JP2006022045A - METHOD FOR ISOLATING AND PURIFYING OPTICALLY ACTIVE 1-t-BUTOXYCARBONYL-3-AMINOPYRROLIDINE SALT - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for isolating and purifying an optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt, by which the highly pure optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt can be obtained in a high yield and by which the production of the salt can simply and efficiently be performed in a commercial scale. <P>SOLUTION: This method for isolating and purifying the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt is characterized by forming a salt from the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine and an acid, crystallizing the salt, and isolating the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt as the crystals to leave contaminated impurities such as enantiomer and 1-t-butoxycarbonyl-3-t-butoxycarbonyl-aminopyrrolidine in the mother liquor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for isolating and purifying optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt useful as a pharmaceutical intermediate.

The following methods are known as methods for producing and isolating and purifying optically active 1-t-butoxycarbonyl-3-aminopyrrolidine.
(1) Optically active 1-t-butoxycarbonyl-3-aminopyrrolidine is produced by selectively t-butoxycarbonylating the amino group at position 1 of optically active 3-aminopyrrolidine. A method of isolating and purifying the filtrate concentrate by distillation after repeating the operation of concentration and filtering off the precipitated inorganic salt (Patent Document 1)
(2) Optically active 1-t-butoxycarbonyl-3-aminopyrrolidine is produced by selectively t-butoxycarbonylating the amino group at the 1-position of optically active 3-aminopyrrolidine. A method of distilling off the solvent, adding an acidic aqueous solution and washing with an organic solvent, adjusting the reaction solution to basic, extracting, and further concentrating under reduced pressure (Patent Document 2)
(3) Hydrogenolysis of optically active 1-t-butoxycarbonyl-3- (benzyloxycarbonylamino) pyrrolidine in the presence of a palladium catalyst, the catalyst is filtered off, the filtrate is concentrated, and silica gel column chromatography is performed. (PTL 3)
(4) A method in which optically active 1-t-butoxycarbonyl-3- (trifluoroacetylamino) pyrrolidine is hydrolyzed with lithium hydroxide and then neutralized, and the reaction solution is concentrated (Non-patent Document 1).
(5) A method in which optically active 1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine is reacted with ammonia, methylene chloride is added to the reaction solution, the precipitated salt is filtered off, and the filtrate is concentrated ( Patent Document 4)
However, in the conventional technique (1), it is necessary to repeat complicated concentration and filtration operations before distillation, and in the conventional techniques (2), (4), and (5), only inorganic salts and the like are removed by extraction and filtration operations. Therefore, a high purification effect cannot be expected. In the prior art (3), purification is performed by expensive and complicated silica gel column chromatography, which is difficult to implement on a commercial scale. Furthermore, what is common to these methods is that it cannot be purified at all when optical isomers are mixed.

Under such circumstances, an isolation and purification method suitable for production on a commercial scale of the compound (1) useful as a pharmaceutical intermediate has a particularly important significance, not only for improving chemical purity. At the same time, it is desired to establish an isolation and purification method capable of improving the optical purity.
WO03 / 055858 JP 2002-275155 A WO04 / 013097 JP 2000-53642 A J. et al. Med. Chem. 2001, 44, 2933-2949

  In view of the above situation, the present invention provides an isolation and purification method capable of obtaining high-quality optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine in a high yield and capable of being carried out easily and efficiently on a commercial scale. The purpose is to do.

  The inventors of the present invention have found that a contaminated impurity can be efficiently removed by forming a salt from 1-t-butoxycarbonyl-3-aminopyrrolidine and an acid and crystallization.

  That is, the present invention provides the following formula (1);

（式中、＊は不斉炭素原子を表す。）で表される光学活性な１−ｔ−ブトキシカルボニル−３−アミノピロリジンと酸から塩を形成させ、晶析することによって、混入している不純物を母液に残し、該塩を結晶として取得することを特徴とする、光学活性な１−ｔ−ブトキシカルボニル−３−アミノピロリジン塩の単離精製方法である。

(In the formula, * represents an asymmetric carbon atom.) A salt is formed from an optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) and an acid, and is mixed by crystallization. A method for isolating and purifying an optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine salt, wherein impurities are left in a mother liquor and the salt is obtained as crystals.

  According to the present invention, high-quality optically active 1-t-butoxycarbonyl-3-aminopyrrolidine can be obtained in high yield, and 1-t-butoxycarbonyl-3-aminopyrrolidine can be obtained easily and efficiently on a commercial scale. Can be isolated and purified.

  The present invention is described in detail below.

  The optically active 1-t-butoxycarbonyl-3-aminopyrrolidine used in the present invention is represented by the following formula (1);

で表される。式中、＊は不斉炭素原子を表す。前記化合物（１）は例えば、特開２０００−５３６４２や特表平０７−５０６１１０に記載の方法にて得られた光学活性な１−ベンジル−３−アミノピロリジンのベンジル基を脱保護することにより、光学活性３−アミノピロリジンを取得し、これをＷＯ０３／０５５８５８や特開２００２−２７５１５５に記載の方法にて１位のアミノ基を選択的にｔ−ブトキシカルボニル化することにより、簡便に製造することができる。

It is represented by In the formula, * represents an asymmetric carbon atom. The compound (1) can be obtained by, for example, deprotecting the benzyl group of optically active 1-benzyl-3-aminopyrrolidine obtained by the method described in JP-A-2000-53642 or JP-T-07-506110. An optically active 3-aminopyrrolidine is obtained, which is easily produced by selectively t-butoxycarbonylating the amino group at the 1-position by the method described in WO03 / 055858 or JP-A-2002-275155. Can do.

  The optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine used in the present invention contains various impurities depending on the production method. Examples of the impurities include optically active 1-tert-butoxycarbonyl-3-amino. Pyrrolidine enantiomer, and the following formula (2);

（式中、＊は前記に同じ）で表される光学活性な１−ｔ−ブトキシカルボニル−３−ｔ−ブトキシカルボニルアミノピロリジンなどが考えられる。

An optically active 1-t-butoxycarbonyl-3-t-butoxycarbonylaminopyrrolidine represented by the formula (wherein * is the same as above) can be considered.

  It is known that the compound (2) is mixed as an impurity when manufactured by the method described in WO03 / 055858 or JP-A-2002-275155. Further, in the method described in JP-A-2000-53642, the compound (1) is produced by amination of optically active 1-t-butoxycarbonyl-3- (methanesulfonyloxy) pyrrolidine with ammonia. Since the compound (1) obtained by this method is partially mixed with enantiomers (enantiomers), only those having low optical purity can be obtained.

  In general, it is difficult to remove impurities (analogous substances) having a similar structure, and it has been necessary to develop an excellent isolation and purification method in order to obtain the high-quality target product by removing the impurity group. As a result of intensive studies, the inventors of the present invention have formed a salt from the compound (1) and an acid, and crystallized to cause impurities, especially the enantiomer of the compound (1) and the compound (2). ) Was left in the mother liquor and the salt was obtained as crystals, leading to the development of a method for isolating optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine as a salt.

  The acid used in the present invention is classified into an optically active acid and a non-optically active acid. Examples of the optically active acid include sulfonic acids such as camphorsulfonic acid; carboxylic acids such as malic acid, mandelic acid, and tartaric acid. A nitrogen-protected amino acid such as N- (benzenesulfonyl) phenylalanine; Preferably, it is a non-optically active acid which can be obtained at low cost, for example, mineral acids such as hydrogen chloride, hydrogen bromide, phosphoric acid and sulfuric acid; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; Examples thereof include carboxylic acids such as acids. Among them, hydrogen chloride, hydrogen bromide, methanesulfonic acid, or acetic acid is preferable from the viewpoint of high yield and low hygroscopicity of the obtained crystal, and from the viewpoint of good crystal filterability, hydrogen chloride, Or acetic acid is particularly preferred. These acids can be used alone or in combination of two or more. As these acids, for example, acid aqueous solutions such as hydrochloric acid and hydrobromic acid which are easy to handle may be used.

  The amount of the acid used is not particularly limited, but an amount that can form a salt with the optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) and precipitate as crystals is used. From the viewpoint of obtaining an excellent purification effect with a good yield, the optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) is preferably 0.1. -3 times molar amount, more preferably 0.5-1.5 times molar amount, and still more preferably 0.8-1.2 times molar amount.

  The isolation and purification method of the present invention is preferably carried out in a solvent. The solvent that can be used in the present invention is an organic solvent, for example, alcohols such as isopropanol, ethanol, and methanol; polyhydric alcohols such as ethylene glycol and propylene glycol; fatty acid esters such as ethyl acetate and methyl acetate; Hydrocarbons such as toluene and hexane; Ethers such as diethyl ether, tetrahydrofuran and methyl t-butyl ether; Polyethers such as glyme; Halogenated hydrocarbons such as methylene chloride; Amides such as dimethylformamide; Dimethyl sulfoxide and the like The sulfoxides can be mentioned. Preferred are fatty acid esters, hydrocarbons, and alcohols, and more preferred are ethyl acetate, toluene, hexane, isopropanol, and ethanol. These solvents may be used alone or in combination of two or more. Moreover, what is necessary is just to select suitably the kind, usage-amount, and mixing ratio of these solvents according to the solubility of the salt to acquire.

Next, the method for crystallizing the salt formed from the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) and an acid is not particularly limited. Is mentioned.
(A) A method in which an optically active 1-t-butoxycarbonyl-3-aminopyrrolidine and an aqueous solution of an acid are mixed and then concentrated to distill off water to cause crystallization. In this case, a solvent that can azeotrope with water (for example, ethyl acetate, toluene, etc.) can be used, and water can be more efficiently distilled off due to the azeotropic effect.
(B) A method of crystallizing optically active 1-t-butoxycarbonyl-3-aminopyrrolidine by mixing with an acid in a solvent.
(C) Optically active 1-t-butoxycarbonyl-3-aminopyrrolidine and an acid are mixed in a solvent, or 1-t-butoxycarbonyl-3-aminopyrrolidine salt is dissolved in a solvent and then cooled. And crystallizing.
(D) A method in which an optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt is dissolved in a solvent, and then crystallized by adding a poor solvent or concentrating to the poor solvent.

  The crystallization method may be appropriately selected depending on the combination of the acid type and the solvent. For example, since hydrogen chloride or hydrogen bromide is easier to handle with hydrochloric acid or hydrobromic acid which is an aqueous solution thereof, the method (a) is suitable, and methanesulfonic acid, acetic acid and the like are usually used. In the case of using an acid that is easy to use as a non-hydrous material, it is preferable to select the method (b). Furthermore, the salt suspension obtained by the method (a) or (b) is re-dissolved by the method (c) and then cooled and crystallized, etc. (a), (b), Crystallization can also be performed by appropriately combining the methods (c) and (d).

  Examples of the solvent used in the crystallization method include the same solvents as those described above, and examples of the poor solvent used in the method (d) include toluene and hexane.

  Examples of the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt in the methods (c) and (d) include the optically active 1-t once obtained by the methods (a) and (b). -Butoxycarbonyl-3-aminopyrrolidine and a salt formed from an acid may be used, and it is produced by coexisting an acid in producing optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine. Alternatively, an optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt may be used.

  In addition, when the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt is dissolved in a solvent, for example, heating or the like can be performed. The heating temperature in that case is not particularly limited, but may be appropriately set at a temperature equal to or higher than the temperature at which the optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine salt is dissolved in the solvent species or mixed solvent species to be used. In addition, seed crystals may be added during crystallization.

  The implementation temperature in the crystallization methods (a) to (d) is not particularly limited, but may be appropriately selected depending on the type of salt and the type of solvent used. What is necessary is just to set according to the target precipitation amount and the quality of a crystal | crystallization below the temperature which active 1-t-butoxycarbonyl-3-aminopyrrolidine salt melt | dissolves.

The crystals of the optically active 1-t-butoxycarbonyl-3-aminopyrrolidine salt precipitated by the crystallization methods (a) to (d) are separated by a method such as vacuum filtration, pressure filtration, or centrifugation, Can be acquired. Further, when the mother liquor remains in the acquired crystal and the purity of the crystal is lowered, the quality can be improved by further washing with a solvent, if necessary.
As a method for drying the crystals, it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less while avoiding thermal decomposition and melting.

  The optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine salt obtained by the above method has improved chemical purity as well as optical purity, and can be used as a raw material for a pharmaceutical intermediate as it is. By treating with a base such as an alkali metal, the optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the above formula (1) is liberated, and operations such as extraction, concentration, etc. are carried out. The compound (1) having improved purity and optical purity can also be obtained.

    Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

  The optical purity in the following examples was determined by the following method. After mixing about 10 mg of 1-t-butoxycarbonyl-3-aminopyrrolidine salt with 2 ml of isopropanol and 100 mg of triethylamine, 15 mg of dibenzyl dicarbonate was added and stirred for about 30 seconds, and 20 ml of hexane was added thereto to prepare a sample solution. 5 μL was injected into the HPLC, and the optical purity was calculated from the area ratio. CHIRALPACK OD-H (Daicel) 4.6 mmΦ × 250 mm was used for the analytical column. Hexane / isopropanol (95/5 (volume ratio)) was used as the mobile phase, the flow rate was 1.0 mL / min, the column temperature was 30 ° C., and the detection was performed at UV254 nm. The retention time of (S) -1-t-butoxycarbonyl-3-benzyloxycarbonylaminopyrrolidine is 16.0 minutes, and the retention time of (R) -1-t-butoxycarbonyl-3-benzyloxycarbonylaminopyrrolidine is 12. 8 minutes.

(Reference Example 1)
After mixing 20.8 g of 3-trifluoroacetylaminopyrrolidine hydrochloride sold by Tokyo Chemical Industry Co., Ltd., 18.2 ml of N, N-diisopropylethylamine and 250 ml of methylene chloride, di-t-butyl dicarbonate 20 .8 g of methylene chloride (25 ml) solution was added slowly. After stirring at room temperature for 2 hours, 300 ml of saturated aqueous sodium carbonate solution and 500 ml of methylene chloride were added for extraction. The aqueous layer was extracted with 500 ml of methylene chloride, the organic layers were mixed, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 12.2 g of 1-t-butoxycarbonyl-3-aminopyrrolidine. This had a chemical purity of 98.2% by weight and an optical purity of 89.5% ee. (S body excess).

Example 1
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 5 mL of ethyl acetate. To this, 0.28 g of concentrated hydrochloric acid (1.0 molar equivalent relative to 1-t-butoxycarbonyl-3-aminopyrrolidine) was added. The solution was concentrated under reduced pressure, 15 mL of ethyl acetate was added to the concentrate, and the mixture was concentrated again. When 5 mL of ethyl acetate is added to the resulting concentrate, crystals are precipitated. After stirring at room temperature for 1 hour, the crystals are filtered under reduced pressure and dried under vacuum to give hydrochloric acid of 1-tert-butoxycarbonyl-3-aminopyrrolidine. 0.43 g of salt was obtained. The optical purity was improved to 98.3% ee.

(Example 2)
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 5 mL of ethyl acetate. To this, 0.16 g of acetic acid (1.0 molar equivalent relative to 1-t-butoxycarbonyl-3-aminopyrrolidine) was added. This solution was concentrated under reduced pressure, and 20 mL of hexane was added to the concentrate to precipitate crystals. After stirring at room temperature for 1 hour, the crystals were filtered off under reduced pressure and vacuum-dried to obtain 0.57 g of 1-t-butoxycarbonyl-3-aminopyrrolidine acetate. The optical purity was improved to 93.0% ee.

Example 3
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 5 mL of ethanol. To this was added 0.26 g of methanesulfonic acid (1.0 molar equivalent based on 1-t-butoxycarbonyl-3-aminopyrrolidine). The solution was concentrated under reduced pressure, and 10 mL of ethyl acetate was added to the concentrate to precipitate crystals. After stirring at room temperature for 1 hour, the crystals were filtered off under reduced pressure and vacuum dried to obtain 0.66 g of 1-t-butoxycarbonyl-3-aminopyrrolidine methanesulfonate. The optical purity was improved to 91.1% ee.

Example 4
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 5 mL of ethanol. To this was added 0.28 g of hydrochloric acid (1.0 molar equivalent with respect to 1-t-butoxycarbonyl-3-aminopyrrolidine). This solution was concentrated under reduced pressure, 15 mL of ethanol was added to the concentrate, and the mixture was concentrated again. When 10 mL of ethyl acetate was added to the resulting concentrate, crystals were precipitated. After stirring at room temperature for 1 hour, the crystals were filtered off under reduced pressure and vacuum dried to obtain 0.42 g of 1-t-butoxycarbonyl-3-aminopyrrolidine hydrochloride. The optical purity was improved to 96.9% ee.

(Example 5)
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 5 mL of ethyl acetate. To this was added 0.14 g of acetic acid (0.9 molar equivalents relative to 1-t-butoxycarbonyl-3-aminopyrrolidine). When 25 mL of hexane is added to this solution, crystals are precipitated. After stirring at room temperature for 1 hour, the crystals are filtered off under reduced pressure and dried under vacuum to give 1-tert-butoxycarbonyl-3-aminopyrrolidine acetate as a salt. 55 g was obtained. The optical purity was improved to 94.6% ee.

(Example 6)
0.50 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 98.2% by weight and an optical purity of 89.5% ee (S-form excess) was dissolved in 10 mL of ethyl acetate. To this was added 0.14 g of acetic acid (0.9 molar equivalents relative to 1-t-butoxycarbonyl-3-aminopyrrolidine). When 15 mL of hexane was added to this solution, crystals were precipitated. This was heated to 50 ° C. to dissolve the crystals, and then gradually cooled to 5 ° C. to precipitate crystals. After stirring for 1 hour, the crystals were filtered off under reduced pressure and dried under vacuum to obtain 0.57 g of 1-t-butoxycarbonyl-3-aminopyrrolidine acetate. The optical purity was improved to 91.6% ee.

(Example 7)
1-t-butoxy having a chemical purity of 81.8% by weight (containing 16.8% by weight of 1-t-butoxycarbonyl-3-t-butoxycarbonylaminopyrrolidine) and optical purity of 89.5% ee (S-form excess) 0.60 g of carbonyl-3-aminopyrrolidine was dissolved in 5 mL of ethyl acetate. To this was added 0.14 g of acetic acid (0.9 molar equivalents relative to 1-t-butoxycarbonyl-3-aminopyrrolidine). When 15 mL of hexane was added to this solution, crystals were precipitated. After stirring at room temperature for 1 hour, the crystals were filtered off under reduced pressure. To the obtained crystals, 10 mL of ethyl acetate, 2 mL of water, and 0.53 g of 30% aqueous sodium hydroxide solution were added, and the aqueous layer was removed. The organic layer was concentrated under reduced pressure to obtain 0.35 g of 1-t-butoxycarbonyl-3-aminopyrrolidine. The chemical purity was 98.6% by weight, 1-t-butoxycarbonyl-3-t-butoxycarbonyl-aminopyrrolidine was completely removed, and the optical purity was improved to 96.9% ee.

(Example 8)
0.46 g of 1-t-butoxycarbonyl-3-aminopyrrolidine having a chemical purity of 80.2 wt% and an optical purity of 96.6% ee was dissolved in 4 mL of isopropanol, and 0.21 g of concentrated hydrochloric acid (1-t-butoxycarbonyl- 1.0 molar equivalents relative to 3-aminopyrrolidine) was added and concentrated under reduced pressure. When 8 mL of ethyl acetate was added to the concentrate, crystals precipitated. After stirring at 25 ° C. for 10 minutes, the crystals were filtered under reduced pressure and dried under vacuum to give hydrochloride of 1-t-butoxycarbonyl-3-aminopyrrolidine. 0.41 g was obtained. The optical purity was improved to 99.0% ee. 0.35 g of this crystal was dissolved in 2 mL of isopropanol and concentrated under reduced pressure. When 8 mL of ethyl acetate was added to the concentrate, the crystal was precipitated, and stirred at 25 ° C. for 10 minutes. The wet crystals were washed with This was vacuum-dried to obtain 0.34 g of 1-t-butoxycarbonyl-3-aminopyrrolidine hydrochloride. The optical purity was improved to 99.7% ee.

Claims (5)

Following formula (1);

(In the formula, * represents an asymmetric carbon atom.) A salt is formed from an optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) and an acid, and is mixed by crystallization. A method for isolating and purifying an optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine salt, wherein impurities are left in a mother liquor and the salt is obtained as crystals.   The isolation and purification method according to claim 1, wherein the acid is a non-optically active acid.   The isolation and purification method according to claim 2, wherein the non-optically active acid is hydrogen chloride, hydrogen bromide, methanesulfonic acid, or acetic acid.   The isolation and purification method according to claim 2, wherein the non-optically active acid is hydrogen chloride or acetic acid. The contaminated impurity is an enantiomer of optically active 1-tert-butoxycarbonyl-3-aminopyrrolidine represented by the formula (1) and / or the following formula (2);

(Wherein * represents an asymmetric carbon atom), which is an optically active 1-t-butoxycarbonyl-3-t-butoxycarbonylaminopyrrolidine represented by any one of claims 1 to 4. Isolation and purification method.