KR100524257B1 - Practical Synthetic Method of Teprenone - Google Patents

Abstract

The present invention provides a practical method for synthesizing teprenone of the general formula (1) used as a raw material for medicines and cosmetics because of the prevention and treatment of white gastritis and the whitening effect.

According to the present invention, the C8 sulfone compound (Formula 2) is easily synthesized in four steps from inexpensive and readily available isoprene, and the coupling and desulfonation reaction with C15 farnesyl halide, and acetal The hydrolysis reaction of Tefrenone is efficiently provided.

Description

Practical Synthetic Method of Teprenone

The present invention relates to a method for producing an isoprenoid compound, and more particularly, to an efficient and practical synthesis method of teprenone. Tefrenone is widely used for the prevention and treatment of widespread gastritis such as gastric ulcer, and recently as a raw material of cosmetics due to the whitening effect.

Representative synthetic methods of Tefrenone include C20 geranylgeranyl halide (A) and ethyl acetoacetate (A) as claimed in US Pat. No. 4,169,157 (Sep. 25, 1979.09). B, R = CH ₃ CH _2- ) using a coupling reaction and decarboxylation reaction, and C20 geranyllinalool (C) to methyl acetoacetate (B, R = CH _3- ) Two methods of applying the used Carroll reaction are known. Both of these methods are useful methods of extending the C3 carbon chain, but the development of efficient and practical synthesis of C20 geranylgeranyl halide (A) or geraninulaul (C) is preceded by this method for synthesizing tepenone. Should be done.

On the other hand, the contents of the Republic of Korea Patent No. 195-0011103 (1995.09.28), which forms a carbon-carbon bond in a Julia method using a sulfone compound and an allylic halide compound of a suitable length in a relatively practical manner (Scheme 2) Coupling reaction of C10 geranyl sulfone (D) with C13 allylic halide (E) derived from geranyl acetone, or C15 farnesyl sulfone Coupling reaction of (F) with C8 allylic halide (G) derived from prenyl acetone to form the C23 carbon backbone required for the synthesis of tepenone, followed by reductive desulfonation Reaction and hydrolysis reaction of acetal used as protecting group of ketone group.

The method is a relatively simple step of synthesizing Teflon from 8 steps of C10 geraniol and C13 geranyl acetone or C15 fanesol and C8 prenyl acetone as starting materials. It is an efficient method but has the following problems.

First, in the synthesis of allyl halide, the oxidation reaction is carried out using expensive and harmful selenium oxide (SeO ₂ ), and second, the selectivity of oxidation of the reaction is reduced, so that some aldehyde is produced by sodium borohydride (NaBH). ₄ ), it should be reduced back to the allylic alcohol, which is known to have a poor yield. Third, the reaction to form allyl halides from allylic alcohols generally proceeds under acidic conditions, in which case the choice of reaction reagents is very limited because the reaction must proceed with an acetal group that is acid labile, with by-products Due to the production of, there is a disadvantage that it is not suitable for the synthesis of mass production. Therefore, it is required to develop a more economical and practical synthesis of Tefrenon to overcome the above disadvantages.

The technical problem to be achieved by the present invention, in the synthesis of tepenone of the formula (1) in the way of Julia to form a carbon-carbon bond efficiently using a sulfone compound, an allyl halide compound containing the acetal group (Scheme 2) In order to overcome the problems of the synthesis of (E) or (G)) of the newly proposed C8 sulfone compound containing acetal group of formula (2) from the cheap and easily available C5 isoprene in a four-step efficient method will be.

Another technical problem to be achieved by the present invention is to provide a more practical and economical method for preparing teprenone (Teprenone) using the C8 sulfone compound of Formula (2).

The first technical problem of the present invention is to obtain a C5 chloro-sulfone compound (H) by forming a radical from benzenesulfonyl chloride and adding it to isoprene; (2) A sulfone compound (I) containing a keto-ester by coupling an anion obtained by treating a base with ethyl acetoacetate and a chloro-sulfone compound (H) through a coupling reaction. Obtaining; (3) hydrolyzing the ester group of the sulfone compound (I) and carrying out a decarboxylation reaction to obtain a C8 keto-sulfone compound (J); And (4) protecting the ketone groups of the keto-sulfone compound (J) with neopentyl glycol to obtain the corresponding acetals, wherein the C8 acetal-sulfone compound of Formula 2 is prepared. By the method (Scheme 3).

In the step (1), the radical reaction of benzenesulfonyl chloride is carried out in a small amount of copper chloride (I) (CuCl) and triethylamine hydrochloride (Et ₃ NHCl) in a solvent such as acetonitrile (CH ₃ CN) containing isoprene. After adding, it is preferable to heat it to the high temperature of 100 degreeC or more.

In step (2), various base / solvent conditions may be used for deprotonation and coupling reaction of ethyl acetoacetate, and sodium hydride (NaH) / tetrahydrofuran (THF) or Using conditions of sodium ethoxide (NaOEt) / ethanol (EtOH) is preferred in view of economics and yield of the reaction.

In the step (4), various lower alcohols can be used in the reaction for forming acetal by protecting the ketone group with alcohol, and diol such as ethylene glycol, in particular, neopentyl glycol, and the like. The use of a compound is preferred in view of the stability of the protecting group.

The second technical problem of the present invention is to (1) deprotonation of a C8 acetal-sulfone compound of formula (2) by treatment with a base, and then to C15 farnesyl halide obtained by halogenation of farnesol. Reacting to synthesize acetal-sulfone compound (K); And (2) applying a reductive desulfonation reaction to the acetal-sulfone compound (K), and then hydrolyzing the acetal protecting group under acidic conditions. (Scheme 4).

Wherein X is selected from Cl, Br or I.

In the step (1), the deprotonation reaction of the C8 sulfone compound (Formula 2) requires the addition of one equivalent of a base dropwise at a low temperature, preferably at 0 ° C. or less, wherein n is the base. -BuLi, s -BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t- Use BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, etc.

In the step (2), the desulfonation reaction is preferably reacted by dropwise addition of an excess alkali metal, alkaline earth metal or amalgam thereof to the compound (K) in a solvent such as alcohol, ammonia, primary amine, THF, and the like. Tefrenone can be obtained by hydrolysis of acetal under acidic conditions, without further purification of the desaturation fonning reaction.

As described above, the C8 acetal-sulfone compound of formula (2) according to the present invention contains acetal group in synthesizing tepenone of formula (1) in the way of Julia, which forms a carbon-carbon bond efficiently using a sulfone compound. It is a compound proposed to overcome the problems of the synthesis of allyl halide compounds ((E) or (G) of Scheme 2) and to synthesize tepenone (Formula 1) in a more economical and efficient manner. Let's explain.

Benzenesulfonyl chloride is known to form radical formation by the action of small amounts of copper chloride (I) and to efficiently react 1,4-addition to isoprene ( Journal of Organic Chemistry , 1970 , 35 , 4217-4220). ). This reaction is a very efficient method of attaching two functional groups of sulfone and chloride regio-selectively to isoprene, which needs to be heated to a high temperature above 100 ° C, in order to prevent evaporation of low-boiling isoprene. It is necessary to use a long length reflux condensor. The white solid C5 chloro-sulfone compound (H) can be easily crystallized with cold methanol solvent.

Ethyl acetoacetate contains methylene hydrogen, which is highly acidic under the influence of a toketo group, which is easily deprotonated by a base such as NaH or a metal alkoxide. The anion thus formed undergoes a coupling reaction with the C5 chloro-sulfone compound (H) synthesized by the above-mentioned method. At this time, it is preferable to use THF or alcohol as a solvent for the reaction. In general, in the coupling reaction between a nucleophile and a chloro-sulfone compound (H), the dehydro-chlorination reaction proceeds as a main side reaction, but in this reaction, the coupling reaction is very high due to the stability of the nucleophilic anion. It proceeds efficiently.

The decarboethoxylation reaction of sulfone (I) containing the keto-ester group thus obtained gives C8 keto-sulfone compound (J). At this time, the conditions of general decarbo-alkoxylation reaction heated in aqueous solution of NaOH or KOH can be used.

In the reaction for preparing an acetal compound (Formula 2) by protecting the ketone group in order to efficiently perform the coupling reaction and the desulfonation reaction of the Julia method using the keto-sulfone compound (J), acetal may be formed using various lower alcohols. Although it can be formed, it is preferable to use ethylene glycol, especially neopentyl glycol, in terms of stability of acetal, and to remove water by refluxing using a Dean-Stark tube under a benzene solvent in which a catalytic amount of acid is present. The general method of acetal formation can be used.

C8 acetal-sulfone compound of formula 2 according to the present invention can be effectively used for the synthesis of isoprenoid compounds by carbon-carbon bond formation and reductive desulfonation reaction by the method of allyl halide compound and Julia. The synthesis of Tefrenone by reaction with Nesyl halide will be described in detail.

The C8 acetal-sulfone compound of Formula 2 prepared by the above method was treated with a base such as alkyllithium, metal amide, sodium hydride (NaH), and metal alkoxide. By forming a stabilized anion and reacting it with the farnesyl halide obtained by the halogenation of farnesol to synthesize a C23 sulfone compound (K) containing a carbon skeleton necessary for the synthesis of tepenone. At this time, it is preferable to use anhydrous THF as a solvent for the reaction. On the other hand, the halogenation of farnesol is HCl, SOCl ₂ , (COCl) ₂ , PCl ₃ , NCS ( N- chlorosuccinimide) / PPh ₃ , CCl ₄ / PPh ₃ , HBr, PBr ₃ , P / Br ₂ , NBS ( N Halogenation reactions under general acidic conditions such as -bromosuccinimide) / PPh ₃ , CBr ₄ / PPh ₃ , HI, I ₂ / PPh ₃ , and NIS ( N -iodosuccinimide) / PPh ₃ can be used. In view of this, bromination reaction using PBr ₃ is preferred.

The reductive desulfonation reaction of the acetal-sulfone compound (K) is, as is known, an excess of an alkali metal such as lithium, sodium, or alkaline earth metal such as magnesium in a solvent such as alcohol, ammonia or primary amine at low temperature or room temperature. Or, it is preferable to proceed by adding these amalgams dropwise. Thus obtained teprenone acetal, without a separate purification process, to provide the tepenone (Formula 1) by the hydrolysis reaction in acid conditions.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited only to the following Examples.

Synthesis Example 1. 1-Benzenesulfonyl-4-chloro-2-methyl-2-butene (H)

Isoprene (20.4 g, 300 mmol) and benzenesulfonyl chloride (35.3 g, 200 mmol) are dissolved in acetonitrile (21 mL), and cuprous chloride (CuCl, 1.0 g, 10 mmol) and triethylamine hydrochloride ( Et ₃ NHCl, 0.96 g, 10 mmol) is added and the reaction mixture is heated to 140 ° C. and refluxed for 10 hours. After the reaction was cooled to room temperature, the temperature was lowered using ice water, and cold methanol (50 mL) was added thereto, and the resulting solid was filtered using a glass funnel. The chloro-sulfone (H) thus obtained was recrystallized using cold ethanol to give a white pure solid (34.3 g, 140 mmol) in 70% yield.

¹ H NMR δ 1.88 (3H, s), 3.77 (2H, s), 3.97 (2H, d, J = 7.9 Hz), 5.31 (1H, t, J = 7.9 Hz), 7.52-7.89 (5H, m) ppm.

¹³ C NMR δ 16.9, 39.3, 65.5, 128.5, 129.1, 129.8, 130.5, 133.9, 138.0 ppm.

Synthesis Example 2. 2-Acetyl-6-benzenesulfonyl-5-methyl-4-hexenoic acid, ethyl ester (I)

Ethyl acetoacetate (1.84 g, 14.1 mmol) was dissolved in tetrahydrofuran (30 mL) and NaH (0.68 g, 28.2 mmol) was slowly added to this solution at 0 ° C., followed by chloro-sulfone compound (H) (3.64 g, 14.1 mmol) is dissolved in tetrahydrofuran (5 ml), and then stirred well at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate (50 mL), washed well with distilled water, dried over anhydrous MgSO ₄ , filtered and the solvent is removed under reduced pressure. The crude product was purified by silica gel column chromatography to give the sulfone compound (I) (3.91 g, 11.56 mmol) containing pure keto-ester group in 82% yield.

¹ H NMR δ 1.26 (3H, t, J = 7.1 Hz), 1.78 (3H, s), 2.20 (3H, s), 2.51 (2H, t, J = 7.3 Hz), 3.34 (1H, t, J = 7.3 Hz), 3.71 (2H, s), 4,18 (2H, q, J = 7.1 Hz), 5.06 (1H, t, J = 7.3 Hz), 7.49-7.87 (5H, m) ppm.

¹³ C NMR δ 14.1, 17.0, 26.8, 29.3, 58.7, 61.6, 65.9, 126.4, 128.4, 129.0, 131.4, 133.7, 138.5, 169.0, 202.2 ppm.

Synthesis Example 3. 7-Benzenesulfonyl-6-methyl-5-heptene-2-one (J)

To a sulfone compound (I) containing keto-ester group (14.1 g, 41.7 mmol) was added 50 ml of an aqueous 1 M NaOH solution, refluxed at 100 ° C. for 3 hours, cooled to room temperature and neutralized with an aqueous 1 M HCl solution. The organic material of the reaction mixture is extracted with chloroform (50 mL), washed well with distilled water, dried over anhydrous MgSO ₄ , filtered and the solvent is removed under reduced pressure. The crude product was purified by silica gel column chromatography to give pure keto sulfone compound (J) (9.1 g, 34.2 mmol) in 82% yield.

¹ H NMR δ 1.76 (3H, s), 2.09 (3H, s), 2.20 (2H, dt, J _d = 7.0, J _t = 7.3 Hz), 2.31 (2H, t, J = 7.3 Hz), 3.71 ( 2H, s), 5.05 (1H, t, J = 7.0 Hz), 7.52-7.92 (5H, m) ppm.

¹³ C NMR δ 16.7, 22.4, 29.8, 42.4, 66.0, 124.5, 128.4, 128.9, 133.5, 134.4, 138.5, 207.6 ppm.

Synthesis Example 4. 2- (5-benzenesulfonyl-4-methyl-3-pentenyl) -2,5,5-trimethyl- [1,3] dioxane (Formula 2)

Keto sulfone compound (J) (9.7 g, 36.3 mmol) was dissolved in benzene (100 mL), neopentyl glycol (15.1 g, 0.145 mol) and p- TsOH (0.35 g, 1.8 mmol) were added, followed by 10 to 80 ° C. The resulting water is removed using a Dean-Stark tube while refluxing for time. The reaction mixture was cooled to room temperature, diluted with diethyl ether, washed well with 1M aqueous NaOH solution and distilled water, dried over anhydrous K ₂ CO ₃ , filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give pure acetal sulfone compound (Formula 2) (11.5 g, 32.7 mmol) in 90% yield.

¹ H NMR δ 0.88 (3H, s), 1.01 (3H, s), 1.32 (3H, s), 1.67 (2H, m), 1.78 (3H, s), 2.07 (2H, dt, J _d = 7.0, J _t = 8.8 Hz), 3.38 (2H, A part of ABq, J = 11.3 Hz), 3.54 (2H, B part of ABq, J = 11.3 Hz), 3.73 (2H, s), 5.05 (1H, t, J = 7.0 Hz), 7.49-7.90 (5H, m) ppm.

¹³ C NMR δ 13.5, 16.6, 20.1, 22.3, 22.4, 22.7, 29.9, 37.3, 66.2, 70.3, 98.3, 123.4, 128.5, 128.8, 133.5, 136.0 ppm.

Synthesis Example 5. 2- (5-benzenesulfonyl-4,8,12,16-tetramethyl-3,7,11,15-heptadecatetraenyl) -2,5,5-trimethyl- [1, 3] dioxane (K)

Acetal sulfone compound (Formula 2) (1.95 g, 5.54 mmol) was dissolved in THF (50 mL), slowly added t- BuOK (785 mg, 6.64 mmol) at -20 ° C, and stirred well at the same temperature for 30 minutes. Farnesyl bromide (1.89 g, 6.65 mmol) is dissolved in tetrahydrofuran (10 mL) and carefully added. The reaction mixture was stirred at -20 ° C. for 4 hours, diluted with diethyl ether, washed well with distilled water, dried over anhydrous K ₂ CO ₃ , filtered and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give 71% yield of C23 acetal sulfone compound (K) (2.19 g, 3.92 mmol) containing the carbon skeleton required for pure tepenone synthesis.

¹ H NMR δ 0.87 (3H, s), 1.00 (3H, s), 1.30 (3H, s), 1.39 (2H, m), 1.57 (3H, s), 1.59 (3H, s), 1.61 (3H, s), 1.87-2.32 (12H, m), 2.62 (1H, m), 2.81 (1H, m), 3.36 (2H, A part of ABq, J = 11.2 Hz), 3.53 (2H, B part of ABq, J = 11.2 Hz), 4.87 (1H, t, J = 6.6 Hz), 4.98-5.23 (3H, m), 7.45-7.86 (5H, m) ppm.

¹³ C NMR δ 13.5, 16.0, 16.3, 17.7, 20.1, 22.0, 22.4, 22.7, 23.7, 26.4, 26.7, 29.9, 37.2, 39.6, 39.7, 70.2, 74.0, 98.3, 118.6, 123.8, 124.2, 126.7, 128.7, 128.8, 131.2, 133.3, 135.1, 135.8, 137.9, 138.3 ppm.

Synthesis Example 6. 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one: teprenon (Formula 1)

Acetal sulfone compound (K) (978 mg, 1.75 mmol) was dissolved in methanol (30 mL), disodium hydrogen phosphate (Na ₂ HPO ₄ , 1.00 g, 7.02 mmol) and sodium amalgam (Na (Hg)) , 5.24 g, 14.04 mmol) was added thereto, followed by stirring at room temperature for 4 hours. Then, 1M HCl was added to terminate the reaction. The organic material of the reaction mixture is extracted with chloroform, washed with distilled shoe and the solvent is removed under reduced pressure. The crude product was dissolved in THF (30 mL), 3M HCl (30 mL) was added, and the mixture was stirred under reflux for 3 hours at reflux. The temperature of the reaction mixture was cooled to room temperature, the organics were extracted with diethyl ether, washed with distilled water, dried over anhydrous Na ₂ SO ₄ , filtered, and purified by silica gel column chromatography to obtain pure teprenone (Formula 1) (476). mg, 1.44 mmol) in 82% yield.

¹ H NMR δ 1.59 (12H, s), 1.68 (3H, s), 1.89 to 2.05 (12H, m), 2.13 (3H, s), 2.19 to 2.32 (1H, m), 2.33 to 2.51 (2H, m ), 2.60 to 2.72 (1H, m), 5.10 (4H, m) ppm.

¹³ C NMR δ 15.9, 17.6, 21.7, 22.4, 25.6, 26.4, 26.5, 26.6, 26.8, 29.9, 39.6, 39.7, 42.9, 43.7, 122.4, 123.9, 124.0, 124.1, 124.3, 131.1, 134.8, 134.9, 136.3, 208.9 ppm.

As described above, according to the present invention, when synthesizing Tefrenone using Julia's sulfone chemistry, which can be most efficiently used to form carbon-carbon bonds in isoprenoid compound synthesis, it contains an acetal group of the conventional method. It is possible to simplify the synthesis of C8 acetal-sulfone compounds of the formula (2), which is a new and useful intermediate that overcomes the problems of allyl halide synthesis, and to prepare efficient teprenon using the same. In addition, while the conventional method uses relatively expensive C13 geranyl acetone or C8 prenyl acetone as a starting material, the price competitiveness of the production of teprenone is inferior, and according to the present invention, inexpensive and easily available C5 isoprene is synthesized. It is possible to economically produce teprenone using it as a starting material.

Claims (7)

(1) Benzenesulfonyl chloride (PhSO ₂ Cl) was added to isoprene in acetonitrile (MeCN) solvent to add a copper chloride (I) (CuCl) catalyst and heated to a temperature between 30 ° C. and 150 ° C. to give 1,4- Addition reaction to obtain C5 chloro-sulfone compound (H); (2) an anion obtained by treating ethyl acetoacetate with a base selected from the group of sodium hydride (NaH), sodium ethoxide (NaOEt), sodium methoxide (NaOMe) and the C5 chloro-sulfone compound (H ) Using a solvent selected from the group consisting of tetrahydrofuran (THF), ethanol and methanol, and reacting at a temperature between 0 ° C and 35 ° C to obtain a C8 sulfone compound (I) containing a keto-ester group; (3) obtaining keto-sulfone compound (J) by a decarboethoxylation reaction which proceeds by heating the C8 sulfone compound (I) to a boiling point of a solvent in an aqueous base solution selected from KOH and NaOH. ; And (4) a C8 acetal-sulfone compound of formula (2) comprising the step of obtaining the acetal by reacting the ketone group of the keto-sulfone compound (J) with neopentyl glycol to a boiling point of the solvent under a benzene solvent Method of preparation. (1) The C8 acetal-sulfone compound of formula 2 is dissolved in tetrahydrofuran (THF) solvent and n- BuLi, s- BuLi, t- BuLi, NaH, NaNH ₂ , lithium diisopropylamide at a temperature of 0 ° C. or lower; (lithium diisopropylamide), lithium hexamethyldissalzide, sodium hexamethyldisilazide, t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ Treatment with a base selected from the group of ONa to deprotonation, followed by reaction with a C15 farnesyl halide to obtain a C23 acetal-sulfone compound (K); And (2) at least 8 equivalents of alkali metals and alkaline earth metals based on compound (K) under a solvent selected from the group consisting of methyl alcohol, ethyl alcohol, ammonia, ethyl amine, methyl amine and THF. , Reacted with a metal selected from the group of amalgams of alkali metals and amalgams of alkaline earth metals to carry out a reductive desulfonylation reaction to obtain a Tefrenone acetal compound in which the sulfone group is replaced with hydrogen, without further purification. A method for producing tepenone of the general formula (1) characterized by restoring a ketone group by a hydrolysis reaction in an acidic aqueous solution condition. Wherein X is selected from Cl, Br, I. delete delete delete delete delete