JPH0867646A - Synthetic intermediate for conagenin and its production - Google Patents

Abstract

PURPOSE: To obtain a new compound useful for converting conagenin which is a low-molecular immunomodulator and its derivative as a synthetic reagent, an organic synthetic reagent or an organic new material. CONSTITUTION: The optically active alcohol derivative of formula I (R<1> to R<4> are each H, a <=3C alkyl, etc.; R<5> is H, benzyl, t-butylsilyl, an aryl or o- nitrobenzyl). The compound of formula I is obtained by protecting the OH group of an alcohol derivative of formula II with acetonide, providing an optically active diol derivative, then catalytically reducing the resultant diol derivative and removing the protecting group. Furthermore, a new optically active α,α-disubstituted oxazinone derivative of formula III (R<8> and R<9> are each a <=4C alkyl, phenyl, etc.; R<10> is tertiary butoxycarbonyl, benzyl, etc.; R<11> is a <=3C alkyl; R<12> is H, methoxymethyl, etc.) and its intermediate are within the scope of this invention. The compound is useful as a low-molecular immunomodulator, a synthetic intermediate, etc., for an α-methylserine segment of conagenin.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a synthetic reagent for conagenin (Japanese Patent Laid-Open No. 306953/1990) and its derivatives known as immunomodulators, as a reagent for organic synthesis of the general formula, or a new organic material. Relates to a novel optically active diol compound useful as The present invention also provides an intermediate for producing the diol compound, an optically active α,
The present invention relates to an α-disubstituted oxazinone compound, a method for producing them, and a method for synthesizing an α-methylserine derivative using them.

[0002]

BACKGROUND OF THE INVENTION Conagenin is Streptomyces roseosporus M1696-A.
It is a low molecular weight immunomodulator isolated from the culture medium of F3, and shows an activating effect of T cells, an antitumor activity, a thrombocytosis effect, and a toxicity reducing effect by chemotherapeutic agents and radiation in experimental animals. Has been reported (Japanese Patent Application Laid-Open No. 5-
229939 and JP-A-6-65072). Regarding the method for producing conagenin, a production method by fermentation is disclosed in JP-A-2-306953, but since there are four asymmetric points in the molecule of conagenin, there is a possibility that conagenin may be produced by chemical synthesis. Manufacturing is difficult and no established method is known.

From the structure of conagenin, the synthesis of conagenin is obtained by cleaving conagenin at the amide bond site, and a hydroxy acid segment having three consecutive asymmetric centers and α-methyl-.
It is predicted that this can be achieved by performing condensation with a segment having a (L) -serine structure, but all the segments also have asymmetric centers. Having a hydroxy acid segment and α-
At present, the methylserine segment cannot be selectively and efficiently produced, and as a result, a method for synthesizing conagenin has not been established.

The optically active diol compound as a conventionally known organic synthetic reagent and its production method are reported, for example, by Panek. James s. And Cirilo, pier F. (Journal of Organic Chemistry, Vol. 58). , No. 5,
pp999-1002. 1993) and a report by Irie et al. (Tetrahedron Le
tters. Vol. 34, No. 39, p6285-6288, 1993).
Also, regarding optically active α, α-disubstituted oxazinone compounds and their production methods, see Robert M. Williams and Myeong-N.
Report by yeo Im (Journal of American Chemical Society,
Vol. 113, p.9276-9286, 1991).

As a method for producing optically active α-methyl- (L) -serine, α-methyl- (D, L) -serine is used as C
₁₈ Method for fractionating desired α-methyl- (L) -serine by high performance liquid column chromatography using a reverse phase column (T. Zhenpig et al., Journal of Chromatography. Vo
l. 53, p.297-302, 1991), and subjecting methyl-α-isocyanocarboxylate and paraformaldehyde to an aldol reaction in the presence of a chiral aminoalkylferrocenylphosphine-gold (I) complex. To obtain an optically active 4-alkyl-2-oxazoline-carboxylate, and a method of obtaining the desired optically active substance by hydrolyzing the product (Ito et al., Tetrahedro
n Letter, Vol. 29, p.235-238, 1988)), etc., but it is not always industrially satisfactory in terms of reaction yield, optical activity purity of products, etc. Is.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides an optically active hydroxy acid segment useful for the synthesis of conagenin and α-
Optically active diol compounds and optically active α, α-disubstituted oxazinone compounds, which are useful for the synthesis with a methylserine segment, and are also useful as reagents for general organic synthesis or as materials for organic synthesis. And intermediates of
-An object of the present invention is to provide a method for producing an optically active α-methylserine or a derivative thereof using a disubstituted oxazinone compound as a starting material.

[0007]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the hydroxy acid segment of conagenin is a γ, δ-epoxy which has already been developed by the present inventors. Stereospecific methylation reaction between acrylic acid ester and trimethylaluminum (Miyashita et al., Journal of Organic Chemistry, Vol. 56, p.6483,
1991) to obtain the optically active diol derivative represented by the general formula (II) from the optically active hydroxy ester, which is further converted into the optically active alcohol derivative represented by the general formula (I). By doing so, they have found a method capable of stereoselectively and efficiently producing.

The present inventors have further investigated the purpose of converting α-methylserine segment of conagenin to α-methyloxazinone as an optically active α, α-disubstituted oxazinone compound represented by the general formula (III). The present inventors have found a selective and efficient production method comprising leading to α-methylserine ester of As a result of further studies based on these findings, the present invention has been completed.

That is, the first invention of the present invention relates to an optically active alcohol derivative of the following general formula (I) as a novel substance. General formula (I): [In the formula, R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or an alkyl group having 3 or less carbon atoms, or R ² and R ⁴ are bonded to each other to form the following formula: (R ⁶ and R ⁷ are the same or different from each other and represent an alkyl group having 3 or less carbon atoms), and R ⁵ is a hydrogen atom, a benzyl group, a tert-butylsilyl group, an aryl group, Or represents an orthonitrobenzyl group].

The alcohol derivative of the general formula (I) has the following general formula (II) [Wherein R ¹ , R ³ and R ⁵ are the same as those in the general formula (I)] and include an optically active alcohol derivative. Of the compounds of general formula (II), it is preferred that R ⁵ is a benzyl group.

The second invention of the present invention relates to an optically active α, α-disubstituted oxazinone derivative represented by the following general formula (III) as a novel substance. General formula (III): [Wherein R ⁸ and R ⁹ are the same or different and each represents an alkyl group having 4 or less carbon atoms, a cycloalkyl group, or a phenyl group, and R ¹⁰ is a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, R ¹¹ has 3 carbon atoms
The following alkyl group, R ¹² represents a hydrogen atom, an alkyl group having 3 or less carbon atoms, a methoxymethyl group, a 2-methoxyethoxymethyl group, or a methylthiomethyl group].

In the compound of the general formula (III), it is preferable that R ¹⁰ is a tertiary butoxycarbonyl group and R ¹² is a hydrogen atom or a methoxymethyl group.

A third invention of the present invention is the general formula (I
This is a method for producing a synthetic intermediate which is an optically active alcohol derivative represented by I).

This third method of the present invention has the general formula (Ia) [In the formula, R ¹ represents an alkyl group having 3 or less carbon atoms, R ³ represents an alkyl group having 3 or less carbon atoms, R ⁵ represents a hydrogen atom, a benzyl group, a tert-butylsilyl group, an aryl group,
Or an orthonitrobenzyl group, R ¹³ is a triethylsilyl group, a trimethylsilyl group, a dimethylsilyl group,
A triphenyl group or a tertiary butyl group] is represented by an epimeric mixture of alcohols, for example,
The general formula (Ib) is obtained by oxidation by the Swern oxidation method. [Wherein, R ¹ , R ³ , R ⁵ and R ¹³ have the same meanings in the general formula (Ia)], and then a protecting group of R ¹³ is formed from the ketone under acidic conditions. After removal with β-hydroxyketone, the β-hydroxyketone is stereoselectively reduced with a reducing agent.

A fourth invention of the present invention is the general formula (I
It is a process for producing an optically active alcohol represented by the general formula (I) from an optically active alcohol derivative (synthetic intermediate) represented by I).

This fourth method according to the present invention has the general formula (II)
After protecting the hydroxyl group of the alcohol derivative represented by acetonide with acetonide, an optically active diol derivative is obtained, and then the protecting group is removed by catalytic reduction.

The fifth invention of the present invention is the general formula (II
This is a process for producing an optically active α, α-disubstituted oxazinone represented by the general formula (III) by using the compound represented by Ia) as a starting material.

The method according to the fifth aspect of the present invention has the general formula (IIIa) [Wherein, R ⁸ , R ⁹ and R ¹⁰ have the same meanings as shown in the general formula (III)], the compound represented by the general formula (IIIb) [Wherein R ⁸ , R ⁹ and R ¹⁰ have the same meanings as above]
Α-methyl oxazinone represented by the formula (1) is obtained, and then hydroxymethylation is carried out stereoselectively with paraformaldehyde in the presence of lithium diisopropyramide as a catalyst. A compound in which ¹² is a hydrogen atom is produced.

The sixth invention of the present invention is the general formula (II
This is a process for producing an optically active α-methyl- (L) -serine represented by the general formula (IV) using an α, α-disubstituted oxazinone derivative represented by I) as a starting material.

The method according to the sixth aspect of the present invention is represented by the following formula (III
c) [Wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the above-mentioned meanings]
The primary hydroxyl group of the optically active α, α-disubstituted oxazinone derivative represented by is protected with a methoxymethyl group, followed by reduction, and esterification of the resulting carboxylate. ) [Wherein R ¹⁰ and R ¹¹ are the same as those in the general formula (III), R ¹⁴ is a methoxymethyl group, and Me is a methyl group], and an optically active α-methylserine ester derivative can be produced. .

The present invention will be described in detail below. The optically active alcohol derivative of the general formula (I) according to the present invention is not only useful as a synthetic intermediate for the hydroxy acid segment of the low molecular weight immunomodulator conagenin, but also as a novel reagent for organic synthesis and also for organic synthesis. It will be useful as a material.

In the compound represented by the above general formula (I), R ¹ , R ² , R ³ and R ⁴ are each a hydrogen atom or, for example, a methyl group, an ethyl group, a normal propyl group or an isopropyl group. It may be a (C ₁ -C ₃ ) alkyl group, or R ² and R ⁴ may be bonded to each other to form [R ⁶ and R ⁷ may be the same or different from each other and may be, for example, a (C ₁ -C ₃ ) alkyl group such as a methyl group, an ethyl group, a normal propyl group or an isopropyl group]. Alternatively, R ⁶ may be a hydrogen atom or an acid-resistant hydroxyl-protecting group such as a benzyl group, a tert-butylsilyl group, an aryl group, or an orthonitrobenzyl group. In the compound of the general formula (I), preferably, R ¹ and R ³ may be methyl groups, R ² and R ⁴ may be hydrogen atoms, or R ² and R ⁴ may be bonded to each other to form a compound represented by the following formula: (R ⁶ and R ⁷ may be mutually methyl groups) and R ⁴ may be a hydrogen atom or a benzyl group.

The above-mentioned general formula (II
The optically active α, α-disubstituted oxazinone derivative represented by I) is not only useful as a synthetic intermediate of α-methylserine segment of conagenin, a small molecule immunomodulator, but also as a novel reagent for organic synthesis. Also, it becomes useful as a new organic material.

In the above general formula (III), R ⁸ and R ⁹ are the same or different and are, for example, a methyl group, an ethyl group,
It may be an alkyl group having a carbon number of 4 or less such as a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, and a tertiary butyl group, or a cycloalkyl group, or a phenyl group, preferably a phenyl group.
¹⁰ is, for example, a methylcarbonyl group, a 9-fluorenylmethylcarbonyl group, a 2,2,2-trichloroethylcarbonyl group, a 2-trimethylsilylethylcarbonyl group, a tertiary-butylcarbonyl group or a p-nitrobenzylcarbonyl group. Thus, it may be an amino group-protecting group, preferably a tertiary butoxycarbonyl group,
It may be a benzyloxycarbonyl group or a benzyl group, and R ¹¹ is a methyl group, an ethyl group, a normal propyl group,
It may be an alkyl group having 3 or less carbon atoms such as an isopropyl group, preferably a methyl group. R ¹² may be an alkyl group having a carbon number of 3 or less such as hydrogen atom, methyl group, ethyl group, n-propyl group, iso-propyl group, or, for example, methoxymethyl group, 2-methoxyethoxymethyl group, methylthiomethyl group. It may be a hydroxyl group-protecting group such as a group, preferably a hydrogen atom or a methoxymethyl group.

The optically active alcohol derivative (synthetic intermediate) represented by the above general formula (II) can be produced by carrying out according to the following method according to the third aspect of the present invention.

That is, the general formula (Ia) [In the formula, R ¹ and R ³ are, for example, a methyl group, an ethyl group,
Such as a normal propyl group and an isopropyl group (C _1-
It may be a C ₃ ) -alkyl group, preferably a methyl group, and R ⁵ is an acid-resistant hydroxyl group such as a benzyl group, a tert-butylsilyl group, an aryl group, or an orthonitrobenzyl group. It may be a protecting group, preferably a benzyl group, and R ¹³ is
For example, it may be a hydroxyl group-protecting group such as a triethylsilyl group, a trimethylsilyl group, a dimethylsilyl group, a triphenyl group, or a tertiary butyl group, preferably a triethylsilyl group. The mixture is oxidized, for example by Swern oxidation, to give the general formula (Ib) [In the formula, R ¹ and R ³ are, for example, a methyl group, an ethyl group,
Such as a normal propyl group and an isopropyl group (C _1-
C ₃ ), which may be an alkyl group, preferably a methyl group, R ⁵ is a hydrogen atom, or is, for example, a benzyl group, a tert-butylsilyl group, an aryl group, or orthonitrobenzyl. It may be an acid-resistant hydroxyl-protecting group such as a group, preferably a benzyl group, and R ¹³ is, for example, a triethylsilyl group,
It may be a hydroxyl group-protecting group such as a trimethylsilyl group, a dimethylsilyl group, a triphenyl group, or a tert-butyl group, preferably a triethylsilyl group], and then a group R ¹³ Is removed under acidic conditions and [Wherein R ¹ , R ³ and R ⁵ are the same as those defined above], and then β-hydroxyketone is introduced, and this is reacted with a reducing agent to perform stereoselective reduction. By the method, the optically active alcohol derivative of the general formula (II) can be produced.

In the method of the third aspect of the present invention, β-
The reducing agent used to carry out the stereoselective reduction of the hydroxy ketone, from among the general reducing agent used, for _{example, Zn (BH 4) 2,} Et 3 -NaBH 4, LI-
It is preferable to appropriately select and use a reducing agent such as L-Selectride which gives a desired stereoselective product.

Alcohols represented by the general formula (Ia) used as a raw material in the method of the third aspect of the present invention include, for example, the following reaction scheme (1). (In the above formula, Bn represents a benzyl group, Et represents an ethyl group, and TES represents a triethylsilyl group),

According to the reaction steps shown in (Z) -4-benzyloxy-2-buten-1-ol {(Z) -4-benzyl
oxy-2-butene-1-ol} to Katsuki-Sharpless asymmetric epoxy reaction (Katuki and Sharpless, Journal of American C
(2R, 3S) -4-benzyloxy-2,3-epoxybutanol {(2R, 3S) -4-benzlyoxy-2,3-epoxybutanol obtained by the Chemical Society, vol.102, p.5976, 1980). }
(Compound a) was subjected to Swern oxidation to form an aldehyde, and then H
The γ, δ-epoxy acrylate (compound b) is obtained by subjecting it to an orner-Emmons reaction, and this product is then prepared by the method of Miyashita et al. (Miyashita et al., Tetrahedron Asymmetry, v
ol.4, p.1573, 1993), and regioselectively at the γ position,
In addition, the syn-formation (compound c) is obtained in high yield by stereoselective methylation, and the hydroxyl group of the product is protected with a triethylsilyl group according to a conventional method to obtain triethylsilyl ether (compound d). Then, it can be prepared as a compound e by subjecting it to ozone oxidation, cleaving the dipolymeric bond to give an aldehyde, and then performing methylation with methyllithium. Details of this reaction step are shown in Reference Example 1 below.

In the fourth method of the present invention, the optically active alcohol derivative represented by the general formula (I) is an optically active alcohol derivative represented by the general formula (II) (synthesis intermediate) according to the following method. Manufactured from the body).

That is, the general formula (II) [Wherein R ¹ and R ³ are the same or different from each other,
It may be a hydrogen atom or a (C ₁ -C ₃ ) alkyl group such as, for example, a methyl group, an ethyl group, a normal propyl group or an isopropyl group, and preferably they are mutually hydrogen atoms, or R ⁵ may be a hydrogen atom or an acid-resistant hydroxyl-protecting group such as a benzyl group, a tert-butylsilyl group, an aryl group, or an orthonitrobenzyl group, and preferably a hydrogen atom. By reacting the indicated optically active alcohol derivative with, for example, 2,2-dimethoxypropane in the presence of pyridinium paratoluenesulfonic acid,
It can be prepared by a process which consists in obtaining the acetonide and then removing the radical R ⁵ by catalytic reduction.

A preferred example of the optically active alcohol derivative (synthetic intermediate) represented by the general formula (II) in the present invention is that R ¹ and R ³ are methyl groups, R ² and R ⁴ are hydrogen atoms. , R ⁵ is a compound represented by a benzyl group.

According to the fifth aspect of the present invention, the optically active α, α-disubstituted oxazinone derivative represented by the general formula (III) is prepared by using the compound represented by the general formula (IIIa) as a starting material, and It can be manufactured according to the method.

That is, in this method, the general formula (III
a) [Wherein R ⁸ and R ⁹ are the same or different and are, for example, an alkyl group having 4 or less carbon atoms such as a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, and a tertiary butyl group. Group, a cycloalkyl group, or a phenyl group, preferably a phenyl group, and R ¹⁰ is, for example, protection of an amino group such as a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, and a benzyl group. May be a group, preferably a tertiary butoxycarbonyl group may be) an optically active compound represented by, for example,
After reaction with sodium bistrimethylsilyl or the like to give an enolate, for example, stereoselective methylation using a methylating reagent such as iodomethane gives the compound of general formula (IIIb) The α-methyl oxazinone represented by can be produced. The stereoselective methylation reaction of the compound represented by the general formula (IIIa) is not limited to the above-mentioned methylating agent, and can be carried out by using an appropriate combination of general methylating agents.

The compound represented by the general formula (IIIb) thus obtained is then reacted with a hydroxymethylating agent such as paraformaldehyde in the presence of a base such as lithium diisopropylamine. Therefore, it can also be carried out by performing stereoselective hydroxymethylation. This stereoselective hydroxymethylation reaction is not limited to the above-mentioned base and hydroxymethylating agent, and can be carried out by appropriately combining and using a general strong base and a general hydroxymethylating agent.

According to the sixth aspect of the present invention, the general formula (I
The optically active α-methyl- (L) -serine derivative represented by V) can be produced by the following method.

That is, the following equation (IIIc) [Wherein R ⁸ and R ⁹ are the same or different and each represents an alkyl group having a carbon number of 4 or less, such as a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group or a tertiary butyl group, a cyclo group It may be an alkyl group or a phenyl group, R ¹⁰ may be an amino group-protecting group such as a tertiary butoxycarbonyl group, a benzyloxycarbonyl group or a benzyl group, and R ¹¹ may be, for example:
A methyl group, an ethyl group, a normal propyl group, an isopropyl group or an alkyl group having a carbon number of 3 or less], and an optically active α, α-disubstituted oxazinone primary hydroxyl group is, for example, a methoxymethyl group or a methylthiomethyl group. Base,
After protecting with a hydroxyl-protecting group such as a tetrahydrothiopyranyl group and a tetrahydrothiofuranyl group to obtain methoxymethyl ether, the resulting carboxylate is reduced with, for example, metallic sodium in the presence of liquid ammonia. , An optically active α-methyl- (L) -serine derivative of the general formula (IV) can be prepared by a method comprising esterification with an alkylating agent such as iodomethane.

In each of the above-mentioned production methods of the present invention, the reaction temperature can be selected in the range of about -100 ° C to about + 100 ° C, and the range of -85 ° C to + 50 ° C provides good yield and selectivity. It is preferable in that Further, thus obtained alcohol derivative of the formula (I), diol derivative of the formula (II), α, α-disubstituted oxazinone of the formula (III), and α-methyl- (L) -of the formula (IV). The serine derivative can be isolated and purified by a method known per se, for example, a method such as crystallization or chromatography.

[0039]

Reference Example Next, Reference Example 1 will be used to explain a method for producing an epimer mixture of alcohols represented by the general formula (Ia) that can be used as a raw material for the synthesis of a novel compound according to the present invention.

Reference Example 1 (a) Oxalyl chloride (1.74 ml, 20.00 mmol) was added to methylene chloride (20 ml) cooled to −78 ° C., and then dimethyl sulfoxide (hereinafter abbreviated as DMSO) (2.84 ml, 40.00).
methylene chloride (20 ml) solution was added dropwise and stirred for 5 minutes, and then (2R, 3S) -4-benzyloxy-2,3-epoxybutanol (compound a) (1.94 g, 10.00 mmol) (ee> 87).
%) In methylene chloride (20 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Triethylamine (7.03 ml,
(50.00 mmol) was added and the mixture was stirred for 10 minutes, then returned to room temperature and diluted with ethyl acetate. The ethyl acetate solution was washed twice with water and once with saturated brine, the organic solvent layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain an aldehyde.

(B) Sodium hydride (6 in mineral oil
To a tetrahydrofuran suspension (30 ml) of 0% concentration, 800 mg, 20.00 mmol) was added triethyl phosphonoacetate (3.97 ml,
(20.00 mmol) was added and the mixture was stirred for 15 minutes. This solution is -78 ℃
After cooling to room temperature, a tetrahydrofuran solution (20 ml) of the above aldehyde (about 10 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture,
After removing the tetrahydrofuran by distillation, the mixture was extracted twice with ether. The organic solvent layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by flash column chromatography using Kieselgel Art.9385 (manufactured by Merck) (developing solvent; hexane: ethyl acetate = 12: 1 (v / v)) to give a yellow oily substance of the following formula: [Wherein Et represents an ethyl group and Bn represents a benzyl group], a γ, δ-epoxy acrylic ester (compound b) (2.14 g, yield = 82%) (Z: E = 1: 40) Got IR
νmax (CHCl ₃ ) cm ^-1 : 1711, 1658 ¹ H-NMR (90MHz): 1.29 (3H, t, J = 7.2Hz), 3.35-3.71 (4H,
m), 4.20 (2H, q, J = 7.2Hz), 4.48 (1H, d, J = 11.9Hz),
4.64 (1H, d, J = 11.9), 6.12 (1H, dd, J = 15.8, 0.8Hz),
6.76 (1H, dd, J = 15.8, 6.6Hz), 7.32 (5H, s).

[0042]

(C) Water (379 μl, 21.04 mmol) was added to an ethylene dichloride solution (45 ml) of the γ, δ-epoxy acrylic ester (689 mg, 2.63 mmol) thus obtained, and the mixture was cooled to -30 ° C. Then, a hexane solution of trimethylaluminum (1M solution, 26.30 ml, 26.30 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After excess water was carefully added to the reaction mixture to decompose excess trimethylaluminum, the temperature was returned to room temperature and 2% hydrochloric acid was added. The aqueous layer and the organic solvent layer were separated, and the aqueous layer was extracted twice with methylene chloride. The organic solvent layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off. Flash column chromatography of the residue using Kiesselgel Art. 9385 (Merck)
(Developing solvent; hexane: ethyl acetate = 3: 1 (v / v)) and purified as a yellow oil with the following formula: [Wherein Et represents an ethyl group and Bn represents a benzyl group], a hydroxyacrylic ester (compound c) (6
94 mg, yield = 95%) (de> 99%) were obtained.

IR ν max (CHCl ₃ ) cm ⁻¹ : 3570, 1708, 165
1.

¹ H-NMR (90 MHz): 1.13 (3 H, d, J = 6.8 Hz),
1.28 (3H, t, J = 7.0Hz), 2.30-2.70 (1H, m), 2.45 (1H, d,
J = 4.1Hz, -OH), 3.35 (1H, dd, J = 9.4, 7.1Hz), 3.53 (1
H, dd, J = 9.4, 3.2Hz), 3.70 (1H, m), 4.18 (2H, q, J =
7.0Hz), 4.52 (2H, s), 5.83 (1H, dd, J = 15.8, 1.1Hz),
6.89 (1H, dd, J = 15.8, 8.2Hz), 7.32 (5H, s).

[0046]

(D) Hydroxyacrylic acid ester thus obtained (1.34 g, 4.83 mmol) in methylene chloride solution (4
To 0 ml), imidazole (435 mg, 7.25 mmol), 4-dimethylaminopyridine (59.0 mg, 0.48 mmol) and then triethylchlorosilane (1.22 ml, 7.25 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine. The organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by flash column chromatography using Kiesselgel Art. 9385 (manufactured by Merck) (developing solvent; hexane: ethyl acetate = 15: 1 (v / v)) to give a yellow oily substance of the following formula: A triethylsilyl ether compound (compound d) (1.79 g, yield = 95%) represented by the formula [Et represents an ethyl group, TES a triethylsilyl group, and Bn a benzyl group] was obtained.

IR ν max (CHCl ₃ ) cm ⁻¹ : 1707, 1651 ¹ H-NMR (90MHz): 0.42-1.08 (18H, m), 1.28 (3H, t, J = 7.
0Hz), 2.48-2.76 (1H, m), 3.34-3.42 (2H, m), 3.72 (1H,
m), 4.18 (2H, q, J = 7.0Hz), 4.49 (2H, s), 5.78 (1H, dd,
J = 15.8, 1.3Hz), 6.97 (1H, dd, J = 15.8, 7.7Hz), 7.31
(5H, s).

HR-MS m / z: theoretical value C ₂₂ H ₃₆ O ₄ Si (M ⁺ ): 392.2383 actual value: 392.2391 elemental analysis: theoretical value C ₂₂ H ₃₆ O ₄ Si: C, 67.30; H, 9.25% Operating value: C, 67.05; H, 9.18% [α] _D ²⁰ : −15.2 ° (c = 0.47, CHCl ₃ ).

(E) A solution of the triethylsilyl ether compound (1.00 g, 2.55 mmol) thus obtained in dichloromethane.
After cooling (30 ml) to −78 ° C., ozone was passed until the dichloroethane solution turned blue, and the mixture was stirred at the same temperature for 30 minutes. After blowing in oxygen to drive off excess ozone, dimethyl sulfide (937 μl, 12.75 mmol) was added to the reaction mixture and allowed to stir at room temperature. The solvent was distilled off under reduced pressure to obtain an aldehyde compound.

After cooling the above-mentioned aldehyde derivative (about 2.5 mmol) in ether (30 ml) to −78 ° C., add methyllithium in ether (1.12 M solution, 4.55 ml, 5.10 mmol) dropwise and add at the same temperature. It was stirred for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ether. The organic solvent layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Residue
Purified by flash column chromatography using Kiesselgel Art. 9385 (Merck) (developing solvent; hexane: ethyl acetate = 15: 1 (v / v)) to give a yellow oily substance of the following formula: An epimer mixture of alcohol (compound e) (562 mg, yield = 65%) represented by the formula [TES represents a triethylsilyl group and Bn represents a benzyl group] was obtained.

IR νmax (CHCl ₃ ) cm ⁻¹ : 3655, 1725, 1688 ¹ H-NMR (90MHz): 0.45-1.28 (21H, m), 1.58-1.66 (1H,
m), 3.34-3.56 (2H, m), 3.72-4.11 (2H, m), 4.51 (2H,
s), 7.31 (5H, s).

HR-MS m / z: theoretical value C ₁₉ H ₃₄ O ₃ Si (M ⁺ ): 338.2277 actual value: 338.2268 elemental analysis: theoretical value C ₁₉ H ₃₄ O ₃ Si: C, 67.40; H, 10.12% Operating value: C, 67.03; H, 9.90% [α] _D ²³ : −15.2 ° (c = 0.47, CHCl ₃ ).

[0054]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 Synthesis of Ketone (Compound 1) from Alcohol Epimer (Compound e) (COCl ₂ ) (22) in Dichloromethane (5 ml) cooled to −78 ° C.
After adding 3 μl, 2.56 mmol), a solution of dimethyl sulfoxide (363 μl, 5.12 mmol) in dichloromethane (5 ml) was added dropwise and stirred for 1 minute, and then the epimeric mixture of optically active alcohols obtained in Reference Example 1 ( A solution of 433 mg, 1.28 mmol) in dichloromethane (5 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Triethylamine (898 μl, 6.40 mm) in the reaction mixture
ol) was added and the mixture was stirred for 10 minutes, then, returned to room temperature and diluted with ethyl acetate. The ethyl acetate solution was washed twice with water and once with saturated brine, the organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Kieselgel Art.9385 residue
Flash column chromatography using (Merck) {developing solvent; hexane: ethyl acetate = 10: 1 (v /
v)} with the following formula A ketone (compound I) as a colorless oil, represented by the formula: TES represents a triethylsilyl group and Bn represents a benzyl group, was obtained as a colorless oil (346 mg, yield = 81).
%).

IR ν max (CHCl ₃ ) cm ⁻¹ : 1702.

¹ H-NMR (90 MHz): 0.42-1.26 (18 H, m), 2.14
(3H, 3), 2.69-2.84 (1H, m), 3.39 (2H, d, J = 5.3Hz), 4.
03-4.22 (1H, m), 4.47 (2H, s), 7.30 (5H, s).

[0058]

Example 2 Synthesis of β-Hydroxyketone (Compound 2) from Ketone (Compound 1) 2% hydrochloric acid (0.2 ml) was added to a tetrahydrofuran solution (1 ml) of Compound 1 (33.6 mg, 0.1 mmol) obtained in Example 1. ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, washed twice with water and once with saturated brine. After drying the organic solvent layer with anhydrous sodium sulfate, the solvent was distilled off A β-hydroxyketone (compound 2) represented by the formula [Bn represents a benzyl group] was obtained.

IR ν max (CHCl ₃ ) cm ⁻¹ : 3570, 1702.

¹ H-NMR (90 MHz): 1.15 (3 H, d, J = 7.3 Hz),
2.18 (3H, s), 2.69-2.82 (1H, m), 3.42-3.48 (2H, m), 4.
08-4.25 (1H, m), 4.52 (2H, d, s), 7.32 (5H, s).

[0062]

Example 3 Synthesis of diol (compound 3) The ether solution (1 ml) of the compound 2 (about 0.1 mmol) obtained in Example 2 was cooled to 0 ° C., and then the Zn (BH ₄ ) ₂ ether solution (about 0.15M solution, 1 ml, 0.15 mmol) was stirred at the same temperature for 25 minutes. Water should not be added carefully to the reaction mixture as excess Zn
(BH ₄ ) ₂ was decomposed. The aqueous layer and the organic solvent layer were separated, and the aqueous layer was extracted with ether. The organic solvent layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified on a Merck thin-layer plate (Kieselgel Art.9385) using hexane: ethyl acetate = 3: 2 (v / v) as a solvent, A diol (compound 3) represented by the formula [Bn represents a benzyl group] was obtained as a colorless oily substance (19 mg, yield = 8).
Five%).

IR νmax (CHCl ₃ ) cm ⁻¹ : 3450 ¹ H-NMR (90MHz): 0.92 (3H, d, J = 7.0Hz), 1.18 (3H, d, J
= 6.6Hz), 1.50-1.61 (1H, m), 3.45-3.52 (2H, m), 3.97-
4.18 (2H, m), 4.55 (2H, s), 7.33 (5H, s).

[0065]

Example 4 Synthesis of acetonide (compound 4) 2,2 of the compound 3 (101 mg, 0.45 mmol) obtained in Example 3
-A catalytic amount of pyridinium p-toluenesulfonate was added to the dimethoxypropane solution (3 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified on a Merck thin-layer plate (Kieselgel Art.9385) using hexane: ethyl acetate = 8: 1 (v / v) as a solvent,
As a colorless oily substance, the following formula 106 mg (yield 89%) of acetonide (compound 4) represented by [in the formula, Bn represents a benzyl group] was obtained.

IR ν max (CHCl ₃ ) cm ⁻¹ : 1118 ¹ H-NMR (400MHz): 0.83 (3H, d, J = 7.0Hz), 1.12 (3H, d,
J = 6.2Hz), 1.40 (3H, s), 1.42-1.48 (1H, m), 1.46 (3H,
s), 3.45 (1H, dd, J = 30.6, 9.5Hz), 3.47 (1H, dd, J = 30.
6, 9.9Hz), 4.10 (1H, bq, J = 6.2, 2.4Hz), 4.17 (1H, dt,
J = 6.2, 2.Hz), 4.49 (1H, d, J = 12, 1Hz), 4.61 (1H, d,
J = 12.1Hz), 7.33 (5H, s).

HR-MS m / z: theoretical value C ₁₆ H ₂₄ O ₃ (M ⁺ ): 264, 1724 actual value: 224, 1729 elemental analysis: theoretical value C ₁₆ H ₂₄ O ₃ : C, 70.69; H, 9.15% Found: C, 70.32; H, 9.04% [α] D ²¹ : + 150 ° (c = 1.06, CHCl ₃ ).

Example 5 Debenzylation reaction of acetonide (Compound 4) The acetonide (Compound 4) obtained in Example 4 (60.7 mg, 0.
A catalytic amount of palladium carbon was added to an ethanol solution (4 ml) of 23 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. Palladium carbon was filtered and washed well with ethyl acetate. The filtrate and the washing solution were combined and the solvent was distilled off. The residue was purified on a Merck thin-layer plate (Kieselgel Art. 9385) using hexane: ethyl acetate = 2: 1 (v / v) as a solvent, The alcohol (compound 5) represented by was obtained as a colorless oily substance (32.5 mg, yield = 81%).

¹ H-NMR (90 MHz): 0.85 (3 H, d, J = 6.6 Hz),
1.12 (3H, d, J = 6.2Hz), 1.33-1.46 (1H, m), 1.42 (3H,
s), 1.46 (3H, s), 3.39-3.81 (2H, m), 3.98-4.23 (2H,
m).

Example 6 Methylation reaction of oxazinone (5S, 6R) -4 (tertiarybutyloxycarbonyl) -5,6-
Diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazine-
2-on {(5S, 6R) -4 (tert-butyloxycarbonyl) -5,6-diphe
nyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (35.3mg,
0.10 mmol)} in tetrahydrofuran solution (1.5 ml)
After cooling to 8 ℃, sodium bis (trimethylsilyl)
Tetrahydrofuran solution of amide {NaN (SiMe ₃ ) ₂ } (1.0
M solution (110 μl, 0.11 mmol) was added dropwise and stirred for 30 minutes.

Aqueous saturated ammonium chloride solution was added to the reaction mixture, and the product was extracted twice with ether. The organic solvent layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified on a Merck thin-layer plate (Kieselgel Art. 9385) using hexane: ethyl acetate = 6: 1 (v / v) as a solvent to give white crystals of the following formula: [In the formula, Ph represents a phenyl group and Boc represents a tertiary butoxycarbonyl group] to obtain α-methyloxazinone (Compound 6) (30.7 mg, yield = 83%).

IR ν max (CHCl ₃ ) cm ⁻¹ : 1754, 1693.

¹ H-NMR (90 MHz): 1.12 (6H, s), 1.46 (3H,
m), 1.77 (3H, d, J = 7.5Hz), 4.93-5.25 (2H, m), 5.91 (1
H, d, J = 3.1Hz), 6.50-6.61 (2H, m), 6.93-7.32 (8H,
m).

Elemental analysis: Theoretical value C ₂₂ H ₂₅ O ₄ N: C, 71.92; H, 6.86% Actual value: C, 71.92; H, 6.86%

Example 7 Hydroxymethylation Reaction of α-Methyloxazinone (Compound 6) Diisopropylamine (1.18 ml, 8.62) cooled to −78 ° C.
solution of normal butyl lithium in hexane (1.62M solution, 5.32ml, 8.6
2 mmol) was added and stirred for 10 minutes. A tetrahydrofuran solution (20 ml) of the compound 6 (1.58 g, 4.31 mmol) obtained in Example 6 above was added dropwise to this solution, and the mixture was stirred at the same temperature for 3 times.
Stirred for 0 minutes. Add formaldehyde (1.94
Formaldehyde gas generated by thermally decomposing (g, 64.65 mmol) at 150 ° C was blown in, and the mixture was stirred at -40 ° C for 15 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture,
The product was extracted twice with ether. The organic solvent layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Kieselgel Art.9385 residue
Flash column chromatography using (Merck) {developing solvent; hexane: ethyl acetate = 2: 1 (v /
v)} and purified as white crystals. [Wherein Ph represents a phenyl group and Boc represents a tert-butoxycarbonyl group] to obtain an α, α-disubstituted oxazinone (Compound 7) (1.69 g, yield = 99).
%).

IR ν max (CHCl ₃ ) cm ⁻¹ : 3620, 1737, 169
0.

¹ H-NMR (90 MHz): 1.42 (6 H, s), 1.59 (3 H,
s), 1.78 (3H, s), 3.95 (1H, br), 4.64 (1H, br), 5.38 (1
H, s), 6.23 (1H, d, J = 3.3Hz), 7.01-7.43 (10H, m).

[0079]

Example 8 Synthesis of methoxymethyl ether from α, α-disubstituted oxazinone (Compound 7) To a solution of the compound 7 (1.69 g, 4.26 mmol) obtained in Example 7 in methylene chloride (50 ml) was added diisopropylethylamine. (3.71ml, 2.30mmol) and chloromethyl ether (1.62ml)
ml, 21.30 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was washed twice with water and once with saturated brine. The organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by flash column chromatography (solvent: hexane: ethyl acetate = 4: 1, v / v) using Kieselgel Art.9385 (manufactured by Merck) to give white crystals of the following formula: [Wherein Ph represents a phenyl group, Boc represents a tertiary butoxycarbonyl group, and MOM represents a methoxymethyl group] to obtain a methoxymethyl ether (compound 8) (1.67 g, yield = 89%). .

IR ν max (CHCl ₃ ) cm ⁻¹ : 1738, 1691 ¹ H-NMR (90MHz): 1.43 (6H, s), 1.55 (3H, s), 1.80 (3H,
br), 3.37 (3H, s), 3.78 (1H, d, J = 9.7Hz), 4.67 (3H,
m), 5.41 (1H, br), 6.24 (1H, d, J = 3.5Hz), 7.12-7.28 (1
0H, m).

[0082]

Example 9 Synthesis of α-methylserine ester from methoxymethyl ether (compound 8) To liquid ammonia (about 50 ml) cooled to −78 °, sodium (149 mg, 6.5 mmol) was added under an argon atmosphere to give 1
Stirred for 0 minutes. A tetrahydrofuran solution (7 ml) of the compound 8 (221 mg, 0.50 mmol) obtained in Example 8 and ethanol (500 μl) was added dropwise to this solution, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was returned to normal temperature and ammonia was allowed to spontaneously evaporate. The solvent was distilled off under reduced pressure, and α-
The sodium salt of methylserine was obtained. Thus obtained sodium salt of α-methylserine (about 0.5 mmol) of N, N-
Add iodomethane (3 ml) to the dimethylformamide solution (4 ml).
11 μl, 5.00 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with a large amount of ethyl acetate, washed with 50% saturated saline solution three times, and the water tank was extracted twice with ethyl acetate. The organic solvent layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by developing it on a Merck thin-layer plate (Kieselgel Art.9385) using hexane: ethyl acetate = 3: 1 (v / v) as a developing solvent to obtain a yellow oil. , The following formula [In the formula, Boc represents a tertiary butoxycarbonyl group,
Me represents a methyl group and MOM represents a methoxymethyl group]
Α-Methylserine ester (Compound 9) represented by was obtained (55.6 mg, yield = 40%).

IR νmax (CHCl ₃ ) cm ⁻¹ : 3425, 1725 ¹ H-NMR (90MHz): 1.44 (9H, s), 1.54 (3H, s), 3.33 (3H,
s), 3.76 (3H, s), 3.82 (2H, s), 4.60 (2H, s).

[0085]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 43/164 43/178 C 7419-4H D 7419-4H 69/734 Z 9546-4H 201/12 205/34 7537-4H 269/00 271/22 9451-4H C07D 265/32 319/06 C07F 7/18 A // C07M 7:00 (72) Inventor Yuji Koura 3-91-4 Tomachi, Nagasaki City, Nagasaki Prefecture

Claims (10)

[Claims] 1. The general formula (I) [In the formula, R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or an alkyl group having 3 or less carbon atoms, or R ² and R ⁴ are bonded to each other to form the following formula: (R ⁶ and R ⁷ are the same or different from each other and represent an alkyl group having 3 or less carbon atoms), and R ⁵ is a hydrogen atom, a benzyl group, a tert-butylsilyl group, an aryl group, Or an ortho-nitrobenzyl group]. 2. The general formula (II) [Wherein R ¹ , R ³ and R ⁵ are the same as those in formula (I)], which is an optically active alcohol derivative. 3. The compound according to claim 1, wherein R ⁵ is a benzyl group among the compounds of the general formula (I) according to claim 1. 4. The compound according to claim 2, wherein R ⁶ is a benzyl group in the compound of the general formula (II) according to claim 2. 5. The general formula (III) [Wherein R ⁸ and R ⁹ are the same or different and each represents an alkyl group having 4 or less carbon atoms, a cycloalkyl group, or a phenyl group, and R ¹⁰ is a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, or a benzyl group. Indicates R
¹¹ represents an alkyl group having 3 or less carbon atoms, R ¹² represents a hydrogen atom, an alkyl group having 3 or less carbon atoms, a methoxymethyl group, 2
-Representing a methoxyethoxymethyl group or a methylthiomethyl group], an optically active α, α-disubstituted oxazinone derivative. 6. The compound according to claim 5, wherein R ¹⁰ is a tertiary butoxycarbonyl group and R ¹² is a hydrogen atom or a methoxymethyl group in the compound of the general formula (III) according to claim 5. 7. The general formula (Ia) [In the formula, R ¹ represents an alkyl group having 3 or less carbon atoms, R ³ represents an alkyl group having 3 or less carbon atoms, R ⁵ represents a hydrogen atom, a benzyl group, a tert-butylsilyl group, an aryl group,
Or an orthonitrobenzyl group, R ¹³ is a triethylsilyl group, a trimethylsilyl group, a dimethylsilyl group,
A triphenyl group or a tertiary butyl group] is oxidized to form an epimer mixture of alcohols, and the compound of the general formula (Ib) [Wherein R ¹ , R ³ , R ⁵ and R ¹³ have the same meaning in the general formula (Ia)], and then a ketone of the general formula (Ib) is used to protect R ¹³ . The method for producing an alcohol compound represented by the general formula (II) according to claim 2, wherein the group is removed under acidic conditions to obtain β-hydroxyketone, and then the compound is stereoselectively reduced. 8. The compound of general formula (II) according to claim 2, wherein the hydroxyl group is protected to form acetonide, and then the protecting group is removed from this acetonide by catalytic reduction.
A method for producing the compound according to claim 3. 9. The general formula (IIIa) [Wherein R ⁸ , R ⁹ and R ¹⁰ are the same as those in the general formula (III)], the compound represented by the general formula (IIIb) [Wherein R ⁸ , R ⁹ and R ¹⁰ are the same as those in the general formula (III)] to obtain an α-methyloxazinone derivative,
Next, the general formula (III) according to claim 5, wherein R ¹² is a hydrogen atom, which is characterized in that hydroxymethylation is stereoselectively carried out with paraformaldehyde in the presence of lithium diisopropylamine as a catalyst. ) The manufacturing method of the compound of. 10. The general formula (IIIc) [Wherein R ⁸ and R ⁹ are the same or different and each represents an alkyl group having 4 or less carbon atoms, a cycloalkyl group, or a phenyl group, and R ¹⁰ is a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, or a benzyl group. , R ¹¹ represents an alkyl group having 3 or less carbon atoms], the primary hydroxyl group of the optically active α, α-disubstituted oxazinone derivative is protected with a methoxymethyl group, and then the resulting carboxylate is reduced. General formula (IV) characterized by esterification [Wherein R ¹⁰ and R ¹¹ are the same as those in the general formula (IIIc), R ¹⁴ represents a methoxymethyl group, and Me represents a methyl group], and a method for producing an optically active α-methylserine derivative.