DE1493965C - Process for the preparation of Racema ten optically active nitriles - Google Patents

Description

1 2

The present invention relates to a mutated α-amino acids, such as, for example, methyl driving for the production of racemates of optically active 5-hydroxytryptophari, "-Methylhistidin," -Methyltryp-Nitrile of the general formula tophan and the like. It therefore exists

a need for a good process for the race-5 mization of an optically active "-aminonitrile, the

_R in the α-position is a quaternary carbon atom

| ² owns. -

' _H So far, the racemization of optically active

¹ ν - c «-amino acids and their derivatives only slightly

'ίο to be carried out if the α-amino acid is a water

CN has a substance atom on the carbon atom. The Race

mization can then by an enolization or a similar unsaturated "form. So far

where R _{1 is} a low molecular weight alkyl radical, R ₂ is considered impossible to racemize a quaternary organic radical via a carbon atom of 15 carbon atom, since there is no such double bond bonded to the asymmetric carbon atom without cleavage of the molecule and Ac den Means acyl radical of a carboxylic acid. can.

This method is characterized in that it has now been found that it is possible to

one is a solution or melt of an enantiomorphically active nitrile in which an α-acylamino group this compound with at least 0.01 mole of a substituent and the nitrile group on a quaternary one Base, preferably with NaCN, per mole of the primary carbon atom, in particular the α-acyl compound treated. amino-a-lower alkyl-hydroxy- or -methoxyphenyl-

Suitable bases are those which replace the propionitrile or the higher alkyl nitriles, which are replaced by ( Hydrogen atom on an amide nitrogen enables the above general formula to be shown are, such as cyanides, hydroxides, alkylates, hydrides, 35 to racemize when these compounds with a Phenolates or carbonates of alkali or alkaline earth are treated to remove a base metallic or quaternary ammonium cyanides. Hydrogen atom on an amide nitrogen enabled

Preferred for the method according to the invention are.

Compounds are enantiomorphic forms of such It is completely unexpected and could not have been foreseen

Compounds of the formula above, in which the 30 contains a quaternary carbon atom that only contains the stick radical R ₂ bonded to the group or carbon, somehow

could easily be racemized. One possible explanation would be that the cyanide ion is under

(R ₃ O) ₀ simultaneous formation of a double bond between

35 separates the carbon atom and the amide nitrogen atom, after which an abutment of the cyanide ion takes place. This assumption is supported in particular by the fact that the effective catalysts are (R ₄ O) & those bases containing a hydrogen atom of

4 "are able to subtract from an amide nitrogen atom.

It is an advantage of the present invention that

denotes where R ₃ and R _{1 are} each a hydrogen - their use is the return of the undesired atom or a methyl group or, if (R ₃ O) and th enantiomorphs in the syntheses of amino (R ₄ O) are in the ortho position, acidify together with a minimum of costs. (a methylene radical; α 1 or 2 and £ 0 or 1 mean: 45 Another advantage of the present invention is, In these compounds, Ac means a low - that the recycling of the undesired enantimolecular alkanoyl or alkenoyl radical, benzoyl, omorph is carried out without That a breakdown of Chlörbenzpyl, Brombenzoyl, Toluyl, Dimethylben- to the ketone precursor is necessary. Verbinzoyl, a mono-, dir ^; or trihalogenubstituierten dung, which is cleaved, remains the same and low molecular weight alkanoyl- or phenylsubstituier- 50 can be fed back into the cleavage process will,
th low molecular weight alkanoyl radical. The nitriles, which according to the invention

The racemization will be racemized by the way the acyl \ · drive can be normal group unaffected; Substituents that are sensitive to bases according to the Strecker reaction from ketones sindj, but must not be present. placed. This reaction consists in condensation The development of a-methyl-S ^ -dihydroxyphe- 55 of the ketone with ammonium cyanide to an aminonylalanine as a major antihypertensive agent nitrile and subsequent acylation of aminonitrile has a need for new manufacturing processes with an acid anhydride. The resulting race of these Connected with itself. This anti- mate are made by chemical methods or by hypertonic agents are optically split by a 4- or 5-stage direct crystallization. examples for Synthesized and then converted into its optical 60 optically active nitriles, which are race isomers by the process split, since the antihypertensive host can be mized, are a-phenyl-a-acetaminokung only applies to the L-shape. This leads to a propionitrile, α-benzyl-α-acetaminopropionitrile, 1-Cy buildup the unusable η-form. There were ano-l-acetaminocyclohexane (made from Cycloviele Efforts made to find ways to hexanone), a-imidazölylmethyl-a-acetamino-low- and to racemize the D-form to the ni-form, so that 65 alkyl nitriles and "-S-hydroxy-S-indolylmethyl-a-acetate can also be used. amino-lower alkyl nitriles.

Similar problems occur with other tertiary amino The compounds for which the present

nitriles, which are particularly valuable in the production of «-substi- racemization processes are

3 4

the a-acylamino-x-substituted-benzylnitrile of the general formula at 190 ° C., however, becomes full in a few minutes constantly racemized. The catalysts that make the Race

effect mization according to the method of the invention,

Ri are bases that have such a strong alkalinity

'(R O) ·' · '■ 5 that they remove a proton from an amide nitrogen.

³ i ^ —CH ₈ -C-CN In general, they are bases, the cations of which are alkali

I || ₍ I or alkaline earth ions or quaternary ammonium

ions are. The anion can be hydroxyl, carbonate, cyanide, hydride or phenolate. For example, if Ac ¹⁰ add sodium hydride to a solution of Dx-Me-

ethyl - «- vanillylpropionitrile is added in the cold, hydrogen is released and the sodium in R _{1 is} a low molecular weight alkyl radical, phenolate of the aminonitrile is formed; the solution racs-Ac has the meanings described above, mises rapidly on heating. R ₃ and R _{4 are} preferably hydrogen atoms or methyl radicals or, 15 the anion cyanide, since after the mass action R ₃ O and R ₄ O are in the o-position to each other, additional cyanide ions are the equilibrium of the, together a methylene radical, α 1 or 2 and move reaction to the left. Others will mean i, 0 or 1. The main compounds used anions, so the yields due to this class are the compounds of the structure by decomposition, probably by deacylation

20 of the amine, lower. As a result, only limited amounts (less than Oj6 mol) of _{such R 1 anions}

'I used as catalysts, while with cyanides

CH ₂ -C-CN such a restriction is insignificant. It who

for example compounds such as sodium cyanide,

R ₄ O-

as sodium hydride, sodium carbonate, potassium cyanide, ca-

lium hydride, potassium carbonate, lithium cyanide, Rübia . dium cyanide or cesium cyanide, as catalysts

..- ■■■■ '■. ■ used. Quaternary Am

monium compounds, especially the cyanides of

in which R ₁ , Ac, R ₃ and R _{4 have} the abovementioned meanings, strongly basic tetraalkylammonium compounds. These compounds are important such as Tetraäthylammoniumcyartid, vertung, since they turn intermediates in the synthesis of. A particularly preferred catalyst is an α-methyl-3,4-dihydroxyphenylalanine, this alkali metal cyanide such as sodium cyanide. The catalyst intermediates can be easily cleaved by direct cleavage in amounts of at least 0.01 mol per mol of preliminary process. The acylaminonitrile according to the invention is used. Preferably, according to the method, a compound step is therefore the amount used, which is 0.4 to 0.6 mol, which means that the undesired D-isomer is directly 0.5 mol per mol of nitrile.
cleavage after racemization to the DL form A solvent is in the process of the invention

can be traced back. Although preferred, it can be according to the invention

To carry out the method of the invention 40 Räcemisierungsverfahren also in a melt of the the enantiomorph to be racemized is carried out with an acylamirionitrile to be racemized Base treats that will remove a hydrogen. The temperature is either as the on or the capable of effecting atoms of an amide nitrogen. Absence of a solvent, but made possible The process can be in a solvent or in the use of solvents the uniform of a melt of the material to be racemized 45 Adjustment of the temperatures, In addition, certain be performed. It can be used at temperatures of solvents such as, for example, the sulfoxides Ziimnertempei "atur up to high temperatures through catalyst and enable a closer contact, The extent of racemization is, as is well known, that they also facilitate proton tinting Function of: Varying: time, temperature under directional stereo-specific conditions, peraturj KohzehtratiOn des Acylaminonitrile and Art 50 For these reasons, the use of a of the catalyst. There are several competing solvents preferred. The solvent must Reactions which, however, are free of hydroxyl groups due to the time of exposure / useful Catalyst in terms of the yield influencing solvents can therefore be considered high-boiling, no be flowing. Hydroxyl group-containing solvents for the

In order to avoid a possible decomposition it is to be defined 55 acyläminörtitrile. The dialkyl sulfoxides, such as, for example, di-temperatures and short times, are particularly useful before the racemization is carried out at high rates. methyl sulfoxide, methyl ethyl sulfoxide, diethy | sulfoxide, temperatures above 10O ⁰ C (the most appropriate of dipropyl sulfoxide or dibutyl sulfoxide. It can 150 ° C upwards, whereby a limit only by the however also other sulfoxides, which likewise with the boiling point of the solvent or the application 60 temperature of the reaction are liquid, such as is set by pressure) are preferred. The time is wise methylphenylsulfoxide, ditolyisulfoxide or didanrt shortened to minutes to use the racemization with allyl sulfoxide. The solvent will complete a minimum of decomposition. It is expedient to use in such an amount that low temperatures are much longer times than when more than 2 units of volume of solvent are present at the preferred temperature of 190 ° C., which is required for 65 unit weight of nitrile. Borrowed under volume unity. At room temperature L -. \ - acetamino and weight units are meant such a relationship, Λ-vanillylpropionitrile by sodium hydride in di- such as milliliters to grams. Preferably methyl sulfoxide in 16 hours to 12 ° / "racemized; per part by weight of acylaniinonitrile about 4 volts

5 6

units solvent used. Other solution areas 1 2

medium, such as dimethylformamide or di-

Ethylene glycol dimethyl ethers can also be processed under the conditions of. Example 1

be turned. using D-a-acetamino-a-veratrylpro-

In general, the exclusion of air is pionitrile (mp = 142 to 143 ° C), D-a-acetamino-

Carrying out the process according to the invention a-3,4-dihydroxybenzylpropionitrile (melting point = 189 to

expedient in those cases in which Dihy- 192 ° C), D-oc-acetamino-a-vanillylbutyronitril ■ and

droxyphenylreste are present, such as D-Ä-acetamino-a-vaniliylvaleronitril, all through

in which for the present. Invention particularly suitable cleavage of the corresponding, by implementation of

Neten dihydroxybenzoyl or vanillylacylamino io acetic anhydride with the corresponding amino

nitrile, air is expediently excluded in order to obtain a riitrile, prepared racemate

Decomposition of the material to be racemized by D - «- acetamino-a-vanillyIpropionitril and

Avoid oxidation. Exclusion of air using D-a-acetamino-a-piperonyl-

is made by purging with nitrogen and propionitrile. The products obtained are practically

the reaction is carried out under nitrogen. 15 table completely racemized. DL-a-acetamino-a-ver

The following examples illustrate the invention; atrylpropionitrile has a melting point of 139

up to 144 ° C and DL-a-Acetamino-a ^^ - dihydroxyben-

For example, zylpropionitrile has a melting point of 202 to 204 ⁰ C.

A slurry of 1 g of D - «- Acetamido-» o B e i s ρ 1 e 1 3

a-vanillylpropionilril and 100 mg sodium cyanide in Man works according to the process conditions of

4 ml of dimethyl sulfoxide is flushed through with nitrogen. Example 1 using D-a-propionamido-

The mixture is then stirred within a-vanillylpropionitrile, D-arbutyramido-a-vanillyl-

1 minute to reflux at 194 ° C using propionitrile, D-a-valeramido-a-vanillylpropionitrile,

an oil bath of 200 ⁰ C and heated for 3 minutes at «5 Da-acrylamido-Ä-vanillylpropionitril, Da-Benz-

kept this temperature. During this time amido - «- vanillylpropionitrile, D-a-p-chlorobenzamido-

all the solids dissolve, and a-vanillylpropionitrile, D-a-o-bromobenzamido-a ^ vanil-

a pale yellow solution. The reaction mixture is lylpropionitrile, Dwx-p-tolamido-a-vanillylpropionitrile,

removed from the oil bath and quickly put in an ice bath D-a-2,4-dimethylbenzamido - «- vanillylpropionitrile,

to a temperature of 60 to 70 ⁰ C within about 30 D-ac-chloroacetamino-a-vanillylpropionitril, D - «- Di-

Cooled 1 minute. The excess dimethyl cMoracetamino-α-vanillylpropionitril, D-a-trichloro-

sulfoxide is acetamino-a-vanillylpropionitrile, D-a-trifluoroacet-

distilled off in a water bath of 60 to 70 ^{0 C.} amino-Ä-vanillylpropionitril and Da-phenylacit-

The brown viscous syrup obtained is then replaced by amino - «- vanilrylpropionitrile as an optically active nitrile.

Addition of 10 ml of a 0.6N HCl at 0 ⁰ C with stirring 35 These nitriles were converted by reacting the corresponding

deterred. The temperature of the quenched chenden acid anhydride with DL-a-amino- <x-vantjlyl-

The mixture is kept at S to 10 ° C. It must be made propionitrile and then cleavage.

Caution should be exercised, as hydrogen cyanide causes the The products were virtually completely racemized.

Operation is released. While stirring _. ' -V *. ^^

at 5 ° C. for 30 minutes the product 40 ^{B e} ' ^s P- ¹ crystallizes. ^c » ⁴

out. The product is filtered off and one after the other one works according to the process conditions of

twice with 1 ml of water at 0 to 5 ° C and twice Example 1 using b-a-Benzyl-a-ace.t-

washed with 5 ml of cold sec-butanol. The ausaminopropionitrile (melting point = 171 to 173 ° C) (from Met ^ yl-

yield is 916 mg (91.6 ° / ₀₎ of racemic N-acetyl benzyl ketone), "- + • Imidazolyhncthyl-a-acetariiinopro-

tylaminonitrile, mp = 171 to 176 ° C. The phases 45 pionitrile (from. 4-Imidazolylacetöri), ix-5-Hydfqxy-

Solubility analysis shows that the product is a pure S-indolylmethyl-a-acetaminopropionitrile (from 5-Hy-

degree of security from 96 to 97 ° / ₀ . Droxy-3-indolylacetone), Dap-MetKoxybenzyl-a-acet-

One works using potassium cyanide aminopropionitrile (two crystal forms, of which

instead of sodium cyanide. The product is melted into one at 145 ° C and the other at 16i ° C)

obtained a yield of 90%. The racemization So and D-Ä-p-Hydroxybenzyl-Ä-acetamiriopropionitrile

is practically quantitative (99.7%). (Mp. = 214 to 216 ° C) instead of that in Example 1

If sodium hydride is used instead of the sodium nitrile used. The products are practically yoU-

triumeyanids so a yield of 82% product is constantly racemized. DL-Ä-Benzyl-Ä-acetaminopropio-

obtained which is practically completely racemized. nitrile showed a melting point of 14l to 143 ⁰ C,

If sodium carbonate instead of sodium cyanide 55 DL-a-p-methoxybenzyl-ix-acetaminoprppionitnl of

is used, the yield is 80% of acetone 113 to 117 ⁰ C and DL-ap-hydroxybenzyl-at-acet-

aminonitrile, which is practically 100% racemized. aminöpropionjtrii from 177 to 178 ⁹ C. Λ

Using twice the amount of sodium. .

cyanide is a complete racemization (prak- Example 5

table 100%). The yield of purified 60 A mixture of 1.0 g of b-acetamino-ix-variiliyl-

Product after removing the colored secondary propionitrile and 100 mg sodium cyanide in 4 ml di-

products is 85%. methylformamide is flushed with nitrogen and

If the amount of sodium cyanide was heated to half for 10 minutes under reflux (about 155 ⁰ C)

is reduced, the yield of acet- The solvent is removed in vacuo and the

aminonitrile 86%; it is 91.6% racemized. 65 Product by stirring the remaining öh

If only half the volume of the dimethyl is made to crystallize with 10 ml of 0.6N HCl. Dk

sulfoxide is used, the yield is practically Crystals are removed and washed with water and kai

table to 100% racemized product 91.6%. tem isopropanol washed. This gives 940 mj

Product of melting point = 180 to 197 ^° C. with an optical purity of 70% (ie 30% racemized).

If you work according to the above procedure using 4 ml of diethylene glycol dimethyl ether instead of the dimethylformamide, 938 mg of product with a melting point of 190 ° to 198 ° C. are obtained with an optical 85% purity (15% racemization).

Example 6

A mixture of 2 g of D-α-acetamido-α-vanillylpropionitrile and 200 mg of sodium cyanide is pulverized in a mortar. The mixture becomes good with nitrogen rinsed and then placed in an oil bath preheated to 210 ° C. The mixture gradually melts and will go dark within 5 minutes. It is cooled and triturated with 20 ml of 0.6N HCl. The dark brown solid is filtered off, washed with 0.6N HCl and with water and dried. 1.7 g of a product with a melting point of 164 ° to 174 ° C. are obtained in this way. ao

The reaction product is recrystallized first from methanol and then from isopropanol and yields 0.98 g of substance with a melting point of 175 to 197 ° C with an optical purity of 55% (i.e. 45% racemization).

Claims (5)

Claims: 25 1. Process for the preparation of racemates of optically active nitriles of the general formula R ₂ R ₁ -C-NH-Ac CN where R _{1 is} a low molecular weight alkyl radical, R _{2 is} an organic radical which is bonded to the asymmetric carbon atom via a carbon atom 35 is, and Ac denotes the acyl radical of a carboxylic acid, characterized in that a solution or melt of an enantiomorphic form of this compound with at least 0.01 mol of a strong base, preferably with NaCN, treated per mol of the compound. 2. The method according to claim 1, characterized in that one uses an enantiomorphic form of a compound in which R _{2 is} the group (R ₃ O), (R ₄ O) ₆ CH ₂ denotes in which R ₃ and R ₄ each represent a hydrogen atom or a methyl group or, if R ₃ O and R ₄ O are in the ortho position, together represent a methylene radical, a 1 or 2 and b 0 or 1. 3. The method according to claim 1 and 2, characterized in that one is an enantiomorph Used in the form of a compound in which Ac is a low molecular weight alkanoyl or alkenoyl radical, a benzoyl, chlorobenzoyl, bromobenzoyl, toluyl, Dimethylbenzoyl, a mono-, di- or trihalogenated low molecular weight alkanoyl or mean a phenyl-substituted low molecular weight alkanoyl radical. 4. The method according to any one of claims 1 to 3, characterized in that the racemization by heating, especially at above 100 ⁰ C, is carried out. 5. The method according to any one of claims 1 to 4, characterized in that the solvent a liquid organic sulfoxide, especially dimethyl sulfoxide, is used and the reaction occurs 185 to 195 ° C carried out. 009 549/386