KR20090125015A - Process for preparing oxazolidin-2-one by using isocyanate - Google Patents

Abstract

PURPOSE: A method for preparing oxazolidine-2-one compound is provided to perform synthesis and rearrangement of cyclic iminocarbonate. CONSTITUTION: A method for preparing oxazolidin-2-one compound comprises: a step of reacting diol compound with isocyanate to prepare hydroxyl carbamate containing two kinds of position isomer; a step of dehydrating the hydroxyl carbamate with dehydrating agent to produce cyclic iminocarbonate; and a step of performing rearrangement of cyclic iminocarbonate with halogenation nucleophile to produce the oxzolidine-2-one. A diol starting material is 1,2-alkandiol, (S,S)-(-)-hydrobenzoin or tartaric acid diester. The dehydrating agent is dialkylcarbodiimide.

Description

Method for producing oxazolidin-2-one compound using isocyanate {PROCESS FOR PREPARING OXAZOLIDIN-2-ONE BY USING ISOCYANATE}

The present invention relates to a method for synthesizing an oxazolidin-2-one compound under environmentally friendly conditions.

Cyclic iminocarbonate rearrangement (CIR) is a conversion of diols to aminoalcohol derivatives, characterized by maintaining stereochemistry ( J. Org. Chem. 1999, 64, 8745; Tetrahedron Lett 2000, 41, 5553-5556; Bull.Korean Chem. Soc. 2002, 23, No. 1). The reaction has been applied to the synthesis of a number of drugs and bioactive substances, and is shown in Scheme 1 below.

As shown in Scheme 1, the cyclic imino carbonate relocation reaction first activates two hydroxy groups of diol with dibutyl tin oxide and then reacts with isothiocyanate to synthesize cyclic iminocarbonate. Then, when the synthesized cyclic iminocarbonate is reacted with a halogenated nucleophile (for example, lithium iodide), two nucleophilic substitution reactions, that is, nucleophilic substitution ring opening reaction and nucleophilic substitution ring formation reaction, occur continuously. The type iminocarbonate is converted to an oxazolidin-2-one functional group, wherein the stereochemistry is maintained in its original form through two inversions.

The synthetic applicability of this method has already been demonstrated by the synthesis of many pharmaceuticals and bioactive substances ( Tetrahedron Lett 2000, 41, 5553-5556; Bull. Korean Chem. Soc. 2001, 22, 432; J. Org. Chem. 2001, 66, 6833; Tetrahedron Lett 2002, 43, 639), dibutyl tin oxide is used in the first step, activating the two hydroxyl groups of the diol, and because of the toxicity of the tin compounds, There was a limit to industrial application.

It is an object of the present invention to provide a method for preparing an oxazolidin-2-one compound under environmentally friendly conditions that do not use toxic tin compounds.

Another object of the present invention is to provide a production process in which the production reaction and the displacement reaction of the cyclic imino carbonate are carried out continuously in the same reactor.

According to the above object, in the present invention, iii) preparing a hydroxy carbamate comprising two regioisomers by reacting a diol compound with an isocyanate; Ii) dehydrating the hydroxy carbamate with a dehydrating agent to produce a cyclic iminocarbonate; And iii) shifting the cyclic imino carbonate with the halogenated nucleophile to produce an oxazolidin-2-one.

In addition, the present invention provides a method for preparing an oxazolidin-2-one compound further comprising the step of separating the hydroxy carbamate comprising two regioisomers prepared in step i) to each regioisomer to provide.

The present invention synthesizes cyclic iminocarbonate intermediates without the use of toxic tin compounds, utilizes dehydrating agent-induced dehydration in this process, and separates or separates hydroxy carbamate into two positional isomers. Dehydration of the same cyclic imino carbonate without dehydration without the problem caused by regioisomers, cyclic imino carbonate production and its displacement reaction can proceed continuously in the same reactor Compared with the prior art, the industrial applicability is high.

The present invention will be described in more detail as follows.

The present invention provides a method for preparing hydroxycarbamate comprising two regioisomers by reacting a diol compound with an isocyanate, and ii) synthesizing the hydroxy carbamate by dehydration under dehydrating agent-induction. After transforming to iii), the present invention relates to a method for preparing oxazolidin-2-one by performing a displacement reaction of cyclic iminocarbonate produced under environmentally friendly conditions without using tin.

The present invention also relates to a method for preparing oxazolidin-2-one further comprising the step of separating hydroxy carbamate comprising two regioisomers prepared in step i) into each regioisomer. will be.

The reaction process according to a preferred embodiment of the present invention is shown in Scheme 2 below.

Referring to Scheme 2, first, in step i), the starting material diol compound (e.g. 1,2-heptanediol) is reacted with an isocyanate (e.g. phenylisocyanate) to about 4: 1 (regioisomers). 1: Regioisomer 2) Synthesize two regioisomers of hydroxy carbamate. The hydroxy carbamate is then separated into regioisomer 1 (secondary hydroxy-first carbamate) and regioisomer 2 (primary hydroxy-secondary carbamate) by conventional isomer separation methods such as recrystallization. Diol compounds usable in the present invention include 1,2-alkanediols such as 1,2-heptane diol, (S, S)-(-)-hydrobenzoin or tartaric acid diester, and the like. Isocyanates which can be used in the invention include aryl isocyanates such as phenyl isocyanates or acyl isocyanates. ArNCO may be used as the reaction solvent. In the present invention, step iii) may be carried out at 20 to 180 ° C., preferably at 75 ° C., for 3 to 14 days, preferably for about 4 days.

In step ii), each of the isomers is dehydrated with a dehydrating agent (eg dicyclohexylcarbodiimide (hereinafter DCC)) to synthesize cyclic iminocarbonate intermediates. Dehydrating agents that can be used in the present invention include dialkyl carbodiimides such as dicyclohexyl carbodiimide (DCC). In addition, step ii) may be carried out at 60 to 180 ° C., preferably at 85 to 90 ° C., for 3 to 20 days, preferably for about 12 days.

In step iii), a halogenated nucleophile (for example lithium iodide) is added to the cyclic iminocarbonate intermediate to incubate to prepare an oxazolidin-2-one compound, each from hydroxy carbamate two position isomers. It can be seen that the synthesized oxazolidin-2-one product is the same substance, ie the same stereoisomer. Halogenated nucleophiles that can be used in the present invention include lithium iodide, lithium bromide, tetrabutylammonium iodide or tetrabutylammonium bromide. The step iii) may be carried out at 60 to 180 ° C., preferably at 85 to 90 ° C., for 6 to 48 hours, preferably for about 15 hours.

In the process of the present invention, when the hydroxy carbamate is separated into two regioisomers, the oxazolidin-2-one compound can be obtained in high yield even if the steps ii) and iii) are continuously performed in the same reactor.

In addition, the same cyclic iminocarbonate intermediate and oxazolidin-2-one compound may be obtained by performing steps ii) and iii) without separating the hydroxy carbamate into regioisomer 1 and regioisomer 2 in step i). Can be prepared. At this time, the oxazolidin-2-one compound can be obtained with high yield even if the steps iii), ii) and iii) are continuously performed in the same reactor.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1 Preparation of Oxazolidin-2-one Using 1,2-heptanediol as Starting Material (1)

Step 1 Preparation of Hydroxy Carbamate Containing Two Regioisomers

10 mmol (1.32 g) of 1,2-heptanediol and 10 mmol (1.09 mL) of phenyl isocyanate were dissolved in 100 mL of toluene and reacted at 75 ° C. for 4 days. After confirming that the reaction was completed by thin layer chromatography (TLC), ethyl acetate was added to the reaction mixture, washed with distilled water and brine, and dried over sodium sulfate. The crude product thus obtained was concentrated, partially purified by flash silica column chromatography (n-hexane: ethyl acetate = 5: 1-> 1.5: 1), and then recrystallized (ethyl acetate-hexane) was obtained. Final purification through gave hydroxy carbamate comprising two regioisomers 1,2. The resulting hydroxy carbamate two regioisomers were each separated through recrystallization (ethylacetate-hexane). The NMR results of the two positional isomers separated are as follows.

Regioisomer 1 (Secondary hydroxy-first carbamate) 1 H NMR (CDCl ₃ ) δ 7.39-7.26 (4H, m), 7.05 (1H, t, J = 6.92 Hz), 6.74 (1H, s), 4.28 (1H, dd, J = 11.35Hz, 2.85Hz), 4.06 (1H, dd, J = 11.35Hz, 7.3Hz), 3.90 (1H, m), 2.18 (1H, s), 1.56-1.34 (6H, m ), 1.26 (3H, t, J = 7.14 Hz), 0.92 (3H, t, J = 7.09 Hz)

Regioisomer 2 (primary hydroxy-secondary carbamate) 1 H NMR (CDCl ₃ ) δ 7.53-7.26 (4H, m), 7.07 (1H, t, J = 7.11 Hz), 6.68 (1H, s), 4.92 -4.88 (1H, m), 3.77 (1H, dd, J = 12.05, 3.05), 3.69 (1H, dd, J = 12.05 Hz, 6.25 Hz), 1.92 (1H, s), 1.63 (2H, m), 1.39-1.33 (4H, m), 0.93 (3H, t, J = 7.5 Hz)

Step 2 Preparation of Oxazolidin-2-one

1 mmol (251 mg) of pure enantiopure secondary hydroxy-first carbamate and 1 mmol (206 mg) of dicyclohexylcarbodiimide (DCC) prepared in step 1 were dissolved in 10 ml of tetrahydrofuran 85 Heated at ˜90 ° C. for 12 days. After confirming that the cyclic iminocarbonate was produced by TLC, 1 mmol (134 mg) of lithium iodide was added, and reacted at a temperature of 85 to 90 ° C for 15 hours. After confirming the completion of the replacement reaction by TLC, ethyl acetate was added to the reaction mixture, washed with distilled water and brine in that order and dried over sodium sulfate. The crude product thus obtained was concentrated and purified by flash silica column chromatography (n-hexane: ethyl acetate = 10: 1) to give oxazolidin-2-one (60.5 mg, yield 26%).

[α] 26.6 (sodium D) +26.7 (c 0.53, EtOH)

1 H NMR (CDCl ₃ ) δ 7.56-7.10 (5H, m), 4.66-4.61 (1H, m), 4.08 (1H, dd, J = 7.44 Hz, 15.92 Hz), 3.66 (1H, dd, J = 7.44, 1.48), 1.95-1.75 (2H, m), 1.55-1.38 (4H, m), 0.94 (3H, t, J = 7.5 Hz)

Example 2 Preparation of Oxazolidin-2-one Using 1,2-heptanediol as Starting Material (2)

1 mmol (251 mg) of pure enantiomer primary hydroxy-secondary carbamate and 1 mmol (206 mg) of dicyclohexylcarbodiimide synthesized in Step 1 of Example 1 were dissolved in 10 ml of tetrahydrofuran 85 Heated at ˜90 ° C. for 12 days. After confirming that the cyclic iminocarbonate was produced by TLC, 1 mmol (134 mg) of lithium iodide was added, and reacted at a temperature of 85 to 90 ° C for 15 hours. After confirming the completion of the displacement reaction through TLC, ethyl acetate was added to the reaction mixture, washed with distilled water and brine in that order and dried over sodium sulfate. The crude product thus obtained was concentrated and purified by flash silica column chromatography (n-hexane: ethyl acetate = 10: 1) to give oxazolidin-2-one (31.4 mg, 14% yield). The spectroscopic properties of the obtained compound were the same as in Example 1.

Example 3: Preparation of oxazolidin-2-one using 1,2-heptanediol as starting material (3)

1.47 mmol (370 mg) and dicyclohexylcarbodiimide 1: 4 mixture of the pure enantiomer primary hydroxy-secondary carbamate and secondary hydroxy-first carbamate synthesized in step 1 of Example 1 above 2.94 mmol (606 mg) was dissolved in 15 ml of tetrahydrofuran and heated at 85-90 ° C. for 19 days. After confirming that the cyclic iminocarbonate was produced by TLC, 2.9 mmol (394 mg) of lithium iodide was added and reacted at a temperature of 85 to 90 ° C for 15 hours. After confirming the completion of the displacement reaction through TLC, ethyl acetate was added to the reaction mixture, washed with distilled water and brine in that order and dried over sodium sulfate. The crude product thus obtained was concentrated and purified by flash silica column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain oxazolidin-2-one (36.2 mg, yield 10.5%). The spectroscopic properties of the obtained compound were the same as in Example 1.

Example 4: Preparation of oxazolidin-2-one using (S, S)-(-)-hydrobenzoin as starting material

Step 1 Preparation of Hydroxy Carbamate

5 mmol (1.07 g) of (S, S)-(-)-hydrobenzoin and 5 mmol (544.9 μl) of phenyl isocyanate were dissolved in 50 mL of toluene, and then reacted at 70 to 80 ° C. for 9 days. After TLC confirmed that the starting material disappeared completely and the desired product was produced, ethyl acetate was added to the reaction mixture, washed with distilled water and brine, and dried over sodium sulfate. The crude product thus obtained was concentrated and purified by flash silica column chromatography (n-hexane: ethyl acetate = 4: 1-> 2.5: 1-> ethyl acetate) to yield hydroxy carbamate (1.07 g, 64% yield). Obtained.

1 H NMR (CDCl ₃ ) δ 7.37-7.21 (14H, m), 7.15 (1H, t, J = 1.65 Hz), 6.67 (1H, s), 5.89 (1H, dJ = 7.43), 4.97 (1H, dd, J = 7.43Hz, 3.61Hz), 2.68 (1H, d, J = 3.65Hz)

Step 2 Preparation of Oxazolidin-2-one

1 mmol (333 mg) of hydroxycarbamate and 1 mmol (206 mg) of dicyclohexylcarbodiimide synthesized in Step 1 were dissolved in 10 ml of tetrahydrofuran and heated at 85˜90 ° C. for 12 days. After confirming that the cyclic iminocarbonate was produced through TLC, 1 mmol (134 mg) of lithium iodide was added and reacted at a temperature of 85 to 90 ° C for 15 hours. After confirming that the desired product was produced by TLC, ethyl acetate was added to the reaction mixture, washed with distilled water and brine in that order, and dried over sodium sulfate. The crude product thus obtained was concentrated and purified by flash silica column chromatography (n-hexane: ethyl acetate = 10: 1) to give oxazolidin-2-one (38.8 mg, yield 12.3%).

1 H NMR (CDCl ₃ ) δ 7.42-7.33 (10H, m), 7.28-7.26 (4H, m), 7.05 (1H, t, J = 6.7 Hz), 5.32 (1H, d, J = 6.5 Hz), 5.19 (1H, d, J = 6.5 Hz)

Claims (11)

Iii) reacting the diol compound with an isocyanate to produce a hydroxy carbamate comprising two regioisomers; Ii) dehydrating the hydroxy carbamate with a dehydrating agent to produce a cyclic iminocarbonate; And Iii) shifting the cyclic iminocarbonate with a halogenated nucleophile to produce oxazolidin-2-one Method for producing an oxazolidin-2-one compound comprising a. The method of claim 1, Separating the hydroxy carbamate comprising two regioisomers prepared in step i) into each regioisomer. The method according to claim 1 or 2, The diol starting material is selected from the group consisting of 1,2-alkanediol, (S, S)-(-)-hydrobenzoin and tartaric acid diester. The method according to claim 1 or 2, The isocyanate is aryl isocyanate or acyl isocyanate. The method according to claim 1 or 2, The dehydrating agent is a dialkyl carbodiimide. The method according to claim 1 or 2, The halogenated nucleophile is selected from the group consisting of lithium iodide, lithium bromide, tetrabutylammonium iodide and tetrabutylammonium bromide. The method of claim 1, Wherein step iii), ii) and iii) are carried out continuously in the same reactor. The method of claim 2, The process of step ii) and iii) being carried out continuously in the same reactor. The method according to claim 1 or 2, The step iii) is carried out at 20 to 180 ℃ for 3 to 14 days. The method according to claim 1 or 2, The step ii) characterized in that the step is carried out at 60 to 180 ℃ for 3 to 20 days. The method according to claim 1 or 2, The step iii) is carried out at 60 to 180 ℃ for 6 to 48 hours.