Preparation method of chiral non-natural beta-amino acid

Abstract

The invention provides a preparation method of chiral non-natural beta-amino acid, and belongs to the field of organic synthesis. The preparation method of the chiral non-natural beta-amino acid provided by the invention comprises the following steps: step 1, mixing and stirring racemic non-natural beta-amino acid, chiral alpha-phenylethylamine and acetone, filtering, and taking a solid; step 2, pulping the solid by using acetone to obtain alpha-phenylethylamine salt of chiral non-natural beta-amino acid; 3, acid is added into the alpha-phenylethylamine salt of the chiral non-natural beta-amino acid for dissociation, and the chiral non-natural beta-amino acid is obtained. The process is simple, the yield of the obtained chiral non-natural beta-amino acid is high, and the ee value of the chiral non-natural beta-amino acid can reach 99% or above.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing a chiral non-natural β-amino acid. Background Art

[0002] The paper "A New Class of Highly Potent and Selective Endomorphin-1 Analogues Containing α-Methylene-β-aminopropanoic Acids (Map)" (J. Med. Chem. 2012, 55, 6224-6236) synthesizes a series of endorphin-1 analogues by introducing unnatural β-amino acids into positions 3 and / or 4 of endorphin-1. The results of this paper show that most of the synthesized endorphin-1 analogues exhibit high affinity for the μ-opioid receptor and are more stable than endorphin-1.

[0003] The article "Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists" (J. Med. Chem. 2013, 56, 3102-3114) provides a method for preparing the above-mentioned non-natural β-amino acids, as follows:

[0004]

[0005] Although the above synthetic route can achieve ideal yield and ee value, it requires the use of a chiral catalyst that has not yet been commercialized, and the dosage is as high as 20%, which is not conducive to industrial production. Summary of the Invention

[0006] The present invention is made to solve the above problems and aims to provide a method for preparing chiral non-natural β-amino acids with simple process, high yield and high ee value.

[0007] The present invention provides a method for preparing a chiral non-natural β-amino acid, which has the following characteristics and comprises the following steps:

[0008] Step 1: Mix and stir the racemic non-natural β-amino acid, chiral α-phenylethylamine and acetone, filter and collect the solid;

[0009] Step 2, beating the solid with acetone to obtain an α-phenylethylamine salt of a chiral non-natural β-amino acid;

[0010] Step 3, adding acid to the α-phenylethylamine salt of the chiral non-natural β-amino acid to liberate it, thereby obtaining the chiral non-natural β-amino acid.

[0011] The structural formula of the racemic non-natural β-amino acid is shown in Formula I:

[0012]

[0013] In Formula I, R is a C6-C10 aryl group, a C3-C5 heteroaryl group, or a C6-C10 aryl group substituted by a halogen or an alkoxy group, and PG is an amino protecting group.

[0014] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein R is selected from any one of the following groups:

[0015]

[0016] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein PG is tert-butyloxycarbonyl or benzyloxycarbonyl.

[0017] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein the molar ratio of the racemic non-natural β-amino acid to the chiral α-phenylethylamine is 1:(1.0-1.2).

[0018] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein, in step 1, the mass volume ratio of the racemic non-natural β-amino acid to acetone is 1 g: (15-25) mL.

[0019] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein, in step 2, the mass volume ratio of the solid to acetone is 1 g: (15-25) mL.

[0020] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein step 3 comprises the following steps:

[0021] The α-phenylethylamine salt of the chiral non-natural β-amino acid is dissolved in ethyl acetate, and the pH value is adjusted to 3-4 using a 1-3 mol / L hydrochloric acid aqueous solution. The liquids are separated, and the organic phase is collected and concentrated to obtain the chiral non-natural β-amino acid.

[0022] The method for preparing the chiral non-natural β-amino acid provided by the present invention may also have the following characteristics: wherein the racemic non-natural β-amino acid is The chiral α-phenylethylamine is Chiral unnatural β-amino acids are

[0023] Functions and effects of the invention

[0024] According to the method for preparing a chiral non-natural β-amino acid involved in the present invention, because the applicant unexpectedly discovered that the two chiral molecules of the α-phenylethylamine salt of the non-natural β-amino acid involved in the present application have a significant difference in solubility in acetone, the present application uses chiral α-phenylethylamine to form a salt of the non-natural β-amino acid and perform chiral resolution. This method is not only simple in process, but also has a high yield of the obtained chiral non-natural β-amino acid and an ee value of up to 99% or more. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the HPLC spectrum of the crude product in Example 1 of the present invention;

[0026] Figure 2 is the HPLC spectrum of compound R-Ia prepared in Example 1 of the present invention; and

[0027] Figure 3 It is the HPLC spectrum of the crude product in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0028] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to embodiments and drawings.

[0029] In the following examples, the preparation method of compound Ia is as follows:

[0030]

[0031] The method for preparing compound 2 from compound 1 was based on the paper "Reductive BOC-amination of aldehydes" (Tetrahedron Letters, 42 (2001), 5093–5094). The method for preparing compound Ia from compound 2 was based on the paper "N-Carbamate Protected r-Amidoalkyl-p-tolylsulfones: Convenient Substrates in the aza-Morita-Baylis-Hillman Reaction" (J. Org. Chem., 2008, 73, 8643–8646). Compound Ia prepared by the above method is racemic.

[0032] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0033] <Example 1>

[0034] A method for preparing chiral non-natural β-amino acid

[0035] This embodiment provides a method for preparing a compound represented by formula R-Ia, and the specific steps are as follows:

[0036]

[0037] Step 1: 10 g of compound Ia (35.5 mmol, 1.0 eq) was added to a container, and then 200 mL of acetone and 4.3 g of R-α-phenylethylamine (35.5 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 2 h. A solid precipitated and was filtered to obtain 6.7 g of a crude product. The sample was dissolved in ethyl acetate and neutralized with hydrochloric acid to pH 3-4. The organic phase was then sent to HPLC for detection. The detection results were as follows: Figure 1 As shown, the ee value of the crude product is 73% (in Figure 1 , the peak at Rt=6.519 min is the peak of compound R-Ia, and the peak at Rt=8.165 min is the peak of the enantiomer of compound R-Ia).

[0038] Step 2: Add 134 mL of acetone to 6.7 g of the wet product obtained in step 1, beat for 2 h, filter, and collect the solid to obtain the phenylethylamine salt of compound R-Ia;

[0039] Step 3: The phenylethylamine salt of compound R-Ia obtained in step 2 was dissolved in 45 mL of ethyl acetate, and a 2 mol / L aqueous hydrochloric acid solution was added dropwise until the pH value of the system was 3-4. The liquids were separated, and the organic phase was taken, dried over anhydrous sodium sulfate, and concentrated to obtain 4.57 g of compound R-Ia. The sample was sent for HPLC detection. The test results were as follows: Figure 2 As shown, the ee value of compound R-Ia prepared in this example is 99.1% (in Figure 2 , the peak at Rt=6.463 min is the peak of compound R-Ia, and the peak at Rt=8.016 min is the peak of the enantiomer of compound R-Ia).

[0040] Comparative Example 1

[0041] A method for preparing chiral non-natural β-amino acid

[0042] This embodiment provides a method for preparing a compound represented by formula R-Ia, and the specific steps are as follows:

[0043]

[0044] Step 1: 10 g of compound Ia (35.5 mmol, 1.0 eq) was added to a container, and then 200 mL of acetone and 11.5 g of quinine (35.5 mmol, 0.55 eq) were added. The mixture was stirred at room temperature for 2 h. A solid precipitated and was filtered to obtain 1.8 g of a crude product. A sample was dissolved in ethyl acetate and neutralized with hydrochloric acid to pH 3-4. The organic phase was then sent to HPLC for detection. The detection results were as follows: Figure 3 As shown, the ee value of the crude product is -27% (in Figure 3 , the peak at Rt=6.432 min is the peak of compound R-Ia, and the peak at Rt=7.973 min is the peak of the enantiomer of compound R-Ia).

[0045] Functions and Effects of the Embodiments

[0046] According to the method for preparing the chiral non-natural β-amino acid involved in the above embodiment, because the applicant unexpectedly discovered that the two chiral molecules of the α-phenylethylamine salt of the non-natural β-amino acid involved in this application have a significant difference in solubility in acetone, the present application uses chiral α-phenylethylamine to salt the non-natural β-amino acid and perform chiral resolution. This method is not only simple in process, but also has a high yield of the obtained chiral non-natural β-amino acid and an ee value of up to 99% or more.

[0047] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. A method for preparing a chiral non-natural β-amino acid, characterized in that: The steps include: Step 1: Mix and stir the racemic non-natural β-amino acid, chiral α-phenylethylamine and acetone, filter and collect the solid; Step 2, beating the solid with acetone to obtain an α-phenylethylamine salt of a chiral non-natural β-amino acid; Step 3, adding acid to the α-phenylethylamine salt of the chiral non-natural β-amino acid to liberate it, thereby obtaining the chiral non-natural β-amino acid. The structural formula of the racemic non-natural β-amino acid is shown in Formula I: In Formula I, R is a C6-C10 aryl group, a C3-C5 heteroaryl group, or a C6-C10 aryl group substituted by a halogen or an alkoxy group, and PG is an amino protecting group.

2. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, R is selected from any one of the following groups:

3. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, PG is tert-butyloxycarbonyl or benzyloxycarbonyl.

4. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, The molar ratio of the racemic non-natural β-amino acid to the chiral α-phenylethylamine is 1:(1.0-1.2).

5. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, In step 1, the mass volume ratio of the racemic non-natural β-amino acid to acetone is 1 g: (15-25) mL.

6. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, In step 2, the mass volume ratio of the solid to acetone is 1 g: (15-25) mL.

7. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, Step 3 includes the following steps: The α-phenylethylamine salt of the chiral non-natural β-amino acid is dissolved in ethyl acetate, and the pH value is adjusted to 3-4 using a 1-3 mol / L hydrochloric acid aqueous solution. The liquids are separated, and the organic phase is collected and concentrated to obtain the chiral non-natural β-amino acid.

8. The method for preparing a chiral non-natural β-amino acid according to claim 1, wherein: in, The racemic non-natural β-amino acid is The chiral α-phenylethylamine is Chiral unnatural β-amino acids are

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