CN102649769A - New preparation process of 5-aminolevulinic acid (5-ALA) ester hydrochloride - Google Patents
New preparation process of 5-aminolevulinic acid (5-ALA) ester hydrochloride Download PDFInfo
- Publication number
- CN102649769A CN102649769A CN2011100466262A CN201110046626A CN102649769A CN 102649769 A CN102649769 A CN 102649769A CN 2011100466262 A CN2011100466262 A CN 2011100466262A CN 201110046626 A CN201110046626 A CN 201110046626A CN 102649769 A CN102649769 A CN 102649769A
- Authority
- CN
- China
- Prior art keywords
- ala
- wasserstoffatoms
- levulinate
- ester hydrochloride
- aminoguanidine hydrochloride
- 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.)
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Links
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N NCC(CCC(O)=O)=O Chemical compound NCC(CCC(O)=O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a new preparation process of 5-aminolevulinic acid (5-ALA) ester hydrochloride. The 5-aminolevulinic acid ester hydrochloride is a derivative of 5-ALA, and has a structural general formula shown in the specification, wherein 5-ALA methyl ester hydrochloride and 5-ALA n-hexyl ester hydrochloride can more easily pass through a biolipid membrane compared with 5-ALA. The 5-ALA methyl ester hydrochloride has been used for treating photosensitive keratosis and basal cell tumors in clinical application. The 5-ALA n-hexyl ester hydrochloride has been used for diagnosing bladder carcinoma in clinical application. According to the new preparation process, 3-(2-(N-benzyl) acetyl) propionate hydrochloride or 3-(2-(N, N-dibenzyl) acetyl) propionate is subjected to catalytic hydrogenation or ester formation at the time of catalytic hydrogenation to prepare the 5-ALA ester hydrochloride.
Description
Technical field
The present invention relates to a kind of new preparation process of aminoguanidine hydrochloride levulinate.Photo-dynamical medicine is to develop field faster at some cancer diagnosis and treatment, skin diseases treatment in recent years.The aminoguanidine hydrochloride levulinate is the verivate of cylinder metabolism-ure 5-ALA, and general structure is following:
Wherein aminoguanidine hydrochloride methyl ester levulinate, the just own ester of aminoguanidine hydrochloride levulinic acid are compared 5-ALA, more are prone to pass biological adipose membrane.The aminoguanidine hydrochloride methyl ester levulinate is used to treat photosensitivity keracele and basal cell tumor clinically.The just own ester of aminoguanidine hydrochloride levulinic acid is used for diagnosis of bladder cancer clinically.The present invention is with N-benzyl or N, and the aminoguanidine hydrochloride levulinate of N-dibenzyl is a reaction substrate, becomes ester to prepare the aminoguanidine hydrochloride levulinate simultaneously through catalytic hydrogenation or catalytic hydrogenation.
Technical background
Synthesizing of aminoguanidine hydrochloride levulinate, bibliographical information mainly carries out through two kinds of synthetic routes.Wherein a kind of is at SOCL
2Exist down, alcohol and its formation active ester carry out prepared in reaction aminoguanidine hydrochloride levulinate with 5-ALA again.Route is following:
Acta?Poloniae?Pharmaceutca-Drug?Research，2003，V60(3)，219-224。
Change order of addition(of ingredients) in the above-mentioned route, also can obtain corresponding aminoguanidine hydrochloride levulinate.
International?Journal?of?Medicine?and?Medical?Science，2009，V1(7)，278-287
US006034267A discloses 5-ALA and pure under hydrochloric acid catalysis, also can directly obtain the aminoguanidine hydrochloride levulinate:
From existing document, all be starting raw material synthetic hydrochloric acid amino-laevulic acid ester with 5-ALA.
Summary of the invention
According to the structural performance of aminoguanidine hydrochloride levulinate, the present invention has designed the new synthetic route of synthetic hydrochloric acid amino-laevulic acid ester, and the compound for catalysis hydrogenation through following structure A is also carried out esterification simultaneously and prepared the aminoguanidine hydrochloride levulinate:
Structure A:
R
1, R
2With R
3Can be Wasserstoffatoms, 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 Wasserstoffatoms, title 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate, structure is following:
Remove aforesaid method, also can the compound of structure B be prepared the aminoguanidine hydrochloride levulinate as the direct catalytic hydrogenation of substrate.
Structure B:
R
4Can be benzyl or Wasserstoffatoms.R
2Can be Wasserstoffatoms, halogen or-oxyl.R is the hydrocarbyl substituent of the straight or branched except that Wasserstoffatoms and benzyl.R
2, R
4When being Wasserstoffatoms, title 3-(2-(N-benzylamino) acetyl) propionate salts hydrochlorate, structure is following:
Embodiment:
The preparation of aminoguanidine hydrochloride methyl ester levulinate
2.0 gram 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionates are joined in 150 milliliters of hydrogenation stills, add 30 ml methanol, stir 1.2 grams of adding down, 10% palladium carbon.In logical hydrogen to the still internal pressure of 30-40 degree is 30 kilograms, stirs 24 hours.Remove by filter palladium carbon, palladium carbon washs with small amount of methanol.Filtrating concentrates under 40 degree, adds 30 milliliters of acetone, places refrigerator to solidify, and gets white solid.Suction filtration, solid washs with small amount of acetone, and normal temperature vacuum-drying gets 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 aminoguanidine hydrochloride levulinic acid
700 milligrams of 3-(2-(N-benzylamino) acetyl) just own ester of propionic acid is joined in 150 milliliters of hydrogenation stills, add 30 ml methanol, stir 160 milligram of 10% palladium carbon of adding down.In logical hydrogen to the still internal pressure of 30-40 degree is 30 kilograms, stirs 22 hours.Remove by filter palladium carbon, palladium carbon washs with small amount of methanol.Filtrating is concentrated into dried under 40 degree, adds 15 milliliters of acetone, places-18 degree crystallizations, gets white solid.Suction filtration, solid washs with small amount of acetone, and normal temperature vacuum-drying gets 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 (3)
1. aminoguanidine hydrochloride levulinate, structure is:
A kind of new preparation process is characterised in that to comprise:
With following structure A is midbody, also becomes ester to prepare the aminoguanidine hydrochloride levulinate simultaneously through catalytic hydrogenation:
R
1, R
2With R
3Can be Wasserstoffatoms, halogen or-oxyl etc. can be identical substituting group, also can be different substituting groups.Work as R
1, R
2With R
3When being all Wasserstoffatoms, title 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate, structure is following:
With following structure B is midbody, directly prepares the aminoguanidine hydrochloride levulinate through catalytic hydrogenation:
R
4Can be benzyl or Wasserstoffatoms.R
2Can be Wasserstoffatoms, halogen or-oxyl.R is the hydrocarbyl substituent of the straight or branched except that Wasserstoffatoms and benzyl.R
2, R
4When being Wasserstoffatoms, title 3-(2-(N-benzylamino) acetyl) propionate salts hydrochlorate, structure is following:
2. prepare the aminoguanidine hydrochloride levulinate according to claim 1 by compd A; Be to be reaction substrate with the compd A; Hydrogen chloride solution with alcohol (ROH) is a solvent, adopts palladium reagent such as metal catalysts such as palladium carbon, palladium hydroxide or platinum black, prepares through pressure hydration.
3. preparing the aminoguanidine hydrochloride levulinate according to claim 1 by compd B, is to be reaction substrate with the compd B, with methanol solvate, adopts palladium reagent such as metal catalysts such as palladium carbon, palladium hydroxide or platinum black, prepares through pressure hydration.
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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| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102649769A true CN102649769A (en) | 2012-08-29 |
| CN102649769B CN102649769B (en) | 2015-12-16 |
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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 |
|---|---|
| CN102649769B (en) | 2015-12-16 |
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