KR101943889B1 - Process of preparing β-keto sulfones using xanthate compounds - Google Patents

Abstract

The present invention relates to a method for producing a? -Ketosulfone compound using a novel zwitterion compound and an olefin compound. According to the present invention, a? -Ketosulfone compound can be easily produced in a high yield using commercially available and synthetically easily available materials.

Description

[0001] The present invention relates to a process for preparing [beta] -ketosulfone compounds using zanthate compounds,

More particularly, the present invention relates to a method for producing a? -Ketosulfone compound using a novel zwitterion compound and an olefin compound as starting materials, And a method for producing the same.

[beta] -ketosulfone compounds are very important compounds in organic synthesis due to their diverse use in synthesis. For example, β-ketosulfone is an important compound used as a key intermediate in the synthesis of alkenes, alkenes, ketones and heterocyclic compounds. In addition, the? -Ketosulfone compound has antifungal properties [Wolf, WM J. Mol . Struct . 1999 , 474 , 113] and antimicrobial activity (Curti, C; Laget, M .; Carle, AO; Gellis, A .; Vanelle, P. Eur . J. Med . Chem ., 2007 , 42 , 880], and recently it has been reported that it has biochemical activity as an inhibitor of 11? -Hydroxysteroid dehydrogenase Type I (11? -HSD1) Reference literature: Xiang, J; Ipek, M .; Suri, V .; Tam, M .; Xing, Y .; Huang, N .; Zhang, Y .; Tobin, J .; Mansour, TS; Mckew, J. Bioorg . Med . Chem . 2007 , 17 , 4396].

Thus, various synthetic methods for? -Ketosulfone have been reported in the literature, for example, by reacting a terminal alkyne and a sulfinic acid with oxygen to form an oxidative radical process a method of synthesizing? -ketosulfone or a method of synthesizing? -ketosulfone by reacting an alkene and a sulfonyl hydrazide with oxygen in the presence of a catalytic amount of CF ₃ CO ₂ H has been reported in literature (refer to Lu, O .; Zhang, J .; Zhao, G .; Qi, Y .; Wang, H .; Lei, A. J. Am . Chem . Soc . 2013 , 135 , 11481; Liu, C .; Ding, L .; Guo, G .; Liu, W. Eur . J. Org . Chem . 2016 , 910].

However, these synthetic methods generally have disadvantages such as limited range of substrates or difficulty in purchasing starting materials commercially, or requiring vigorous reaction conditions. Therefore, there is a need for the development of a new synthetic method that can produce beta -ketosulfone from olefinic compounds under mild reaction conditions using commercially available starting materials.

 Wolf, W. M. J. Mol. Struct. 1999, 474, 113  Curti, C; Laget, M .; Carle, A. O .; Gellis, A .; Vanelle, P. Eur. J. Med. Chem., 2007, 42, 880  Xiang, J; Ipek, M .; Suri, V .; Tam, M .; Xing, Y .; Huang, N .; Zhang, Y .; Tobin, J .; Mansour, T. S .; Mckew, J. Bioorg. Med. Chem. 2007, 17, 4396  Lu, O .; Zhang, J .; Zhao, G .; Qi, Y .; Wang, H .; Lei, A. J. Am. Chem. Soc. 2013, 135, 11481  Liu, C .; Ding, L .; Guo, G .; Liu, W. Eur. J. Org. Chem. 2016, 910

It is an object of the present invention to provide a method for producing a? -Ketosulfone compound using a novel zwitterion compound and an olefin compound.

Another object of the present invention is to provide a novel zonate compound for the production of [beta] -ketosulfone compounds.

It is a further object of the present invention to provide a process for preparing the abovementioned zantite compounds.

One embodiment of the present invention relates to a process for producing a? -Ketosulfone compound represented by the following formula (3) using a novel zirconate compound and an olefin compound,

(i) subjecting a zertate compound of the formula (1) to an addition reaction with an olefin compound of the formula (2) to obtain a zertate adduct of the formula (7) And

(ii) subjecting the azide adduct of the formula (7) to a radical reduction reaction.

[Chemical Formula 1]

(2)

(7)

(3)

In this formula,

Xa is -SC (= S) OEt,

R ¹ is a C ₁ -C ₆ alkyl or aryl group,

R ² is a C ₁ -C ₆ alkyl group, an aryl group, an aryloxy group, -OCOR ³ or -R ⁴ COR ⁵ ,

R ³ , R ⁴ and R ⁵ are each independently a C ₁ -C ₆ alkyl group.

As used herein, the C ₁ -C ₆ alkyl group means a linear or branched hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -Butyl, t -butyl, n -pentyl, n -hexyl, and the like.

As used herein, an aryl group includes both an aromatic group and a heteroaromatic group and a partially reduced derivative thereof. The arometric group is a simple or fused ring group of 5 to 15-ary, and the heteroaromatic group means an arometric group containing at least one of oxygen, sulfur or nitrogen. Representative aryl groups include, but are not limited to, phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, But are not limited to, oxazolyl, thiazolyl, tetrahydronaphthyl, and the like.

As used herein, an aryloxy group means an oxygen functional group that is mono-bonded to an aryl group, and includes, but is not limited to, phenoxy, benzyloxy, and the like.

The C ₁ -C ₆ alkyl, aryl and aryloxy groups may be substituted by one or more of the hydrogens selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ cycloalkyl group -C _10, C ₃ -C ₁₀ a heterocycloalkyl group, C ₃ -C ₁₀ heteroaryl cycloalkyloxy groups, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ of the alkoxy group, C ₁ - C ₆ thioalkoxy group, aryl group, acyl group, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxy, carbamoyl, cyano, nitro and the like.

In an embodiment of the present invention,

R ¹ is a C ₁ -C ₆ alkyl group; Or phenyl which is unsubstituted or substituted by a C ₁ -C ₆ alkyl group,

R ² is a C ₁ -C ₆ alkyl group, phenyl, benzyloxy, -OCOR ³ or -R ⁴ COR ⁵ ,

R ³ , R ⁴ and R ⁵ are each independently a C ₁ -C ₆ alkyl group.

In an embodiment of the present invention,

R ¹ is methyl; Or phenyl unsubstituted or substituted by methyl,

R ² is n-pentyl, phenyl, benzyloxy, acetoxy or methylcarbonylmethyl.

Hereinafter, the production method of the present invention will be described in more detail with reference to Reaction Scheme 1 below. The method described below exemplifies the representative method, but the reaction reagent, the reaction conditions, and the like may be changed as required.

[Reaction Scheme 1]

Zertate adduct ( 7 ) can be obtained by the addition reaction of zertate compound ( 1 ) with olefin compound ( 2 ). Specifically, the glass Tate compound (1) an olefin compound (2) and the glass Tate radicals transferred to the olefin compound (2) from when refluxed in a radical reaction condition glass Tate compound (1) glass Tate adduct (7) up and with the .

The addition reaction may be carried out using a catalytic amount of a radical initiator, and examples of the radical initiator include dilauroyl peroxide (DLP), dibenzoyl peroxide (BPO), dicumyl peroxide dicumyl peroxide: CPO), di - t - butyl peroxide (di- t -butyl peroxide: DTBP) , tetrabutyl ammonium peroxydisulfate (tetra (n -butyl) ammonium peroxydisulfate , TBAP) , but such can be used, whereby But is not limited thereto.

Examples of the reaction solvent include 1,2-dichloroethane (DCE), chlorobenzene, cyclohexane, diisopropyl ether, and the like, but are not limited thereto.

In this process, a reductant dexanthation is partially caused by the side reaction at the same time that the zetate adduct 7 is produced, so that a small amount of the? -Ketosulfone compound ( 3 ) may be produced .

The? -ketosulfone compound ( 3 ) can be obtained by a radical reduction reaction of the zetate adduct ( 7 ). Specifically, the radical reduction reaction of the zetate adduct ( 7 ) in the presence of hypophosphorous acid (H ₃ PO ₂ ), triethylamine (Et ₃ N) and azobisisobutyronitrile (AIBN) The reaction occurs to produce the? -Ketosulfone compound ( 3 ). At this time, examples of the reaction solvent include 1,4-dioxane, chlorobenzene, 1,2-dichloroethane (DCE), diisopropyl ether, etc. But is not limited thereto.

The radical reduction reaction may be carried out by refluxing in i -propyl alcohol (IPA) solvent using DLP as a radical initiator, but i -propyl alcohol (IPA) is not limited as a reaction solvent.

Yet another embodiment of the present invention relates to a novel zwitterionic compound,

[Chemical Formula 1]

In this formula,

Xa is -SC (= S) OEt,

R ¹ is a C ₁ -C ₆ alkyl or aryl group.

The quaternate compound of the present invention can be usefully used as a starting material for preparing the? -Ketosulfone compound of the above formula (3).

Another embodiment of the present invention relates to a process for preparing a zirconate compound of formula 1,

Reacting the 1,3-dichloroacetone of formula (4) with a sodium sulphinate compound of formula (5) and potassium O -ethylantietate of formula (6).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 1]

In this formula,

Xa is -SC (= S) OEt,

R ¹ is a C ₁ -C ₆ alkyl or aryl group.

Hereinafter, the production method of the zanthate compound will be described in more detail with reference to Reaction Scheme 2 below. The method described below exemplifies the representative method, but the reaction reagent, the reaction conditions, and the like may be changed as required.

[Reaction Scheme 2]

Zanthate compound ( 1 ) can be prepared by sequentially reacting 1,3-dichloroacetone ( 4 ) with sodium sulfinate compound ( 5 ) and potassium O-ethylantanate ( 6 ).

The reaction temperature is preferably room temperature, and as a reaction solvent, dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetone, or the like may be used, but the present invention is not limited thereto.

The 1,3-dichloroacetone ( 4 ), the sodium sulphinate compound ( 5 ) and the potassium O-ethylantate ( 6 ) are commercially available.

According to the production method of the present invention, the? -Ketosulfone compound can be easily produced in high yield from a novel quaternate compound and an olefin compound which is easily commercially available and easy to manufacture.

In addition, the novel zonate compounds can be easily produced in high yield using reagents that are easy to obtain and commercially available.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

Example  One: O -Ethyl S- [2-oxo-3- ( Phenylsulfonyl )profile] Carbonodithioate  ( O -Ethyl S -[2- oxo -3- ( phenylsulfonyl ) propyl ] karbonodithioate , 1a)

Sodium benzenesulfinate solution ( 5a , 492.5 mg, 3.0 mmol, 8 mL dry DMSO) was dissolved in 1,3-dichloroacetone using a canola. solution ( 4 , 380.9 mg, 1.0 eq., 2 mL dry DMSO) and stirred at room temperature for 10 hours under argon gas. Potassium back to the reaction solution O - ethyl lactate glass (potassium O -ethyl xanthate) was added (6, 480.9 mg, 1.0 eq) and stirred for another 4 hours at room temperature, CH ₂ Cl ₂ in the resulting reaction solution (30 mL) and H ₂ O (25 mL) were added and shaken, and the lower organic layer was separated using a separatory funnel. The upper aqueous layer was further washed with CH ₂ Cl ₂ (10 mL x 2) and the combined organic layers were washed with saturated aqueous NaCl solution (15 mL x 3). The obtained organic layer over anhydrous MgSO ₄ (5 g) and treated to remove the solvent under reduced pressure, filtered and the obtained residue was purified by flash column chromatography (silica gel:: Merck 70-230, mobile phase CH ₂ Cl ₂ / hexane = 10/1) pure title Compound ( 1a , 601.8 mg, 63%) was obtained.

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.40 (t, J = 7.2 Hz, 3 H), 4.19 (s, 2 H), 4.42 (s, 2 H), 4.60 (q, J = 7.2 Hz, 2 H), 7.55-7.94 (m, 5 H).

Example  2:  O -Ethyl S- {3 - [(4- Methylphenyl ) Sulfonyl ]-2- Oxopropyl } Carbonodithio It O - Ethyl S - {3 - [(4- 메틸 피닐 ) ulfonyl ]-2- 옥시opropyl } karbonodithioate , 1b)

Sodium p - toluene sulfinate (Sodium p -toluenesulfinate) solution (5b, 534.5 mg, 3.00 mmol , 8 mL dry DMSO) to cache using Cronulla 1, 3-dichloroacetone (1,3-dichloroacetone) solution ( 4 , 380.9 mg, 1.0 eq., 2 mL dry DMSO) and stirred at room temperature for 10 hours under argon gas. Potassium back to the reaction solution O - ethyl lactate glass (potassium O -ethyl xanthate) was added (6, 480.9 mg, 1.0 eq) and stirred for another 4 hours at room temperature, CH ₂ Cl ₂ in the resulting reaction solution (30 mL) and H ₂ O (25 mL) were added and shaken, and the lower organic layer was separated using a separatory funnel. The upper aqueous layer was further washed with CH ₂ Cl ₂ (10 mL x 2) and the combined organic layers were washed with saturated aqueous NaCl solution (15 mL x 3). The obtained organic layer over anhydrous MgSO ₄ (5 g) processed and filtered and the column and the residue obtained by removing the solvent under reduced pressure was purified by flash chromatography (silica gel: Merck 70-230, mobile phase: CH ₂ Cl ₂ / hexane = 8/1) to give pure The title compound ( 1b , 598.5 mg, 60%) was obtained.

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.41 (t, J = 7.2 Hz, 3 H), 2.46 (s, 3 H), 4.20 (s, 2 H), 4.39 (s, 2 H), 4.61 ( q, J = 7.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H) 7.78 (d, J = 8.2 Hz, 2H).

Example  3: O -Ethyl S- [3- ( Methylsulfonyl )-2- Oxopropyl ] Carbonodithioate ( O -Ethyl S - [3- ( methylsulfonyl )-2- 옥시opropyl ] karbonodithioate , 1c)

Sodium methanesulfinate solution ( 5c , 306.3 mg, 3.00 mmol, 8 mL dry DMSO) was dissolved in 1,3-dichloroacetone using a canula. solution ( 4 , 380.9 mg, 1.0 eq., 2 mL dry DMSO) and stirred at room temperature for 10 hours under argon gas. Potassium back to the reaction solution O - ethyl lactate glass (potassium O -ethyl xanthate) was added (6, 480.9 mg, 1.0 eq) and stirred for another 4 hours at room temperature, CH ₂ Cl ₂ in the resulting reaction solution (30 mL) and H ₂ O (25 mL) were added and shaken, and the lower organic layer was separated using a separatory funnel. The upper aqueous layer was further washed with CH ₂ Cl ₂ (10 mL x 2), and the combined organic layers were combined and washed with saturated aqueous NaCl solution (15 mL x 3). The obtained organic layer over anhydrous MgSO ₄ (5 g) processed and filtered and the column and the residue obtained by removing the solvent under reduced pressure was purified by flash chromatography (silica gel: Merck 70-230, mobile _{phase: CH 2 Cl 2 / EtOAc =} 40/1) to give pure The title compound ( 1c , 392.2 mg, 51%) was obtained.

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.44 (t, J = 7.2 Hz, 3 H), 3.07 (s, 2 H), 4.19 (s, 2 H), 4.30 (s, 2 H), 4.65 ( q, J = 7.2 Hz, 2H).

Example  4:  O -Ethyl S- [5-oxo-1- Phenyl -6- ( Phenylsulfonyl ) Hexane -2 days] Carbonodithio Eight O - Ethyl S - [5- oxo -One- phenyl -6- ( phenylsulfonyl ) hexan -2-yl] carbonodithioate, 7a)

Anhydrous DCE (3 mL) solution containing the minor acid compound ( 1a , 159.2 mg, 0.5 mmol) obtained in Example 1 and allylbenzene ( 2a , 66.2 μL, 1.0 eq.) Was heated at 100 ° C. After refluxing for 10 min, DLP (39.9 mg, 0.2 eq.) Was added and refluxed under argon for 1 h. The reaction solution was cooled to room temperature and the solvent was removed using a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3/1) to give pure title compound 7a , 172.5 mg, 79%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.42 (t, J = 7.2 Hz, 3 H), 1.69-1.81 (m, 1 H), 1.98-2.08 (m, 1 H), 2.72-2.97 (m, 3 H), 3.14 (dd, J ₁ = 14.0 Hz, J ₂ = 6.0 Hz, 1H), 3.88-3.97 (m, 1H), 4.12 (d, J = 2.4 Hz, 2 H), 4.62 (q, J = 7.2 Hz, 2 H), 7.22-7.35 (m, 5 H), 7.53-7.88 (m, 5 H).

Further, the title compound ( 3a , 4.7 mg, 3%), in which the zetate functional group was removed as a byproduct during the separation, was obtained at the same time.

Example  5: O -Ethyl S- [2-oxo-1- ( Phenylsulfonyl ) Undecan -5-yl] carbonyldithioate ( O - Ethyl S -[2- oxo -One-( phenylsulfonyl ) undecan -5- yl ] karbonodithioate , 7b)

Anhydrous DCE (3 mL) solution containing the minor acid compound ( 1a , 159.2 mg, 0.5 mmol) obtained in Example 1 and 1-octene ( 2b , 78.5 μL, 1.0 eq) After refluxing at 100 < 0 > C for 10 min, DLP (39.9 mg, 0.2 eq) was added and refluxed under argon for 1 h. The obtained reaction solution was cooled to room temperature and the solvent was removed by a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 4/1) to give pure title compound ( 7b , 157.2 mg, 73%).

¹ H NMR (CDCl ₃ , 400 MHz)? 0.88 (t, J = 6.8 Hz, 3 H), 1.20-1.50 (m, 11 H), 1.58-1.69 (m, 2 H), 1.75-1.87 1 H), 4.16 (d, J ), 2.01-2.12 (m, 1H), 2.86 (t, J = 7.2 Hz, 2H), 3.65-3.75 = 3.2 Hz, 2 H), 4.64 (q, J = 6.8 Hz, 2 H), 7.55-7.94 (m, 5 H).

Further, the title compound ( 3b , 4.7 mg, 3%) in which the zetate functional group was removed as a by-product in the separation process was obtained at the same time.

Example  6: S -[One-( Benzyloxy ) -5-oxo-6- ( Phenylsulfonyl ) Hexane -2 days] O -ethyl Carbonodithioate  ( S -[One-( Benzyloxy ) -5- oxo -6- ( phenylsulfonyl ) hexan -2- yl ] O - ethyl  carbonodithioate, 7c)

A solution of anhydrous DCE (3 mL) containing the minor acid compound ( 1a , 159.2 mg, 0.5 mmol) obtained in Example 1 and allyl benzyl ether ( 2c , 77.3 μL, 1.0 eq) After refluxing at 100 < 0 > C for 10 min, DLP (39.9 mg, 0.2 eq) was added and refluxed under argon for 1 h. The resulting reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3.5 / 1) to give pure title compound ( 7c , 165.6 mg, 71%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.41 (t, J = 7.2 Hz, 3 H), 1.86-1.98 (m, 1 H), 2.14-2.25 (m, 1 H), 2.78-2.96 (m, 2 H), 3.58 (dd, J ₁ = 9.9 Hz, J ₂ = 6.6 Hz, 1 H), 3.71 (dd, J 1 = 9.9 Hz, J ₂ = 4.0 Hz, 1H), 3.89-3.98 (m, 1H), 4.10 (s, 2H), 4.53 (s, 2H), 4.63 (q, J = 7.2 Hz, 2H), 7.26-7.39 (m, 5 H), 7.53 - 7.90 (m, 5 H).

Further, the title compound ( 3c , 6.9 mg, 4%), in which the zetate functional group was removed as a by-product in the separation process, was obtained at the same time.

Example  7: 2 - [( Ethoxycarbonyl oil ) Sulfanyl ] -5-oxo-6- ( Phenylsulfonyl ) Hexyl  Acetate (2 - [( Ethoxycarbonothioyl ) sulfanyl ] -5- oxo -6- ( phenylsulfonyl ) hexyl  acetate, 7d)

Anhydrous DCE (3 mL) solution containing the minor acid compound ( 1a , 159.2 mg, 0.5 mmol) obtained in Example 1 and allyl acetate ( 2d , 53.9 μL, 1.0 eq) At reflux for 10 min, then DLP (39.9 mg, 0.2 eq) was added and refluxed under argon for another hour. The obtained reaction solution was cooled to room temperature and the solvent was removed by a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 2/1) to give pure title compound ( 7d , 163.2 mg, 78%).

¹ H NMR (CDCl ₃ , 400 MHz)? 1.44 (t, J = 6.8 Hz, 3 H), 1.80-1.92 (m, 1H), 2.05-2.19 (m, 4H), 2.89-2.98 2 H), 3.92-4.00 (m, 1 H), 4.17 (s, 2 H), 4.22 (dd, J 1 = 11.5 Hz, J ₂ = 6.0 Hz, 1H), 4.30 (dd, J ₁ = 11.5 Hz, J ₂ = 4.6 Hz, 1H), 4.65 (q, J = 6.8 Hz, 2H), 7.56-7.94 (m, 5H).

Further, the title compound ( 3d , 6.0 mg, 4%) in which the zetate functional group was removed as a by-product in the separation process was obtained at the same time.

Example  8: O -ethyl S - [2,8- Dioxo -One-( Phenylsulfonyl ) Nonan -5 days] Carbonodithioate ( O - Ethyl S - [2,8- dioxo -One-( phenylsulfonyl ) nonan -5- yl ] karbonodithioate , 7e)

Anhydrous DCE (5 ml) containing the minor acid compound ( 1a , 159.2 mg, 0.5 mmol) obtained in Example 1 and 5-hexen-2-one ( 2e , 58.4 μL, 1.0 eq) 3 mL) was refluxed under argon gas at 100 < 0 > C for 10 min. DLP (39.9 mg, 0.2 eq) was added and refluxed for 1 h under argon gas. The obtained reaction solution was cooled to room temperature and the solvent was removed by a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 1.5 / 1) to give pure title compound ( 7e , 166.6 mg, 80%).

¹ H NMR (CDCl ₃ , 400 MHz)? 1.43 (t, J = 7.2 Hz, 3H), 1.76-1.92 (m, 2H), 1.98-2.10 ), 2.60 (t, J = 7.2 Hz, 2 H), 2.88 (t, J = 7.2 Hz, 2 H), 3.65-3.74 (m, 1 H), 4.16 (d, J = 1.2 Hz, 2 H), 4.64 (q, J = 7.2 Hz, 2 H), 7.56-7.92 (m, 5 H).

Further, the title compound ( 3e , 4.4 mg, 3%) in which the zetate functional group was removed as a by-product in the separation process was obtained at the same time.

Example  9: O -ethyl S - {6 - [(4- Methylphenyl ) Sulfonyl ] -5-oxo-1- Phenyl hexane -2 days} Carbonodithioate ( O - Ethyl S - {6 - [(4- 메틸 피닐 ) ulfonyl ] -5- oxo -One- 파henylhexan -2-yl} karbonodithioate , 7f)

Anhydrous DCE (3 mL) solution containing the minor acid compound ( 1b , 166.3 mg, 0.5 mmol) obtained in Example 2 and allylbenzene ( 2a , 66.2 μL, 1.0 eq.) Was heated at 100 ° C. After refluxing for 10 min, DLP (39.9 mg, 0.2 eq.) Was added and refluxed under argon for 1 h. The resulting reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3.5 / 1) to give pure title compound ( 7f , 180.2 mg, 80%).

¹ H NMR (CDCl ₃ , 400 MHz)? 1.42 (t, J = 7.2 Hz, 3 H), 1.68-1.80 ), 2.71-2.95 (m, 3 H), 3.14 (dd, J ₁ = 14.0 Hz, J ₂ = 6.0 Hz, 1H), 3.88-3.97 (m, 1H), 4.07 (d, J = 2.8 Hz, 2 H), 4.62 (q, J = 6.8 Hz, 2 H), 7.21-7.38 (m, 7 H), 7.71 (d, J = 8.4 Hz, 2 H).

Further, the title compound ( 3f , 6.6 mg, 4%), in which the zetate functional group was removed as a by-product in the separation process, was obtained at the same time.

Example  10: O -ethyl S - {1 - [(4- Methylphenyl ) Sulfonyl ]-2- Oxoundecane -5 days} Carbonodithioate  ( O - Ethyl S - {1 - [(4- 메틸 피닐 ) ulfonyl ]-2- oxoundecan -5- yl } carbonodithioate, 7g)

A solution of anhydrous DCE (2 mL) containing the minor acid compound ( 1b , 166.3 mg, 0.5 mmol) obtained in Example 2 and 1-octene ( 2b , 78.5 μL, 1.0 eq) After refluxing at 100 < 0 > C for 10 min, DLP (39.9 mg, 0.2 eq) was added and refluxed under argon for 1 h. The obtained reaction solution was cooled to room temperature and the solvent was removed by a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 5/1) to give pure title compound ( 7 g , 182.3 mg, 82%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 0.88 (t, J = 7.0 Hz, 3 H), 1.20-1.47 (m, 11 H), 1.58-1.68 (m, 1 H), 1.74-1.86 (m, 1 H), 2.00-2.12 (m, 1 H), 2.47 (s, 3 H), 2.85 (t, J = 7.2 Hz, 2 H), 3.64-3.74 (m, 1 H), 4.14 (d, J = 4.0 Hz, 2H), 4.64 (q, J = 7.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H) 7.75 (d, J = 8.4 Hz, 2H).

Further, the title compound ( 3 g , 6.5 mg, 4%) in which the zetate functional group was removed as a by-product in the separation process was obtained at the same time.

Example  11: O -ethyl S - [6- ( Methylsulfonyl ) -5-oxo-1- Phenyl hexane -2 days] Carbonodithioate  ( O - Ethyl S - [6- ( methylsulfonyl ) -5- oxo -One- 파henylhexan -2- yl ] carbonodithioate, 7h)

Anhydrous DCE (3 mL) solution containing the minor acid compound ( 1c , 128.2 mg, 0.5 mmol) obtained in Example 3 and allylbenzene ( 2a , 66.2 μL, 1.0 eq.) Was stirred at 100 ° C. After refluxing for 10 min, DLP (39.9 mg, 0.2 eq.) Was added and refluxed under argon for 1 h. The obtained reaction solution was cooled to room temperature and the solvent was removed by a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 2.5 / 1) to give pure title compound ( 7h , 149.8 mg, 80%).

^One1 H NMR (CDCl 3₃, 400 MHz) [delta] 1.42 (t,J = 7.0 Hz, 3H), 1.74-1.86 (m, 1H), 2.04-2.18 (m, 1H), 2.74-2.95 (m, 3H), 3.02J _One = 13.8 Hz,J ₂ = 6.2 Hz, 1H), 3.92-4.02 (m, 3H), 4.62 (q,J = 7.0 Hz, 2 H), 7.21-7.35 (m, 5 H).

Further, the title compound ( 3h , 3.8 mg, 3%), in which the zetate functional group was removed as a by-product in the separation process, was obtained at the same time.

Example  12: O -ethyl S -[One-( Methylsulfonyl )-2- Oxoundecane -5 days] Carbonodithioate ( O - Ethyl S -[One-( methylsulfonyl )-2- oxoundecan -5- yl ] karbonodithioate , 7i)

The retardant compound obtained in Example 3 Anhydrous DCE (3 mL) solution containing 1-octene ( 1c , 128.2 mg, 0.5 mmol) and 1-octene ( 2b , 78.5 μL, 1.0 eq.) Was refluxed in an argon atmosphere at 100 ° C. for 10 min DLP (39.9 mg, 0.2 eq) was added and refluxed under argon for another hour. The obtained reaction solution was cooled to room temperature and the solvent was removed using a rotary evaporator. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3/1) to give pure title compound ( 7i , 138.2 mg, 75%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 0.88 (t, J = 6.8 Hz, 3 H), 1.28 (bs, 8 H), 1.43 (t, J = 7.0 Hz, 3 H), 1.57-1.71 (m , 2 H), 1.80-1.92 (m , 1 H), 2.08-2.19 (m, 1 H), 2.87 (t, J = 7.0 Hz, 2H), 3.06 (s, 3H), 3.70-3.79 (m, 1H), 4.04 (s, 2H), 4.64 (q, J = 7.0 Hz, 2H).

In addition, the title compound ( 3i , 5.0 mg, 4%) in which the zetate functional group was removed as a by-product in the separation process was obtained at the same time.

Example  13: 6- Phenyl -One-( Phenylsulfonyl ) Hexane One (6- Phenyl -1- (phenylsulfonyl) hexan-2-one, 3a)

To a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7a , 131.0 mg, 0.3 mmol) obtained in Example 4 was added H ₃ PO ₂ (164.2 μL, 5.0 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 2.5 / 1 ) To obtain the title compound ( 3a , 75.9 mg, 80%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.58-1.68 (m, 4 H), 2.61 (t, J = 7.0 Hz, 2 H), 2.73 (t, J = 6.6 Hz, 2 H), 4.12 (s, 2 H), 7.13-7.32 (m, 5 H), 7.53-7.90 (m, 5 H).

Example  14: 1- ( Phenylsulfonyl ) Undecan One (1- ( Phenylsulfonyl ) undecan -2- one , 3b)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7b , 129.2 mg, 0.3 mmol) obtained in Example 5 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 4.5 / 1 ) To obtain the title compound ( 3b , 76.4 mg, 82%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (bs, 10 H), 1.50-1.62 (m, 4 H), 2.70 (t, J = 7.2 Hz , 2 H), 4.15 (s, 2 H), 7.55-7.92 (m, 5 H).

Example  15: 6- ( Benzyloxy )-One-( Phenylsulfonyl ) Hexane One (6- ( Benzyloxy ) -1- (phenylsulfonyl) hexan-2-one, 3c)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7c , 140.0 mg, 0.3 mmol) obtained in Example 6 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3/1 ) To give the title compound ( 3c , 76.9 mg, 74%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.55-1.72 (m, 4 H), 2.73 (t, J = 7.0 Hz, 2 H), 3.46 (t, J = 6.2 Hz, 2 H), 4.11 (s , 2H), 4.74 (s, 2H), 7.28-7.38 (m, 5H), 7.53-7.92 (m, 5H).

Example  16: 5-oxo-6- ( Phenylsulfonyl ) Hexyl  Acetate (5- Oxo -6- (phenylsulfonyl) hexyl acetate , 3d)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the adduct of the residue ( 7d , 125.6 mg, 0.3 mmol) obtained in Example 7 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 2/1 ) To give the title compound ( 3d , 60.0 mg, 67%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.57-1.70 (m, 4 H), 2.05 (s, 3 H), 2.77 (t, J = 6.6 Hz, 2 H), 4.05 (t, J = 6.0 Hz , 2 H), 4.16 (s, 2 H), 7.56 - 7.92 (m, 5 H).

Example  17: 1- ( Phenylsulfonyl ) Nonan -2,8- Dion  (One-( Phenylsulfonyl ) nonan -2,8-dione, 3e)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7e , 125.0 mg, 0.3 mmol) obtained in Example 8 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), and then saturated aqueous NH ₄ Cl solution (10 mL) was added to shake. The organic layer was separated with a separatory funnel, and the upper aqueous layer was further washed with CH ₂ Cl ₂ mL). The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The resulting residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EOAc = ) To give the title compound ( 3e , 68.5 mg, 77%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.22-1.34 (m, 2 H), 1.53-1.64 (m, 4 H), 2.13 (s, 3 H), 2.42 (t, J = 7.2 Hz, 2 H), 2.72 (t, J = 7.4 Hz, 2 H), 4.14 (s, 2 H), 7.56 - 7.92 (m, 5 H).

Example  18: 1 - [(4- Methylphenyl ) Sulfonyl ] -6- Phenyl hexane (1 - [(4-Methylphenyl) sulfonyl] -6-phenylhexan-2-one, 3f)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a solution of 1,4-dioxane (3 mL) containing the minor adduct ( 7f , 135.2 mg, 0.3 mmol) obtained in Example 9 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and then treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3.5 / 1 ) To give the title compound ( 3f , 78.3 mg, 79%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.52-1.68 (m, 4 H), 2.44 (s, 3 H), 2.60 (t, J = 6.0 Hz, 2 H), 2.73 (t, J = 6.0 Hz , 2H), 4.10 (s, 2H), 7.12-7.38 (m, 7H), 7.73 (d, J = 8.4 Hz, 2H).

Example  19: 1 - [(4- Methylphenyl ) Sulfonyl ] Undecan (1 - [(4-Methylphenyl) sulfonyl] undecan-2-one, 3g)

To a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7 g , 133.4 mg, 0.3 mmol) obtained in Example 10 was added H ₃ PO ₂ (164.2 μL, 5.0 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), and then saturated aqueous NH ₄ Cl solution (10 mL) was added to shake. The organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ And extracted twice more. The separated organic layers were combined and then treated with anhydrous MgSO ₄ , filtered, and the solvent was removed using a rotary evaporator. The obtained residue was purified byprofessional column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 5/1 ) To give the title compound ( 3 g , 75.9 mg, 78%).

¹ H NMR (CDCl ₃ , 400 MHz)? 0.88 (t, J = 6.8 Hz, 3 H), 1.25 (bs, 12 H), 1.51-1.61 2.69 (t, J = 7.2 Hz , 2 H), 4.12 (s, 2 H), 7.37 (d, J = 8.0 Hz, 2 H) 7.75 (d, J = 8.0 Hz, 2 H).

Example  20: 1- ( Methylsulfonyl ) -6- Phenyl hexane One (1- ( Methylsulfonyl ) -6-phenylhexan-2-one, 3h)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the minor adduct ( 7h , 112.4 mg, 0.3 mmol) obtained in Example 11 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), shaken with saturated aqueous NH ₄ Cl solution (10 mL), and the organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ ). ≪ / RTI > The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 2.5 / 1 ) To give the title compound ( 3h , 58.7 mg, 77%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 1.59-1.72 (m, 4 H), 2.63 (t, J = 6.8 Hz, 2 H), 2.73 (t, J = 6.8 Hz, 2 H), 3.03 (s , 3 H), 3.99 (s, 2 H), 7.14-7.32 (m, 5 H).

Example  21: 1- ( Methylsulfonyl ) Undecan One (1- ( Methylsulfonyl ) undecan -2- one , 3i)

H ₃ PO ₂ (164.2 μL, 5.0 mmol) was added to a 1,4-dioxane (3 mL) solution containing the zetate adduct ( 7i , 110.6 mg, 0.3 mmol) obtained in Example 12 equivalents, 50wt% in H ₂ O) and Et ₃ N (230.0 μL, was added to 5.5 eq.) was added AIBN (29.6 mg, 0.6 eq) to the reaction solution was refluxed for 10 minutes in 100 ℃ under an argon gas, and another 1 After refluxing under argon gas for a period of time, it was cooled to room temperature. The reaction solution was diluted with CH ₂ Cl ₂ (20 mL), and then saturated aqueous NH ₄ Cl solution (10 mL) was added to shake. The organic layer was separated with a separatory funnel. The upper aqueous layer was washed with CH ₂ Cl ₂ And extracted twice more. The separated organic layers were combined and treated with anhydrous MgSO ₄ , filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel: Merck 70-230, mobile phase: hexane / EtOAc = 3/1 ) To give the title compound ( 3i , 62.6 mg, 84%).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 0.88 (t, J = 7.4 Hz, 3 H), 1.26 (bs, 12 H), 1.53-1.68 (m, 2 H), 2.70 (t, J = 7.2 Hz, 2 H), 3.05 (s, 3 H), 4.02 (s, 2 H).

Claims (8)

(i) reacting 1,3-dichloroacetone represented by the following formula (4) with a sodium sulfinate compound represented by the following formula (5) and potassium O -ethylantoate represented by the following formula (6) sequentially at room temperature to obtain a 4- ;
(ii) subjecting a zwitterion compound of the formula (1) to an addition reaction with an olefin compound of the formula (2) to obtain a zirconate adduct of the formula (7); And
(iii) a step of subjecting a side-chain adduct of the following formula (7) to a radical reduction reaction to prepare a? -ketosulfone compound of the following formula
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 1]

(2)

(7)

(3)

In this formula,
Xa is -SC (= S) OEt,
R ¹ is a C ₁ -C ₆ alkyl group; Or phenyl which is unsubstituted or substituted by a C ₁ -C ₆ alkyl group,
R ² is a C ₁ -C ₆ alkyl group, phenyl, benzyloxy, -OCOR ³ or -R ⁴ COR ⁵ ,
R ³ , R ⁴ and R ⁵ are each independently a C ₁ -C ₆ alkyl group. delete The method according to claim 1,
R ¹ is methyl; Or phenyl unsubstituted or substituted by methyl,
Wherein R < ² > is n-pentyl, phenyl, benzyloxy, acetoxy or methylcarbonylmethyl. The process according to claim 1, wherein the addition reaction is carried out using a radical initiator. 5. The process according to claim 4, wherein the radical initiator is dilauryl peroxide. The process according to claim 1, wherein the radical reduction reaction is carried out in the presence of hypophosphorous acid (H ₃ PO ₂ ), triethylamine (Et ₃ N) and azobisisobutyronitrile (AIBN). delete delete