Synthesis method of chiral cis (cis)-2-amino-1-cyclopropylcarboxylic acid

Abstract

The invention provides a method for synthesizing chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid, wherein 1,2-cyclopropane dicarboxylic acid anhydride is subjected to alcoholysis in the presence of a catalyst to obtain chiral cis (cis)-1,2-cyclopropane dicarboxylic acid monoester, and then the carboxyl group is converted into an amino group by rearrangement reaction, and the ester is hydrolyzed to obtain chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid. The invention avoids the intermediate of dangerous and easily decomposable alkyl diazo compounds, improves the safety of the process, and the post-processing does not need to use column chromatography to purify and separate the product, and most of the steps can be directly performed backward without purifying the crude product, and the final product is purified by recrystallization, with a total yield of 50%-60%, and a purity of more than 95%, saving production costs, and greatly shortening the time, so that the method is suitable for industrial mass production and also suitable for small-scale laboratory preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and relates to chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid, and in particular to a synthesis method of chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid with simple and readily available raw materials, low cost and simple operation. Background Art

[0002] β-Aminocyclopropane carboxylic acid (β-ACC), as an important non-natural amino acid, is present in a variety of biologically active molecules, such as RIPK1 inhibitors (WO2023099648A1), Neuropeptide Y1 receptor (Analogues of Neuropeptide Y Containing β-Aminocyclopropane Carboxylic Acids are the Shortest Linear Peptides That Are Selective for the Y1 Receptor, Norman Koglin Dipl.-Biochem, etc., Angew. Chem., Int. Ed. 2003, 42, 202), etc.

[0003] However, most of the currently reported synthetic methods can only synthesize trans-β-aminocyclopropanecarboxylic acid (e.g., Stereoselective synthesis of both enantiomers of trans-2-(diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool approach and their incorporation in dipeptides, Tamara Meiresonne et al., Tetrahedron, 68 (2012), 9566-9577 and reference 10 and 11 therein). Due to its strong ring strain and inherent instability, there are few reports on the method of synthesizing cis-β-aminocyclopropanecarboxylic acid (e.g., The Synthesis of Diastereo-and Enantiomerically Pure β-Aminocyclopropanecarboxylic Acids, Raphael Beumer et al., Chem. Rev. 2003, 103, 1603-1623, J. Org. Chem. 2000, 65, 8960-8969), and it is difficult to achieve high chiral purity (e.g., Stereoselective synthesis of both enantiomers of trans-2-(diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool approach and their incorporation in dipeptides, Tamara Meiresonne et al., Tetrahedron, 68 (2012), 9566-9571). In addition, the construction of this three-membered ring requires unstable and easily decomposed alkyl diazo compounds and expensive noble metal catalysts, which is not suitable for industrial scale-up production (e.g., Enantioselective Preparation of cis-β-Azidocyclopropane Esters by Cyclopropanation of Azido Alkenes Using a Chiral Dirhodium Catalyst, Peiming Gu et al., Organic Letters, 2012, Vol 14, No 9, 2246-2249). The synthetic route is as follows:

[0004]

[0005] Therefore, there is a need for a method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid that is efficient, safe and suitable for industrial scale-up production. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a method for synthesizing chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid which is efficient, safe and suitable for industrial scale-up production. The present invention uses cheap and readily available cyclopropane dicarboxylic acid as a raw material to synthesize 1,2-cyclopropane dicarboxylic acid anhydride, utilizes organic catalysis to synthesize chiral cis (cis)-1,2-cyclopropane dicarboxylic acid monoester with high stereoselectivity, and then synthesizes chiral cis (cis)-2-amino-1-cyclopropyl carboxylic acid: (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid through hydrolysis and rearrangement reactions.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The present invention provides a method for synthesizing chiral cis-2-amino-1-cyclopropyl carboxylic acid, which comprises the following steps:

[0009] (a) reacting the compound represented by formula I with an alcohol in the presence of a catalyst to obtain a compound represented by formula II;

[0010] (b) the compound of formula II is amidated, then rearranged and hydrolyzed to obtain the compound of formula III; or the compound of formula II is rearranged and hydrolyzed to obtain the compound of formula III;

[0011] (c) the compound represented by formula III is protected to obtain the compound represented by formula IV;

[0012] Wherein, the compound represented by formula I is:

[0013] The compound shown in formula II:

[0014] The compound shown in formula III:

[0015] The compound shown in formula IV:

[0016] In the formula, R is any alkyl group or aryl group, and P is any amino protecting group.

[0017] As a preferred embodiment of the present invention, in step (a), the reaction temperature is -20°C to 50°C.

[0018] As a preferred embodiment of the present invention, in step (a), the catalyst is a chiral alcoholysis catalyst.

[0019] As a preferred embodiment of the present invention, the catalyst includes N-[(S)-(6-methoxyquinolin-4-yl)(2-vinyl-4-azabicyclo[2.2.2]oct-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenesulfonamide, {[(1R,2R)-2-(dimethylamino)cyclohexyl]amino}(phenylamino)methylthione or {[(1R,2R)-2-(dimethylamino)-1,2-diphenylethyl]amino}(phenylamino)methylthione.

[0020] As a preferred embodiment of the present invention, in step (b), the reagent used for amidation includes thionyl chloride and ammonia water, oxalyl chloride and ammonia water, N,N-carbonyldiimidazole and ammonia water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and ammonia water, or ammonium bicarbonate plus pyridine plus Boc anhydride.

[0021] As a preferred embodiment of the present invention, in step (b), the reagents used for the rearrangement reaction include bromine and sodium hydroxide, dibromohydantoin and sodium hydroxide, sodium hypochlorite and sodium hydroxide, diphenylphosphoryl azide plus triethylamine or N-chloro(bromo)succinimide and sodium hydroxide.

[0022] As a preferred embodiment of the present invention, in step (b), the reagent used for hydrolysis includes sodium hydroxide or potassium hydroxide.

[0023] As a preferred embodiment of the present invention, in step (b), the reaction temperature is -20°C to 80°C.

[0024] As a preferred embodiment of the present invention, in step (c), the reagent used for the upper protection includes di-tert-butyl dicarbonate, acetic anhydride, benzyl chloroformate, benzoic anhydride, 9-fluorenylmethyl chloroformate, p-toluenesulfonyl chloride, trifluoroacetic anhydride or benzyl bromide.

[0025] As a preferred embodiment of the present invention, in step (c), the reaction temperature is -20°C to 100°C.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1) The present invention avoids the use of dangerous and easily decomposable intermediates of alkyl diazo compounds, thereby improving the safety of the process.

[0028] 2) The post-treatment of the present invention does not require the use of column chromatography to purify and separate the product. Most of the steps can be directly performed without purifying the crude product. The final product is purified by recrystallization, with a total yield of 50%-60% and a purity of more than 95%, which saves production costs and greatly shortens the time. It is suitable for industrial mass production and also suitable for small-scale preparation in the laboratory.

[0029] 3) The present invention is different from the prior art in terms of starting materials, process route and post-processing process, and the raw materials of the present invention are simple and easy to obtain, low in cost and simple to operate.

[0030] 4) The present invention uses cheap and readily available cyclopropanedicarboxylic acid as a raw material to synthesize 1,2-cyclopropanedicarboxylic acid anhydride, uses organic catalysis to synthesize chiral cis (cis)-1,2-cyclopropanedicarboxylic acid monoester with high stereoselectivity, and then synthesizes chiral cis (cis)-2-amino-1-cyclopropylcarboxylic acid: (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid through hydrolysis and rearrangement reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0032] Figure 1 It is the synthesis route diagram of the present invention.

[0033] Figure 2 It is the NMR spectrum of Example 1 of the present invention. DETAILED DESCRIPTION

[0034] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0035] The invention provides a method for synthesizing chiral cis (cis)-2-amino-1-cyclopropylcarboxylic acid (also called (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid). The method comprises the following steps: subjecting 1,2-cyclopropanedicarboxylic acid anhydride to alcoholysis in the presence of a catalyst to obtain chiral cis (cis)-1,2-cyclopropanedicarboxylic acid monoester, converting the carboxyl group into an amino group through a rearrangement reaction, and hydrolyzing the ester to obtain (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid.

[0036] As a preferred technical solution of the present invention, the synthesis method of the present invention is:

[0037] (a) dissolving the substance represented by formula I in a solvent, adding a catalyst and an alcohol, reacting at -20°C to 50°C until the reaction is complete, and extracting, washing, and concentrating the reaction solution to obtain the compound represented by formula II;

[0038] (b) dissolving the substance represented by formula II in a solvent, adding an amidating agent to obtain an amide, and then adding a rearrangement agent to rearrange at -20-80°C and hydrolyze until the reaction is completed after the product is separated, and the reaction solution is extracted and washed to obtain an aqueous solution of the compound represented by formula III; or dissolving the substance represented by formula II in a solvent, adding a rearrangement agent to rearrange at -20°C to 80°C, and then adding a hydrolysis agent to hydrolyze until the reaction is completed, and the reaction solution is extracted and washed to obtain an aqueous solution of the compound represented by formula III;

[0039] (c) The substance represented by formula III is dissolved in a solvent, a protecting group reagent is added, and the reaction is carried out at -20°C to 100°C until the reaction is completed. The reaction solution is extracted, washed, concentrated and crystallized to obtain the compound represented by formula IV.

[0040] Wherein, the compound represented by formula I is:

[0041] The compound shown in formula II:

[0042] The compound shown in formula III:

[0043] The compound shown in formula IV:

[0044] In the formula, R is any alkyl group or aryl group, and P is any amino protecting group.

[0045] Preferably, the catalyst is a chiral alcoholysis catalyst such as N-[(S)-(6-methoxyquinolin-4-yl)(2-vinyl-4-azabicyclo[2.2.2]oct-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenesulfonamide, {[(1R,2R)-2-(dimethylamino)cyclohexyl]amino}(phenylamino)methylthione or {[(1R,2R)-2-(dimethylamino)-1,2-diphenylethyl]amino}(phenylamino)methylthione.

[0046] Preferably, the reagents used for the amidation include thionyl chloride and ammonia water, oxalyl chloride and ammonia water, N,N-carbonyldiimidazole and ammonia water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and ammonia water, or ammonium bicarbonate plus pyridine plus Boc anhydride, etc., which are reagents for converting carboxylic acids into amides.

[0047] Preferably, the reagents used for the rearrangement include reagents that convert carboxyl groups or amides into amino groups, such as bromine and sodium hydroxide, dibromohydantoin and sodium hydroxide, sodium hypochlorite and sodium hydroxide, diphenylphosphoryl azide or N-chloro(bromo)succinimide and sodium hydroxide.

[0048] Preferably, the reagent used for the upper protection includes amino protecting reagents such as di-tert-butyl dicarbonate, acetic anhydride, benzyl chloroformate, benzoic anhydride, 9-fluorenylmethyl chloroformate, p-toluenesulfonyl chloride, trifluoroacetic anhydride or benzyl bromide.

[0049] In the present invention, the raw materials, reagents or equipment used can be purchased from the market.

[0050] In the present invention, the catalyst is homemade, and the synthesis method is as follows:

[0051] The catalyst N-[(S)-(6-methoxyquinolin-4-yl)(2-vinyl-4-azabicyclo[2.2.2]oct-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenesulfonamide was synthesized according to patent WO2020052545.

[0052] The catalysts {[(1R,2R)-2-(dimethylamino)cyclohexyl]amino}(phenylamino)methanthione and {[(1R,2R)-2-(dimethylamino)-1,2-diphenylethyl]amino}(phenylamino)methanthione were synthesized according to the literature (Highly enantioselective desymmetrizations of meso-anhydrides, Ellen Schmitt et al., Tetrahedron 66, 2010, 6349-6357).

[0053] Example 1

[0054] See also Figure 1, this embodiment provides a method for synthesizing methyl (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylate:

[0055] (a) Cyclopropanedicarboxylic anhydride (50 g, 446 mmol) was dissolved in tetrahydrofuran (1000 mL), and catalyst N-[(S)-(6-methoxyquinolin-4-yl)(2-vinyl-4-azabicyclo[2.2.2]octan-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenesulfonamide (5.3 g, 89 mmol) and methanol (50 mL) were added, and the mixture was stirred at 20° C. until the reaction was completed. Concentrate under reduced pressure to remove about 500 mL of THF, add saturated sodium bicarbonate aqueous solution (200 mL), stir and stand for stratification, discard the upper organic phase, add ethyl acetate (200 mL) to the lower aqueous phase, adjust the pH to 1-3 with hydrochloric acid, stir and stand for stratification, take the upper organic phase, extract the lower aqueous phase once with ethyl acetate, combine the organic phases, wash once with saturated brine, and concentrate to dryness to obtain 62 g of (1R, 2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid. The product has a chiral purity of 98.0% and is directly used in the next step without purification. (Product mass spectrometry molecular weight: M + +H=145.0).

[0056] (b) The (1R, 2S)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (62 g, 430 mmol) obtained in the previous step was dissolved in acetonitrile (300 mL), triethylamine (87 g, 860 mmol) was added, diphenylphosphoryl azide (130 g, 473 mmol) was added, and the temperature was raised to 70°C for 2 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove most of the solvent, ethyl acetate and water were added, and then the pH was adjusted to 1-2 with hydrochloric acid, and the upper organic phase was discarded after stirring and standing for stratification. The lower aqueous phase obtained was the aqueous solution of the product (1S, 2R)-2-aminocyclopropane-1-carboxylic acid methyl ester, which was directly used in the next step reaction. (Product mass spectrometry molecular weight: M + +H=102.1).

[0057] (c) sodium hydroxide was added to the aqueous solution of (1S, 2R)-2-aminocyclopropane-1-carboxylic acid obtained in the previous step to adjust the pH to 7-8, sodium bicarbonate (54g, 645mmol), di-tert-butyl dicarbonate (94g, 430mmol), 50mL tetrahydrofuran were added, and the reaction was stirred at room temperature until the reaction was completed. The reaction solution was extracted twice with 100mL ethyl acetate, the organic phase was combined, washed once with water, washed once with saturated brine, dried over anhydrous magnesium sulfate and spin-dried to obtain a crude product of (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid, and then recrystallized from dichloromethane and normal heptane to obtain 48g of the product (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid methyl ester. (Total product yield 50%, purity 98%, product mass spectrometry molecular weight: M + +H=216.1.

[0058] See also Figure 2 The NMR spectrum data of the product (1S,2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid methyl ester are as follows: 1 H-NMR (500MHz, CDCl3) δ (ppm): 3.7 (s, 3H), 3.4 (s, 1H), 1.9 (m, 1H), 1.4 (s, 9H), 1.3 (m, 2H), 1.2 (m, 1H)).

[0059] Example 2

[0060] See also Figure 1 , this embodiment provides a method for synthesizing (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid:

[0061] (a) Cyclopropanedicarboxylic anhydride (20 g, 178 mmol) was dissolved in methyl tert-butyl ether (400 mL), and the catalyst {[(1R, 2R)-2-(dimethylamino)cyclohexyl]amino}(phenylamino)methylthioketone (7.5 g, 27 mmol) and benzyl alcohol were added.

[0062] (20mL), stir at 0℃ until the reaction is complete. Concentrate half of the reaction solution, add saturated sodium bicarbonate aqueous solution (100mL), stir and stand for stratification, discard the upper organic phase, add ethyl acetate (100mL) to the lower aqueous phase, adjust the pH to 1-3 with hydrochloric acid, stir and stand for stratification, take the upper organic phase, extract the lower aqueous phase with ethyl acetate once, combine the organic phases, wash twice with water, wash once with semi-saturated brine, and concentrate to dryness to obtain 35g of (1R, 2S)-2-[(benzyloxy)carbonyl]cyclopropane-1-carboxylic acid, the product chiral purity is 98.5%, and it is directly used in the next step without purification. (Product mass spectrum molecular weight: M++H=221.1).

[0063] (b) The (1R, 2S)-2-[(benzyloxy) carbonyl] cyclopropane-1-carboxylic acid (35 g, 159 mmol) obtained in the previous step was dissolved in toluene (150 mL), thionyl chloride (21 g, 175 mmol) was added, the temperature was raised to 90 ° C for 2 hours, and the mixture was concentrated to dryness under reduced pressure. 200 mL of ammonia water was added to precipitate a solid, which was collected by filtration and dried; 70 mL of acetonitrile, 150 mL of water, and sodium hydroxide (25 g, 636 mmol) were added to the obtained solid, the mixture was stirred and cooled to 0 ° C, 10% sodium hypochlorite solution (142 mL, 191 mmol) was added dropwise, and the temperature was raised to 25 ° C for reaction until the reaction was completed. Add methyl tert-butyl ether and water to the reaction solution, stir and stand to separate, discard the upper organic phase, then adjust the pH of the aqueous phase to 1-2 with hydrochloric acid, add methyl tert-butyl ether, stir and stand to separate, discard the upper organic phase, and the lower aqueous phase is the aqueous solution of the product (1S, 2R)-2-aminocyclopropane-1-carboxylic acid, which is directly used in the next step reaction. (Product mass spectrometry molecular weight: M + +H=102.1).

[0064] (c) Sodium hydroxide was added to the aqueous solution of (1S,2R)-2-aminocyclopropane-1-carboxylic acid obtained in the previous step to adjust the pH to 7-8, and sodium hydroxide (6.4 g, 159 mmol), di-tert-butyl dicarbonate (35 g, 159 mmol) and 20 mL of tetrahydrofuran were added, and the reaction was stirred at room temperature until the reaction was completed. 100 mL of methyl tert-butyl ether was added to the reaction solution, stirred and allowed to stand for stratification, and the upper organic phase was discarded; dilute hydrochloric acid was added to the lower aqueous phase to adjust the pH to 3-5, extracted twice with dichloromethane, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous magnesium sulfate and spin-dried to obtain a crude product of (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid, and then recrystallized from dichloromethane and n-heptane to obtain 22 g of the product (1S, 2R)-2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid. (Total yield 61%, purity 95%, product mass spectrometry molecular weight: M ++H=202.1. 1 H-NMR (500MHz, CDCl3) δ (ppm): 6.0 (s, 1H), 5.7 (s, 1H), 2.7 (m, 1H), 2.6 (m, 2H), 2.0 (m, 1H), 1.5 (s, 9H)).

[0065] Example 3

[0066] See also Figure 1 , this embodiment provides a method for synthesizing (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid:

[0067] (a) Cyclopropanedicarboxylic anhydride (20 g, 178 mmol) was dissolved in dioxane (400 mL), and a catalyst {[(1R, 2R)-2-(dimethylamino)-1,2-diphenylethyl]amino}(phenylamino)methanone (7.5 g, 27 mmol) and isopropanol (20 mL) were added, and the mixture was stirred at -10°C until the reaction was completed. The reaction solution was concentrated by half, saturated sodium bicarbonate aqueous solution (100 mL) was added, stirred and allowed to stand for stratification, the upper organic phase was discarded, ethyl acetate (100 mL) was added to the lower aqueous phase, the pH was adjusted to 1-3 with hydrochloric acid, stirred and allowed to stand for stratification, the upper organic phase was taken, the lower aqueous phase was extracted once with ethyl acetate, the organic phases were combined, washed once with water, washed once with semi-saturated brine, and concentrated to dryness to obtain 29 g of (1R, 2S)-2-[(propan-2-yloxy)carbonyl]cyclopropane-1-carboxylic acid, the chiral purity of the product was 98.7%, and it was directly used in the next step without purification. (Product mass spectrum molecular weight: M++H=173.1).

[0068] (b) The (1R, 2S)-2-[(propan-2-yloxy) carbonyl] cyclopropane-1-carboxylic acid (29 g, 168 mmol) obtained in the previous step was dissolved in dichloromethane (150 mL), N, N-carbonyldiimidazole (27 g, 168 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to near dryness, 200 mL of aqueous ammonia was added, a solid was precipitated, and the solid was collected by filtration and dried; 60 mL of acetonitrile, 120 mL of water, and sodium hydroxide (27 g, 672 mmol) were added to the obtained solid, and bromine (30 g, 185 mmol) was added dropwise. The reaction was stirred until the reaction was completed. Add ethyl acetate and water to the reaction solution, stir and stand for separation, discard the upper organic phase, then adjust the pH of the aqueous phase to 1-2 with hydrochloric acid, add ethyl acetate, stir and stand for separation, discard the upper organic phase, and the lower aqueous phase is the aqueous solution of the product (1S, 2R)-2-aminocyclopropane-1-carboxylic acid, which is directly used in the next step reaction. (Product mass spectrometry molecular weight: M + +H=102.1).

[0069] (c) Sodium hydroxide was added to the aqueous solution of (1S,2R)-2-aminocyclopropane-1-carboxylic acid obtained in the previous step to adjust the pH to 7-8, and sodium carbonate (27 g, 252 mmol), di-tert-butyl dicarbonate (37 g, 168 mmol) and 20 mL of tetrahydrofuran were added, and the reaction was stirred at room temperature until the reaction was completed. 100 mL of methyl tert-butyl ether was added to the reaction solution, stirred and allowed to stand for stratification, and the upper organic phase was discarded; dilute hydrochloric acid was added to the lower aqueous phase to adjust the pH to 3-5, extracted twice with ethyl acetate, the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous magnesium sulfate and spin-dried to obtain a crude product of (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid, and then recrystallized from dichloromethane and n-heptane to obtain 20 g of the product (1S, 2R)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)cyclopropane-1-carboxylic acid. (Total yield 56%, purity 95%, product mass spectrometry molecular weight: M + +H=202.1. 1 H-NMR (500MHz, CDCl3) δ (ppm): 6.0 (s, 1H), 5.7 (s, 1H), 2.7 (m, 1H), 2.6 (m, 2H), 2.0 (m, 1H), 1.5 (s, 9H)).

[0070] The present invention is different from the prior art in terms of starting materials, process routes and post-processing processes, and the raw materials of the present invention are simple and easy to obtain, low in cost, simple to operate, and avoids dangerous and easily decomposable alkyl diazo compound intermediates, thereby improving the safety of the process.

[0071] The post-treatment of the present invention does not need to use column chromatography to purify and separate the product, and most of the steps can be directly performed without purifying the crude product. The final product is purified by recrystallization, with a total yield of 50%-60%, and a purity of more than 95%, which saves production costs and greatly shortens the time. It is suitable for industrial mass production and also suitable for small-scale preparation in the laboratory.

[0072] The invention avoids operations such as column purification which are not suitable for industrial production, avoids dangerous and easily decomposable intermediates of alkyl diazo compounds, improves process safety, and is more suitable for industrial mass production.

[0073] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid, characterized in that: The synthetic method comprises the following steps: (a) reacting the compound represented by formula I with an alcohol in the presence of a catalyst to obtain a compound represented by formula II; (b) the compound of formula II is amidated, then rearranged and hydrolyzed to obtain the compound of formula III; or the compound of formula II is rearranged and hydrolyzed to obtain the compound of formula III; (c) the compound represented by formula III is protected to obtain the compound represented by formula IV; Wherein, the compound represented by formula I is: The compound shown in formula II: The compound shown in formula III: The compound shown in formula IV: In the formula, R is any alkyl group or aryl group, and P is any amino protecting group.

2. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (a), the reaction temperature is -20°C to 50°C.

3. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (a), the catalyst is a chiral alcoholysis catalyst.

4. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 3, characterized in that: The catalyst includes N-[(S)-(6-methoxyquinolin-4-yl)(2-vinyl-4-azabicyclo[2.2.2]oct-8-yl)methyl]-3,5-bis(trifluoromethyl)benzenesulfonamide, {[(1R,2R)-2-(dimethylamino)cyclohexyl]amino}(phenylamino)methylthione or {[(1R,2R)-2-(dimethylamino)-1,2-diphenylethyl]amino}(phenylamino)methylthione.

5. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (b), the reagent used for amidation includes thionyl chloride and ammonia water, oxalyl chloride and ammonia water, N,N-carbonyldiimidazole and ammonia water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and ammonia water, or ammonium bicarbonate plus pyridine plus Boc anhydride.

6. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (b), the reagents used for the rearrangement reaction include bromine and sodium hydroxide, dibromohydantoin and sodium hydroxide, sodium hypochlorite and sodium hydroxide, diphenylphosphoryl azide or N-chloro(bromo)succinimide and sodium hydroxide.

7. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (b), the reagent used for hydrolysis includes sodium hydroxide or potassium hydroxide.

8. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (b), the reaction temperature is -20°C to 80°C.

9. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (c), the reagent used for the upper protection includes di-tert-butyl dicarbonate, acetic anhydride, benzyl chloroformate, benzoic anhydride, 9-fluorenylmethyl chloroformate, p-toluenesulfonyl chloride, trifluoroacetic anhydride or benzyl bromide.

10. The method for synthesizing chiral cis-2-amino-1-cyclopropylcarboxylic acid according to claim 1, characterized in that: In step (c), the reaction temperature is -20°C to 100°C.

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