Method for preparing diazoketone by one-pot method

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing diazonium ketone by a one-pot method, which comprises the following steps: reacting carboxylic acid active intermediates such as acyl chloride and mixed anhydride with diazomethane precursor N-methyl-N-nitrosourea in an organic solvent under the action of alkali to obtain a corresponding diazonium ketone compound with medium to good yield. According to the method disclosed by the invention, the diazomethane is generated in situ by using the cheap and easily available diazomethane precursor N-methyl-N-nitrosourea to participate in the reaction, so that the direct use of a highly toxic reagent diazomethane is avoided, and the danger in the process of preparing the diazoketone by the Ardt-Eistern reaction is greatly reduced; and the carboxylic acid substrate can be directly converted into corresponding active intermediates for further serial preparation to obtain corresponding diazonium ketone, and the method has the characteristics of wide application range of the substrate, mild and simple reaction conditions, green steps, low pollution, high economic benefit and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and specifically relates to a method for preparing diazoketones through a one-pot process. Background Art

[0002] Diazoketones, as an important class of organic synthesis intermediates, are highly reactive and can participate in a variety of reactions, finding widespread application in drug development and the construction of functional material molecules. Among existing methods for preparing diazoketones, the Arndt–Eistert reaction, which uses carboxylic acid intermediates such as acyl chlorides or mixed anhydrides with diazomethane as raw materials, can proceed rapidly under mild conditions with high reaction yields and excellent atom economy, making it a commonly used method for preparing diazoketones. However, diazomethane reagents are highly toxic and explosive, making them unavailable for commercial purchase. The synthesis, storage, and transfer processes are also extremely dangerous.

[0003] The in situ generation of diazomethane from a diazomethane precursor via a one-pot process can avoid the storage and transportation of diazomethane reagents, effectively reducing safety risks. This process has been applied in the preparation of methyl carboxylates. However, the in situ generation of diazomethane from diazomethane precursors is typically performed in aqueous reaction systems. These reaction conditions are unsuitable for water-sensitive carboxylic acid reactive intermediates and have therefore not yet been applied to the preparation of diazoketones. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing diazoketones by a one-pot process.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A one-pot method for preparing diazoketones, the reaction equation is:

[0007]

[0008] The carboxylic acid active intermediate represented by formula I, N-methyl-N-nitrosourea represented by formula II, a base and an organic solvent are mixed in proportion, reacted at 0°C to room temperature for 6-24 hours, and post-treated to obtain the diazoketone compound represented by formula III;

[0009] Wherein, R is an alkyl, cycloalkyl, aryl, or heteroaryl group, and the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted by a halogen or an unsaturated group;

[0010] R' is X or -OCOR"; X is halogen F, Cl, Br; in the mixed anhydride, R" is ethyl, benzyl or isopropyl.

[0011] Furthermore, the molar ratio of the carboxylic acid active intermediate to N-methyl-N-nitrosourea is 1:2 to 5. Preferably, the molar ratio of the carboxylic acid active intermediate to N-methyl-N-nitrosourea is 1:3.

[0012] Furthermore, the solvent is any one of ethylene glycol, acetonitrile, tetrahydrofuran, dichloromethane or a mixed solvent of tetrahydrofuran and dichloromethane. Preferably, the organic solvent is a mixed solvent of dichloromethane and tetrahydrofuran, and the volume ratio of dichloromethane to tetrahydrofuran is 2:1.

[0013] Furthermore, the base is potassium carbonate.

[0014] Furthermore, the molar ratio of the carboxylic acid active intermediate to the base is 1:2 to 5. Preferably, the molar ratio of the carboxylic acid active intermediate to the base is 1:3.

[0015] Furthermore, the reaction temperature is 0°C to 25°C, preferably 0°C.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] (1) The one-pot method for preparing diazoketones of the present invention uses the cheap and readily available diazomethane precursor N-methyl-N-nitrosourea to in situ generate diazomethane to participate in the reaction, avoiding the direct use of the highly toxic reagent diazomethane, greatly reducing the danger in the process of preparing diazoketones by the Arndt–Eistert reaction, and has the characteristics of mild reaction conditions, high safety yield, convenient post-processing, green steps, low pollution, and high economic benefits.

[0018] (2) The carboxylic acid active intermediate in the raw material can be commercially available acyl chloride and mixed anhydride, or can be prepared in situ from carboxylic acid, and the substrate has a wide range of uses.

[0019] (3) The present invention uses N-methyl-N-nitrosourea as a diazomethane precursor and generates diazomethane in situ through a "one-pot method", thereby avoiding the use of diazomethane, a highly toxic and explosive reagent.

[0020] (4) The present invention uses an organic phase solvent and does not require the addition of water, and is compatible with water-sensitive carboxylic acid active intermediate substrates. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the H NMR spectrum of the target product 2-diazoacetophenone in Example 1.

[0022] Figure 2 This is the H NMR spectrum of the target product 2-diazo-1-(p-tolyl)ethanone in Example 4.

[0023] Figure 3This is the H NMR spectrum of the target product (R)-tert-butyl 4-diazo-3-oxo-1-phenylbutan-2-ylcarbamate of Example 5.

[0024] Figure 4 This is the H NMR spectrum of the target product (R)-tert-butyl 4-diazo-3-oxobutan-2-ylcarbamate of Example 6.

[0025] Figure 5 This is the H NMR spectrum of the target product (S)-tert-butyl 1-diazo-2-oxo-5-methylhexane-3-ylcarbamate of Example 7.

[0026] Figure 6 This is the H NMR spectrum of the target product (R)-tert-butyl 1-benzyloxy-4-diazo-3-oxobutan-2-ylcarbamate of Example 8. DETAILED DESCRIPTION

[0027] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 efforts are within the scope of protection of the present invention.

[0028] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0029] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0030] Example 1

[0031] To a 10 mL reaction tube, benzoyl chloride (0.5 mmol, 1 eq.), N-methyl-N-nitrosourea (1.5 mmol, 3 eq.), potassium carbonate (1.5 mmol, 3 eq.), and 2 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran were added sequentially. The reaction mixture was stirred in an ice-water bath overnight and allowed to warm to room temperature. After completion, saturated ammonium chloride was added to quench the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the desired product. The structural formula of the compound is:

[0032]

[0033] The above 2-diazoacetophenone was characterized, as shown in FIG. Figure 1 As shown, the result is: light yellow solid.

[0034] data: 1 H NMR (400MHz, Chloroform-d) δ7.71–7.61(m,2H),7.48–7.40(m,1H),7.37–7.33(m,2H),5.84(s,1H)ppm.

[0035] According to the characterization data, the obtained reaction product is 2-diazoacetophenone (purity>98%); the product yield is calculated to be 70%.

[0036] Example 2

[0037] To a 100 mL flask, benzoyl chloride (5 mmol, 1 eq.), N-methyl-N-nitrosourea (15 mmol, 3 eq.), potassium carbonate (15 mmol, 3 eq.), and 20 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran were added sequentially. The reaction mixture was stirred in an ice-water bath overnight and allowed to warm to room temperature. After completion, saturated ammonium chloride was added to quench the reaction solution, which was then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the desired product, 2-diazoacetophenone. The yield was calculated to be 66%.

[0038] Example 3

[0039] Benzoic acid (5 mmol, 1 eq.) was added to a 100 mL flask and dissolved in dichloromethane. Oxalyl chloride (6 mmol, 1.2 eq.) was then added dropwise under an ice-water bath. After complete addition, the reaction was stirred at room temperature for a period of time, and then the acyl chloride product was obtained by vacuum distillation. The product was then dissolved in 20 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran. N-methyl-N-nitrosourea (15 mmol, 3 eq.) and potassium carbonate (15 mmol, 3 eq.) were then added sequentially. The reaction mixture was stirred in an ice-water bath overnight and allowed to warm to room temperature. After completion, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the desired product, 2-diazoacetophenone. The yield was calculated to be 64%.

[0040] Example 4

[0041] To a 10 mL reaction tube, p-methylbenzoyl chloride (0.5 mmol, 1 eq), N-methyl-N-nitrosourea (1.5 mmol, 3 eq), potassium carbonate (1.5 mmol, 3 eq), and 2 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran were added sequentially. The reaction mixture was stirred at room temperature overnight. After completion, 10 mL of saturated ammonium chloride was added to quench the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the desired product. The structural formula of the compound is:

[0042]

[0043] The above 2-diazo-1-(p-tolyl) ethyl ketone was characterized, as shown in FIG. Figure 2 The result is: light yellow solid. The H NMR spectrum is: 1 H NMR (400MHz, CDCl3) δ7.63–7.50 (m, 2H), 7.13 (d, J = 8.1Hz, 2H), 5.82 (s, 1H), 2.29 (s, 4H) ppm.

[0044] According to the characterization data, the obtained reaction product is 2-diazo-1-(p-tolyl)ethanone (purity>98%); the product yield is calculated to be 76%.

[0045] Example 5

[0046] To a 10 mL reaction tube, add N-tert-butyloxycarbonyl-L-phenylalanine (1 mmol, 1 eq.) and triethylamine (2 mmol, 2 eq.) and dissolve in tetrahydrofuran. Add ethyl chloroformate (1.1 mmol, 1.1 eq.) dropwise in an ice-water bath. Stir for 3 hours after completion, then distill under reduced pressure to obtain the mixed anhydride active intermediate. Dissolve the mixture in 4 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran, then add N-methyl-N-nitrosourea (3 mmol, 3 eq.) and potassium carbonate (3 mmol, 3 eq.). Stir the reaction mixture in an ice-water bath overnight and allow it to warm to room temperature. After completion, saturated ammonium chloride is added to quench the reaction mixture, which is then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to obtain the desired product. The structural formula of this compound is:

[0047]

[0048] The above-mentioned (R)-4-diazo-3-oxo-1-phenylbutan-2-ylcarbamic acid tert-butyl ester was characterized, as shown in FIG. Figure 3 As shown, the result is: light yellow solid.

[0049] data: 1 H NMR(400MHz,Chloroform-d)δ7.33–7.30(m,2H),7.27–7.26(m,1H),7.22–7.16(m,2H),5.2 3(s,1H),5.10(d,J=7.6Hz,1H),4.41(d,J=7.6Hz,1H),3.04–3.01(m,2H),1.41(s,9H)ppm.

[0050] According to the characterization data, the obtained reaction product is p-methylbenzenediazoketone (purity>98%); the product yield is calculated to be 68%.

[0051] Example 6

[0052] To a 10 mL reaction tube, add N-tert-butyloxycarbonyl-L-alanine (1 mmol, 1 eq.) and triethylamine (2 mmol, 2 eq.) and dissolve in tetrahydrofuran. Add ethyl chloroformate (1.1 mmol, 1.1 eq.) dropwise in an ice-water bath. Stir for 3 hours after completion, then distill under reduced pressure to obtain the mixed anhydride active intermediate. Dissolve the mixture in 4 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran, then add N-methyl-N-nitrosourea (3 mmol, 3 eq.) and potassium carbonate (3 mmol, 3 eq.). Stir the reaction mixture in an ice-water bath overnight and allow it to warm to room temperature. After completion, saturated ammonium chloride is added to quench the reaction mixture, which is then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to obtain the desired product. The structural formula of this compound is:

[0053]

[0054] The above-mentioned (R)-4-diazo-3-oxobutane-2-ylcarbamic acid tert-butyl ester was characterized, as shown in FIG. Figure 4 As shown, the result is: light yellow solid.

[0055] data: 1 H NMR (400MHz,) δ5.45 (s, 1H), 5.12 (s, 1H), 4.23-4.22 (m, 1H), 1.45 (s, 9H), 1.33 (d, J = 7.1Hz, 3H) ppm.

[0056] According to the characterization data, the obtained reaction product is (R)-tert-butyl 4-diazo-3-oxobutan-2-ylcarbamate (purity>98%); the product yield was calculated to be 72%.

[0057] Example 7

[0058] To a 10 mL reaction tube, add N-tert-butyloxycarbonyl-L-leucine (1 mmol, 1 eq.) and triethylamine (2 mmol, 2 eq.) and dissolve in tetrahydrofuran. Add ethyl chloroformate (1.1 mmol, 1.1 eq.) dropwise in an ice-water bath. Stir for 3 hours after completion, then distill under reduced pressure to obtain the mixed anhydride active intermediate. Dissolve the mixture in 4 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran, then add N-methyl-N-nitrosourea (3 mmol, 3 eq.) and potassium carbonate (3 mmol, 3 eq.). Stir the reaction mixture in an ice-water bath overnight and allow it to warm to room temperature. After completion, saturated ammonium chloride is added to quench the reaction mixture, which is then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to obtain the desired product. The structural formula of this compound is:

[0059]

[0060] The above-mentioned (S)-1-diazo-2-oxo-5-methylhexane-3-ylcarbamic acid tert-butyl ester was characterized, as shown in FIG. Figure 5 As shown, the result is: light yellow solid.

[0061] data: 1 H NMR(400MHz,Chloroform-d)δ5.45(s,1H),4.95(d,J=8.6Hz,1H),4.19(s,1H),1.76– 1.69(m,1H),1.64(s,1H),1.59–1.53(m,1H),1.44(s,9H),0.95(d,J=6.6Hz,6H)ppm.

[0062] According to the characterization data, the obtained reaction product is (S)-tert-butyl 1-diazo-2-oxo-5-methylhexane-3-ylcarbamate (purity>98%); the product yield was calculated to be 64%.

[0063] Example 8

[0064] To a 10 mL reaction tube, add N-tert-butyloxycarbonyl-O-benzyl-L-serine (1 mmol, 1 eq.) and triethylamine (2 mmol, 2 eq.) and dissolve in tetrahydrofuran. Ethyl chloroformate (1.1 mmol, 1.1 eq.) is added dropwise under an ice-water bath. After complete addition, the mixture is stirred for 3 hours and then distilled under reduced pressure to obtain the mixed anhydride active intermediate. The mixture is then dissolved in 4 mL of a 2:1 mixture of dichloromethane and tetrahydrofuran. N-methyl-N-nitrosourea (3 mmol, 3 eq.) and potassium carbonate (3 mmol, 3 eq.) are then added sequentially. The reaction mixture is stirred in an ice-water bath overnight and allowed to warm to room temperature. After completion of the reaction, saturated ammonium chloride is added to quench the reaction mixture, which is then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to obtain the desired product. The structural formula of the compound is:

[0065]

[0066] The above-mentioned (R)-1-benzyloxy-4-diazo-3-oxobutan-2-ylcarbamic acid tert-butyl ester was characterized, as shown in FIG. Figure 6 As shown, the result is: light yellow solid.

[0067] data: 1 H NMR(400MHz,Chloroform-d)δ7.38–7.25(m,5H),5.57(s,1H),5.46(d,J=8.1Hz,1H),4.56- 4.48(m,2H),4.33(d,J=8.1Hz,1H),3.88-3.84(m,1H),3.62-3.59(m,1H),1.45(s,9H)ppm.

[0068] According to the characterization data, the obtained reaction product is (R)-tert-butyl 1-benzyloxy-4-diazo-3-oxobutan-2-ylcarbamate (purity>98%); the product yield was calculated to be 59%.

[0069] Example 9

[0070] Example 9 is basically the same as Example 1, except that the solvent is different, as shown in Table 1 below.

[0071] Table 1

[0072] solvent Yield water 0 Tetrahydrofuran + water (10:1) 6％ Tetrahydrofuran 45.3％ Acetonitrile 18％ dichloromethane 59.8％ Dichloromethane and tetrahydrofuran (1:1) 61％ Dichloromethane and tetrahydrofuran (2:1) 70％ Dichloromethane and tetrahydrofuran (4:1) 33.9％

[0073] As can be seen from Table 1, under the same reaction conditions, different solvents, such as tetrahydrofuran, acetonitrile, dichloromethane, and a mixed solvent of dichloromethane and tetrahydrofuran, can all be successfully synthesized. The best effect is achieved with dichloromethane and tetrahydrofuran (2:1), with the highest yield of 70%. The acyl chloride is unstable in water as a solvent or in a water-containing solvent, and almost no product is obtained.

[0074] Example 10

[0075] Example 10 is substantially the same as Example 1, except that the equivalent of the base is different, as shown in Table 2 below.

[0076] Table 2

[0077]

[0078]

[0079] As can be seen from Table 2, under the same reaction conditions, different equivalents of base, such as 2 equivalents, 3 equivalents, and 5 equivalents, can all be successfully synthesized, with 3 equivalents having the best effect, with the highest yield of 70%.

[0080] Example 11

[0081] Example 11 is basically the same as Example 1, except that the equivalent weight of N-methyl-N-nitrosourea is different, as shown in Table 3 below.

[0082] Table 3

[0083] equivalent Yield 2 52.5％ 3 70％

[0084] As can be seen from Table 3, under the same reaction conditions, different equivalents of urea, such as 2 equivalents and 3 equivalents, can be successfully synthesized, and the equivalent effect is the best, with the highest yield of 70%.

[0085] Example 12

[0086] Example 12 is basically the same as Example 2, except that the base is different, as shown in Table 4 below.

[0087] Table 4

[0088] alkali Yield potassium hydroxide 0％ sodium carbonate 32％ potassium carbonate 70％ Triethylamine 0％ none 0％

[0089] As can be seen from Table 4, under the same reaction conditions, different bases, such as sodium carbonate and potassium carbonate, can be successfully synthesized, and potassium carbonate has the best effect, with the highest yield of 70%.

[0090] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing diazoketone by a one-pot process, characterized in that, The reaction equation is: The carboxylic acid active intermediate represented by formula I, N-methyl-N-nitrosourea represented by formula II, a base and an organic solvent are mixed in proportion, reacted at 0°C to room temperature for 6-24 hours, and post-treated to obtain the diazoketone compound represented by formula III; Wherein, R is an alkyl, cycloalkyl, aryl, or heteroaryl group, and the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally substituted by a halogen or an unsaturated group; R' is X or -OCOR"; X is halogen F, Cl, Br; R" is ethyl, benzyl or isopropyl.

2. the method for preparing diazoketone by one pot process according to claim 1, is characterized in that: The molar ratio of the carboxylic acid active intermediate to N-methyl-N-nitrosourea is 1:2-5.

3. the method for preparing diazoketone by one pot process according to claim 2, is characterized in that: The molar ratio of the carboxylic acid active intermediate to N-methyl-N-nitrosourea is 1:

3.

4. the method for preparing diazoketone by one-pot process according to claim 1, is characterized in that: The solvent is any one of ethylene glycol, acetonitrile, tetrahydrofuran, dichloromethane or a mixed solvent of tetrahydrofuran and dichloromethane.

5. the method for preparing diazoketone by one-pot process according to claim 4, is characterized in that: The solvent is a mixed solvent of dichloromethane and tetrahydrofuran.

6. the method for preparing diazoketone by one-pot process according to claim 5, is characterized in that: The volume ratio of the dichloromethane to tetrahydrofuran is 2:

1.

7. the method for preparing diazoketone by one-pot process according to claim 1, is characterized in that: The base is potassium carbonate.

8. the method for preparing diazoketone by one-pot process according to claim 1, is characterized in that: The molar ratio of the carboxylic acid active intermediate to the base is 1:2-5.

9. the method for preparing diazoketone by one-pot process according to claim 8, is characterized in that: The molar ratio of the carboxylic acid active intermediate to the base is 1:

3.

10. The method for preparing diazoketone by a one-pot process according to claim 1, wherein: The reaction temperature was 0°C.

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