JPH03188091A - Optically active 3,4-bisphosphinopyrrolidine compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, R',-COR'' or- COOR'' ' (R', R'' and R''' are alkyl, aryl and arylalkyl); R<2> is cyclohexyl or phenyl having 1-3 pieces of substituting group such as di(lower alkyl)amino group]. EXAMPLE:(3R,4R)-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]pyrrolid ine. USE:Used as a ligand of rhodium metallic complex catalyst simultaneously satisfiable of asymmetric yield and reaction efficiency. PREPARATION:1-substituted-3,4-dimethane sulfonyl oxypyrrolidine is reacted with phosphinometal expressed by formula II (M is alkali metal) in the presence of crown ether. Besides, said pyrrolidine is preferably obtained by using optically active tartaric acid as raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel optically active 3,4-bisphosphinopyrrolidine compounds.

More specifically, the present invention provides compounds having asymmetric carbon atoms by hydrogenating carbon-carbon double bond structures, carbon-nitrogen double bond structures, and/or carbon-oxygen double bond structures. The general formula as a ligand in a metal complex compound used as a catalyst in carrying out a reaction to produce a metal complex, R1 (wherein, R1 is a hydrogen atom, R', -COR'', -CO
OR"' or -CONHR", R', R1), R
``'' and R'' each represent an alkyl group, an aryl group, or an arylalkyl group, and R2 represents one to one of the substituents selected from a cyclohexyl group, a di(lower alkyl)amino group, a lower alkoxyl group, or a lower alkyl group. Optical activity 3, represented by a phenyl group having 3
This invention relates to 4-bisphosphinopyrrolidine compounds.

Conventionally, in the field of synthetic chemistry, many studies have been conducted on asymmetric reduction reactions that can directly synthesize optically active compounds. As one example, many bisphosphine ligands have been synthesized, and asymmetric reduction reactions have been attempted using combinations of these ligands and various metals.

Asymmetric yield (optical yield) and reaction yield (Note: Regarding the reaction rate, if the reaction rate is slow, the amount used will be large, so one way to show the relationship is to calculate the molar ratio of the substrate and the ligand. Many researchers are searching for a ligand that simultaneously satisfies the following: (expressed as a ratio).

The present inventor has conducted intensive research to develop an asymmetric synthesis method that can simultaneously satisfy both the asymmetric yield and the reaction efficiency in an asymmetric reduction reaction, and through this research, the above problems have been solved. The present inventors have succeeded in providing a novel optically active 3,4-bisphosphinopyrrolidine compound as an excellent ligand, and have now provided a novel asymmetric synthesis method using this compound. The present invention will be explained in detail below.

Wolfgang Beck et al. optically active 3,4-bis-(diphenylphosphino) represented by the formula, (wherein Ph represents a phenyl group and R represents hydrogen, an alkyl group, an arylalkyl group or an acyl group) Synthesize pyrrolidine and use it to create β-substituted-α
- Performing asymmetric hydrogenation of acylaminoacrylic acid (
JP-A-60-185793).

The present inventor synthesized (3R,4R)-1-benzyl-3,4-bis(diphenylphosphino)pyrrolidine [Degphos], which is one of the compounds represented by the above formula (II). hydrogenation of acid at 5 atm;
When I tried it at 50℃ for 20 hours, the substrate/catalyst =
10,000 (molar ratio), conversion rate 44%, asymmetric yield 8
1% (see Reduction Example 8).

It is estimated that one of the two diphenylphosphino groups of the compound represented by formula (n) affects the catalytic efficiency, and the other affects the asymmetric yield. (Reference: Pharmacia Review Vol. 24, p. 71) If a phenyl group with 1 to 3 of an alkyl group, an alkoxyl group, or a dialkylamino group, which is an electron-donating substituent, is used instead of the phenyl group of the diphenylphosphino group of the compound represented by If), the electron-donating group We thought that we could expect to improve the catalytic efficiency and the asymmetric yield by attaching a bulky group.

An optically active 3°4-bisphosphinopifinovirolidine compound represented by the general formula (I) was synthesized, an asymmetric hydrogenation was attempted using it, and it was found that it is suitable for that purpose.

For example, (3R,4R)-1-benzyl-3,4-bis[
Di(3,5-dimethyl-4-methoxyphenyl)phosphinocopyrrolidine [MOD-Deg] was synthesized and hydrogenation of α-acetamidocinnamic acid was performed under the same conditions as above (5 atm,
50℃, 20 hours) Substrate/Catalyst =
10,000 (molar ratio), the conversion rate was 100% and the asymmetric yield was 92% (see Reduction Example 3).

In this way, by using the optically active 3,4-bisphosphinopyrrolidine compound represented by the formula (I) of the present invention as a ligand of a catalyst in asymmetric hydrogenation, the asymmetric yield and reaction efficiency can be improved. It has been found that extremely excellent results can be obtained in both industrial implementations.

The compound of the present invention, an optically active 3,4-bisphosphinobifinobyrolidine compound represented by the general formula (1), can be produced, for example, by the following method.

1-Substituted-3,4 obtained using optically active tartaric acid as a raw material
-dimethanesulfonyloxypyrrolidine and the general formula, (wherein R2 is phenyl having 1 to 3 substituents selected from a cyclohexyl group, a di(lower alkyl)amino group, a lower alkoxyl group, or a lower alkyl group. and M represents an alkali metal) in the presence of a crown ether.

At this time, if we start from (+)-tartaric acid, (3R,4R
) body, starting from (−)-tartaric acid, (3S, 4S
) body can be obtained.

In the optically active 3゜4-bisphosphinopyrrolidine compound represented by the general formula (1), the substituent R1 at position 01 in the formula is a hydrogen atom, R', -COR", -COOR"
' or -CONHR'', R', Rjj, Rjj
9 and R" each represent an alkyl group, an aryl group, or an arylalkyl group, and R', R11, R"'
Examples of each alkyl group of R'' include C1 to C6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, 5eC-butyl, tert-butyl, etc. Examples of aryl groups include: Examples of arylalkyl groups include phenyl and pyridyl groups, and benzyl groups are examples of arylalkyl groups. It can have a group, etc.

R2 is a phenyl group having 1 to 3 substituents selected from a cyclohexyl group, a di(lower alkyl)amino group, a lower alkoxyl group, or a lower alkyl group, such as 2-dimethylaminophenyl, 3-dimethyl Aminophenyl, 4-dimethylaminophenyl, 3,5-dimethyl-4-dimethylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2
, 4-dimethoxyphenyl, 3.5-dimethyl-4-methoxyphenyl, 2-tolyl, and 4-tolyl groups.

Optical activity 3 represented by formula (I) obtained in this way
, 4-bisphosphinopyrrolidine compounds can be used in asymmetric hydrogenation as ligands for rhodium metal complex catalysts.

As a method for preparing a catalyst used for asymmetric hydrogenation, the formula (I
), a rhodium complex such as a rhodium-cyclooctadiene-chlor complex or a rhodium-norbornadiene-chlor complex, and tetrafluoroboric acid, hexafluorophosphoric acid or perchlorine. It can be prepared by reaction with an alkali metal salt or silver salt of an acid. In addition, rhodium cation complexes such as rhodium-dicyclooctadiene-perchlorate complex and rhodium-dicyclooctadiene-tetrafluoroboric acid complex, and optically active 3,4-bisphosphophos represented by formula (I) It can be prepared by reacting with a finopyrrolidine compound.

These may be prepared in the hydrogenation reaction system at the time of use, or may be prepared and isolated in advance.

The method for carrying out the asymmetric hydrogenation reaction will be explained by taking as an example the case where N-acetylphenylalanine is produced from α-acetamidocinnamic acid.

Common solvents used in catalytic reduction reactions, such as water, methanol, ethanol, isopropyl alcohol, acetic acid,
Using ethyl acetate, tetrahydrofuran, dioxane, etc. as a solvent, 25 mmol of α-acetamidocinnamic acid, 0.25 mmol to 0.00025 mmol of rhodium-dicyclooctadiene-perchloric acid complex, and a ligand in 40 ml of the solvent. Add optically active 3,4-bisphosphinopyrrolidine compound (I) as 1.0 to 2.0 times the mole of the rhodium-dicyclooctadiene-perchloric acid complex, preferably at normal pressure or under pressure. is reaction temperature 0℃-1
The hydrogenation reaction is carried out at 50°C. After the reaction is completed, the solvent is distilled off and the residue is appropriately treated to obtain optically active N-acetylphenylalanine as a reaction product in high yield.

Below, examples of production of the optically active 3,4-bisphosphinopyrrolidine compound according to the present invention and examples of asymmetric reduction using the same are listed to further explain the present invention, but are not intended to limit the present invention. .

Reference example 1 40% in 4-bromo-2,6-xylidine (6.9g)
Formalin aqueous solution (6.4 g) and formic acid (51.5 g
) and heat for 2 hours, boiling under reflux. After cooling, add concentrated hydrochloric acid (
5 ml) was added, concentrated under reduced pressure, and vacuum distilled until the boiling point was 135.
A fraction of N,N-dimethyl-4-bromo-2,6-xylidine (7.8 g) was obtained at ~145°C/3 Torr.

Under an argon atmosphere, magnesium (3°6 g) was placed in tetrahydrofuran (hereinafter abbreviated as THF) (5 ml), and a THF (150 ml) solution of N,N-dimethyl-4-bromo-2,6-xylidine (23 g) was added. Drip. After boiling under reflux for 2 hours, a solution of diethylbosphite (4.1 g) in THF (30 ml) was added dropwise while cooling with water. After stirring overnight at room temperature, boil under reflux for 1 hour.

After cooling, saturated ammonium chloride aqueous solution (150 ml) was added, stirred for 30 minutes, filtered, and the residue was washed with ethyl acetate. The washing solution is separated into layers, and the aqueous layer is extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain bis(3,5
4.5 g of -dimethyl-4-dimethylaminophenyl)phosphine oxide were obtained as an oil.

Cerium chloride heptahydrate (8.4 g) was dried under reduced pressure at 120°C, cooled, and THF (20 ml) was added under an argon atmosphere, followed by stirring for 30 minutes. Water-cooled condensed lithium aluminum hydride (2,Qg) is added. Bis(3,5-dimethyl-4-dimethylaminophenyl)phosphine oxyto(
Add a solution of 4°0 g) dissolved in THF (50 ml). - Boil under reflux overnight. After cooling with water, degassed toluene (50 m
1) and stirred at 40°C for 30 minutes.

Cool again and separate the toluene layer by decanting. It was extracted again with degassed toluene (50 ml), the toluene layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and vacuum distilled to obtain 2.0 g of bis(3,5-dimethyl-4-dimethylaminophenyl)phosphine. . (boiling point 220-24
Example 1 Under an argon atmosphere, bis(3,5-dimethyl-4-methoxyphenyl)phosphine (4°7g) was dissolved in THF (2 Torr).
0 ml) and cooled to -40°C. 1.57M
-n-Butyllithium-hexane solution W (9.8 ml) was added and stirred for 15 minutes. Crown ether (12-C
(4.1 ml) was added dropwise and stirred for an additional 15 minutes.

(3S, 4S) -1-benzyl-3,4-dimethanesulfonyl-sibirolidine (1,8 g) in THF (10
ml) solution dropwise.

Add degassed DMF until it becomes red and transparent, and store at -30°C.
Stir overnight.

The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (3R,4R)-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphinocopyrrolidine (
880 m as an oily substance (hereinafter abbreviated as MOD-Deg)
I got g.

'H-NMR(CDCl2)δ: 2.16(
24H, d, J=22.4Hz, m-C)13-)
, 2.40-2.51 (2) 1. m, P-CH)
, 2°82~2.94 (4H, m, N-C) (2)
, 3.40 (IH, d, J=13.5Hz, N-
CHPh), 3.64 (IH, d, J=13.5H
z, N-CHPh), 3.66 (12H, d, J
=8. ．． 8Hz, CthO), 6.93-7.29
(13H, m, arom,).

I R(KBr) ν1Iax cm-': 1473
．． 1206.1102°1iot.

[a]n +54-7' (c O,72
,) toluene, 22°C) Example 2 Bis(4-methoxyphenyl)phosphine was reacted, post-treated and purified in the same manner as in Example 1 to form (3R,4R)-bis[di(4-methoxyphenyl)phosphine. Finocopyrrolidine (hereinafter abbreviated as PMO-Deg) was obtained as an oil.

'HNMR (CDCIa) δ: 2.45-2.58
(2)1. m.

P-CH), 2.72-3.15 (4N, m, N
-Cl42), 3.50 (IH.

d, J=13.2Hz, N-C)lPh), 3.
72(IH, d, J=13.2Hz, N-CI(P
h), 3.76 (12H, d, J=1.5Hz,
Ch,), 6゜61~7.34 (21H, m, ar
om,).

T RCKBr) VvsaX Cm-': 15
86.1490.1247°1240, 1165.11
10° [α]D+110.5° (co, 83.
) Ruesi, 22°C) Example 3 Bis(3,5-dimethyl-4-dimethylaminophenyl)phosphine was reacted, worked up and purified in the same manner as in Example 1 to give (3R,4R)-bis[di( 3,5-dimethyl-
4-dimethylaminophenyl)phosphinocopyrrolidine (hereinafter abbreviated as XYL-Deg) was obtained as an oil.

'HNMR (CDCl2) δ: 2.18 (24) 1
．． d, J=12.8Hz, m-Ch-)s 2.
10-2.27.2.45-2.57.2.80-2.
89 (6H, m, P-CH, N-CH2), 2.7
7 (241 (, d.

J=3.4. (CH3)2-N), 3.39(1N
, d, J=13.5Hz, N-CHPh), 3
．． 60(l)I, d, J-13,5Hz, N-C
HPh), 6.95-7.28 (13) 1. m,
arom,).

IR (Br) l/+++ex Cm-': 14
60.1262.1164°1115° [αID-7,8° (c O,75,) Ruesi,
22℃) Example 5 Methanol (20 ml) and 5% rhodium-carbon (0.5 g) were added to (3R,4R)-bis(diphenylphosphono)pyrrolidine (1.0 g), and the hydrogen pressure was 10 in an autoclave.
The reaction is stirred at 100° C. for 5 days at 0 atmospheric pressure. The catalyst was removed from the oven and concentrated under reduced pressure to obtain 3R,4R)-bis(dicyclohexylphosphono)pyrrolidine (o, ssg) as an amorphous solid.

Under an argon atmosphere, (3R,4R)-bis(dicyclohexylphosphono)pyrrolidine (0.50 g) was dissolved in acetonitrile (40 ml) and triethylamine (1.6 g) was added.
) add. Trichlorosilane (3.0 ml) was added dropwise under water cooling.

After refluxing for 40 hours, a 30% aqueous solution of caustic soda (30 ml) and benzene (30 ml) were added to the reaction mixture under water cooling, and the mixture was stirred at room temperature for 1 hour. The benzene layer is separated, and the aqueous layer is further extracted with benzene.

The benzene layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain (3R,4R)-bis(dicyclohexylphosphino)pyrrolidine (0.42 g) as an oil.

Bis(dicyclohexylphosphino) under argon atmosphere
Dissolve pyrrolidine (0.46 g) in benzene (20 ml) and add triethylamine (222B). Under water cooling,
Benzoyl chloride (155 mg) is added dropwise.

After 3 hours at room temperature, the reaction solution was washed with saturated aqueous sodium bicarbonate (10 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and
R,4R)-1-benzoyl-bis(dicyclohexylphosphino)pyrrolidine (0.34 g) was obtained as an amorphous solid.

Under argon atmosphere (3R,4R)-1-benzoyl-bis(dicyclohexylphosphino)pyrrolidine (0,3
0 g) in THF (10 ml), lithium aluminum hydride (114 mg) was added under water cooling, and the mixture was stirred at room temperature for 3 hours.

After decomposition by adding water, filter and wash with toluene.

The furnace liquid and washing liquid were combined and concentrated under reduced pressure, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (3R,
4R)-1-benzyl-bis(dicyclohexylphosphino)pyrrolidine (hereinafter abbreviated as Cy-Deg) 'HNMR (CDCl2) δ: 1.00-2.2
1 (44H, m, cyclohexyl), 2.5
4-3.03 (6N, m, P-C)l, N-C)
+2), 3.63 (IH, d, J=13.5Hz,
N-CHPh), 3.78 (IH, d, J=13
．． 5Hz, N-C)lPh), 7.28-7.45
(5)1. m.

arom, )- J R (KBr) ν+*ax cm-': 14
55. 1140. 1103°[α]o −6,5
1″ (c O,8+1.)Luene, 2
2℃) Reduction Examples 1 to 15 Under an argon atmosphere, rhodium-dicyclooctadiene-perchlorate complex (1.1 mg), asymmetric ligand (0,003 mol) and degassed methanol (1 ml) were added for 10 minutes. Stir. α-acetamidocinnamic acid (513 mg) in methanol (4 m
l) Add the solution and the above catalyst solution, replace with hydrogen, bring to a predetermined hydrogen pressure, and perform the hydrogenation reaction with stirring at 50° C. for 20 hours. After the reaction was completed, the solvent was distilled off, dissolved in 0.5N aqueous sodium hydroxide solution, insoluble matter was removed in an oven, and the solution was made acidic with dilute hydrochloric acid.
Extract with ether. After washing the organic layer with water and drying, the solvent was distilled off to obtain optically active (S)-N-acetylphenylalanine.

When substrate/Rh=10,000, 1 ml of O was measured out from the above prepared solution using a microsyringe and used.

When substrate/Rh=20,000, use a microsyringe to measure out 0.05ml from the above prepared solution.
Reduction conditions) Substrate/Rh Hydrogenation conditions 1.000 5atm 150℃/20hr10.00
0 20atm150℃/20hr10.000 5
atm150℃/20hr20.000 50atm1
50℃/20hr20.000 20atm150℃/
20hr1.000 5atm150℃/20hr1
0.000 20atm150℃/20hr10.00
0 5atm150℃/20hr20.000 50
atm150℃/20hr20.000 20atm1
50℃/20hr1.000 5atm150℃/2
0hrto, 000 20atm150°C/20hr
10.000 5atm150℃/20hr20.0
00 50atm150℃/20hr20.000 2
0atm 150℃/20hr.

The results are shown in Table 1.

table asymmetric ligand MOD-Deg MOD　-Deg MOD-Deg MOD-Deg MOD-Deg PMO-Deg PMO-Deg PMO-Deg PMO-Deg PMO-Dea XYL-Deg xvt, -1) eg KYL-Deg XYL-Deg XYL-Deg Table l.

No, conversion rate 1100χ 2100χ 3 100% 4100χ 5100χ 6100χ 7100χ 8 100% 66z 1055χ 11 100χ 12 100$ 13 100χ 14 100% 15 100χ (Result) Optical purity 94χ ee (S) 92χee (S) 921ee (S) 87χee ( S) 91χee (S) 92Xee (S) 91χee (S) 92χee (S) 84χee (S) 75χee (S) 90χee (S) 92χee (S) 87χee (S) 90χee (S) 89χee (S) Reduction example 16~ 20 Using Degphos as the asymmetric ligand, the reaction and post-treatment were carried out in the same manner as in Reduction Example 1. The results are shown in Table 2.

Table chiral ligand Degphos Degphos Degphos Degphos Degphos 2, (reduction conditions) Substrate/Rh Hydrogenation conditions 1.000 5atm150℃/20hr10.00
0 20atm150℃/20hr10.000 5
atm150℃/20hr20.000 50atm1
50℃/20hr20.000 20atm150℃/
20hr table 2. (Conversion rate 0oz 100% 4X 32χ 24χ result) Optical purity 90χee (S) 761ee (S) 81$ee (S) 72χee (S) 79Xee (S)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom, R^3, -COR'', -
COOR"' or -CONHR"", R', R"
, R'' and R'' each represent an alkyl group, an aryl group, or an arylalkyl group, and R^2 is a substituent selected from a cyclohexyl group, a di(lower alkyl)amino group, a lower alkoxyl group, or a lower alkyl group. Base 1~
An optically active 3,4-bisphosphinopyrrolidine compound represented by (representing a phenyl group having three groups). 2. The optically active 3,4-bisphosphinopyrrolidine compound according to claim 1, wherein in the general formula (I), R^2 is a 3,5-dimethyl-4-methoxyphenyl group. 3. The optically active 3,4-bisphosphinopyrrolidine compound according to claim 1, wherein R^2 in the general formula (I) is a 3,5-dimethyl-4-dimethylaminophenyl group.