Synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone

Abstract

The present invention discloses a synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone, which comprises the following steps: (1) Under the action of a Lewis base, 4-methylsulfonylbenzaldehyde and methyl acrylate are reacted to obtain intermediate III; (2) Under the action of imidazole, intermediate III undergoes a hydroxyl protection reaction with TBSCl to obtain compound IV; (3) Compound IV undergoes an ester group reduction reaction with DIBAL-H to obtain compound V; (4) Under the action of imidazole, compound V undergoes a hydroxyl protection reaction with TBSCl to obtain compound VI; (5) Compound VI undergoes an oxidation reaction under the action of ozone to obtain compound II; (6) Compound II is deprotected under acidic conditions to obtain compound I, namely the said 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone. This method improves the yield of the product, and the post-treatment is simple, making it more suitable for practical applications.

Description

Technical Field

[0001] The present invention relates to a preparation method of a florfenicol intermediate, and specifically to a synthesis method of 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone. Background Art

[0002] Florfenicol is a monofluoro derivative of synthetic thiamphenicol and is a new broad-spectrum antibacterial drug of the chloramphenicol class specifically for veterinary use successfully developed in the late 1980s.

[0003] The functional group of dihydroxy ketone not only exists in natural products but is also an important synthetic fragment for synthesizing ketoses.

[0004] WO2022166838 can convert 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone into chiral 1,3-dihydroxy-2-amino-1-(p-methylsulfonyl)propane through the ω-transaminase ATA117 mutant. This provides a new synthesis method for synthesizing thiamphenicol analogs. However, there are few methods for synthesizing 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone.

[0005] Similar synthesis methods include:

[0006] 1) Starting from 1,4-dioxacyclohexene, after five steps of lithiation, condensation, oxidation, reductive ring-opening, and acidic hydrolysis reactions, 1,3-dihydroxy-1-phenylpropanone is obtained by column chromatography (Tetrahedron Lett, 1985, 26(40), 4925 - 4928). The yield is 18.6%.

[0007]

[0008] This route involves five steps of reactions, with a low yield, and uses relatively expensive reagents such as tert-butyllithium, sodium borohydride, and m-chloroperoxybenzoic acid. At the same time, the first two steps require low-temperature reactions, and the last step uses column chromatography for purification.

[0009] 2) In addition, a simple synthesis method is reported, where 1 eq of lithium salt (3 mmol) and 3 eq of benzaldehyde react under the action of a tertiary amine, and column chromatography purification is required. It is easy to form isomers with carbonyl transfer and is not easy to separate. It cannot be scaled up for preparation (Eur. J. Org. Chem, 2006, 1121 - 1123).

[0010]

[0011] The above methods have cumbersome operations, low yields, and long production cycles, which are not conducive to industrial production. Summary of the Invention

[0012] In view of the problems existing in the above technologies, the present invention provides a new method for preparing 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone, which method improves the yield of the product, with the highest yield reaching 77.5%, and the post-treatment is simple.

[0013] The technical solution of the present invention is as follows:

[0014] A synthesis process of 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone, comprising the following steps:

[0015] (1) Under the action of a Lewis base, p-methylsulfonylbenzaldehyde and methyl acrylate undergo a Baylis–Hillman reaction to obtain intermediate III;

[0016] (2) Under the action of imidazole, intermediate III and TBSCl undergo a hydroxyl protection reaction to obtain compound IV;

[0017] (3) Compound IV and DIBAL-H undergo an ester reduction reaction to obtain compound V;

[0018] (4) Under the action of imidazole, compound V and TBSCl undergo a hydroxyl protection reaction to obtain compound VI;

[0019] (5) Compound VI undergoes an oxidation reaction under the action of ozone to obtain compound II;

[0020] (6) Compound II is deprotected under acidic conditions to obtain compound I, which is the 1,3-dihydroxy-1-(p-methylsulfonyl)phenylpropanone as described;

[0021] The reaction formula is as follows:

[0022]

[0023] Preferably, in step (1), the reaction is carried out in at least one of tetrahydrofuran, acetonitrile, DMF, and DMSO, and more preferably in tetrahydrofuran.

[0024] In step (1), the Lewis base is at least one of DABCO (triethylenediamine), triethylamine, and triphenylphosphine, and more preferably DABCO.

[0025] In step (1), the reaction temperature is 20-50 °C, and the reaction time is 12-36 h.

[0026] In step (1), the post-treatment process is as follows:

[0027] First, concentrate the reaction solution, then add ethyl acetate and hydrochloric acid, stir and then let it stand for liquid separation, wash the organic phase with brine, and concentrate to obtain the intermediate III.

[0028] Preferably, in step (2), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene, and more preferably in dichloromethane.

[0029] In step (2), the reaction temperature is 0 to 10 °C and the reaction time is 12 to 36 h.

[0030] In step (2), the post-treatment process of the reaction is as follows:

[0031] First, quench the reaction with water, then let it stand for liquid separation. Wash the organic phase with brine, then add toluene, and concentrate to obtain the compound IV.

[0032] Preferably, in step (3), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene, and more preferably in dichloromethane.

[0033] In step (3), the reaction temperature is -5 to -20 °C and the reaction time is 0.5 to 5 h.

[0034] After the reaction in step (3), the post-treatment process is as follows:

[0035] Quench the reaction with water, then stir to form a white gel, filter, and wash with dichloromethane. Concentrate the filtrate to dryness to obtain the compound V;

[0036] Preferably, in step (4), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene;

[0037] In step (4), the reaction temperature is 0 to 10 °C and the reaction time is 12 to 36 h.

[0038] In step (4), the post-treatment process of the reaction is as follows:

[0039] First, quench the reaction with water, then let it stand for liquid separation. Wash the organic phase with brine, then add toluene, and concentrate to obtain the compound IV.

[0040] Preferably, in step (5), the reaction is carried out in methanol or tetrahydrofuran, and more preferably in methanol;

[0041] In step (5), the reaction temperature is -70 to -80 °C and the reaction time is 20 to 60 min.

[0042] In step (5), the post-treatment process of the reaction is as follows:

[0043] Quench the reaction with trimethyl phosphite, then concentrate to dryness under reduced pressure, and then obtain the compound II by column chromatography.

[0044] ]>Preferably, in step (6), the reaction is carried out in a mixed system of THF and water;

[0045] The acid used under the described acidic conditions is acetic acid, and the reaction effect is poor when using other acids. Further, the volume ratio of THF, H2O, and AcOH is 1:1.0 - 1.2:3.0 - 3.6.

[0046] In step (6), the reaction temperature is 10 - 30 °C, and the reaction time is 10 - 30 h.

[0047] In step (6), the post-treatment process is as follows:

[0048] The reaction solution is concentrated under reduced pressure to dryness, then dichloromethane is added, stirred, filtered, washed, and dried to obtain the compound I.

[0049] Compared with the prior art, the technical effects of the present invention are as follows:

[0050] The present invention uses p-methylsulfonylbenzaldehyde and methyl acrylate as raw materials, and obtains 1,3-dihydroxy-1-p-methylsulfonylphenylacetone through a series of steps including Baylis–Hillman reaction, hydroxyl TBS protection, ester group reduction, TBSCl protection, ozonation reaction, and deprotection. The reaction conditions of the whole reaction route are mild, the post-treatment is simple, and the yields of each step are relatively high, and the overall yield of the whole route is significantly improved. Specific Embodiments

[0051] Example 1

[0052] 1) Preparation of Compound III

[0053]

[0054] At 20 - 30 °C, add tetrahydrofuran (20 mL) to a 100 mL three-necked flask, start stirring, and then add methyl acrylate (12.9 g, 0.15 mol), p-methylsulfonylbenzaldehyde (18.4 g, 0.10 mol), and DABCO (2.2 g, 0.02 mol). React at room temperature for 1 day. TLC detects that the raw materials have completely reacted.

[0055] Concentrate to dryness under reduced pressure at 40 °C. Add 100 mL of ethyl acetate and 50 mL of hydrochloric acid (1 M) to the concentrated solution, stir for 10 minutes. Let it stand for layering. Wash with saturated brine (50 mL). Concentrate to dryness under reduced pressure to obtain 27.0 g of a pale yellow oil, and the yield is 100%. Directly used for the next step of the reaction.

[0056] 2) Preparation of Compound IV

[0057]

[0058] Dissolve the compound III obtained in the previous step in 100 mL of dichloromethane, add it to a 250 mL reaction flask, and start stirring. Control the temperature at 0 - 10 °C, add imidazole (18.0 g), and then slowly add TBSCl (23.8 g). React overnight. Detect the completion of the reaction by TLC.

[0059] Control the temperature at 0 - 10 °C, add 40 mL of water to quench. The solid dissolves completely. Let it stand for liquid separation. Wash the organic phase with saturated brine (40 mL) again. Add toluene (50 mL) to dissolve it clearly, and concentrate to dryness again. Obtain 34.2 g of a pale yellow oily substance.

[0060] 3) Preparation of compound V

[0061]

[0062] Dissolve compound IV (7.3 g, 0.019 mol) in 60 mL of dichloromethane, transfer it to a 250 mL three-necked flask, displace with nitrogen 3 times, cool down to -10 °C, and add DIBAL-H (diisobutylaluminum hydride, 15 mL, 0.023 mol). Finish adding in about 30 minutes. React for 2 h until the raw materials are reacted completely.

[0063] Add 10 mL of water to quench, and stir for 1 h to form a white gel, then filter. Wash with 30 mL of dichloromethane. Concentrate the filtrate to dryness to obtain 6.7 g of a colorless oily substance. Directly use it for the next step of the reaction.

[0064] 4) Preparation of compound VI

[0065]

[0066] Dissolve the compound V obtained in the previous step (6.7 g, 0.019 mol) in 100 mL of dichloromethane, add it to a 250 mL reaction flask, and start stirring. Control the temperature at 0 - 10 °C, add imidazole (2.7 g), and then slowly add TBSCl (3.62 g). React overnight. Detect the completion of the reaction by TLC.

[0067] Control the temperature at 0 - 10 °C, add 10 mL of water to quench. The solid dissolves completely. Let it stand for liquid separation. Wash the organic phase with saturated brine (20 mL) again. Add toluene (30 mL) to dissolve it clearly, and concentrate to dryness again. Obtain 8.05 g of a pale yellow oily substance.

[0068] 5) Preparation of compound II

[0069]

[0070] Dissolve the compound VI (8.05 g) obtained in the previous step in methanol (50 mL). After purging with nitrogen, cool the solution to -78 °C and introduce ozone for about 30 minutes until the solution turns blue. Monitor the reaction by TLC until the starting material has completely reacted. Quench the reaction by adding 2.0 g of trimethyl phosphite. Remove ozone by purging with nitrogen. Concentrate the resulting solution under reduced pressure to dryness at 40 °C to obtain 9.2 g of an oily substance.

[0071] After elution by silica gel column chromatography (n - heptane / ethyl acetate = 10:1), 8.0 g of a colorless oily substance was obtained as compound II, which turned into a waxy solid upon standing. The overall yield of the first five steps was 79%.

[0072] 1 H NMR (CDCl3, 500 MHz) δ - 0.005 (t, 9H), 0.11 (s, 3H), 0.90 (t, 9H), 0.95 (s, 9H), 3.03 (s, 3H), 4.59 (dd, 2H), 5.32 (s, 1H), 7.65 (d, 2H), 7.92 (d, 2H) ppm.

[0073] 13 C NMR (CDCl3, 125 MHz) δ - 5.55, - 5.25, - 4.94, 18.18, 18.46, 25.66, 25.74, 44.53, 66.06, 79.09, 126.87, 127.67, 140.31, 144.62, 207.01 ppm.

[0074] 6) Preparation of compound I

[0075]

[0076] Add THF (10 mL) to compound II (4.0 g, 0.008 mol) and stir for 10 minutes. Transfer the mixture to a 250 - mL reaction flask and, while controlling the temperature at 10 - 20 °C, add acetic acid (30 mL) and water (10 mL). Maintain the reaction at room temperature for 18 h. Monitor the reaction by TLC until it is complete. Stop the reaction. Concentrate the reaction mixture to dryness under reduced pressure to obtain 3.0 g of an off - white solid.

[0077] Add dichloromethane (40 mL), stir for 2 h. Filter and wash with dichloromethane to obtain 2.1 g of a wet product. Dry the wet product under vacuum at 40 °C to obtain 1.8 g of compound I as a white solid. The yield is 87.1%.

[0078] 1 H NMR (CDCl3, 500 MHz) δ 3.14 (s, 1H), 3.29 - 3.31 (m, 2H), 3.56 (d, 1H), 3.86 (d, 1H), 7.89 - 7.91 (m, 2H), 7.96 - 7.97 (m, 2H).

[0079] HPLC-MS (M-1): 243.0。

[0080] Example 2

[0081] Other steps are the same as those in Example 1, and the process of step 6) is as follows:

[0082] Preparation of Compound I

[0083]

[0084] Add THF (5 mL) to Compound II (2.0 g, 0.004 mol), stir for 10 minutes until completely dissolved. Add it to a 50 mL reaction flask. Under nitrogen protection, while controlling the temperature at 10 - 20 °C, add a tetrahydrofuran solution (17 mL) of TBAF (1 M). Keep the reaction at room temperature for 2 h. Detect the completion of the reaction by TLC. Stop the reaction. Concentrate under reduced pressure to dryness.

[0085] Purify by silica gel column chromatography, elute with dichloromethane / methanol / THF (40:1:10) to obtain 0.55 g of white solid, and the yield is 53.2%.

Claims

1. A synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone, characterized in that, It includes the following steps: (1) Under the action of a Lewis base, p-methylsulfonylbenzaldehyde and methyl acrylate undergo a Baylis–Hillman reaction to obtain intermediate III; (2) Under the action of imidazole, intermediate III undergoes a hydroxyl protection reaction with TBSCl to obtain compound IV; (3) Compound IV undergoes an ester reduction reaction with DIBAL-H to obtain compound V; (4) Under the action of imidazole, compound V undergoes a hydroxyl protection reaction with TBSCl to obtain compound VI; (5) Compound VI undergoes an oxidation reaction under the action of ozone to obtain compound II; (6) Compound II is deprotected under acidic conditions to obtain compound I, which is the described 1,3-dihydroxy-1-p-methylsulfonylacetophenone; The reaction formula is as follows:

2. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propan-1-one according to claim 1, characterized in that, In step (1), the reaction is carried out in at least one of tetrahydrofuran, acetonitrile, DMF, and DMSO; The Lewis base is at least one of DABCO, triethylamine, and triphenylphosphine; In step (1), the reaction temperature is 20 - 50 °C, and the reaction time is 12 - 36 h.

3. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone according to claim 1, characterized in that, In step (2), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene; In step (2), the reaction temperature is 0 - 10 °C, and the reaction time is 12 - 36 h.

4. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone according to claim 1, characterized in that, In step (3), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene; In step (3), the reaction temperature is -5 - -20 °C, and the reaction time is 0.5 - 5 h.

5. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propan-1-one according to claim 1, wherein In step (4), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene; In step (4), the reaction temperature is 0 - 10 °C, and the reaction time is 12 - 36 h.

6. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone according to claim 1, characterized in that, In step (5), the reaction is carried out in methanol or tetrahydrofuran.

7. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propan-1-one according to claim 1, characterized in that, In step (5), the reaction temperature is -70 - -80 °C, and the reaction time is 20 - 60 min.

8. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propanone according to claim 1, characterized in that, In step (5), the post-treatment process of the reaction is as follows: Add trimethyl phosphite to quench the reaction, then concentrate to dryness under reduced pressure, and then obtain the compound II by column chromatography.

9. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propan-1-one according to claim 1, characterized in that, In step (6), the reaction is carried out in a mixed system of THF and water; The acid used under the acidic conditions is acetic acid.

10. The synthesis process of 1,3-dihydroxy-1-(4-methylsulfonylphenyl)propan-1-one according to claim 1, characterized in that, In step (6), the reaction temperature is 10 - 30 °C, and the reaction time is 10 - 30 h.

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