; easy and simple to handle; good product quality, the yield height is easy to suitability for industrialized production.
2-(2-methacryloyl amido three glycyl) amidomalonic acid ester and preparation method thereof, application, take following scheme to realize:
A kind of 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) as following structural formula
Figure G2009102132574D00041
R=(C wherein 1-C 5) alkyl (I).
Described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that it is selected from compound: 2-(2-methacryloyl amido three glycyl) amidomalonic acid dimethyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diethyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-n-propyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisopropyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-n-butyl; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisobutyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di tert butyl carbonate; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-secondary butyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid two n-pentyl esters; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisoamyl ester; a kind of in 2-(2-methacryloyl amido three glycyl) amidomalonic acid two tert-pentyl esters.
Described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I), its preparation method comprises:
(a) be raw material with the amidomalonic acid ester (II) as following structural formula, compound (III) reaction with as following structural formula makes the compound (IV) as following structural formula;
Amidomalonic acid ester (II) structural formula is:
Figure G2009102132574D00051
R=(C wherein 1-C 5) alkyl;
The structural formula of compound (III) is:
Figure G2009102132574D00052
Wherein P is 9-fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (Boc) protection;
The structural formula of compound (IV) is:
Figure G2009102132574D00053
Wherein P is 9-fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (Boc) protection, R=(C 1-C 5) alkyl;
(b) structural formula that makes the further deprotection reaction of compound (IV) make compound (V) compound (V) as following structural formula is:
Figure G2009102132574D00061
R=(C wherein 1-C 5) alkyl (V)
(c) make compound (V) and 2-methacrylic acid carry out condensation reaction and make 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I)
R=(C wherein 1-C 5) alkyl.(I)
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that amidomalonic acid ester (II) is selected from: a kind of in amidomalonic acid dimethyl ester, amidomalonic acid diethyl ester, amidomalonic acid di-n-propyl ester, amidomalonic acid diisopropyl ester, amidomalonic acid di-n-butyl, amidomalonic acid diisobutyl ester, amidomalonic acid di tert butyl carbonate, amidomalonic acid di-secondary butyl ester, amidomalonic acid two n-pentyl esters, amidomalonic acid diisoamyl ester, amidomalonic acid two tert-pentyl esters;
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that compound (III) is selected from: a kind of in 9-fluorenylmethyloxycarbonyl glycyl glycyl glycine, the tertbutyloxycarbonyl glycyl glycyl glycine;
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that compound (IV) is selected from: 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid dimethyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diethyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisopropyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-n-butyl, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisobutyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-secondary butyl ester, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters, 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisoamyl ester, a kind of in 2-(9-fluorenylmethyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid two tert-pentyl esters;
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that compound (IV) is selected from: 2-(9-tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid dimethyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diethyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisopropyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-n-butyl, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisobutyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid di-secondary butyl ester, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters, 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid diisoamyl ester, a kind of in 2-(tertbutyloxycarbonyl glycyl glycyl glycyl) amidomalonic acid two tert-pentyl esters;
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that compound (V) is selected from: 2-(glycyl glycyl glycyl) amidomalonic acid dimethyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid diisopropyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid di-n-butyl, 2-(glycyl glycyl glycyl) amidomalonic acid diisobutyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate, 2-(glycyl glycyl glycyl) amidomalonic acid di-secondary butyl ester, 2-(glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters, 2-(glycyl glycyl glycyl) amidomalonic acid diisoamyl ester, a kind of in 2-(glycyl glycyl glycyl) amidomalonic acid two tert-pentyl esters;
The preparation method of described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I), further represent with chemical equation:
Figure G2009102132574D00081
Wherein: R=(C 1-C 5) alkyl
Described 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I), its preparation method comprises:
(a) amidomalonic acid ester (II), acetonitrile, I-hydroxybenzotriazole (HOBT) are mixed with compound (III), cooling, gradation adds dicyclohexylcarbodiimide (DCC), behind the room temperature reaction 10～30 hours, the solid that filtering is separated out concentrates and removes solvent, adds diethyl ether and separates out solid, filter, drying makes compound (IV);
Wherein amidomalonic acid ester (II) is 1: 0.1～0.3 with I-hydroxybenzotriazole (HOBT) mol ratio; Amidomalonic acid ester (II) is 1: 0.75～1.0 with compound (III) mol ratio; Amidomalonic acid ester (II) is 1: 1 with the dicyclohexylcarbodiimide mol ratio;
(b) with above-claimed cpd (IV), wherein blocking group P is a 9-fluorenylmethyloxycarbonyl, and room temperature reaction is after 15～60 minutes in dimethyl formamide with anhydrous piperidines, and adding diethyl ether separates out solid, filters, and drying makes compound (V); Wherein compound (IV) is 1: 3～5 with the mol ratio of anhydrous piperidines; Dimethyl formamide and ether volume ratio are: 1: 8～12;
Or with above-claimed cpd (IV), wherein blocking group P is a tertbutyloxycarbonyl, in methylene dichloride with trifluoroacetic acid room temperature reaction 25～40 hours, cooling, filter, the gained solid in water with reaction of sodium bicarbonate, ethyl acetate extraction, drying is filtered, distill compound (V); Wherein compound (IV) is 1: 2～5 with the mol ratio of trifluoroacetic acid; Compound (IV) is 1: 1～3 with the mol ratio of sodium bicarbonate.
(c) compound (V), 2-methacrylic acid, acetonitrile are mixed with I-hydroxybenzotriazole (HOBT); cooling; gradation adds dicyclohexylcarbodiimide (DCC); behind the room temperature reaction 10～30 hours; the solid that filtering is separated out concentrates and removes solvent, adds diethyl ether and separates out solid; filter, drying makes 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I).
Wherein compound (V) is 1: 0.1～0.3 with I-hydroxybenzotriazole (HOBT) mol ratio; Compound (V) is 1: 1～1.5 with 2-methacrylic acid mol ratio; 2-methacrylic acid and dicyclohexylcarbodiimide mol ratio are 1: 1;
Described a kind of 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) preferred compound is: 2-(2-methacryloyl amido three glycyl) amidomalonic acid diethyl ester, its molecular formula is: C 17H 26N 4O 8,
Figure G2009102132574D00091
Described a kind of 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is used for the preparation of amino malonate platinum complex compound Prolindac.Be expressed as follows with chemical equation:
Figure G2009102132574D00101
Figure G2009102132574D00111
R=(C wherein 1-C 5) alkyl,
AIBN is the abbreviation of Diisopropyl azodicarboxylate, and BPO is the abbreviation of dibenzoyl peroxide.
2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is used to prepare amino malonate platinum complex compound Prolindac; the preparation method is easy; synthesis step is short; the yield height; prepared amino malonate platinum complex compound Prolindac constant product quality is easy to suitability for industrialized production.The production cost that the amino malonate platinum complex compound Prolindac that adopts the present invention to prepare is used for preparation is lower, can reduce the medical expense of tumour patient to a great extent, has certain social benefit and economic benefit.
Description of drawings
The invention will be further described below in conjunction with accompanying drawing;
Fig. 1 is the molecular gel color atlas of polymethyl acrylic acid hydroxypropyl ester group-three glycyl amidomalonic acid diethyl ester (claiming AP5195 again);
Fig. 2 is the molecular gel color atlas of amino malonate platinum complex compound Prolindac;
Molecular gel color atlas detection method is:
Figure G2009102132574D00121
The HPLC system is furnished with RID differential detector, PLAquagel-OH Mixed-H chromatographic column, and moving phase is: methyl alcohol: 10mM lithium perchlorate (35/65).Accompanying drawing shows does not have other polymeric impurities among prepared polymethyl acrylic acid hydroxypropyl ester group-three glycyl amidomalonic acid diethyl ester and the amino malonate platinum complex compound Prolindac.
Embodiment
Further specify the present invention below by embodiment.Should correct understanding be: the method in the embodiments of the invention is only used for the present invention is described and provides, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
The abbreviation explanation of describing among the following embodiment:
Fmoc is the abbreviation of 9-fluorenylmethyloxycarbonyl,
Boc is the abbreviation of tertbutyloxycarbonyl,
DCC is the abbreviation of dicyclohexylcarbodiimide,
AIBN is the abbreviation of Diisopropyl azodicarboxylate,
BPO is the abbreviation of dibenzoyl peroxide,
HOBT is the abbreviation of I-hydroxybenzotriazole,
AME is the abbreviation of amidomalonic acid ester.
Embodiment 1:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diethyl ester
(1) preparation of 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid diethyl ester
In reaction flask, drop into amidomalonic acid diethyl ester hydrochloride 21.2g (0.1mol) and 40ml deionized water, slowly add 11.5 gram (0.14mol) sodium bicarbonate powder after the stirring and dissolving, there are a large amount of bubbles to emit, added the back stirring reaction 20 minutes, ethyl acetate (50ml*3) extraction merges organic layer, dry, remove by filter siccative, concentrating under reduced pressure removes and desolvates, and gets amidomalonic acid diethyl ester (stand-by).
In another reaction flask, drop into 2g I-hydroxybenzotriazole (HOBT) (0.015mol), acetonitrile 800ml, previously prepared amidomalonic acid diethyl ester (0.1mol) and 37 restrain Fmoc-glycyl glycyl glycine (0.09mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 20.6g dicyclohexylcarbodiimide (DCC; 0.1mol), temperature control is below 5 ℃.Added the back room temperature reaction 25 hours.The solid that filtration is separated out concentrates and removes the stirring that adds diethyl ether of desolvating, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get white solid 46g, yield 89.9%.
Ultimate analysis:
Calcd(C 28H 32N 4O 9)：C，59.15；H，5.67；N，9.85。
Found(C 28H 32N 4O 9)：C，59.02；H，5.69；N，9.92。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester
Go on foot product 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid diethyl ester 50g (0.088mol), anhydrous piperidines 30g (0.35mol) and dimethyl formamide 200ml in reaction flask, dropping into; stir; room temperature reaction 40 minutes; slowly add the 2000ml ether in reaction flask, have a large amount of solids to separate out, stirring makes its crystallization complete half an hour; filter; the washing of filter cake ether, drying under reduced pressure gets 24g off-white color solid, yield 78.7%.
Ultimate analysis:
Calcd(C 13H 22N 4O 7)：C，45.08；H，6.40；N，16.18。
Found(C 13H 22N 4O 7)：C，45.11；H，6.29；N，16.22。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diethyl ester
In reaction flask, drop into 1.35 gram HOBt (0.01mol), acetonitrile 300ml, 17.3 grams upward step product 2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester (0.05mol) and 2-methacrylic acid 5.2 grams (0.06mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3 gram DCC (0.05mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out, the concentrated 100ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get the 17.8g white solid, yield 85.9%.
Fusing point: 175～180 ℃
Ultimate analysis:
Calcd(C 17H 26N 4O 8)：C，49.27；H，6.32；N，13.52。
Found(C 17H 26N 4O 8)：C，49.18；H，6.30；N，13.56。
NMR(DMSO-d6)：1.18～1.23(m，6H)，1.88(s，3H)，3.72～3.85(m，6H)，4.16～4.24(m，4H)，5.18(d，1H)，5.40(s，1H)，5.80(s，1H)，8.06～8.21(m，3H)，8.78～8.83(d，1H)。
Embodiment 2:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diethyl ester
(1) preparation of 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diethyl ester
In reaction flask, drop into amidomalonic acid diethyl ester hydrochloride 318g (1.5mol) and 700ml deionized water, stir and slowly add 161 gram (1.92mol) sodium bicarbonate powder down, added the back stirring reaction 20 minutes, ethyl acetate (800ml*3) extraction, merge organic layer, drying removes by filter siccative, concentrating under reduced pressure removes and desolvates, and gets the amidomalonic acid diethyl ester.
In a reactor, drop into 30g I-hydroxybenzotriazole (HOBT) (0.22mol), acetonitrile 12L, previously prepared amidomalonic acid diethyl ester (1.5mol) and 389 restrain Boc-glycyl glycyl glycine (1.35mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 309g dicyclohexylcarbodiimide (1.5mol), temperature control is below 5 ℃.Added the back room temperature reaction 30 hours.The solid that filtration is separated out, the concentrated 4000ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get solid 519g, yield 86.1%.
Ultimate analysis:
Calcd(C 18H 30N 4O 9)：C，48.42；H，6.77；N，12.55。
Found(C 18H 30N 4O 9)：C，48.07；H，6.72；N，12.61。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester
In reaction flask, drop into and go on foot product 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diethyl ester (0.09mol) and methylene dichloride 200ml on the 40.2g; stir and slowly add trifluoroacetic acid 41g (0.36mol) down; stirring at room reaction 35 hours; there are a large amount of solids to separate out; be cooled to 0 ℃, make its crystallization complete, filter; the washing of filter cake ether, 40 ℃ of drying under reduced pressure 6h get 2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester trifluoroacetate.
2-(glycyl glycyl glycyl) amidomalonic acid diethyl ester trifluoroacetate is mixed stirring with 50ml water; slowly add 15g sodium bicarbonate powder (0.18mol); added the back stirring reaction 20 minutes; ethyl acetate (60ml*3) extraction; merge organic layer, drying removes by filter siccative; 40 ℃ of concentrating under reduced pressure remove desolvate solid 23.7g, yield 76%.
Ultimate analysis:
Calcd(C 13H 22N 4O 7)：C，45.08；H，6.40；N，16.18。
Found(C 13H 22N 4O 7)：C，45.01；H，6.33；N，16.12。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diethyl ester
In reaction flask, drop into 0.86 gram HOBt (0.064mol), acetonitrile 300ml, 22 gram 2-(glycyl glycyl glycyl) amidomalonic acid diethyl esters (0.064mol) and 2-methacrylic acid 5.5 grams (0.064mol); nitrogen protection; be cooled to 0 degree left and right sides gradation and add 13.2 gram DCC (0.064mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 30 hours.The solid that filtration is separated out concentrates and removes the stirring that adds diethyl ether of desolvating, and separates out solid, filters, and 40 ℃ of drying under reduced pressure get the 23.9g white solid, yield 90.1%.
Fusing point: 176～179 ℃.
Ultimate analysis:
Calcd(C 17H 26N 4O 8)：C，49.27；H，6.32；N，13.52。
Found(C 17H 26N 4O 8)：C，49.17；H，6.26；N，13.48。
Embodiment 3:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid dimethyl ester
(1) preparation of 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid dimethyl ester
In reaction flask, drop into amidomalonic acid dimethyl ester hydrochloride 14.7g (0.1mol) and 40ml deionized water, slowly add 12.6 gram (0.15mol) sodium bicarbonate powder after the stirring and dissolving, there are a large amount of bubbles to emit, added the back stirring reaction 20 minutes, ethyl acetate (50ml*3) extraction merges organic layer, dry, remove by filter siccative, concentrating under reduced pressure removes and desolvates, and gets amidomalonic acid dimethyl ester (stand-by).
In another reaction flask, drop into 1.35g I-hydroxybenzotriazole (HOBT) (0.01mol), acetonitrile 800ml, amidomalonic acid dimethyl ester (0.1mol) and 30.8 restrain Fmoc-glycyl glycyl glycine (0.075mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 20.6g dicyclohexylcarbodiimide (0.1mol), temperature control is below 5 ℃.Added the back room temperature reaction 10 hours.The solid that filtration is separated out, the concentrated 200ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get pale solid 30.4g, yield 75%.
Ultimate analysis:
Calcd(C 26H 28N 4O 9)：C，57.77；H，5.22；N，10.37。
Found(C 26H 28N 4O 9)：C，57.56；H，5.17；N，10.29。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid dimethyl ester
Go on foot product 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid dimethyl ester 27g (0.05mol), anhydrous piperidinyl-1 2.8g (0.15mol) and dimethyl formamide 110ml in reaction flask, dropping into; stir; room temperature reaction 15 minutes; in reaction flask, slowly add the 880ml ether, have a large amount of solids to separate out, stir 30min and make its crystallization complete; filter; the washing of filter cake ether, drying under reduced pressure gets 11.7g off-white color solid, yield 73.5%.
Ultimate analysis:
Calcd(C 11H 18N 4O 7)：C，41.51；H，5.70；N，17.60。
Found(C 11H 18N 4O 7)：C，41.44；H，5.55；N，17.51。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid dimethyl ester
In reaction flask, drop into 0.81 gram HOBt (0.006mol), acetonitrile 80ml, 6.4 grams upward step product 2-(glycyl glycyl glycyl) amidomalonic acid dimethyl ester (0.02mol) and 2-methacrylic acid 2.6 grams (0.03mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 4.13 gram DCC (0.02mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 10 hours.The solid that filtration is separated out, the concentrated 60ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get the 6.5g white solid, yield 84.1%.
Fusing point: 155～159 ℃
Ultimate analysis:
Calcd(C 15H 22N 4O 8)：C，46.63；H，5.74；N，14.50。
Found(C 15H 22N 4O 8)：C，46.61；H，5.55；N，14.44。
Embodiment 4:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester
(1) preparation of 2-(Boc-glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester
In reaction flask, drop into amidomalonic acid di-n-propyl ester hydrochloride 12g (0.05mol) and 80ml deionized water, stir and slowly add 8.4 gram (0.1mol) sodium bicarbonate powder down, added the back stirring reaction 30 minutes, ethyl acetate (100ml*3) extraction, merge organic layer, drying removes by filter siccative, concentrating under reduced pressure removes and desolvates, and gets the amidomalonic acid di-n-propyl ester.
In a reactor, drop into 2g I-hydroxybenzotriazole (HOBT) (0.015mol), acetonitrile 150mL, previously prepared amidomalonic acid di-n-propyl ester (0.05mol) and 14.4 restrain Boc-glycyl glycyl glycine (0.05mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3g dicyclohexylcarbodiimide (0.05mol), temperature control is below 5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out, the concentrated 50ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get solid 19g, yield 80.2%.
Ultimate analysis:
Calcd(C 20H 34N 4O 9)：C，50.62；H，7.22；N，11.81。
Found(C 20H 34N 4O 9)：C，50.45；H，7.16；N，11.77。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester
In reaction flask, drop into and go on foot product 2-(Boc-glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester (0.038mol) and methylene dichloride 150ml on the 18g; stir and slowly add trifluoroacetic acid 8.7g (0.076mol) down; stirring at room reaction 25 hours; there is solid to separate out; be cooled to 0 ℃, make its crystallization complete, filter; the washing of filter cake ether, 40 ℃ of drying under reduced pressure 6h get 2-(glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester trifluoroacetate.
2-(glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester trifluoroacetate is mixed stirring with 50ml water; slowly add 3.2g sodium bicarbonate powder (0.038mol); added the back stirring reaction 15 minutes; ethyl acetate (60ml*3) extraction; merge organic layer, drying removes by filter siccative; 40 ℃ of concentrating under reduced pressure remove desolvate solid 11.2g, yield 79%.
Ultimate analysis:
Calcd(C 15H 26N 4O 7)：C，48.12；H，7.00；N，14.96。
Found(C 15H 26N 4O 7)：C，47.97；H，6.92；N，14.87。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid di-n-propyl ester
In reaction flask, drop into 0.81 gram HOBt (0.006mol), acetonitrile 100ml, 11 gram 2-(glycyl glycyl glycyl) amidomalonic acid di-n-propyl esters (0.03mol) and 2-methacrylic acid 3.1 grams (0.036mol); nitrogen protection; be cooled to 0 degree left and right sides gradation and add 6.2 gram DCC (0.03mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 15 hours.The solid that filtration is separated out, the concentrated 50ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure get the 11g white solid, yield 82.9%.
Ultimate analysis:
Calcd(C 19H 30N 4O 8)：C，51.58；H，6.83；N，12.66。
Found(C 19H 30N 4O 8)：C，51.48；H，6.81；N，12.59。
Embodiment 5:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisopropyl ester
(1) preparation of 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diisopropyl ester
In reaction flask, drop into amidomalonic acid diisopropyl ester hydrochloride 24g (0.1mol) and 150ml deionized water, stir and slowly add 16.8 gram (0.2mol) sodium bicarbonate powder down, added the back stirring reaction 30 minutes, ethyl acetate (200ml*3) extraction, merge organic layer, drying removes by filter siccative, concentrating under reduced pressure removes and desolvates, and gets the amidomalonic acid diisopropyl ester.
In a reactor, drop into 2.7g I-hydroxybenzotriazole (HOBT) (0.02mol), acetonitrile 300mL, previously prepared amidomalonic acid diisopropyl ester (0.1mol) and 23 restrain Boc-glycyl glycyl glycine (0.08mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 20.6g dicyclohexylcarbodiimide (0.1mol), temperature control is below 5 ℃.Added the back room temperature reaction 15 hours.The solid that filtration is separated out, the concentrated 100ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get solid 35g, yield 73.8%.
Ultimate analysis:
Calcd(C 20H 34N 4O 9)：C，50.62；H，7.22；N，11.81。
Found(C 20H 34N 4O 9)：C，50.52；H，7.19；N，11.72。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid diisopropyl ester
In reaction flask, drop into and go on foot product 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diisopropyl ester (0.05mol) and methylene dichloride 300ml on the 23.7g; stir and slowly add trifluoroacetic acid 28.5g (0.25mol) down; stirring at room reaction 40 hours; there is solid to separate out; be cooled to 0 ℃, make its crystallization complete, filter; the washing of filter cake ether, 40 ℃ of drying under reduced pressure 6h get 2-(glycyl glycyl glycyl) amidomalonic acid diisopropyl ester trifluoroacetate.
2-(glycyl glycyl glycyl) amidomalonic acid diisopropyl ester trifluoroacetate is mixed stirring with 100ml water; slowly add 12.6g sodium bicarbonate powder (0.15mol); added the back stirring reaction 20 minutes; ethyl acetate (100ml*3) extraction; merge organic layer, drying removes by filter siccative; 40 ℃ of concentrating under reduced pressure remove desolvate solid 14.2g, yield 75.9%.
Ultimate analysis:
Calcd(C 15H 26N 4O 7)：C，48.12；H，7.00；N，14.96。
Found(C 15H 26N 4O 7)：C，48.05；H，6.98；N，14.82。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisopropyl ester
In reaction flask, drop into 0.81 gram HOBt (0.006mol), acetonitrile 100ml, 11 gram 2-(glycyl glycyl glycyl) amidomalonic acid diisopropyl esters (0.03mol) and 2-methacrylic acid 3.4 grams (0.039mol); nitrogen protection; be cooled to 0 degree left and right sides gradation and add 6.2 gram DCC (0.03mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out, the concentrated 50ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure get the 11.5g white solid, yield 86.6%.
Ultimate analysis:
Calcd(C 19H 30N 4O 8)：C，51.58；H，6.83；N，12.66。
Found(C 19H 30N 4O 8)：C，51.52；H，6.79；N，12.61。
Embodiment 6:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate
(1) preparation of 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate drops into amidomalonic acid di tert butyl carbonate hydrochloride 13.4g (0.05mol) and 40ml deionized water in reaction flask; slowly add 8.4 gram (0.1mol) sodium bicarbonate powder after the stirring and dissolving; there are a large amount of bubbles to emit; added the back stirring reaction 20 minutes; ethyl acetate (50ml*3) extraction; merge organic layer; dry; remove by filter siccative; concentrating under reduced pressure removes and desolvates, and gets amidomalonic acid di tert butyl carbonate (stand-by).
In another reaction flask, drop into 1.35g I-hydroxybenzotriazole (HOBT) (0.01mol), acetonitrile 500ml, previously prepared amidomalonic acid di tert butyl carbonate (0.05mol) and 16.4 restrain Fmoc-glycyl glycyl glycine (0.04mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3g dicyclohexylcarbodiimide (0.05mol), temperature control is below 5 ℃.Added the back room temperature reaction 24 hours.The solid that filtration is separated out, the concentrated 60ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get pale solid 26.1g, yield 83.7%.
Ultimate analysis:
Calcd(C 32H 40N 4O 9)：C，61.47；H，6.45；N，8.97。
Found(C 32H 40N 4O 9)：C，60.47；H，6.42；N，8.92。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate
Go on foot product 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate 25g (0.04mol), anhydrous piperidinyl-1 7g (0.2mol) and dimethyl formamide 120ml in reaction flask, dropping into; stir; room temperature reaction 1 hour; in reaction flask, slowly add the 1440ml ether, have a large amount of solids to separate out, stir 30min and make its crystallization complete; filter; the washing of filter cake ether, drying under reduced pressure gets 12.1g off-white color solid, yield 75.2%.
Ultimate analysis:
Calcd(C 17H 30N 4O 7)：C，50.74；H，7.51；N，13.92。
Found(C 17H 30N 4O 7)：C，50.58；H，7.46；N，13.85。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate
In reaction flask, dropped into 0.81 gram HOBt (0.006mol), acetonitrile 100ml, 8g product 2-of last step (glycyl glycyl glycyl) amidomalonic acid di tert butyl carbonate (0.02mol) and 2-methacrylic acid 2.1 grams (0.024mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 4.1 gram DCC (0.02mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 10 hours.The solid that filtration is separated out, the concentrated 50ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get the 8.6g white solid, yield 76.3%.
Ultimate analysis:
Calcd(C 21H 34N 4O 8)：C，53.61；H，7.28；N，11.91。
Found(C 21H 34N 4O 8)：C，53.52；H，7.14；N，11.86。
Embodiment 7:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisobutyl ester
(1) preparation of 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diisobutyl ester drops into amidomalonic acid diisobutyl ester hydrochloride 13.4g (0.05mol) and 40ml deionized water in reaction flask; slowly add 8.4 gram (0.1mol) sodium bicarbonate powder after the stirring and dissolving; there are a large amount of bubbles to emit; added the back stirring reaction 20 minutes, ethyl acetate (50ml*3) extraction merges organic layer; dry; remove by filter siccative, concentrating under reduced pressure removes and desolvates, and gets the amidomalonic acid diisobutyl ester.
In a reactor, drop into 2.0 gram I-hydroxybenzotriazoles (HOBT) (0.015mol), acetonitrile 400mL, previously prepared amidomalonic acid diisobutyl ester (0.05mol) and 11.5 restrain Boc-glycyl glycyl glycine (0.04mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3g dicyclohexylcarbodiimide (0.05mol), temperature control is below 5 ℃.Added the back room temperature reaction 25 hours.The solid that filtration is separated out, the concentrated 40ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get solid 14.8g, yield 73.5%.
Ultimate analysis:
Calcd(C 22H 38N 4O 9)：C，52.58；H，7.62；N，11.15。
Found(C 22H 38N 4O 9)：C，52.46；H，7.53；N，11.10。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid diisobutyl ester
In reaction flask, drop into and go on foot product 2-(Boc-glycyl glycyl glycyl) amidomalonic acid diisobutyl ester (0.02mol) and methylene dichloride 100ml on the 10g; stir and slowly add trifluoroacetic acid 6.8g (0.06mol) down; stirring at room reaction 30 hours; there are a large amount of solids to separate out; be cooled to 0 ℃, make its crystallization complete, filter; the washing of filter cake ether, 40 ℃ of drying under reduced pressure 6h get 2-(glycyl glycyl glycyl) amidomalonic acid diisobutyl ester trifluoroacetate.
2-(glycyl glycyl glycyl) amidomalonic acid diisobutyl ester trifluoroacetate is mixed stirring with 50ml water; slowly add 3.4g sodium bicarbonate powder (0.04mol); added the back stirring reaction 30 minutes; ethyl acetate (60ml*3) extraction; merge organic layer, drying removes by filter siccative; 40 ℃ of concentrating under reduced pressure remove desolvate solid 5.6g, yield 69.6%.
Ultimate analysis:
Calcd(C 17H 30N 4O 7)：C，50.74；H，7.51；N，13.92。
Found(C 17H 30N 4O 7)：C，50.66；H，7.44；N，13.93。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisobutyl ester
In reaction flask, drop into 0.38 gram HOBt (2.8mmol), acetonitrile 80ml, 5.5 gram 2-(glycyl glycyl glycyl) amidomalonic acid diisobutyl esters (0.014mol) and 2-methacrylic acid 1.7 grams (0.02mol); nitrogen protection; be cooled to 0 degree left and right sides gradation and add 2.9 gram DCC (0.014mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out concentrates and removes the stirring that adds diethyl ether of desolvating, and separates out solid, filters, and 40 ℃ of drying under reduced pressure get the 5.6g white solid, yield 85.5%.
Ultimate analysis:
Calcd(C 21H 34N 4O 8)：C，53.61；H，7.28；N，11.91。
Found(C 21H 34N 4O 8)：C，52.99；H，7.25；N，11.84。
Embodiment 8:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisoamyl ester
(1) preparation of 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid diisoamyl ester
In reaction flask, drop into amidomalonic acid diisoamyl ester hydrochloride 14.8g (0.05mol) and 60ml deionized water, slowly add 8.4 gram (0.1mol) sodium bicarbonate powder after the stirring and dissolving, there are a large amount of bubbles to emit, added the back stirring reaction 20 minutes, ethyl acetate (80ml*3) extraction merges organic layer, dry, remove by filter siccative, concentrating under reduced pressure removes and desolvates, and gets amidomalonic acid diisoamyl ester (stand-by).
In another reaction flask, drop into 1.35g I-hydroxybenzotriazole (HOBT) (0.01mol), acetonitrile 500ml, previously prepared amidomalonic acid diisoamyl ester (0.05mol) and 16.4 restrain Fmoc-glycyl glycyl glycine (0.04mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3g dicyclohexylcarbodiimide (0.05mol), temperature control is below 5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out, the concentrated 60ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get pale solid 26.2g, yield 80.2%.
Ultimate analysis:
Calcd(C 34H 44N 4O 9)：C，62.56；H，6.79；N，8.58。
Found(C 34H 44N 4O 9)：C，62.49；H，6.66；N，8.49。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid diisoamyl ester
Go on foot product 2-(Fmoc-glycyl glycyl glycyl) amidomalonic acid diisoamyl ester 26.1g (0.04mol), anhydrous piperidinyl-1 3.6g (0.16mol) and dimethyl formamide 120ml in reaction flask, dropping into; stir; room temperature reaction 30min; in reaction flask, slowly add the 1200ml ether, have a large amount of solids to separate out, stir 30min and make its crystallization complete; filter; the washing of filter cake ether, drying under reduced pressure gets 12.6g off-white color solid, yield 73.2%.
Ultimate analysis:
Calcd(C 19H 34N 4O 7)：C，53.01；H，7.96；N，13.01。
Found(C 19H 34N 4O 7)：C，52.95；H，7.88；N，12.94。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisoamyl ester
In reaction flask, dropped into 0.76 gram HOBt (5.6mmol), acetonitrile 120ml, 12g product 2-of last step (glycyl glycyl glycyl) amidomalonic acid diisoamyl ester (0.028mol) and 2-methacrylic acid 2.9 grams (0.034mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 5.8 gram DCC (0.028mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 10 hours.The solid that filtration is separated out, the concentrated 80ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 4h get the 11g white solid, yield 79.5%.
Ultimate analysis:
Calcd(C 23H 38N 4O 8)：C，55.41；H，7.68；N，11.24。
Found(C 23H 38N 4O 8)：C，55.33；H，7.62；N，11.19。
Embodiment 9:
The preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters
(1) preparation of 2-(Boc-glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters
In reaction flask, drop into amidomalonic acid two n-pentyl ester hydrochloride 14.8g (0.05mol) and 40ml deionized waters, slowly add 8.4 gram (0.1mol) sodium bicarbonate powder after the stirring and dissolving, there are a large amount of bubbles to emit, added the back stirring reaction 20 minutes, ethyl acetate (50ml*3) extraction merges organic layer, dry, remove by filter siccative, concentrating under reduced pressure removes and desolvates, and gets amidomalonic acid two n-pentyl esters.
In a reactor, drop into 2.0 gram I-hydroxybenzotriazoles (HOBT) (0.015mol), acetonitrile 400mL, previously prepared amidomalonic acid two n-pentyl esters (0.05mol) and 11.5 restrain Boc-glycyl glycyl glycine (0.04mol); nitrogen protection; be cooled to 0 ℃ of left and right sides gradation and add 10.3g dicyclohexylcarbodiimide (0.05mol), temperature control is below 5 ℃.Added the back room temperature reaction 25 hours.The solid that filtration is separated out, the concentrated 40ml ether that adds except that desolvating stirs, and separates out solid, filters, and 40 ℃ of drying under reduced pressure 6h get solid 20.2g, yield 76.1%.
Ultimate analysis:
Calcd(C 24H 42N 4O 9)：C，54.33；H，7.98；N，10.56。
Found(C 24H 42N 4O 9)：C，54.28；H，7.84；N，10.47。
(2) preparation of 2-(glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters
In reaction flask, drop into and go on foot product 2-(Boc-glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters (0.038mol) and methylene dichloride 200ml on the 20g; stir and slowly add trifluoroacetic acid 17.1g (0.15mol) down; stirring at room reaction 30 hours; there are a large amount of solids to separate out; be cooled to 0 ℃, make its crystallization complete, filter; the washing of filter cake ether, 40 ℃ of drying under reduced pressure 6h get 2-(glycyl glycyl glycyl) amidomalonic acid two n-pentyl ester trifluoroacetates.
2-(glycyl glycyl glycyl) amidomalonic acid two n-pentyl ester trifluoroacetates are mixed stirring with 100ml water; slowly add 6.7g sodium bicarbonate powder (0.08mol); added the back stirring reaction 30 minutes; ethyl acetate (100ml*3) extraction; merge organic layer, drying removes by filter siccative; 40 ℃ of concentrating under reduced pressure remove desolvate solid 12g, yield 73.6%.
Ultimate analysis:
Calcd(C 17H 30N 4O 7)：C，50.74；H，7.51；N，13.92。
Found(C 17H 30N 4O 7)：C，50.66；H，7.44；N，13.93。
(3) preparation of 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters
In reaction flask, drop into 0.38 gram HOBt (2.8mmol), acetonitrile 80ml, 5.5 gram 2-(glycyl glycyl glycyl) amidomalonic acid two n-pentyl esters (0.014mol) and 2-methacrylic acid 1.7 grams (0.02mol); nitrogen protection; be cooled to 0 degree left and right sides gradation and add 2.9 gram DCC (0.014mol), temperature control is at 0～5 ℃.Added the back room temperature reaction 20 hours.The solid that filtration is separated out concentrates and removes the stirring that adds diethyl ether of desolvating, and separates out solid, filters, and 40 ℃ of drying under reduced pressure get the 5.6g white solid, yield 85.5%.
Ultimate analysis:
Calcd(C 23H 38N 4O 8)：C，55.41；H，7.68；N，11.24。
Found(C 23H 38N 4O 8)：C，55.40；H，7.60；N，11.20。
Embodiment 10:
The preparation (AP5195) of polymethyl acrylic acid hydroxypropyl ester group-three glycyl-amidomalonic acid diethyl ester drops into 57.6g Rocryl 410 (HPMA in reaction flask; 0.4mol), press 10.4 gram 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diethyl esters (0.025mol), the 250mL dry toluene of embodiment 1 preparation; add 1.21g benzoyl peroxide (BPO behind the stirring and evenly mixing; 0.005mol); 85 ℃ of lucifuges were reacted 20 hours, and solid is separated out in cooling.Concentrate and remove most of solvent after-filtration, filter cake is with the making beating of 150ml ethyl acetate and stir 1 hour (removing toluene and small amount of impurities) as far as possible, filters, and the filter cake drying under reduced pressure gets white 54.8 grams.Yield 80.6%.
Prepared product is through the gel chromatography analysis, and color atlas is seen accompanying drawing 1.
Detection method:
Figure G2009102132574D00251
The HPLC system is furnished with RID differential detector, PL Aquagel-OHMixed-H chromatographic column, and moving phase is: MeOH: 10mMLiClO 4(35/65).
Embodiment 11:
The preparation of amino malonate platinum complex compound Prolindac (AP5346)
In the reaction flask of 50ml, drop into 2.8 gram (6.44mol) cyclohexanediamine nitros and close platinum DACHPt (NO 3) 2, 26mL water and 0.2mL5% nitric acid, wrap up reaction flask (lucifuge) with aluminium foil, be heated to 70 ℃ of reactions 1 hour, a clear liquor, cool to room temperature is standby.
In another reaction flask, drop on 10.0 grams and go on foot reaction product (5.066mmol Ame, embodiment 10) and 56.6ml water, transfer PH to 12.6 with the 2mol/L sodium hydroxide solution, kept this pH value normal-temperature reaction 30 minutes, pH value is motionless substantially, and PH to 7.4 is transferred in hydrolysis back 5% nitric acid fully, with 0.22 μ m membrane filtration, filtrate moves on in the reaction flask, adds above-mentioned reserve liquid under the vigorous stirring.PH value drops to 4.8, transfer PH to 5.2 with the 2mol/L sodium hydroxide solution, and keep this pH value to react 2 hours, transfer PH to 7.4 with the 2mol/L sodium hydroxide solution, be warmed up to 38 ℃, insulation reaction is 17 hours under this pH value, 0.22 this reaction solution of μ m filtering with microporous membrane, filtrate is flow through filter equipment purifying with cut, and (seeing through volume is 5 times of amounts), the refined solution thin up adds 1.1688 gram (20mmol) sodium-chlor, 1.56 gram (6.4mmol) Sodium phosphate dibasic (Na to 100mL 2HPO 4.7H 2O) and 0.2208 gram (1.6mmol) SODIUM PHOSPHATE, MONOBASIC (NaH 2PO 4.H2O), stirring and dissolving is transferred PH to 7.4, and is heated to 38 ℃, this PH is incubated 38 ℃ of standing and reacting 4.5 hours down, the membrane filtration of 0.22 μ m, filtrate cut stream purifying, (seeing through volume is 7 times of amounts), gained solution gets 8.95 gram off-white color solids, yield 76.3% through freeze-drying.
Prepared product is seen accompanying drawing 2 through the gel chromatography analysis.Detection method is with embodiment 10.
Embodiment 12:
The preparation of polymethyl acrylic acid hydroxypropyl ester group-three glycyl-amidomalonic acid diisopropyl ester
In reaction flask, drop into 77.8g Rocryl 410 (HPMA; 0.54mol), press 2-(2-methacryloyl amido glycyl glycyl glycyl) amidomalonic acid diisopropyl ester 15 gram (0.034mol), the 300mL dry toluenes of embodiment 5 preparation; add 0.8g Diisopropyl azodicarboxylate (AIBN behind the stirring and evenly mixing; 0.005mol); 85 ℃ of lucifuges were reacted 18 hours, and solid is separated out in cooling.Concentrate and remove most of solvent after-filtration, filter cake is with the making beating of 250ml ethyl acetate and stir 1 hour (removing toluene and small amount of impurities) as far as possible, filters, and the filter cake drying under reduced pressure gets white 78 grams, yield 84.1%.
Embodiment 13:
The preparation of amino malonate platinum complex compound Prolindac (AP5346)
In the reaction flask of 50ml, drop into 13.4 gram (0.031mmol) cyclohexanediamine nitros and close platinum DACHPt (NO 3) 2, 125mL water and 1mL5% nitric acid, wrap up reaction flask (lucifuge) with aluminium foil, be heated to 70 ℃ of reactions 1 hour, a clear liquor, cool to room temperature is standby.
In another reaction flask, drop into 48 gram polymethyl acrylic acid hydroxypropyl ester group-three glycyl-amidomalonic acid diisopropyl ester (0.024mol Ame; embodiment 12) and 270ml water; transfer PH to 12.6 with the 2mol/L sodium hydroxide solution; kept this pH value normal-temperature reaction 30 minutes; pH value is motionless substantially, and PH to 7.4 is transferred in hydrolysis back 5% nitric acid fully, with 0.22 μ m membrane filtration; filtrate moves on in the reaction flask, adds above-mentioned reserve liquid under the vigorous stirring.PH value drops to 4.8, transfer PH to 5.2 with the 2mol/L sodium hydroxide solution, and keep this pH value to react 2 hours, transfer PH to 7.4 with the 2mol/L sodium hydroxide solution, be warmed up to 38 ℃, insulation reaction is 17 hours under this pH value, 0.22 this reaction solution of μ m filtering with microporous membrane, filtrate is flow through filter equipment purifying with cut, and (seeing through volume is 5 times of amounts), the refined solution thin up adds 5.61 gram (0.096mol) sodium-chlor, 7.49 gram (60.04mol) Sodium phosphate dibasic (Na to 200mL 2HPO 4.7H 2O) and 1.06 gram (7.7mmol) SODIUM PHOSPHATE, MONOBASIC (NaH 2PO 4.H 2O), stirring and dissolving is transferred PH to 7.4, and is heated to 38 ℃, this PH is incubated 38 ℃ of standing and reacting 4.5 hours down, the membrane filtration of 0.22 μ m, filtrate cut stream purifying, (seeing through volume is 7 times of amounts), gained solution gets 39.5 gram off-white color solids, yield 70% through freeze-drying.

Claims (6)

1. 2-(2-methacryloyl amido three glycyl) the amidomalonic acid ester cpds (I) of a kind as following structural formula
Figure FSB00000582920500011
R=(C wherein 1～C 5) alkyl (I).
2. 2-according to claim 1 (2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that it is selected from compound: 2-(2-methacryloyl amido three glycyl) amidomalonic acid dimethyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diethyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-n-propyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisopropyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-n-butyl; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisobutyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di tert butyl carbonate; 2-(2-methacryloyl amido three glycyl) amidomalonic acid di-secondary butyl ester; 2-(2-methacryloyl amido three glycyl) amidomalonic acid two n-pentyl esters; 2-(2-methacryloyl amido three glycyl) amidomalonic acid diisoamyl ester; a kind of in 2-(2-methacryloyl amido three glycyl) amidomalonic acid two tert-pentyl esters.
3. the preparation method of the described 2-of claim 1 (2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that comprising:
(a) be raw material with the amidomalonic acid ester (II) as following structural formula, compound (III) reaction with as following structural formula makes the compound (IV) as following structural formula;
Amidomalonic acid ester (II) structural formula (II)
R=(C wherein 1～C 5) alkyl;
The structural formula of compound (III) is:
Figure FSB00000582920500022
Wherein P is 9-fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (Boc) protection;
The structural formula of compound (IV) is:
Figure FSB00000582920500023
Wherein P is 9-fluorenylmethyloxycarbonyl (Fmoc) or tertbutyloxycarbonyl (Boc) protection, R=(C 1～C 5) alkyl;
(b) make compound (IV) further deprotection reaction make compound (V) as following structural formula
The structural formula of compound (V) is:
Figure FSB00000582920500024
R=(C wherein 1～C 5) alkyl (V)
(c) make compound (V) and 2-methacrylic acid carry out condensation reaction and make 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I)
R=(C wherein 1～C 5) alkyl.(I)
4. according to the preparation method of the described 2-of claim 3 (2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I), it is characterized in that comprising:
(a) amidomalonic acid ester (II), acetonitrile, I-hydroxybenzotriazole (HOBT) are mixed with compound (III), cooling, gradation adds dicyclohexylcarbodiimide (DCC), behind the room temperature reaction 10～30 hours, the solid that filtering is separated out concentrates and removes solvent, adds diethyl ether and separates out solid, filter, drying makes compound (IV);
Wherein amidomalonic acid ester (II) is 1: 0.1～0.3 with I-hydroxybenzotriazole (HOBT) mol ratio; Amidomalonic acid ester (II) is 1: 0.75～1.0 with compound (III) mol ratio; Amidomalonic acid ester (II) is 1: 1 with the dicyclohexylcarbodiimide mol ratio;
(b) with above-claimed cpd (IV), wherein blocking group P is a 9-fluorenylmethyloxycarbonyl, and room temperature reaction is after 15～60 minutes in dimethyl formamide with anhydrous piperidines, and adding diethyl ether separates out solid, filters, and drying makes compound (V); Wherein compound (IV) is 1: 3～5 with the mol ratio of anhydrous piperidines; Dimethyl formamide and ether volume ratio are: 1: 8～12;
Or with above-claimed cpd (IV), wherein blocking group P is a tertbutyloxycarbonyl, in methylene dichloride with trifluoroacetic acid room temperature reaction 25～40 hours, cooling, filter, the gained solid in water with reaction of sodium bicarbonate, ethyl acetate extraction, drying is filtered, distill compound (V); Wherein compound (IV) is 1: 2～5 with the mol ratio of trifluoroacetic acid; Compound (IV) is 1: 1～3 with the mol ratio of sodium bicarbonate;
(c) compound (V), 2-methacrylic acid, acetonitrile are mixed with I-hydroxybenzotriazole (HOBT), cooling, gradation adds dicyclohexylcarbodiimide (DCC), behind the room temperature reaction 10～30 hours, the solid that filtering is separated out concentrates and removes solvent, adds diethyl ether and separates out solid, filter, drying makes 2-(2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I);
Wherein compound (V) is 1: 0.1～0.3 with I-hydroxybenzotriazole (HOBT) mol ratio; Compound (V) is 1: 1～1.5 with 2-methacrylic acid mol ratio; 2-methacrylic acid and dicyclohexylcarbodiimide mol ratio are 1: 1.
5. a kind of 2-according to claim 2 (2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is characterized in that its compound is 2-(2-methacryloyl amido three a glycyl) amidomalonic acid diethyl ester.
6. 2-according to claim 1 (2-methacryloyl amido three glycyl) amidomalonic acid ester cpds (I) is used for the preparation of amino malonate platinum complex compound Prolindac.
CN2009102132574A 2009-11-04 2009-11-04 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof Expired - Fee Related CN101724018B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2009102132574A CN101724018B (en) 2009-11-04 2009-11-04 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2009102132574A CN101724018B (en) 2009-11-04 2009-11-04 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN101724018A CN101724018A (en) 2010-06-09
CN101724018B true CN101724018B (en) 2011-12-14

Family

ID=42445632

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2009102132574A Expired - Fee Related CN101724018B (en) 2009-11-04 2009-11-04 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN101724018B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146408A1 (en) * 2010-05-17 2011-11-24 Access Pharmaceuticals, Inc. Hpma polymer platinum chelates

Also Published As

Publication number Publication date
CN101724018A (en) 2010-06-09

Similar Documents

Publication Publication Date Title
CN103502203B (en) The method preparing L-Orn phenyl acetate salt
MX2012009782A (en) Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds.
CN108017583A (en) A kind of preparation method for winning U.S.
CN105936634A (en) Synthetic method of linagliptin
CN102417491A (en) Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material
CN106349245A (en) Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities
CN105906627A (en) Synthesis method of linagliptin intermediate
CN103833593B (en) A kind of preparation method of N-(the 9-fluorenylmethyloxycarbonyl)-O-tert-butyl group-TYR
CN104826544B (en) Lipopeptid molecular surface active agent containing diphenyl diimide photosensitive group and synthetic method thereof
CN106946722B (en) A kind of deuterium exchange synthesis L-Aspartic acid (3,3-D2) method
CN102702292A (en) Preparation method of azacitidine
CN103087148A (en) Synthesis method of N-(2)-L-alanyl-L-glutamine
CN104710605A (en) Methoxypolyethylene glycol with single-end amino (mPEG-NH2) and preparation method thereof
CN101724018B (en) 2-(2-methacrylamide triglycyl) aminomalonate ester as well as preparation method and application thereof
CN104592081B (en) A kind of synthetic method of aztreonam main ring
CN103119051B (en) The preparation method of Zemuron
CN104387421B (en) Adefovir ester monohydrate and preparation method thereof
CN106565607B (en) A kind of synthetic method of N-BETA-Alanyl-L-histidine
CN102464661A (en) Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester
CN107602563A (en) The preparation method of paraquat emetic triazole pyrimidone
CN104326927B (en) A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate
CN101007785B (en) 2[(3-phenyl) acrylketone]-3-methylquinoxaline chemical synthesis method
CN102887838A (en) Preparation method of guanfacine hydrochloride
CN107739328A (en) For synthesizing preparation methods of the Ba Rui for the key intermediate 1 of Buddhist nun
CN108586574B (en) Aminoglucose glycopeptide compound and the preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: ACCESS PHARMACEUTICAL CO., LTD.

Effective date: 20130624

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20130624

Address after: 211112 No. 699, Jian Lu, Jiangning Academy of Sciences, Jiangsu, Nanjing

Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd.

Patentee after: ACCESS Pharmaceutical Co., Ltd.

Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699

Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd.

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20111214

Termination date: 20151104

EXPY Termination of patent right or utility model