JP3310084B2 - Process for producing optically active 4-methyl-2-oxetanone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing optically active 4-methyl-2-oxetanone, which is useful as an intermediate in the synthetic organic chemical industry such as a raw material for a polymer, a raw material for synthesizing a drug or a liquid crystal material.

[0002]

2. Description of the Related Art Conventionally, 4-methyl-2-oxetanone ("β-butyrolactone" or "β-methyl-β-
"Propiolactone") is, for example,
Ketene and acetaldehyde are reacted as described in US Pat.
It has been produced by hydrogenating 4-methylene-2-oxetanone (also referred to as "diketen") using palladium black as described in U.S. Pat. No. 763,644.

The 4-methyl-2-oxetanone is described, for example, in Yuya Yamashita et al. (Industrial Chemistry Magazine, Vol. 66, No. 1, 110-
As reported on page 115 (1963)), it has been used as a raw material for polymers and the like. In recent years, for example, N. Tanahashi et al .; Macromolecules, Vol.
As reported in pp.5732-5733 (1991), the optically active substance has been particularly noted as being useful. In the above-mentioned conventional production method, only a racemic form of 4-methyl-2-oxetanone can be produced, and at present, the following method has been reported as a method for producing an optically active substance.

A method of optically resolving 3-bromobutyric acid obtained by adding hydrobromic acid to crotonic acid using optically active naphthylethylamine, followed by cyclization (J. Reid
Shelton et al; Polymer Letters, Vol.9, pp.173-178 (1
971) and T. Sato et al .; Tetrahedron Lett., Vol. 21, pp. 3
377-3380 (1980)).

The reaction of optically active 3-hydroxybutyric acid with triethylorthoacetic acid allows the production of optically active 2-ethoxy-
2,6-dimethyl-1,3-dioxan-4-one is obtained,
Pyrolysis of this (A. Griesbeck et al .; Helv. Chim. Ac
ta, Vol. 70, pp. 1320-1325 (1987) and R. Breitschuh
Chimia, Vol. 44, pp. 216-218 (1990)).

A method of reacting an optically active 3-hydroxybutyrate with methanesulfonyl chloride to mesylate a hydroxyl group, hydrolyzing the resulting ester, and then condensing and cyclizing with sodium hydrogen carbonate (Y. Zhang et al.) ; M
acromolecules, Vol.23, pp.3206-3212 (1990)).

[0007] 4-methylene-2-oxetanone is
In an aprotic solvent such as methylene chloride or tetrahydrofuran, [RuCl [(S)-or (R)-
BINAP] (benzene)] Cl or Ru ₂ Cl
₄ [(S)-or (R) -BINAP] ₂ (NE
t ₃ ) (wherein “BINAP” represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and Et represents an ethyl group) and a method for asymmetric hydrogenation (T .
Ohta et al., J.CHEM.SOC., CHEM.COMMUN., Pp.1725-1726 (199
2)). In this method, the importance of using an aprotic solvent is emphasized.
It was generally understood that an unnecessary reaction was expected to occur between the starting compound and the protic solvent in view of the structure, and the yield was reduced.

[0008]

The processes for producing optically active 4-methyl-2-oxetanone which have been reported so far have the following problems, and are not sufficiently satisfactory. I could not say. In other words, the method requires a special optically active amine as an optical resolving agent in an equimolar amount with the raw material compound, and an unnecessary enantiomer is by-produced in an equimolar amount with the target substance, so that the method is wasteful and economically advantageous. is not.

In the methods (1) and (2), it is not easy to synthesize optically active 3-hydroxybutyric acid or an ester thereof as a starting compound. That is, an optically active poly-3-hydroxybutyrate produced by a microorganism is thermally decomposed, or a racemic 4-methyl-2-oxetanone is converted to an acetoacetate by an alcoholysis reaction followed by asymmetric reduction. It has to be performed, the number of steps is large, and the operation is complicated.

Although the method has solved many of the problems of the above-mentioned methods, it still has some problems. That is, since the catalyst activity is deactivated during the reaction, the amount of the catalyst used is large and the reaction time is long. When methylene chloride was used as the solvent, the reaction time was shorter than in the case where tetrahydrofuran was used, but the selectivity of the product was lowered, and it was not an industrially satisfactory method.

Therefore, there is a need for a method of overcoming these problems and efficiently producing optically active 4-methyl-2-oxetanone, and the present invention is directed to solving the problem.

[0012]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, asymmetric hydrogenation of 4-methylene-2-oxetanone using a ruthenium-optically active phosphine complex as a catalyst has been carried out. In the method for producing active 4-methyl-2-oxetanone, by using a solvent containing an alcohol which is a protic solvent, the amount of catalyst is surprisingly smaller than that of the above method,
The inventors have found that asymmetric hydrogenation is possible with a shorter reaction time, and completed the present invention.

That is, the present invention relates to 4-methylene-2-
A process for producing optically active 4-methyl-2-oxetanone by asymmetric hydrogenation of oxetanone using a ruthenium-optically active phosphine complex as a catalyst, comprising using a solvent containing alcohols.
The present invention provides a method for producing 2-oxetanone.

As the solvent containing alcohols used in the present invention, any solvent can be used as long as it contains alcohols. That is, a single alcohol solvent, a mixed solvent of multiple alcohols,
Alternatively, any of alcohols and a mixed solvent other than alcohols may be used. However, the content ratio of alcohols to the entire solvent varies depending on the type of alcohols used, but is preferably about 10 to 100% by weight, particularly preferably about 10 to 50% by weight.

In the present invention, "alcohols"
Methanol, ethanol, isopropanol, tert
Monohydric alcohols such as -butyl alcohol; polyhydric alcohols such as 1,3-butanediol; and compounds such as hydroxy acids having an alcoholic hydroxyl group such as methyl 3-hydroxybutyrate.

When an alcohol and a mixed solvent other than the alcohol are used, the solvent other than the alcohol is methylene chloride, acetone, methyl ethyl ketone, or the like.
Aprotic solvents such as methyl butyl ketone, tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate and the like. In the presence of an acid such as acetic acid or propionic acid, a side reaction occurs, which is not preferable.

According to the present invention, except that a solvent containing an alcohol is used as the solvent as described above,
Using a ruthenium-optically active phosphine complex as a catalyst,
Optically active 4-methyl-2-oxetanone can be produced by asymmetric hydrogenation of methylene-2-oxetanone.

That is, for example, a solvent containing a ruthenium-optically active phosphine complex, 4-methylene-2-oxetanone as a starting compound and alcohols is added to a pressure-resistant container under a nitrogen atmosphere, and asymmetric hydrogen is added under a hydrogen atmosphere. Should be done.

The starting compound 4-methylene-2-oxetanone used in the method of the present invention can be prepared, for example, by the method reported by RJ Clemens et al. (Chem. Rev., Vol. 8).
6, pp. 241-318 (1986)), and can be easily obtained by synthesis by thermally decomposing acetic acid or acetic anhydride.

Examples of the ruthenium-optically active phosphine complex used as a catalyst in the method of the present invention include, for example, optically active complexes represented by the following general formulas (1) to (5).

Optically active complex 1: RuxHyClz (CBP) ₂ (A) w (1) (where CBP is R ¹ -BINAP or BIPHEP)
A represents a tertiary amine, and when y is 0, x is 2, z is 4, w is 1, and when y is 1, x is 1, z represents 1 and w represents 0) where R ¹ -BINAP is represented by the formula (6)

Embedded image Wherein R ¹ represents an aryl group or a cycloalkyl group having 3 to 8 carbon atoms, and BIP
HEP is given by equation (7)

Embedded image R ² represents an aryl group or a cyclohexyl group, R ³ represents a methyl group or a methoxy group, R ⁴ represents a hydrogen atom, a methyl group or a methoxy group, and R ⁵ represents a tertiary phosphine represented by Represents a hydrogen atom, a methyl group, a methoxy group or a di-lower alkyl-substituted amino group;
³ and R ⁴ may together form a tetrahydronaphthyl group with an adjacent phenyl group.

Optically active complex 2: [RuHm (CBP) n] Tp (2) (wherein CBP has the same meaning as above, and T is Cl
O ₄ , PF ₆ or BF _4. When m is 0, n is 1 and p is 2; when m is 1, n is 2 and p is 1.)

Optically active complex 3: [RuXa (Q) b (CBP)] Lc (3) [wherein CBP has the same meaning as described above, X represents a halogen atom, and Q has a substituent. Represents benzene or acetonitrile which may be substituted, L is a halogen atom, ClO
₄ , PF ₆ , BF ₄ or BPh ₄ (where Ph represents a phenyl group; the same applies hereinafter), and when Q is benzene which may have a substituent, a, b and c all represent 1 And when Q is acetonitrile, when a is 0, b is 4 and c is 2; when a is 1, b is 2 and c is 1. In addition, when Q is p-cymene among benzenes having a substituent, and X and L are iodine atoms, a and b
And c are both 1, and a may be 1, b may be 1, and c may be 3.]

Optically active complex 4: Ru (CBP) J ₂ (4) wherein CBP has the same meaning as described above, and J is chlorine, bromine, iodine, or O ₂ CR ⁶ (where R ⁶
Represents a lower alkyl group or a halogenated lower alkyl group).

Optically active complex 5: RuG ₂ (CBP) (5) (wherein CBP has the same meaning as described above, and G represents an allyl group or a methallyl group)

In the above general formulas (1) to (5), CB
When P is R ¹ -BINAP represented by the general formula (6), the aryl group represented by R ¹ means a phenyl group, a p-substituted phenyl group, an m-substituted phenyl group, and an m-di-substituted phenyl. A phenyl group having a substituent such as a phenyl group means a substituent that may be substituted on the phenyl group, and a lower alkyl group such as a methyl group and a tert-butyl group ("lower" means a group having 1 to carbon atoms) 4 straight or branched), methoxy groups and chlorine atoms.
Further, the cycloalkyl group having 3 to 8 carbon atoms represented by R ^1, in particular cyclopentyl and cyclohexyl are preferred.

Specific examples of the tertiary phosphine represented by R ¹ -BINAP include the following. (A) 2,2′-bis (diphenylphosphino) -1,1 ′
-Binaphthyl (hereinafter simply abbreviated as "BINAP") (b) 2,2'-bis (di-p-tolylphosphino)-
1,1′-binaphthyl (hereinafter abbreviated as “Tol-BINAP”) (c) 2,2′-bis (di-p-tert-butylphenylphosphino) -1,1′-binaphthyl t-B
abbreviated as "u-BINAP") (d) 2,2'-bis (di-m-tolylphosphino)-
1,1′-Binaphthyl (hereinafter referred to as “m-Tol-BINA”
P). (E) 2,2′-bis [di- (3,5-dimethylphenyl) phosphino] -1,1′-binaphthyl (hereinafter “DM”)
(F) 2,2′-bis (di-p-methoxyphenylphosphino) -1,1′-binaphthyl (hereinafter “Methoxy-BI”)
(G) abbreviated as “NAP”) (g) 2,2′-bis (di-p-chlorophenylphosphino) -1,1′-binaphthyl (hereinafter “p-Cl-BIN”)
(H) AP)) (h) 2,2'-bis (dicyclopentylphosphino)-
1,1'-binaphthyl (hereinafter abbreviated as "CpBINAP") (i) 2,2'-bis (dicyclohexylphosphino)-
1,1′-Binaphthyl (hereinafter abbreviated as “CyBINAP”)

These tertiary phosphines are disclosed in
-JP-63690, JP-A-3-20290, JP-A-3-255090, JP-A-1-68386 or JP-A-4-74192.

In the above general formulas (1) to (5), CB
When P is BIPHEP represented by the general formula (7),
The aryl group represented by R ² includes a phenyl group and p-
Substituted phenyl group, a phenyl group having a substituent such as an m-substituted phenyl group and an m-di-substituted phenyl group,
The substituents that may be substituted on the phenyl group include a methyl group, t
Examples thereof include a lower alkyl group such as an tert-butyl group ("lower" means a straight or branched chain having 1 to 4 carbon atoms), a methoxy group and a chlorine atom. Also, R ⁵
Is a di-lower alkyl-substituted amino group, the lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms.

Specific examples of the tertiary phosphine represented by BIPHEP include the following. (J) 2,2'-dimethyl-6, '6'-bis (diphenylphosphino) -1,1'-biphenyl (hereinafter referred to as "BIPH
(K) 2,2′-dimethyl-6,6′-bis (dicyclohexylphosphino) -1,1′-biphenyl (hereinafter “BI”)
CHEP ”) (1) 2,2′-bis (diphenylphosphino) -5,
5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl (hereinafter abbreviated as “OcHBINAP”) (m) 2,2′-dimethyl-4,4 ′ -Bis (dimethylamino) -6,6'-bis (diphenylphosphino) -1,1 '
-Biphenyl (n) 2,2 ', 4,4'-tetramethyl-6,6'-bis (diphenylphosphino) -1,1'-biphenyl (o) 2,2'-dimethoxy-6,6' -Bis (diphenylphosphino) -1,1'-biphenyl (p) 2,2 ', 3,3'-tetramethoxy-6,6'-bis (diphenylphosphino) -1,1'-biphenyl (q ) 2,2 ', 4,4'-Tetramethyl-3,3'-dimethoxy-6,6'-bis (diphenylphosphino) -1,1'
-Biphenyl (r) 2,2'-dimethyl-6,6'-bis (di-p-tolylphosphino) -1,1'-biphenyl (s) 2,2'-dimethyl-6,6'-bis (di -P-te
rt-butylphenylphosphino) -1,1-biphenyl (t) 2,2 ′, 4,4′-tetramethyl-3,3′-dimethoxy-6,6′-bis (di-p-methoxyphenylphosph Fino) -1,1'-biphenyl

These tertiary phosphines are disclosed in
JP-A-135397, JP-A-3-275691, JP-A-4-139140, R. Schmid et a
l .; Helv. Chim. Acta, Vol. 74, pp. 370-389 (1991), R. Sc
hmid et al .; Helv. Chim. Acta, Vol. 71, pp. 897-929 (198
8) or N. Yamamoto et al .; Chem. Pharm. Bull., Vol. 3
9, pp. 1085-1087 (1991).

The ruthenium represented by the general formula (1)
Among the optically active phosphine complexes (hereinafter, abbreviated as “optically active complex 1”), compounds in which CBP is R ¹ -BINAP represented by the general formula (6) in the general formula (1) are, for example, T.I. Ikariya et al. (T. Ikariya et al .; J. Chem. Soc., Ch.
em.Commun., pp.922-924 (1985)) or JP-A-61-
No. 63690 can be obtained.

[0033] That is, ruthenium and cycloocta-1,5-diene chloride (hereinafter, abbreviated as "COD") and reacted with ethanol in a solvent obtained by [RuX ₂ (C
OD)] q (q is a natural number) and further reacted with R ¹ -BINAP by heating in the presence of a tertiary amine represented by A in a solvent such as toluene or ethanol. . The tertiary amine represented by A includes triethylamine, tributylamine, ethyldiisopropylamine, 1,8-bis (dimethylamino)-
Examples thereof include naphthalene, dimethylaniline, pyridine, and N-methylpiperidine, and triethylamine is particularly preferably used.

The compound of formula (1) in which CBP is BIPHEP represented by formula (7) can be obtained by the method described in JP-A-63-13597.

Specific examples of the optically active complex 1 include the following. Ru ₂ Cl ₄ (BINAP) ₂ NEt ₃ (Et represents an ethyl group; the same applies hereinafter) Ru ₂ Cl ₄ (Tol-BINAP) ₂ NEt ₃ Ru ₂ Cl ₄ (t-Bu-BINAP) ₂ NEt ₃ Ru ₂ Cl ₄ (m-Tol-BINAP) ₂ NEt ₃ Ru ₂ Cl ₄ (DM-BINAP) ₂ NEt ₃ Ru ₂ Cl ₄ (Methoxy-BINAP) ₂ NEt ₃ Ru ₂ Cl ₄ (CpBINAP) ₂ NEt ₃ Ru ₂ Cl ₄ ( CyBINAP) ₂ NEt ₃ RuHCl (BINAP) ₂ RuHCl (Tol-BINAP) ₂ RuHCl (DM-BINAP) ₂ Ru ₂ Cl ₄ (BIPHEMP) ₂ NEt ₃ RuHCl (BIPHEMP) ₂ Ru ₂ Cl ₄ (BICHEP) ₂ NEt ₃ RuHCl (BICHEP) ₂ Ru ₂ Cl ₄ (OcHBINAP) ₂ NEt ₃

The ruthenium represented by the general formula (2)
The optically active phosphine complex (hereinafter, abbreviated as “optically active complex 2”) can be obtained, for example, by the method described in JP-A-63-41487 or JP-A-63-145292.

That is, in the general formula (2), the compound in which m is 0, n is 1, and p is 2 is a compound of Ru ₂ Cl ₄ (CBP) ₂ NEt ₃ and MT ( M is N
a, K, Li, Mg, and Ag are shown, and T has the same meaning as described above. The same applies to the following) in the presence of a quaternary ammonium salt or a quaternary phosphonium salt as a phase transfer catalyst.

In the general formula (2), m is 1, n is 2,
The compound in which p is 1 is the compound of Ru of the optically active complex 1 described above.
It is produced by reacting HCl (CBP) ₂ with MT using a phase transfer catalyst.

Specific examples of the optically active complex 2 include the following. [Ru (BINAP)] (ClO ₄ ) ₂ [Ru (Tol-BINAP)] (PF ₆ ) ₂ [Ru (BINAP)] (BF ₄ ) ₂ [Ru (Methoxy-BINAP)] (BF ₄ ) ₂ [RuH (BINAP) ₂ ] ClO ₄ [RuH (t-Bu-BINAP) ₂ ] PF ₆ [RuH (Tol-BINAP) ₂ ] BF ₄ [RuH (BIPHEMP) ₂ ] ClO ₄

The ruthenium represented by the general formula (3)
The optically active phosphine complex (hereinafter, abbreviated as “optically active complex 3”) can be obtained, for example, by the method described in JP-A-2-191289.

That is, in the formula (3), a compound wherein Q is benzene which may have a substituent and X and L are both halogen atoms is [RuX ₂ (Q ')] ₂ (X is Q ′ has the same meaning, and Q ′ represents benzene which may have a substituent. The same shall apply hereinafter) and CBP in an appropriate solvent. Examples of the solvent used here include methanol, ethanol, benzene, methylene chloride, and a mixed solvent thereof.

The compound wherein Q is p-cymene, X and L are iodine atoms, a is 1, b is 1 and c is 3 can be obtained by the method described in JP-A-5-111039. Can be. That is, a compound represented by the following formula [RuI (p-cymene) (CBP)] I obtained by the above method is added to an appropriate solvent such as methanol for 1 hour.
It can be obtained by reacting iodine at 5 to 30 ° C for 1 to 5 hours.

In the formula (3), a compound wherein Q is benzene which may have a substituent and L is ClO ₄ , PF ₆ , BF ₄ or BPh ₄ is obtained by the above-mentioned [RuX
(Q ′) (CBP)] by reacting X with a salt represented by ML ′ (M has the same meaning as described above, and L ′ represents ClO ₄ , PF ₆ , BF ₄ or BPh ₄ ) Manufactured.

The optionally substituted benzene represented by Q is benzene and benzene substituted with a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a halogen atom, etc. "Means one carbon atom
To 4), specifically, benzene, toluene, xylene, trimethylbenzene, hexamethylbenzene, ethylbenzene, tert.
-Butylbenzene, p-cymene, cumene, anisole,
Examples thereof include methyl anisole, methyl benzoate, methyl methyl benzoate, methyl chlorobenzoate, chlorobenzene, dichlorobenzene, trichlorobenzene, bromobenzene, and fluorobenzene.

Further, in the formula (3), a compound wherein Q is acetonitrile, a is 1, b is 2, and c is 1 is, for example, [Ru
X (Q ′) (CBP)] X is dissolved in acetonitrile,
It is produced by a heating reaction at about 50 ° C.

Further, Q is acetonitrile, a is 0,
A compound in which b is 4 and c is 2 is [RuX (Q ′) (C
BP)] X is dissolved in a mixed solvent of acetonitrile and another appropriate solvent, and the mixture is heated and reacted at a temperature of about 25 to 50 ° C. Here, examples of the solvent used by mixing with acetonitrile include methanol, ethanol, acetone, and methylene chloride.

Specific examples of the optically active complex 3 include the following. [RuCl (benzene) (BINAP)] Cl [RuCl (benzene) (Tol-BINAP)] Cl [RuCl (benzene) (p-Cl-BINAP)] C
l [RuBr (benzene) (BINAP)] Br [RuI (benzene) (BINAP)] I [RuI (benzene) (Tol-BINAP)] I [RuI (p-cymene) (BINAP)] I [RuI (p- Shimen) (Tol-BINAP)] I [RuI (p-cymene) (m-Tol-BINAP)]
I [RuI (p-cymene) (Methoxy-BINAP)] I [RuI (p-cymene) (BINAP)] I ₃ [RuI (p-cymene) (Tol-BINAP)] I ₃ [RuI (p-cymene) (DM-BINAP)] I ₃ [RuCl (methyl benzoate) (BINAP)] Cl [RuCl (benzene) (BINAP)] ClO ₄ [RuCl (benzene) (t-Bu-BINAP)] C
10 ₄ [RuCl (benzene) (BINAP)] PF ₆ [RuCl (benzene) (BINAP)] BF ₄ [RuCl (benzene) (BINAP)] BPh ₄ [Ru (acetonitrile) ₄ (BINAP)] (BF ₄ )
₂ [RuCl (acetonitrile) ₂ (BINAP)] Cl [RuBr (benzene) (DM-BINAP)] Br [RuCl (benzene) (BIPHEMP)] Cl [RuCl (p-cymene) (BIPHEMP)] Cl [RuI (p -Cymene) (BIPHEMP)] I [RuI (benzene) (OcHBINAP)] I [RuI (p-cymene) (OcHBINAP)] I

The ruthenium represented by the general formula (4)
Among the optically active phosphine complexes (hereinafter abbreviated as “optically active complex 4”), compounds in which J is a chlorine atom, a bromine atom or an iodine atom in the general formula (4) are, for example, J.I.
The method of P. Genet et al. (Tetrahed
ron: Asymmetry, Vol. 2, No. 7, pp. 555-567 (1991)).

That is, CBP dissolved in an appropriate solvent
To a methanol solution of an acid represented by HJ (J has the same meaning as described above). Suitable solvents used here include methylene chloride, toluene, acetone and the like.

In the general formula (4), compounds wherein J is O ₂ CR ⁶ are described, for example, in JP-A-62-265293.
As No. disclosed in Japanese or Japanese 63-145291 JP, Ru ₂ of optically active complex 1 described above
It is produced by reacting Cl ₄ (CBP) ₂ NEt ₃ with a carboxylate corresponding to the group represented by O ₂ CR ³ in an alcohol solvent. Here, the lower alkyl group represented by R ⁶ means a linear or branched alkyl group having 1 to 4 carbon atoms, and the halogenated lower alkyl group represented by R ⁶ means that the halogen atom is A linear or branched alkyl group having 1 to 4 carbon atoms, which is substituted by one or more, means monochloromethyl group, dichloromethyl group, trichloromethyl group, trifluoromethyl group and the like. Can be. The compound in which R ⁶ is a trifluoromethyl group is produced, for example, by reacting Ru (CBP) (O ₂ CCH ₃ ) ₂ obtained as described above with trifluoroacetic acid.

Specific examples of the optically active complex 4 include the following. Ru (BINAP) Cl ₂ Ru (BINAP) Br ₂ Ru (BINAP) I ₂ Ru (Tol-BINAP) Br ₂ Ru (t-Bu-BINAP) Br ₂ Ru (BINAP) (O ₂ CCH ₃ ) ₂ Ru (Tol) —BINAP) (O ₂ CCH ₃ ) ₂ Ru (BINAP) (O ₂ CCF ₃ ) ₂ Ru (Tol-BINAP) (O ₂ CCF ₃ ) ₂ Ru (DM-BINAP) Cl ₂ Ru (BIPHEMP) Br ₂ Ru ( BICHEP) (O ₂ CCH ₃ ) ₂ Ru (OcHBINAP) (O ₂ CCH ₃ ) ₂

The ruthenium represented by the general formula (5)
An optically active phosphine complex (hereinafter, abbreviated as “optically active complex 5”) is also described in, for example, JP Genet et al.
t etal.) method (Tetrahedron: Asymmetry, Vol. 2, No.
7, pp. 555-567 (1991)).

That is, it is produced by heating and reacting RuG ₂ (COD) (G has the same meaning as described above) and CBP in a solvent such as hexane at about 50 ° C. in an argon atmosphere.

When this optically active complex 5 is used in the production method of the present invention, as described in the above-mentioned JP Genet et al., The complex is added to a complex in the presence of a solvent such as acetone or toluene. , Hydrochloric acid, trifluoroacetic acid, hydrobromic acid and the like are added, and the excess acid and solvent are distilled off under reduced pressure before use.

Specific examples of the optically active complex 5 include the following. Ru (C ₃ H ₅ ) ₂ (BINAP) (where C ₃ H ₅ represents an allyl group; the same applies hereinafter) Ru (C ₃ H ₅ ) ₂ (t-Bu-BINAP) Ru (C ₄ H ₇ ) ₂ (BINAP) (wherein C ₄ H ₇ represents a methallyl group; the same applies hereinafter) Ru (C ₄ H ₇ ) ₂ (Tol-BINAP) Ru (C ₃ H ₅ ) ₂ (DM-BINAP) Ru (C ₄ H _{7) 2} (BIPHEMP)

The phosphine derivatives in the above optically active complexes 1 to 5 can be obtained as either (+)-form or (-)-form, but their illustration is omitted. Also,
In the method of the present invention, these (+) forms or (−)
By choosing any of the bodies, 4-methyl-2-oxetanone of the desired absolute configuration can be obtained.

Further, in order to carry out the present invention advantageously, the above-mentioned ruthenium-optically active phosphine complex has a molar ratio of metal ruthenium to optically active phosphine of 1: 1 to 1: 1.
It is preferable to use one prepared at a ratio of 1: 0.95.
Usually, when preparing a ruthenium-optically active phosphine complex, about 1.05 to 1.2 equivalents of an optically active phosphine ligand are used per equivalent of ruthenium, but in the present invention, this is suppressed to within 1 equivalent. By using the compound, the polymerization reaction of 4-methylene-2-oxetanone which is a side reaction can be prevented. In addition, the optically active phosphine ligand is 0.1.
If it is less than 95 equivalents, the metal ruthenium becomes excessive,
It is uneconomical.

In the method of the present invention, the amount of the above-mentioned ruthenium-optically active phosphine complex used as a catalyst is about 0.0001 mol to 0.01 mol based on 1 mol of the starting compound 4-methylene-2-oxetanone. Although it is not particularly limited as long as it is within the range, the deactivation of the catalyst activity is considerably suppressed according to the method of the present invention.
About 002 mol is enough. In addition, the catalyst is 0.000
When the amount is less than 1 mol, the effect as a catalyst is not sufficiently exhibited, and when the amount is more than 0.01 mol, it becomes uneconomical.

The reaction temperature and reaction time of the asymmetric hydrogenation of the present invention vary depending on the type of catalyst and solvent and other reaction conditions, but are usually from room temperature to 100 ° C, particularly preferably from about 30 ° C to 30 ° C.
The reaction is preferably performed at a temperature of 60 ° C. for about 3 to 50 hours. The hydrogen pressure is about 5 kg / cm ^{2 to} 100 kg /
cm ² , particularly preferably about 30 kg / cm ^{2 to} 100 kg
/ Cm ² .

After the reaction as described above, the desired optically active 4-methyl-2-oxetanone can be obtained by purifying the reaction product by a method such as solvent distillation or distillation.

[0061]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The ruthenium-optically active phosphine complex used in Examples and Comparative Examples was prepared so that the molar ratio of metal ruthenium to optically active phosphine was about 1: 1.

Example 1 A 100 ml stainless steel autoclave was charged with nitrogen.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 45.1 mg (0.025 mmol) is precisely weighed and
3.2 ml and tetrahydrofuran 25.5 ml were added.
I got it. 4.2 g of 4-methylene-2-oxetanone was added to this.
(0.05mol), hydrogen pressure 100kg / cm^Two, Reaction temperature
The mixture was stirred at 50 ° C for 25 hours. Distill the obtained reaction solution
Distillation is performed using an apparatus, and the boiling point is 71 ° C to 73 ° C / 29 mmH
3.04 g (yield: 70.6%) of g fraction was obtained. Generate
The product is analyzed by gas chromatography in comparison with the standard.
As a result, it was confirmed that the compound was 4-methyl-2-oxetanone.
It has been certified. Analysis by liquid chromatography
As a result, it was confirmed that this was an (R) form,
The chemical purity was determined to be 90.3% ee.

EXAMPLE 2 A 100 ml stainless steel autoclave was charged with nitrogen.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 45.1 mg (0.025 mmol) is precisely weighed and added to ethanol.
3.15 ml and 25.5 ml of tetrahydrofuran
added. This is followed by 4-methylene-2-oxetanone 4.2
g (0.05mol), hydrogen pressure 98kg / cm^Two, Reaction temperature
The mixture was stirred at 50 ° C for 45 hours. Distillation as in Example 1
And (R) -4-methyl-2-oxetanone 3.18 g
(Yield: 73.9%). Also, as in the first embodiment,
And the optical purity was measured to be 91.0% ee.
Was.

Example 3 In a 100 ml stainless steel autoclave, under a nitrogen atmosphere, [RuI (benzene) ((-)-Tol-B) was used.
INAP))] I 111 mg (0.1 mmol) was precisely weighed,
3.2 ml of methanol and 25.5 m of tetrahydrofuran
1 was added. To this, 4-methylene-2-oxetanone
4.2g (0.05mol) is charged and hydrogen pressure is 100kg / c
m ^2, and stirred for 9 hours at reaction temperature 50 ° C.. Distillation was conducted in the same manner as in Example 1 to obtain 3.32 g of (R) -4-methyl-2-oxetanone (yield: 77.1%). The optical purity was measured in the same manner as in Example 1.
ee.

Example 4 A 100 ml stainless steel autoclave was charged with nitrogen.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 45.1 mg (0.025 mmol) is precisely weighed,
16.2 ml of lopanol and 14.2 of tetrahydrofuran
ml was added. To this, 4-methylene-2-oxetanone
 4.2g (0.05mol) is charged and hydrogen pressure is 100kg / c
m^TwoThe mixture was stirred at a reaction temperature of 50 ° C. for 23 hours. Example 1 and
Distill in the same manner to obtain (R) -4-methyl-2-oxetanone.
2.84 g (yield: 66.1%) were obtained. Also, the embodiment
When the optical purity was measured in the same manner as in Example 1, 86.9%
ee.

EXAMPLE 5 A 100 ml stainless steel autoclave was charged with nitrogen.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 45.1 mg (0.025 mmol) was precisely weighed, and
6.0 ml of methyl droxybutyrate and tetrahydrofuran
7.1 ml were added. This has 4-methylene-2-oxe
Add 2.1g (0.025mol) of Tanone, 100kg of hydrogen pressure
/ Cm^TwoThe mixture was stirred at a reaction temperature of 50 ° C. for 44 hours. Example
(R) -4-methyl-2-oxeta
1.76 g of nonone (yield: 82.0%) was obtained. In addition,
The optical purity was measured in the same manner as in Example 1.
It was 2% ee.

Example 6 Ru ((−)-Tol-BINAP) (O ₂ ) was placed in a 100 ml stainless steel autoclave under a nitrogen atmosphere.
22.3 mg (0.025 mmol) of CCF ₃ ) _{2 was} precisely weighed, and 16 ml of methanol was added. 4-methylene-2-
Oxetanone 2.1 g (0.025 mol) is charged and hydrogen pressure is 10
The mixture was stirred at 0 kg / cm ² and a reaction temperature of 50 ° C. for 4 hours. Distillation was carried out in the same manner as in Example 1 to obtain 1.73 g of (R) -4-methyl-2-oxetanone (yield: 80.4%). When the optical purity was measured in the same manner as in Example 1,
It was 75.4% ee.

Example 7 In a 100 ml stainless steel autoclave, under a nitrogen atmosphere, [RuI (benzene) ((-)-Tol-B) was used.
INAP)] I (55.6 mg, 0.05 mmol) was precisely weighed, and 8.0 ml of methanol and 4.7 ml of methylene chloride were added. This is followed by 4-methylene-2-oxetanone 2.
1 g (0.025 mol), hydrogen pressure 100 kg / cm ² ,
The mixture was stirred at a reaction temperature of 50 ° C. for 4.5 hours. Distillation was carried out in the same manner as in Example 1, and (R) -4-methyl-2-oxetanone 1.
36 g (yield: 63.1%) were obtained. When the optical purity was measured in the same manner as in Example 1, it was 76.6% e.
e.

Comparative Example 1 A 100 ml stainless steel autoclave was charged with nitrogen.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 45.1 mg (0.025 mmol) is precisely weighed and
28 ml of hydrofuran were added. This is 4-methylene
-2-oxetanone 4.2g (0.05mol)
The pressure was 100 kg / cm2, and the reaction temperature was 50 ° C for 117 hours.
Stirred. Distillation was carried out in the same manner as in Example 1, and (R) -4-methyl
3.32 g of -2-oxetanone (yield: 77.1%) was obtained.
Was. The optical purity was measured in the same manner as in Example 1.
However, it was 91.6% ee.

(R) -4 in Example 1 and Comparative Example 1
FIG. 1 shows the change over time in the conversion to -methyl-2-oxetanone. As shown in FIG. 1, in Example 1 using a mixed solvent of alcohol and tetrahydrofuran as a solvent, a reaction was performed more efficiently in a shorter time than in Comparative Example 1 in which only tetrahydrofuran was used as a solvent and the other conditions were the same as in Example 1. It is clear that is progressing.

Comparative Example 2 Nitrogen was placed in a 100 ml stainless steel autoclave.
Under atmosphere, Ru_TwoCl_Four ((-)-Tol-BINAP)
_TwoNEt_Three 90.1 mg (0.05 mmol) is precisely weighed and
28 ml of hydrofuran were added. This is 4-methylene
-2-oxetanone 4.2g (0.05mol)
Pressure 100kg / cm^Two, Stirred at a reaction temperature of 50 ° C. for 47 hours
did. Distillation was carried out in the same manner as in Example 1, and (R) -4-methyl-
3.30 g of 2-oxetanone (yield: 76.7%) was obtained.
Was. The optical purity was measured in the same manner as in Example 1.
However, it was 91.5% ee.

(R) -4 in Example 2 and Comparative Example 2
FIG. 2 shows the change over time in the conversion to -methyl-2-oxetanone. From FIG. 2, it can be seen that Example 2 in which a mixed solvent of alcohol and tetrahydrofuran was used as the solvent was performed with a catalyst amount half that of Comparative Example 2 in which only tetrahydrofuran was used as the solvent, although Comparative Example 2 was used. It is evident that the reaction is proceeding efficiently to the same extent as in.

Comparative Example 3 In a 100 ml stainless steel autoclave, under a nitrogen atmosphere, [RuI (benzene) ((−)-Tol-B) was used.
INAP))] I 111 mg (0.1 mmol) was precisely weighed,
28 ml of tetrahydrofuran were added. 4.2 g (0.05 mol) of 4-methylene-2-oxetanone was added thereto, and hydrogen pressure was 100 kg / cm ² , and the reaction temperature was 30 ° C. at 30 ° C.
Stirred for hours. Distillation was conducted in the same manner as in Example 1, and (R) -4-
2.11 g of methyl-2-oxetanone (yield: 49.1)
%). The optical purity was measured in the same manner as in Example 1. As a result, it was 89.0% ee.

(R) -4 in Example 3 and Comparative Example 3
FIG. 3 shows the change over time in the conversion to -methyl-2-oxetanone. As shown in FIG. 3, Example 3 in which a mixed solvent of alcohol and tetrahydrofuran was used as the solvent performed a shorter and more efficient reaction than Comparative Example 3 in which only tetrahydrofuran was used as the solvent and the other conditions were the same as in Example 3. It is clear that is progressing.

[0075]

According to the method of the present invention, optically active 4-methyl-2-oxetanone, which is useful as an intermediate in the organic synthetic chemistry industry such as a raw material for a polymer, a raw material for a medicine, or a liquid crystal material, is converted into a catalyst having a smaller amount than conventional methods. This method enables efficient production in a small amount and a short reaction time, and is economically superior and industrially advantageous.

[Brief description of the drawings]

FIG. 1 shows (R) -4- in Example 1 and Comparative Example 1.
It is a graph which shows the time-dependent change of the conversion rate to methyl-2-oxetanone.

FIG. 2 shows (R) -4- in Example 2 and Comparative Example 2.
It is a graph which shows the time-dependent change of the conversion rate to methyl-2-oxetanone.

FIG. 3 shows (R) -4- in Example 3 and Comparative Example 3.
It is a graph which shows the time-dependent change of the conversion rate to methyl-2-oxetanone. that's all

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Akio Yamaguchi 1-4-11, Nishi-Hachiman, Hiratsuka-shi, Kanagawa Prefecture, Takasago International Corporation Co., Ltd. (56) References JP-A-61-191679 (JP, A) JP-A-3-204870 (JP, A) Tetrahedron Let t. , Vol. 33, No. 5, p. 635-638 (1992) Am. Chem. Soc. , Vol. 23, p. 1725-1726 (1992) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 305/12 CA (STN)

Claims (2)

(57) [Claims] 1. A method for producing optically active 4-methyl-2-oxetanone by asymmetric hydrogenation of 4-methylene-2-oxetanone using a ruthenium-optically active phosphine complex as a catalyst, wherein a solvent containing alcohols is used. A process for producing optically active 4-methyl-2-oxetanone, characterized by the following: 2. The ruthenium-optically active phosphine complex according to claim 1, wherein the molar ratio of the metal ruthenium to the optically active phosphine is from 1: 1 to 1: 0.95. The method for producing optically active 4-methyl-2-oxetanone described in the above item.