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Synthesis of L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol/phenylalanine

A compound and crude product technology, applied in the field of synthesis of L-3-hydroxy-4-methoxy-5-methyl-phenylalaninol/acid compound, can solve the problems affecting the yield of the synthesis process, the yield is not Ideal, expensive and other problems, to achieve the effect of easy industrialization, cheap reagents, and easy operation

Inactive Publication Date: 2009-11-25
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Although this synthetic route has the advantages of cheap raw materials and short routes, in the preparation of compound three, the yield of formyl groups introduced by the Riemer-Tiemann reaction is only 25% to 30%, which directly affects the yield of the entire synthetic process, and The introduction of 5-methyl uses some expensive drugs
In addition, through Dakin oxidation as a key step, compound three is converted into L-3-hydroxyl-4-methoxy-5-methyl-phenylalanine, and the yield is not very satisfactory (about 50%), which needs to be improved
[0017] It can be seen that the method for preparing L-3-hydroxyl-4-methoxyl group-5-methyl-phenylalaninol / acid compound still has many deficiencies at present, especially from the point of view of industrialization

Method used

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  • Synthesis of L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol/phenylalanine
  • Synthesis of L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol/phenylalanine
  • Synthesis of L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol/phenylalanine

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Effect test

Embodiment 1

[0034] Embodiment 1: Compound five (R group is Cbz), namely the preparation of L-N-Cbz-3-methyl-4-methoxyl-phenylalanine methyl ester:

[0035] Add 1.62mmol of L-N-Cbz-3-hydroxymethyl-tyrosine (compound 4 whose R group is Cbz) into a 50mL round bottom flask, under the protection of argon, add 6.5mL of acetone, after the product dissolves, add 4.85mmol Potassium carbonate, 4.85mmol dimethyl sulfate, heated to reflux under magnetic stirring, reflux temperature 60°C, reacted under reflux conditions for 7h, TLC detected the reaction end point, after the reaction, distilled off acetone, added appropriate amount of water, extracted with ethyl acetate Three times, anhydrous Na 2 SO 4 After drying, the solvent was evaporated to obtain the crude product as light yellow liquid. Under argon protection, 14 mL of CH was added to the crude product 2 Cl 2 , then add 5.55mmol Et 3 SiH and 22.19 mmol CF 3 COOH, stirred at room temperature for 10h, after the reaction, dilute Na 2 CO 3 T...

Embodiment 2

[0036] Embodiment 2: Preparation of compound six (R group is Cbz), i.e. L-N-Cbz-3-formyl-4-methoxy-5-methyl-phenylalanine methyl ester:

[0037] Add 1.362mmol of compound five (the R group is Cbz) in a 25mL round bottom flask, and add 5mL of CH 2 Cl 2 , then cool down to -10°C, add 3.268mmolTiCl 4 and 1.634 mmol Cl 2 CHOCH 3 , reacted for 3h, after the reaction, the reaction solution was poured into a beaker filled with ice water, stirred for 1h, extracted three times with ethyl acetate, anhydrous Na 2 SO 4 Drying and evaporating off the solvent gave the crude yellow-green liquid product, which was separated by a chromatographic column to obtain compound six (the R group is Cbz), with a yield of 89%; [α] D 26 +63(c 1.1, CHCl 3 );IR(neat)v max : 3314, 2954, 2866, 1748, 1692, 1541, 1259, 1214, 1058, 1006, 749, 698cm -1 ; 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 10.32 (1H, s), 7.42 (1H, s), 7.25-7.37 (5H, m), 7.19 (1H, s), 5.31 (1H, d, J = 8.0), 5.12 (1H , d, J=12.2), 5.07 ...

Embodiment 3

[0038] Embodiment 3: Preparation of compound seven (R group is Cbz), i.e. L-N-Cbz-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol:

[0039] Add 1.1mmol compound six (the R group is Cbz) and 11mL dichloromethane into a 25mL round bottom flask, add 1.65mmol m-chloroperoxybenzoic acid after the reactant is dissolved, stir at room temperature for 13h, then wash with dilute Na 2 CO 3 The solution was neutralized, extracted three times with dichloromethane, the organic phases were combined, washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 Dry and evaporate the solvent to obtain a yellow liquid crude product, add THF to the crude product without treatment, the concentration is 0.1mol / L, add 2eq of LiBH 4 , After reacting for 2h, the solvent was distilled off under reduced pressure, extracted three times with ethyl acetate, anhydrous Na 2 SO 4 Drying and evaporating the solvent gave the yellow-green liquid crude product, which was separated by a chromatographic column to o...

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Abstract

The invention provides a preparation method of amino protected L-3-formyl-4-methoxyl-5-methyl-phenylalanine methyl ester (structural formula is below), highly effectively converts the amino protected L-3-formyl-4-methoxyl-5-methyl-phenylalanine methyl ester into amino protected L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol / phenylalanine, and develops a simple and practical new method for synthesizing a L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol / phenylalanine compound. The L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol / phenylalanine compound is an important intermediate for chirally synthesizing tetrahydroisoquinoline alkaloids with high anti-cancer activity such as Ecteinascidin 743, Saframycin A and Cribrostatin IV. The method overcomes the disadvantages of the prior synthesis, has the advantages of short steps, high yield, cheap raw material, moderate conditions, simple and convenient operation, and easy industrial production, and is a good method for preparing the L-3-hydroxyl-4-methoxyl-5-methyl-phenylalaninol / phenylalanine compound.

Description

field of invention [0001] The present invention relates to the synthesis of L-3-hydroxyl-4-methoxyl-5-methyl-phenylalanine L-3-hydroxyl-4-methoxyl-5-methyl-phenylalanine compounds new method. Background of the invention [0002] L-3-hydroxy-4-methoxy-5-methyl-phenylalaninol compounds and L-3-hydroxy-4-methoxy-5-methyl-phenylalanine compounds are chiral An important intermediate for the synthesis of marine tetrahydroisoquinoline alkaloids. Many of these alkaloids and their derivatives have shown a high degree of anticancer, antibacterial and other activities, and have attracted much attention in the research fields of chemistry, biology, and medicine. Ecteinascidin 743 [J.Org.Chem.1990, 55, 4512], Saframycin A [Chem.Pharm.Bull.1985, 33, 905], Cribrostatin IV [J.Nat.Prod.2000, 63, 793], etc. belong to this kind of compounds. Among them, Ecteinascidin 743 is the first to be used in Europe and the United States as a highly potential new anticancer drug for the treatment of va...

Claims

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Application Information

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IPC IPC(8): C07B41/06C07B41/02C07B41/08C07C271/22C07C271/16C07C269/06C07C217/60C07C213/02
Inventor 陈小川陈瑞蛟
Owner SICHUAN UNIV
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