JPH0441494A - 1-aza-4-silacyclohexanes and production thereof - Google Patents

Abstract

NEW MATERIAL:1-Aza-4-silacyclohexanes expressed by formula I (R1 is H, lower alkyl, lower alkenyl, cycloalkyl, aryl, acyl or alkyloxycarbonyl; R2 and R3 are lower alkyl, lower alkenyl, cycloalkyl, aryl, alkoxy or alkyloxycarbonyl; R4 is H or lower alkyl). EXAMPLE:1-Benzyl-4,4-dimethyl-1-aza-4-silacyclohexane. USE:Useful as a synthetic intermediate for medicine and agricultural chemical, e.g. intermediate for synthesizing a quinolone derivative having 1-aza-4- silacyclohexane skeleton and exhibiting excellent antimicrobial action. PREPARATION:A compound expressed by formula II (X is halogen) is reacted with an amine expressed by formula III to provide the compound expressed by formula I. The above-mentioned reaction is carried out at 0-150 deg.C, preferably room temperature.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides 1-aza-
The present invention relates to 4-silacyclohexane and a method for producing the same.

<Prior art> There are very few studies related to the synthesis of 1-aza-4-silacyclohexanes, and only a few studies have been conducted.
.

The only example reported is Volume 37b, page 657 (198K).

In particular, the 4,4-disubstituted-1-aza-4-silacyclohexane derivative according to the present invention is a compound that has not been described in any literature.

<Problems to be Solved by the Invention> The present inventors have obtained the knowledge that a quinolone derivative having a ■-other 4-silacyclohexane skeleton exhibits excellent antibacterial activity, and have previously filed a patent application.

However, according to the conventional technology, 1-other-4-
Obtaining quinolone derivatives from silacyclohexanes is extremely difficult in the current field of organic chemistry. That is,
1-Aza-4-silacyclohexanes derived by conventional techniques have the defect that the substituent at the 1-position is limited to an alkyl or phenyl group, and a hydrogen atom cannot be obtained.

Furthermore, the method described in 5ynthesis, p. 414 (1982) uses organic mercury, which is extremely toxic, as a reaction reagent, which is not preferred from the standpoint of safety.

Therefore, the main object of the present invention is to provide a common intermediate capable of synthesizing various derivatives of pharmaceuticals and agricultural chemicals having a 1-aza-4-silacyclohexane skeleton.

An incidental object of the present invention is to provide a simple and safe method for producing various derivatives having such a 1-aza-4-silacyclohexane skeleton.

<Means for Solving the Problems> As a result of extensive research, the present inventors have discovered 4, as a common intermediate that can synthesize various derivatives of pharmaceuticals and agricultural chemicals having a 1aza-4-silacyclohexane skeleton. 4-disubstituted-1-
We have now discovered an aza-4-silacyclohexane derivative.

Furthermore, a general synthesis method for the 1-position derivatives of (1)-other 4-silacyclohexanes was established, and the present invention was completed.

The 1-aza-4-silacyclohexane according to the present invention has the general formula ['l] [wherein R is hydrogen, a lower alkyl group which may have a substituent, a lower alkenyl group, a cycloalkyl group, R2-R3 means an aryl group, acyl group, or alkyloxycarbonyl group that may have a substituent, and R2-R3 represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a substituent that may have a substituent. R4 means an optional aryl group, alkoxy group, or alkylcarbonyloxy group, and R4 means hydrogen or a lower alkyl group optionally having a substituent.

].

Specific examples of the lower alkyl group which may have a substituent include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, dobutyl, pentyl,
Straight chain or branched saturated hydrocarbon residues having 1 to 6 carbon atoms such as hexyl group, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoro Halogenoalkyl groups such as ethyl, trichloroethyl, fluoropropyl, chloropropyl groups, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl groups, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl groups Alkoxyalkyl groups such as acetoxymethyl, acetoxyethyl,
Examples include alkoxyalkyl groups such as acetoxypropyl, propoxymethyl, propoxyethyl, propoxyprobyl groups, substituted benzyl groups such as benzyl group, p-chlorobenzyl, p-nitrobenzyl, p-methoxybenzyl group, etc. Specific examples of alkenyl groups include linear or branched carbon atoms having 1 to 6 carbon atoms such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, dimethylallyl, pentenyl, and hexenyl groups. Specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc. Specific examples of acyl groups include formyl, acetyl, 1 to 6 carbon atoms such as trifluoroacetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl group, etc.
Specific examples of alkyloxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-
Specific examples of the aryl group which may have a substituent include phenyl group, thienyl group, furyl group, pyranyl group, pyrrolyl group, pyridyl group, 2-chlorophenyl group, etc. 3-chlorophenyl, 4-chlorophenyl, 2.3-dichlorophenyl, 2,4-dichlorophenyl, 2.5-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4
- Aryl having 1 to 3 groups selected from halogen atoms, hydroxyl groups, alkoxy groups, acyloxy groups, nitro groups, etc. as substituents on the aryl ring such as methoxyphenyl, 4-acetoxyphenyl, 4-nitrophenyl groups, etc. Specific examples of alkoxy groups include methoxy, ethoxy,
Examples include propoxy, butoxy, pentyloxy, methoxymethoxy, methoxyethoxy groups, and the like.

According to the method of the present invention, the 1-aza-4-silacyclohexanes represented by maximum [I] in formula 1, R2, R3
means a lower alkyl group, lower alkenyl group, cycloalkyl group, which may have a substituent, an aryl group, an alkoxy group, or an alkylcarbonyloxy group which may have a substituent, and R4 is hydrogen, a substituted It means a lower alkyl group which may have a group, and X means a halogen atom. ] and a compound represented by the formula [wherein R□ represents hydrogen, a lower alkyl group which may have a substituent, a lower alkenyl group, a cycloalkyl group, an aryl group which may have a substituent] means. It can be produced by reacting with the amines shown in ].

The reaction can be easily carried out without a solvent or in an appropriate solvent.

As the solvent, for example, water, chloroform, dichloromethane, methanol, ethanol, isopropanol, ether, dioxane, benzene, toluene, dimethylformamide, etc. can be used, and usually from θ°C to 150°C.
℃, preferably at room temperature, and chloroform, dichloromethane, methanol, ethanol solvents are preferred.

The amine used is preferably used in an amount of at least 1 equivalent, usually 2 to 5 equivalents. Additionally, as acid acceptors, e.g.
potassium carbonate, sodium carbonate, sodium bicarbonate,
By adding a base such as sodium hydroxide, potassium hydroxide, triethylamine, quinoline, DBU, etc., the amount of amines can be reduced and the reaction can be further accelerated.

After the reaction is completed, the compound of general formula [I] of the present invention is obtained by isolation according to a conventional method.

Formula [wherein R2, R3, and R4 have the meanings described above]. ]
The 1-aza-4-silacyclohexanes represented by the formula [wherein R□ means a protecting group, R4, R3, and R4
means the above. ] It can also be produced by deprotecting the 1-aza-4-silacyclohexane derivative shown in or a salt thereof.

As a method of deprotection, for example, catalytic reduction is preferable,
As the protecting group in this case, benzyl, p-nitrobenzyl, p-chlorobenzyl, trityl group, etc. can be used. As the catalyst, for example, palladium, platinum, platinum oxide, rhodium, etc., or a mixture thereof with carbon or asbestos can be used, and Pd-C and PtO□ are preferable. Examples of solvents include methanol, ethanol,
Isopropyl alcohol, acetic acid, ethyl acetate, water, etc. can be used, with methanol being preferred.

The reaction proceeds quantitatively, and the product can be obtained simply by filtering the catalyst and concentrating the solvent.

Furthermore, the general formula [I] of the present invention is represented by the formula [wherein R2, R3, and R4 have the meanings described above. ]
A 1-aza-4-silacyclohexane derivative represented by
means an optional aryl group, acyl group, alkyloxycarbonyl group, Y means a halogen atom, OZ,
Z means hydrogen or a leaving group. ] It can also be produced by reacting with the compound shown in and optionally reducing.

The alkylation reaction is carried out by conventional known methods. After the reaction is completed, the compound of general formula [I] of the present invention is obtained by isolation according to a conventional method.

Acylation and alkyloxycarbonylation reactions are also carried out by commonly known methods. Similarly, after the completion of the reaction, one of the most important aspects of the present invention is
The compound is obtained.

Note that it is also preferable to reduce the carbonyl group after the acylation reaction, as this can more advantageously lead to an alkyl derivative. The reduction reaction of the carbonyl group is also easily carried out by a method known per se.

<Effect of the invention> The 1-aza-4-silacyclohexanes according to the present invention are
It is a compound useful as an intermediate for medicines and agricultural chemicals. For example, the inventors of Tsu have previously filed a patent application based on the knowledge that quinolone derivatives having a 1-aza-4-silacyclohexane skeleton exhibit excellent antibacterial activity.

Furthermore, we discovered a 1-aza-4-silacyclohexane derivative, which is a common intermediate from which various derivatives can be easily synthesized,
It is also highly useful as a general synthesis method for various derivatives.

Furthermore, the method of the present invention for producing such 1-aza-4-silacyclohexanes is easy to operate, and
Other treatments are also simple, and furthermore, it has the advantage of being a highly safe synthesis method.

The present invention will be explained in more detail with reference to Examples below.

Production Examples, etc. 〉 Production Example 1 1-benzyl-4,4-dimethyl-1-aza-4-silacyclohexane A) Dimethyldivinylsilane 8.60 (j, water cooling,
Do not introduce Her gas under ultraviolet light (iooB pressure mercury pressure water lamp).After confirming the disappearance of dimethyldivinylsilane, CHC
The solution was dissolved in 1360ml of water, washed with water, dried over Na and SO4, and concentrated under reduced pressure to obtain 20.5g of bis(2-bromoethyl)dimethylsilane as a colorless oil.

” H-NMR (CDC11) δ: 0.10 (6) 1
．． s, -5HMe2), 1.2-1.7(4)
1. ie, -3iCH2-), 3-3-3.8
(4Hra, -CH2Br).

B) bis(2-bromoethyl)dimethylsilane io,
og, benzylamine 19. Shun, triethylamine 15
．． m, and a mixture of CHCl380+sl, 16
Refluxed for an hour.

After concentration under reduced pressure, add 50gg1 of 5% NaOH, and add Et20
Extraction, washing with water, drying with Ha 304, and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, E[
20/hexane=1/4) and purified with a colorless oil to obtain 5.30 g of 1-benzyl-4,4-dimethyl-1-aza-4-silacyclohexane.

M S rs/z: EI/Old; 219 (M+)
(base peak).

CI/DI (i-Bu); 220 (M+1)”
(base peak).

"H-NMR (CDCI, ) δ: 0.03 (6H,
s, -3iHe2), 0.6-0.9(4H,m,
-3iCHz -) + 2.5-2°8 (4H, I,
-CH2-), 3.50(21,s, -C
Hz Ph).

7.18 (5H, brs, ArH).

Treated with 21XHCI-MeOH to give 1-benzyl-4,
4-dimethyl-1-aza-4-silacyclohexane Production Example 2 1.4.4-)Lynthyl-1-aza-4-silacyclohexane Production Example 1 Bis(2-bromoethyl)dimethylsilane 10, Og, 40% methylamine in HeOH 1
4. ig, triethylamine 15. m, and CICC
A mixture of 5100 lCl was stirred at room temperature for 46 hours.

After concentration under reduced pressure, 50ml of 5% NaOH 1-1Et2
0 extraction, washing with water, drying at <50% Ha, and concentration under reduced pressure. The residue was purified by column chromatography (silica gel, E
t20/hexane=1/1) to produce 1,4.4-)lynchyl-1-aza-
2.459 of 4-silacyclohexane was obtained.

bp:65-70℃(2511H!11)bV 1ic
rotube OVenMS m/z: EI/GC;
143 (M”), 142; 72 (base p
eak), CI/GC(i-Bu); 144(M
+1)” (basepeak).

"H-NMR (CDCl2) δ: 0.04 (6H,
s, -3iHe2), 0.6-1.0(4H,'
a, -3iCH,-), 2.23(3H,S
, NMe), 2.4-2.7 (4H, mm, -t
4cH2-).

ll Example 3 4.4-Dimethyl-1-aza-4-silacyclohexane 1-benzyl-4,4-dimethyl-1-aza-4-silacyclohexane hydrochloride under hydrogen stream 4.
80(], 110%Pd-C40Gm(), and Me
A mixture of 150 ml of OH was stirred at room temperature for 4 hours.

The catalyst was filtered, concentrated under reduced pressure, and crystallized from methyl ethyl ketone to give 4,4-dimethyl-1-aza-
4-silacyclohexane hydrochloride 3.03
I got g.

Treated with 2N NaOH to give 4,4-dimethyl-1aza-
4-silacyclohexane was obtained.

MS m/z: EI/DI; 129 (M
”), 101 (base peak),
CI/mouth I (i-Bu); 130 (M+1)
” (base peak).

"H-NMR (CDCl2) δ: 0.06 (61,
s, -3iue2), 0.6-0.9(4H,l,
-3ICH2-), 1.77(IH,S, -N
H), 2.8-3.1 (4H, ■, -NCH2-)
.

Production example 4 1.4.4-) dimethyl-1-aza-4-silacyclohexane 4.4-dimethyl-1-aza-4-silacyclohexane 1.8 (kj, 98% HCOOH2,67ii1,
and 35% HCH32,21el at 50-6
Stirred at 0°C for 1 hour.

The mixture was poured into water, made basic with 10% NaOH, extracted with E20, washed with water, dried with Ha304, and concentrated to give a light yellow oil of 1,4,4-trimethyl-1-aza-4-silacyclohexane. 68 (obtained J.

Purification by distillation gave 1.4° 4-trimethyl-1-aza-4-silacyclohexane as a colorless oil.

Various spectral data were consistent with the compound of Production Example 2.

Procedural amendment (voluntary) August 29, 1990

Claims (4)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R_1 is hydrogen, a lower alkyl group that may have a substituent, a lower alkenyl group, a cycloalkyl group, R_2 and R_3 mean an aryl group, acyl group, or alkyloxycarbonyl group that may have a substituent, and R_2 and R_3 represent a lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a substituent that may have a substituent. means an aryl group, alkoxy group, or alkylcarbonyloxy group that may have R_
4 means hydrogen or a lower alkyl group which may have a substituent. ] 1-aza-4-silacyclohexane shown by. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_2, R_3, and R_4 mean the above, and X means a halogen atom. ] A compound represented by the formula H_2NR_1 [wherein R_1 represents hydrogen, a lower alkyl group that may have a substituent, a lower alkenyl group, a cycloalkyl group, an aryl group that may have a substituent] do. ] By reacting with the amines shown in the general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R_1 is hydrogen, a lower group that may have a substituent, It means an alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group which may have a substituent, an acyl group, an alkyloxycarbonyl group, and R_2 and R_3 are a lower alkyl group which may have a substituent, R_
4 means hydrogen or a lower alkyl group which may have a substituent. ] A method for producing 1-aza-4-silacyclohexane. (3) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 means a protecting group, and R_2, R_3, and R_4 have the above meanings. ] By deprotecting the 1-aza-4-silacyclohexane derivative or its salt, the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_2, R_3, and R_4 mean the above do. ] A method for producing 1-aza-4-silacyclohexane. (4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_2, R_3, and R_4 have the above meanings. ] A 1-aza-4-silacyclohexane derivative represented by the formula R_5Y [wherein R_5 is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, which may have a substituent, Y means a halogen atom or OZ, and Z means hydrogen or a leaving group. ] By reacting with the compound shown in and optionally reducing, the general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R_1, R_2, R_3, and R_4 are means the above. ] A method for producing 1-aza-4-silacyclohexane.