KR100369410B1 - A PROCESS FOR THE PREPARATION OF d,l-3-METHYL-CYCLOPENTADECAN-1-ONE - Google Patents

Abstract

A cyclopentadecan-1-one ethylene ketal compound was prepared by carrying out a ketalization reaction while removing the water produced by heating the starting cyclopentadecan-1-one compound under anhydrous cyclo-hexane and para-toluenesulfonic acid catalyst. The obtained compound was prepared in anhydrous tetrahydrofuran using phenyltrimethylammoniumtribromide to prepare a 2-bromocyclopentadecan-1-one ethylene ketal compound, and then the obtained compound was hydroxylated in the presence of dimethyl sulfoxide and PEG. After preparing a 2-cyclopentadeceen-1-one ethylene ketal compound using sodium, the obtained compound was used as an acid catalyst using magnesium sulfate-oxalic acid hydrate as an acid catalyst in acetone and water at room temperature. Was prepared, and the obtained compound was reacted with the reaction compound in anhydrous toluene at -40 to 0 ° C while using the same iodide as a catalyst. Method for producing a high-cyclopenta-decane-1-one compound in high yield, high purity - seven lithium or a methyl magnesium bromide, methyl DL-3, characterized in that the shift is added to the division by a predetermined amount.

Description

Method for preparing DL-3-methyl-cyclopentadecan-1-one {A PROCESS FOR THE PREPARATION OF d, l-3-METHYL-CYCLOPENTADECAN-1-ONE}

The present invention relates to an improved process for the preparation of DL-3-methyl-cyclopentadecan-1-one represented by structural formula (I) which acts on the central nervous system.

In general, dl-3-methyl-cyclopentadecan-1-one (d, l-3-methyl-cyclopentadecan-1-one) represented by Structural Formula (I) is a pharmaceutical agent acting on the central nervous system and the cardiovascular system. As a compound, among them, L-3-methyl-cyclo pentadecane-1-one is widely used as a musk substitute such as whey of sulfur, and thus, DL-methyl-cyclo pentadecane-1-one is a precursor or substitute thereof. It is expected to serve as a substance.

There are many known methods for the preparation of the above compound of formula (I). For example, J. Org. Chem. 36 (26) and 4124 (1971) have an acid catalyst starting from cyclopentadecan-1-one as a starting material. Although a method of preparing the compound of formula (I) through ketalization, bromination, dehydrobromination, hydrolysis, and methylation under the present method, DBN (1,5-diazabicyclo [4.3.0] used in the dehydrogenation bromination reaction was proposed. non-5-ene) or DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) is very expensive, the overall reaction yield is about 50-60%, and the purity is also low and separation by chromatography However, there is a disadvantage in that purification should be performed.

Accordingly, the present inventors have been studying for a long time to solve the problems of the conventional technical method as described above, in the production method of the compound of formula (I), the yield and net without performing a separate purification method such as chromatography method Invented a significantly improved manufacturing method in the drawing to obtain a patent No. 196888 (registered on Feb. 1999).

However, the patented method shows improvement in yield and purity but still has some problems.

1) Anhydrous benzene, which is used as a reaction solvent under heating conditions in the ketalization reaction, is difficult to handle because it is harmful to the human body.

2) The use of strong bases such as expensive alkoxides in the dehydrogenation bromide reaction has the disadvantage of high manufacturing cost, and after the reaction is terminated, undesirable by-products are produced.

3) When hydrolysis using acid catalyst, the reaction time was longer than 24 hours,

4) Using methyl ether when performing methylation reaction, it is not only difficult to handle but also has high risk of accident during the reaction, and undesirable by-products are produced after the reaction is completed. Excessive use has a significant effect on the manufacturing cost.

The present inventors have invented a new manufacturing method which is much improved than the method described in the cited patent, and is filed as a patent.

Accordingly, the present invention avoids the use of a solvent that is harmful to the human body to ensure the safety of the reaction process, to shorten the reaction time, and to reduce the amount of expensive reagents such as alkoxides or iodide iodide, improved structural formula in terms of cost It is an object of the present invention to provide a new production method for maintaining the high yield and high purity of the compound of (I) and enabling industrial mass production.

Hereinafter, the technical configuration of the present invention with the structural formula as follows.

The cyclopentadecane-1-one compound of Structural Formula (II), which is a starting material, was dissolved in anhydrous cyclo-hexane and then subjected to a ketalization reaction while removing water produced by heating under a para-toluene sulfonic acid catalyst. Cyclopentadecan-1-one ethylene ketal compound was prepared, and the obtained structural formula (III) compound was brominated with phenyltrimethylammoniumtribromide (hereinafter referred to as "PTT") in anhydrous tetrahydrofuran to give structural formula (IV) 2-bromocyclopentadecan-1-one-ethylene-ketal compound was prepared, and then the obtained structural formula (IV) compound was dehydrogenated using a base such as sodium hydroxide in the presence of dimethylsulfoxide and polyethylene glycol (PEG). After the reaction to prepare 2-cyclopentadeceen-1-one ethylene ketal compound of formula (V), the obtained compound of formula (V) was reacted with magnesium sulfate and jade in acetone and water at room temperature. Hydrolysis Using Salmonic Acid Hydrate as Acid Catalyst to Prepare 2-cyclopentadeceen-1-one Compound of Structural Formula (VI), and then the Compound of Structural Formula (VI) Prepared in Anhydrous Toluene at -40 to 0 ° C. Using copper as a catalyst, a compound of structural formula (VI) and methyllithium or methylmagnesium bromide are added in alternating amounts to be added in alternating manner to proceed with methylation to prepare the compound of structural formula (I). Safe and inexpensive high yield, high purity to get the target.

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

The cyclo pentadecane-1-one of formula (II) is dissolved in anhydrous cyclo-hexane, added with ethylene glycol and para-toluenesulfonic acid hydrate, and heated and stirred while removing the resulting water.

After completion of the reaction, the ethylene glycol layer was extracted using anhydrous cyclo-hexane to obtain the compound of formula (III) in high yield (100%) and high purity (98.6%).

In this reaction, the ketal compound of formula (III) can be obtained by an improved manufacturing method in terms of safety of the work process by changing the reaction solvent from anhydrous benzene, which is a solvent that is harmful to the human body, to anhydrous cyclo-hexane, which is less harmful to the human body. Could.

Subsequently, the compound of formula (III) was dissolved in anhydrous tetrahydrofuran, and then the PTT solution dissolved in anhydrous tetrahydrofuran was added dropwise at 0 ° C. for 2 hours to obtain the bromine substituted derivative compound of formula (IV) in high yield (100%). %), High purity (98%) was obtained.

Subsequently, the compound of formula (IV) was dissolved in dimethyl sulfoxide, a base and polyethylene glycol (PEG) were added, and the mixture was stirred at 60 to 80 ° C. to give the compound of formula (V) with high purity (98%) and high yield (99%). Could get.

In this reaction, as the kind of base, potassium hydroxide, lithium hydroxide, sodium hydroxide, etc. may be used, but sodium hydroxide is most preferred, and the amount of base used is 2-3 moles per mole of the compound of formula (IV). The temperature is most preferably reacted at 65 to 70 ° C. for 7 to 8 hours.

PEG-400, -600, -4000, -6000, etc. may be used as the type of PEG used in the present invention, but PEG-400 or -600 is preferably used, and the amount of PEG is used per 1 mole of the compound of formula (IV). 10 to 100 times mole% may be used but most preferably 30 to 50 times mole%.

When the amount of sodium hydroxide and PEG is small, the reaction time is long, and when the amount is high or the reaction temperature is high, the purity is low.

In this reaction, the compound of formula (V) was obtained by an improved production method in terms of production cost and safety of operation by changing base alkoxide, which is inconvenient to use conventionally and expensive alkoxide, to hydroxide of inorganic metal.

In particular, the removal of a small amount of by-products can be easily obtained to ensure a high purity material.

Subsequently, the compound of formula (VI) obtained by hydrolysis using an acid catalyst to the compound of formula (V) was obtained in a total yield of 95% and a purity of 97-98% from the compound of formula (II) as a starting material.

As the acid catalyst in this reaction, it is most preferable to use magnesium sulfate (10 mol%) and oxalic acid hydrate (10 mol%) with respect to 1 mol of the structural formula (V) compound.

Conventionally, the acid catalyst was used as para-toluene sulfonic acid hydrate (20 mol%), but in the present invention, the reaction time was changed from 24 hours to 4 to 5 hours by changing to magnesium sulfate (10 mol%) and oxalic acid hydrate (10 mol%). The compound of formula (VI) of high purity was obtained in high yield.

Subsequently, the methylation reaction of the compound of the formula (VI) is carried out by using the first copper compound as a catalyst in anhydrous toluene, and adding the compound of the formula (VI) and methyllithium or methylmagnesium bromide in alternating amounts to add the structural formula (I). To prepare the target compound, a compound of).

In this reaction, the compound of formula (I) was obtained by an improved reaction method in terms of purity by securing operational safety by reducing the reaction solvent from conventional ethyl ether to toluene and reducing the production of by-products.

Copper chloride, copper iodide, copper bromide, copper cyanide and the like may be used as the first copper compound, but copper iodide is preferred.

This can be explained by dividing the compound of formula (VI) with methyllithium or methylmagnesium bromide by a predetermined amount, i.e., adding one mole of the compound of formula (VI) and four times with 0.25 to 0.62 equivalents of methyllithium or magnesium magnesium bromide. It looks like this:

First, 0.25 to 0.32 equivalents of first copper iodide is added to anhydrous toluene, and the temperature of the reaction solution is maintained at 0 ° C, and 0.5 to 0.62 equivalents of methyllithium or methylmagnesium bromide are added.

The temperature of the reaction solution was lowered to -20 ° C and 0.25 equivalent of the compound of formula (VI) dissolved in anhydrous toluene was added to the reaction solution for 30 to 60 minutes.

After the addition, 0.25 to 0.28 equivalents of methyllithium or methylmagnesium bromide are added to the reaction solution, and 0.25 equivalents of the compound of formula (VI) dissolved in anhydrous toluene are added to the reaction solution for 30 to 60 minutes.

Thereafter, the above addition operation was repeated twice to obtain a compound of formula (I) having a yield of 99% and a purity of 96% from the compound of formula (VI).

In this reaction, a small amount of copper iodide, a high-priced catalyst (0.25), was added by dividing the compound of formula (VI) and methyllithium or methylmagnesium bromide alternately, instead of using the conventional method of producing iodide in an amount of 1.5 to 2.5 mol. Equivalent) can be used, and the amount of methyllithium or methylmagnesium bromide can also be reduced so that the target compound of Structural Formula (I) was obtained by an improved manufacturing method in terms of cost.

Hereinafter, 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.

Example 1

Synthesis of cyclopentadecan-1-one ethylene ketal (III)

Into a 1 L round two-necked flask, 50 g of the title compound (II) cyclopentadecan-1-one, 500 ml of anhydrous cyclo-hexane, 200 ml of ethylene glycol, and 4.24 g of para-toluenesulfonic acid hydrate were added to reflux. After 10 hours, the mixture was cooled to room temperature and an ethylene glycol layer was separated using a separatory filter. The separated ethylene glycol layer was extracted with 50 ml of anhydrous cyclo-hexane and combined with the previously separated cyclo-hexane layer, followed by distillation under reduced pressure. The colorless oily solid of the title compound (III) was obtained with a purity of 98-99%, yield. Obtained at 100% (59.8 g).

Example 2

Synthesis of 2-bromocyclopentadecan-1-one ethylene ketal (IV)

500 ml dropping funnel and thermometer were added to a 1 L three-necked flask, 90.46 g of PTT was dissolved in 200 ml of anhydrous tetrahydrofuran and placed in a dropping funnel. 59.8 g of the titled compound (III) prepared in Example 1 was added to anhydrous tetra After dissolving in 130 ml of hydrofuran and placing it in the flask, the solution was kept at 0 ° C. and tetrahydrofuran solution of PTT was added dropwise for 2 hours.

After the dropwise addition of the PTT tetrahydrofuran solution, the mixture was poured into 250 ml of saturated sodium bicarbonate solution, stirred for 30 minutes, the tetrahydrofuran was distilled off under reduced pressure, the residue was extracted three times with 50 ml of normal-hexane, and the normal-hexane layer was saturated. Wash with 50 ml of brine.

The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to obtain a pale yellow oily substance as the title compound (IV), with a purity of 98% and a yield of 100% (77.12 g).

3 to implementation

Synthesis of 2-cyclopentadecene-1-one ethylene ketal (Ⅴ)

Into a 1 L three-neck flask, 77.12 g of the title compound (IV) prepared in Example 2, 350 ml of dimethyl sulfoxide, 26.75 g of sodium hydroxide and 53.38 g of PEG-600 were added, and the temperature of the solution was 7 to 7 to 65 to 70 ° C. Stir vigorously for 8 hours.

After the reaction was completed, poured into 1.5 L of saturated brine, acidified with 440 ml of 1N hydrochloric acid, extracted three times with 100 ml of normal-hexane, and then combined the normal-hexane layer. Then, 125 ml of 1N-sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred. The oily solid was filtered and the normal-hexane layer obtained using the separating filter was distilled off under reduced pressure to obtain a yellowish brown oily substance as the title compound (V) with a purity of 99% and a yield of 99% (58.7 g).

Example 4

Synthesis of 2-cyclopentadeceen-1-one (Ⅵ)

Into a 2 L one-neck flask, add 58.7 g of the title compound (V) prepared in Example 3, 110 ml of acetone, 19 ml of water, 3.25 g of magnesium sulfate, and 2.0 g of oxalic acid hydrate, and stir at room temperature for 4 to 5 hours.

After the reaction was completed, acetone was distilled off under reduced pressure, 100 ml of water was added to the residue, and 100 ml of normal-hexane was extracted three times.

The normal-hexane layer was washed with 100 ml of saturated salt water and 100 ml of water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain a yellowish brown oily substance, the title compound (VI), with a purity of 97% and a total yield of 98% (48.5 g). Got it.

Example 5

Synthesis of DL-3-Methyl-cyclopentadecan-1-one (Ⅰ)

A 3 L three-necked flask was equipped with a calibrated 250 ml dropping funnel and a thermometer, filled with nitrogen, 25 ml of anhydrous toluene and 10.4 g of iodide dilute, and 78 ml of 1.4 M methyllithium was maintained at 0 ° C. and toluene 170 Prepare a colorless Dimethyl Cooper Lithium solution diluted in ml.

The temperature of the reaction solution is maintained at -20 ° C. Here prepared in Example 4 48.5 g of the title compound (VI) was added dropwise while dissolved in 50 ml of anhydrous toluene, and added as follows. The solution dissolved in toluene was added to a dropping funnel, and a 1/4 portion of the title compound (VI) was added dropwise for 30 minutes, again, 39 ml of 1.4 M methyllithium was added, and a 1/4 portion of the title compound (VI) was added dropwise for 30 minutes. do.

Thereafter, 39 ml of 1.4 M methyllithium was added thereto, and the obtained solution was repeatedly added twice to add 1/4 portion of the title compound (VI) for 30 minutes, and then poured into 500 ml of saturated ammonium chloride solution, and 28% aqueous ammonia 60 ml is added and the resulting solution is stirred three times with 50 ml of normal-hexane.

The normal-hexane layer was washed with 50 ml of 20% ammonia water, 50 ml of water, and 50 ml of saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure and distilled to give the title compound (I, DL-3-methyl-cyclopenta) as light yellow. Decan-1-one) was obtained with a purity of 94-96%, yield 98% (52.6 g).

According to the present invention, by avoiding the use of a solvent that is harmful to the human body to ensure the stability of the reaction process, to shorten the reaction time, eliminating the need or use of expensive reagents, such as alcohol side or iodide iodide, As an improved process in the mask, the compound of formula (I) is safe and inexpensive to maintain high yield, high purity, and industrially mass production is possible, the present invention can be seen that the invention is very useful industrially .

Claims (6)

The cyclopentadecane-1-one compound of formula (II), which is a starting material, was heated under anhydrous cyclo-hexane and para-toluenesulfonic acid catalyst, followed by a ketalization reaction to remove the water, thereby forming a cyclopenta of formula (III). A decan-1-one ethylene ketal compound was prepared and 2-bromocyclopentadecan-1-one ethylene of the formula (IV) was prepared by using phenyltrimethylammonium tribromide in anhydrous tetrahydrofuran. After preparing the ketal compound, the obtained compound of formula (IV) was prepared by using sodium hydroxide in the presence of dimethyl sulfoxide and PEG to prepare 2-cyclopentadeceen-1-one ethylene ketal compound of formula (V), and then The 2-cyclopentadeceen-1-one compound of formula (VI) was prepared by using the compound of formula (V) at room temperature in magnesium acetate and oxalic acid hydrate in acetone and water as acid catalysts. Using the compound of formula (VI) prepared in -40 to 0 ℃ anhydrous toluene as a catalyst, alternating addition of the compound of formula (VI) four times, each 0.25 equivalents, and methyllithium or methylmagnesium bromide The reaction is performed by adding 0.25 ~ 0.62 equivalents four times with respect to 1 mol of the compound of formula (VI), followed by the addition of methyllithium or methylmagnesium bromide first, followed by alternating addition of the compound of formula (VI) To prepare a DL-Methyl-cyclopentadecan-1-one compound. The method according to claim 1, wherein the amount of sodium hydroxide is used 2 to 3 times mole with respect to 1 mole of the compound of the formula (IV), and the reaction temperature is used at 65 to 70 ° C. The polyethylene glycol (PEG) is one selected from PEG-400, -600, -4000, -6000, and the amount of the polyethylene glycol (PEG) is 30 to 50 times molar with respect to 1 mol of the compound of the formula (IV) How to use%. The method according to claim 1, wherein the amount of magnesium sulfate and oxalate hydrate is used in an amount of 10 times mole% each with respect to 1 mole of the compound of formula (V). The method according to claim 1, wherein the first copper iodide as a catalyst is used in a ratio of 0.25 to 0.32 equivalents based on 1 equivalent of the compound of formula (VI). delete