Synthesis method of multi-configuration long-chain phenyl amino acid compound

A technology of amino acids and synthetic methods, applied in the field of organic compound synthesis, can solve the problems of acetyl residue, low yield of final product compound 4, long reaction time and the like

Inactive Publication Date: 2020-10-16
苏州爱玛特生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the above synthesis method, too many solvents are used, including ethanol, hydrochloric acid, acetic acid, etc., the operation steps are cumbersome, the reaction time is too long, and the reaction needs to use sodium, which is less safe; on the other hand, the used acetamido propane Acetyl diethyl ester is easy to cause the residue of acetyl group in subsequent steps, and it is easy to irritate the eyes; the yield of final product compound 4 is also low

Method used

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  • Synthesis method of multi-configuration long-chain phenyl amino acid compound
  • Synthesis method of multi-configuration long-chain phenyl amino acid compound
  • Synthesis method of multi-configuration long-chain phenyl amino acid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Synthesis of 2-amino-5-phenylpentanoic acid

[0073]

[0074] Under nitrogen, add iodobenzene (2.04g, 10mmol), N-tert-butoxycarbonyl-propargylglycine (2.13g, 10mmol), CuCl (0.04g, 0.40mmol), dissolve in 40mL tetrahydropyrrole, Then add Pd(PPh 3 ) 2 Cl 2 (0.14g, 0.2mmol), stirred at room temperature (25°C) for 1h, after the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin off most of the solvent, purified by silica gel column chromatography, using petroleum ether / Elution with ethyl acetate (V / V=15 / 1) gave 2-((tert-butoxycarbonyl)amino)-5-phenyl-4-pentynoic acid (2.6 g), which was then added with 10% Pd / C (1.16g) was dissolved in EtOH (15mL), THF (15mL) mixed solution, in H 2 After reacting for 2 hours at room temperature (25°C) under the conditions, after removing the solvent, add 20% (V / V) TFA / CH 2 Cl 2 (30 mL), the reaction mixture was stirred at room temperature (25°C) for 1 h, the aqueous phase was extracted three times with...

Embodiment 2

[0079] (R)-2-Amino-5-phenylpentanoic acid

[0080]

[0081] In this example, with iodobenzene (10mmol) and (R)-N-tert-butoxycarbonyl-propargylglycine (10mmol) as starting materials, the others are the same as in Example 1, and the final product (R)-2-amino- The yield of 5-phenylpentanoic acid was 89%.

[0082] Carry out NMR test to product, the result is as follows:

[0083] 1 H NMR (400MHz,D 2 O)δ7.26(m,3H),7.15(ddq,2H),3.83(tt,1H),2.55(tt,2H),1.82(m,2H),1.70(pd,2H).

[0084] 13 C NMR (125MHz,D 2 O) δ176.95(dd), 142.24(tt), 128.58(m), 126.41(tq), 56.70(ddd), 35.12(p), 30.83(td), 26.66(q).

Embodiment 3

[0086] (S)-2-Amino-5-phenylpentanoic acid

[0087]

[0088] In this example, with iodobenzene (10mmol) and (S)-N-tert-butoxycarbonyl-propargylglycine (10mmol) as starting materials, others are the same as in Example 1, and the final product (S)-2-amino- The yield of 5-phenylpentanoic acid was 90%.

[0089] Carry out NMR test to product, the result is as follows:

[0090] 1 H NMR (400MHz,D 2 O)δ7.26(m,3H),7.15(ddq,2H),3.83(tt,1H),2.55(tt,2H),1.82(m,2H),1.70(pd,2H).

[0091] 13 C NMR (125MHz,D 2 O) δ176.95(dd), 142.24(tt), 128.57(m), 126.41(tq), 56.94(ddd), 35.12(p), 30.84(ddd), 26.66(q).

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Abstract

The invention relates to a method for synthesizing a multi-configuration long-chain phenyl amino acid compound. The method comprises the following steps: reacting a compound shown in a formula I witha compound shown in a formula II or an isomer thereof in the presence of a solvent and a catalyst under the protection of inert gas to prepare a first intermediate or an isomer thereof; reacting the first intermediate or the isomer thereof with H2 in the presence of a solvent and a catalyst to prepare a second intermediate or an isomer thereof; carrying out a de-protection reaction on the second intermediate or the isomer thereof under an acidic condition to obtain a compound shown as a formula III or an isomer thereof; wherein the formula I, the formula II, and the formula III are shown in the specification, in the formula I, the formula II and the formula III, R is one of H, alkyl and alkoxyl; n is an integer from 3 to 6, and n' is equal to n-2. The synthesis method is safe, efficient, easy and convenient to operate and easy to control, and the product yield reaches 87% or above.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a synthesis method of multi-configuration long-chain phenyl amino acid compounds. Background technique [0002] Long-chain phenyl amino acid compounds are an important class of amino acids in pharmaceutical intermediates, and are widely used in the field of medicinal chemistry. For example, it can be used as an intermediate in the synthesis of cathepsin inhibitors, etc. [0003] At present, there are few synthesis methods for this type of amino acid structure, but for the synthesis method published now, refer to the synthesis method disclosed in the patent US20100322855A1, the route is as follows: [0004] [0005] The synthesis steps are as follows: (1) Add absolute ethanol to the flask, add sodium in batches, stir, then add the ethanol solution of diethyl acetamidomalonate, heat to 50°C for 1.5h, then reflux for 10min, the system becomes Clou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C227/40C07C227/42C07C229/36C07C269/06C07C271/22
CPCC07C227/18C07C227/40C07C227/42C07C269/06C07B2200/07C07C271/22C07C229/36Y02P20/55
Inventor 汪明中朱明新苏道李金金
Owner 苏州爱玛特生物科技有限公司
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