JP5757126B2 - Sharpless asymmetric epoxidation using flow reactor - Google Patents

Description

  The present invention relates to a production method that can be carried out on a large scale while being inexpensive, safe, and labor-saving in a sharpless asymmetric epoxidation reaction, and the compound obtained in the present invention is useful as an intermediate material for pharmaceuticals and the like. Compound.

The Sharpless asymmetric epoxidation reaction was first reported as a reaction using an equivalent amount of a metal complex as a substrate (for example, Non-Patent Document 1). Subsequently, the reaction progressed to a catalytic reaction system, and the progress of the reaction at a complex usage amount of 5 mol% was reported by adding molecular sieves (for example, Non-Patent Documents 2 and 3).

Regarding the application of the sharpless asymmetric epoxidation reaction to the flow reactor, which is the main requirement of the present invention, there is a description in Patent Document 1 that suggests that the sharpless asymmetric epoxidation is performed in a microreactor. There is no example, and there is no description about the unexpected side effect (catalytic reaction progress without molecular sieves) described in this specification.

Special table 2003-532646

Katsuki, T .; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. Hanson, R. M .; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922. Sharpless, K. B. et al. J. Am. Chem. Soc. 1987, 109, 5765.

Non-Patent Document 2 states that “When asymmetric epoxidation is performed at a catalyst amount of 5 mol% without adding molecular sieves, the optical purity is low (39-80% ee), and the reaction proceeds slowly. In general, the reaction stops at 50-60% conversion, "and the necessity of molecular sieves in the catalytic reaction is described.

However, since molecular sieves have a small particle size, they are likely to be clogged during filtration, and this is a factor that reduces production efficiency in mass production.
Therefore, it has been desired to develop a method for efficiently proceeding sharpless asymmetric epoxidation without adding molecular sieves.

As a result of intensive studies to solve the above-mentioned problems, the present inventors conducted a sharp-press asymmetric epoxidation reaction on a flow reactor, so that the same batch reaction with molecular sieves was added without using molecular sieves. It was found that the reaction can be carried out with a catalyst amount of a level.

  That is, the present invention relates to an optically active epoxy alcohol obtained by reacting an allyl alcohol compound, a catalytic amount of titanium tetraalkoxide, a catalytic amount of an optically active tartaric acid ester, and an oxidizing agent while circulating in a tube in a solvent. It is a manufacturing method of a compound.

According to the production method of the present invention, the reaction can be carried out with the same amount of catalyst as the batch reaction to which molecular sieves are added, without using molecular sieves. Thereby, an optically active epoxy alcohol compound useful as an intermediate raw material for pharmaceuticals and the like can be efficiently mass-produced.

Hereinafter, the present invention will be described in more detail.
The allyl alcohol compound is not particularly limited as long as the sharpless asymmetric epoxidation reaction proceeds, and examples thereof include an allyl alcohol compound represented by the formula (1). Specific examples thereof include methallyl alcohol and cinnamyl alcohol.

(In the formula, R ¹ , R ² and R ³ each independently represent a hydrocarbon group or a hydrogen atom , or two of them may be combined to form a ring structure.)
Examples of the titanium alkoxide include a compound represented by the formula (3).

(In the formula, R ⁴ represents an alkyl group.)
Specific examples thereof include titanium tetraisopropoxide, titanium tetraethoxide, titanium tetramethoxide, and titanium tetrabutoxide. Preferably, titanium tetraisopropoxide can be used.
Examples of the optically active tartaric acid ester include a compound represented by the formula (4).

(In the formula, R ⁵ represents a hydrocarbon group or a silyl group.)
Specific examples thereof include diisopropyl tartrate, diethyl tartrate, and dibutyl tartrate.
For example, when methallyl alcohol is used as a substrate, diisopropyl tartrate is preferred.

The oxidizing agent is preferably an organic peroxide, and for example, cumene hydroperoxide, tert-butyl hydroperoxide and the like can be used.

The solvent to be used is not limited as long as it is not involved in the reaction, and examples thereof include methylene chloride, chloroform, ethyl acetate, toluene and the like, and preferably methylene chloride. The solvent may be mixed with other solvents.

The amount of titanium alkoxide used is 0.1 mol% to 100 mol%, preferably 1 to 30 mol%, more preferably 3 to 10 mol%, with respect to allyl alcohol represented by the formula (1).

The amount of the optically active tartaric acid ester used is 0.5 to 2 mol times, preferably 1.0 to 1.5 mol times that of the titanium alkoxide.

The amount of oxidizing agent used is 0.1 to 10 equivalents, preferably 1 to 3 equivalents.

The amount of the solvent used can be 0 to 100 times by weight, preferably 3 to 20 times by weight, based on the allyl alcohol represented by the formula (1).

Examples of the method of reacting while circulating in the tube include a method of mixing using a flow reactor (flow reactor).

A flow type reactor (flow type reactor) is a device in which a reagent is continuously fed into a reactor so that a reactant can be continuously taken out, and an elongated flow passage having an inner diameter of about 1 μm to 10 cm is usually used. An apparatus generally called a microrear taku is a type of flow reactor.

In the present invention, the shape and material of the mixer and the flow passage are not particularly limited.
For example, as a mixer, a T-tube with an inner diameter of 1 mm, a static mixer such as YMC Co. static type mixer (trade name Deneb), and a helix type such as YMC Helix type mixer (trade name Spica) A mixer, etc. can be used.

Of these, the static type is preferable in the region where the flow rate is large (for example, 2 mL / min or more) because pressure is not applied. preferable.

As the material of the mixer, stainless steel, glass, and polytetrafluoroethylene resin are preferable.

For example, as the flow passage, 100 mm ² from the cross-sectional area 100 [mu] m ^2, preferably one 300m from length 1 cm, a 30 m m ^2, 50 m tube length from 1m more preferably the cross-sectional area 0.5 mm ^2.

The material of the flow path is preferably glass, stainless steel, or polytetrafluoroethylene resin.

The flow rate is determined by the time required for the reaction, that is, the required residence time and the size of the flow path, and is, for example, 0.1 mL / min to 100 mL / min, that is, 0.1 mL to 100 mL per minute.

The reaction temperature is usually from −40 ° C. to the boiling point of the solvent used, preferably in the range of −10 to 20 ° C., more preferably in the range of −10 to 10 ° C. In order to increase the heat removal efficiency, the mixer section may be set at a lower temperature than the subsequent sections.

The order of adding the reagents is not particularly limited, but a method of adding an oxidizing agent to the flow path of the allyl alcohol solution and further adding a mixed solution of titanium alkoxide and optically active tartaric acid ester, or circulation of the allyl alcohol solution. A method of adding a mixed solution of titanium alkoxide and optically active tartaric acid ester to the path and further adding an oxidizing agent is preferable. A mixed solution of allyl alcohol and an oxidizing agent, a mixed solution of titanium alkoxide and an optically active tartaric acid ester may be mixed in the flow path.

The allyl alcohol solution concentration is 1 to 100% by weight, preferably 5 to 50% by weight.

The oxidizing agent concentration is 1% to 100% by weight, preferably 5% to 50% by weight.

The solution concentration of titanium alkoxide and optically active tartaric acid ester is 1% to 80% by weight, preferably 5% to 50% by weight, as titanium alkoxide.

The epoxy alcohol compound represented by the formula (2) obtained by the reaction can be obtained by, for example, quenching an excess oxidizing agent with an appropriate reducing agent after the completion of the reaction, and then extracting with an appropriate solvent and washing with water. If necessary, it can be purified by recrystallization, distillation, silica gel column chromatography or the like. Moreover, it can also use for next reaction as it is, without refine | purifying a reaction liquid after reaction.

According to the present invention, the reaction can proceed with a catalyst amount similar to that of the batch reaction to which molecular sieves are added, for example, 5 mol%, without using molecular sieves.

Further, in the production method of the present invention, advantages that can be easily inferred from the use of a flow-type reactor, such as precise temperature control with a large heat removal capability, improvement of production efficiency by continuous production, and securing of safety. Can also be enjoyed together.

Next, the content of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
The analysis conditions are as follows.

[Analysis conditions]
HPLC (quantitative yield)
Column: Develosil C-30 UG-3, 5 μm (4.6 mm ID x 150 mm) Nomura Chemical, eluent: acetonitrile / water / phosphoric acid = 60/40 / 0.1, flow rate: 0.7 mL / min, oven temperature: 20 ° C, UV Detection wavelength: 254 nm, retention time 5.9 minutes.

HPLC (optical purity)
Column: CHIRALPAK AD-H (4.6 mm ID x 250 mm) Daicel chemistry, eluent: hexane / 2-propanol = 6/1, flow rate: 1.2 mL / min, oven temperature: 30 ° C, UV detection wavelength: 254 nm, retention time ( R)-(2-methoxyoxiran-2-yl) methyl 4-nitrobenzenesulfonate 23.1 minutes, (S)-(2-methoxyoxiran-2-yl) methyl 4-nitrobenzenesulfonate 25.2 minutes.

[Analysis conditions of Example 4]
HPLC
Column: YMC-Pack SIL 5μm (6mmID × 300mm) + CHIRALPAK AS (4.6mmID × 250mm), Eluent condition: Hexane: IPA = 9: 1, Oven temperature: 40 ° C, UV detection wavelength: UV220nm, Flow rate: 1.0ml / min, retention time: ((2R, 3R) -3-phenyloxiran-2-yl) methanol 26.0 min, ((2S, 3S) -3-phenyloxiran-2-yl) methanol 30.0 min.

A solution A was obtained by adding 100 g of methylene chloride to 20.0 g of methallyl alcohol and 79.2 g of cumene hydroperoxide to obtain a uniform solution.
(L) -Diisopropyl tartrate (3.9 g, 6 mol%) and methylene chloride (100 g) were added with titanium tetraisopropoxide (3.9 g, 5 mol%) to obtain a uniform solution B.
Liquid A and liquid B were each fed at 0.2 mL / min, mixed with a T-tube with an inner diameter of 1 mm in a thermostatic bath at 0 ° C., and 20 times inside a polytetrafluoroethylene resin tube with an inner diameter of 1 mm and a length of 11.7 m. Circulated for a minute.
The reaction solution obtained from the tube is placed in a flask for a certain period of time, quenched by adding triethyl phosphite, derivatized with p-nitrobenzenesulfonic acid chloride in the presence of triethylamine and N, N-dimethylaminopyridine, and then HPLC. When the quantitative yield and optical purity of (S)-(2-methoxyoxiran-2-yl) methyl p-nitrobenzenesulfonate were measured, the yield was 63.7% and the optical purity was (S) 97.8% ee.

Solution A was made uniform by adding 150 g of methylene chloride to 30.0 g of methallyl alcohol and 119 g of cumene hydroperoxide.
(L) -Diisopropyl tartrate (5.8 g, 6 mol%) and methylene chloride (150 g) were added with titanium tetraisopropoxide (5.9 g, 5 mol%) to obtain a uniform solution B.
Liquid A and liquid B were each fed at 1.0 mL / min, mixed with a 0.2 mm inner diameter helix-type mixer (trade name Spica) (material name: SUS) in a 10 ° C constant temperature bath, and 5 mm in inner diameter A 4 meter-long polytetrafluoroethylene resin tube was circulated for 40 minutes.
Furthermore, 47.9 g of triethyl phosphite fed at 0.2 mL / min was added to a 1 mm inner diameter in a 10 ° C constant temperature bath.
The mixture was mixed with a T-shaped tube and allowed to circulate in a tube made of polytetrafluoroethylene resin having an inner diameter of 5 mm and a length of 3 m for 27 minutes.
The effluent was placed in a flask, derivatized with triethylamine, N, N-dimethylaminopyridine, and p-nitrobenzenesulfonic acid chloride, and then (S)-(2-methoxyoxiran-2-yl) methyl p-nitrobenzenesulfonate by HPLC. The quantitative yield and optical purity of the product were measured, and the yield was 79.0% and the optical purity (S) was 93.3% ee.

550 g of methylene chloride was added to 110 g of methallyl alcohol and 435 g of cumene hydroperoxide to obtain a uniform solution.
(L) -Diisopropyl tartrate (21.5 g, 6 mol%) and methylene chloride (550 g) were added with titanium tetraisopropoxide (21.7 g, 5 mol%) to obtain a uniform solution B.
Liquid A and liquid B were each fed at 8 mL / min, mixed with a static mixer (trade name Deneb) (material SUS) with a 0.2 mm inner diameter in a thermostatic chamber at -10 ° C, and then 10 ° C Was passed through a tube made of polytetrafluoroethylene resin having an inner diameter of 5 mm and a length of 40 m in the thermostat for 50 minutes.
In addition, 176 g of triethyl phosphite was fed at 1.5 mL / min, mixed with the reaction solution using a T-tube with an inner diameter of 1 mm in a -10 ° C constant temperature bath, and then 5 mm in length inside the 10 ° C constant temperature bath. A 30 m polytetrafluoroethylene resin tube was circulated for 34 minutes.
Take the effluent in a flask at -10 to -5 ° C for 1 hour, add 101.1 g of triethylamine and 9.4 g of N, N-dimethylaminopyridine, and add 1 solution of 228.2 g of p-nitrobenzenesulfonic acid chloride and 332.4 g of methylene chloride. It was added dropwise over time. After further stirring for 1 hour, celite filtration was performed.
The filtrate was separated with 525 g of 10% aqueous citric acid, and the organic layer was washed twice with 523 g of water and then treated with 105 g of silica gel. Concentration under reduced pressure yielded 160 g of (S)-(2-methoxyoxiran-2-yl) methyl p-nitrobenzenesulfonate as a crude liquid.
The quantitative yield and optical purity of (S)-(2-methoxyoxiran-2-yl) methyl p-nitrobenzenesulfonate were measured by HPLC, and the yield was 81.4% and the optical purity (S) was 92.3% ee. It was.

[Reference Example 1] In a batch type molecular sieve addition flask, 11.6 g of methylene chloride, 1.0 g of diisopropyl (L) -tartrate, 0.1 g of molecular sieve 3A powder and 0.5 g of methallyl alcohol were added and stirred.
After cooling to 1 ± 3 ° C., 0.1 g (5 mol%) of titanium tetraisopropoxide was added and stirred for 30 minutes.
Cumene hydroperoxide (2.0 g) was added dropwise, washed with 11.6 g of methylene chloride, and then stirred for 4 hours.
After quenching with 0.7 g of triethyl phosphite and derivatization with triethylamine, N, N-dimethylaminopyridine and p-nitrobenzenesulfonic acid chloride, quantitative yield and optical purity were measured by HPLC, yield 79.3% The optical purity was 94.5% ee.

[Reference Example 2] 2.9 g of methylene chloride, 0.058 g of (L) -diisopropyl tartrate and 0.30 g of methallyl alcohol were added to a batch type flask without addition of molecular sieves and stirred. After cooling to −10 ± 3 ° C., 0.058 g (5 mol%) of titanium tetraisopropoxide was added and stirred for 30 minutes. Cumene hydroperoxide (1.2 g) was added dropwise, washed with 0.16 g of methylene chloride, and then stirred for 23 hours.
After quenching with 0.97 g of triethyl phosphite and derivatization with triethylamine, N, N-dimethylaminopyridine and p-nitrobenzenesulfonic acid chloride, quantitative yield and optical purity were measured by HPLC, yield 25.6% The optical purity was 72.2% ee.

Methylene chloride was added to 20.0 g of cinnamyl alcohol to make 100 mL.
Methylene chloride was added to 2.13 g of (D) -diisopropyl tartrate and 2.20 mL of titanium tetraisopropoxide to make 100 mL, which was designated as solution B.
Methylene chloride was added to 411.40 g of cumene hydroperoxide having a purity of 82% to prepare a solution C.
Liquid A and liquid C were fed at 25 μL / min and 70 μL / min, respectively, and mixed with a helix-type mixer (trade name Spica) manufactured by YMC Co., Ltd., which was temperature-controlled at −10 ° C., and then 40 μL / min. The solution B was mixed with a helix type mixer (trade name Spica) manufactured by YMC Co., Ltd., which was temperature-controlled at −10 ° C., and made of polytetrafluoroethylene resin having an inner diameter of 1.0 mm at −10 ° C. A tube 10 m was circulated (residence time 60 minutes). The effluent was obtained in a methylene chloride solution of triethyl phosphite for 21 minutes, and ((2R, 3R) -3-phenyloxiran-2-yl) methanol was quantified by LC. The yield was 90%. . The optical purity was 91% ee

  The method of the present invention provides a highly efficient method for producing an optically active epoxy alcohol compound useful as an intermediate raw material for pharmaceuticals and the like.

Claims (3)

An allyl alcohol compound, 10 mol% or less of titanium tetraalkoxide, 10 mol% or less of optically active tartaric acid ester, and an organic peroxide are allowed to react while circulating in a tube in a solvent without using molecular sieves. To produce an optically active epoxy alcohol compound. The allyl alcohol compound is represented by the formula (1)

An optically active epoxy alcohol compound represented by formula (2):

The manufacturing method of Claim 1 which is an optically active epoxy alcohol compound represented by these.
(In the formulas (1) and (2), R ¹ , R ² and R ³ each independently represents a hydrocarbon group or a hydrogen atom , or two of them together form a ring structure. May be.) The process according to claim 1, wherein the organic peroxide is tert-butyl hydroperoxide or cumene hydroperoxide.