JP4195231B2 - Optically active secondary phosphine borane derivative and method for producing the same - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention is a method for producing an optically active secondary phosphine borane derivative useful as an intermediate material for an optically active phosphine derivative having an asymmetric center on a phosphorus atom, and is useful as an intermediate material for the optically active secondary phosphine borane derivative. The present invention relates to a method for producing a novel alkoxycarbonylphosphine borane and a method for producing an optically active alkoxycarbonylphosphine borane.
[0002]
[Prior art]
J. et al. Am. Chem. Soc. 1998, 120, 1635-1636, JP-A-11-80179, etc., a bisphosphine ligand having 1,2-bis (phosphino) ethane as a skeleton is excellent in asymmetric selectivity and catalytic activity. Therefore, the development of an efficient method for producing a bisphosphine ligand is desired.
[0003]
On the other hand, it is known that the use of a secondary phosphine borane derivative as an intermediate material in the production of the bisphosphine ligand is useful because it has active hydrogen atoms and is highly reactive. Yes. Further, it has been shown by the present inventors that, among these secondary phosphine borane derivatives, in particular, optically active substances can induce various optically active substances having an asymmetric center on a phosphorus atom with high optical purity and high yield. ing.
[0004]
For this reason, it is desirable that the optically active secondary phosphine borane derivative can be synthesized with high optical purity and industrially advantageously because the bisphosphine ligand can be easily produced.
[0005]
Conventionally, as a method for producing such an optically active secondary phosphine borane, for example, the following reaction formula (1)
[0006]
Embedded image
[0007]
Then, (-)-sparteine- (S) -butyllithium complex is allowed to act on phosphine borane (compound (11)) and oxidized to obtain optically active phosphine borane alcohols (compound (12)). And a method (J. Org. Chem., Vol. 65, No. 13, 2000) for obtaining an optically active secondary phosphine borane derivative (compound (13)) by decarboxylation via oxidation has been proposed. Yes. Further, the following reaction formula (2)
[0008]
Embedded image
[0009]
Then, dichlorophosphine (compound (14)) was allowed to react with lithium 2-boronethiolate, methylmagnesium bromide and borane-THF complex to obtain bornylthiomethylphosphine borane (compound (15)), and then HPLC. To obtain an optically active bornylthiomethylphosphine borane (compound (16)), and then reductively cleave the PS bond with lithium naphthalenide to obtain an optically active secondary phosphine borane (compound). (17)) is also proposed (J. Org. Chem., Vol. 65, No. 6, 2000).
[0010]
[Problems to be solved by the invention]
However, the method using the above reaction formula (1) cannot obtain both enantiomers of the optically active secondary phosphine borane derivative because the natural product (-)-sparteine is used as an asymmetric source. In addition, there is a problem that the optical purity is not high depending on the substituent of phosphine. Further, although the method using the above reaction formula (2) has high optical purity of the obtained secondary phosphine borane derivative, a special separation means such as HPLC must be used as a means for separating the diastereomeric mixture, There is a problem that the cost is high and a large amount cannot be manufactured in a short time.
[0011]
Accordingly, the object of the present invention is to be able to optionally obtain an optically active secondary phosphine borane with high optical purity for both enantiomers and to produce a large amount in a short time at a low cost. An object is to provide a method for producing an optically active secondary phosphine borane and a method for producing an intermediate thereof.
[0012]
[Means for Solving the Problems]
Under such circumstances, the present inventor firstly prepared a racemic phosphine borane derivative represented by the above general formula (1) and an optically active carbonic ester halide represented by the above general formula (2). After reacting with one kind to obtain a diastereomeric mixture of alkoxycarbonylphosphine borane represented by the above general formula (3), the diastereomeric mixture is divided by a simple method such as a recrystallization method, It was found that the optically active secondary phosphine borane derivative represented by the general formula (5) can be optionally obtained with high optical purity by hydrolysis in the presence of an alkaline agent, and the present invention was completed. It came to do.
[0013]
That is, the present invention provides the following general formula (1)
[0014]
Embedded image
[0015]
(Wherein R¹And R²Represents a linear or branched alkyl group, aryl group or aralkyl group. However, R¹And R²Are not the same group. Racemic phosphine borane derivatives represented by the following general formula (2)
[0016]
Embedded image
[0017]
(Wherein R^*Has optical activityRingFormula terpene group, X represents a halogen atom. And the optically active carbonate halide represented by the following general formula (3):
[0018]
Embedded image
[0019]
(Wherein R¹, R²And R^*Is as defined above. The production method of the 1st intermediate of the optically active secondary phosphine borane derivative characterized by the above-mentioned is obtained.
[0020]
In the present invention, the first intermediate of the optically active secondary phosphine borane derivative is divided into the following general formula (4):
[0021]
Embedded image
[0022]
(Wherein R¹, R²And R^*Is as defined above. P^*Represents an asymmetric phosphorus atom. And a second step of obtaining an optically active alkoxycarbonylphosphine borane represented by the above formula (2): a process for producing a second intermediate of an optically active secondary phosphine borane derivative.
[0023]
In the present invention, the second intermediate of the optically active secondary phosphine borane derivative is hydrolyzed in the presence of an alkali agent to give the following general formula (5):
[0024]
Embedded image
[0025]
(Wherein R¹, R²And P^*Is as defined above. It provides a method for producing an optically active secondary phosphine borane derivative, characterized in that it has a third step of obtaining an optically active secondary phosphine borane derivative represented by formula (1).
[0026]
DETAILED DESCRIPTION OF THE INVENTION
First, a method for producing an optically active secondary phosphine borane derivative according to the present invention will be described. This method is a method relating to racemic resolution of a phosphine borane derivative, in which only one of the phosphine borane derivatives is optionally obtained after making the racemic form of the phosphine borane derivative into a diastereomer, specifically, the above general formula ( The racemic phosphine borane derivative represented by 1) is reacted with the optically active carbonate halide represented by the general formula (2) in the presence of a base, and represented by the general formula (3). First step of obtaining a diastereomeric mixture of alkoxycarbonylphosphine borane, Second step of dividing the diastereomeric mixture of alkoxycarbonylphosphine borane to obtain an optically active alkoxycarbonylphosphine borane represented by the above general formula (4) And the optically active alkoxycarbonylphosphine borane in the presence of an alkaline agent. Water splitting to those having a third step of obtaining an optically active secondary phosphine borane derivative represented by the above general formula (5).
[0027]
<First step>
The racemic phosphine borane derivative used in the first step is represented by the above general formula (1). In the present invention, the general formula (1) is used to mean a racemic body containing an equivalent amount of (R) isomer and (S) isomer having a P atom as an asymmetric center.
[0028]
In general formula (1), R¹And R²Represents a linear or branched alkyl group, aryl group or aralkyl group having 1 to 18 carbon atoms. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an iso-butyl group, a tert-butyl group, an n-hexyl group, an iso-hexyl group, an n-heptyl group, and an n-octyl group. Iso-octyl group, n-dodecyl group, iso-dodecyl group, n-octadecyl group, iso-octadecyl group, cyclopentyl group, cyclohexyl group and the like. Examples of the aryl group include a phenyl group, a tolyl group, a xylyl group, and a naphthyl group. Examples of the aralkyl group include a benzyl group and a phenethyl group. However, in the general formula (1), R¹And R²Are not the same group.
[0029]
Among the racemic phosphine borane derivatives represented by the general formula (1), preferred compounds include, for example, ethylmethylphosphineborane, isopropylmethylphosphineborane, n-propylmethylphosphineborane, isobutylmethylphosphineborane, n- Butylmethylphosphine borane, tert-butylmethylphosphineborane, sec-butylmethylphosphineborane, isoheptylmethylphosphineborane, n-heptylmethylphosphineborane, isohexylmethylphosphineborane, n-hexylmethylphosphineborane, cyclopentylmethylphosphineborane, Cyclohexylmethylphosphineborane, benzylmethylphosphineborane, isopropylethylphosphineborane, n-propylethylphosphineborane , Isobutylethylphosphine borane, n-butylethylphosphineborane, tert-butylethylphosphineborane, sec-butylethylphosphineborane, isoheptylethylphosphineborane, n-heptylethylphosphineborane, isohexylethylphosphineborane, n-hexylethyl Phosphine borane, cyclopentylethylphosphine borane, cyclohexylethylphosphine borane, benzylethylphosphine borane, isopropyl-n-propylphosphineborane, isobutyl-n-propylphosphineborane, n-butyl-n-propylphosphineborane, tert-butyl-n- Propylphosphine borane, sec-butyl-n-propylphosphineborane, isoheptyl-n-propylphosphineborane n-heptyl-n-propylphosphine borane, isohexyl-n-propylphosphineborane, n-hexyl-n-propylphosphineborane, cyclopentyl-n-propylphosphineborane, cyclohexyl-n-propylphosphineborane, benzyl-n-propylphosphine Borane, isobutylisopropylphosphineborane, n-butylisopropylphosphineborane, tert-butylisopropylphosphineborane, sec-butylisopropylphosphineborane, isoheptylisopropylphosphineborane, n-heptylisopropylphosphineborane, isohexylisopropylphosphineborane, n-hexyl Isopropylphosphine borane, cyclopentylisopropylphosphine borane, cyclohexyl isop Propylphosphine borane, benzylisopropylphosphineborane, isobutyl-tert-butylphosphineborane, n-butyl-tert-butylphosphineborane, sec-butyl-tert-butylphosphineborane, benzyl-tert-butylphosphineborane, tert-octylmethyl Examples include phosphine borane, adamantylmethylphosphine borane, and n-tetradecyl-tert-butylphosphine borane. Of these, in particular, tert-butylmethylphosphine borane, cyclohexylmethylphosphineborane, tert-octylmethylphosphineborane, and adamantylmethylphosphineborane have two substituents R¹And R²Among them, one is bulky and the other is bulky, which is preferable since it exhibits excellent stereoselectivity when used as a ligand intermediate for an asymmetric synthesis catalyst.
[0030]
The phosphine borane represented by the general formula (1) as a raw material can be produced by a known method. For example, using the method described in JP-A-2001-253889, the following reaction formula (3)
[0031]
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[0032]
Can be manufactured easily. In the reaction formula (3), R¹, R²And X are as defined above.
[0033]
The method will be explained in detail. A monoalkylphosphine (compound (18)) and a borane-formant of borane-tetrahydrofuran complex are reacted for about 1 hour at a temperature of about 0 ° C. or more with respect to the monoalkylphosphine. Thereafter, the reaction solution is concentrated, and then the residue is distilled to obtain a monoalkylphosphine borane (compound (19)). Next, the obtained monoalkylphosphine borane (compound (19)) and halide (compound (20)) are heated to about 0 ° C. in an inert solvent such as hexane in the presence of a base such as n-butyllithium. The phosphine borane represented by the general formula (1) is produced by reacting at a temperature.
[0034]
The optically active carbonate halide used in the first step is represented by the above general formula (2). In the present invention, R^*Is R^*Means only one kind selected from a plurality of optically active substances such as (R) and (S). For example, R^*Is a structure that can theoretically take (R) and (S) isomers, R in general formula (2)^*Refers to either the (R) or (S) isomer. Accordingly, in the present invention, the general formula (2) represents only one type of optically active substance. The optically active carbonate halide represented by the general formula (2) reacts with the racemic phosphine borane derivative represented by the general formula (1) to diastereomerize the racemic form.
[0035]
In the general formula (2), X represents a halogen atom such as chlorine, bromine or iodine, and among them, a chlorine atom is preferable because of high reactivity. In addition, R shown in the formula^*Represents an optically active alkyl group or cyclic terpene group. R used in the present invention^*Examples thereof include alkyl groups such as an optically active S-butyl group, and cyclic terpene groups such as menthyl, isomenthyl, bornyl, and isobornyl. Of these, R^*Is a cyclic terpene group, it is preferable because the diastereomeric mixture of alkoxycarbonylphosphine borane obtained in this step and represented by the general formula (3) is easy to form a crystal, and when it is a bornyl group, Diastereomer mixtures are more preferred because they are easier to produce crystals.
[0036]
Specific examples of the optically active carbonate halide represented by the general formula (2) include, for example, (1S) -endo-2-bornyl chloroformate, (1S) -exo-2-bornyl chloroformate Mate, (1R) -endo-2-bornylchloroformate, (1R) -exo-2-bornylchloroformate, (+)-menthylchloroformate, (-)-menthylchloroformate, etc. It is done.
[0037]
The optically active carbonate ester halide can be produced by a known method. For example, the following reaction formula (4)
[0038]
Embedded image
[0039]
According to the formula (X represents a halogen atom), (-)-borneol (compound (21)) is easily reacted with quinoline and triphosgene in an inert solvent such as toluene at 60 ° C. for about 12 hours. (1S) -endo-2-bornyl chloroformate (compound (2)) can be produced.
[0040]
The base used in the first step is not particularly limited. For example, metal hydrides such as sodium hydride, amines such as trimethylamine and triethylamine, alkali hydroxides such as potassium hydroxide and sodium hydroxide, sodium hydroxide Examples thereof include alkoxides such as methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, piperidine, pyridine, potassium cresolate, alkyllithium and the like, and these are used singly or in combination. Among these bases, alkyllithium is preferable, and examples of the alkyllithium include n-butyllithium and sec-butyllithium. In this step, the base is an initiator for the reaction between the racemic phosphine borane derivative and the optically active carbonate halide.
[0041]
In the first step, a solvent is used in the reaction, but it is preferable to use an inert solvent as the solvent because the reaction efficiency can be increased. Examples of the inert solvent include one or more of chain or cyclic ethers such as diethyl ether, tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene.
[0042]
In the first step, the mixing ratio of the raw materials is such that the blending amount of the optically active carbonate ester represented by the general formula (2) is the racemic blend of the phosphine borane derivative represented by the general formula (1). The amount is usually 1 to 3 times mol, preferably 1 to 1.2 times mol. A blending ratio within this range is preferable because separation and purification of the product is easy and economical.
[0043]
Moreover, the addition amount of a base is 1-3 times mole normally with respect to the racemic body of the phosphine borane derivative represented by the said General formula (1), Preferably it is 1-1.2 times mole. A blending ratio within this range is preferable because separation and purification of the product is easy and economical.
[0044]
As reaction conditions, the reaction temperature is −78 to 60 ° C., preferably −78 to 0 ° C., and the reaction time is 0.5 to 12 hours, preferably 1 to 2 hours.
[0045]
After completion of the reaction, the reaction solution is quenched by adding, for example, 1M HCl aqueous solution, the product is extracted with a polar solvent such as ethyl acetate, and the extract is concentrated and purified by column chromatography or the like. A diastereomeric mixture of alkoxycarbonylphosphine borane represented by the general formula (3) is obtained as the first intermediate of the optically active secondary phosphine borane derivative.
[0046]
In the present invention, the general formula (3) is a reaction product of the (R) isomer having the P atom as an asymmetric center and the optically active carbonate halide represented by the general formula (2), and the reaction. A diastereomer mixture of the product, in which an equivalent product of the reaction product of the (S) isomer having the P atom as an asymmetric center and the optically active carbonate halide represented by the general formula (2) is mixed. Used in the meaning shown. In general formula (3), R¹, R²And R^*Is as defined above.
[0047]
<Second step>
The second step is obtained by the first step and is represented by the above general formula (4) by dividing the diastereomeric mixture of alkoxycarbonylphosphine borane represented by the above general formula (3) into each diastereomer. In this step, optically active alkoxycarbonylphosphine borane is obtained.
[0048]
Examples of the resolution method that can be used for the resolution of the diastereomeric mixture in the second step include a column chromatography method and a recrystallization method using a difference in solubility between diastereomeric isomers. The recrystallization method is preferable because it is easy and can be processed in large quantities at low cost.
[0049]
The solvent used in the recrystallization method is usually toluene, methanol, ethanol, ethyl acetate, diethyl, although depending on the kind of the diastereomeric mixture of alkoxycarbonylphosphine borane represented by the general formula (3). Examples include organic solvents such as ether, tetrahydrofuran, dioxane, cyclohexane, and n-hexane, and these can be used alone or in combination of two or more. For example, when the diastereomeric mixture of alkoxycarbonylphosphine borane represented by the above general formula (3) is [(1S) -endo-2-bornyloxycarbonyl] (tert-butyl) methylphosphine borane, As n-hexane, it is preferable because crystals are easily formed and diastereomers can be efficiently separated.
[0050]
The recrystallization method will be described with specific examples. For example, when the diastereomeric mixture of alkoxycarbonylphosphine borane is [(1S) -endo-2-bornyloxycarbonyl] (tert-butyl) methylphosphine borane, recrystallization usually results in (Rp, 1S) The body precipitates as crystals. For this reason, by separating the crystals from the filtrate, it can be divided into (Rp, 1S) isomers and (Sp, 1S) isomers that remain in the filtrate in excess of the (Rp, 1S) isomers. Here, Rp indicates that the phosphorus atom is in the R form, and Sp indicates that the phosphorus atom is in the S form. In addition, (Sp, 1S) body which remains excessively in a filtrate can be divided | segmented by separation means, such as column chromatography, for example.
[0051]
When the diastereomeric mixture is divided, the optically active alkoxycarbonylphosphine borane represented by the general formula (4) is obtained as the second intermediate of the optically active secondary phosphine borane derivative. In addition, in this invention, General formula (4) is each optically active substance isolate | separated by the diastereomeric resolution among the diastereomeric mixtures of the alkoxycarbonylphosphine borane represented by the said General formula (3), ie, Used to indicate one type of optically active substance. For example, when the diastereomeric mixture of alkoxycarbonylphosphine borane represented by the general formula (3) is a mixture of (Rp, 1S) and (Sp, 1S), it is represented by the general formula (4). The optically active alkoxycarbonylphosphine borane refers to any one selected from (Rp, 1S) or (Sp, 1S).
[0052]
<Third step>
The third step is obtained by the second step, and is hydrolyzed in the presence of an alkali agent to obtain the desired general formula (5), which is obtained by hydrolyzing the optically active alkoxycarbonylphosphine borane represented by the general formula (4). To obtain an optically active secondary phosphine borane derivative.
[0053]
The type of alkali agent used in the present invention is not particularly limited, but for example, caustic alkalis such as sodium hydroxide and potassium hydroxide are preferable, and potassium hydroxide is particularly preferable. The amount of these alkali agents added is usually 1 mol or more, preferably 15 to 20 mol per mol of the optically active alkoxycarbonylphosphine borane represented by the general formula (4).
[0054]
Examples of the solvent used in the hydrolysis include water, acetonitrile, methanol, ethanol, isopropanol, and the like, and these can be used alone or in combination of two or more. Among these, a mixed solvent composed of acetonitrile, water, and methanol is preferable because the reaction proceeds smoothly, and the mixed solvent having a volume ratio of acetonitrile: water: methanol = 10: 6: 3 is a substrate solubility. Is particularly preferable. The hydrolysis temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C., and the reaction time is 1 hour or longer, preferably 4 to 5 hours.
[0055]
After completion of hydrolysis, an acid such as 1M HCl is added to the reaction solution to neutralize it, and then the organic substance is extracted with a polar solvent such as diethyl ether, and the solvent is distilled off to obtain a crude product. When this is purified by chromatography or the like, the optically active secondary phosphine borane derivative represented by the general formula (5) can be obtained with a high optical purity of 95% ee or more. In the present invention, the general formula (5) is used to indicate any one of the racemic phosphine borane derivatives represented by the general formula (1).
[0056]
In addition, the optically active secondary phosphine borane derivative represented by the general formula (5) is desired by selecting the optically active carbonate halide (R), (S), etc. in the first step. One of the optical isomers having such a structure can be optionally obtained. For example, when t-butylmethylphosphine borane is reacted with (1S) -endo-2-bornyl chloroformate, (S) -t-butylmethylphosphine borane is finally obtained.
[0057]
The optically active secondary phosphine borane derivative represented by the general formula (5) obtained in the present invention can be used as a raw material for an optically active bisphosphine borane derivative.
[0058]
The use of the optically active secondary phosphine borane derivative represented by the general formula (5) obtained in the present invention will be described in more detail. For example, the following reaction formula (5)
[0059]
Embedded image
[0060]
In accordance with the present invention, one of the optically active optically active secondary phosphine borane derivatives obtained in the present invention (compound (5)) and 1,2-dichloroethane are reacted in the presence of a base such as n-butyllithium. It is already known that an optically active bisphosphine borane derivative (compound (22)) can be obtained by using (J. Org. Chem., Vol. 65, No. 6, 2000). It is also known that (22) is a precursor of a ligand that is very useful as a catalyst for asymmetric reduction reactions such as dehydroamino acids. Therefore, the optically active secondary phosphine borane derivative represented by the general formula (5) obtained in the present invention is very useful.
[0061]
Next, the manufacturing method of the 1st intermediate body of the optically active secondary phosphine borane derivative based on this invention is demonstrated. In the present invention, the first intermediate of the optically active secondary phosphine borane derivative represents a diastereomeric mixture of alkoxycarbonylphosphine borane as described above. In this method, only the first step is performed in the method for producing the optically active secondary phosphine borane derivative. The diastereomeric mixture of alkoxycarbonylphosphine borane represented by the general formula (3) obtained by the method is used, for example, as a raw material in the second step of the method for producing the optically active secondary phosphine borane derivative. Can do.
[0062]
Next, the manufacturing method of the 2nd intermediate body of the optically active secondary phosphine borane derivative based on this invention is demonstrated. In the present invention, the second intermediate of the optically active secondary phosphine borane derivative refers to the optically active alkoxycarbonylphosphine borane as described above. In this method, the first step and the second step are performed in the method for producing the optically active secondary phosphine borane derivative. The optically active alkoxycarbonylphosphine borane represented by the general formula (4) obtained by the method can be used as a raw material in the third step of the method for producing the optically active secondary phosphine borane derivative, for example.
[0063]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these.
[0064]
Production Example 1
<Synthesis of tert-butylmethylphosphine borane used in the first step>
Tert-butylphosphine borane (205 mg, 2 mmol) prepared above and 6 ml of dehydrated THF were added to a 25 ml flask that had been sufficiently removed of water and replaced with argon gas, and cooled to 0 ° C. in an ice bath. An n-butyllithium / hexane aqueous solution (1.27 ml, 2 mmol) was added dropwise thereto with a syringe. After stirring for 30 minutes, 284 mg (2 mmol) of methyl iodide was slowly added dropwise with a microsyringe. After completion of the dropwise addition, the flask was gradually warmed and stirred at room temperature for 1 hour, and then the reaction solution was poured into 10 g of ice for quenching. To this, 2 ml of dilute hydrochloric acid and 2 ml of saturated saline were added and stirred, and then 10 ml of ethyl acetate was added, and the organic layer and the aqueous layer were separated with a separatory funnel. After 5 ml of ethyl acetate was added to the separated aqueous layer and extraction was performed three times, the organic layer was collected and washed with 1 ml of diluted hydrochloric acid, 5 ml of pure water and 5 ml of saturated brine. After sodium sulfate was added for dehydration, the solvent was removed with an evaporator. The obtained organic matter was separated and purified by silica gel column chromatography. The fraction in which the target product was eluted was collected, and the solvent was removed by an evaporator to obtain 153 mg of white solid tert-butylmethylphosphine borane (yield 65%).
[0065]
(Identification data)
Mp 33-37 ℃
Bp 90-91 ℃ / 15 mmHg
¹H NMR (300.4 MHz, CDCl_Three) δ = 0.49 (br q, J_HB= 98.6 Hz, 3H), 1.21 (d,^ThreeJ_HP= 14.7 Hz, 9H), 1.33 (dd,²J_HP= 10.7 Hz, J = 6.0 Hz, 3H), 4.41 (dm, J_HP= 354.8 Hz, 1H)
¹³C NMR (75.4 MHz, CDCl_Three) δ = 2.1 (d, J_CP= 34.8 Hz), 26.0 (d, J_CP= 34 Hz), 26.2 (d,²J_CP= 3.0)
³¹P NMR (121.5 MHz,¹H decoupled, CDCl_Three ) δ = -12.1 (br q, J_PB= 51.4 Hz)
IR (KBr) 2970, 2380, 1463
HRMS EI m / z 117.1009.Calcd for C_FiveH₁₅BP (M⁺-H) 117.1005.
[0066]
Production Example 2
<Synthesis of (1S) -endo-2-bonyl chloroformate used in the first step>
In an argon stream, 150 ml of toluene in which 15.1 g (50.8 mmol) of triphosgene was dissolved was cooled to 0 ° C., and 150 ml of toluene in which (−)-borneol 23.1 g (149 mmol) and 19.3 g (149 mmol) of quinoline were dissolved were added for 1 hour. It was dripped over. The reaction solution was stirred at 0 ° C. for 1 hour, then heated to 60 ° C. and further stirred for 3 hours. After completion of the reaction, by-product quinoline salt was removed by filtration, the filtrate was concentrated, and the residue was distilled under reduced pressure to obtain 28.1 g of (1S) -endo-2-bornyl chloroformate. The yield was 87%.
[0067]
(Identification data)
Bp 54-55 ℃ / 0.2 mmHg
¹H NMR (300.4 MHz, CDCl_Three) δ 0.86 (6H), 0.87 (3H), 1.11-1.19 (m, 1H), 1.20-1.40 (m, 2H), 1.66-1.80 (m, 2H), 1.80-1.94 (m, 1H), 2.30- 2.44 (m, 1H), 4.95 (dm, 1H)
¹³C NMR (75.45 MHz, CDCl_Three) δ18.7, 19.6, 26.7, 27.8, 36.0, 44.6, 48.0, 49.3, 89.3, 150.6
IR (KBr) 2958, 1777, 1171, 1151
HRMS EI m / z 216.0899. Calcd for C₁₁H₁₇O₂Cl (M⁺216.0917.
[0068]
Example 1
<Synthesis of t-butylmenthyloxycarbonylmethylphosphine borane>
Under an argon atmosphere, 236 mg (2 mmol) of t-butylmethylphosphine borane obtained in Production Example 1 was dissolved in 2 ml of THF and cooled to −78 ° C. A n-butyllithium hexane solution (1.3 ml, 1.50 M hexane solution, 2 mmol) was carefully added dropwise thereto with a syringe. After 10 minutes, (+)-menthyl chloroformate (481 mg, 2.2 mmol) was carefully added. After stirring at this temperature for 1 hour, the temperature was gradually raised to room temperature. Thereafter, the cooled hydrochloric acid solution was carefully added to the reaction solution to stop the reaction. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. These organic layers were washed with water and saturated brine, dehydrated with sodium sulfate, and concentrated with an evaporator. The obtained residue was purified by silica gel column chromatography to obtain 412 mg of a diastereomeric mixture of t-butylmenthyloxycarbonylmethylphosphine borane as a colorless oily substance. The yield was 67%.
[0069]
(Identification data)
¹H NMR (300.4 MHz, CDCl_Three) δ 0.56 (br q, J_HB= 85.0 Hz, 6H), 0.74-0.77 (m, 6H), 0.8-0.9 (m, 2H), 0.89-0.97 (m, 12H), 0.98-1.17 (m, 4H), 1.21-1.33 (m, 18H ), 1.42-1.49 (m, 6H), 1.46-1.56 (m, 4H), 1.65-1.77 (m, 4H), 1.86-2.07 (m, 4H), 4.84-4.97 (m, 2H)
¹³C NMR (75.4 MHz, CDCl_Three) δ4.5 (d, J_CP = 34.8Hz), 4.7 (d, J_CP = 34.8Hz), 15.7, 15,9 20.7, 20.8, 21.9, 22.0, 22,9 23.1, 25.4-25.6 (m), 25.9, 26.1, 28.6 (d, J_CP = 28.6Hz), 28.7 (d, J_CP = 28.6Hz), 31.4-31.5 (m), 33.9, 34.0, 40.6, 40.8, 46.7, 47.0, 77.2, 77,4 171.3, 172.3
³¹P NMR (121.5 MHz,¹H decoupled, CDCl_Three ) δ40.4-42.4 (m)
IR (KBr) 2957, 2871, 2402, 2343, 1702, 1459, 1370
HRMS EI m / z 299.2281.Calcd for C₁₆H₃₃PB (M⁺-H) 299.2312.
[0070]
Example 2
<Synthesis of [(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane>
Under an argon atmosphere, 3.76 g (31 mmol) of t-butylmethylphosphine borane obtained in Production Example 1 was dissolved in 80 ml of THF and cooled to −78 ° C. A hexane solution of n-butyllithium (23 ml, 1.50 M hexane solution, 34 mmol) was carefully added dropwise thereto with a syringe. After 10 minutes, 7.1 g (33 mmol) of (1S) -endo-2-bornyl chloroformate obtained in Preparation Example 2 was carefully added. After stirring at this temperature for 1 hour, the temperature was gradually raised to room temperature. Thereafter, the cooled hydrochloric acid solution was carefully added to the reaction solution to stop the reaction. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. These organic layers were washed with water and saturated brine, dehydrated with sodium sulfate, and concentrated with an evaporator. The obtained residue was purified by silica gel column chromatography to obtain 6.49 g of a diastereomeric mixture of [(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane as a white solid. It was. The yield was 70%.
[0071]
(Identification data)
Mp 50-65 ℃
¹H NMR (300.4 MHz, CDCl_Three) δ 0.60 (br q, J_HB= 88.6 Hz, 6H), 0.87 (3H), 0.874 (3H), 0.90 (6H), 0.91 (6H), 1.0-1.1 (m, 2H), 1.22-1.33 (m, 18H), 1.22-1.44 (m , 4H), 1.47 (d,²J_HP = 9.6Hz, 6H), 1.70-1.86 (m, 4H), 1.93-2.20 (m, 2H), 5.0-5.17 (m, 2H)
¹³C NMR (75.4 MHz, CDCl_Three) δ4.5 (d, J_CP = 35.4Hz), 13.3, 13.6, 18.8, 19.6, 25.5 (m), 27.1, 27.8, 27.9, 28.6 (d, J_CP = 28.4Hz), 28.7 (d, J_CP = 28.4Hz), 36.7, 36.8, 44.7, 44.8, 48.9, 49.2, 82.8, 83.3, 172.3 (d, J_CP = 70.0Hz), 172.4 (d, J_CP = 69.5Hz)
³¹P NMR (121.5 MHz,¹H decoupled, CDCl_Three ) δ40.8-43.0 (m)
IR (KBr) 2956, 2880, 2378, 1704, 1475, 1368
HRMS EI m / z 297.2155. Calcd for C₁₆H₃₁PB (M⁺-H) 297.2155.
[0072]
Example 3
<Diastereoresolution of diastereomeric mixture of [(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane>
9.96 g of the diastereomeric mixture of [(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane obtained in Example 2 was added to 60 ml of hexane, and this was heated to 60 ° C. And dissolved. Thereafter, the solution was gradually cooled to 0 ° C., and the crystals formed after maintaining at 0 ° C. for 3 hours were filtered off. The filtrate was concentrated and recrystallized again from hexane. A series of procedures consisting of filtering off the crystals, concentrating the filtrate, and recrystallizing from hexane was repeated until no crystals were precipitated. The collected crystals are recrystallized again from hexane to give a 95% diastereomeric (R_P)-[(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane was obtained in 32% yield.
[0073]
(Identification data)
Mp 97.6-99.0 ℃
¹H NMR (300.4 MHz, CDCl_Three) δ 0.60 (br q, J_HB= 90.0 Hz, 3H), 0.87 (3H), 0.89 (3H), 0.90 (3H), 1.01-1.09 (m, 1H), 1.28 (d,^ThreeJ_HP = 14.4 Hz, 9H), 1.27-1.43 (m, 2H), 1.47 (d,²J_HP = 9.8Hz, 3H), 1.69-1.86 (m, 2H), 1.93-2.01 (m, 2H), 2.33-2.50 (m, 2H), 5.00-5.09 (m, 1H)
¹³C NMR (75.4 MHz, CDCl_Three) δ4.5 (d, J_CP = 35.1Hz), 13.6, 18.8, 19.6, 25.5 (d,²J_CP = 1.9Hz), 27.1, 27.8, 28.6 (d, J_CP = 28.6Hz), 36.8, 44.8, 48.0, 49.0, 83.4, 172.4 (d, J_CP = 69.5Hz)
³¹P NMR (121.5 MHz,¹H decoupled, CDCl_Three ) δ41.0-43.0 (m)
IR (KBr) 2956, 2880, 2377, 1702, 1474, 1368
HRMS EI m / z 297.2143.Calcd for C₁₆H₃₁PB (M⁺-H) 297.2155.
[0074]
Example 4
<Synthesis of (S) -t-butylmethylphosphine borane>
Obtained in Example 3 (R_P)-[(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane 596 mg (2 mmol, 95% de) was dissolved in a mixed solution of acetonitrile (10 ml) / methanol (3 ml). A 27% aqueous KOH solution (40 mmol) was added thereto at room temperature, and the mixture was vigorously stirred. After 4 hours, the consumption of the raw material was confirmed by thin layer chromatography, the reaction solution was treated with 1 M aqueous hydrochloric acid, and the organic matter was extracted three times with diethyl ether. The extract solution was washed with water and saturated brine, dehydrated with sodium sulfate, and concentrated with an evaporator. The residue was purified by silica gel column chromatography, and the fraction from which the target product was eluted was concentrated to obtain 177 mg of (S) -t-butylmethylphosphine borane as a white solid. The yield was 75%. When the optical purity of this product was analyzed by chiral HPLC with a 2-picolyl group introduced into (S) -t-butylmethylphosphine borane, it was 95% ee. (Chiral Daicel AD-H column (10% 2-propanol / hexane, 1 mL / min)
[0075]
(Identification data)
[α]²⁰ _D+3.4 (c 1.18, CHCl_Three); The other physical property identification data was the same as that of t-butylmethylphosphine borane.
[0076]
Example 5
<Synthesis of (S) -t-butylmethylphosphine borane>
The amount of KOH used is (R_P)-[(1S) -endo-2-bornyloxycarbonyl] (t-butyl) methylphosphine borane 596 mg (2 mmol, 95% de) to 40 mmol (20 equivalents) to 30 mmol (15 equivalents) The title compound was synthesized under the same conditions as in Example 4 except that the amount was changed to 4), and the yield was 65% and the optical purity of the product was 95% ee.
[0077]
【The invention's effect】
According to the method for producing an optically active secondary phosphine borane derivative according to the present invention, an optically active second compound that is particularly useful as an intermediate material for a bisphosphine ligand having a skeleton of 1,2-bis (phosphino) ethane. A grade phosphine borane derivative can be optionally obtained with high optical purity and can be produced in a large amount at a low cost in a short time.

Claims (5)

The following general formula (1)
(In the formula, R ¹ and R ² represent a linear or branched alkyl group, aryl group or aralkyl group having 1 to 18 carbon atoms, provided that R ¹ and R ² are the same group. A racemic phosphine borane derivative represented by the following general formula (2):
(Wherein, R ^* is a cyclic terpene group that have a optically active, X is a halogen atom.) Is reacted with an optically active carbonate ester halide represented by the presence of a base, the following general formula ( 3)
(Wherein R ¹ , R ^2, and R ^* are as defined above). A diastereomeric mixture of alkoxycarbonylphosphine borane represented by the first intermediate of the optically active secondary phosphine borane derivative is obtained. Body manufacturing method. The following general formula (1)
(In the formula, R ¹ and R ² represent a linear or branched alkyl group, aryl group or aralkyl group having 1 to 18 carbon atoms, provided that R ¹ and R ² are the same group. A racemic phosphine borane derivative represented by the following general formula (2):
(Wherein, R ^* is a cyclic terpene group that have a optically active, X is a halogen atom.) Is reacted with an optically active carbonate ester halide represented by the presence of a base, the following general formula ( 3)
(Wherein R ¹ , R ² and R ^* are as defined above), a first step of obtaining a diastereomeric mixture of alkoxycarbonylphosphine borane, and a diastereomeric mixture of the alkoxycarbonylphosphine borane. The following general formula (4)
(Wherein R ¹ , R ² and R ^* are as defined above, P ^* represents an asymmetric phosphorus atom), and a second step of obtaining an optically active alkoxycarbonylphosphine borane represented by A method for producing a second intermediate of an optically active secondary phosphine borane derivative. The method for producing an optically active alkoxycarbonylphosphine borane according to claim 2, wherein the diastereomer mixture is divided by a recrystallization method. The following general formula (1)
(In the formula, R ¹ and R ² represent a linear or branched alkyl group, aryl group or aralkyl group having 1 to 18 carbon atoms, provided that R ¹ and R ² are the same group. A racemic phosphine borane derivative represented by the following general formula (2):
(Wherein, R ^* is a cyclic terpene group that have a optically active, X is a halogen atom.) Is reacted with an optically active carbonate ester halide represented by the presence of a base, the following general formula ( 3)
(Wherein R ¹ , R ² and R ^* are as defined above), a first step of obtaining a diastereomeric mixture of alkoxycarbonylphosphine borane represented by The following general formula (4)
(Wherein R ¹ , R ² and R ^* are as defined above, P ^* represents an asymmetric phosphorus atom), and a second step of obtaining an optically active alkoxycarbonylphosphine borane represented by Hydrolysis of carbonylphosphine borane in the presence of an alkali agent gives the following general formula (5)
(Wherein R ¹ , R ^2, and P ^* are as defined above), and having a third step of obtaining an optically active secondary phosphine borane derivative represented by the formula: Manufacturing method.   The method for producing an optically active secondary phosphine borane derivative according to claim 4, wherein the diastereomer mixture is divided by a recrystallization method.