JPS6035436B2 - Method for producing N-substituted phenylglycine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N-substituted phenylglycine.

N-phenylglycine has been proposed as a pharmaceutical raw material in, for example, U.S. Pat.
No. 3, etc., and is an industrially useful compound. Conventionally, the following two or three methods are known as methods for producing N-substituted phenylglycine.

For example, benzaldehydes are reacted with sodium cyanide or potassium cyanide in the presence of an appropriate amine or amine nutrient salt to form an aminonitrile converter, which is then hydrolyzed to produce the corresponding N-substitution. There is a method to use phenylglycine. Also known is a method in which phenylacetic acid or its derivative is once brominated to form Q-bromophenylacetic acid or its modest conductor, and this is reacted with various amines to form N-substituted phenylglycine.

The former synthesis method requires the use of an extremely toxic hydrocyanic acid derivative as a reaction reagent, and has a major drawback in terms of reaction operation and waste disposal. In addition, even in the latter synthetic method, a phenylacetic acid derivative with extremely strong lachrymatory properties and a poisonous odor toxin must be used.
The present invention is completely different from the above-mentioned methods and provides a method for synthesizing pure N-substituted phenylglycine easily and in a good yield in one step using only extremely safe and easy-to-handle reagents. That is, in the present invention, in the presence of a tetraalkylammonium salt and carbon dioxide gas,
H=N-R' (where R is a substituted or unsubstituted aromatic hydrocarbon residue, and R' consists of ■ a substituted or unsubstituted alkyl group having 2 or more carbon atoms and ■ a substituted or unsubstituted cycloalkyl group) This is a method for producing N-substituted phenylglycine by electrolytically reducing penzylidene amines (one type of group selected from the group) using a mercury cathode. The tetraalkylammonium salt used in the present invention is for imparting conductivity to the electrolytic solution and is not particularly limited, and any salt that can be used for this purpose may be appropriately selected and used.

In general, those that are soluble in the solvent to the extent that they impart conductivity are preferably used. Further, it is preferable to use one that can be easily separated from the target product obtained by electrolytic reduction or the target product obtained by treating the reaction solution obtained by electrolytic reduction. Generally, it is represented by the general formula R4''N derived from Xe, in particular R'' is an alkyl group having 1 to 6 carbon atoms, and X is CI, Br, 1, OH, OS
Tetraalkylammonium salts such as 03CH3, BF4, CI04, etc. are preferably used.

In particular, taking into consideration the pre-existing properties, tetraalkylammonium halides are inexpensive and easily available, and tetraethylammonium iodide is particularly suitable. Furthermore, a polar non-aqueous solution is preferably used as the electrolytic solution solvent of the present invention. Generally acetonitrile, propionitrile,
N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoamide, benzonitrile and the like are preferably used alone or in combination. Acetonitrile is particularly suitable because it is easily available, inexpensive, has a low boiling point, and is easy to remove by distillation. The carbon dioxide gas used in the present invention can be produced by blowing carbon dioxide gas into the electrolytic solution, but electrolysis can also be performed under pressure with carbon dioxide gas, or while adding solid carbon dioxide (dry ice) in small amounts as appropriate. It's okay.

Other means for the presence of carbon dioxide gas in the electrolytic system may be appropriately selected and employed as required. The most important feature of the present invention is the general formula R-CH=N-R' (where R is a substituted or unsubstituted aromatic hydrocarbon residue, and R' is a substituted or unsubstituted alkyl group having 2 or more carbon atoms. and (1) a group selected from the group consisting of substituted or unsubstituted cycloalkyl groups) is electrolytically reduced.

The aromatic hydrocarbon residue R in the above general formula is generally a substituted or unsubstituted phenyl group, and the substituent is not particularly limited as long as it is inert under the electrolytic conditions of the present invention. Typical substituents that are generally preferably used include halogen atoms such as chlorine, bromine, and iodine, atoms or groups such as alkyl groups, ester groups, ether groups, and carboxyl groups. R' in the above general formula is a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group having 2 or more carbon atoms, and examples of the alkyl group include a propyl group, a butyl group, an isoamyl group, a stearyl group, etc. If it is 2 or more, it can be used without any particular restriction, but in general, those having 2 to 2 carbon atoms, preferably 3 to 1 carbon atoms, are most widely used.

Furthermore, the most common cycloalkyl group is a cyclohexyl group. Furthermore, the substituent for the substituted alkyl group or substituted cycloalkyl group is not particularly limited and may be used as long as it is inert under the electrolytic conditions of the present invention, but generally one or more hydrogen atoms are substituted with a halogen atom such as chlorine or bromine. , an ester group, an ether group, a carboxyl group, an aromatic hydrocarbon residue, and the like are suitable, and in addition to these, an alkyl group is also preferably used as a substituent for the cycloalkyl group. Note that when R' is an alkyl group or substituted alkyl group having 1 carbon atom, such as a methyl group or a benzyl group, the detailed reason is not clear at all, but as described in the comparative example below, Under electrolytic conditions, the yield of the corresponding phenylglycine decreases significantly, making it virtually impossible to obtain the target product. The electrolytic reduction in the present invention is not particularly limited as long as it uses a mercury cathode,
Known means and devices can be used.

That is, mercury is used as the cathode, but there are no particular restrictions on the anode, and it is desirable to use materials that are generally resistant to corrosion under electrolytic conditions, such as platinum or carbon (graphite). As the electrolytic means in the present invention, a constant current electrolysis method, a constant voltage electrolysis method, a constant potential electrolysis method, etc. may be selected as necessary, as long as conditions for reducing at least the raw material penzylidene amine can be set.

Although it is generally convenient to carry out electrolytic reduction at room temperature, the temperature is not particularly limited, and there is no particular problem as long as it is between the freezing point and boiling point of the solvent. Although it is convenient to carry out the reaction under normal pressure in a carbon dioxide atmosphere, there is no problem in carrying out the reaction under increased pressure with carbon dioxide or other inert gas that cannot be reduced by the cathode. It is preferable to mix the electrolyte with a commonly used method; however, when electrolysis is carried out while blowing carbon dioxide or other inert gas into the solution, the liquid drop produced by blowing may be sufficient. be. The electrolytic cell used in the present invention is not particularly limited, and any known cell can be used.

The cathode and anode chambers may be partitioned with a sieve-like glass partition of appropriate roughness, but if there is a risk of reduction in product yield or current efficiency due to mass transfer, a cation exchange membrane may be used. preferable. The electrolytic reduction reaction mechanism in the present invention is shown by the following equation.

As shown in the above formula, the target product of the present invention is N-substituted phenylglycine in which carbon dioxide gas is involved in the reaction, but pendylamines are also obtained as by-products, and these pendylamines are known alone as polymer stabilizers and pharmaceutical intermediates. belongs to.

Therefore, if the pendylamines are separated from the reaction product together with the N-substituted phenylglycine, if necessary, it can be carried out industrially advantageously as a co-production method. Furthermore, as is clear from the above equation, it is necessary to first involve carbon dioxide gas in the reaction, and the intervention of a proton donor such as water in this point electrolyte is necessary to improve the yield of N-substituted phenylglycine. It is desirable to avoid this as much as possible. If the desired product obtained by the present invention is insoluble in the electrolyte, it can be isolated simply by filtration.

However, the reduction products are generally soluble in the electrolyte;
Isolated as free N-substituted phenylglycine by work-up. The method of separating by post-processing is not particularly limited, and any necessary method may be adopted as appropriate, but a typical single-machine method will be exemplified below. That is, after the electrolysis is completed, the solvent is removed by distillation, water is added to the residue, and penzylamines are extracted with a solvent that does not mix with water, such as chloroform or ether. By distilling off this extraction solvent, penzylamines are obtained. Next, the aqueous layer exhibiting alkalinity after extraction with the above solvent is made neutral or weakly acidic (p
H2-6) gives the corresponding N-substituted phenylglycine as a white solid. N obtained in this way
-Transformed phenylglycine is a pure product in most cases, but if further purification is required, it may be recrystallized from a solvent such as alcohol or ethyl acetate. Identification of the target product is preferably carried out using instrumental analysis means such as infrared absorption spectroscopy, mass spectroscopy, IH nuclear magnetic resonance spectroscopy, in addition to screening and elemental analysis as described in the Examples below.

Next, the present invention will be specifically described in detail with reference to the following examples, but the present invention is not limited to these examples.

Note that the yield of the target product in the Examples was calculated from the weight of the target product obtained relative to the weight of penzylidene amine used. Example 1 Penzylidene fn tibutylamine (1.0
8 days, 6.7 hours), tetraethylammonium iodide (1 day), anhydrous acetonitrile (100 days)
and mercury (12%) were added as a cathode, tetraethylammonium (6.0%) and anhydrous acetonitrile (70%) were added to the anode side, and a platinum cylinder was used as an anode for 15%.
3.1 hours (1715 coulombs) at 3 mA (constant current)
I turned on the electricity.

After the electrolysis was completed, the catholyte was separated from the mercury, the acetonitrile was distilled off, and 15 parts of water was added to the residue. This product was extracted with 200 g of chloroform to obtain 0.30 g of a colorless oil from the chloroform residue. This substance shows an absorption based on NH' at 3310-1 in the infrared absorption spectrum, and a molecular ion peak at m/e 163 in the mass spectrum.
The elemental analysis results are the composition formula C,. It matched 7N.
From the above results, it was revealed that this substance was N÷n nabutylaniline. The yield was 27.4% based on the penzylidene fn nabutylaniline used. On the other hand, the aqueous solution extracted with chloroform was acidified with hydrochloric acid to obtain a white precipitate of 0.50%. This one is 5
Sublimation point is 243-24 when recrystallized from 0% ethanol water
It is a white crystal at 9℃, with an infrared absorption spectrum of 3200
-210 ratio 1-1 showed an absorption based on amino acids, and the mass spectrum showed a peak based on M■-COO at 0/e162 (intensity 100%). Furthermore, the elemental analysis value was 8.4 days.
5%, C69.85%, N6.61% and composition formula C
, 2nd, 7N02 (207.27) corresponds to the theoretical values of 8.27%, C69.54%, and N6.76%. Furthermore, the IH nuclear magnetic resonance spectrum measured in trifluoroacetic acid (tetramethylsilane standard) shows 61.
C9 leather proton with triple line in 00, 61.46, 1.82
Signals of 3 types of CH2 protons at '3.72', protons of 65.7o' string 2, and 5 aromatic protons at 6ppm7.50 were shown. From the above results, it was revealed that the white crystals obtained by acidifying with hydrochloric acid were N÷n)-butyl-2-phenylglycine. The yield was 36.0% based on the penzylidene fn tibutylamine used. Example 2 Penzylidenecyclohexylamine (1.02 pm, 5.43 hmole) was energized for 9.2 hours (1153 coulombs) at an average of 3&A in the same manner as in Example 1.

When 20 parts of water and 200 parts of benzene were added to the catholyte, 0.73% of a white solid was precipitated. When this substance is recrystallized from a large amount of 50% ethanol water, the sublimation point is 250 to 270.
It is a white crystal with an infrared absorption spectrum of 320
It showed absorption based on amino acids at 0 to 2000 k-1, and a molecular ion peak at /e233 in the mass spectrum.

Furthermore, the results of elemental analysis showed composition formula C, 4th, 9N02 (2
33.30).

The above results revealed that this product was N-cyclohexy-2-phenylglycine. The yield was 57.4% (3.11 mmole). The above-mentioned benzene solution was dried and then filtered to remove the benzene, yielding 0.27 g of a white solid. When this substance is recrystallized from methanol, it becomes white needle-like crystals with a melting point of 142-143°C, and the infrared absorption spectrum shows an NH absorption at 3280 arc-1, and the mass spectrum shows a molecular ion peak at kite/e189. It was confirmed that it was aniline. The yield was 26.4% (1.43 hmole
)Met. Example 3 Penzylidene laurylamine 1.
21 yen (4.41 mmole) with an average of 21 orbit and 2.6
Power was on for an hour.

During electrolysis, 0.35% of white precipitate was formed. this thing 5
When recrystallized from 0% ethanol water, the melting point ranges from 67.5 to Iso.
White needle-like crystals with a molecular weight of 530 were obtained. The infrared absorption spectrum shows NH absorption at 3280 arc-1, and the mass spectrum shows a molecular ion peak at skin e275 (intensity 23%), and its elemental analysis value is HIO. 48%, C75.0
5%, N4.24%, composition formula C, rainbow 33N (27
The theoretical value of 5.46) HIO. 4%, C75.19%, N
4.24%, and it was confirmed that it was N-laurylaniline. The yield was 28.4% (1.28 hmol
e). Next, the acetonitrile solution was dried and water was added to the residue to precipitate a white precipitate. This product has an infrared absorption spectrum of 3220 to 2500 skin-1 based on amino acids, and a mass spectrum of skin/e275 based on M-C0.
2, and the elemental analysis value matched the composition formula C2 mountain 33NQ (319.47), confirming that it was N-Rau 1"-2-phenylglydine.

The yield was 63.5% (2.80 hmole). Example 4 Under substantially the same conditions as in Example 1, electrolytic carbonation was carried out for 2.6 hours using dibenzylidene ethylene diamine at a concentration of 1.20 and 21%. By treating the electrolyte in the same manner as in Example 1, N,N'-bis(q-carboxyl-penzyl)ethylenediamine (yield 41.4%), which is the corresponding amino acid with a sublimation point of 295 to 30 p0, was obtained. 0.43 yen (yield: 35.2%) of N,N' dibenzylethylene diamine having a melting point of 100 to 10 yo was obtained.

Example 5 Penzylidene 3 was prepared under almost the same conditions as Example 1.
-Phenethylamine 1.50 with 63hA 5. Immediate electrolytic carbonation was performed.

By treating the electrolyte in the same manner as in Example 2, N-(B-phenethyl)-2-phenylglycine with a sublimation point of 265°C (yield 44.6%) and a melting point of 121-12
Zo○ no N-(3-phenethyl)ani1''n0.68 evening (
Yield: 44.8%). Example 6 Same as Example 1 p-chlorobenzylidene n-nabutylamine 1.83
5. Average sawing 88 hA. Electrolytic carbonation was performed for a long time.

By treating the electrolyte, N-in-nabutyl-2-P
- Chlorphenylglycine 0.94 m (yield G9.5%)
) and N÷nnabutyl P-chloroaniline (0.57 units) (yield 30.1%) were obtained. Example 7 In the same manner as in Example 1, electrolytic carbonation was carried out for 6.1 hours at penzylidene 2-methylcyclobentylamine of 1.39 and an average stiffness of 75 hA.

By treating the electrolyte, 0.83 N-(2-methylcyclobentyl)-2-phenylglycine (yield: 4
8.1%) of N-(2-methylcyclobentyl)aniline (yield: 34.9%) was obtained. Example 8 Same as Example 1, m-oxycarbonylbenzylidene n
- Hexylamine 2.00 per evening with an average of 9 shoes A and 6. Early electrolytic carbonation was performed.

By treating the electrolyte, N-hexyl-2-
1.10 units of (m-oxycarbonyl)phenylglycine (yield: 46.3%) and 0.17 units of N-hexyl-m-oxycarbonylaniline (yield: 8.5%) were obtained. Example 9 Same as Example 1 p-ethoxycarponylbenzylidine y-methoxy-n-benthylamine 1.74 5
9. Periodic electrolytic carbonation was performed.

By treating the electrolyte, N-(y-methoxyn-
(yield 53.8%) and N-(y-methoxy-n-pentyl)-p-ethoxycarbonylaniline 0.52 units (yield 29%). .9%). Comparative Example Same as Example 1, penzylidenebenzylamine 1.80
8 at 54mA in the evening. Anchor time electrolytic carbonation was performed.

Claims (1)

[Claims] 1 In the presence of a tetraalkylammonium salt and carbon dioxide gas, the general formula R-CH=N-R' (where R is a substituted or unsubstituted aromatic hydrocarbon residue, and R' is a substituted or N-substituted phenylglycine characterized by electrolytically reducing the benzylidene amines (which are one type of group selected from the group consisting of unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups) with a mercury cathode. Manufacturing method.