JP5079416B2 - Process for producing 5- (3-benzyloxycyclobutane) hydantoin - Google Patents

Description

  The present invention relates to a compound having a hydantoin ring, which is important as an optical material, an electronic material, a pharmaceutical and agrochemical raw material and an intermediate, a diagnostic pharmaceutical raw material and an intermediate, and a method for producing the same.

  A compound having a hydantoin ring is a compound useful as an optical material, an electronic material, a pharmaceutical and agrochemical raw material and intermediate, a diagnostic pharmaceutical raw material and a synthetic intermediate of the intermediate.

  As a method for producing a compound having a hydantoin ring (5- (3-benzyloxycyclobutane) hydantoin, hereinafter also referred to as a hydantoin derivative), 3-benzylcyclobutanone is mixed with ammonium carbonate, ammonium chloride, potassium cyanide in a water / methanol mixed solvent. A synthesis method in which is reacted is known (Non-patent Document 1). The hydantoin derivative obtained by this method coexists with the syn isomers and anti isomers of geometric isomers.

  In many cases, pharmaceuticals used for humans and animals are effective in one isomer such as geometric isomers and optical isomers. When both isomers are mixed, there is a case where the other isomer exhibits significant phytotoxicity. In order to avoid this problem, it is necessary to selectively isolate only one isomer that functions as a pharmaceutical and use it as a pharmaceutical. In this way, the safety and effectiveness of pharmaceuticals are ensured.

  In Non-Patent Document 1, column chromatography is employed to separate a hydantoin derivative consisting of a syn form and an anti form into respective isomers. The separation conditions by column chromatography described in Non-Patent Document 1 are that 1 g of hydantoin derivative is developed using a column packed with 95 g of silica gel, and 500 mg of a hydantoin derivative is isolated.

  However, column chromatography is suitable for small-scale purification, and it is difficult to design a large-scale facility.In addition, column chromatography requires a long time for separation, so that work efficiency is low, and a large amount of eluent is required. Since a large amount of waste liquid is generated because it is necessary, it is not economical. In addition, since a large amount of silica gel is used, a large amount of industrial waste is generated, and there is a problem that the amount of sine that can be obtained at one time is extremely small. Therefore, the method for separating geometric isomers by column chromatography is not an effective method for industrial production from the viewpoints of operability, workability, and economy. Accordingly, there is a demand for an industrial production method that can produce a syn-body with high selectivity.

Furthermore, in the case of the production method of Non-Patent Document 1, the yield is at most about 50%, and a production method of a syn-hydantoin derivative with a higher yield is demanded.
Applied Radiation and Isotopes, 58, P657, 2003 2.2 Chemistry

  As a result of various studies to solve the above-mentioned problems, the present inventors have found that in the production of a hydantoin derivative, (1) the amount of reaction raw materials is set to a specific ratio, and (2) the reaction temperature is within a predetermined temperature range. It was discovered that the reaction yield and the selectivity for the syn form can be improved simultaneously by maintaining the same.

  The present invention has been completed based on the above discovery, and an object of the present invention is to provide a method for producing a hydantoin derivative having a high reaction yield and a high syn-body selectivity.

  The present invention for achieving the above object is described below.

[1] In a method for producing 5- (3-benzyloxycyclobutane) hydantoin, in which 3-benzyloxycyclobutanone, ammonium carbonate, potassium cyanide, and ammonium chloride are reacted in the presence of water and an alcohol.
Ammonium carbonate and potassium cyanide are reacted in an amount of 1.0 to 2.0 mol with respect to 1.0 mol of 3-benzyloxycyclobutanone, and 0.2 to 1.0 mol of ammonium chloride with respect to 1.0 mol of ammonium carbonate. A process for producing 5- (3-benzyloxycyclobutane) hydantoin, characterized in that the reaction is carried out by controlling the reaction temperature within a temperature range of 50 to 58 ° C.

  [2] The reaction temperature is raised to 50 to 58 ° C. within 1 hour after the start of the reaction, and then the reaction is performed within the temperature range. (Oxycyclobutane) Hydantoin production method.

  [3] The process for producing 5- (3-benzyloxycyclobutane) hydantoin according to [1] or [2], wherein methanol is used as the alcohol.

  [4] The process for producing 5- (3-benzyloxycyclobutane) hydantoin according to any one of [1] to [3], which comprises a step of distilling off alcohol from the reaction mixture obtained after completion of the reaction under normal pressure.

  In the method for producing 5- (3-benzyloxycyclobutane) hydantoin of the present invention, the amount of the other raw material compound with respect to the starting material 3-benzyloxycyclobutanone is about 1 compared with the amount of Non-Patent Document 1. / 10 or less. As a result, as can be seen from the data of Examples and Comparative Examples described later, workability, yield, purity and the like can be improved, although the reason is not clear.

  In the method for producing 5- (3-benzyloxycyclobutane) hydantoin of the present invention, the reaction is carried out while controlling the reaction temperature at 50 to 58 ° C. By controlling the temperature in this manner, sublimation of sublimable ammonium carbonate can be suppressed, and clogging of the cooling pipe by ammonium carbonate can be effectively prevented during the reaction. Furthermore, if the sublimation amount of ammonium carbonate closing the cooling pipe is large, it is considered that the produced 5- (3-benzyloxycyclobutane) hydantoin and the sublimated ammonium carbonate are likely to come into contact with each other. It seems to break down this. In the present invention, the amount of ammonium carbonate is small, and as a result, the decomposition of 5- (3-benzyloxycyclobutane) hydantoin is reduced, and the yield is finally greatly improved (30%) compared to the conventional method. . Moreover, purity can be improved more by raising reaction temperature to 50-58 degreeC within 1 hour after reaction start.

  Moreover, 5- (3-benzyloxycyclobutane) hydantoin can be taken out without any problem in production by distilling off the alcohol from the reaction mixture obtained after completion of the reaction under normal pressure.

  Hereinafter, the present invention will be described in detail.

  In the process for producing 5- (3-benzyloxycyclobutane) hydantoin of the present invention, as shown in the following reaction formula (A), 3-benzyloxycyclobutanone (1) as a starting material, ammonium carbonate, and chloride Ammonium and potassium cyanide are reacted to produce syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- (3-benzyloxycyclobutane) hydantoin (3).

  The starting material 3-benzyloxycyclobutanone (1) can be produced, for example, by the method described in the column 2.2.2 of Non-Patent Document 1.

  The compounding quantity of ammonium carbonate is 1.0-2.0 mol with respect to 1.0 mol of 3-benzyloxycyclobutanone (1) which is a starting material, and 1.0-1.5 mol is more preferable. . When the compounding amount of ammonium carbonate is less than 1.0 mol, the yield of 5- (3-benzyloxycyclobutane) hydantoin decreases. When the compounding amount of ammonium carbonate exceeds 2.0 mol, the selectivity for the syn form tends to decrease. In addition, ammonium carbonate sublimates during the reaction and precipitates in the cooling pipe, making it easy to block the cooling pipe. As a result, 5- (3-benzyloxycyclobutane) hydantoin is decomposed and the reaction yield tends to decrease. It is in.

  The compounding quantity of ammonium chloride is 0.2-1.0 mol with respect to 1.0 mol of ammonium carbonate, and 0.3-0.9 mol is more preferable. When the amount of ammonium chloride is less than 0.2 mol, the hydantoinization reaction is slowed, impurities are increased, and the yield of 5- (3-benzyloxycyclobutane) hydantoin is lowered. When the compounding amount of ammonium chloride exceeds 1.0 mol, the selectivity for the syn form tends to decrease and the impurities tend to increase. In addition, the reaction yield tends to decrease.

  The compounding quantity of potassium cyanide is 1.0-2.0 mol with respect to 1.0 mol of 3-benzyloxycyclobutanone (1) which is a starting material, and 1.0-1.5 mol is more preferable. When the compounding quantity of potassium cyanide is less than 1.0 mol, the yield of 5- (3-benzyloxycyclobutane) hydantoin decreases. When the compounding amount of potassium cyanide exceeds 2.0 mol, the selectivity for the syn form decreases and the impurities tend to increase. In addition, the reaction yield tends to decrease.

  The reaction is carried out in the presence of water and alcohol. The blending amounts of water and alcohol are not particularly limited as long as the reaction can proceed sufficiently. Further, the mixing ratio of water and alcohol is not particularly limited, and may be appropriately determined according to the blending amount of the starting materials, reaction conditions, and the like. In general, the mixing ratio of water and alcohol is preferably 1:99 to 99: 1, more preferably 10:90 to 90: on a mass basis.

  As alcohol, C1-C3 alcohol is preferable. Specifically, methanol, ethanol, 1-propanol, and 2propanol are general-purpose and preferable, and methanol is more preferable.

  The reaction is carried out in a reaction solution in which the above raw materials (3-benzyloxycyclobutanone (1), ammonium carbonate, ammonium chloride, potassium cyanide) are mixed. Ammonium carbonate and ammonium chloride are dissolved or suspended in water, 3-benzyloxycyclobutanone (1) is dissolved in alcohol, water in which ammonium carbonate and ammonium chloride are dissolved or suspended, and 3-benzyloxycyclobutanone (1) It is preferable to carry out the reaction by mixing the alcohol in which is dissolved and finally mixing potassium cyanide. A yield can be made higher by mixing a raw material in such a procedure. In the present invention, the reaction start refers to the time when all the raw materials are mixed. In the above case, the reaction starts when the potassium cyanide is mixed.

  The reaction temperature of the reaction solution in which the raw materials are mixed is controlled to 50 to 58 ° C. When the reaction temperature is less than 50 ° C., the reaction does not substantially proceed. When the reaction temperature exceeds 58 ° C., the sublimation of ammonium carbonate becomes remarkable, and the cooling pipe provided for the reflux of alcohol tends to be blocked. Furthermore, the tendency for the deposited ammonium carbonate to decompose the generated syn-5- (3-benzyloxycyclobutane) hydantoin (2) is recognized. Therefore, after adding ammonium carbonate, it is not preferable to set the liquid temperature to a temperature exceeding 58 ° C.

  In the present invention, it is possible to set the reaction temperature to 50 to 58 ° C. immediately after the start of the reaction by setting the temperature of water and alcohol used to 50 to 58 ° C. In consideration of operability, it is preferable to control the reaction solution so that the reaction temperature is in the temperature range of 50 to 58 ° C. after mixing all the raw materials. That is, when starting the reaction, the temperature of the reaction solution is set to a temperature lower than 50 ° C., the reaction temperature is increased to 50 to 58 ° C. after the start of the reaction, and the reaction is subsequently performed within the temperature range. preferable. In this case, the time taken to control the temperature of the reaction solution in the temperature range of 50 to 58 ° C. is preferably within 1 hour after the start of the reaction, and more preferably within 50 minutes. Impurities can be reduced by controlling the reaction temperature to 50 to 58 ° C. within 1 hour after the start of the reaction.

  The reaction time is preferably 0.5 to 100 hours, more preferably 1 to 50 hours. When the reaction time is less than 0.5 hours, the yield decreases. In addition, this reaction time points out time when reaction temperature is controlled by the temperature range of 50-58 degreeC.

  After the reaction under the above reaction conditions, a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- (3-benzyloxycyclobutane) hydantoin (3) is simply added from the resulting reaction mixture. Release. The isolation method is not particularly limited, and any isolation method such as solvent distillation, extraction, adsorption, crystallization and the like can be adopted.

  When distilling off the solvent, it is preferable to first distill off the alcohol from the reaction mixture under normal pressure. By distilling off the alcohol under normal pressure, sublimation of ammonium carbonate remaining in the reaction mixture can be suppressed. Furthermore, syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- A mixture of (3-benzyloxycyclobutane) hydantoin (3) can be safely removed. When the alcohol is removed under reduced pressure, the cause is not clear, but bubbles may be generated from the reaction mixture, which may cause bumping, and may reduce operability.

  Therefore, a particularly preferred isolation method is to distill off the alcohol in the reaction mixture under normal pressure, and then syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- (3-benzyl By cooling the reaction mixture containing a mixture of oxycyclobutane) hydantoin (3), syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- (3-benzyloxycyclobutane) hydantoin (3 ). These target compounds (2) and (3) can be further purified.

Isomeric ratio (syn isomer) of a mixture of the target compound syn-5- (3-benzyloxycyclobutane) hydantoin (2) and anti-5- (3-benzyloxycyclobutane) hydantoin (3) obtained as described above / Anti-body) is 78/22 to 85/15. If more conditions are selected, those of 81/19 to 85/15 are obtained. According to the present invention, a thin body having high selectivity is obtained. be able to.

Hereinafter, the present invention will be described more specifically with reference to examples.

Comparative Example 1
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin

  A thermometer, a condenser, and a stirring blade were attached to a 20 L four-necked separable flask. 1250 g (13 mol) of ammonium carbonate, 278 g (5.2 mol) of ammonium chloride and 9 kg of ion-exchanged water were added to the flask and dissolved. Next, 236 g (1.3 mol) of 3-benzyloxycyclobutanone dissolved in 7.1 kg of ethanol was added to the flask and stirred at 25 ° C. for 30 minutes. Further, 380 g (5.8 mol) of potassium cyanide was added, and the mixture was added over 60 hours. The temperature was raised to ° C and stirred for 12 hours. During the reaction, the condenser was clogged every 30 minutes, so the condenser was replaced each time. After completion of the reaction, the solvent was distilled off under reduced pressure. Since foaming occurred, the solid was dried under normal pressure to obtain a yellow solid. 10 kg of ion exchange water was added thereto, and the mixture was stirred for 1 hour, then solid-liquid separated and washed with 100 g of cold ion exchange water. The obtained wet body was dried at 60 ° C. for 12 hours, and 164 g (yield 51%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin was obtained. Obtained. When analyzed by high-performance liquid chromatography (hereinafter also referred to as HPLC), the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 22%, and the syn form / anti form = 80/20. The column used in Comparative Example 1 and the Examples and Comparative Examples described below are octadecyl silica gel GL Sciences, Inc., trade name: Inertosyl ODS-3, and the eluent is acetonitrile / phosphate buffer = 1. / 2 (v / v). As the phosphate buffer, a 20 mmol / L potassium dihydrogen phosphate aqueous solution was used.

Example 1
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin

  A thermometer, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up to 55 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, no blockage of the condenser occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. When methanol was distilled off under normal pressure, no foaming occurred. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 2246 g (yield 80%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 1%, and the syn isomer / anti isomer = 83/17.

Example 2
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate and 251 g (4.7 mol) of ammonium chloride were added to 3 kg of ion exchange water and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was added to the flask. Thereafter, the temperature was raised to 55 ° C. over 10 minutes, followed by stirring for 12 hours. During the reaction, no blockage of the condenser occurred. After completion of the reaction, the mixture was cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration, and washed with 500 g of cold ion exchange water. Thereafter, the crystals were subjected to solid-liquid separation, and the obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 1966 g (yield 70%) of a mixture of syn-5- (3-benzyloxycyclobutanone) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 0.5%, and the syn form / anti form = 82/18.

Example 3
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride, and 3 kg of ion exchange water were placed in a flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of ethanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Thereafter, the temperature was raised to 55 ° C. over 45 minutes and stirred for 12 hours. During the reaction, no blockage of the condenser occurred. After completion of the reaction, ethanol was distilled off at normal pressure, followed by cooling to 8 ° C., and the crystals were subjected to solid-liquid separation by filtration, and washed with 500 g of cold ion-exchanged water. When ethanol was distilled off at normal pressure, no foaming occurred. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 2106 g (yield 75%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 3.0%, and the syn form / anti form = 82/18.

Example 4
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 2084 g (21.7 mol) of ammonium carbonate, 1036 g (19.38 mol) of ammonium chloride and 3 kg of ion-exchanged water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 1413 g (21.7 mol) of potassium cyanide was further added to the flask. Then, it heated up at 58 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, a slight amount of white crystals was observed, but no clogging of the capacitor occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. When methanol was distilled off under normal pressure, no foaming occurred. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 2190 g (yield 78%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 1.5%, and the syn form / anti form = 81/19.

Example 5
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up at 58 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, no blockage of the condenser occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. When methanol was distilled off under normal pressure, no foaming occurred. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 2246 g (yield 80%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 1%, and the syn isomer / anti isomer = 83/17.

Example 6
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up to 52 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, no blockage of the condenser occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. When methanol was distilled off under normal pressure, no foaming occurred. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 2162 g (yield 77%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 1%, and the syn isomer / anti isomer = 83/17.

Comparative Example 2
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 874 g (9.1 mol) of ammonium carbonate, 5.9 g (0.11 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 593 g (9.1 mol) of potassium cyanide was further added to the flask. Then, it heated up at 58 degreeC in 45 minutes, and stirred for 12 hours. No capacitor blockage was observed during the reaction.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 561 g (yield 20%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 10%, and the syn form / anti form = 80/20.

Comparative Example 3
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 2411 g (25.1 mol) of ammonium carbonate, 1583 g (29.6 mol) of ammonium chloride and 3 kg of ion-exchanged water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 1635 g (25.1 mol) of potassium cyanide was further added to the flask. Then, it heated up at 58 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, the condenser was blocked every 30 minutes, so the condenser was replaced every time.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 1488 g (yield 53%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 1%, and the syn form / anti form = 80/20.

Comparative Example 4
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up to 45 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, the condenser was not blocked at all, but as a result of high performance liquid chromatography analysis, it was confirmed that the reaction did not proceed at all.

Comparative Example 5
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 2411 g (25.1 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion-exchanged water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up to 55 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, the condenser was clogged every 30 minutes, so the condenser was replaced and reacted each time.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 1865 g (yield 60%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 5%, and the syn form / anti form = 77/23.

Comparative Example 6
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 1583 g (29.6 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 766 g (11.8 mol) of potassium cyanide was further added to the flask. Then, it heated up to 55 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, no blockage of the condenser occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 1544 g (yield 55%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, which was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 10%, and the syn form / anti form = 77/23.

Comparative Example 7
Synthesis of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin A thermoliter, a condenser, and a stirring blade were attached to a 10 L four-necked flask. 1110 g (11.6 mol) of ammonium carbonate, 251 g (4.7 mol) of ammonium chloride and 3 kg of ion exchange water were added to the flask and dissolved. Next, 2 kg (11.4 mol) of 3-benzyloxycyclobutanone dissolved in 1600 g of methanol was added to the flask, and 1635 g (35.1 mol) of potassium cyanide was further added to the flask. Then, it heated up to 55 degreeC in 45 minutes, and stirred for 12 hours. During the reaction, no blockage of the condenser occurred.

  After completion of the reaction, methanol was distilled off at normal pressure, and then cooled to 8 ° C., and the crystals were separated into solid and liquid by filtration. The crystals were separated into solid and liquid and washed with 500 g of cold ion exchange water. The obtained wet body was dried under reduced pressure at 40 ° C. for 12 hours. The obtained dried product was 1460 g (yield 55%) of a mixture of syn-5- (3-benzyloxycyclobutane) hydantoin and anti-5- (3-benzyloxycyclobutane) hydantoin, and was analyzed by high performance liquid chromatography. As a result, the amount of impurities other than 5- (3-benzyloxycyclobutane) hydantoin was 9%, and the syn form / anti form = 77/23.

Claims (4)

In the method for producing 5- (3-benzyloxycyclobutane) hydantoin, in which 3-benzyloxycyclobutanone, ammonium carbonate, potassium cyanide, and ammonium chloride are reacted in the presence of water and an alcohol.
Ammonium carbonate and potassium cyanide are reacted in an amount of 1.0 to 2.0 mol with respect to 1.0 mol of 3-benzyloxycyclobutanone, and 0.2 to 1.0 mol of ammonium chloride with respect to 1.0 mol of ammonium carbonate. A process for producing 5- (3-benzyloxycyclobutane) hydantoin, characterized in that the reaction is carried out while controlling the reaction temperature within a temperature range of 50 to 58 ° C. The 5- (3-benzyloxycyclobutane) according to claim 1, wherein the reaction temperature is raised to 50 to 58 ° C within 1 hour after the start of the reaction, and thereafter the reaction is controlled within the temperature range. A method for producing hydantoin. The method for producing 5- (3-benzyloxycyclobutane) hydantoin according to claim 1 or 2, wherein methanol is used as the alcohol. The method for producing 5- (3-benzyloxycyclobutane) hydantoin according to any one of claims 1 to 3, comprising a step of distilling off alcohol from the reaction mixture obtained after completion of the reaction under normal pressure.