JPS62215558A - Oxime derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R is alkyl, aralkyl or alkyl- substituted silyl). EXAMPLE:Anti-isomer and syn-isomer of (p-tolylmethyl)phenyl ketone (o- octyloxime). USE:A synthetic intermediate for 1-phenyl-2-(p-tolyl)ethylamine useful as an optical resolution agent. PREPARATION:The compound of formula can be produced by reacting (p- tolylmethyl)phenyl ketone oxime with an alkylating agent, aralkylating agent or silylating agent of formula R-X (X is halogen or sulfuric acid ester residue when R is alkyl or X is halogen when R is alkyl or alkyl-substituted silyl) in the presence of a base (e.g. pyridine) in a solvent (e.g. toluene) at -10-+50 deg.C.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides novel oxime derivatives represented by the general formula (I) (wherein R represents an alkyl group, an aralkyl group, or an alkyl-substituted silyl group). and its manufacturing method.

Problems to be solved by conventional techniques and inventions〉(
p-tolylmethyl)phenylketone oxime ((I)
Compounds in which R corresponds to hydrogen in the structural formula of 1) are known.

For example, J, Am, Chem, Soc, , 76
, 8719 (1954) (p-tolylmethyl)
It is described that the corresponding oxime was obtained by reacting phenylketone with hydroxylamine.

However, nothing is known about the oxime derivative represented by general formula (I).

Means for Solving the Problems> The present inventors synthesized (p-tolylmethyl)phenylketone oximes, and as a result of repeated research, discovered that a novel oxime derivative has optical activity 1 as an optical resolving agent.
-Phenyl-2-(p-tolyl)ethylamine (below)
The present invention was completed after discovering that the present invention could be an important production intermediate for ``TEA'' (abbreviated as TEA) and conducting various studies.

That is, the present invention provides an oxime derivative represented by the general formula (I) R (wherein R represents an alkyl group, an aralkyl group, or an alkyl-substituted silyl group) and a method for producing the same.

The target compound of the present invention is an oxime derivative represented by the above general formula (I), and specifically, R is methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, n-pentyl, cyclopentyl, n-hexyl, 2-hexyl, cyclohexyl, n-hebutyl,
2-heptyl, 8-heptyl, cycloheptyl, n-octyl, 2-octyl, cyclooctyl, n-nonyl,
Alkyl groups having 1 to 10 carbon atoms such as n-decyl, aralkyl groups having 7 to 12 carbon atoms such as benzyl, phenethyl, naphthylmethyl, naphthylethyl, trimethylsilyl, triethylsilyl, dimethyl-butylsilyl, tri-n
Examples include oxime derivatives such as alkylsilyl groups having 8 to 12 carbon atoms such as -propylsilyl and tri-n-butylsilyl.

In addition, the oxime derivative of general formula (1) has two stereoisomers in which the relationship between the phenyl group and the OR group is syn-isomer and anti-isomer, and the target compounds of the present invention are these isomers and It includes mixtures of isomers in any ratio.

Such oxime derivatives (I) are, for example, (p-tolylmethyl)phenylketone oxime with the general formula The base,
When R is an aralkyl group or an alkyl-substituted silyl group, it represents a halogen atom. ) It can be produced by reacting an alkylating agent, an aralkylating agent, or a silylating agent shown in the following.

Here, as the alkylating agent, for example, as an alkyl group, methyl, ethyl, n-propyl, isopropyl, n-
-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, 2-hexyl, cyclohexyl, n-
heptyl, 2-hebutyl, 8-hebutyl, cycloheptyl, n-octyl, 2-octyl, cyclooctyl, n
Examples include alkyl chlorides, alkyl bromides, alkyl iodides, and alkyl sulfates having -nonyl, n-decyl, and the like.

As the aralkylating agent, for example, as an aralkyl group,
Examples include halogenated aralkyl such as benzyl, phenethyl, β-phenethyl, 1-naphthylmethyl, and the like.

Examples of the silylating agent include trialkylsilyl chloride, trialkylsilyl bromide, and iodine containing trimethylsilyl, triethylsilyl, dimethyl-t-butylsilyl, tri-n-propylsilyl, tri-n-butylsilyl, etc. as the alkyl ma silyl group. Examples include trialkylsilyl halides such as trialkylsilyl oxide.

When reacting the compound represented by the general formula (I[) with (p-tolylmethyl)phenylketone oxime, a two-step method may be used in which the oxime is first converted into an alkali salt and then reacted. However, it is also possible to adopt a one-step method in which the oxime is reacted in the presence of a base.

First, the two-step method will be explained.

The mono-alkali salt in the two-step process can be easily produced by reacting the oxime with a base.

Examples of the base in this ξ include alkali gold hydride 11 such as sodium hydride and lithium hydride, and the amount used is usually 1 to 5 equivalents, preferably 1 equivalent to the oxime.
~2 equivalents. The solvent may be any solvent as long as it does not react with the base, and N,N'-dimethylformamide, tetrahydrofuran, hexamethylenephosphoric triamide and the like are usually used. The reaction temperature is usually -1
It is in the range of 0 to 100°C, preferably 0 to Gθ°C. The reaction time is usually about 10 minutes to 5 hours, and the progress of the reaction can be confirmed by the amount of hydrogen generated.

The O-alkaline salt is produced in this way, and the compound of the present invention (Il) is obtained by reacting this with the compound of general formula (II). 1 to 5 equivalents, preferably 1 to 2 equivalents, and the reaction temperature is usually in the range of -10 to 100°C, preferably 0 to 60°C.The reaction time is usually 10 minutes to 10 hours. Progress of the reaction can be confirmed by gas chromatography or the like.

Next, (p-tolylmethyl)phenylketone oxime and the compound of general formula (n) are reacted in the presence of a base.
Explain the step method.

The compound of general formula (II) is usually 1 to 1 to
5 equivalents are used, preferably 1 to 2 equivalents. The solvent used may be any aprotic solvent, such as aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as toluene and benzene, and halogenated hydrocarbons such as chloroform and chlorobenzene.

As the base, organic bases such as pyridine, triethylamine, and N-methylmorpholine are usually used, and the amount used is 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the oxime.
It is equivalent.

The reaction temperature is usually -80 to 100°C, preferably -10 to
The temperature is 50° C., and the progress of the reaction can be confirmed by gas chromatography or the like.

Further, the oxime derivative of the present invention is prepared by reacting (p-trimethyl)phenyl ketone with a hydroxylamine derivative represented by the general formula (III) H2NOR, (11) (wherein R2 represents an alkyl group or an aralkyl group). It can also be manufactured by

Here, as the hydroxylamine derivative represented by the general formula (III), for example, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, 2-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 8-
Alkyl groups having 1 to 10 carbon atoms such as hebutyl, cycloheptyl, n-octyl, 2-octyl, cyclooctyl, n-nonyl, and n-decyl, and 7 to 10 carbon atoms such as benzyl, phenethyl, naphthylmethyl, and naphthylethyl. Examples include hydroxyl atomyl derivatives such as 12 aralkyl groups.

Such hydroxylamine derivatives can usually be prepared manually in the form of salts such as hydrochloride and sulfate, and are reacted with the ketone in the presence of a base.

The amount of the hydroxylamine derivative used relative to the ketone is usually 1 to 10 equivalents, preferably 1 to 8 equivalents.

Here, the bases include pyridine, triethylamine, N-
Examples include organic bases such as methylmorpholine, and inorganic bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate.
The amount is at least 1 equivalent, preferably 1 to 8 equivalents.

The solvent is not particularly limited as long as it does not react with the hydroxylamine derivative. Examples include aromatic hydrocarbons such as toluene and benzene, halogenated hydrocarbons such as chloroform, methylene chloride, and chlorobenzene, alcohols such as methanol and ethanol, and amines such as pyridine and triethylamine.

The reaction temperature is usually -20 to 150°C and is not particularly limited, but the reaction proceeds smoothly even at around room temperature.

Compound +11 of the present invention is produced by the method described above, but can be separated from the reaction mixture by conventional operations such as extraction, concentration, distillation, and crystallization. In addition, ξ is further purified by recrystallization, various chromatography, etc.
You can also do it. Separation of the syn-isomer and the anti-isomer is difficult in the case of the known compound (p-methyltolyl)phenylketone oxime, but it is easy in the case of the compound of the present invention, so separation can be carried out if necessary.

<Effect of the invention> The oxime derivative (I) of the present invention is thus obtained, but
This derivative can be an intermediate for producing optically active PTEA useful for optical resolution.

For example, the oxime derivative (I) is easily reduced with hydrogen or lithium aluminum hydride, a metal hydride such as diborane, etc. in the presence of a catalyst to give highly pure racet tPTEA in an extremely high yield. Such racet tPTEA can be optically resolved by a known method to yield useful optically active PTEA.

Further, by allowing a reducing agent having an asymmetric source to act on the syn or anti oxime derivative (I), an asymmetric synthesis reaction occurs, and optically active PTEA can be obtained all at once with extremely high optical purity.

<Example> Hereinafter, the present invention will be explained in more detail than in Example ζ.
The present invention is not limited to these examples.

Example 1 (p-tolylmethyl)phenylketone oxime 257η
was dissolved in N,N-dimethylformamide 5-, 58% hydrogenated thorium 66II9 was added at room temperature, and after stirring for 80 minutes, n-octylbromide 882'9 was added, and the mixture was stirred at room temperature for 4 hours. Next, dilute hydrochloric acid and toluene were added to the reaction solution and stirred, and then the organic layer was separated and concentrated. The residue was purified by silica gel column chromatography to obtain (p-tolylmethyl)phenylketone (mo-octyloxime).
Anti-isomer 886''IP (yield: 87%) and syn-isomer 87'' (yield: 10%) were obtained.

(Anti body) NMR (CDC/3) a p p m o, 88 (t, 8H), 1.28 (bs, 10H),
1.5-1.8 (m, 2H), 2.28 (s, 8H
), 4.09 (a.

2H), 4.14 (t, 2H), 7.08 (a, 4
H).

7.2-7.8 (m, 5H) no -1-5848 (synthesis) NMR (CDC/3) δppm 0.88 (t, 8H), 1.27 (bs, 10) 1)
, 1.5-1.8 (m, 2H), 8.79 (S, 8
H), 4.08 (t.

2H), 7.08 (S, 4H), 7.26 (S, 5
H)nD'! 1-5818 Example 2 In Example 1, (p-)lylmethel)phenylketone oxime 82 g 119.58% sodium hydride 84"
The same procedure as in Example 1 was carried out except that 860 mg of cyclohexyl bromide was used in place of n-octyl bromide to obtain the anti-isomer of (1)-tolylmethyl)phenyl ketone (a-cyclohexyl oxime) 84M9 (yield: 19 %) and synisomer 7''! (yield 2%).

(Anti) N tvl R (CL) CI! a) δppm2.27
(s, 8H), 4.01(sJ)i), 4.09(
s.

2H), 7.07 (s, 4H), 7.25-7.6
1 (m, 5M) no gx 1-5765 (synthesis) NMRCCI) C13) δ pprn2.27 (
8,8H), 8.78 (s, 2H), C88 (s.

8H), 7.08(s, 4l-I), 7.25(s
, 511)nl) Chicks 1-5700 Example 3 (p-tolylmethyl)phenylketone oxime 4581
'f (2.01 mmol) was dissolved in 20 mmol of toluene, and 0.81 l of triethylamine was added at room temperature, followed by dropwise addition of 0.26 lI of trimethylsilyl chloride, and stirring was continued for 8 hours.

The mixture was then washed with water, 10% aqueous sodium hydroxide solution, 2% hydrochloric acid, and saturated brine in this order, and the first few layers were dried with sodium sulfate and then concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography. 1)-Tolylmethyl)phenylketone (t
k-trimethylsilyloxime) anti-isomer 401#f
(yield 7796) and syn-isomer 68q (yield 11%)
I got it.

(Anti body) NMR (CDC/,) i ppm 0.27 (s, 9H), 2.27 (s, 3f (),
4.15 (s.

2H), 7.06 (!1, 4H).

7.02 to 7.78 (m, 5H) mp s+aw 8g to 40°C (synthetic body) NMR (CDCI!s) δppm 0.28 (s, 9) 1), 2.27 (s, 3H),
8.82 (s.

2H), 7.08 (s, 4H), 7.28 (m, 5
M) Example 4 (I)-Tolylmethyl)phenylketone oxime 538
11!9 (2,89 mmol) was dissolved in toluene 20- and at room temperature triethylamine aoo IHl, t-butyldimethylsilyl chloride 482''P and a catalytic amount of N,
N-dimethylaminopyridine was added and left to stand for 8 days.

Next, post-treatment was carried out in the same manner as in Example 3 to obtain 520 wxp (yield: 64.1
%) and syn-isomer 166 rtwp (yield 21%) were obtained.

(Anti body) NMR (CDC/3) a ppm 0.28 (8,6H), 0.96 (11,9H),
2.04 (B.

8H), 4.15 (s, 2H), 7.07 (s, 4
H).

7.20-7.72 (m, 5H) nL) -1,5225 (Syn) NMR (CDC/,) δppm 0.18 (s, 8) (),' 0.88 (s, '91i
), 2.27 (s.

3i(), 8.82(s, 2H), 7.01(s,
4H).

7.28(m, 5H) nL)sm 1-5277 Example 5 (pt-lylmethyl)phenylketone 427 lI9
was dissolved in pyridine 2-2, and 200"7 of methylhydroxylamine hydrochloride was added thereto, followed by reaction at room temperature for 12 hours.

Next, water was added to the reaction solution, extracted with ether, and the organic layer was washed with 2% hydrochloric acid, dried over Glauber's salt, and then the solvent was distilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography to obtain the anti-isomer of p-tolylmethyl)phenylketone (S-methyloxime) 806 aP (yield 63%).
) and syn-isomer 157■ (yield 82%) were obtained.

(Anti body) NtvlR(CL)CI! s) δppm2.27(s,
8) 1), 4. ot(8, ai(), 4.09(s
.

2H), 7.07 (s, 4H), 7.25-7.6
1 (m, 5) 1) nL) Ilm l-5766 (symbolite) NMR (CDCl!, ) J P Pm2.27 (8
, 811), 8.78 (S, 2i-1), 8.88
(L8) 1), 7.08 (s, 4H), 7.25 (
a, 5H) no "" 1-5700 Example 6 (p-
)limethyl)phenylketone (bee-penzyloxime)
Anti-isomer 8114 wq (yield 58%) and syn-isomer 207 q (yield 82%) were obtained.

(Anti body) NMR (CDCI!!S) δppm 2.26 (S, 8H), 4.12 (2H, s), 5
．． 213 (2H.

s), 7.04 (4M), 7.28-7.70 (m
, 10) 1) mp ■ 58-55°C (synthetic body) NMR (CDCl!,) δ9. □ 2.26 (s, 8H), 8.77 (s, 2K), 5
．． 14 (s.

2)i), 6.99 (s, 4H), 7.26 (s,
5M).

7.81 (s, 5H) Reference Example 1 Anti-(p-)sulfmethyl)phenylketone (-a-methyloxime) 95W9 (0,4
mmol) in 4WJ of ethanol and 10% Pd-
caoq was added, and the mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 6 hours. Next, after removing the catalyst, the reaction solution was concentrated to 82η(
0.89 mmol, yield 97%) racemic PTE
I got an A.

Reference examples 2 to 4 (→-)) Lt F, Dorin 126 '9 (0,8
A solution of 8 mmol of tetrahydrofuran (T) iF) was cooled to 0°C, and 1.66 mmol of borane was added.
After dropping the HF solution, the temperature was gradually raised to room temperature.

Anti-(p-tolylmethyl) obtained in Example 1 with
Phenylketone (turtle-octyloxime) 0.271
A limol T ) I F solution was added dropwise, and the mixture was stirred at room temperature for 12 hours, then heated to 60° C. and stirred at the same temperature for 5 hours.

Next, 18% hydrochloric acid was added and the mixture was stirred at the same temperature for 1 hour, and then concentrated under reduced pressure. Next, an aqueous solution of caustic soda was added to make the mixture alkaline, and then toluene was added for extraction. The resulting organic layer was concentrated and purified using an alumina column to obtain optically active PTEA. Optical purity was measured by liquid chromatography using an optically active column. The results are shown in Table 1.

Table 1 also shows the results when the anti-form of a real silyl oxime and the anti-form of a silyl oxime were used in place of the octyl oxime.

Reference Example 5 185 m9 (0.50 mmol) of (tt)-2-amino-1,1-diphenyl-4-methylpentanol was dissolved in T)IF and cooled to -78°C, and 1 mmol of borane was added thereto. T) After adding the LF bath solution, the temperature was raised to room temperature. Then syn-(1)-)lylmethyl) obtained in Example 5
Phenylketone (Ten-methyl oxime) 95'W (0
, 4 mmol) in THF was added dropwise. Next, in the same manner as in Reference Example 2, 58■ (yield 68%) of optically active PT
Got EA.

The optical purity was 98%.

Reference Example 6 In Reference Example 2, H)-Norephedrine 802'4F
(2 mol), 4 mmol of borane and anti-
Instead of the octyl body, the same (1)-
) lylmethyl) phenylketone oxime 158'?
(0.7 mmol, syn/anti-14/8G(N
The same procedure as in Reference Example 2 was carried out except that MR measurement)) was used to obtain optically active PTEA of 81''IP (yield 21%).The optical purity was 80%.

Claims (2)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R can also be an alkyl group or an aralkyl group. Alternatively, it represents an alkyl-substituted silyl group. ) An oxime derivative represented by (2) (p-tolylmethyl)phenylketone oxime with the general formula (II) R-X(II) (wherein R represents an alkyl group, an aralkyl group, or an alkyl-substituted silyl group, and When R is an aralkyl group or an alkyl-substituted silyl group, R is a halogen atom or a sulfuric ester residue, and R is a halogen atom. A method for producing an oxime derivative represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (wherein R has the same meaning as above).