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

A compound, C1-C14 technology, applied in the field of synthesis of L-3-hydroxy-4-methoxy-5-methyl-phenylalaninol/acid compounds, can solve the problem of affecting the yield and yield of the synthesis process It is not ideal and needs to be improved to achieve the effect of easy industrialization, cheap reagents and low toxicity

Inactive Publication Date: 2012-06-20
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] 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
[0016] 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

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1: Preparation of compound five (R group is Cbz), namely L-N-Cbz-3-methyl-4-methoxy-phenylalanine methyl ester:

[0034] Add 1.62mmol of LN-Cbz-3-hydroxymethyl-tyrosine (Compound 4 with Cbz as the R group) in a 50mL round bottom flask, under the protection of argon, add 6.5mL of acetone, add 4.85mmol after the product is dissolved Potassium carbonate, 4.85mmol dimethyl sulfate, heated to reflux under magnetic stirring, reflux temperature 60℃, react for 7h under reflux conditions, TLC detects the end of the reaction, after the reaction, acetone is evaporated, appropriate amount of water is added, and ethyl acetate is extracted Three times, anhydrous Na 2 SO 4 After drying and evaporating the solvent, a light yellow liquid crude product was obtained. Under argon protection, add 14mLCH to the crude product 2 Cl 2 , Then add 5.55mmol Et 3 SiH and 22.19mmol CF 3 COOH, stirring at room temperature for 10h, after the reaction, use dilute Na 2 CO 3 Neutralize the solution,...

Embodiment 2

[0035] Example 2: Preparation of compound six (R group is Cbz), that is, L-N-Cbz-3-formyl-4-methoxy-5-methyl-phenylalanine methyl ester:

[0036] Add 1.362mmol of compound five (R group is Cbz) in a 25mL round-bottomed flask, under the protection of argon, add 5mL CH 2 Cl 2 , Then lower the temperature to -10℃, add 3.268mmolTiCl 4 And 1.634mmol Cl 2 CHOCH 3 , React for 3h, after the reaction, pour the reaction solution into a beaker filled with ice water, stir for 1h, extract three times with ethyl acetate, anhydrous Na 2 SO 4 After drying and evaporating the solvent, a yellow-green liquid crude product is obtained. After the crude product is separated by a chromatographic column, compound six (R group is Cbz) is obtained 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...

Embodiment 3

[0037] Example 3: Preparation of compound seven (R group is Cbz), namely L-N-Cbz-3-hydroxy-4-methoxy-5-methyl-phenylalaninol:

[0038] In a 25mL round-bottom flask, add 1.1mmol of compound six (R group is Cbz) and 11mL of dichloromethane. After the reactants are dissolved, add 1.65mmol of m-chloroperoxybenzoic acid. After stirring for 13h at room temperature, use dilute Na 2 CO 3 Neutralize the solution, extract three times with dichloromethane, combine the organic phases, wash with saturated NaCl solution, anhydrous Na 2 SO 4 After drying and evaporating the solvent, a yellow liquid crude product was obtained. Without treatment, THF was added to the crude product at a concentration of 0.1 mol / L, and 2 eq of LiBH was added. 4 After reaction for 2h, the solvent was distilled off under reduced pressure, extracted three times with ethyl acetate, anhydrous Na 2 SO 4 After drying and evaporating the solvent, a yellow-green liquid crude product is obtained, which is separated by a chromat...

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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

Invention field [0001] The invention relates to the synthesis of L-3-hydroxy-4-methoxy-5-methyl-phenylalanol and L-3-hydroxy-4-methoxy-5-methyl-phenylalanine compounds new method. Background of the invention [0002] L-3-hydroxy-4-methoxy-5-methyl-phenylalanine compounds and L-3-hydroxy-4-methoxy-5-methyl-phenylalanine compounds are hand It is an important intermediate for synthetic marine tetrahydroisoquinoline alkaloids. Many of these alkaloids and their derivatives show a high degree of anti-cancer, antibacterial and other activities, and have been attracting 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 class of compounds. Among them, Ecteinascidin 743 has taken the lead in being used in Europe and the United States as a promising new anti-cancer drug for the treatment of various tumors (d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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