Synthesis method of benzil compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a benzil compound synthesis method, which comprises: mixing an acyloin compound with ethanol, adding reduced iron powder and sodium hydroxide, carrying out a stirring reaction at a room temperature, adding a saturated salt solution and ethyl acetate to the reaction liquid after the reaction is completed, extracting, filtering to recover iron powder, and drying to obtain the benzil compound. And separating out an organic phase from the filtrate, washing the organic phase with water, and drying to obtain the target compound benzil substance. The target product is rapidly synthesized by using benzoin or a derivative thereof as an initial raw material, oxygen in air as an oxidant and reduced iron powder as an additive, the environmental pollution is low, and the additive is simple in recovery method, can be repeatedly used, can effectively reduce the reaction cost, and is easy to popularize and use.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a pharmaceutical intermediate benzil compound. Background Art

[0002] Benzil substances are a very important class of organic synthesis intermediates. In addition to being widely used in the field of new materials, their important value also lies in their application in the fields of medicine and life sciences, as core intermediates in the synthesis of the anti-epileptic drug Dilantin and its derivatives.

[0003] With the advancement of technology, new methods for synthesizing benzil-based substances are continuously reported, including synthesis methods using benzoin-based substances as raw materials, synthesis methods using diphenylacetylene and diphenylethylene-based substances as raw materials, synthesis methods using phenylbenzyl ketone-based substances as raw materials, synthesis methods using oximes, hydrazones, etc. as raw materials, and synthesis methods using aromatic esters, acids, acyl halides, etc. as raw materials. Among them, the direct oxidation method based on benzoin-based substances using trivalent iron-based oxidants to prepare benzil-based substances is the most classic method, but its low efficiency and cumbersome post-processing have greatly limited its further application space.

[0004] Therefore, it is of great significance to explore the use of additives with small molecular weight, simple recovery method and low price to synthesize benzil and its derivatives when air-oxidizing benzoin and its analogs. Summary of the invention

[0005] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a more efficient synthesis method of benzil compounds. The present invention adopts reduced iron powder as an additive, air as an oxidant, and ethanol as a solvent, has low environmental pollution, a simple additive recovery method, and can be repeatedly used, which can effectively reduce the reaction cost and is easy to promote and use.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for synthesizing a benzil compound comprises the following steps:

[0008] The acyloin compound is mixed with ethanol, and reduced iron powder and sodium hydroxide are added. The mixture is stirred at room temperature. After the reaction is completed, saturated brine and ethyl acetate are added to the reaction solution for extraction. The iron powder is recovered by filtration. The filtrate is separated into an organic phase. The organic phase is washed with water, dried, and concentrated to remove the solvent to obtain the target compound, the benzil substance.

[0009] The reaction equation is as follows:

[0010]

[0011] A further improvement of the present invention is:

[0012] The acyloin compound is selected from the following compounds:

[0013]

[0014] Furthermore, the molar ratio of the acyloin compound, the reduced iron powder and the sodium hydroxide is 1:1-3:1-3.

[0015] Furthermore, the organic solvent is one or a mixture of two or more of ethanol, methanol or DMSO.

[0016] Preferably, the organic solvent is ethanol, and the ethanol is 75% ethanol. 2 to 3 ml of ethanol needs to be added for every 1 mmol of acyloin compound.

[0017] The ethanol is 75% ethanol, and 2 to 3 ml of ethanol needs to be added for every 1 mmol of acyloin compound.

[0018] Furthermore, the reaction time is 0.5 to 2 hours.

[0019] Furthermore, the iron powder additive recovered by filtration can be reused 1-6 times.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The invention adopts reduced iron powder as an oxidation additive, which has small molecular weight, small flux, low price and low production cost; after the reaction is finished, the reduced iron powder can be recovered by filtering and can be reused, thereby reducing production cost and environmental impact. The oxidation product benzil of the invention does not need additional purification, the operation steps are simple, and the product yield is significantly improved. DETAILED DESCRIPTION

[0022] The present invention is described in detail below in conjunction with specific embodiments.

[0023] The present invention discloses a method for synthesizing a benzil substance, and the specific steps are as follows:

[0024]

[0025] Dissolve acyloin compounds 1a-1k (2 mmol) in 5 ml of organic solvent, add reduced iron powder (4 mmol) and sodium hydroxide (4 mmol), and stir the reaction at room temperature. TLC tracking until the raw material point disappears. After the reaction is completed, add 20 ml of saturated brine and 50 ml of ethyl acetate to the reaction solution, and filter to recover the iron powder. Pour the filtrate into a separatory funnel to separate the organic phase, wash with water and dry over anhydrous sodium sulfate to obtain the target compounds 2a-2k.

[0026] The recovered iron powder does not need to be dried or supplemented, and the above operation can be directly repeated 4 times, and the yield remains basically unchanged.

[0027] Example 1: Synthesis of Benzil (Compound 2a)

[0028] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0029]

[0030] Yellow solid (323 mg, yield 76.9%). mp 89-92°C.

[0031] 1 H NMR (400MHz DMSO-d6): δ7.93 (d, J = 4.0Hz, 4H), 7.77 (dd, J = 8.0Hz, J' = 4.0Hz, 2H), 7.61 (dd, J = 8.0Hz, J' = 8.0Hz, 4H). 13 C NMR (100MHz DMSO-d6): δ195.2,135.9,132.7,130.0129.9.

[0032] HRMS (ESI, m / z) calculated for C 14 H 10 O2211.0754,[M+H] + found:211.0752.

[0033] Example 2: Synthesis of Compound 2b

[0034] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0035]

[0036] Yellow solid (490 mg, yield 90.7%). mp 130-132°C.

[0037] 1 H NMR (400MHz DMSO-d6): δ7.87 (d, J = 8.0 Hz, 4H), 7.13 (d, J = 8.0 Hz, 4H), 3.87 (s, 6H). 13 C NMR (100MHz DMSO-d6): δ194.0,165.2,132.5,125.9,115.3,56.3.

[0038] HRMS (ESI, m / z) calculated for C16 H 14 O4271.0965,[M+H] + found:271.0964.

[0039] Example 3: Synthesis of Compound 2c

[0040] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0041]

[0042] Pale yellow solid (360 mg, yield 66.6%). mp 69-73°C.

[0043] 1 H NMR (400MHz DMSO-d6): δ7.52(t,J=8.00Hz 2H),7.45(s,2H),7.41(d,J=8.00Hz,2H),7.36(d,J=8.00Hz,2H)3.83(s,6H). 13 C NMR (100MHz DMSO-d6): δ194.9,160.3,134.0,131.2,123.3,122.3,113.2,56.0.

[0044] HRMS (ESI, m / z) calculated for C 16 H 14 O4271.0965,[M+H] + found:271.0962.

[0045] Example 4: Synthesis of Compound 2d

[0046] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0047]

[0048] White solid (536 mg, yield 99.3%). mp 125-128°C.

[0049] 1 H NMR (400MHz DMSO-d6): δ7.97(d,J=8.00Hz,2H),7.68(t,J=8.00Hz,2H),7.20(d,J=8.00Hz,2H),7.19(t,J=8.00Hz,2H)3.52(s,6H). 13C NMR (100MHz DMSO-d6): δ192.4,160.5,136.6,129.9,123.0,121.8,113.7,56.4.

[0050] HRMS (ESI, m / z) calculated for C 16 H 14 O4271.0965,[M+H] + found:271.0966.

[0051] Example 5: Synthesis of Compound 2e

[0052] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0053]

[0054] White solid(440mg,yield 92.4%).mp95.5-100℃. 1 H NMR (400MHz DMSO-d6): δ7.80(d,J=4.0Hz,4H), 7.41(d,J=4.00Hz,4H), 2.39(s,6H). 13 C NMR(100MHz DMSO-d6):δ195.0,146.8,130.4,130.0,21.8.HRMS(ESI,m / z)calculated for C 16 H 14 O2239.1067,[M+H] + found:239.1064.

[0055] Example 6: Synthesis of Compound 2f

[0056] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0057]

[0058] Pale yellow solid (365 mg, yield 76.6%). mp 87-96°C.

[0059] 1 H NMR (400MHz DMSO-d6): δ7.75(s,2H),7.70(d,J=8.00Hz,2H),7.59(d,J=8.00Hz,2H),7.50(dd,J=8.00Hz,J'=8.00Hz,2H),2.37(s,6H).13 C NMR (100MHz DMSO-d6): δ195.4,139.6,136.6,132.8,130.0,129.8,127.4,21.2.

[0060] HRMS (ESI, m / z) calculated for C 16 H 14 O2239.1067,[M+H] + found:239.1067.

[0061] Example 7: Synthesis of Compound 2g

[0062] In this embodiment, the organic solvent is 75% methanol, and the reaction equation is as follows:

[0063]

[0064] Yellow solid (427 mg, yield 89.7%). mp 87-96°C.

[0065] 1 H NMR (400MHz DMSO-d6): δ7.66(d,J=8.00Hz,2H),7.62(t,J=8.00Hz,2H),7.46(d,J=8.00Hz,2H),7.39(t,J=8.00Hz,2H),2.62(s,6H). 13 C NMR (100MHz DMSO-d6): δ196.6,140.5,134.1,132.7,132.6,131.0,126.4,21.2.

[0066] HRMS (ESI, m / z) calculated for C 16 H 14 O2239.1067,[M+H] + found:239.1066.

[0067] Example 8: Synthesis of Compound 2h

[0068] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0069]

[0070] White solid (90 mg, yield 18.3%). mp 99-103°C.

[0071] 1H NMR(400MHz DMSO-d6):7.78-7.74(m,4H),7.70-7.62(m,4H). 13 C NMR (100MHz DMSO-d6): δ192.6, 162.7 (d, J = 246Hz), 134.8 (d, J = 7Hz), 132.2 (d, J = 7Hz), 126.9 (d, J = 3Hz), 123.0 (d, J = 21Hz), 116.1 (d, J = 22Hz).

[0072] HRMS (ESI, m / z) calculated for C 14 H8F2O2247.0565,[M+H] + found:247.0558.

[0073] Example 9: Synthesis of Compound 2i

[0074] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0075]

[0076] Yellow solid (270 mg, yield 54.9%). mp 112-125°C.

[0077] 1 H NMR (400MHz DMSO-d6): δ8.06-8.02(m,4H),7.48-7.44(m,4H). 13 C NMR (100MHz DMSO-d6): δ193.1, 166.73 (d, J = 254Hz), 133.46 (d, J = 10Hz), 129.51 (d, J = 3Hz), 117.21 (d, J = 22Hz).

[0078] HRMS (ESI, m / z) calculated for C 14 H8F2O2247.0565,[M+H] + found:247.0559.

[0079] Example 10: Synthesis of Compound 2j

[0080] In this embodiment, the organic solvent is 75% ethanol, and the reaction equation is as follows:

[0081]

[0082] Yellow solid (168 mg, yield 44.2%). mp 159-161°C.

[0083] 1 H NMR (400MHz DMSO-d6): δ8.23 (d, J = 1.6Hz), 7.55 (d, J = 3.6Hz, 2H), 6.84 (dd, J = 1.6Hz, J' = 3.6Hz, 2H). 13 C NMR (100MHz DMSO-d6): δ178.3,151.3,149.1,125.2,114.0.

[0084] HRMS (ESI, m / z) calculated for C 10 H6O4191.0339,[M+H] + found:191.0335.

[0085] Example 11: Synthesis of Compound 2k

[0086] In this embodiment, DMSO is selected as the organic solvent, and the reaction equation is as follows:

[0087]

[0088] White solid (575 mg, yield 96.4%). mp 153-156°C.

[0089] 1 H NMR (400MHz DMSO-d6): δ7.96(d,J=8.00Hz,2H),7.67(t,J=8.00,2H),7.15(m,4H),3.91(q,J=8.00Hz,4H),0.69(t,J=8.00Hz,6H). 13 C NMR (100MHz DMSO-d6): δ192.5,159.9,136.6,129.7,123.1,121.4,113.7,64.9,13.5.

[0090] HRMS (ESI, m / z) calculated for C 18 H 18 O4299.1278,[M+H] + found:299.1275.

[0091] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a benzil compound, characterized in that: The following steps are involved: The acyloin compound is dissolved in an organic solvent, reduced iron powder and sodium hydroxide are added, and the reaction is stirred at room temperature. After the reaction is completed, saturated brine and ethyl acetate are added to the reaction solution for extraction, and the iron powder is recovered by filtration. The filtrate is separated into an organic phase, and the organic phase is washed with water, dried, and concentrated to remove the solvent to obtain the target compound benzil substance.

2. The method for synthesizing a benzil compound according to claim 1, wherein: The acyloin compound is selected from the following compounds:

3. The method for synthesizing a benzil compound according to claim 1, wherein: The molar ratio of the acyloin compound, the reduced iron powder and the sodium hydroxide is 1:1-3:1-3.

4. The method for synthesizing a benzil compound according to claim 1, wherein: The organic solvent is one or a mixture of two or more of ethanol, methanol or DMSO.

5. The method for synthesizing a benzil compound according to claim 4, wherein: The organic solvent is ethanol, and the ethanol is 75% ethanol. 2 to 3 ml of ethanol needs to be added for every 1 mmol of acyloin compound.

6. The method for synthesizing a benzil compound according to claim 1, wherein: The reaction time is 0.5 to 2 hours.

7. The method for synthesizing a benzil compound according to claim 1, wherein: The iron powder additive recovered by filtration can be reused 1-6 times.

Images