CN101962351A - Alpha-amino acid derivatives and preparation method, intermediate and application thereof - Google Patents
Alpha-amino acid derivatives and preparation method, intermediate and application thereof Download PDFInfo
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- CN101962351A CN101962351A CN201010292611XA CN201010292611A CN101962351A CN 101962351 A CN101962351 A CN 101962351A CN 201010292611X A CN201010292611X A CN 201010292611XA CN 201010292611 A CN201010292611 A CN 201010292611A CN 101962351 A CN101962351 A CN 101962351A
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Abstract
The invention discloses alpha-amino acid derivatives shown as a formula I, and a preparation method, an intermediate and application thereof. In the formula I, R is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3,, CH2CH2SCH3, CH2C6H5, CH2COOH, CH2CH2COOH, CH2CH2CH2CH2NH2, CH2CH2CH2NH(NH2)C=NH, CH2OH, CH(OH)CH3, CH2C6H4-p-OH or CH2SH. The alpha-amino acid derivatives I serving as coding molecules can be applied to the multivariate detection of a Raman spectrum.
Description
Technical field
The present invention relates to a class alpha-amino acid derivatives, its preparation method, intermediate and the application in field of biomedicine technology thereof.
Background technology
Nano material has represented significant superiority because of its unique character in the cancer diagnosis analysis, the nano biological medical science that nanotechnology is combined with biomedical technology has become one of research field with the fastest developing speed in the nanotechnology.
In the bio-medical analysis technical field, Raman spectrum is widely used in the structural analysis of small-molecule substance, and adopts the nano gold mark macromole to be used for the biomacromolecule multivariate detection and to have become one of research focus of bioanalysis to strengthen its Raman signal in recent years.Surface enhanced Raman spectroscopy (SERS) technology has very high susceptibility, the Raman signal that is adsorbed in textured metal (as gold and silver, copper) surface molecular can be amplified 10
6～10
14Doubly, can detect the unimolecular layer or the inferior unimolecular layer that are adsorbed on material surface, and the structural information of associated molecule is provided.By multivariate detection, detect when can also realize multiple target molecules at the multiple different coding molecule of nanometer gold finishing.
Summary of the invention
Technical problem to be solved by this invention has provided a class and the diverse alpha-amino acid derivatives of prior art, its preparation method, intermediate and application thereof.Alpha-amino acid derivatives of the present invention can be used for the Raman spectrum multivariate detection as coding molecule.
The present invention relates to a class suc as formula the alpha-amino acid derivatives shown in the I;
Wherein, R is H, CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
The invention further relates to the preparation method of above-mentioned alpha-amino acid derivatives I, it is characterized in that comprising the following step: I removes trityl-protecting group with Compound I, gets final product;
Wherein, the definition of R group is ditto described.
Wherein, the described method of trityl and ordinary method and the condition that condition all can be this type of reaction of this area of removing, preferred following method of the present invention and condition: (1) is in organic solvent, in the presence of alkali, with Compound I I and Silver Nitrate effect; (2) in organic solvent,, get final product step (1) products therefrom and hydrogen sulfide effect.
Wherein, organic solvent described in the step (1) can be the conventional solvent of this type of reaction of this area, that preferable is methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), N, one or more in the dinethylformamide, and better is the mixed solution of methyl alcohol and tetrahydrofuran (THF); The volume mass of described organic solvent and Compound I I than preferable be 20～100ml/g, that better is 48ml/g.Alkali described in the step (1) can be the conventional alkali of this type of reaction of this area, and preferable is diisopropyl ethyl amine, triethylamine, pyridine, N-methylmorpholine or 4-methylamine yl pyridines, and better is pyridine; What the mol ratio of described alkali and Compound I I was preferable is 50: 1～100: 1, and better is 84: 1.What the mol ratio of Silver Nitrate described in the step (1) and Compound I I was preferable is 1: 1～3: 1, and better is 2.2: 1.
Wherein, organic solvent described in the step (2) can be the conventional solvent of this type of reaction of this area, and that preferable is methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), N, one or more in the dinethylformamide, that better is N, dinethylformamide; The volume mass of described organic solvent and Compound I I than preferable be 20～100ml/g, that better is 45ml/g.
Compound I I described in the present invention can be made by following method: compound III and compound IV are carried out the condensation reaction of amino and carboxyl, get final product;
Wherein, the definition of R group is ditto described.
Wherein, the method of described condensation reaction and condition all can be the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in organic solvent, in the presence of alkali, condensing agent, compound III and compound IV are carried out the condensation reaction of amino and carboxyl, get final product.
Wherein, described organic solvent can be the conventional solvent of this type of condensation reaction of this area, and that preferable is methylene dichloride, chloroform, tetrahydrofuran (THF) or N, dinethylformamide, and better is tetrahydrofuran (THF); The volume mass of described organic solvent and compound III than preferable be 100～250ml/g.
Wherein, described alkali can be the conventional alkali of this type of condensation reaction of this area, and preferable is diisopropyl ethyl amine, triethylamine, pyridine, N-methylmorpholine or 4-methylamine yl pyridines, and better is diisopropyl ethyl amine; What the mol ratio of described alkali and compound III was preferable is 4: 1～10: 1, and better is 6: 1.
Wherein, described condensing agent can be the conventional condensing agent of this type of condensation reaction of this area, and that preferable is DCC, EDC/HOBt, BOP, PyBOP, TBTU or HATU, and that better is EDC/HOBt;
When the condensing agent that uses during as EDC/HOBt, what the mol ratio of EDC and compound III was preferable is 1: 1～3: 1, and better is 2.5: 1; What the mol ratio of HOBt and compound III was preferable is 1: 1～4: 1, and better is 3: 1.
Wherein, what the mol ratio of compound IV and compound III was preferable is 1: 1～2: 1, and better is 1.5: 1.
Compound III described in the present invention can be made by following method: the sulfydryl trityl as protecting group with in 2-mercaptoethylamine or its hydrochloride molecule gets final product;
Wherein, the method of described reaction with the trityl as protecting group sulfydryl and ordinary method and the condition that condition all can be this type of reaction of this area; preferred especially following method of the present invention and condition: in organic solvent; under the effect of acid; trityl chloride and 2-mercaptoethylamine or the reaction of its hydrochloride get final product.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, preferable is methylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), ether, positive propyl ether, isopropyl ether, benzene or toluene, better is methylene dichloride, the volume mass of described organic solvent and 2-mercaptoethylamine or its hydrochloride than preferable be 15～50ml/g.
Wherein, described acid can be the conventional acid that this area is used for this type of reaction, and preferable is inorganic acid or organic acid, and better is trifluoroacetic acid; What the mol ratio of acid and 2-mercaptoethylamine or its hydrochloride was preferable is 2: 1～3: 1, and better is 2: 1.
Wherein, what the mol ratio of described trityl chloride and 2-mercaptoethylamine or its hydrochloride was preferable is 1: 1～1: 2, and better is 1: 1.
On the basis that meets this area general knowledge, above-mentioned each technical characterictic optimum condition can arbitrary combination obtain each preferred embodiments among the present invention.
The invention still further relates to a class suc as formula the midbody compound of the preparation shown in the II suc as formula the alpha-amino acid derivatives shown in the I,
Wherein, R is H, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
The invention further relates to suc as formula the application of the alpha-amino acid derivatives shown in the I in Raman spectrum multivariate detection technology.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is: the invention provides a series of brand-new alpha-amino acid derivatives, thereby lay a good foundation for the finishing that realizes nanometer gold, silver particles, make it can be applied to the Raman spectrum multivariate detection.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Raw materials used and reagent is except that specifying among the embodiment, all commercially available getting.
Embodiment 1 preparation 2-triphen methylthio group ethamine III
1.13g (10mmol) 2-mercaptoethylamine hydrochloride and 2.79g (10mmol) trityl chloride are dissolved in 1.5ml (20mmol) trifluoroacetic acid, and to reaction end revolved desolvate in two hours by decompression for stirring at room, gets red oil; It is dissolved in the 30ml methylene dichloride, uses 3M NaOH solution, water, saturated NaHCO successively
3Solution and saturated aqueous common salt respectively wash three times, spend the night with anhydrous sodium sulfate drying again; Filter, remove siccative, filtrate decompression is revolved desolvate, obtain faint yellow solid 2.3g after the vacuum-drying, yield 63%, the nuclear magnetic data of product is as follows:
1HNMR (400MHz, CDCl
3) δ 7.41 (m, 6H), 7.27 (m, 6H), 7.20 (m, 3H), 2.57 (t, J=8Hz, 2H), 2.33 (t, J=8Hz, 2H).
Embodiment 2 preparation 2-triphen methylthio group ethamine III
1.13g (10mmol) 2-mercaptoethylamine hydrochloride and 2.1g (7.5mmol) trityl chloride are dissolved in 1.9ml (25mmol) trifluoroacetic acid, and to reaction end revolved desolvate in two hours by decompression for stirring at room, gets red oil; It is dissolved in the 30ml methylene dichloride, uses 3M NaOH solution, water, saturated NaHCO successively
3Solution and saturated aqueous common salt respectively wash three times, spend the night with anhydrous sodium sulfate drying again; Filter, remove siccative, filtrate decompression is revolved desolvate, obtain faint yellow solid 1.4g after the vacuum-drying, yield 60%, the nuclear magnetic data of product is as follows:
1H NMR (400MHz, CDCl
3) δ 7.39 (m, 6H), 7.28 (m, 6H), 7.19 (m, 3H), 2.57 (t, J=8Hz, 2H), 2.34 (t, J=8Hz, 2H).
Embodiment 3 preparation 2-triphen methylthio group ethamine III
1.13g (10mmol) 2-mercaptoethylamine hydrochloride and 1.4g (5mmol) trityl chloride are dissolved in 2.3ml (30mmol) trifluoroacetic acid, and to reaction end revolved desolvate in two hours by decompression for stirring at room, gets red oil; It is dissolved in the 30ml methylene dichloride, uses 3M NaOH solution, water, saturated NaHCO successively
3Solution and saturated aqueous common salt respectively wash three times, spend the night with anhydrous sodium sulfate drying again; Filter, remove siccative, filtrate decompression is revolved desolvate, obtain faint yellow solid 0.93g after the vacuum-drying, yield 58%, the nuclear magnetic data of product is as follows:
1H NMR (400MHz, CDCl
3) δ 7.42 (m, 6H), 7.26 (m, 6H), 7.19 (m, 3H), 2.55 (t, J=8Hz, 2H), 2.32 (t, J=8Hz, 2H).
(IVa is that R is CH in the compound IV to the condensation product IIa of the phenylalanine IVa of embodiment 4 preparation 2-triphen methylthio group ethamine III and Fmoc protection
2C
6H
5Compound; IIa is that R is CH among the Compound I I
2C
6H
5Compound)
Phenylalanine IVa, 67mg (0.35mmol) EDC and 56mg (0.42mmol) HOBt of 50mg (0.14mmol) 2-triphen methylthio group ethamine III, 81mg (0.21mmol) Fmoc protection are joined in the 10ml anhydrous tetrahydro furan successively.After treating that solid dissolves fully, add 110mg (0.84mmol) diisopropyl ethyl amine (DIPEA) in solution, reaction is 4.5 hours under room temperature.Reaction finishes, with the NH of 2ml 25%
4The cancellation of the Cl aqueous solution adds the dilution of 25ml methylene dichloride, separatory, and organic phase is water (5ml * 2) and saturated aqueous common salt (5ml * 2) washing successively, spends the night with anhydrous sodium sulfate drying again.Filter, remove siccative, filtrate decompression is revolved desolvate, obtain thick product, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3 (V/V)), obtain product 86mg, yield 80%, the nuclear magnetic data of product is as follows:
1H NMR (400MHz, CDCl
3) δ 7.1-7.8 (m, 28H), 5.56-5.24 (m, 2H), 4.33 (m, 3H), 4.17 (t, 2H), 3.17-2.85 (m, 3H), 2.23 (m, 2H).
(IVa is that R is CH in the compound IV to the condensation product IIa of the phenylalanine IVa of embodiment 5 preparation 2-triphen methylthio group ethamine III and Fmoc protection
2C
6H
5Compound; IIa is that R is CH among the Compound I I
2C
6H
5Compound)
Phenylalanine IVa, 27mg (0.14mmol) EDC and 19mg (0.14mmol) HOBt of 50mg (0.14mmol) 2-triphen methylthio group ethamine III, 54mg (0.14mmol) Fmoc protection are joined in the 10ml anhydrous chloroform successively.After treating that solid dissolves fully, add 0.081ml (0.56mmol) triethylamine in solution, reaction is 4.5 hours under room temperature.Reaction finishes, with the NH of 2ml 25%
4The cancellation of the Cl aqueous solution adds the dilution of 25ml methylene dichloride, separatory, and organic phase is water (5ml * 2) and saturated aqueous common salt (5ml * 2) washing successively, spends the night with anhydrous sodium sulfate drying again.Filter, remove siccative, filtrate decompression is revolved desolvate, obtain thick product, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3 (V/V)), obtain product 84mg, yield 78%, the nuclear magnetic data of product is as follows:
1HNMR (400MHz, CDCl
3) δ 7.0-7.8 (m, 28H), 5.52-5.25 (m, 2H), 4.35 (m, 3H), 4.15 (t, 2H), 3.16-2.85 (m, 3H), 2.27 (m, 2H).
(IVa is that R is CH in the compound IV to the condensation product IIa of the phenylalanine IVa of embodiment 6 preparation 2-triphen methylthio group ethamine III and Fmoc protection
2C
6H
5Compound; IIa is that R is CH among the Compound I I
2C
6H
5Compound)
Phenylalanine IVa, 81mg (0.42mmol) EDC and 75mg (0.56mmol) HOBt of 50mg (0.14mmol) 2-triphen methylthio group ethamine III, 108mg (0.28mmol) Fmoc protection are joined in the 10ml dry DMF successively.After treating that solid dissolves fully, add 0.11ml (1.4mmol) pyridine in solution, reaction is 4.5 hours under room temperature.Reaction finishes, with the NH of 2ml 25%
4The cancellation of the Cl aqueous solution adds the dilution of 25ml methylene dichloride, separatory, and organic phase is water (5ml * 2) and saturated aqueous common salt (5ml * 2) washing successively, spends the night with anhydrous sodium sulfate drying again.Filter, remove siccative, filtrate decompression is revolved desolvate, obtain thick product, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 3 (V/V)), obtain product 89mg, yield 83%, the nuclear magnetic data of product is as follows:
1HNMR (400MHz, CDCl
3) δ 7.0-7.9 (m, 28H), 5.57-5.26 (m, 2H), 4.31 (m, 3H), 4.18 (t, 2H), 3.17-2.87 (m, 3H), 2.22 (m, 2H).
(Ia is that R is CH in the Compound I to the condensation product Ia of the phenylalanine of embodiment 7 preparation 2-mercaptoethylamines and Fmoc protection
2C
6H
5Compound)
0.33g (0.48mmol) Compound I Ia is dissolved in the mixed solution of 13ml methyl alcohol and 3ml tetrahydrofuran (THF), add 3.25ml (40mmol) pyridine, stirring reaction is after 30 minutes under the room temperature, in system, add 0.18g (1.05mmol) Silver Nitrate, the adularescent precipitation generates, filter, the white precipitate that obtains is dissolved among the 15ml DMF, more at normal temperatures and pressures, in gained DMF solution, feed hydrogen sulfide (latm) 1hr, tail gas absorbs with calcium hydroxide, generates black precipitate at once, and reaction finishes, filter membrane (0.22 μ m) filters, discard filter residue, filtrate decompression concentrates, and promptly gets the thick product of Compound I a, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 1 (V/V)), obtain product 0.11g, yield 50%, the nuclear magnetic data of product is as follows:
1HNMR (400MHz, CDCl
3) δ 7.1-7.8 (m, 13H), 6.12 (m, 1H), 5.46 (m, 1H), 4.43 (m, 3H), 4.17 (t, 2H), 3.57-2.85 (m, 4H), 2.63-2.45 (m, 2H).
(Ia is that R is CH in the Compound I to the condensation product Ia of the phenylalanine of embodiment 8 preparation 2-mercaptoethylamines and Fmoc protection
2C
6H
5Compound)
0.33g (0.48mmol) Compound I Ia is dissolved in 16ml methyl alcohol, add 1.95ml (24mmol) pyridine, stirring reaction is after 30 minutes under the room temperature, in system, add 82mg (0.48mmol) Silver Nitrate, the adularescent precipitation generates, filter, the white precipitate that obtains is dissolved in the 15ml methyl alcohol, more at normal temperatures and pressures, in the gained methanol solution, feed hydrogen sulfide (latm) 1hr, tail gas absorbs with calcium hydroxide, generates black precipitate at once, and reaction finishes, filter membrane (0.22 μ m) filters, discard filter residue, filtrate decompression concentrates, and promptly gets the thick product of Compound I a, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 1 (V/V)), obtain product 88mg, yield 40%, the nuclear magnetic data of product is as follows:
1HNMR (400MHz, CDCl
3) δ 7.1-7.7 (m, 13H), 6.09 (m, 1H), 5.45 (m, 1H), 4.43 (m, 3H), 4.16 (t, 2H), 3.56-2.85 (m, 4H), 2.61-2.45 (m, 2H).
(Ia is that R is CH in the Compound I to the condensation product Ia of the phenylalanine of embodiment 9 preparation 2-mercaptoethylamines and Fmoc protection
2C
6H
5Compound)
0.33g (0.48mmol) Compound I Ia is dissolved among the 16mlDMF, add 7ml (48mmol) triethylamine, stirring reaction is after 30 minutes under the room temperature, in system, add 0.25g (1.44mmol) Silver Nitrate, the adularescent precipitation generates, filter, the white precipitate that obtains is dissolved among the 15ml DMF, more at normal temperatures and pressures, in the gained tetrahydrofuran solution, feed hydrogen sulfide (latm) 1hr, tail gas absorbs with calcium hydroxide, generates black precipitate at once, and reaction finishes, filter membrane (0.22 μ m) filters, discard filter residue, filtrate decompression concentrates, and promptly gets the thick product of Compound I a, column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 1 (V/V)), obtain product 0.12g, yield 53%, the nuclear magnetic data of product is as follows:
1H NMR (400MHz, CDCl
3) δ 7.0-7.8 (m, 13H), 6.11 (m, 1H), 5.46 (m, 1H), 4.41 (m, 3H), 4.17 (t, 2H), 3.55-2.83 (m, 4H), 2.66-2.45 (m, 2H).
Other amino acid whose condensation products of embodiment 10 preparation 2-mercaptoethylamines and Fmoc protection are with other amino acid of Fmoc protection
Wherein, R is H, CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH with 2-triphen methylthio group ethamine III reaction, removes trityl again, obtains the amino acid whose condensation product of corresponding 2-mercaptoethylamine and Fmoc protection, and experimental technique and condition are with embodiment 4 and embodiment 7.
Claims (12)
1. a class is suc as formula the alpha-amino acid derivatives shown in the I,
Wherein, R is H, CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
2. the preparation method of Compound I as claimed in claim 1, it is characterized in that comprising the following step: I removes trityl-protecting group with Compound I, gets final product;
Wherein, R is H, CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
3. the preparation method of Compound I as claimed in claim 2 is characterized in that, described Compound I is made by following method: (1) is in organic solvent, in the presence of alkali, with Compound I I and Silver Nitrate effect; (2) in organic solvent,, get final product step (1) products therefrom and hydrogen sulfide effect.
4. the preparation method of Compound I as claimed in claim 3 is characterized in that, the organic solvent in the described step (1) is methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), N, one or more in the dinethylformamide; Alkali in the described step (1) is diisopropyl ethyl amine, triethylamine, pyridine, N-methylmorpholine or 4-methylamine yl pyridines; Alkali in the described step (1) and the mol ratio of Compound I I are 50: 1～100: 1; The mol ratio of described Silver Nitrate and Compound I I is 1: 1～3: 1; Organic solvent in the described step (2) is methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), N, one or more in the dinethylformamide.
5. the preparation method of Compound I as claimed in claim 2 is characterized in that, described Compound I I is made by following method: compound III and compound IV are carried out the condensation reaction of amino and carboxyl, get final product;
Wherein, R is H, CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
6. the preparation method of Compound I as claimed in claim 5, it is characterized in that described Compound I I is made by following method: in organic solvent, in the presence of alkali, condensing agent, compound III and compound IV are carried out the condensation reaction of amino and carboxyl, get final product.
7. the preparation method of Compound I as claimed in claim 6 is characterized in that, described organic solvent is methylene dichloride, chloroform, tetrahydrofuran (THF) or N, dinethylformamide; Described alkali is diisopropyl ethyl amine, triethylamine, pyridine, N-methylmorpholine or 4-methylamine yl pyridines; The mol ratio of described alkali and compound III is 4: 1～10: 1; Described condensing agent is DCC, EDC/HOBt, BOP, PyBOP, TBTU or HATU; When the condensing agent that uses during as EDC/HOBt, the mol ratio of EDC and compound III is 1: 1～3: 1, and the mol ratio of HOBt and compound III is 1: 1～4: 1; The mol ratio of described compound IV and compound III is 1: 1～2: 1.
8. the preparation method of Compound I as claimed in claim 5 is characterized in that, described compound III is made by following method: the sulfydryl trityl as protecting group with in 2-mercaptoethylamine or its hydrochloride molecule gets final product;
9. the preparation method of Compound I as claimed in claim 8 is characterized in that, described compound III is made by following method: in organic solvent, under the effect of acid, trityl chloride and 2-mercaptoethylamine or the reaction of its hydrochloride get final product.
10. the preparation method of Compound I as claimed in claim 9 is characterized in that, described organic solvent is methylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), ether, positive propyl ether, isopropyl ether, benzene or toluene; Described acid is inorganic acid or organic acid; The mol ratio of described acid and 2-mercaptoethylamine or its hydrochloride is 2: 1～3: 1; The mol ratio of described trityl chloride and 2-mercaptoethylamine or its hydrochloride is 1: 1～1: 2.
11. a class is suc as formula the midbody compound of the preparation Compound I as claimed in claim 1 shown in the II,
Wherein, R is H, CH (CH
3)
2, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3, CH
2CH
2SCH
3, CH
2C
6H
5, CH
2COOH, CH
2CH
2COOH, CH
2CH
2CH
2CH
2NH
2, CH
2CH
2CH
2NH (NH
2) C=NH, CH
2OH, CH (OH) CH
3, CH
2C
6H
4-p-OH or CH
2SH.
12. the application of Compound I as claimed in claim 1 in Raman spectrum multivariate detection technology.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373940A (en) * | 2012-04-26 | 2013-10-30 | 长春百克生物科技股份公司 | Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain |
| CN107522758A (en) * | 2017-08-19 | 2017-12-29 | 湖南华腾制药有限公司 | A kind of adriamycin Pegylation Gamboges acid derivative and preparation method thereof |
| CN110256310A (en) * | 2019-07-01 | 2019-09-20 | 吉尔生化（上海）有限公司 | A kind of preparation method of N- fluorenylmethyloxycarbonyl-S- (4- Methoxytrityl)-L- homocysteine |
-
2010
- 2010-09-27 CN CN201010292611XA patent/CN101962351A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373940A (en) * | 2012-04-26 | 2013-10-30 | 长春百克生物科技股份公司 | Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain |
| CN103373940B (en) * | 2012-04-26 | 2015-07-15 | 长春百克生物科技股份公司 | Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain |
| CN107522758A (en) * | 2017-08-19 | 2017-12-29 | 湖南华腾制药有限公司 | A kind of adriamycin Pegylation Gamboges acid derivative and preparation method thereof |
| CN110256310A (en) * | 2019-07-01 | 2019-09-20 | 吉尔生化（上海）有限公司 | A kind of preparation method of N- fluorenylmethyloxycarbonyl-S- (4- Methoxytrityl)-L- homocysteine |
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