KR100208427B1 - A process for producing d, l, -3-methyl-cyclopentadecan-1-one - Google Patents

Abstract

The present invention relates to a novel process for preparing DL-3-methyl-cyclopentadecan-1-one, wherein (±) -2- (tolylsulfinyl) -cyclopentadecan-1-one is used in the presence of an anhydrous benzene solvent. After adding a base and heating to 60 ~ 80 ℃ to prepare 2-cyclopentadeceen-1-one and without separating it is prepared by reacting the same compound and alkylating agents such as alkyl magnesium halide.

The present invention does not use bromine, which is a toxic substance, and reacts under mild reaction conditions to produce a target compound in high yield (more than 95.0%) and high purity (more than 98.0%).

Description

Method for preparing DL-3-methyl-cyclopentadecan-1-one

The present invention relates to a novel process for preparing DL-3-methyl-cyclopentadecan-1-one represented by formula (I).

In general, DL-methyl-cyclopentadecan-1-one represented by the structural formula (I) is expected to be useful for drug development as a precursor of a compound that acts on the central nervous system.

Therefore, various preparation methods for preparing this compound are widely known. In the case of preparing the compound of formula (I) according to such a conventional method, the yield is low, the purity of each reaction step is low, In addition, not only the reaction conditions are difficult, but also the reaction process is not preferable for industrialization and mass production due to the complicated manufacturing process problems that are produced through several steps.

For example, J. Org. Chem., 42 (12), 2326 (1977), used electrophoresis to obtain dimethyl tetradecane ester derivatives from methyl hydrogen suberate, to which the Ruhlmann reagents (silyl derivatives and sodium) are derived. To react 1,2-bis (trimethylsilyloxy) cyclotetradecene as an intermediate derivative, and react with diezinc zinc and diiomethane having a low boiling point to obtain a derivative having a cyclopropane ring. After converting to a structure, and subsequently methylated and reduced to provide a method for producing a compound represented by the above formula (I), in the case of preparing a compound represented by the above formula (I) according to such a method Electrophoresis and the use of explosive sodium and low boiling compounds such as silyl compounds and diiomethane to treat storage containers and low boiling solvents. The facilities are to follow, because of course you need to use expensive reagents (Pd / C) and the like, the manufacturing costs expensive problem final yield is low at 23%, undesirable hagieneun mass production and industrialization.

In addition, J. Org. Chem., 36 (26), 4124 (1971), describes the process of ketalization, bromination, dehydrobromation, hydrolysis, and methylation under an acid catalyst using a cyclopentadecanone derivative, cyclopentadecan-1-one, as a starting material. Although a method of preparing the compound represented by the above structural formula (I) has been proposed, the yield improvement (about 50%) is seen when prepared according to this method, but when the compound (I) is prepared, the ketalization reaction is performed for a long time. (More than 14 hours) and the reaction does not proceed completely, there is more than 30% by-products to replace bromine in the 2-position of cyclopentadecan-1-one, expensive reagent used for dehydrobromation reaction Neutralization of final reaction solution and the problem of using DBN (1,5-diazabicyclo [4.3.0] non-5-ene) or DBU (1,8-diazabicyclo [5.3.0] undec-7-ene) And production in several stages (6-8 stages), including separation by chromatography Therefore, the final yield is very low, this method is also unsuitable for mass production or industrial production of the target compound represented by the above formula (I).

Accordingly, the present inventors have been studying for a long time to solve the problems of the prior art method, and as a result, it is possible to industrially mass production, and to shorten the reaction process to three processes to improve the manufacturing process problems and patent application (Application No. 94-22981) However, there was also a problem to improve the process or yield. Therefore, while continuing the research, not only bromine, which is a toxic substance, was reacted at a milder reaction temperature, and higher yield, higher purity (more than 95.0%, more than 98.0%) of DL-3 represented by the above formula (I). An improved method for the preparation of -methyl-cyclopentadecan-1-one is invented and is filed as a patent.

Accordingly, an object of the present invention is to provide a novel production method capable of producing the compound of formula (I) of high yield and purity in a method that is simple in synthesis, inexpensive and industrially mass-produced. I am doing it.

Hereinafter, the present invention will be described in detail.

The present invention uses (±) -2- (tolylsulfinyl) -cyclopentadecan-1-one of the following structural formula (II) as a starting material, in the presence of anhydrous benzene solvent, adding anhydrous base, and heating and Synthesis of 2-cyclopentadecene-2-one represented by the following formula (I) and reaction of a copper (Cu) compound with an alkylating agent alkylmagnesium halide or alkyllithium without the separation of the compound of formula (III) It is characterized by the production of the indicated Di--3-methyl-cyclopentadecan-1-one.

Wherein X is SOTol and Tol means a tolyl group.

Hereinafter, the present invention will be described in more detail.

(±) -2- (tolylsulfinyl) -cyclopentadecan-1-one of Structural Formula (II) as a starting material was dissolved in anhydrous benzene, and anhydrous base was added thereto, followed by heating and stirring to give the compound represented by Structural Formula (III). To prepare. At this time, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, etc. are used as the anhydrous base, and among them, calcium carbonate is most preferably used, and the amount of use is 0.1 to 0.3 moles with respect to the compound of formula (III) and the reaction temperature. Most preferably, the reaction is carried out at 60-80 ° C. for 6 hours to 9 hours. However, the portion such as the case of using calcium carbonate, the reaction time, but it takes a long time, the amount of by-products by the side reaction is generated no more than 5% due to the reaction at a lower temperature, especially a double bond substances of C ₃ positions in question There is an advantage that no product is produced.

Subsequently, the diel-3-methyl-cyclopentadecan-1-one represented by the above formula (I) is an alkylmagnesium halide which is a copper compound and an alkylating agent under anhydrous ethyl ether to the compound represented by the above formula (III). Alternatively, alkyl lithium is added to produce a target compound represented by Structural Formula (I). At this time, copper chloride, copper iodide, copper bromide, etc. are used, among which copper chloride is most suitable, and alkyl magnesium Magnesium bromide, methylmagnesium iodine, methylmagnesium chloride, etc. are used as the halide, and magnesium iodine is most suitable, and the amount of cuprous chloride and magnesium magnesium iodine is 1: 2-3 molar ratio to prepare the complex compound. Is the best, and it is most preferable to keep the color of the complex solution at that time ultramarine blue. Alkyllithium is preferably methyllithium, and when copper chloride and methyllithium are used, the amount of alkyl lithium is most suitably used in a molar ratio of 1: 1-2. The reaction conditions are most preferably reacted at -10 ℃ to 10 ℃.

In the case of preparing a complex compound of cuprous chloride and methylmagnesium iodine, when 3 mol or more of magnesium magnesium iodine is used with respect to iodine chloride, the by-products by side reaction are mainly generated because of reduced magnesium due to excess magnesium. If the temperature is 10 ℃ or more, the reduction reaction proceeds first, rather than 1,4-addition reaction by methylmagnesium iodine is not preferable because the yield and purity is lowered.

For reference, the structural formula (II) compound which is a starting material of the present invention may be prepared by the following method. First, the method for preparing alkyl para-toluene sulfinate ester of the following formula (IV) is to dissolve the reactants obtained by adding thionyl chloride and para-toluene sodium sulfinate salt under anhydrous conditions in an organic mixed solvent, and then various alkyl groups or It is prepared by acylation reaction to introduce the L-mentyl group. In this case, instead of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus trioxide may be used. Among them, thionyl chloride is the most preferable, and the amount of the thionyl chloride is most preferably 5 to 10 molar ratio based on the reactants. Most preferably, the reaction is carried out at room temperature for 2-3 hours. Meanwhile, as the organic mixed solvent, various nonpolar solvents and polar solvents were reacted, and at this time, the nonpolar solvent used was selected from among ethyl ether, methyl ethyl ether, or isopropyl ethyl ether, and the polar solvent. As an alcohol, methyl alcohol, methyl alcohol, propyl alcohol, butyl alcohol, isobutyl alcohol or pyridine was selected and used, but it was better to use a mixed solvent than when using a single solvent as described above. Most preferred is a 2: 1 to 3: 1 mixed solvent of anhydrous ethyl ether and pyridine, and the reaction temperature is most preferably carried out at 0 ° C to 10 ° C, preferably at 0 ° C.

Subsequently, the cyclopentadecane-1-one represented by the structural formula (V) is dissolved in a nonpolar solvent, and then, by adding an agent, a sulfinylation reaction with the structural formula (IV) compound is carried out to form a structural formula (II) compound as a starting material of the present invention. In this case, various ethers are used as the non-polar solvent, of which double ether is most suitable.

In this case, as the enolating agent, a salt of H ₂ (nanrium hydroxide, calcium hydroxide, lithium hydroxide) or an amidated salt (sodium or lithium) is used. Among them, sodium amidide is most preferable, and the amount of the enolating agent is used in the structural formula (V) compound. It is most preferable to use 0.1-5.0 molar ratio with respect to the compound, and 0.5-2.0 molar ratio with respect to the compound of formula (V) is used. The reaction conditions are most preferably carried out at 30 to 50 degrees for 1 to 2 hours.

On the other hand, the reaction time is shortened when the reaction is performed using an enolating agent, sodium amidide, and the other side product (C ₂ position) is treated by a recrystallization method to produce a pure target compound. If a large amount of product is produced and the target compound is obtained purely after the reaction, the treatment method is complicated.

The present invention will be described in detail with reference to the following examples.

The scope of the claims of the present invention is not limited by the examples.

Reference Example 1

[Method for producing alkyl para-toluene sulfinic acid ester]

1) Preparation of (-)-(S) -menthyl para-toluenesulfinic acid ester (IV-1)

280.4 g of thionyl chloride was added to a 500 ml anhydrous round two-necked flask, and stirred well. 60.0 g of purified sodium para-toluenesulfinate was added little by little, paying attention to the generation of hydrochloric acid gas and SO ₂ gas, and yellow with white solid. The oil is plugged into anhydrous calcium chloride tube and stirred at room temperature for 2-3 hours. When the reaction is complete, the temperature of the water bath is set to 60 ° C. or lower, and excess thionyl chloride is removed using a reduced pressure pump. After dissolving the concentrated yellow oil product in a concentrated solvent of 100 ml of anhydrous pyridine and 200 ml of ethyl ether, the temperature of the water bath was cooled to 0 ° C., and 53.1 g of L-menthol was dissolved in 80 ml of anhydrous ethyl ether, using a dropping funnel. The mixture was slowly added dropwise and then stirred at room temperature for another hour to complete the reaction. 300 ml of distilled water is poured into the crude product, and the organic layer is collected by quenching. The aqueous layer is extracted twice with 100 ml of ethyl ether and combined with the organic layer. The organic layer was washed three times with 150 ml of 20% aqueous hydrochloric acid solution, washed with water and brine and dried over anhydrous forget-me-not. The residue obtained by distillation under reduced pressure on the organic layer was recrystallized with acetone to obtain 87.5 g (87%) of a white solid of the title compound (IV-1).

2) Preparation of Methyl Para-Toluene Sulfinic Acid Ester (IV-2)

15 ml of anhydrous methanol was dissolved in 10 ml of anhydrous ethyl ether and slowly added dropwise using a dropping funnel, and then the same operation as in the case of 1) of Reference Example 1 was performed in the same manner as in the manufacturing method of Reference Example 1 above. The obtained residue was distilled under reduced pressure to obtain 17 g (63%) of a colorless liquid of the title compound (IV-2).

Reference Example 2

[Method for Producing (±) -2- (tolylsulfinyl) -cyclopentadecan-1-one (II)]

In a 500 ml round two-necked flask, 2.1 g of sodium amidide was added to 100 ml of anhydrous ethyl ether, and the ammonia gas generated was completely removed. Then, 11.22 grams of cyclopentadecan-1-one (V) was added to a solution containing a white oily solid. Was dissolved in 50 ml of anhydrous ethyl ether, and added dropwise using a dropping funnel. The mixture was refluxed for 1 hour, and then cooled to room temperature. The compound synthesized in 1) of Reference Example 1 was previously prepared. (IV-1) 15.5 g is dissolved in 100 ml of anhydrous ethyl ether and slowly added dropwise using a dropping funnel, followed by further reflux stirring for 1 hour to complete the reaction. After cooling the reaction solution to room temperature, 30 ml of distilled water was added thereto, followed by decantation, washing with brine and distilled water three times each time, and the residue obtained by filtration of the organic layer under reduced pressure was recrystallized with acetone to obtain white of the title compound (II). Obtained 17.32 g of solid (yield 95.5%, purity 100%).

Example 1

[Manufacturing Method of DL-3-Methyl-cyclopentadecan-1-one (I)]

In a 1 L round two-necked flask, 32.83 g of the title compound (II) obtained in Reference Example 2 was dissolved in 450 ml of anhydrous benzene, and 1.3 g of anhydrous calcium carbonate was added and stirred under reflux for 7-8 hours, and then the reaction solution was cooled to room temperature. Then, transfer to the separatory filter and add 150 ml of distilled water to separate the organic layer. The aqueous layer is extracted twice with 100 ml of benzene and combined with the organic layer. The organic layer is washed with distilled water, brine and saturated sodium bicarbonate, and then dried over anhydrous forget-me-not. The organic layer was filtered off under reduced pressure to obtain 31.24 g of crude material (III). A dropping funnel was placed in a 1 L round three-necked flask, and 9.8 g of anhydrous cuprous chloride and 91 ml of methyl magnesium bromide (3.0 mol ether solution) were added to 500 ml of anhydrous ethyl ether. After cooling the temperature of the reaction solution to 5 ° C, 31.24 g of crude 2-cyclopentadeceen-1-one (III) prepared by the above method was dissolved in 100 ml of anhydrous ethyl ether, and then used for 1 hour using a dropping funnel. The mixture was slowly added dropwise over time, and the temperature of the reaction solution was gradually increased, followed by stirring at 10 ° C. for about 2 hours. When all of the starting compound (II) react, the temperature of the reaction solution is cooled to 0 ° C. and 200 ml of cold 10 ° C. aqueous hydrochloric acid solution is added dropwise slowly, taking care to foam. The black solid is filtered off, the organic layer is separated, and the aqueous layer is extracted twice with 100 ml of ethyl ether and combined with the organic layer. The organic layer obtained by filtration was filtered under reduced pressure, and the residue obtained by distillation under reduced pressure was distilled under reduced pressure. %) (Total yield 95% or more, GC phase purity 98% or more)

Claims (4)

2-Cyclopentadecene represented by formula (III) by heating (±) -2- (tolylsulfinyl) -cyclopentadecan-1-one represented by formula (II) with anhydrous base in the presence of anhydrous benzene solvent and heating. After preparing -1-one, Di--3-methyl-cyclo represented by Structural Formula (I) by reacting a copper (Cu) compound with an alkylating agent alkylmagnesium halide or alkyllithium without separation of Structural Formula (III) Method for preparing pentadecane-1-one. In the formula, X means SOTol, Tol means tolyl group. The method of claim 1, wherein the anhydrous base is one of anhydrous calcium carbonate, sodium carbonate, sodium bicarbonate or potassium carbonate. The method according to claim 1, wherein the reaction temperature in the preparation of the compound of formula III is carried out for 6 to 9 hours in a temperature range of 60 to 80 ℃. The method according to claim 1, wherein the amount of base used is from 0.1 to 0.3 molar ratio with respect to the compound of formula (II).