JP2017104053A - Method for producing halogenolactone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing (1S,4S,5S)-4-halogeno-6-oxabicyclo[3.2.1]octane-7-one [a compound (1-X)] which is an intermediate for synthesis of a compound expressing the inhibitory action of activated blood coagulation factor X.SOLUTION: There is provided a method for producing a compound (1-X) by optically resolving a racemic form which is a compound (1-X-rac) with an esterase in the presence of a solvent and a pH adjuster. Preferably, there is provided a production method in which a solvent is water and a pH adjuster is potassium carbonate. Preferably, there is provided a production method in which the pH in the optically resolving process is maintained in the range of 7 to 8. (X represents a bromine atom or an iodine atom.)SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an intermediate compound in the production of a compound that exhibits an inhibitory action on activated blood coagulation factor X (hereinafter sometimes referred to as FXa) and is useful as a preventive and / or therapeutic agent for thrombotic diseases. About.

Examples of compounds that exhibit FXa inhibitory action and are useful as preventive and / or therapeutic agents for thrombotic diseases include, for example, N ^1- (5-chloropyridin-2-yl) -N ² represented by the following formula (I): -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] amino} cyclohexyl) ethanediamide, or a monohydrate of the p-toluenesulfonate salt represented by the following formula (II) is known (for example, Patent Document 2-5).

  As an intermediate compound for the production of these FXa inhibitor compounds, compound (1-I)

(1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one represented by the formula is known (for example, see Patent Document 1-5 and Non-Patent Document 1). . Further, the compound (1-Br) which is a bromo derivative of the compound (1-I)

(1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octane-7-one represented by the formula (2)

It is reported that the compound can be synthesized by a halogeno lactonization (bromo lactonization) reaction of an optically active (S) -3-cyclohexene-1-carboxylic acid represented by (for example, see Non-Patent Document 2) (for example, (See Patent Document 3-7).

  Further, as shown in the following scheme, an optically active salt compound (2−2) obtained by fractional recrystallization of a salt compound obtained from a racemic compound (2-r) and an optically active amine compound (3). A method for producing compound (1-Br) via s) is known (see, for example, Patent Documents 6 and 7).

  Also, as shown in the following scheme, a method for producing a salt / monohydrate represented by the formula (II) from the compound (1-Br) is known (see, for example, Patent Document 6).

International Publication No. 2003/000657 Pamphlet International Publication No. 2003/000680 Pamphlet International Publication No. 2003/016302 Pamphlet International Publication No. 2004/058715 Pamphlet International Publication No. 2001/074774 Pamphlet International Publication No. 2014/157612 Pamphlet International Publication No. 2014/081047 pamphlet

K. Miyashita et al., Tetrahedron, 67 (11), 2011, 2044-2050. H.M.Schwartz et al., J. Am. Chem. Soc., 100, 5199-5203, 1978. F. Chen et al., Tetrahedron Letters, 51 (6), (2010), 3433-3435. M. Chini et al., Tetrahedron, 48 (3), 539-544, 1992. Y. Fujimoto et al., Heterocycles, 23 (8), 2035-2039, 1985. C. Iwata et al., Heterocycles, 31 (6), 987-991, 1990. J.C.S., Perkin Trans. 1, (1994), 7,847-51.

  An object of the present invention is to provide (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane-7-one (compound (1-I)) which is important as an intermediate compound for the production of FXa inhibitor compounds Or a method for efficiently producing (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octane-7-one (referred to as compound (1-Br)). Is to provide.

  The compound (1-I) and the compound (1-Br) are collectively referred to as the compound (1-X).

As a result of earnest examination on the production method of the compound (1-X) known so far,
(1) The conventional methods have found that the efficiency of optical resolution by the optically active amine compound (3) is low, and in order to obtain high optical purity, repeated crystallization must be performed.
(2) The optically active salt compound (2-s) has also been found to require a step for making it free, which is a cause of low efficiency.
(3) Furthermore, in the process of making free, it was necessary to use a halogenated solvent, and it was found that there is room for improvement as an environmental measure.

In order to overcome these problems, the present inventors first performed a halogenolactone reaction, and obtained the racemic 4-iodo-6-oxabicyclo [3.2.1] octane-7-one. (Referred to as compound (1-I-rac)) or 4-bromo-6-oxabicyclo [3.2.1] octane-7-one (referred to as compound (1-Br-rac)) The compound (1-X-rac)) was efficiently resolved to produce an optically active compound (1-X) by enzymatic kinetic resolution, and the present invention was completed.
That is, the present invention provides the following inventions.

[1] Compound (1-X)

(In the formula, X represents a bromine atom or an iodine atom.)
Wherein the compound (1-X-rac)

(In the formula, X represents a bromine atom or an iodine atom.)
The compound (1-X) is produced by optically resolving the racemic compound, which is a compound, with an esterase in the presence of a solvent and a pH adjuster.

[2] Compound (1-Br)
A compound (1-Br-rac)

The compound (1-Br) is produced by optically resolving the racemic compound, which is a compound, with an esterase in the presence of a solvent and a pH adjuster.
[3] The production method according to [1] or [2], wherein the solvent in the optical resolution is water.
[4] The production method according to any one of [1] to [3], wherein the pH adjuster in the optical resolution is potassium carbonate.
[5] The production method according to any one of [1] to [4], provided that the pH in the optical resolution is maintained in the range of 7-8.
[6] Compound (1-X)

(In the formula, X represents a bromine atom or an iodine atom.)
A method of manufacturing
(1) After producing the compound (1-X-rac) by stirring the compound (2) in the presence of a solvent and a halogenating agent,

(In the formula, X represents a bromine atom or an iodine atom.)
(2) A method for producing a compound (1-X) by optically resolving a racemate which is the compound (1-X-rac) with an esterase in the presence of a solvent and a pH adjuster.

(In the formula, X represents a bromine atom or an iodine atom.)

[7] Compound (1-Br)

A method of manufacturing
(1) After producing the compound (1-Br-rac) by stirring the compound (2) in the presence of a solvent and a brominating agent,

(2) A method for producing a compound (1-Br) by optically resolving a racemate which is the compound (1-Br-rac) with an esterase in the presence of a solvent and a pH adjuster.

[8] The production method according to [6] or [7], wherein the solvent in (1) is water.
[9] The method according to [7] or [8], wherein the brominating agent in (1) is 1,3-dibromo-5,5-dimethylhydantoin.
[10] The method according to any one of [6] to [9], wherein the solvent in (2) is water.
[11] The production method according to any one of [6] to [10], wherein the pH adjuster in (2) is potassium carbonate.
[12] The production method according to any one of [6] to [11], provided that the pH in (2) is maintained in the range of 7-8.
[13] After the compound (1-Br) is produced by the method according to any one of [2]-[5] or the method according to any one of [7]-[12], the compound ( A method for producing p-toluenesulfonate monohydrate represented by the formula (II) using 1-Br).

  The present invention provides a method for efficiently producing compound (1-X), which is important as an intermediate compound for producing an FXa inhibitor compound.

  As a feature of this production method, there is an advantage that an inexpensive solvent such as water can be used in the process of producing the compound (1-X-rac) from the compound (2), and crystallization can be performed in one pot. . In addition, in the step of producing the compound (1-X) from the compound (1-X-rac), the reaction can be performed with an inexpensive solvent such as water, and the compound (1-X) has high stereoselectivity. After the reaction, the compound (1-X) can be easily obtained only by filtration.

  Hereinafter, the present invention will be described in detail.

(In the formula, X represents a bromine atom or an iodine atom.)

[Step 1] Halogenolactonization step This step is a step for producing compound (1-X-rac) from compound (2), and is a step carried out by reacting in a solvent in the presence of a reagent.
The reagent used in this step is a halogenating agent, and the iodinating agent is iodine (preferably used is 1.0-1.2 eq, more preferably 1.0), and the brominating agent is Is N-bromosuccinimide (1.0-1.2 eq is preferable and 1.0 is more preferable) or 1,3-dibromo-5,5-dimethylhydantoin ( 0.4-0.6 eq, more preferably 0.5 eq).
The solvent used in this step is water, preferably 1-10 vol., More preferably 1 vol.
The reaction temperature in this step is preferably -25-10 ° C, more preferably -10 ° C.
The reaction time in this step is preferably about 1 hour, more preferably about 10 minutes.

[Step 2] Kinetic optical resolution step with enzyme This step is a step of producing compound (1-X) by optical resolution of compound (1-X-rac) with enzyme, and the enzyme and neutralizing agent The reaction is carried out by reacting in a solvent in the presence of. Only one optical isomer is selectively hydrolyzed by the enzyme to give a hydroxy-carboxylic acid derivative. Since only the hydroxy-carboxylic acid derivative remains in the aqueous layer, both isomers can be easily separated by a liquid separation operation.
The enzyme used in this step is preferably an esterase, more preferably a pig liver-derived esterase or a genetically modified esterase. Specifically, the esterase AC “Amano” is an esterase described in the Examples. ”, PLE (pig liver-derived esterase) manufactured by Roche and the like.
The neutralizing agent used in this step is preferably potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or the like.
The solvent used in this step is water, preferably 3-10 vol., More preferably 3 vol.
The reaction temperature in this step is preferably 30-40 ° C, more preferably 30 ° C.
The reaction time in this step depends on the amount of enzyme used (0.01 wt-0.05 wt), but is preferably about 11-52 hours.

[Step 3] Purification step This step is a step in which the compound (1-X) obtained in Step 2 is heated and dissolved in a solvent and then purified by crystallization to improve the purity.
The solvent used in this step is acetone, and the amount used is preferably 5-10 vol, more preferably 6 vol.
In this step, the temperature for heating and dissolving the compound (1-X) in a solvent is preferably about 60 ° C., and crystallization is performed by lowering the temperature to about 0-25 ° C.
In this step, the time for heating and dissolving the compound (1-X) in the solvent is about 1 hour, and then the temperature is gradually lowered to crystallize in about 1 hour.

  Examples are described below, but the present invention is not limited thereto.

  The optical purity (% ee) of the obtained compound was determined by HPLC analysis using an optically active column. Detailed analysis conditions are as follows.

[Optical purity analysis conditions]
Eluent: n-hexane: 2-propyl alcohol (IPA) = 98: 2 (% v / v)
Column: CHIRALPAK AD-H (250X4.6) mm, 5μm
Flow rate: 1.0 mL / min.
Detection: UV at 215 nm
Injection volume: 40 μL
Column temperature: 35 ° C
Tray temperature: 25 ° C
Analysis time: 30 minutes Sample preparation: About 100 mg of compound (1-Br) was dissolved in 10 mL of IPA to prepare a sample solution.
Retention time: Compound (1-Br): 12 minutes, Compound (1-Br) enantiomer: 14 minutes

Example 1 First Step (Bromolactone Step)
4-Bromo-6-oxabicyclo [3.2.1] octane-7-one: Compound (1-Br-rac)
Add 123.9 mL (1 equivalent, 1.585 mol) of 48% aqueous potassium hydroxide to 200 mL of water, add 200 g (1.585 mol) of 3-cyclohexene-1-carboxylic acid dropwise, and add 1,3-dibromo-5,5-dimethyl Hydantoin 226.7g (0.5 equivalent, 0.793mol) was added over about 3 hours at -10 degrees C or less, and it stirred at 0 degreeC for 1 hour.
An aqueous solution obtained by dissolving 40.0 g of sodium sulfite (0.2 equivalent, 0.317 mol) in 200 mL of water was added dropwise to the reaction solution, stirred for 1 hour at 30 ° C., the crystals were filtered, washed with 400 ml of water, and dried under reduced pressure. As a result, 165.5 g (yield 51%) of the title compound was obtained.

(Example 2) First step (bromolactonization step): (using N-bromosuccinimide)
4-Bromo-6-oxabicyclo [3.2.1] octane-7-one: Compound (1-Br-rac)
To 20 mL of water was added 1 M sodium hydroxide aqueous solution 7.9 mL (1 equivalent, 7.925 mmol), 3-cyclohexene-1-carboxylic acid 1 g (7.925 mmol) was added dropwise, and N-bromosuccinimide 1.41 g (1.0 equivalent, 7.925 mmol) was added at 5 ° C. or lower and stirred at 0 ° C. for 30 minutes. The crystals were filtered, washed with 10 ml of water and dried under reduced pressure to give 710 mg (44% yield) of the title compound. Got in.

Example 3 Second Step (Kinetic Optical Resolution Process with Enzyme): Esterase AC “Amano”
(1S, 4S, 5S) -4-Bromo-6-oxabicyclo [3.2.1] octane-7-one: Compound (1-Br) crude crystal
4-Bromo-6-oxabicyclo [3.2.1] octane-7-one and 30.0 g (0.1463 mmol) of compound (1-Br-rac) were added to 90 mL of water, and the mixture was stirred at 30 ° C., and esterase AC “Amano” (1.5 g, 0.05 wt) was added. During the reaction, 1M-aqueous potassium carbonate solution was added dropwise so as to maintain pH = 7-8, and the mixture was stirred for 11 hours.
The crystals were filtered, washed with 30 mL of water, and dried under reduced pressure to obtain 15.0 g (yield 50%) of the title compound. The optical purity of the obtained compound was 95% ee.

(Example 4) Second step (kinetic optical resolution step by enzyme): Pig liver-derived esterase (PLE)
(1S, 4S, 5S) -4-Bromo-6-oxabicyclo [3.2.1] octane-7-one: Compound (1-Br) crude crystal
To 60 mL of water, 4-bromo-6-oxabicyclo [3.2.1] octane-7-one and 20.0 g (0.0975 mmol) of the compound (1-Br-rac) were added, stirred at 30 ° C., and PLE (Roche) Technical grade 1 mL, 0.05 vol) was added. During the reaction, the mixture was added dropwise with 1M potassium carbonate aqueous solution so as to maintain pH = 7-8, and stirred for 24 hours.
The crystals were filtered, washed with 20 mL of water, and dried under reduced pressure to obtain 8.92 g (yield 45%) of the title compound (1-Br). The optical purity of the obtained compound was 94% ee.

(Example 5) First and second steps (bromolactone wet product charging, continuous enzyme reaction)
(1S, 4S, 5S) -4-Bromo-6-oxabicyclo [3.2.1] octane-7-one: Compound (1-Br) crude crystal
To 140 mL of water, 112 mL (0.7 equivalent, 1.106 mol) of 48% aqueous potassium hydroxide was added, 200 g (1.585 mol) of 3-cyclohexene-1-carboxylic acid was added dropwise, and 48% aqueous potassium hydroxide 12.4 was added to 60 mL of water. To the solution washed with a solution to which mL (0.3 eq, 0.476 mol) was added, 226.7 g (0.5 eq, 0.793 mol) of 1,3-dibromo-5,5-dimethylhydantoin was added at −10 ° C. or less over about 3 hours. The mixture was added and stirred at 0 ° C. for 1 hour.
An aqueous solution in which 40.0 g (0.2 equivalents, 0.317 mol) of sodium sulfite was dissolved in 200 mL of water was added dropwise to the reaction solution, and the mixture was stirred at 30 ° C. for 1 hour. 289.6 g of water-wet product crystals were obtained.
The obtained crystals were added to 480 mL of water, stirred at 30 ° C., and esterase AC “Amano” (8.0 g) was added. During the reaction, 264 mL was added dropwise with 1M potassium carbonate aqueous solution so as to maintain pH = 7-8, and the mixture was stirred for 11 hours. The crystals were filtered, washed with 200 mL of water, and dried under reduced pressure at room temperature to obtain 86.4 g (yield 26.5%) of compound (1-Br). The optical purity of the obtained compound was 95% ee.

(Example 6) Third step (refining step 92% ee → 99% ee)
(1S, 4S, 5S) -4-Bromo-6-oxabicyclo [3.2.1] octane-7-one, compound (1-Br) crystal, (1S, 4S, 5S) -4-bromo in 120 ml of acetone -6-Oxabicyclo [3.2.1] octane-7-one and 20 g (0.0975 mol) of crude crystals of compound (1-Br) were added and heated to 50 ° C. The obtained suspension was filtered, washed with 40 mL of acetone, the obtained solution was concentrated to 80 mL under reduced pressure, the crystals were dissolved at 50 ° C., and 120 mL of water was added dropwise.
The resulting slurry was cooled to 25 ° C. and stirred for 1 hour. The crystals were filtered, washed with 50 mL of 40% acetone aqueous solution and dried under reduced pressure to obtain 17.88 g (yield 89%) of compound (1-Br) fine crystals. The optical purity of the obtained compound was 99% ee.

(Example 7) Third step (purification step 95% ee → 99% ee)
Add 80 g (0.390 mol) of (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one (1-Br) crude crystals to 480 ml of acetone and heat to 50 ° C. did. The obtained suspension was filtered and washed with 80 mL of acetone. The obtained solution was concentrated under reduced pressure to 320 mL, the crystals were dissolved at 50 ° C., and 480 mL of water was added dropwise.
The resulting slurry was cooled to 5 ° C. and stirred for 1 hour. Crystals were filtered, washed with 200 mL of 40% acetone aqueous solution, and dried under reduced pressure to obtain 75.04 g (yield 94%) of compound (1-Br) fine crystals. The optical purity of the obtained compound was 99% ee.

(Example 8) Second-stage enzyme screening
4-Bromo-6-oxabicyclo [3.2.1] octane-7-one, compound (1-Br-rac) 2 mg is added to 1 mL 0.1 M phosphate buffer, 0.2 mL dimethyl sulfoxide, and about 2 mg of enzyme is added. And stirred at room temperature for 16 hours.
The reaction solution was subjected to separation / extraction with 3 mL of methylene chloride, the organic layer was concentrated, and the optical purity was measured.
In esterase, compound (1-Br) was obtained with high selectivity.

Claims (13)

Compound (1-X)
(In the formula, X represents a bromine atom or an iodine atom.)
Wherein the compound (1-X-rac)
(In the formula, X represents a bromine atom or an iodine atom.)
The compound (1-X) is produced by optically resolving the racemic compound, which is a compound, with an esterase in the presence of a solvent and a pH adjuster. Compound (1-Br)
A compound (1-Br-rac)
The compound (1-Br) is produced by optically resolving the racemic compound, which is a compound, with an esterase in the presence of a solvent and a pH adjuster. 3. The production method according to claim 1, wherein the solvent in the optical resolution is water. The production method according to claim 1, wherein the pH adjusting agent in the optical resolution is potassium carbonate. 5. The production method according to claim 1, wherein the pH in the optical resolution is maintained in the range of 7-8. Compound (1-X)
(In the formula, X represents a bromine atom or an iodine atom.)
A method of manufacturing
(1) After producing the compound (1-X-rac) by stirring the compound (2) in the presence of a solvent and a halogenating agent,
(In the formula, X represents a bromine atom or an iodine atom.)
(2) A method for producing a compound (1-X) by optically resolving a racemate which is the compound (1-X-rac) with an esterase in the presence of a solvent and a pH adjuster.
(In the formula, X represents a bromine atom or an iodine atom.) Compound (1-Br)
A method of manufacturing
(1) After producing the compound (1-Br-rac) by stirring the compound (2) in the presence of a solvent and a brominating agent,
(2) A method for producing a compound (1-Br) by optically resolving a racemate which is the compound (1-Br-rac) with an esterase in the presence of a solvent and a pH adjuster.
The production method according to claim 6 or 7, wherein the solvent in (1) is water. 9. The production method according to claim 7, wherein the brominating agent in (1) is 1,3-dibromo-5,5-dimethylhydantoin. 10. The production method according to claim 6, wherein the solvent in (2) is water. The method for production according to any one of claims 6 to 10, wherein the pH adjuster in (2) is potassium carbonate. The method according to any one of claims 6-11, wherein the pH in (2) is maintained within a range of 7-8. After producing the compound (1-Br) by the method according to any one of claims 2-5 or the method according to any one of claims 7-12, using the compound (1-Br), A method for producing p-toluenesulfonate monohydrate represented by the formula (II).