CN102649768B - A kind of preparation technology of 5-ALA - Google Patents

Abstract

The present invention relates to the new preparation process of a kind of 5-ALA (5-ALA). 5-ALA is as second generation sensitising agent, and structure is as follows:

Description

A kind of preparation technology of 5-ALA

Technical field

The present invention relates to the new preparation process of a kind of 5-ALA (5-ALA). Photo-dynamical medicine is in recent years to existSome cancer diagnosis and treatment, treating skin disease develop field faster. 5-ALA is as second generation sensitising agent,Be used for the treatment of actinic keratoma in the U.S. now. Be used for the treatment of Dermatology condyloma acuminatum in China. About fitting of 5-ALAAnswer disease clinically also in expansion. The present invention is taking 4-allyl acetic acid benzyl ester as initiation material, by oxidation, addition, oxidation, catalysisHydrogenation is successfully synthesized and is obtained 5-ALA.

Technical background

5-ALA's is synthetic, and bibliographical information is more. CN101462974 discloses following route:

Synthesis, 1999 (4), 568-570 has reported similar method.

Pol. 196899 following route is disclosed:

NOTE：Reactants：2，Reagents：4，Solvents：4，

Steps：3，Stages：11，Moststagesinanyonestep：5

Chinese Journal of Pharmaceuticals, 2006,37 (4), 223-224; CN1490305; ActaPoloniaePharmaceutica，2003，60(3)，219-224；ZeitschriftfuerNaturforschung，TeilB：AnorganischeChemie, OrganischeChemie, 1986,41B (12), 1593-4 discloses or has reported similar closingBecome route.

Document ArchivesofPharmacalResearch, 2005,28 (10), 1111-1113 has reported by closingBecome the synthetic 5-ALA of 4-cyano group-4-oxygen-butyrate, route is as follows

NOTE：3)Pd/Ccatalystused，

Reactants：3，Reagents：3，Catalysts：1，Solvents：3，

Steps：3，Stages：4，Moststagesinanyonestep：2

JP2005272360; TetrahedronLetters, 1984,25 (28), 2977-80 also discloses and has reported classLike method.

Russ.2260585, Russ.2146667 discloses by preparation 5-nitro-4-oxygen-valerate and has prepared 5-ALA'sMethod,

NOTE：electrochemical，

Reactants：1，Reagents：2，Solvents：1，

Steps：1，Stages：1

Organic chemistry, 2005,25 (11), 1431-1433; Report and prepared 5-nitro-4-oxygen-valerate with different substratesAnd then prepare the method for 5-ALA.

Some other bibliographical information synthesizes 5-ALA by furan derivatives, in the following example (Synthesis, 1995 (3), 303-6)

NOTE：1)Ritterreaction，2)photochem.，Sephadexresinused，3)ultrasaund，

Reactants：2，Reagents：7，Solvents：3，

Steps：4，Stages：5，Moststagesinanyonestep：2

From existing document, synthetic 5-ALA or because raw material is rare or be difficult to separate or because of reaction because of intermediate productYield is not high, and the preparation cost of 5-ALA is higher, thereby has limited the application of 5-ALA and derivative thereof. Find economical, efficientSynthetic route, has positive effect to the application of 5-ALA and derivative thereof.

Summary of the invention

According to the architectural characteristic of 5-ALA, the present invention has designed the synthetic route that synthetic 5-ALA is new, by following structure A's5-ALA is prepared in compound for catalysis hydrogenation:

Structure A:

R₁，R₂With R₃Can be hydrogen atom, halogen or oxyl etc., can be identical substituting group, also can be different replacementsBase. Work as R₁，R₂With R₃While being all hydrogen atom for preferably, title 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate, structure asUnder:

Preparation 5-(N, N-dibenzyl amino)-4-hydroxyl-benzyl valerianate, relates to the intermediate with new construction, as structureB：

R₁，R₂With R₃Can be hydrogen atom, halogen or oxyl etc., can be identical substituting group, also can be different replacementsBase. Work as R₁，R₂With R₃While being all hydrogen atom for preferably, title 5-(N, N-dibenzyl amino)-4-hydroxyl-benzyl valerianate, structure asUnder:

By the compound of preparation structure A, B, and then catalytic hydrogenation prepares 5-ALA, taking preferred structure as example, reaction equation asUnder:

Adopting 4-allyl acetic acid ester is raw material, adopt epoxidation or dewater at alkaline environment after forming hydroxyl halide,To epoxide 3-epoxy ethyl benzyl propionate. The epoxidation reagent using is hydrogen peroxide, Peracetic acid, m-chloro peroxide benzeneFormic acid etc.

Epoxide and dibenzylamine occur in alcoholic solution addition reaction occur, and preparation is as the preferred chemical combination in structure BThing 5-(N, N-dibenzyl amino)-4-hydroxyl-benzyl valerianate.

Adopt oxidant as IBX (two iodoxy benzoic acid), DMP (1,1,1-, tri-ethoxy acyl group-1,1-dihydroxy-1,2-Benzenesulfonyl-3 (1H)-one), Cr VI reagent is as Jone ' s reagent is oxidized compd B, can obtain as structure A preferablyCompound 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate.

Under hydrochloric acid exists, 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate, through catalytic hydrogenation, can directly obtain5-ALA (5-ALA). Used catalyst be palladium reagent as palladium carbon, palladium dydroxide, platinum reagent is as metals such as platinum blackCatalyst.

Embodiment:

The preparation of epoxides 4-epoxy benzyl valerianate

In 5000 ml flasks, 155 grams of 4-alkene-benzyl valerianates are dissolved in to 1730 milliliters of carrene, add between 195 gramsChloroperoxybenzoic acid, maintains reaction temperature Celsius 30 from 35 degree, stirs 24 hours, separates out white solid in course of reaction. TLC(solvent: cyclohexane-ethyl acetate 4: 1) followed the tracks of and reacted to the disappearance of raw material 4-alkene-benzyl valerianate. Water-bath is cooling, adds 3% AsiaSulfuric acid solution, with potassium iodide starch test paper detection, test paper is aobvious blue. Add sodium bicarbonate solution, make dissolution of solid, pH7-8.Be transferred to separatory funnel, layering. Organic one-tenth washs by 200 mL of saline. Separate organic layer, spend the night with anhydrous sodium sulfate drying.Suction filtration, concentrated, decompression distillation under 6 millimetres of mercury vacuum, the component of collecting 145-147 degree Celsius, obtains 130 grams of products.

¹HNMR(CDCl3)δ1.7-2.0(m，2H，-COCH₂CH ₂ )，δ2.5(m，3H，CH ₂(O)CH-，-COCH ₂ CH₂)，δ2.7(m，1H，CH₂(O)CH-)，δ3.0(m，1H，CH ₂(O)CH-)，δ5.1(s，2H，-CH2Ph)，δ7.4(m，5H，-CH₂ Ph)

5-(N, N-dibenzyl amino)-4-hydroxyl-benzyl valerianate

Add 8 grams of 4-epoxy benzyl valerianates at 250 ml flasks, add 64 milliliters of isopropyl alcohols, add 8 grams of dibenzylamine,30-40 degree stirred in water bath Celsius, TLC follows the tracks of to react to dibenzylamine and is exhausted. Reduced pressure concentration, obtains faint yellow grease 15.5Gram. Need not separate, be directly used in next step oxidation reaction.

3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate

Above-mentioned 5-(N, N-dibenzyl amino)-4-hydroxyl-benzyl valerianate dissolving crude product, in 300 milliliters of acetone, is addedIn 500 milliliters of there-necked flasks, ice-water bath is cooled to solution 0 degree left and right Celsius, drips 90 milliliters of Qiong Shi reagent, and temperature is no more than to be taken the photographFamily name 3 spends. Dropwise 0-3 degree reaction Celsius 7 hours. At the cooling lower dropping 2N sodium hydroxide solution of ice bath, regulator solution extremelyAlkalescent pH8. Suction filtration, filter cake washs with acetone. In 30 degree water-baths Celsius, decompression steams most of acetone. The remaining aqueous solutionBe extracted with ethyl acetate (3 times, each 100 milliliters). After organic layer merges, wash with 2% sodium sulfite solution, then use saturated saltWater washing (3 times, each 50 milliliters), anhydrous sodium sulfate drying spends the night. Reduced pressure concentration, silica gel column chromatography separates, eluant, eluent: hexamethyleneAlkane-ethyl acetate 6: 1. Obtain 8.8 grams of light yellow viscous liquids.¹HNMR(CDCl₃)δ2.5(m，2H，-COCH₂CH ₂CO₂CH₂Ph)，δ2.7(m，2H，-COCH ₂CH2CO₂CH₂Ph)，δ3.2(s，2H，-NCH ₂ CO-)，δ3.6(s，4H，-N(CH ₂Ph)₂)，δ5.1(s，2H，-CH2Ph)，δ7.2(m，15H，-N(CH₂ Ph)₂，-OCH₂ Ph)

5-ALA (5-ALA)

2.0 grams of 3-(2-(N, N-dibenzyl amino) acetyl) benzyl propionate is joined in 150 milliliters of hydrogenation reaction cauldrons, addedEnter 30 milliliters of oxolanes, 5 ml waters, add 0.7 gram of 10% palladium carbon under stirring. Be 30 in 30 logical hydrogen to the still internal pressures in degree left and rightKilogram, stir 24 hours. Remove by filter palladium carbon, a small amount of water washing of palladium carbon. Filtrate is concentrated into dry under 60 degree, adds 60 millilitersAcetone, is placed in refrigerator and solidifies, and obtains white solid. Suction filtration, solid washs with a small amount of acetone, and normal-temperature vacuum is dry, obtains 0.8 gram of classWhite solid.¹HNMR(D₂O)δ2.6(t，2H，-COCH₂CH ₂CO₂H)，δ2.8(t，2H，-COCH ₂CH2CO₂H)，δ4.1(s，2H，-NCH ₂ CO-)。

Claims (9)

1. a preparation technology for 5-ALA (5-ALA) is as intermediate, through catalytic hydrogenation taking following structure APreparation 5-ALA:

R₁、R₂With R₃For hydrogen atom, halogen or oxyl, can be identical substituting group, also can be different substituting groups.

2. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 1, R in structure A₁、R₂With R₃WithFor hydrogen atom.

3. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 1, the compound of preparation structure A,Using the compound of structure B as intermediate:

R₁、R₂With R₃For hydrogen atom, halogen or oxyl, can be identical substituting group, also can be different substituting groups.

4. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 3, R in structure B₁、R₂With R₃WithFor hydrogen atom.

5. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 3, preparation structure B compound, adoptsWith 4-allyl acetic acid benzyl ester be raw material, adopt epoxidation or by forming after hydroxyl halide in alkaline environment dehydration, obtain epoxidationCompound, it is as the intermediate of preparation structure B; The structure of epoxide:

R₁For hydrogen atom, halogen or oxyl.

6. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 5, epoxide R₁For hydrogen formerSon, structure is:

The epoxidation reagent using is hydrogen peroxide, Peracetic acid, metachloroperbenzoic acid.

7. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 5, epoxide and dibenzylamineOr fragrant nuclear substituted dibenzylamine generation addition reaction, preparation is as the compound of structure B.

8. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 3, adopts oxidant IBX (diiodo-Acyl group benzoic acid), DMP (1,1,1-, tri-ethoxy acyl group-1,1-dihydroxy-1,2-benzenesulfonyl-3 (1H)-one), Qiong Shi reagent be to changingCompound B is oxidized, and obtains as the compound of structure A.

9. the preparation technology of a kind of 5-ALA (5-ALA) as claimed in claim 1, structure A compound adopts palladiumThe catalyst that carbon, palladium dydroxide, platinum black are catalytic hydrogenation; Under existing, hydrochloric acid through catalytic hydrogenation, prepares aminoguanidine hydrochloride secondAcyl propionic acid (5-ALA).