CN102649769B - A kind of preparation technology of 5-aminolevulinic acid ester - Google Patents
A kind of preparation technology of 5-aminolevulinic acid ester Download PDFInfo
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- CN102649769B CN102649769B CN201110046626.2A CN201110046626A CN102649769B CN 102649769 B CN102649769 B CN 102649769B CN 201110046626 A CN201110046626 A CN 201110046626A CN 102649769 B CN102649769 B CN 102649769B
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- acid ester
- aminolevulinic acid
- hydrogen atom
- ester
- ala
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of new preparation process of 5-aminolevulinic acid ester.5-aminolevulinic acid ester, as 5-ALA derivative, has following general structure:
Description
Technical field
The present invention relates to a kind of new preparation process of 5-aminolevulinic acid ester.Photo-dynamical medicine in recent years develops field faster at some cancer diagnosis and treatment, skin diseases treatment.5-aminolevulinic acid ester is the derivative of cylinder metabolism-ure 5-ALA, and general structure is as follows:
Wherein the just own ester of 5-ALA methyl esters, 5-ALA compares 5-ALA, more easily through biological adipose membrane.5-ALA methyl esters is used for the treatment of photosensitivity keracele and basal cell tumor clinically.The just own ester of 5-ALA is clinically for the diagnosis of bladder cancer.The present invention for reaction substrate, simultaneously becomes ester to prepare 5-aminolevulinic acid ester by catalytic hydrogenation or catalytic hydrogenation with the 5-aminolevulinic acid ester of N-benzyl or N, N-dibenzyl.
technical background
The synthesis of 5-aminolevulinic acid ester, bibliographical information carries out mainly through two kinds of synthetic routes.Wherein one is at SOCL
2under existence, alcohol and its formation active ester, then carry out reaction with 5-ALA and prepare 5-aminolevulinic acid ester.Route is as follows:
ActaPoloniaePharmaceutca-DrugResearch，2003，V60(3)，219-224。
Change order of addition(of ingredients) in above-mentioned route, also can obtain corresponding 5-aminolevulinic acid ester.
InternationalJournalofMedicineandMedicalScience，2009，V1(7)，278-287
US006034267A discloses 5-ALA and alcohol under hydrochloric acid catalysis, also directly can obtain 5-aminolevulinic acid ester:
From existing document, be all starting raw material synthetic hydrochloric acid amino-laevulic acid ester with 5-ALA.
Summary of the invention
According to the structural performance of 5-aminolevulinic acid ester, the present invention devises the new synthetic route of synthetic hydrochloric acid amino-laevulic acid ester, is carried out esterification simultaneously prepared 5-aminolevulinic acid ester by the compound for catalysis hydrogenation of following structure A:
Structure A:
R
1, R
2with R
3can be hydrogen atom, halogen or-oxyl etc., can be identical substituting group, also can be different substituting groups.Work as R
1, R
2with R
3be preferred when being all hydrogen atom, title 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate, structure is as follows:
Except aforesaid method, also the compound of structure B can be prepared 5-aminolevulinic acid ester as the direct catalytic hydrogenation of substrate.
Structure B:
R
4can be benzyl or hydrogen atom.R
2can be hydrogen atom, halogen or-oxyl.R is the hydrocarbyl substituent of the straight or branched except hydrogen atom and benzyl.R
2, R
4when being hydrogen atom, title 3-(2-(N-benzylamino) acetyl) propionate hydrochloride, structure is as follows:
Embodiment:
The preparation of 5-ALA methyl esters
2.0 grams of 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate is joined in 150 milliliters of hydrogenation reaction cauldrons, adds 30 ml methanol, under stirring, add 1.2 gram of 10% palladium carbon.Leading to hydrogen to still internal pressure at 30-40 degree is 30 kilograms, stirs 24 hours.Cross and filter palladium carbon, a small amount of methanol wash of palladium carbon.Filtrate is concentrated under 40 degree, adds 30 milliliters of acetone, is placed in refrigerator and solidifies, obtain white solid.Suction filtration, a small amount of washing with acetone of solid, normal-temperature vacuum is dry, obtains 580 milligrams of white solids.
1HNMR(D
2O)δ2.5(t，2H，-COCH
2C
H 2CO
2CH
3)，δ2.7(t，2H，-COC
H 2CH2CO
2CH
3)，δ3.5(s，3H，-COCH
2CH2CO
2C
H 3)，δ3.9(s，2H，-NC
H 2 CO-)
The preparation of the just own ester of 5-ALA
700 milligrams of 3-(2-(N-benzylamino) acetyl) the just own ester of propionic acid is joined in 150 milliliters of hydrogenation reaction cauldrons, adds 30 ml methanol, under stirring, add 160 milligram of 10% palladium carbon.Leading to hydrogen to still internal pressure at 30-40 degree is 30 kilograms, stirs 22 hours.Cross and filter palladium carbon, a small amount of methanol wash of palladium carbon.Filtrate is concentrated into dry under 40 degree, adds 15 milliliters of acetone, is placed in-18 degree crystallizations, obtains white solid.Suction filtration, a small amount of washing with acetone of solid, normal-temperature vacuum is dry, obtains 170 milligrams of white solids.
1HNMR(D
20)δ0.7(t，2H，-COCH
2CH
2CO
2CH
2CH
2(CH
2)
3C
H 3)δ1.1(w，6H，-COCH
2CH
2CO
2CH
2CH
2(C
H 2)
3CH
3)，δ1.4(m，2H，-COCH
2C
H 2CO
2CH
2CH
2(CH
2)
3CH
3)，δ2.5(t，2H，-COCH
2C
H 2CO
2CH
2CH
2(CH
2)
3CH
3)，δ2.7(t，2H，-COC
H 2CH2CO
2-)，δ3.9(m，4H，-NC
H 2 COC
H 2CH
2CO
2CH
2CH
2(CH
2)
3CH
3-)。
Claims (5)
1. prepare a technique for 5-aminolevulinic acid ester, 5-aminolevulinic acid ester structure is as follows:
It is characterized in that: also become ester to prepare 5-aminolevulinic acid ester through catalytic hydrogenation following structure A simultaneously:
R
1, R
2with R
3can be hydrogen atom, halogen or-oxyl, can be identical substituting group, also can be different substituting groups;
Or following structure B is directly prepared 5-aminolevulinic acid ester through catalytic hydrogenation:
R
4can be benzyl or hydrogen atom, R
2can be hydrogen atom, halogen or-oxyl, R is the hydrocarbyl substituent of the straight or branched except hydrogen atom and benzyl.
2. preparation technology according to claim 1, is characterized in that taking compd A as reaction substrate, with the hydrogen chloride solution of alcohol roh for solvent, adopts palladium carbon, palladium hydroxide or platinum black metal catalyst, prepares 5-aminolevulinic acid ester through pressure hydration.
3. preparation technology according to claim 1, it is characterized in that with compd B being reaction substrate, take methyl alcohol as solvent, adopts palladium carbon, palladium hydroxide or platinum black metal catalyst, prepares 5-aminolevulinic acid ester through pressure hydration.
4. preparation technology according to claim 1, is characterized in that structure A preferred R1, R2, R3 are the structure of hydrogen atom, namely
5. preparation technology according to claim 1, is characterized in that structure B preferred R2, R4 are the structure of hydrogen atom, namely
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110046626.2A CN102649769B (en) | 2011-02-25 | 2011-02-25 | A kind of preparation technology of 5-aminolevulinic acid ester |
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|---|---|---|---|
| CN201110046626.2A CN102649769B (en) | 2011-02-25 | 2011-02-25 | A kind of preparation technology of 5-aminolevulinic acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102649769A CN102649769A (en) | 2012-08-29 |
| CN102649769B true CN102649769B (en) | 2015-12-16 |
Family
ID=46691899
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| CN201110046626.2A Active CN102649769B (en) | 2011-02-25 | 2011-02-25 | A kind of preparation technology of 5-aminolevulinic acid ester |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6034267A (en) * | 1995-03-10 | 2000-03-07 | Photocure As | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy |
| CN1490305A (en) * | 2002-10-17 | 2004-04-21 | 北京德众万全药物技术开发有限公司 | Preparation of 5-aminol evulinic acid and its derivatives |
-
2011
- 2011-02-25 CN CN201110046626.2A patent/CN102649769B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6034267A (en) * | 1995-03-10 | 2000-03-07 | Photocure As | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy |
| CN1490305A (en) * | 2002-10-17 | 2004-04-21 | 北京德众万全药物技术开发有限公司 | Preparation of 5-aminol evulinic acid and its derivatives |
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| Publication number | Publication date |
|---|---|
| CN102649769A (en) | 2012-08-29 |
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