CN101007775A - S-1-(4-ethoxybenzyl)-3-azapentane-1,5 diamine preparation method - Google Patents
S-1-(4-ethoxybenzyl)-3-azapentane-1,5 diamine preparation method Download PDFInfo
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- CN101007775A CN101007775A CNA2007100193790A CN200710019379A CN101007775A CN 101007775 A CN101007775 A CN 101007775A CN A2007100193790 A CNA2007100193790 A CN A2007100193790A CN 200710019379 A CN200710019379 A CN 200710019379A CN 101007775 A CN101007775 A CN 101007775A
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Abstract
The invention discloses a making method of S-1-(4-ethoxy benzyl)-3-aza pantane-1, 5 diamine in the organic synthetic technical domain, which comprises the following steps: 1reacting L-tyrosine alkyl ester protected by amino and ethyl iodide catalyzed by anhydrous carbonate alkali to produce L-tyrosine alkyl ester protected by O-ethyl-amino; 2. reacting L-tyrosine alkyl ester protected by O-ethyl-amino and anhydrous ethanediamine to do ester exchange to produce O-ethyl-L-tyrosinamide protected by N-(2-amino ethyl)-amino; 3. stripping protecting group of amino through trifluoroacetic acid; 4. using aluminium lithium hydroxide to reduce; obtaining the product. The invention reduces technical difficulty with mild reacting condition, which can prepare key intermediate of Gadoxetic acid disodium (Gd-EOB-DTPA).
Description
Technical field
The present invention relates to the preparation method of S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines, belong to technical field of organic synthesis.It is liver specificity magnetic resonance contrast agent Gadoxetic acid disodium (Gadoxetic aciddisodium, key intermediate Gd-EOB-DTPA).
Background technology
Nuclear magnetic resonance (MRI) technology has a wide range of applications at biology and medical field, has become a kind of common medical diagnosis means.In order to strengthen the contrast gradient and the sharpness of image, often select in the clinical MRI to use suitable contrast medium, about 30% MRI need use contrast medium.The important research direction of magnetic resonance contrast agent is the contrast medium that development has organ, tissue target tropism in the world, can make contrast medium be enriched in specific organ or tissue, improves the radiography effect, reduces dosage, reduces toxicity.Gadoxetic acid disodium (Gadoxetic aciddisodium) is by the paramagnetism gadolinium ion and lipophilic ethoxy benzyl diethylenetriamine pentaacetic acid part chelating is formed, normal liver cell optionally absorbs the Gd-EOB-DTPA molecule, obviously improve the T1 relaxation efficient of tissue, help detecting of liver lesion, can improve the recall rate of little liver neoplasm especially, thereby help the early diagnosis and therapy of liver neoplasm.
S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines is the key intermediate of Gadoxetic acid disodium. U.S. Pat 5,695, and 739 and document Inorg.Chem 1999,38,1134～1144 have reported synthetic route.With N-benzene methoxycarbonyl-L-L-Tyrosine methyl ester is raw material; Anhydrous potassium carbonate exists down and the iodoethane reaction obtained O-ethyl-N-benzene methoxycarbonyl-L-L-Tyrosine methyl ester in 20 hours; quadrol with 20 times of molar weights carries out transesterify generation N-(2-amino-ethyl)-N-benzene methoxycarbonyl-O-ethyl-L-tyramine amide again; make catalyzer with Pd/C then; 15 normal atmosphere are down with hydrogen reaction deaminize protecting group; obtain S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines with the diborane reducing amide at last.Synthetic route is as follows:
In this synthetic route, the 3rd step deaminize protecting group is made catalyzer with Pd/C, and 15 normal atmosphere are used hydrogen reaction down, and first equipment requirements is higher, and second uses the security requirement of hydrogen also high.Diborane is used in the reduction of the 4th step acid amides, and diborane is a flammable and explosive substance, and transportation, storage require all very high, and the reaction times reaches 32 hours, causes the equipment work efficiency low, and diborane toxicity is big, and is dangerous high.Therefore document method needs to improve.
Summary of the invention
The invention provides the preparation method of a kind of S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines, the objective of the invention is to design a kind of suitable suitability for industrialized production, operational path is new preparation method reasonably.
Technical scheme of the present invention: reaction scheme is as follows:
1. the L-tyrosine alkyl ester with amido protecting is a raw material, under the effect of Carbon Dioxide an alkali metal salt, carry out ethylation reaction and generate O-ethyl-amido protecting-L-tyrosine alkyl ester with iodoethane, the L-tyrosine alkyl ester of amido protecting and iodoethane molar ratio are for waiting mole, temperature of reaction is 20～25 ℃, reaction times is 20 hours, aftertreatment with ethyl acetate extraction after evaporate to dryness, do not need purifying directly to enter the next step; 2.O-carrying out transesterification reaction, ethyl-amido protecting-L-tyrosine alkyl ester and anhydrous ethylenediamine generate N-(2-amino-ethyl)-amido protecting-O-ethyl-L-tyramine amide, O-ethyl-amido protecting-L-tyrosine alkyl ester and anhydrous ethylenediamine molar ratio are 1: 20, temperature of reaction is 50 ℃, and the reaction times is 20 hours; 3. remove amino protecting group with trifluoroacetic acid, the trifluoroacetic acid that adds and the mol ratio of N-(2-amino-ethyl)-amido protecting-O-ethyl-L-tyramine amide are 1.0～3.0: 1, temperature of reaction is 0～30 ℃, reaction times is 0.5～5 hour, and product can directly enter next step reduction reaction behind the concentrating under reduced pressure evaporate to dryness; 4. use lithium aluminum hydride as reductive agent, the reducing amide base makes S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines, the lithium aluminum hydride that adds and the mol ratio of N-(2-amino-ethyl)-O-ethyl-L-tyramine amide are 3.0～4.0: 1, temperature of reaction is 50 ℃, and the reaction times is 2～5 hours, substitutes diborane with lithium aluminum hydride, shorten the reaction times, aftertreatment is simple.
The amino protecting group of the L-tyrosine alkyl ester of the amido protecting that the present invention adopts is any one in tertbutyloxycarbonyl (Boc) or the benzene methoxycarbonyl (Cbz).
The alkyl of the L-tyrosine alkyl ester of the amido protecting that the present invention adopts is any one in methyl or ethyl or propyl group or the sec.-propyl.
The Carbon Dioxide an alkali metal salt that the present invention adopts is any in Anhydrous potassium carbonate or the anhydrous sodium carbonate.
Beneficial effect of the present invention: the S-1-that provides (4-ethoxy benzyl)-3-aza-pentane-1, the preparation method of 5 diamines is on the prior art basis, adopted a kind of safe and reliable working method, avoided high pressure, hydrogen, diborane etc. to equipment, the high condition of security requirement, has reaction temperature and controlled, reaction times is short, easy to operate, safe, the yield height, advantages such as recycled solvent, the suitability for industrialized production of suitable S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines.
Embodiment
Synthesizing of embodiment 1 O-ethyl-N-boc-L-tyrosine ethyl ester:
Add N-boc-L-tyrosine ethyl ester (24.8g in the 500mL three-necked flask, 0.08mol) and 180mLDMF in, add 22.0g Anhydrous potassium carbonate and iodoethane (7mL after the stirring and dissolving successively, 0.08mol), kept 25 ℃ of stirring at room 20 hours, the aftertreatment ethyl acetate extraction, evaporated under reduced pressure gets O-ethyl-N-boc-L-tyrosine ethyl ester (25.2g, 0.075mol), need not purifying and directly supply next step (embodiment 2) reaction, ethyl acetate reclaims to be used.Molar yield is 93.8% (the HPLC detection level is 96.2%).
Synthesizing of embodiment 2 N-(2-amino-ethyl)-N-boc-O-ethyl-L-tyramine amide:
O-ethyl-N-boc-L-tyrosine ethyl ester (25.2g that back (embodiment 1) is obtained, 0.075mol) be dissolved in 100mL methyl alcohol, slowly drop to and be added with anhydrous ethylenediamine (90g in 500mL three-necked flask 1.5mol), dropwises back 50 ℃ and continue to stir 20 hours.Evaporated under reduced pressure adds the 60mL ethyl acetate in the residue, leave standstill after the heating for dissolving, the white solid that collection is separated out, 50 ℃ dry N-(2-amino-ethyl)-N-boc-O-ethyl-L-tyramine amide (20g, 0.054mol), molar yield is 72%, and ethyl acetate reclaims to be used.mp94～96℃，MS：367。
Synthesizing of embodiment 3 N-(2-amino-ethyl)-O-ethyl-L-tyramine amide:
Add N-(2-amino-ethyl)-N-boc-O-ethyl-L-tyramine amide (32g in the 500mL three-necked flask, 0.087mol) and the 400mL methylene dichloride, add trifluoroacetic acid (22.8g after the stirring and dissolving, 0.2mol) stirring at room 1 hour, the concentrating under reduced pressure evaporate to dryness get N-(2-amino-ethyl)-O-ethyl-L-tyrosyl (18g, 0.072mol), molar yield is 83%, mp94～96 ℃ (highly finished product), MS:251.
Synthesizing of embodiment 4 S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines:
In being housed, the 1000mL three-necked flask of dropping funnel and reflux adds LiAlH
4(15g, 0.4mol) and the 250mL tetrahydrofuran (THF), (25g 0.1mol) is dissolved in the 150mL tetrahydrofuran (THF), slowly drops in the flask, keeps that reaction solution is little to boil, 50 ℃ of reactions 3 hours with N-(2-amino-ethyl)-O-ethyl-L-tyramine amide.Add the postcooling reaction solution to room temperature.Filter, filter cake tetrahydrofuran (THF) washed twice, merging filtrate, evaporated under reduced pressure, must white solid (22.5g, 0.095mol), molar yield is 95%, mp170～172 ℃, MS:237 is product S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines.
Claims (4)
1, the preparation method of a kind of S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines is characterized in that branch four step carries out:
(1) the L-tyrosine alkyl ester of amido protecting and iodoethane are made reaction generation O-ethyl-amido protecting L-tyrosine alkyl ester under the catalyzer at the Carbon Dioxide an alkali metal salt, the L-tyrosine alkyl ester of amido protecting and iodoethane molar ratio are for waiting mole, temperature of reaction is 20～25 ℃, reaction times is 20 hours, aftertreatment with ethyl acetate extraction after evaporate to dryness, enter the next step;
(2) O-ethyl-amido protecting L-tyrosine alkyl ester and anhydrous ethylenediamine carry out transesterification reaction generation N-(2-amino-ethyl)-amido protecting-O-ethyl-L-tyramine amide, O-ethyl-amido protecting-L-tyrosine alkyl ester and anhydrous ethylenediamine molar ratio are 1: 20, temperature of reaction is 50 ℃, and the reaction times is 20 hours;
(3) with trifluoroacetic acid deaminize protecting group, the trifluoroacetic acid that adds and the mol ratio of N-(2-amino-ethyl)-amido protecting-O-ethyl-L-tyramine amide are 1.0～3.0: 1, temperature of reaction is 0～30 ℃, reaction times is 0.5～5 hour, enters next step reduction reaction behind the concentrating under reduced pressure evaporate to dryness;
(4) make S-1-(4-ethoxy benzyl)-3-aza-pentane-1 with lithium aluminium hydride reduction, 5 diamines, the lithium aluminum hydride that adds and the mol ratio of N-(2-amino-ethyl)-O-ethyl-L-tyramine amide are 3.0～4.0: 1, and temperature of reaction is 50 ℃, the reaction times is 2～5 hours.
2, S-1-according to claim 1 (4-ethoxy benzyl)-3-aza-pentane-1; the preparation method of 5 diamines, the amino protecting group that it is characterized in that the L-tyrosine alkyl ester of described amido protecting is any one in tertbutyloxycarbonyl or the benzene methoxycarbonyl.
3, the preparation method of S-1-according to claim 1 (4-ethoxy benzyl)-3-aza-pentane-1,5 diamines, the alkyl that it is characterized in that the L-tyrosine alkyl ester of described amido protecting is any one in methyl or ethyl or propyl group or the sec.-propyl.
4, the preparation method of S-1-according to claim 1 (4-ethoxy benzyl)-3-aza-pentane-1,5 diamines is characterized in that described Carbon Dioxide an alkali metal salt is any one in Anhydrous potassium carbonate or the anhydrous sodium carbonate.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188928A (en) * | 2010-03-08 | 2011-09-21 | 中国科学院成都有机化学有限公司 | Fluorocarbon cationic gemini and hybridized gemini surfactants and synthesis method thereof |
| CN103864630A (en) * | 2014-03-21 | 2014-06-18 | 福州大学 | Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride |
| CN103896788A (en) * | 2012-12-27 | 2014-07-02 | 齐鲁制药有限公司 | Preparation method of S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride |
| WO2017208258A1 (en) * | 2016-05-30 | 2017-12-07 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium) |
| WO2018084625A1 (en) * | 2016-11-04 | 2018-05-11 | St Pharm Co., Ltd. | Method for preparation of (s)-n1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
| KR20180050091A (en) * | 2016-11-04 | 2018-05-14 | 에스티팜 주식회사 | A method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrocholoride |
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2007
- 2007-01-16 CN CNB2007100193790A patent/CN100534976C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188928A (en) * | 2010-03-08 | 2011-09-21 | 中国科学院成都有机化学有限公司 | Fluorocarbon cationic gemini and hybridized gemini surfactants and synthesis method thereof |
| CN103896788A (en) * | 2012-12-27 | 2014-07-02 | 齐鲁制药有限公司 | Preparation method of S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride |
| CN103864630A (en) * | 2014-03-21 | 2014-06-18 | 福州大学 | Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride |
| WO2017208258A1 (en) * | 2016-05-30 | 2017-12-07 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium) |
| US11149041B2 (en) | 2016-05-30 | 2021-10-19 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for the preparation of gadolinium complex of (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid disodium (Gadoxetate disodium) |
| WO2018084625A1 (en) * | 2016-11-04 | 2018-05-11 | St Pharm Co., Ltd. | Method for preparation of (s)-n1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
| KR20180050091A (en) * | 2016-11-04 | 2018-05-14 | 에스티팜 주식회사 | A method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrocholoride |
| US10501403B2 (en) | 2016-11-04 | 2019-12-10 | St Pharm Co., Ltd. | Method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
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