A method for preparing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate

Abstract

The invention provides a method for preparing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, and belongs to the field of organic synthesis. The invention relates to a method for synthesizing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate from prenyl acetate and diazoacetate through an asymmetric cyclopropanation reaction. The chiral copper catalyst used is generated in situ by copper salt and chiral tridentate P,N,N-ligand in various polar and non-polar solvents. The invention can conveniently synthesize chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, and has the characteristics of simple operation, easy availability of raw materials, wide application range of substrates, high enantioselectivity, etc.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate. Background Art

[0002] 3-Acyloxymethyl-2,2-dimethylcyclopropanecarboxylate is an important organic synthesis intermediate, which can be used to prepare various natural and non-natural compounds with biological activity, such as caronolactone, caronic acid, etc. Caronolactone is an important intermediate in the production of pyrethroid insecticides such as deltamethrin, and is widely used in the fields of pesticides and medicine; caronic acid is a raw material for the production of caronic anhydride, an important intermediate of hepatitis C protease inhibitors, and is also widely used in pesticides and other organic synthesis fields (CN102952011A).

[0003] In 2008, Norihiko et al. reported that the copper complex obtained by the reaction of salicylaldehyde imine compound and copper salt was a catalyst for cyclopropanation reaction, and the chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate was synthesized with a yield of 75%, but the molar ratio of the catalyst to the molar ratio of ethyl diazoacetate was 1%, the dosage was large, and the production cost was high (EP1950208A1). In 2009, Makoto et al. reported a new catalyst for synthesizing chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate, which was a bisoxazoline structure and could obtain 87 / 13 cis-trans isomers, but the trans configuration ee value was only 33% (EP2053037A1). Qin Dongguang et al. reported that a copper complex synthesized by cuprous trifluoromethanesulfonate and benzonitrile catalyzed isopentenyl acetate and ethyl diazoacetate to produce racemic 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate. The reaction needed to be carried out at a relatively high temperature and required a large amount of complex catalyst (CN104163759A).

[0004] The above-mentioned system has problems such as low reaction activity, harsh reaction conditions, and high ligand cost. Therefore, it is of great significance to develop a chiral asymmetric cyclopropanation catalyst system based on readily available chiral asymmetric cyclopropanation catalyst system for the synthesis of chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with high activity and high stereoselectivity. Summary of the invention

[0005] The purpose of the present invention is to use a class of chiral tridentate P, N, N-ligands to develop a copper-catalyzed method for synthesizing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate by asymmetric cyclopropanation reaction of isopentenyl acetate and diazoacetate. The advantages of this method are mild reaction conditions, reaction at room temperature, high yield, high enantioselectivity, low three waste pollution, and good industrialization prospects.

[0006] The present invention provides a method for preparing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, which comprises: in the presence of a base additive, a chiral copper catalyst catalyzes the synthesis of prenyl acetate and diazoacetate through an asymmetric cyclopropanation reaction in a reaction medium, and the specific steps are:

[0007] (1) Preparation of chiral copper catalyst: under nitrogen protection, copper salt and chiral P, N, N-ligand are stirred in a reaction medium at a molar ratio of 1:0.1-10 for 0.5-2 hours to prepare a chiral copper catalyst;

[0008] (2) Preparation of chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: dissolving isopentenyl acetate and a base additive in a reaction medium, then adding the chiral copper catalyst prepared in the above step (1) to the solution, stirring at room temperature for 1-6 hours; adding diazoacetate dropwise at a uniform rate for 1-12 hours; after removing the solvent by evaporation under reduced pressure, the chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate is evaporated in vacuo.

[0009] The molar ratio of the chiral copper catalyst to the diazoacetate is 0.001-1:1;

[0010] The molar ratio of the base additive to the diazoacetate is 0.001-1:1;

[0011] The molar ratio of isopentenyl acetate to diazoacetate is 1-5:1.

[0012] The chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate has one of the following structures:

[0013]

[0014] In the formula, R is a C1-C40 chain alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a substituted phenyl group, etc.; the substituents on the substituted phenyl group are selected from one or more of a C1-C10 alkyl group and a C1-C20 alkoxy group, and the number of substituents on the phenyl group is 1-5.

[0015] The prenyl acetate and diazoacetate have the following structures II and III:

[0016]

[0017] The substituent R in the formula is the same as any one of the substituents R mentioned above.

[0018] The copper salt is at least one of hydrated copper acetate, hydrated copper sulfate, anhydrous copper acetate, anhydrous copper sulfate, trifluoromethanesulfonate, cupric chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, trifluoromethanesulfonate, Cu(CH3CN)4BF4, and Cu(CH3CN)4ClO4. Preferably, at least one of hydrated copper acetate, trifluoromethanesulfonate, Cu(CH3CN)4BF4, and Cu(CH3CN)4ClO4 is selected.

[0019] The chiral P,N,N-ligand has one of the following structures:

[0020]

[0021] The base additive is various inorganic bases or organic bases, preferably N,N-diisopropylethylamine, triethylamine, DBU, K3PO4, K2CO3, Cs2CO3, Na2CO3 or NaHCO3.

[0022] The catalytic reaction conditions of step (2) are preferably: temperature of 25° C.; reaction medium of ethylene dichloride; pressure of normal pressure; and time of 6 hours.

[0023] The molar ratio of the chiral copper catalyst to the diazoacetate is preferably 0.001-0.1:1;

[0024] The molar ratio of the base additive to the diazoacetate is preferably 0.001-0.1:1;

[0025] The molar ratio of isopentenyl acetate to diazoacetate is preferably 1-5:1;

[0026] Reaction equation of the present invention is:

[0027]

[0028] The present invention has the following advantages:

[0029] 1. The starting materials are cheap and readily available.

[0030] 2. The chiral ligand is easy to synthesize, the catalyst is cheap and easy to obtain, and the amount used is small.

[0031] 3. Good reaction activity and high stereoselectivity.

[0032] 4. Compared with the traditional method, this method can more conveniently synthesize chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate. DETAILED DESCRIPTION

[0033] The following examples will further illustrate the present invention, but are not intended to limit the present invention. Nuclear magnetic resonance was measured by a Bruker 400M nuclear magnetic resonance instrument. GC analysis was performed by an Agilent 7890 series gas chromatograph under the following conditions: chromatographic column: PEG20M: 30m*320μm*0.25μm, column front pressure: 9.8764mp (flow rate 1.5ml / min), injection port temperature: 250 degrees, detector temperature: 250 degrees, column temperature: 50 degrees, maintained for 2 minutes, ramp rate 10 degrees / minute, end temperature 280 degrees, maintained for 5 minutes. HPLC analysis chromatographic column: CHIRALCEL AD-H

[0034] Example 1

[0035] The structural formula of chiral ligand L-1 is:

[0036]

[0037] Cu(OAc)2.H2O (0.1 mmol, 1 mol‰) and chiral ligand L-1 (1 mmol, 5 mol%) were added to the reaction flask, and 1.0 ml of dichloroethane was added under nitrogen protection, and the mixture was stirred at room temperature for 1 hour.

[0038] Under nitrogen protection, the catalyst solution was added to 10.0 ml of a mixed solution of isopentyl acetate (0.2 mol, 2.0 equiv) and sodium bicarbonate (0.1 mmol, 1 mol‰), and stirred at 25°C for 1.0 hour. Ethyl diazoacetate (0.1 mol) was added dropwise at a uniform rate, and after 6 hours of dripping, the mixture was stirred for 0.5 hour. The solvent was removed by rotary evaporation, and chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate was distilled by mechanical pump. 18.2 g was obtained, with a yield of 84.9%. GC analysis: cis / trans = 85 / 15.

[0039] Take 2.14 g of chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate and add it to 5 ml of water, heat it to 50°C, add 3.6 g of 28% sodium hydroxide and react for 2 hours, add 36% concentrated hydrochloric acid to adjust the system pH to 1, keep it at room temperature for 2 hours, then adjust the pH to 8 with 28% sodium hydroxide alkali solution, extract with toluene, evaporate to dryness, and obtain cis-lactone, which is 94% ee by chiral HPLC analysis. Add 36% concentrated hydrochloric acid to the water layer and adjust the pH to 1, stir at room temperature for 1 hour, extract with toluene, evaporate to dryness, and obtain the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid, which is 90% ee by chiral HPLC analysis. The NMR data of (1R,3S)3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylic acid ethyl ester are as follows: 1H NMR (400MHz, CDCl3): δ4.49(dd,2H),4.40(dd,2H),4.11(q,2H),2.05(s,3H),1.59(d,1H),1.44(dt,1H),1.27(s,3H),1.26(t,3H),1.20(s,3H).

[0040] Example 2

[0041] The sodium bicarbonate in Example 1 was replaced by Cs2CO3, and the rest was the same as Example 1. The reaction gave chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 85.2%. GC analysis showed that cis / trans = 89 / 11. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 92% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 89% ee.

[0042] Example 3

[0043] The sodium bicarbonate in Example 1 was replaced by K3PO4, and the rest was the same as Example 1. The reaction gave chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 89.1%. GC analysis showed that cis / trans = 86 / 14. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 91% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 86% ee.

[0044] Example 4

[0045] The Cu(OAc)2·H2O in Example 2 was replaced by Cu(CF3SO3)2. The rest was the same as Example 2 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 81%. GC analysis showed that cis / trans = 82 / 18. The cis-isomer chiral lactone had an HPLC analysis of 95% ee; the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid had an HPLC analysis of 88% ee.

[0046] Example 5

[0047] The Cu(OAc)2·H2O in Example 2 was replaced by Cu(CH3CN)4BF4. The rest was the same as Example 2 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 86%. GC analysis showed that cis / trans = 77 / 23. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 93% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 87% ee.

[0048] Example 6

[0049] The Cu(OAc)2·H2O in Example 2 was replaced by Cu(CH3CN)4ClO4, and the rest was the same as Example 2 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 89%. GC analysis showed that cis / trans = 69 / 31. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 91% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 83% ee.

[0050] Example 7

[0051] The Cu(OAc)2·H2O in Example 3 was replaced by Cu(CH3CN)4BF4. The rest was the same as Example 3 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 83%. GC analysis showed that cis / trans = 75 / 25. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 94% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 89% ee.

[0052] Example 8

[0053] The Cu(OAc)2·H2O in Example 3 was replaced by Cu(CH3CN)4ClO4, and the rest was the same as Example 3 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 78%. GC analysis showed that cis / trans = 87 / 13. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 92% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 85% ee.

[0054] Example 9

[0055] The structural formula of L-2 is:

[0056]

[0057] The Cu(OAc)2·H2O in Example 1 was replaced by Cu(CF3SO3)2, L-1 was replaced by L-2, and the rest was the same as Example 1 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 92%. GC analysis showed that cis / trans = 91 / 9. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 91% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 87% ee.

[0058] Example 10

[0059] L-1 in Example 5 was replaced by L-2, and the rest was the same as Example 5 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 81%. GC analysis showed that cis / trans = 89 / 11. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 92% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 89% ee.

[0060] Embodiment 11

[0061] The structural formula of L-3 is:

[0062]

[0063] L-1 in Example 6 was replaced by L-3, and the rest was the same as Example 6 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 79%. GC analysis showed that cis / trans = 72 / 28. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 94% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 83% ee.

[0064] Example 12

[0065] L-1 in Example 7 was replaced by L-3, and the rest was the same as Example 7 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 76%. GC analysis showed that cis / trans = 74 / 26. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 91% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 85% ee.

[0066] Embodiment 13

[0067] L-1 in Example 8 was replaced by L-3, and the rest was the same as Example 8 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 78%. GC analysis showed that cis / trans = 73 / 27. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 84% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 85% ee.

[0068] Embodiment 14

[0069] The solvent dichloroethane in Example 2 was replaced with ethyl acetate. The rest was the same as Example 2 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 79%. GC analysis showed that cis / trans = 75 / 25. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 89% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 81% ee.

[0070] Embodiment 15

[0071] The solvent dichloroethane in Example 3 was replaced with ethyl acetate. The rest was the same as Example 3 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 77%. GC analysis showed that cis / trans = 79 / 21. Hydrolysis gave a cis-isomer chiral lactone with an HPLC analysis of 88% ee and a trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 83% ee.

[0072] Example 16

[0073] The solvent dichloroethane in Example 9 was replaced with ethyl acetate. The rest was the same as Example 9 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 82%. GC analysis showed that cis / trans = 77 / 23. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 85% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 87% ee.

[0074] Embodiment 17

[0075] The solvent dichloroethane in Example 2 was replaced with toluene. The rest was the same as Example 2 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 83% and GC analysis: cis / trans = 78 / 22. Hydrolysis gave the cis-isomer chiral lactone with a yield of 92% and HPLC analysis of 86% ee; the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with a yield of 82% and HPLC analysis of 91% ee.

[0076] Embodiment 18

[0077] The solvent dichloroethane in Example 12 was replaced with ethyl acetate. The rest was the same as Example 12 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 85%. GC analysis showed that cis / trans = 76 / 24. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 82% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 83% ee.

[0078] Embodiment 19

[0079] The solvent dichloroethane in Example 12 was replaced with toluene. The rest was the same as Example 12 to obtain chiral 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylate with a yield of 88.8%. GC analysis showed that cis / trans = 77 / 23. Hydrolysis gave the cis-isomer chiral lactone with an HPLC analysis of 89% ee and the trans-isomer 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid with an HPLC analysis of 88% ee.

Claims

1. A method for preparing chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, characterized in that: Chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate was synthesized by asymmetric cyclopropanation of prenyl acetate and diazoacetate catalyzed by a chiral copper catalyst in the presence of a base additive in a reaction medium. The specific steps of this method are: (1) Preparation of chiral copper catalyst: under nitrogen protection, copper salt and chiral P, N, N-ligand are stirred in a reaction medium at a molar ratio of 1:0.1-10 for 0.5-2 hours to obtain a chiral copper catalyst; (2) Preparation of chiral ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: dissolving isopentenyl acetate and a base additive in a reaction medium, then adding the chiral copper catalyst prepared in the above step (1) to the solution, stirring at room temperature for 1-6 hours; adding diazoacetate dropwise for 1-12 hours; after removing the solvent by evaporation under reduced pressure, evaporating chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate under vacuum; The chiral P,N,N-ligand in the above step (1) has one or more of the following structures: ， In the above step (2), the molar ratio of the chiral copper catalyst to the diazoacetate is 0.0001-1:1; the molar ratio of the base additive to the diazoacetate is 0.0001-1:1; and the molar ratio of the isopentenyl acetate to the diazoacetate is 1-5:

1.

2. The method according to claim 1, characterized in that: The chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate has one or more of the following four structures: ， Wherein R is C1~C40 chain alkyl, C3~C6 cycloalkyl, phenyl or substituted phenyl; the substituents on the substituted phenyl are selected from one or more of C1~C10 alkyl and C1~C20 alkoxy, and the number of substituents on the phenyl is 1-5.

3. The method according to claim 1, characterized in that: The prenyl acetate and diazoacetate have the following structures II and III: , wherein the substituent R is the same as any one of the substituents R in claim 2.

4. The method according to claim 1, characterized in that: The copper salt is one or more of hydrated copper acetate, hydrated copper sulfate, anhydrous copper acetate, anhydrous copper sulfate, trifluoromethanesulfonate, cupric chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, trifluoromethanesulfonate, Cu(CH3CN)4BF4 or Cu(CH3CN)4ClO4.

5. The method according to claim 1 or 2, characterized in that: The base additive is one or more of N,N-diisopropylethylamine, triethylamine, DBU, K3PO4, K2CO3, Cs2CO3, Na2CO3, or NaHCO3.

6. The preparation of chiral 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate according to claim 1, characterized in that: The catalytic reaction conditions are: temperature of 25° C.; reaction medium of ethylene dichloride; pressure of normal pressure; and time of 6 hours.

7. The method according to claim 1, characterized in that: The molar ratio of the chiral copper catalyst to the diazoacetate is 0.001-0.1:1; The molar ratio of the base additive to the diazoacetate is 0.001-0.1:1; The molar ratio of prenyl acetate to diazoacetate is 1-5:1; The copper salt is one or more of hydrated copper acetate, trifluoromethanesulfonate, cuprous chloride, Cu(CH3CN)4BF4 or Cu(CH3CN)4ClO4; The reaction medium is one or more of methanol, ethanol, dichloromethane and dichloroethane.

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