JPH05306291A - Optically active diphosphinocarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as e.g. an asymmetric reaction catalyst to be used for producing medicines, pesticides or intermediates therefor, by treatment of a 2,3-bisphosphinyl cyclopropanecarboxylic acid with a reducing agent. CONSTITUTION:A 1,2-bisphosphinylethene derivative of formula I [R'' is 1-6C alkyl or (substituted) phenyl] is made to react with an alpha-halogenocarboxylic ester of formula II [R' is H, 1-6C alkyl or (substituted) phenyl; R is H or 1-6C alkyl; X is halogen] under a basic condition to form a 2,3-bisphosphinyl cyclopropanecarboxylic acid of formula III. Thence, this compound is mixed with an optically active dibenzoyltartaric acid followed by dissolution in ethanol, and the crystal deposited is taken through filtration followed by eliminating the optically resolving agent to separate an optically active 2,3-bisphosphinyl cyclopropanecarboxylic acid, which is then reduced, thus obtaining the objective optically active diphosphinocarboxylic acid derivative of formula IV (Z is PR''2).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an asymmetric reaction catalyst and a ligand thereof which are useful for the production of pharmaceuticals and agricultural chemicals or their intermediates.

[0002]

BACKGROUND OF THE INVENTION It is important that biologically active substances are optically active substances because the living body on which they act has an asymmetric structure. In the production of bioactive substances, there is a strong social demand for producing and providing only optically active substances, from the viewpoints of reducing side effects and protecting the environment. The development of a synthetic method of an optically active compound is an important research theme to meet this demand, and it is being actively studied all over the world regardless of public and private sectors. In particular, the development of a method for producing an optically active compound using an asymmetric reaction catalyst is extremely useful in the synthetic chemical industry because it enables the production of a large amount of an optically active compound from a small amount of an asymmetric source. Many asymmetric reaction catalysts have been developed so far (eg V. Caplar, G. Comisso, and V. Sunjic, Syn.
thesis, 1981, 85 or "Homogeneous Catalysis wit
h Metal Phosphine Complex ", ed. by LH Pignolet,
Plenum Press, New York, 1983). Among them, some practical methods have been reported for asymmetric oxidation catalysts and asymmetric reduction catalysts (for example, "Asymmetric Synthesis", Vol.
5, ed. By JD Morrison, Academic Press, Orlando
(1985)). However, from the viewpoint of industrial application, there are still many problems to be solved such as the economical efficiency of the catalyst and the reaction conditions. For example, the asymmetric allylation reaction catalyst specifically exemplified in the examples of the present invention is used. In
There are several known laboratory-level studies (eg
RF Heck, "Palladium Reagents in Organic Synth
esis ", AcademicPress, London, 117 (1985) or J.
Tsuji, Tetrahedron, 42, 4361 (1986)), no industrially available catalyst has yet been discovered.

[0003]

Means for Solving the Problems As a result of earnest search for economically and highly selective asymmetric allylation catalysts industrially available, the present inventors have found that the diphosphino represented by the general formula [1] The inventors have found that a carboxylic acid derivative can serve as an asymmetric ligand for this purpose, and completed the present invention. That is, the general formula [1]

[0004]

[Chemical 2]

[In the formula, R is a hydrogen atom, or 1 to 6 carbon atoms.
Means an alkyl group having 1 to 6 carbon atoms, R ′ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may be branched, or an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. Means an optionally substituted phenyl group, Z is PR ″ ₂
(R "is an alkyl group having 1 to 6 carbon atoms which may be branched,
Or a phenyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms), or P (O) R " ₂ (R" is the same as described above. The compound represented by [means] means a bidentate-coordinating diphosphinocarboxylic acid, which is an asymmetric ligand of a type that has never been known. The asymmetric ligand represented by the general formula [1] is an extremely economical asymmetric ligand because it can be easily produced from inexpensive raw materials as shown in the examples. Can serve as a reaction catalyst when producing an optically active compound. In addition, the major feature of the transition metal catalyst having a ligand represented by the general formula [1] is that it is compatible with water,
Since it can be used as an effective homogeneous catalyst even in water or a mixed solvent of water and an organic solvent, its application field has expanded greatly. Conventionally, asymmetric reaction catalysts having organic ligands are insoluble in water, which limits their applications. Furthermore, the ligand represented by the general formula [1] can form a complex with various transition metal compounds, and can serve as various asymmetric reaction catalysts depending on the type of the central metal of the complex. For example, the present inventors have already revealed that this type of rhodium complex can be a very useful asymmetric reduction catalyst (Minami et al., Chem. Lett., 1
986, 613). In addition, (Ortho-diphenylphosphino) benzoic acid-nickel complex (RF MASO
N, USP 3686351), the nickel complex of this ligand is expected to be a catalyst for asymmetric polymerization of propylene.

The desired optically active diphosphinocarboxylic acid derivative can be synthesized by the following route. That is, a 1,2-bisphosphinylethene derivative [2] substituted with R ″ and an α-halogenocarboxylic acid ester [3]
(X represents halogen) is reacted under basic conditions to obtain cyclopropanecarboxylic acid [4]. When a cis-1,2-bisphosphinylethene derivative is used as a starting material, cis-2,3-bisphosphinylcyclopropanecarboxylic acid is obtained, and a trans-1,2-bisphosphinylethene derivative is used. And trans-2,3-bisphosphinylcyclopropanecarboxylic acid is obtained. As the base, butyl lithium, phenyl lithium, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride and the like are used. Reaction solvent is tetrahydrofuran, hexane, ether, toluene, HM
PA, DMSO, DMF or the like can be used. The reaction can be carried out in the range of -100 ° C to room temperature, preferably -80 ° C to -20 ° C.

2,3-Bisphosphinylcyclopropanecarboxylic acid [4] can be optically resolved by using an optically active carboxylic acid derivative. As the optically active carboxylic acid derivative, dibenzoyl tartaric acid is particularly preferable. Optically resolved 2,3-bisphosphinylcyclopropanecarboxylic acid [5] is a novel compound that can be used as a ligand of an asymmetric reaction catalyst.

When 2,3-bisphosphinylcyclopropanecarboxylic acid [5] is treated with a reducing agent, optically active 2,3
-Bisphosphinocyclopropanecarboxylic acid [6] is obtained. As a reducing agent, hydrogen, trichlorosilane, N
A combination of an inorganic acid such as aBH ₄ , HCl / Fe and a transition metal compound can be used. Reaction is from -100 ℃ to 1
It can be performed in the range of 50 ° C., and high pressure may be preferable depending on the type of reducing agent. Any reaction solvent may be used as long as it does not inhibit the reduction reaction, and the solvent is not always necessary. The optically active 2,3-bisphosphinocyclopropanecarboxylic acid [6] thus obtained is a novel compound and is very useful as a ligand for an asymmetric reaction catalyst.

[0009]

[Chemical 3]

These ligands can form complexes with various transition metal compounds. Examples of transition metal compounds include titanium, vanadium, chromium, manganese, molybdenum, tin, copper, zinc, iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, platinum, and other hydrochlorides, sulfates, nitrates. , Acetate, phosphine, carbonyl complex and the like. Specific examples include palladium chloride, palladium sulfate, palladium nitrate, palladium acetate and the like. By changing the kind of the transition metal compound or the reaction conditions, it can be used as an asymmetric reaction catalyst such as asymmetric alkylation reaction, asymmetric reduction reaction, asymmetric oxidation reaction, asymmetric addition reaction and the like. These do not particularly need to be isolated, and a ligand and a transition metal compound may be added to the reaction system to form a complex in the system.
In this case, the ratio of the added ligand to the transition metal compound is 0.01 mol equivalent to 10 parts of the transition metal compound with respect to the ligand.
It is a molar equivalent, preferably 0.1 molar equivalent to 2 molar equivalents. The amount of catalyst used is 0.01 mol% to 20 mol
%, Preferably 0.1 mol% to 5 mol%.
The reaction temperature and reaction solvent are not particularly limited, but depend on the type of reaction to be performed. In addition, an imidazole derivative,
Other ligands such as pyridine derivatives and phosphine derivatives can coexist.

[0011]

The present invention will be described in detail below with reference to examples (synthesis examples, asymmetric catalytic reaction examples), but the present invention is not limited to these examples. Reference Example Synthesis of t-butyl trans-2,3-bis (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylate Diisopropylamine (DIA) 0.33 ml THF
1.3 ml of a hexane solution of n-butyllithium was added dropwise to 5 ml of the solution at −70 ° C. to prepare LDA, and t-butyl α-chloropropionate (0.33 g, 2 m
3 ml of THF solution of (mol) was added dropwise. After stirring for 30 minutes, trans-1,2-bis (diphenylphosphinyl) ethene (0.43 g, 1 mmol) was added. The mixture was stirred overnight at room temperature and then heated with stirring for 1 hour. 2N
The reaction was stopped by adding hydrochloric acid, and the mixture was extracted with chloroform. After the solvent was distilled off, the residue was separated and purified by TLC (chloroform / ethyl acetate 1/1), and t-butyl trans-2,3-bis (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylic acid was used. (0.45 g, 81% of yield, mp192-197 degreeC) was obtained.

IR (KBr) 1720, 1435, 1190, 1120 cm ^-1 ; 1H
NMR (CDCl ₃ ) d 1.30 (s, 9H, t-Bu), 1.71 (s, 3H, CH
₃ ), 2.10-3.10 (m, 2H, CH), 7.00-8.20 (m, 20H,
Ar-H)

Example 1 Optical Resolution of trans-2,3-bis (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylic acid t-butyl Optically active dibenzoyl tartaric acid and trans-2,3-bis T-Butyl (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylic acid was mixed and dissolved in ethanol, and crystals that precipitated after a while were collected by filtration. The crystals were treated with chloroform-sodium hydroxide to remove the resolving agent, and then subjected to column chromatography or TLC.
Separated and purified in.

[Α] _D −55.86 (c = 1.1
3, methylene chloride) [α] _D +54.32 (c = 1.04, methylene chloride)

(Example 2) (-)-transformer-2,3
-Bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid t-butyl synthesis (-)-trans-2,3-bis (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylic acid
t-Butyl (3.54 g, 6.36 mmol), benzene 5 ml and trichlorosilane 4 ml (40 mmo
l) was reacted in a sealed tube at 110 ° C. for 7 hours. After distilling off excess trichlorosilane and benzene under reduced pressure, a 25% aqueous sodium hydroxide solution was added, and the mixture was extracted with benzene. After the solvent was distilled off, the residue was separated and purified by column chromatography (eluent: chloroform) to give (-)-trans-2,3.
-Bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid t-butyl (3.20 g,
Yield 96%, mp119-121 ° C) was obtained.

IR (KBr) 1710, 1430, 1130 cm ^-1 ; 1H NMR
(CDCl ₃ ) d 1.30 (s, 9H, t-Bu), 1.65 (s, 3H, CH ₃ ),
1.72-2.08 (m, 1H, CH), 2.32-2.82 (m, 1H, CH),
6.90- 7.64 (m, 20H, Ar-H) [α] _D −33.11 (c = 3.66, methylene chloride)

(Embodiment 3) (+)-transformer-2,3
Synthesis of t-butyl-bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid (+)-trans-2,3-bis (diphenylphosphinyl) -1-methyl-1-cyclopropanecarboxylic acid acid
The same treatment is performed using t-butyl as a starting material,
(+)-Trans-2,3-bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid t
-Butyl was obtained.

[Α] _D +30.33 (c = 1.3
8, methylene chloride)

(Example 4) (-)-transformer-2,3
-Synthesis of bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid (-)-trans-2,3-bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid t
-Butyl (0.85 g, 1.62 mmol) in p-toluenesulfonic acid (0.63
g, 3.31 mmol) was added and the mixture was heated under reflux for 2 hours. After adding water and extracting with chloroform, the solvent was distilled off,
The residue was separated and purified by column chromatography (chloroform / ethyl acetate 1/1), and (-)-trans-
2,3-bis (diphenylphosphino) -1-methyl-
1-Cyclopropanecarboxylic acid (0.51 g, yield 7
1%, mp174-179 ° C) was obtained.

IR (KBr) 1690, 1430, 690 cm ^-1 ; 1H NMR
(CDCl ₃ ) d 1.65 (s, 3H, CH ₃ ), 1.76-2.15 (m, 1H, C
H), 2.46-2.90 (m, 1H, CH), 6.80-7.60 (m, 20H,
Ar-H), 9.59 (br s, 1H, COOH) [α] _D −55.39 (c = 6.60, methylene chloride)

(Embodiment 5) (+)-transformer-2,3
Synthesis of -bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid (+)-trans-2,3-bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid t
-Butyl is used as a starting material and the same treatment is performed (+)-
Trans-2,3-bis (diphenylphosphino) -1
-Methyl-1-cyclopropanecarboxylic acid was obtained.

[Α] _D +46.57 (c = 1.2
6, methylene chloride)

Example 6 Reaction Example (Asymmetric Allylation Reaction) (2-Cyclohexenyl) diethylphosphonoacetate Synthesis of 1-menthyl palladium acetate (3.5 mg, 0.015 mmol)
And (-)-trans-2,3-bis (diphenylphosphino) -1-methyl-1-cyclopropanecarboxylic acid (5.6 mg, 0.012 mmol) in 5 ml of a THF suspension in 2-cyclohexenyl acetate ( 0.14
g, 1.0 mmol) was added. Sodium hydride (60% oily, 60 mg,
1.5 mmol) and diethylphosphonoacetate 1-menthyl (0.56 g, 1.7 mmol) prepared from diethylphosphonoacetate 1-menthyl sodium THF
5 ml of the solution was added and reacted at 65 ° C. for 5 hours. 2N
After adding hydrochloric acid to stop the reaction, the mixture was extracted with ethyl acetate, washed with water and dried, and then the solvent was distilled off under reduced pressure. Residue to T
Separation and purification by LC (chloroform / ethyl acetate 1/1), (2-cyclohexenyl) diethylphosphonoacetic acid
1-menthyl was obtained (yield 100%, optical purity 61%
ee).

Claims (4)

[Claims] 1. A formula [1]: [In the formula, R means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R'is a hydrogen atom, and may have 1 carbon atom which may be branched.
~ 6 alkyl group, or a phenyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, Z is PR " ₂ (R" is Alkyl group having 1 to 6 carbon atoms which may be branched, or 1 carbon atom
Means a phenyl group which may be optionally substituted with 4 to 4 alkyl groups and an alkoxy group having 1 to 4 carbon atoms), or P (O) R " ₂ (R" has the same meaning as above). An optically active compound represented by 2. A method for producing an optically active compound in the presence of the compound according to claim 1 and a transition metal compound. 3. A method for producing an optically active compound in the presence of the compound according to claim 1 and a palladium compound. 4. A method for producing an optically active compound using an asymmetric allylation reaction in the presence of the compound according to claim 1 and a palladium compound.