PL194965B1 - Method of obtaining phenoglycine and derivatives thereof - Google Patents

Abstract

1. A method for obtaining phenylglycine and its derivatives represented by general formula 1, wherein R is a hydrogen atom, halogen, a straight or branched alkyl or alkoxy group containing from 1 to 4 carbon atoms in a condensation reaction of the appropriate arylaldehyde with cyanide, characterized in that equimolar amounts of benzaldehyde of formula 2, where R has the same meaning as in formula 1, and alkali metal cyanide are subjected to the condensation reaction in a solvent in the presence of a condensing agent, and the reaction is carried out without isolation of the intermediate product.

Description

Description of the invention

The subject of the invention is a process for the preparation of phenylglycine and its derivatives substituted in the benzene ring.

Phenylglycines (α-amino-α-phenylacetic acid derivatives) and their derivatives are of great synthetic importance. They are a valuable starting material for the synthesis of various biologically active substances, e.g. cephalosporin antibiotics and anticoagulant preparations such as ticlopidine or clopidogrel. On the other hand, phenylglycines can be used as a substrate for the preparation of a number of heteroaromatic nitrogen compounds, including pyridines, pyrimidines and pyrazines.

So far, two basic methods of obtaining phenylglycines have been described. The first of them - the Strecker method (Org. Synth. Coll. Vol. 3, p. 84) consisting in the condensation of benzaldehyde with ammonium chloride and sodium cyanide, with the release of unstable tarry aminonitrile, which requires extraction from the reaction medium. As a result of the time-consuming and laborious preparation process, unsubstituted phenylglycine is obtained with a yield of only 30%. In the case of the ring-substituted phenylglycines, the yield is even lower and does not exceed 10%.

In another method for the preparation of phenylglycines disclosed in J. Org. Chem. 1944, 21, JCS 1962, 144, as a result of the reaction of arylaldehyde with a molar excess of sodium or potassium cyanide and ammonium carbonate, first a substituted hydantoin is obtained, which, after isolation from the reaction medium and crystallization, is subjected to alkaline hydrolysis. The total yields of this two-stage process, based on the starting aldehyde, range from 30 to 60%. This method, requiring the use of a 1.4-1.5 fold molar excess of cyanide in relation to the aldehyde, is unsuitable for use on an industrial scale due to the generation of large amounts of difficult to utilize wastewater.

It turned out that phenylglycine derivatives can be obtained with much higher efficiency in a one-stage process that does not require the isolation of intermediate products and without the need to discharge troublesome wastewater, by condensing equimolar amounts of the corresponding benzaldehyde and alkali metal cyanide.

In the process of the invention for the preparation of phenylglycine derivatives represented by the general formula 1, in which R represents a hydrogen atom, a halogen atom, a straight or branched alkyl or alkoxy group containing from 1 to 4 carbon atoms, equimolar amounts of arylaldehyde of the formula 2, where R has the same meaning as in Formula 1 and alkali metal cyanide are subjected to a condensation reaction in a solvent in the presence of a condensing agent. A suitable condensing agent is a salt of carbonic acid, preferably ammonium carbonate, which is used in a molar excess to both reactants.

The condensation reaction is carried out in a mixture of water and a water-miscible solvent, such as lower aliphatic alcohols or lower aliphatic ketones or mixtures thereof. The lower aliphatic alcohol is selected from the group consisting of, inter alia, methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof. The type of alcohol is selected depending on the substituted arylaldehyde used in the condensation reaction. In a preferred embodiment of the invention, the volume ratio of water to alcohol is 1: 1 and the alcohol is ethanol.

Typically, the reaction temperature is from 40 to 100 ° C, and the time is from 1 to 3 hours. The reaction product is isolated from the reaction mixture in the usual manner. Most often, the inorganic precipitates remaining after the reaction are filtered off, the solution is concentrated to 1 / 3-1 / 4 of the original volume, and a 5-10% solution of an alkali metal hydroxide, e.g. sodium, potassium or barium hydroxide is added thereto. The reaction mixture is then heated to reflux for 6 to 20 hours and, after cooling to room temperature and possible filtration of the tars, it is neutralized to a pH of about 6.0-6.5 with concentrated hydrochloric acid. The crude precipitate of the product obtained can be purified by methods known in the chemistry of amino acids, e.g. by dissolving it in a concentrated hydrochloric acid solution and reprecipitating it with sodium base.

The process according to the invention makes it possible to obtain phenylglycine derivatives in high purity, with a high yield in the range of 65-95%. The method is technologically simple, it allows the use of easily available starting compounds and the reduction of the amount of undesirable sewage.

The following examples illustrate the invention.

P ryclic d 1 o-Chlorophenylglycine (Formula 1, R = o-Cl)

To a solution of 50 g (0.355 m) of o-chlorobenzaldehyde (formula 2, R = o-Cl) in 500 ml of ethanol-water (1: 1) was added 17.4 g (0.355 m) of sodium cyanide and 86.5 g (0.90 m) of ammonium carbonate. It was heated to reflux at ~ 60 ° C for 2 hours. After filtering off the precipitates of inorganic salts, the solution was concentrated to ca 1/5 volume, ~ 230 g of a 10% NaOH solution were added and refluxed for ca. 18 hours. The reaction mixture was then cooled to room temperature, filtered and neutralized to pH> 6.5 with ~ 70 mL of concentrated hydrochloric acid. The precipitate formed was filtered off and purified by redissolving it in 50 ml of 6N hydrochloric acid and, after filtration, neutralizing the solution with 2N sodium hydroxide solution. After drying at 40 ° C, 59.7 g (90.5%) of pure product was obtained, m.p. 219 220 ° C (mp 219.5 ° C - J.Org. Chem. 1944, (9), 21).

Elemental analysis: for OHClNO; (185.5)

Calc: C, 51.75 Found: C, 51.60

H - 4.31 H - 4.18

N - 7.55 N - 7.51

Following the above-mentioned procedure, the following phenylglycine derivatives were obtained: p-Chlorophenylglycine (Formula 1, R = p - Cl)

Yield 86.5%, mp. 261 ° C (mp. 261-2 ° C - J.Org. Chem. 1944 (9), 21)

Elemental analysis: for C ₈ H ₈ ClNO2 (185.5)

Calc: C, 51.75 Found: C, 51.63

H - 4.31 H - 4.25

N - 7.55 N - 7.39 m-Chlorophenylglycine (Formula 1, R = m - Cl)

Ed. 83.8%, mp. 248-250 ° C (mp. 250-254 ° C - JCS 1962, 1440)

Elemental analysis: for C ₈ H ₈ ClNO2 (185.5)

Calc: C, 51.75 Found: C, 51.81

H - 4.31 H - 4.30

N - 7.55 N - 7.49 p-Methoxyphenylglycine (Formula 1, R = p-OCH ₈ )

Ed. 75.5%, mp. 270-272 ° C (mp. 269-271 ° C - JCS 1962 Elemental analysis: for C9H11NO3 (181.27)

Calculate: C - 59.60 Found: C - 59.64

H - 6.07 H - 6.01

N - 7.73 N - 7.72 m-Methoxyphenylglycine (Formula 1, R = m-OPh)

Ed. 81.1%, mp. 208-209 ° C

Elemental analysis: for C14H13NO3 (243.32)

Calc: C, 69.05. Found: C, 68.88

H - 5.34 H - 5.31

N - 5.75 N - 5.62 p-Fluorophenylglycine (Formula 1, R = p-F)

Ed. 74.8%, mp. 248-250 ° C

Elemental analysis: for C ₈ H ₈ FNO2 (169.28)

Calc: C, 56.73 Found: C, 56.53

H - 4.72 H - 4.65

N - 8.27 N - 8.30 p-Isopropylphenylglycine (Formula 1, R = -CH (CH ₈ ) ₈ )

Ed. 90.11%, mp. 285 ° C

Elemental analysis: for CnH1 ₅ NO2 (193.32)

Calc: C, 68.28 Found: C, 68.11

H - 7.75 H - 7.70

N - 7.24 N - 6.99

Phenylglycine (Formula 1, R = H)

Ed. 80.4%, mp. 270 ° C (m.p. 270 ° C; Vogel 1984, 471)

Elemental analysis: for C ₈ HgNO2 (151.15)

Calc .: C, 63.51 Found: C, 63.30

H - 5.95 H - 5.79

N - 9.26 N - 9.24

PL 194 965 B1 p-Bromophenylglycine (Formula 1, R = p-Br)

Ed. 78.8%, mp. 230-232 ° C

Elemental analysis: for C ₈ H ₈ BrNO ₂ (230.35)

Calc: C 41.67 Found C 41.48

H - 3.47 H - 3.46

N - 6.07 N - 5.96

Claims (7)

Patent claims 1.As a result of the removal of phenylooliccyy and its ppoCoOdyC by the formula 1, where R represents a hydrogen atom, a halogen atom, a straight or branched alkyl or alkoxy group containing from 1 to 4 carbon atoms by the condensation of an appropriate arylaldehyde with a cyanide reaction, reacts in a solvent to equimolar amounts of benzaldehyde of formula 2, where R is the same as in formula 1, and alkali metal cyanide, in the presence of a condensing agent, and the reaction is carried out without isolation of the intermediate product. 2. Corresponding to the texts.1, changed. that is, the salt of coal, preferably ammonium carbonate. 3. Provide the service. 1albb2, with changed. ię rOdnkooydnyójeccstooójen ię in n molar bearing in relation to both reactants. 4. Sppoóówae-ugzzntrz.1 zaaiieenytym, that neenojeprc> waadis ięw mienoźninniedl ηπίο water-miscible solvent. 5. Way according to the outside. 4, changed by the fact that γ ^ Ιο ^ I believe there is! in a multiplier of water and a water-miscible solvent in a 1: 1 volume ratio. 6. ίpooóówan-Jg zzaSz ^ zznmieenatym. that reenojępιΌwaadisięw mienźninniewa with an alcohol selected from the group consisting of lower aliphatic alcohols and lower aliphatic ketones or icO mixtures. 7. The method according to p. 6. The process of claim 6, wherein the reaction is carried out in a water-ethanol mixture.