JP2000095780A - Production of crystal of carbamate compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject crystal having a high purity and useful as an intermediate of a medicine such as paroxetine as a treating agent of depression, etc., in a short process and by using an efficient means, by preparing a solution of a specific carbamate compound with a polar solvent and crystallizing out the carbamate from the solution with the polar solvent without changing the amount of the polar solvent substantially. SOLUTION: This method for producing a crystal of a carbamate compound is provided by preparing a solution of a carbamate of the formula (R1 is a lower alkyl or the like) with a polar solvent, having preferably >10 deg.C boiling point, then crystallizing out the above carbamate from the solution with the polar solvent without changing the amount of the polar solvent substantially to obtain the objective crystal. The above polar solvent is preferably a hydroxy compound of the formula: R3OH (R3 is a lower alkyl) (e.g. ethanol), etc. The compound of the formula is preferably obtained by reacting preferably (3S,4 R)-[5-(1,3-dioxaindanyl)-1-methylpiperidine with ethyl chloroformate in a solvent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing purified carbamate crystals. The carbamates in the present invention are compounds useful as intermediates such as paroxetine useful as therapeutics for depression and the like.

[0002]

2. Description of the Related Art (3S, 4R) represented by the following equation (2):
3- [5- (1,3-dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) piperidine is generally called paroxetine and has an inhibitory effect on 5-hydroxytryptamine (5-HT). It is a compound that is effective as a therapeutic agent for various diseases such as depression and Parkinson's disease.

[0003]

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Hitherto, as a method for producing paroxetine, (A) the method of Christensen et al.
7196), (B) the method of Sugu et al. (EP08128)
27A), (C) King et al.'S method (JP-A-9-31607)
2) has been reported.

In the method (A), an N-methylpiperidine derivative [compound of the formula (3) wherein R ² is a methyl group] is reacted with phenyl chloroformate in a methylene chloride solvent to form a phenylcarbamate [formula (1)]. Of the compound of formula (I) wherein R ¹ is a phenyl group], the reaction crude solution is washed with sodium hydroxide, then with hydrochloric acid and dried, and then the methylene chloride solvent is distilled off. To give a solid mixture. The solid mixture is further dissolved in benzene, filtered, and benzene is distilled off to obtain a residue.The residue, potassium hydroxide and methyl cellosolve are refluxed under reduced pressure, water is added, and water is added and extracted with benzene. The phenyl carbamate is purified by distilling off benzene.

In the method (B), a reaction involving a benzyl carbamate in which R ^{1 in} the formula (1) is a benzyl group or a t-butyl carbamate in which R ^{1 in the} formula (1) is a t-butyl group A crude solution was obtained, the crude reaction solution was put in water and toluene, the toluene layer was separated, the aqueous layer was extracted again with toluene, the toluene layers were combined, washed with an aqueous sodium hydroxide solution, and washed with water. After drying and concentration, an oily benzyl carbamate was obtained.

In the method (C), a methyl carbamate in which R ^{1 in} the formula (1) is a methyl group or an ethyl carbamate in which R ^{1 in the} formula (1) is an ethyl group are produced, and the reaction product is concentrated. As a result, a solid or oily carbamate body is obtained.

[0008]

However, the conventional method has the following problems. In the methods (A) and (B), various operations are performed in order to remove impurities contained in the reaction crude product. However, these operations are complicated because they require multiple steps, and are obtained as a result. The phenyl carbamate had a problem that the purity was not always high. In addition, there is a problem that the yield is reduced due to many steps. Further, the benzyl carbamate obtained by the method (B) was in an oily state, and had inconvenience in handling and product management.

In the method (C), since the process proceeds to the next step only by concentration, impurities mixed in from the previous process may remain in the next process or may have an adverse effect. When a target compound produced using such an intermediate is used as a pharmaceutical, in practice, purification of the target compound requires more labor and cost than necessary, which may lead to a great disadvantage. .

[0010]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and provides the following method capable of purifying carbamates by a short-step and efficient means. That is, the present invention provides a method for preparing a carbamate represented by the following formula (1) as a polar solvent solution, and then crystallizing the carbamate from the polar solvent solution without substantially changing the amount of the polar solvent. The present invention provides a method for producing a carbamate crystal. However, R ¹ in the formula (1)
Represents a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, an aralkyl group, an aryl group, an alkyl group substituted with a monovalent heterocyclic group, or a perfluoroalkyl group having 1 to 6 carbon atoms.

[0011]

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[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Carbamates represented by the formula (1) in the present invention [hereinafter referred to as compound (1).
The same applies to other compounds. ] Is a known compound. R ¹ in compound (1) is a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, an aralkyl group, an aryl group, an alkyl group substituted with a monovalent heterocyclic group, or a perfluoroalkyl group having 1 to 6 carbon atoms. Represents a group.

As used herein, the term "lower" as used herein means that the organic group has 1 to 8 carbon atoms. Suitable examples of "lower alkyl group" include methyl group, ethyl group,
Examples thereof include a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, and a hexyl group.

Suitable examples of the "lower alkenyl group" include a vinyl group, an allyl group and a 1-propenyl group, with a vinyl group being preferred. "Lower cycloalkyl group"
Is a cycloalkyl group having 3 to 6 ring carbon atoms,
Suitable examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

The "aryl group" refers to a monovalent aromatic hydrocarbon group. Suitable examples of the aryl group include a phenyl group and a tolyl group. The aryl group may be a substituted aryl group. Suitable examples of the substituted aryl group include a p-halophenyl group, (o
-, M-, or p-) mercaptophenyl group.

"Aralkyl group" refers to an aryl-substituted alkyl group. The aralkyl group is preferably a group in which the alkyl group portion has 4 or less carbon atoms, and suitable examples thereof include a benzyl group, a benzhydryl group, a trityl group, and a phenethyl group. Further, the aralkyl group may be an aryl group having a substituent in the aryl group portion. Suitable examples of the aryl group having a substituent include the same groups as described above.

The "alkyl group substituted with a monovalent heterocyclic group" is preferably a group in which an alkyl group having 4 or less carbon atoms is substituted with a monovalent heterocyclic group. As the monovalent heterocyclic group, a 5- or 6-membered ring group containing an oxygen atom, a nitrogen atom, a sulfur atom or the like is preferable. Suitable examples of the monovalent heterocyclic group include a pyrrolyl group, an imidazolyl group, a pyridyl group, an indolyl group and the like.

The compound (1) in the present invention is not particularly limited as long as it is obtained by a known method, and R ¹ of the compound (1) is preferably a lower alkyl group or an aralkyl group. Further, compound (1) is disclosed in
316072, US40071196, EP081282
7A, compound (1) produced by the method described in JP-B-6-47587, and the like, and in particular, JP-A-9-31607.
Those obtained by the method 2 are preferred.

Of these, compound (1) of the present invention
Is obtained by adding a haloformate represented by the following formula (4) to an N-substituted piperidine represented by the following formula (3) in a solvent:
Compound (1) obtained by reacting in the presence or absence of a base is preferred.

[0020]

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Wherein R ¹ and R ² in the formula each independently represent a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, an aralkyl group, an aryl group or an alkyl group substituted by a monovalent heterocyclic group. Or 1 to 6 carbon atoms
And X represents a halogen atom. R ² of compound (3) is preferably a methyl group, an ethyl group, or a t-butyl group. X of the compound (4) is preferably a chlorine atom or a bromine atom.

Specific examples of the compound (3) include the following compounds. (3R, 4R) -3- [5- (1,3
-Dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) -1-methylpiperidine, (3R, 4
R) -3- [5- (1,3-dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) -1-ethylpiperidine, (3R, 4R) -3- [5- (1 , 3-
Dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) -1- (t-butyl) piperidine.

Specific examples of compound (4) include the following compounds. Methyl chloroformate, ethyl chloroformate, t-butyl chloroformate, phenyl chloroformate, benzyl chloroformate, trifluoromethyl chloroformate, cyclohexyl chloroformate.

Solvents used in the reaction of compound (3) with compound (4) include methylene chloride, chloroform,
Diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, hexane,
Heptane, petroleum ether, methyl acetate, ethyl acetate,
N, N-dimethylformamide or N, N-dimethylacetamide is preferred, especially toluene or tetrahydrofuran.

When a base is used in the reaction between compound (3) and compound (4), the base may be an organic amine,
Alkoxides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkaline earth metal hydrides, carbonates and the like are preferred.

As the compound (1) in the present invention, a compound (1) obtained by various reactions is used, and a compound represented by the formula (3)
A reaction crude product obtained by reacting an N-substituted piperidine represented by the following with a haloformate represented by the formula (4) in a solvent in the presence or absence of a base: When there is a solid in the system, it is preferable to use a solid which is filtered or concentrated as it is. Compound (1) after concentration may be solid or oily.

Further, in order to carry out the method of the present invention efficiently, compound (1) is prepared by high performance liquid chromatography (H
The amount of impurities expressed as area% in PLC) is 5
It is preferable to use one having less than the area%. When the impurity amount in the compound (1) is 5% by area or more, the method of the present invention is repeated twice or more,
Preferably, the purity is 95% by area or more.

The compound (1) in the present invention is preferably a compound (1) in which R ¹ is a lower alkyl group.
Compound (1) in which ¹ is a methyl group, an ethyl group, or a t-butyl group is preferable.

In the present invention, first, compound (1) is made into a polar solvent solution. As the polar solvent, those having a dipole moment of 1.5 to 1.8 are preferable, and those having a dipole moment of 1.6 to 1.7 are particularly preferable. Further, the boiling point of the polar solvent solution is preferably higher than 10 ° C.

Further, as the polar solvent, a hydroxy compound represented by R ³ OH (where R ³ represents a lower alkyl group) or a mixed solvent of the hydroxy compound and water is preferable. R ³ of hydroxy compound represented by R ³ OH is a methyl group, an ethyl group or an isopropyl group is particularly preferred. In the case of a mixed solvent, the amount of water to the hydroxy compound is preferably more than 0 to 1 times by weight, particularly preferably more than 0 to 0.5 times by weight.
The amount of the polar solvent is preferably at least 4 times, more preferably 5 to 16 times the weight of the compound (1).

As a method for preparing a solution of compound (1) in a polar solvent, for example, compound (1) is added to a polar solvent,
Alternatively, there is a method in which the compound (1) is added to a polar solvent, the temperature is adjusted to an appropriate temperature, and if necessary, the compound (1) is dissolved by stirring. An appropriate temperature for preparing the polar solvent solution is preferably 10 ° C or higher and lower than the boiling point of the polar solvent, and particularly preferably 20 to 60 ° C.

Further, in the present invention, the compound (1) is crystallized from a polar solvent solution. As a method of crystallization,
It is preferably carried out by a so-called cooling method, in which the polar solvent solution is cooled to a temperature equal to or lower than the temperature at the time of dissolving the compound (1), preferably 50 ° C. lower than the temperature at the time of dissolution, and left to precipitate crystals. The method is preferred. The temperature during cooling is preferably from -20 ° C to + 20 ° C, and from -10 ° C to
+ 10 ° C is particularly preferred. The leaving time is 12 to 72.
Time is preferred, especially 24-48 hours.

Crystals of the compound (1) corresponding to the desired compound (1) may be added to the polar solvent solution as seed crystals. By adding a seed crystal, the time required for crystallization can be reduced. The amount of the seed crystal is not particularly limited.

The present invention differs from the conventional concentration method in that the compound (1) is crystallized without substantially changing the amount of the polar solvent. The rate of change in the amount of the polar solvent is preferably less than or equal to the change due to volatilization or moisture absorption. 5% by weight over the weight of the polar solvent when dissolved) is preferred, especially -2% by weight (2% by weight over the weight of the polar solvent when dissolved).
Reduced amounts) to ± 0% by weight are preferred.

The obtained crystals of compound (1) are preferably collected by a filtration method such as Kiriyama filtration and then washed with a cooled polar solvent. The temperature of the washing solution is from -20 ° C to 2
0 ° C is preferred, and -10 ° C to 10 ° C is particularly preferred. Further, the amount of the washing liquid is preferably equal to or more than 1 times the weight of the crude compound (1), and particularly preferably 1.5 to 2.0 times the weight. Further, the crystals are preferably dried, and the drying conditions are preferably at a temperature of 20 to 50 ° C. for 24 hours or more. Further, drying under vacuum conditions is preferred.

In the present invention, the compound (1) having a high purity is obtained by crystallizing the compound (1) from a polar solvent solution.
Is obtained. The high-purity compound (1) obtained by the method of the present invention preferably has an impurity amount of 0 to 0.01% when expressed as area% in HPLC. When the impurity amount is 0%, it means that substantially no impurities are detected by HPLC, that is, the compound (1) does not contain impurities that can be detected by HPLC. When the crystal purity of the compound (1) is more than 0.01%, the method of the present invention is preferably repeated according to the purpose. The crystals of the compound (1) obtained by the present invention are high-purity crystals, and thus are particularly suitable as raw materials for pharmaceuticals.

[0037]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited by these examples. In addition,
The HPLC analysis conditions described in the examples are as follows. Column: YMC ODS-AM AM-312 150
mm × 6.0 mm, I.M. D. S-5UM 120A. Eluent: 0.1% aqueous trifluoroacetic acid / acetonitrile = 1/4. Flow rate: 1 mL / min. Detector: UV (293 nm). Injection amount: 10 mL of a polar solvent solution containing compound (1) at 1 mg / mL.

Reference Example 1 Dehydrated tetrahydrofuran 20
1 g of (3S, 4R)-[5- (1,3-dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) -1-methylpiperidine was dissolved in mL, and 2.87 mL of ethyl chloroformate was added. The mixture was gradually added under ice cooling. After heating in an oil bath at 70 ° C. overnight, 4.4 g of potassium carbonate was added,
Heating was continued for 2 days. Ethanol was added to the reaction mixture, the mixture was filtered, and the filtrate was concentrated to obtain an oily ethyl carbamate compound (compound (1) wherein R ¹ is an ethyl group) of 1.22.
g was obtained.

Reference Example 2 Dehydrated tetrahydrofuran 20
1 g of (3S, 4R)-[5- (1,3-dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) -1-methylpiperidine was dissolved in mL, and 3.77 mL of phenyl chloroformate was added. The mixture was gradually added under ice cooling. 70 ° C
After heating in an oil bath overnight, 4.4 g of potassium carbonate was added and heating was continued for 2 days. Ethanol was added to the reaction mixture, followed by filtration, and the filtrate was concentrated to obtain an oily phenyl carbamate (compound (1) in which R ¹ is a phenyl group).
1.36 g were obtained.

Example 1 20 g (purity 98 area%) of the ethyl carbamate obtained in Reference Example 1 was added to ethanol 100
The mixture was added to a mixed solvent of 20 cc of water and 20 cc of water, stirred and dissolved at 25 ° C. After storing in a refrigerator kept at 5 ° C. for 30 hours, the obtained crystals were filtered and 20 cc of ethanol at 5 ° C.
The filter cake was washed with, and the filter cake was dried in vacuo for 24 hours to obtain 18 g of white crystals. As a result of analysis by HPLC, the purity was 10
It was 0 area% (that is, the impurity amount was 0 area%).
The melting point of the white crystals was 62 ° C.

Example 2 20 g of ethyl carbamate obtained in Reference Example 1 (HPLC purity 98 area%) was added to a mixed solvent of 170 cc of isopropyl alcohol and 50 cc of water, and the mixture was stirred and dissolved at 25 ° C. After storing in a refrigerator kept at 5 ° C. for 30 hours, the obtained crystals were filtered,
The filter cake was washed with 20 cc of isopropyl alcohol, and the filter cake was dried in vacuo for 24 hours to obtain 17.0 g of white crystals. As a result of analysis by HPLC, the purity was 100 area% (that is, the impurity amount was 0 area%). The melting point of the white crystals was 62 ° C.

Example 3 20 g of ethyl carbamate (HPLC purity 98 area%) obtained in Reference Example 1 was added to 100 cc of isopropyl alcohol, and the mixture was stirred and dissolved at 25 ° C. After being stored in a refrigerator kept at 5 ° C. for 30 hours, the obtained crystals were filtered, and the filter cake was washed with 20 cc of cold isopropyl alcohol at 5 ° C., and the filter cake was dried under vacuum for 24 hours to obtain 16.0 g of white crystals. I got As a result of analysis by HPLC, the purity was 100 area% (that is, the impurity amount was 0%).
Area%). The melting point of the white crystals was 62 ° C.

Example 4 20 g of compound (1) in which R ¹ is a t-butyl group (HPLC purity 95 area%) was prepared by adding 180 cc of isopropyl alcohol and 60 c of water.
The mixture was added to the mixed solvent (c), stirred and dissolved at 30 ° C. 5
After storing in a refrigerator maintained at 30 ° C. for 30 hours, the obtained crystals were filtered, the filter cake was washed with 20 cc of isopropyl alcohol at 5 ° C., and the filter cake was dried under vacuum for 24 hours to obtain 16.4 g of white crystals. Was. As a result of analysis by HPLC, the purity was 1
00 area% (that is, the impurity amount was 0 area%). The melting point of the white crystal was 76 ° C.

Example 5 20 g of the phenyl carbamate derivative obtained in Reference Example 2 (HPLC purity 98 area%) was added to 200 cc of isopropyl alcohol and stirred at 75 ° C.
And dissolved. After raising the temperature and allowing to cool naturally for 24 hours, the obtained crystals were filtered, the filter cake was washed with 20 cc of isopropyl alcohol at 5 ° C., and the filter cake was dried under vacuum for 24 hours to obtain 19.9 g of white crystals. Was. As a result of analysis by HPLC, the purity was 100 area% (that is, the impurity amount was 0 area%). The melting point of the white crystal was 107 ° C.

Example 6 20 g (purity 98 area%) of the ethyl carbamate obtained in Reference Example 1 was added to ethanol 100
The mixture was added to a mixed solvent of 20 cc of water and 20 cc of water, stirred and dissolved at 25 ° C. After adding a part of the crystals obtained in Example 1 as seed crystals and storing them in a refrigerator kept at 5 ° C. for 24 hours,
The obtained crystals were filtered, the residue was washed with 20 cc of ethanol at 5 ° C., and the residue was dried under vacuum for 24 hours.
8 g were obtained. As a result of analysis by HPLC, the purity was 100 area% (that is, the impurity amount was 0 area%). The melting point of the white crystals was 62 ° C.

Example 7 20 g (purity: 98 area%) of the ethyl carbamate obtained in Reference Example 1 was added to a mixed solvent of 170 cc of isopropyl alcohol and 50 cc of water, and the mixture was stirred and dissolved at room temperature. Some of the crystals obtained in Example 2 were added as seed crystals, and the crystals were stored in a refrigerator kept at 5 ° C. for 24 hours. The obtained crystals were filtered, and the cake was washed with 20 cc of isopropyl alcohol at 5 ° C. The filter cake was dried under vacuum for 24 hours to obtain 17.0 g of white crystals.
As a result of analysis by HPLC, the purity was 100 area% (that is, the impurity amount was 0 area%). The melting point of the white crystals was 62 ° C.

Example 8 20 g (HPLC purity 98 area%) of the ethyl carbamate obtained in Reference Example 1 was added to 100 cc of isopropyl alcohol, and the mixture was stirred and dissolved at room temperature. A part of the crystals obtained in Example 3 was added as seed crystals and stored in a refrigerator kept at 5 ° C. for 24 hours.
Wash the cake with 0 cc and dry the cake in vacuo for 24 hours.
16.0 g of white crystals were obtained. As a result of analysis by HPLC,
Purity is 100 area% (that is, impurity amount is 0 area%)
Met. The melting point of the white crystals was 62 ° C.

Example 9 20 g of compound (1) in which R ¹ is a t-butyl group (HPLC purity 95 area%) was treated with 180 cc of isopropyl alcohol and 60 c of water.
The resulting mixture was added to the mixed solvent (c), stirred and dissolved at room temperature. A part of the crystal obtained in Example 4 was added as a seed crystal and stored in a refrigerator kept at 5 ° C for 24 hours. The obtained crystal was filtered, and the cake was washed with 20 cc of isopropyl alcohol at 5 ° C. The cake was dried under vacuum for 24 hours, and white crystals 1
6.4 g were obtained. As a result of analysis by HPLC, the purity was 10
It was 0 area% (that is, the impurity amount was 0 area%).
The melting point of the white crystal was 76 ° C.

Example 10 20 g (HPLC purity 98 area%) of the phenyl carbamate derivative obtained in Reference Example 2 was added to 200 cc of isopropyl alcohol, and the mixture was stirred for 75 minutes.
The temperature was raised to ° C. to dissolve. After stopping the temperature rise and cooling to 50 ° C., a part of the crystal obtained in Example 5 was added as a seed crystal and left at 24 ° C. for 24 hours while maintaining the temperature at 20 ° C. The obtained crystals were filtered, and the filter cake was washed with 20 cc of isopropyl alcohol at 5 ° C., and the filter cake was dried under vacuum to obtain 19.9 g of white crystals.
I got As a result of analysis by HPLC, the purity was 100 area%.
(That is, the amount of impurities was 0 area%). The melting point of the white crystal was 107 ° C.

[0050]

According to the method of the present invention, the compound (1) obtained in the production process is added with a polar solvent and left alone,
Highly pure crystals of the compound (1) can be obtained. The crystal of compound (1) obtained by the method is a high-purity crystal containing substantially no impurities. Therefore, the crystals of compound (1) obtained by the method of the present invention are high-quality compounds as intermediates of pharmaceuticals. When the reaction is carried out using crystals of the compound (1), there are advantages that the reaction can be carried out efficiently and an extra purification step can be omitted.
Further, the crystals of compound (1) obtained by the method of the present invention are useful as intermediates of various useful pharmaceuticals.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Masahiro Urushihara 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Inside Asahi Glass Co., Ltd. F term (reference) 4C063 AA01 BB08 CC81 DD10 EE01 EE05 4C086 AA04 BC21 GA02 GA07 NA06 ZA02 ZA12 ZC41

Claims (8)

[Claims] 1. A method of preparing a carbamate represented by the following formula (1) as a polar solvent solution, and then crystallizing the carbamate from the polar solvent solution without substantially changing the amount of the polar solvent. A method for producing a carbamate crystal. Here, R ¹ in the formula (1) represents a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, an aralkyl group, an aryl group, an alkyl group substituted with a monovalent heterocyclic group, or a C 1-6 alkyl group. Represents a perfluoroalkyl group. Embedded image 2. A reaction of an N-substituted piperidine represented by the following formula (3) with a haloformate represented by the following formula (4) in a solvent in the presence or absence of a base. The production method according to claim 1, wherein the carbamates obtained by the reaction are used as a polar solvent solution. However, R ¹ and R ² in the formula
Each independently represents a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, an aralkyl group, an aryl group, an alkyl group substituted with a monovalent heterocyclic group, or a perfluoroalkyl group having 1 to 6 carbon atoms. , X represents a halogen atom. Embedded image 3. The method according to claim 1, wherein seed crystals of carbamates are added to the polar solvent solution. 4. The method according to claim 1, wherein the boiling point of the polar solvent solution is higher than 10 ° C. 5. The method according to claim 3, wherein the temperature at which the polar solvent solution is formed is 10 ° C. or higher and lower than the boiling point of the polar solvent. 6. The method according to claim 1, wherein R ¹ is a methyl group, an ethyl group, a t-butyl group, or a phenyl group. 7. A hydroxy compound represented by R ³ OH (where R ³ represents a lower alkyl group);
Alternatively, the production method according to any one of claims 1 to 6, which is a mixed solvent of the hydroxy compound and water. 8. The process according to claim 1, wherein the amount of impurities contained in the carbamate crystals is 0 to 0.01% (area% in high performance liquid chromatography).