A process for the synthesis of an amino-protected 2-aminomethyl olefinic acid derivative

Abstract

This invention relates to a method for synthesizing an amino-protected 2-aminomethylenoic acid derivative, comprising the following steps: (1) reacting the compound shown in formula (II) with 2-methyl-2-butene in the presence of a catalyst and a solvent to generate the compound shown in formula (III); (2) reacting the compound shown in formula (III) with an amino-protecting agent to generate the compound shown in formula (I), which is the amino-protected 2-aminomethylenoic acid derivative. The synthesis method of this invention is simple to operate, has few synthesis steps, produces few byproducts, and has a high product yield, making it more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for synthesizing an amino-protected 2-aminomethylenoic acid derivative. Background Technology

[0002] Amino-protected 2-aminomethylenoic acid derivatives are a type of non-natural amino acid and are an important class of pharmaceutical intermediates. They are widely used in the field of pharmaceutical chemistry, such as being frequently added to bioactive peptides in drug research.

[0003] The traditional synthetic method for this type of compound is to use 3-methylbut-2-enoic acid as the starting material, first alcoholize it and then iodize it with p-toluenesulfonyl chloride to 1-iodo-3-methylbut-2-ene, in preparation for the next step of adding an amino group. After adding an amino acetyl group with diethyl acetaminomalonate, the acetyl group is removed to obtain the target amino acid. Then, an amino protecting group is added to obtain the target product.

[0004]

[0005] Traditional synthesis methods are cumbersome, lengthy, and result in high losses, low yields, and high costs. Summary of the Invention

[0006] The technical problem to be solved by the present invention is that the existing synthesis methods have lengthy steps and low yields. The present invention provides an improved synthesis method for amino-protected 2-aminomethylenoic acid derivatives, which is more suitable for industrial production.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A method for synthesizing an amino-protected 2-aminomethylenoic acid derivative, wherein the structural formula of the amino-protected 2-aminomethylenoic acid derivative is shown in formula (I): The synthesis method includes the following steps:

[0009] (1) React the compound shown in formula (II) with 2-methyl-2-butene in the presence of a catalyst and a solvent to generate the compound shown in formula (III);

[0010] (2) React the compound shown in formula (III) with an amino protecting agent to generate the compound shown in formula (I), namely the amino-protected 2-aminomethyl olefinic acid derivative.

[0011] The structural formula of the compound shown in formula (II) is:

[0012] The structural formula of the compound shown in formula (III) is:

[0013] In formula (I), R is an amino protecting group, and in formulas (I), (II), and (III), n is 1 to 4.

[0014] Furthermore, n is 1, 2, 3, or 4.

[0015] In some embodiments, in step (1), the catalyst comprises at least a ruthenium catalyst.

[0016] In some specific embodiments, the catalyst further includes a Lewis acid catalyst, which is one or a combination of several of B(OPh)3, tributylboron (B(C2H5)3), and tributylfluoroborane (BF3·OEt2).

[0017] Advantageously, the mass ratio of the ruthenium catalyst to the Lewis acid catalyst is 1:1.5 to 2.5.

[0018] In some specific embodiments, the ruthenium catalyst is one or a combination of several of (1,3-dimethylimidazolium-2-ylenedimethyl)(2-isopropoxybenzyl)ruthenium chloride (VI) and phenylmethylenebis(tricyclohexylphosphine) ruthenium dichloride.

[0019] In some embodiments, the molar ratio of the catalyst to the compound shown in formula (II) is 0.005 to 0.05:1; and the molar ratio of 2-methyl-2-butene to the compound shown in formula (II) is greater than 10.

[0020] Further, the molar ratio of 2-methyl-2-butene to the compound shown in formula (II) is 10 to 40:1. Even further, the molar ratio of 2-methyl-2-butene to the compound shown in formula (II) is 15 to 25:1.

[0021] In some embodiments, the solvent in step (1) is ethanol.

[0022] In some embodiments, in step (1), the reaction is carried out at 15–50°C for 3–15 hours. Further, the reaction is carried out at 35–45°C for 3–6 hours.

[0023] In some specific embodiments, step (1) is specifically implemented as follows: under an inert gas atmosphere, the compound shown in formula (II) is reacted with 2-methyl-2-butene in the presence of a catalyst and a solvent at 15-50°C. After the reaction is completed, the mixture is filtered, washed with water, and pulped to obtain the compound shown in formula (I).

[0024] Furthermore, the pulping process uses a mixture of ethyl acetate and n-heptane, wherein the volume ratio of ethyl acetate to n-heptane is 1:5 to 15.

[0025] In some embodiments, R is selected from Boc and Fmoc; the amino protecting agent is selected from di-tert-butyl dicarbonate and fluorenemethyloxycarbonyl succinimide.

[0026] In some embodiments, in step (2), the reaction is carried out in the presence of a solvent, which is a mixture of an organic solvent and water, and the organic solvent is one or a combination of dioxane, tetrahydrofuran, N,N-dimethylformamide (DMF).

[0027] Furthermore, when the amino protecting agent is di-tert-butyl dicarbonate, the organic solvent is dioxane, and the volume ratio of dioxane to water is 1 to 3:1.

[0028] Furthermore, when the amino protecting agent is fluorenemethyloxycarbonyl succinimide, the organic solvent is tetrahydrofuran.

[0029] In some embodiments, in step (2), the reaction is carried out at 15–40°C in the presence of a base.

[0030] Furthermore, the alkali is one or a combination of several of sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, and potassium tert-butoxide.

[0031] In some specific embodiments, when the amino protecting agent is di-tert-butyl dicarbonate, step (2) is specifically implemented as follows: under ice bath conditions, the compound shown in formula (III), solvent and base are added to the reactor, and then the amino protecting agent and base are added to the reactor. The reaction is carried out at 15-40°C for 6-10 hours. The solvent is evaporated, diluted with ethyl acetate in an ice bath, acidified to pH 2-3, extracted, washed with water and combined with organic phases, dried and evaporated to obtain the amino-protected 2-aminomethyl olefinic acid derivative.

[0032] In some specific embodiments, when the amino protecting agent is fluorenemethyloxycarbonyl succinimide, step (2) is specifically implemented as follows: under ice bath conditions, the amino protecting agent is dissolved in a solvent and then added to a reactor containing the compound shown in formula (III), a solvent and a base, and reacted at 15-40°C for 6-10 hours. After extraction, the pH is adjusted to 1-3, extracted, washed with weak acid water, dried, concentrated and recrystallized to obtain the amino-protected 2-aminomethyl olefinic acid derivative.

[0033] The second technical solution adopted by the present invention is: a method for preparing the compound shown in formula (III) above.

[0034] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0035] The synthesis method of the present invention uses 2-aminoenoic acid derivatives as starting materials, reacts with 2-methyl-2-butene in the presence of a catalyst, and then attaches an amino protecting group to the nitrogen to obtain an amino-protected 2-aminomethylenoic acid derivative. The method is simple to operate, has few synthesis steps, few by-products, and high product yield, making it more suitable for industrial production. Attached Figure Description

[0036] Figure 1 The NMR spectrum of 2-((tert-butoxycarbonyl)amino)-5-methylhex-4-enoic acid from Example 1;

[0037] Figure 2 The NMR spectrum of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-5-methylhex-4-enoic acid from Example 2 is shown. Detailed Implementation

[0038] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0039] The raw materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0040] The structure of the compound was determined by nuclear magnetic resonance (¹H-NMR). NMR determination was performed using an ACF-400BRUKER NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated dimethyl sulfoxide (DMSO-D₆), or heavy water (D₂O), with TMS as an internal standard. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0041] Example 1

[0042] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-5-methylhex-4-enoic acid.

[0043]

[0044] The synthesis steps include:

[0045] (1) Under nitrogen atmosphere, 2-aminopent-4-enoic acid (1.15 g, 10 mmol), Hoveyda-Grubbs catalyst ((1,3-dimethylimidazolidine-2-ylene) (2-isopropoxybenzyl)ruthenium chloride (VI)) (62.5 mg, 0.1 mmol) and B(OPh)3 (0.06 g, 0.2 mmol), 2-methyl-2-butene (16.4 mL, 200 mmol) and 5 mL of ethanol solution were added sequentially to a three-necked flask. The mixture was stirred at 40 °C for 5 h. After the reaction was completed, the reaction solution was filtered, washed with water several times, and 2-amino-5-methylhexane-4-enoic acid (1.4 g, 98%) was obtained by slurry treatment of a mixture of ethyl acetate and n-heptane at a volume ratio of 1:10.

[0046] (2) Under ice bath conditions, 2-amino-5-methylhexane-4-enoic acid (1.43 g, 10 mmol), dioxane / H₂O (v / v = 2:1, 30 mL), and NaOH (1 M, 10 mmol) were added to a 150 mL round-bottom flask. (Boc)₂O (Boc anhydride) (3.27 g, 15 mmol) and NaHCO₃ (10 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 8 h. The solvent was evaporated to dryness, and the residue was diluted with ethyl acetate (40 mL) in an ice bath and acidified to pH 2-3 with 1.0 M HCl. The aqueous phase was extracted with EtOAc (2 × 20 mL), washed several times with water, and the organic phases were combined, dried over anhydrous Na₂SO₄, and evaporated to dryness to give 2-((tert-butoxycarbonyl)amino)-5-methylhexane-4-enoic acid (2.36 g, 97.1%).

[0047] MRI results:

[0048] 1 H NMR (400MHz, CDCl3) δ8.63(s,1H),5.05-5.97(m,2H),4.25(m,1H),2.54(ddd,2H),1.68(d,6H),1.45(s,9H).

[0049] Example 2

[0050] This embodiment provides the synthesis of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-5-methylhex-4-enoic acid.

[0051]

[0052] The synthesis steps include:

[0053] (1) Same as Example 1.

[0054] (2) At 0 °C, Fmoc-OSu (1.35 g, 4 mmol) was dissolved in tetrahydrofuran (10 mL) solution and added to a reactor containing 2-amino-5-methylhexane-4-enoic acid (0.58 g, 4 mmol) and 12 mL of 10% Na2CO3 solution. The reaction was then stirred at room temperature for 8 h. After the reaction was completed, the mixture was extracted with diethyl ether, and the pH was adjusted to 2 with 2N hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL × 3), washed with acetic acid, dried, concentrated, and recrystallized to obtain 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-5-methylhexane-4-enoic acid (1.4 g, 96.0%).

[0055] MRI results:

[0056] 1 H NMR (400MHz, DMSO) δ12.62(s,1H),7.56(m,9H),5.14(t,1H),4.27(m,3H),3.96(td,1H),2.37(ddt,2H),1.63(d,6H).

[0057] Example 3

[0058] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-6-methylhept-5-enoic acid.

[0059] n=2

[0060] In this example, 10 mmol of 2-aminohexyl-5-enoic acid was used instead of 2-aminopent-4-enoic acid, and the rest was the same as in Example 1. The final overall yield of 2-((tert-butoxycarbonyl)amino)-6-methylhept-5-enoic acid was 95%.

[0061] 1 H NMR (400MHz, CDCl3) δ8.73(s,1H),5.16-5.51(m,2H),4.15(dt,1H),2.14(m,2H),1.97(dq,1H),1.73(dq,1H),1.64(dp,6H),1.41(s,9H).

[0062] Example 4

[0063] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-7-methyloct-6-enoic acid.

[0064] n=3

[0065] In this example, 10 mmol of 2-aminohept-6-enoic acid was used instead of 2-aminopent-4-enoic acid, and the rest was the same as in Example 1. The final overall yield of 2-((tert-butoxycarbonyl)amino)-7-methyloct-6-enoic acid was 95.6%.

[0066] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),5.14-5.50(m,2H),4.32(dt,1H),2.03(m,2H),1.63(m,10H),1.41(s,9H).

[0067] Example 5

[0068] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-8-methylnon-7-enoic acid.

[0069] n=4

[0070] In this example, 10 mmol of 2-aminooct-7-enoic acid was used instead of 2-aminopent-4-enoic acid, and the rest was the same as in Example 1. The final overall yield of 2-((tert-butoxycarbonyl)amino)-8-methylnon-7-enoic acid was 95.9%.

[0071] 1 H NMR (400MHz, CDCl3) δ8.81(s,1H),5.13-5.44(m,1H),4.32(dt,1H),1.97(m,2H),1.63(m,8H),1.43(m,13H).

[0072] Example 6

[0073] This embodiment provides the synthesis of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-8-methylnon-7-enoic acid.

[0074] n=4

[0075] In this example, 10 mmol of 2-aminooct-7-enoic acid was used instead of 2-aminopent-4-enoic acid, otherwise the same as in Example 2. The final overall yield of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-8-methylnon-7-enoic acid was 95.3%.

[0076] 1 H NMR (400MHz, DMSO) δ12.02(s,1H),7.50(m,9H),5.12(t,1H),4.45(d,2H),4.28(m,2H),1.97(m,2H),1.63(m,8H),1.44(m,4H).

[0077] Example 7

[0078] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-5-methylhex-4-enoic acid, wherein step (1) is:

[0079] Under nitrogen atmosphere, 2-aminopent-4-enoic acid (1.15 g, 10 mmol), Hoveyda-Grubbs catalyst ((1,3-dimethylimidazolidine-2-ylene))(2-isopropoxybenzyl)ruthenium chloride (VI) (62.5 mg, 0.1 mmol), 2-methyl-2-butene (16.4 mL, 200 mmol), and 5 mL of ethanol solution were added sequentially to a three-necked flask. The mixture was stirred at 40 °C for 5 h. After the reaction was completed, the reaction solution was filtered, washed with water several times, and slurried with a mixture of ethyl acetate and n-heptane at a volume ratio of 1:10 to obtain 2-amino-5-methylhexane-4-enoic acid (1.1 g, 78%).

[0080] Everything else is the same as in Example 1.

[0081] Example 8

[0082] This embodiment provides the synthesis of 2-((tert-butoxycarbonyl)amino)-5-methylhex-4-enoic acid, which differs from Example 7 in that dichloromethane is used instead of ethanol in step (1).

[0083] Under nitrogen atmosphere, 2-aminopent-4-enoic acid (1.15 g, 10 mmol), Hoveyda-Grubbs catalyst ((1,3-dimethylimidazolidine-2-ylene))(2-isopropoxybenzyl)ruthenium chloride (VI) (62.5 mg, 0.1 mmol), 2-methyl-2-butene (16.4 mL, 200 mmol), and 5 mL of dichloromethane solution were added sequentially to a three-necked flask. The mixture was stirred at 40 °C for 5 h. After the reaction was completed, the reaction solution was filtered, washed with water several times, and slurried with a mixture of ethyl acetate and n-heptane at a volume ratio of 1:10 to obtain 2-amino-5-methylhexane-4-enoic acid (0.8 g, 56%).

[0084] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0085] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for synthesizing an amino-protected 2-aminomethylenoic acid derivative, wherein the structural formula of the amino-protected 2-aminomethylenoic acid derivative is shown in formula (I): Its features are, The synthesis method includes the following steps: (1) The compound shown in formula (II) is reacted with 2-methyl-2-butene in the presence of a catalyst and a solvent to produce the compound shown in formula (III); the catalyst comprises at least a ruthenium catalyst and further comprises a Lewis acid catalyst; the Lewis acid catalyst is B(OPh)3; the ruthenium catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxybenzyl)ruthenium; the solvent is ethanol; (2) React the compound shown in formula (III) with an amino protecting agent to generate the compound shown in formula (I), namely the amino-protected 2-aminomethyl olefinic acid derivative. The structural formula of the compound shown in formula (II) is: The structural formula of the compound shown in formula (III) is: In formula (I), R is an amino protecting group, and in formulas (I), (II), and (III), n is 1 to 4.

2. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: The molar ratio of the catalyst to the compound shown in formula (II) is 0.005 to 0.05:1; and / or, the molar ratio of the 2-methyl-2-butene to the compound shown in formula (II) is greater than 10.

3. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 2, characterized in that: The molar ratio of 2-methyl-2-butene to the compound shown in formula (II) is 10 to 40:

1.

4. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: In step (1), the reaction is carried out at 15–50 °C for 3–15 h; and / or, step (1) is specifically implemented as follows: under an inert gas atmosphere, the compound shown in formula (II) is reacted with 2-methyl-2-butene in the presence of a catalyst and a solvent at 15–50 °C. After the reaction is completed, the mixture is filtered, washed with water, and pulped to obtain the compound shown in formula (III).

5. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: The R is selected from Boc, Fmoc; and / or the amino protecting agent is selected from di-tert-butyl dicarbonate, fluorenemethyloxycarbonyl succinimide.

6. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: In step (2), the reaction is carried out in the presence of a solvent, which is a mixture of an organic solvent and water, and the organic solvent is one or a combination of several of dioxane, tetrahydrofuran, and N,N-dimethylformamide.

7. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: In step (2), the reaction is carried out at 15–40°C in the presence of a base.

8. The method for synthesizing the amino-protected 2-aminomethylenoic acid derivative according to claim 1, characterized in that: When the amino protecting agent is di-tert-butyl dicarbonate, step (2) is specifically implemented as follows: Under ice bath conditions, the compound shown in formula (III), solvent, and base are added to the reactor, and then the amino protecting agent and base are added to the reactor. The reaction is carried out at 15–40 °C for 6–10 h. The solvent is evaporated, diluted with ethyl acetate in an ice bath, acidified to pH 2–3, extracted, the combined organic phases are washed with water, dried, and evaporated to obtain the amino-protected 2-aminomethylenoic acid derivative; or… When the amino protecting agent is fluorenemethyloxycarbonyl succinimide, the specific implementation of step (2) is as follows: under ice bath conditions, the amino protecting agent is dissolved in a solvent and then added to a reactor containing the compound shown in formula (III), a solvent and a base. The reaction is carried out at 15-40°C for 6-10 hours. After extraction, the pH is adjusted to 1-3, and the mixture is extracted, washed with weak acid water, dried, concentrated and recrystallized to obtain the amino-protected 2-aminomethyl olefinic acid derivative.

9. A method for preparing a compound of formula (III), characterized in that: The compound shown in formula (II) is reacted with 2-methyl-2-butene in the presence of a catalyst and a solvent to produce the compound shown in formula (III); the catalyst comprises at least a ruthenium catalyst and further comprises a Lewis acid catalyst; the Lewis acid catalyst is B(OPh)3; the ruthenium catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxybenzyl)ruthenium; the solvent is ethanol; The structural formula of the compound shown in formula (II) is: The structural formula of the compound shown in formula (III) is: The value of n is 1 to 4.

10. The method for preparing the compound of formula (III) according to claim 9, characterized in that: The molar ratio of the catalyst to the compound shown in formula (II) is 0.005 to 0.05:1; and / or, the molar ratio of the 2-methyl-2-butene to the compound shown in formula (II) is greater than 10.

11. The method for preparing the compound of formula (III) according to claim 9, characterized in that: The molar ratio of 2-methyl-2-butene to the compound shown in formula (II) is 10 to 40:

1.

12. The method for preparing the compound of formula (III) according to claim 9, characterized in that: The solvent is ethanol; and / or the reaction is carried out at 15–50°C for 3–15 h; and / or, specifically, the compound shown in formula (II) is reacted with 2-methyl-2-butene at 15–50°C in the presence of a catalyst and a solvent under an inert gas atmosphere. After the reaction is completed, the mixture is filtered, washed with water, and pulped to obtain the compound shown in formula (III).

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