US2229187A - Amino-alcohol and a process for its production - Google Patents

Amino-alcohol and a process for its production Download PDF

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US2229187A
US2229187A US219917A US21991738A US2229187A US 2229187 A US2229187 A US 2229187A US 219917 A US219917 A US 219917A US 21991738 A US21991738 A US 21991738A US 2229187 A US2229187 A US 2229187A
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Peyer Julius
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Sandoz AG
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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  • the racemates as also the pure optically active alcohols, can be obtained in good yield if aliphatic or araliphatic benzyl-amino fatty- 1o acid esters are reduced, and in given cases, the :racemates of the benzyl-amino-alcohols or the salts of these optically active acids are decomposed into the optically active components by iractional crystallization from a suitable solvent 15 and the benzyl group split out from the According to the present invention therefore it has been ascertainedthat the reduction of the easily accessible benzyl-amino fatty-acid esters which correspond to the general iormula go 5 wherein X represents hydrogen, alkyl and alkoiw, Y represents alkyl and arallryl, Z represents a group carrying the carboxylic acid ester radical and It represents hydrogen, 'alkyl. arallwl andacyl, gives appreciably better results, and that 30 the hitherto unknown
  • benzylamino-alcohols are es- 35 pecially suited to give well crystallized salts with optically active acids which are specially suited for splitting the racemates into optically active components.
  • the reduction of the benzylamino fatty-acid esters can be carried out in the known manner, for example according to the method of Bouveault and Blanc with sodium and alcohol, or 50 by catalytic reduction, wherebyas solvents organic solvents miscible with water or' not miscible with water can be used, such as ethanol, butanol, toluene, tetrahydroand decahydronaphthalene.
  • solvents organic solvents miscible with water or' not miscible with water such as ethanol, butanol, toluene, tetrahydroand decahydronaphthalene.
  • the benzylamino-alcohols thus obtained can be 55 readily isolated from the reaction mixture if they are converted for example into hydrochlorides and precipitatedfrom aqueous solution by an addition of alkali.
  • the optically active benzylamino-alcohols are advantageously subjected to catalytic reduction with hydrogen in the presence for example of palladium as a catalyst, preferably in the presence of an equal quantity of an organic acid.
  • oxalic acid is especially advantageous as in such case the amino-alcohols are obtained as well crystallizing oxalates easy to be isolated.
  • optically active amino-alcohols such as for example dand l-alaninol, dand l-a-aminobutanol, d and l-leucinol and the like in good yields and in pure crystalline form.
  • the optically active forms I use the recently employed kind of designation, which indicates by the amino acids through the letters dand lthe configuration and through the figures and the direction of, the rotation.
  • amino acids For the followingly cited amino acids it has been found that they are present in the nature as levo-forms and must, therefore, be designed as l-(+) -alanine, l-(+) -valine; l-() -leucine, l-(-) -phenyl-a-lanine.
  • (+)-alaninol that has been isolated as a basic splitting product from the ergot alcaloid ergo-basine (Jacobs and Craig, Science 82, 16 (1935)) the authors indicate that it derives from the natural alanine and must therefore be designed as l-(+)-alaninol.
  • From natural l-(+) -valine (weakly) dextro-rotary valinol (Barrow and Ferguson 1. 0.) can be obtained and from natural l-()-1eucine a (weakly) levorotary leucinol (Karrer, Helv. 4, 91, 1921) can be obtained.
  • the optically pure dextro-rotary valinol is therefore to be denoted as 'l-(+) -valinol and optically pure levo-rotary leucinol as l-() leucinol.
  • the two optically active a-benzylaminobutanols are denoted for the present as and according to their direction of rotation, as the genetic relations of the corresponding optical forms of the a-amino-butyric acids are not yet established.
  • One object of the present invention is a process for the manufacture of benzylamino-alcohols, comprising reducing benzylamino-fatty-acid esters of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, Z stands for a group carrying a carboxylic ester coup and It stands for hydrogen, alkyl, aralkyi and acyl.
  • Another object of the present invention is the process of separation of the racemates of the benzylamino-alcohols into their optically.
  • active components comprising the fractional crystalthe benzylamino-alcohols of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, A stands for hydroxyalkyl and R stands for hydrogen, alkyl and aralkyl with optically active acids.
  • Still another object of the present invention is a process for the preparation of optically active amino-alcohols, comprising the treatment of the optically active forms or of the racemates of the above cited benzylamino-alcohols with hydrogen in presence of a catalyst.
  • Still other objects of the present invention are the racemates and the optically active benzylamino-alcohols of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, A stands for hydroxyalkyl and R stands for hydrogen, alkyl and aralnl
  • Still other objects of the present invention are the optically active amino-alcohols of the general formula Y-CH-A
  • Example 1 g. of sodium cut up.into large pieces are placed into a round flask and covered with 300 cc. of tetrahydronaphthalene. The whole is heated in an oil bath at C. (inner temperature). The sodium melts and collects into globular lumps on the bottom of the vessel.
  • a solution of 104 g. of a-benzylaminopropionic acid ethyl ester (0.5 mol.) in 300 cc. of absolute alcohol is allowed to fiow'in slowly so that the inner temperature is maintained as far as possible at 106- 108 C.
  • absolute alcohol is slowly added from a dropping funnel until the sodium is dissolved. The inner temperature thereby slowly sinks down to about 90 C.
  • Optical separation of the dJ-N-benzylalaninol 66 g. dJ-N-benzylalaninol ,0.2 mol.) and 60 g. tartaric acid (0.2 mol.) are dissolved hot in 100 cc. of alcohol and 100 cc. of acetic ester are slowly added .while shaking to the somewhat cooled solution. On cooling, a separation of a colorless syrup ensues. The same is inoculated with a few crystals which have been obtained by a small previous experiment, and the whole is allowed to stand in a closed vessel for 2 days in the ice-cupboard. The greater part of the syrup is then crystallized. The crystal cake is well shaken up and filtered under motion.
  • the contents of the suction filter are freed from adhering syrup by washing with alcohol-acetic ester (1:1), and after drying. are recrystallized for further purification twice from a mixture or cc. of alcohol and 80 cc. of acetic ester.
  • the thin glass spllttering crystals thus obtained consist of the pure bitartrate of the levo-rotary benzylalaninol.
  • the yield amounts to 40-45 g., i. e. Bil-71% of the theory. 0
  • the alcohol-acetic ester mother liquors of the crude ()-N-benzylalaninolbitartrate are evaporated to a syrup in a vacuum, and this is taken up in water and the base completely separated by the addition of an excess of a strong caustic soda solution. It is taken up in ether and after drying over Glaubersala'the solvent is distilled oil.
  • the residual syrup is dissolved in 60 cc. of warm cyclohexanol. After cooling to 40 C. it is filtered by suction from the separated crystals which consist of nearly pure racemate and then washed with cyclohexanol warmed to 40' C. The filtrate is evaporated in a vacuum and the residual syrup (25 g.) dissolved in cc. of water with 19 g.
  • optically active free bases are isolated in the usual manner and purlfied by crystallization from cyclohexanol-petroleum-ether.
  • d-(-) -alaninol-oxalate has a specific rotation In its other properties it naturally corresponds with those of l-(+) -alaninol-oxalate.
  • the product is the pure -mandelic acid salt of ()-Z-benzylaminobutanol-L
  • the first two mother liquors of the ()-mandelic acid levo-rotary compound are evaporated in a vacuum and the base is regenerated (21 g.). It is dissolved with 18 g. of -mandelic acid in 50 cc. of acetic ester. The crystals which separate out on standing are again recrystallized twice from 120 cc. of acetic ester+5 cc. of absolute alcohol. 26 g., i. e., 79%
  • (+)-N-2-benzylamino-butanol-1 are dissolved in 200 cc. of alsolute alcohol, 6.3 g. of crystallized oxalic acid in 100 cc. of water are added and the whole isshaken with hydrogen with the use of 1.5 g. of palladium sponge as catalyst. After about 24 hours, the absorption of hydrogen is terminated.
  • (+)-2-aminobutanol-l-oxalate crystallizes out in form of snow-white needles. Yield 12-13 8., which amounts almost to the theory. M. P. -192 C. (corn).
  • ()-2-amino-butanol-1-oxalate can be prepared in the same manner from its N-benzyl dethis compound corresponds in its properties to the dextro-rotary antipode.
  • Example 3 124.5 g. of the ethyl ester of benzylaminoisocapronlc acid are dissolved in 1 liter of butylalcohol which has been dehydrated with Mgbutylate and the solution is heated to boiling. 100 g. of cut-up sodium are introduced as quickly as possible into the boiling solution. Thereupon it is heated with the addition of a further quantity of dehydrated butyl-alcohol until all the metal is dissolved. It is allowed to cool, treated with 200 g. of ice and neutralized with dilute hydrochloric acid (2:1) with good external cooling. It is filtered from the separated salt and the alcohol is completely distilled off in a vacuum.
  • the pure d,l-N-benzy1-leucinol having the formula allowed to stand over night.
  • the separated crys- I The d,l-N-benzyl-leucinol is diificultly soluble in water, easily soluble in alcohol, ether and benzene.
  • the racemic base was first converted by means of d-dibenzoyl-tartaric acid (Butler and Cretscher, Am. 55, 2605, 1933) in aqueous alcohol solution into the acid salt. on allowing the solution to stand crystallization results of a salt which can be purified to a constant melting point'by recrysallization from alcohol-water. In this way the d- -N-benzyl-leucinol-d-dilbenzoyltartrate is obtained in pure form.
  • Hydrochloride M. P. 160-162 C. Prisms from alcohol-ether or water, which are fairly dimcultly soluble in water.
  • Example 4 By the application of the method of working described in Examples 1 to 3, the d,l-N-benzylvalinol can be obtained in a good yield by the reduction, of a-benzylamino-isovalerianic' acid
  • 2-N-benzylamino-3-phenyl-propane-ol-1 N-ben-. zyl-phenyl-alaninol
  • 2-N-benzylamino-3-phenyl-propane-ol-1 N-ben-. zyl-phenyl-alaninol
  • the d,l-N-2-benzylamino 3 phenylpropane- 01-1 may be separated into its .optically active constituents by fractional crystallization of its salts and the optically active components hydrogenated in presence of palladium sponge in the manner herein above described.
  • Ezamplefi 148.5 parts (0.5 mol.) of N-dibenzyl-a-aminopropionic acid ethylester of the formula cm-cn-coocim N(C.HzCe s)z are mixed with 1000 parts of absolute ethanol and the solution is heated under reflux up to the boiling point. Then 100 parts of sodium cut in small pieces are introduced as rapidly as possible into the solution, which is kept boiling until the metal has been completely dissolved. The solution is then allowed to cool down to about 70 C., 200 parts of broken ice are introduced thereinto and there is carefully neutralized under further cooling down to about 30 C. with diluted hydrochloric acid (2:1).
  • the principal fraction boils at 210-212 C. (14 mm.), and is obtained in form of a weakly colored syrup.
  • Example 8 110.5 parts (0.5 mol.) of N-methyl-benzyl-aaminopropionic acid ethylester of the formula are reduced in the manner described in Examples 1-3, whereby after working up the reduced material the d,l-N-methylbenzylalaninol of the formula will be obtained in form of a colorless oil of boiling point 138-140 C. (14 mm.) easily soluble in ethanol, ether and benzene, very difilcultly soluble in water.
  • 10 parts of d,l-N-methy1benzylalaninol are dissolved in 100 parts of ethanol.
  • a solution of 3.5 parts of crystallized oxalic acid (1 equivalent) in 50 parts of water and 3 parts of palladium sponge are added thereto and the solution shaken with hydrogen under a weak pressure. After 8 hours the absorption of hydrogen is achieved.
  • the solution is then filtered from the catalyst and evaporated in vacuo to a syrup.
  • the base contained in the oxalate has the composition C4HuON and the formula O Caron-onion NIH-CH:-
  • Eaxlmple 9 110.5 parts (0.5 mol.) of N-(p-methylbenzyD- a-aminopropionic acid ethylester CHr-CH-C 0 0 02m NH'CHICOHLCHI(Q CHPCHCHIOH NH-CHr-CsHt-CH:
  • a process for the manufacture of aminoa-lcohols comprising the step of treating with hydrogen compounds of the general formula wherein X stands for a member of the group consisting of hydrogen, lower alkyl and lower alkoxy, Y stands for a member of the group consisting of lower alkyl and phenyl-lower alkyl, Z stands for a carbethoxy group and R stands for a member of the group consisting of hydrogen, lower alkyl and phenyl-lower alkyl.
  • x stands for a member of the group consisting of hydrogen, lower alkyl and lower aikoxy
  • Y stands for a member of the group consisting of lower alkyl and phenyl-lower alkyl
  • Z stands for a carbethoxy group
  • R stands for a member or the group consisting of hydrogen, lower alkyl and phenyi-lower alkyl, in presence of a solvent selected from the group consisting of ethanol, butanol, toluene, tetrahydroand components "by fractional crystallization of its salts with d-dibenzoyltartaric acid.
  • a process for the manufacture of aminoalcohols comprising the steps oi treating with hydrogen the a-benzylamino-fl-phenylpropionic acid ethyl ester in presence of butanol, and separating the d,l-2-N-benzylamino-3-phenylpropanel-1 into its optically active components by fractional crystallization of its salts with anoptically active acid.
  • benzylaminoaloohols selected from the class consisting of racemi'c and optical forms, possessing the formula cm-cu-cmon H-crncm.

Description

Patented Jan. 21, .1941
Swltacrland Noll-swing in! 18. ms. sci-mm.
Application $19,917. In SM!!! Ji 21, I,"
'10 Claims- (CL 260-572) Various methods are already known according to which amino-alcohols may be prepared. The synthesisoicompormdsoi this class is described in theworhs oi Kan-crud a1. (Helv. 4. 16 1192i) 5, 469 (1922)) and is carried out by reduction-oi the co esters of amino acids with sodium and alcohol according to the method of Bouveault and Blane. .In this way these authors succeeded in the amino-alcohols, l alaninol, yalinol, leucinol and phenyl-aianlnol by the application 0! the above mentioned method of working. During the reduction process racemisatlon takes place. Therefore by starting from optically active natural amino acids. the
Is above cited are obtained in the optically inactive form. Only leucinol showed a weak rotation power and was also racemised to the greatest extent. The yields of amino-alcohols according to this process are very bad and amount in general to only a few percent oi theory. Thus for example from 44 grams of the ester or valine only about 3 grams or valinol were obtained, which is a yield of about 10% of theory (Karrer,-Helv. 5, 479 (1922)). Somewhat higher yields are obtained if the ester of the amino acid is first acetylated and the acetylated product then reduced. According to these methods one could obtain by the reduction of the ester of acetylated leucine a yield of leucinol amounting to about 20% of theory (Karrer, Helv.
Barrow and Ferguson have recently found (Soc. 1935, 410) that the yields by this process can be somewhat improved if the reaction is carried out in n-butyl-alcohol completely dehydrated by means of magnesium butylate instead of in the usual absolute alcohol. In this way d,l-valinol-hydrochloride can be obtained in a yield of 45% of the theory from acetylvalineester.
(By using ethyl-alcohol completely dehydrated by means of magnesium ethylate the yield of valinolhydrochloride amounted to only 25% of theory.)
As already stated, the amino-alcohols prepared by Karrer and others are obtained only in the racemic or strongly racemised form only recently through the work of Barrow and Ferguson (1. c.) a member of this series of compounds has been obtained for the first time in an optically pure form. Barrow and Ferguson were able to split d,l-valinol into its optical antipodes by means of tartaric acid.
The preparation of amino-alcohols became of utmost importance since one representative of these compounds has been found forming a part of a highly active natural product, for the synthesis of which a ratlonal method for the preparation or amino-alcohols is needed. The example of Ergobasine (A. Stoll and A, Hoimann. Z. physiol. Chemie 251, (1938)) shows also the necesity oi preparing such amino-alcohols even 6 in optically active form.
According to the present invention it has been found that the racemates, as also the pure optically active alcohols, can be obtained in good yield if aliphatic or araliphatic benzyl-amino fatty- 1o acid esters are reduced, and in given cases, the :racemates of the benzyl-amino-alcohols or the salts of these optically active acids are decomposed into the optically active components by iractional crystallization from a suitable solvent 15 and the benzyl group split out from the According to the present invention therefore it has been ascertainedthat the reduction of the easily accessible benzyl-amino fatty-acid esters which correspond to the general iormula go 5 wherein X represents hydrogen, alkyl and alkoiw, Y represents alkyl and arallryl, Z represents a group carrying the carboxylic acid ester radical and It represents hydrogen, 'alkyl. arallwl andacyl, gives appreciably better results, and that 30 the hitherto unknown benzyl-amino-alcohols thereby obtained canbe very easily isolated and obtained in a pure form on account of their good crystallizing power.
Furthermore the benzylamino-alcohols are es- 35 pecially suited to give well crystallized salts with optically active acids which are specially suited for splitting the racemates into optically active components. By splitting off the benzyl group, which can be done in the known, manner by re- 40 duction for example by hydrogen with palladium as catalyst, it has been possible .for the first time to obtain without great difficulties the for the most part unknown pure optically active aminoalcohols.
The reduction of the benzylamino fatty-acid esters can be carried out in the known manner, for example according to the method of Bouveault and Blanc with sodium and alcohol, or 50 by catalytic reduction, wherebyas solvents organic solvents miscible with water or' not miscible with water can be used, such as ethanol, butanol, toluene, tetrahydroand decahydronaphthalene. The benzylamino-alcohols thus obtained can be 55 readily isolated from the reaction mixture if they are converted for example into hydrochlorides and precipitatedfrom aqueous solution by an addition of alkali. It is possible by vacuum distillation of acid, and the optically active components separated by fractional crystallization from a suitable solvent such as for example water, methanol, ethanol, acetic ester, etc., or from mixtures of these solvents. In order to obtain the unsubstituted optically active amino-alcohols, the optically active benzylamino-alcohols are advantageously subjected to catalytic reduction with hydrogen in the presence for example of palladium as a catalyst, preferably in the presence of an equal quantity of an organic acid. The use of oxalic acid is especially advantageous as in such case the amino-alcohols are obtained as well crystallizing oxalates easy to be isolated.
It is possible according to the present process to obtain optically active amino-alcohols such as for example dand l-alaninol, dand l-a-aminobutanol, d and l-leucinol and the like in good yields and in pure crystalline form.
For the characterization ot the optically active forms I use the recently employed kind of designation, which indicates by the amino acids through the letters dand lthe configuration and through the figures and the direction of, the rotation. For the followingly cited amino acids it has been found that they are present in the nature as levo-forms and must, therefore, be designed as l-(+) -alanine, l-(+) -valine; l-() -leucine, l-(-) -phenyl-a-lanine.
The indication of the configuration of the amino-alcohols can therefore-only then take place when their relation to the respective amino acids has been undoubtedly-defined.
For the natural (+)-alaninol, that has been isolated as a basic splitting product from the ergot alcaloid ergo-basine (Jacobs and Craig, Science 82, 16 (1935)) the authors indicate that it derives from the natural alanine and must therefore be designed as l-(+)-alaninol. From natural l-(+) -valine, (weakly) dextro-rotary valinol (Barrow and Ferguson 1. 0.) can be obtained and from natural l-()-1eucine a (weakly) levorotary leucinol (Karrer, Helv. 4, 91, 1921) can be obtained. The optically pure dextro-rotary valinol is therefore to be denoted as 'l-(+) -valinol and optically pure levo-rotary leucinol as l-() leucinol.
As dextro-rotary N-benzylal-aninol on hydrogenation gives alaninol and levo-rotary N- benzylleucinol gives leucinol, it follows that for these compounds the descriptions l-(+) -N- benzylalaninol and l-(-) :N-benzylleucinol and for the corresponding compounds of opposite rotation the descriptions d-()-N-benzylalaninol and d-(+) -N-benzyl-leucinol may be applied.
The two optically active a-benzylaminobutanols are denoted for the present as and according to their direction of rotation, as the genetic relations of the corresponding optical forms of the a-amino-butyric acids are not yet established.
'lization of the salts of Recently l-(+)-aminobutyric acid has been found as forming part of the natural albumins (Abderhalden and Balm, H. 245, 246 (1937)).
One object of the present invention is a process for the manufacture of benzylamino-alcohols, comprising reducing benzylamino-fatty-acid esters of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, Z stands for a group carrying a carboxylic ester coup and It stands for hydrogen, alkyl, aralkyi and acyl.
Another object of the present invention is the process of separation of the racemates of the benzylamino-alcohols into their optically. active components, comprising the fractional crystalthe benzylamino-alcohols of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, A stands for hydroxyalkyl and R stands for hydrogen, alkyl and aralkyl with optically active acids.
Still another object of the present invention is a process for the preparation of optically active amino-alcohols, comprising the treatment of the optically active forms or of the racemates of the above cited benzylamino-alcohols with hydrogen in presence of a catalyst.
Still other objects of the present invention are the racemates and the optically active benzylamino-alcohols of the general formula wherein X stands for hydrogen, alkyl and alkoxy, Y stands for alkyl and aralkyl, A stands for hydroxyalkyl and R stands for hydrogen, alkyl and aralnl Still other objects of the present invention are the optically active amino-alcohols of the general formula Y-CH-A Example 1 g. of sodium cut up.into large pieces are placed into a round flask and covered with 300 cc. of tetrahydronaphthalene. The whole is heated in an oil bath at C. (inner temperature). The sodium melts and collects into globular lumps on the bottom of the vessel. A solution of 104 g. of a-benzylaminopropionic acid ethyl ester (0.5 mol.) in 300 cc. of absolute alcohol is allowed to fiow'in slowly so that the inner temperature is maintained as far as possible at 106- 108 C. After the ester solution has run in, absolute alcohol is slowly added from a dropping funnel until the sodium is dissolved. The inner temperature thereby slowly sinks down to about 90 C.
After all the sodium is dissolved the contents of the fiask are allowed to cool to 80' C. and 200 g. of crushed ice are carefully added. By placing in cold water it is cooled further to about 30 C. and then it is neutralized with diluted hydrochloric acid (2 vols. of cone. HCl+1 vol. Hi) until distinctly acid to Congo. It is then allowed to stand for about 1 hour at C. and the separated common salt filtered oflon a suction filter and well washed with alcohol. The filtrate is then separated from separated-tetrahydronaphthalene in a separating funnel and the alcoholic solution which still has a distinctly acid reaction to Congo is evaporated in a vacuum until crystallization of common salt takes place. The residue is taken up in absolute alcohol, filtered by suction from common salt which is well washed with absolute alcohol, and the filtrate again evaporated in a vacuum to a syrup. It is now taken up in a little water and thereupon treated with a considerable amount oi a concentrated caustic soda solution. The benzylalaninol thereby separates out as a dark colored oil. It is taken up in ether and the solution dried ,over Glauber salt. Alter distilling oil the ether it is fractionated in a vacuum B. P2o=155157 C. A colorless, thickly fluid, easily crysta'llizable oil is obtained. The yield after recrystallization from 120 cc. of cyclohexanol is of 53 g., i. e. 64% of the theory.
The d,l-N-benzylalaninol of the formula 0 C Hs-CH-C H30 H NH-CHpCeH;
crystallizes from benzol in fine needles, from acetic ester and cyclohexanol in thin water-clear prisms. M.P.=70-72 C. B. P.2u=155-157 C. It is fairly easily soluble in water with a strongly alkaline reaction. It separates out from aqueous solutions on the addition of strong lyes as a colorless oil (method of isolation). It is very readily soluble in alcohol and ether.
(decomp.)
Optical separation of the dJ-N-benzylalaninol 66 g. dJ-N-benzylalaninol ,0.2 mol.) and 60 g. tartaric acid (0.2 mol.) are dissolved hot in 100 cc. of alcohol and 100 cc. of acetic ester are slowly added .while shaking to the somewhat cooled solution. On cooling, a separation of a colorless syrup ensues. The same is inoculated with a few crystals which have been obtained by a small previous experiment, and the whole is allowed to stand in a closed vessel for 2 days in the ice-cupboard. The greater part of the syrup is then crystallized. The crystal cake is well shaken up and filtered under motion. The contents of the suction filter are freed from adhering syrup by washing with alcohol-acetic ester (1:1), and after drying. are recrystallized for further purification twice from a mixture or cc. of alcohol and 80 cc. of acetic ester.
The thin glass spllttering crystals thus obtained consist of the pure bitartrate of the levo-rotary benzylalaninol. The yield amounts to 40-45 g., i. e. Bil-71% of the theory. 0
The alcohol-acetic ester mother liquors of the crude ()-N-benzylalaninolbitartrate are evaporated to a syrup in a vacuum, and this is taken up in water and the base completely separated by the addition of an excess of a strong caustic soda solution. It is taken up in ether and after drying over Glaubersala'the solvent is distilled oil. The residual syrup is dissolved in 60 cc. of warm cyclohexanol. After cooling to 40 C. it is filtered by suction from the separated crystals which consist of nearly pure racemate and then washed with cyclohexanol warmed to 40' C. The filtrate is evaporated in a vacuum and the residual syrup (25 g.) dissolved in cc. of water with 19 g.
Y oxalic acid (cryst.). On cooling the acid oxalate of the -N-benzylalaninol crystallizes out in pure form. Yield: 32 g., l. e. 63% of the theory.
From the two salts the optically active free bases are isolated in the usual manner and purlfied by crystallization from cyclohexanol-petroleum-ether.
d()-N-benzylalaninol crystallizes out from cyclohexanol-petroleum-ether in form of fine light needles. M. P. 47-49". It is more soluble in organic solvents than the racemic compound.
Polarisation: in alcohol (c==4.0)
Hydrochloride: M. P.=136-138 C. Prisms from alcohol-ether. 1
l- -N-benzylalaninol:
Polarisation: in alcohol (c=4.0).
The remaining data are the same as in the case of the levo-form.
16.5 g. .l-(+)-benzyl-alaninol are dissolved in 200 cc. of dilute alcohol, 6.3 g. of cryst. oxalic acid in cc. water are addedand shaken with a slight excess pressure with 1.5 g. of palladium sponge and hydrogen. After about 24 hours the.
absorption of hydrogen is achieved. It is filtered from catalyst and the solution evaporated in a vacuum to a syrup. On distillation with cc. of absolute alcohol, the l(+)-alaninol-oxa.late crystallizes out in snow-white glittering crystal leaflets. Yield of pure compound 11.3 g. corresponding to 95% of the theory. By concentration of the mother liquor a further 0.5 g. can be obtained.
l-( -alaninol-oxalate melm at 171' C. (corn) [011% +l8.8(c -2 in water) Composition: (C4H10O3N) 2. The compound is easily soluble in water. very difllcultly soluble in alcohol. I I The reaction takes place in the case of d-() alaninol in exactly the same way as with the dextro-rotary antipode. I
d-(-) -alaninol-oxalate has a specific rotation In its other properties it naturally corresponds with those of l-(+) -alaninol-oxalate.
Example 2 g. of sodium cut into coarse pieces is added during short intervals to-aboiling solution of 110.5 g. of a-benzylamino-butyric-acid-ethylester (0.5 mol.) in 1 liter of absolute alcohol. It is heated until all the sodium is dissolved, if necessary with the addition of a further quantity of absolute alcohol. vIt is allowed to cool to about 80 C. and 200 g. of ice are added. and it is carefully neutralized after cooling with diluted crystallizes out from cyclohexanol in form of thin prisms. M. P. 58-60 C. B. P.14=155-157 C. It is soluble in water, easily soluble in alcohol and ether. 4.040 mg. substance gave 0.276 cc. 0fNz(21 C.
750 mm). 0.2084 gr. substance used 11.63 cc. of 11/10 HCl. CuHnON calc. N=7.82'% mol. weight=179. found N=7.83% mol. weight=1792. Hydrochloride: M. P.= 127-129 C. Leaflets or needles from alcohol-acetic-ester. Easily soluble in water. Picrate: M. P.=144-146 C. Yellow thin prisms. 35.8 g. of d,l-2-benzylaminobutanol-l (0.2 mol.) and 30.4 g. of ()-mandelic acid (0.2 mol.) are dissolved in 50 cc. of warm acetic ester. On allowing the solution to stand, spontaneous crystallization takes place. After this is complete, it is filtered under suction and washed with acetic ester. The product is recrystallized twice from cc. of acetic ester+5 cc. of absolute alcohol until the melting point is constant. White felted needles of melting point 111-117 C. are obtained. Yield: 23 g., i. e., 69% of the theory. The product is the pure -mandelic acid salt of ()-Z-benzylaminobutanol-L For the preparation of the dextro-rotary compounds the first two mother liquors of the ()-mandelic acid levo-rotary compound are evaporated in a vacuum and the base is regenerated (21 g.). It is dissolved with 18 g. of -mandelic acid in 50 cc. of acetic ester. The crystals which separate out on standing are again recrystallized twice from 120 cc. of acetic ester+5 cc. of absolute alcohol. 26 g., i. e., 79%
Picrate: M. P.- '111-113 0., yellow Polarisation in. alcohol (0:4.0).
I [aE-25.0
Hydrochloride: M. P.=141-143 C., needlesfrom alcoholether, easily soluble in water.
prisms from alcohol of 50%.
(+)-2-benzy1amino-butanol-1:
Polarisation: in alcohol (c=4.0).
17.9 g. (+)-N-2-benzylamino-butanol-1 are dissolved in 200 cc. of alsolute alcohol, 6.3 g. of crystallized oxalic acid in 100 cc. of water are added and the whole isshaken with hydrogen with the use of 1.5 g. of palladium sponge as catalyst. After about 24 hours, the absorption of hydrogen is terminated.
After filtering off from the catalyst the solution is evaporated to a syrup and diluted with cc. of absolute alcohol. (+)-2-aminobutanol-l-oxalate crystallizes out in form of snow-white needles. Yield 12-13 8., which amounts almost to the theory. M. P. -192 C. (corn).
[a]? +11.3 (0 =3 in water) Composition: (CsHnOaNh.
()-2-amino-butanol-1-oxalate can be prepared in the same manner from its N-benzyl dethis compound corresponds in its properties to the dextro-rotary antipode.
Example 3 124.5 g. of the ethyl ester of benzylaminoisocapronlc acid are dissolved in 1 liter of butylalcohol which has been dehydrated with Mgbutylate and the solution is heated to boiling. 100 g. of cut-up sodium are introduced as quickly as possible into the boiling solution. Thereupon it is heated with the addition of a further quantity of dehydrated butyl-alcohol until all the metal is dissolved. It is allowed to cool, treated with 200 g. of ice and neutralized with dilute hydrochloric acid (2:1) with good external cooling. It is filtered from the separated salt and the alcohol is completely distilled off in a vacuum. The residue thus obtained is treated with an excess of a caustic soda solution and the crude d.1-N-benzyl-leucinol which has separated in the form of an oil is taken up with ether. The solution is dried with Glauber salt. The ether having been distilled off, there remains a colorless syrup which is fractionated in a vacuum.
The pure d,l-N-benzy1-leucinol having the formula allowed to stand over night. The separated crys- I The d,l-N-benzyl-leucinol is diificultly soluble in water, easily soluble in alcohol, ether and benzene.
4.418 mg. substance gave 0.263 cc. of N: (21,
750 mm.) 0.2163 g. substance used 10.58 cc. of n/ HCl C13H21ON calc. N=6.'76% mol. weight 207 found N=6.82% mol. weight 204.4.
Hydrochloride: M. P.=151-l53 C. Prisms from water, rather diilicultly soluble in water.
Picrate: M. P.=152-154 C. Yellow'prisms from alcohol, difilcultly soluble in water.
The racemic base was first converted by means of d-dibenzoyl-tartaric acid (Butler and Cretscher, Am. 55, 2605, 1933) in aqueous alcohol solution into the acid salt. on allowing the solution to stand crystallization results of a salt which can be purified to a constant melting point'by recrysallization from alcohol-water. In this way the d- -N-benzyl-leucinol-d-dilbenzoyltartrate is obtained in pure form.
20.7 g. d,l-N-benzyl-leucinol (0.1 mol.) and 37.6 g. d-dibenzoyltartaric acid (0.1 mol.) are dissolved warm in 150 cc. of alcohol of 60%. After cooling to room temperature, it is inoculatedand tals are filtered off by suction. washed with alcohol of 60% and recrystallized three times from 100 cc. of alcohol of 60% until constant melting, point. The pure d-(+)-N-benzyl-leucinol-d-dibenzoyltartrate forms good well-developed colorless prisms of M. P. 169-171 (the M. P. is somewhat dependent on the manner of heating). They are easily soluble in warm alcohol, very difiicultly soluble in water. Yield 50% of the theory.
The crude l-base (11 g.) regenerated from the first two mother-liquors of the dibenzoyltartrate is dissolved warm in 50 cc. of alcohol of 50% with the equivalent quantity of -o-nitromandelic acid (10.5 g.) On cooling the Solution,v
the l- -N-benzyl-leucinol -o-nitromandelate crystallizes out and becomes completely pure after a further recrystallization from a little alcone] of 50%. Pale yellowish green prisms of M. P. 128-130 C. arethus obtained.
From the two salts the free bases are isolated V in the usual way and purified by crystallization Gil from cyclohexane'.
d(+) -N-benzyl-leucinol crystallizes from cyclohexane inform of fine, felted needles of M. P.='77-'l9 C. V Polarisation: in alcohol (c=4.0)
Hydrochloride: M. P. 160-162 C. Prisms from alcohol-ether or water, which are fairly dimcultly soluble in water.
Picrate: M. P.=121-123 C. Yellow prisms 50%-alcohol.
20.7 g. of d-(+) -N-benzyl-leucinol are dissolved in 600 cc. oi absolute alcohol, 6.3 g. of crystalline oxalic acid in 200 cc. of water added thereto and the whole is shaken with 2.5 g. of palladium sponge and hydrogen. After about 12 hours the reduction cleavage is achieved.
The solution freed from crystals is concentrated in a vacuum to a syrup and this is diluted with 100 cc. of alcohol. d-'(+)-leucinol-oxalate crystallizes out in form of glittering leaflets. In order to complete the separation it is diluted from with another cc. of ether. Yield 14-15 g. corresponding to about 90% of the theory. Melting point 216 C. (corn). Polarisation {a1}? +7.2,(o =3 in water) Compositioni (C-zHmOaNh.
-l-()-N-benzyl-leucinol corresponds in its properties with the dextro-rotary antipode fully to the extent of the equal and opposite rotation value. I
. Example 4 By the application of the method of working described in Examples 1 to 3, the d,l-N-benzylvalinol can be obtained in a good yield by the reduction, of a-benzylamino-isovalerianic' acid In asimilar manner to that described above 2-N-benzylamino-3-phenyl-propane-ol-1 (N-ben-. zyl-phenyl-alaninol) can be obtained by the reduction of a-benzylamino-/3-phenyl-propionic acid ethyl ester.
. The new compound having the iormula CoECHz-CH-CHzOH NHCH C H needles of M. P.=69-71 C. and B. P.5=l98- 200 C., difilcultly soluble in water, easily soluble in alcohol, ether and benzene.
3.901 mg. substance gave 0.205 cc. of N2 (21,
740 mm.). ,I
0.2182 g. substance used 9.02 cc. of n/ 10 HCl.
CmI-InON calc. N=5.81% mol. weight=241.
found N=5.94% mol. weight=24l.9.
Hydrochloride: M. P.=147-149 C. Small prisms or tablets from alcohol-ether.
Plcrate: M. P.=166-'168 C. Yellow rhombs from alcohol, difllcultly soluble in water and alcohol.
The d,l-N-2-benzylamino 3 phenylpropane- 01-1 may be separated into its .optically active constituents by fractional crystallization of its salts and the optically active components hydrogenated in presence of palladium sponge in the manner herein above described.
P.=131-133 C. Yellow prisms from crystallizes out from cyclohexanol in form of thin 1 The optically active amino-alcohols of the formula cnncm-em-cmon in. will thus be obtained.
Ezamplefi 148.5 parts (0.5 mol.) of N-dibenzyl-a-aminopropionic acid ethylester of the formula cm-cn-coocim N(C.HzCe s)z are mixed with 1000 parts of absolute ethanol and the solution is heated under reflux up to the boiling point. Then 100 parts of sodium cut in small pieces are introduced as rapidly as possible into the solution, which is kept boiling until the metal has been completely dissolved. The solution is then allowed to cool down to about 70 C., 200 parts of broken ice are introduced thereinto and there is carefully neutralized under further cooling down to about 30 C. with diluted hydrochloric acid (2:1).
After the precipitation of sodium chloride has taken place, the solution is filtered, the precipitate washed with ethanol and the filtrate freed from ethanol by distillation in vacuo. The remaining, dark-brown colored syrup is dissolved in water and the solution made strongly alkaline by addition of a sodium or potassium hydroxide solution. The oily precipitated base is then extracted. with ether. After drying of the ethereal solution with anhydrous sodium sulphate the solvent is distilled oil and the residue fractionated in vacuo.
The principal fraction boils at 210-212 C. (14 mm.), and is obtained in form of a weakly colored syrup.
Further purification is carried out by using the well crystallized hydrochloride The syrup is dissolved in 100 parts of ethyl acetate and neutralized with a hydrochloric acid solution in absolute ethanol. After short standing in the cold the hydrochloride crystallizes out in nearly theoretical yield, it is filtered and washed with ethyl acetate. After one recrystallization from a double quantity of ethanol under addition of ether, the salt will be obtained in pure form. M. P.=18l-183 C. The base isolated therefrom in the usual manner is dissolved in ether, dried over sodium sulphate and will be obtained after evaporation of the solvent in form of a colorless syrup, which on cooling becomes crystalline. The dJ-N-dibenzylalaninol obtained in this manner has the formula i om-cn-om-on mom-0.11.)
and crystallizes out from cyclohexane-petrolether in form of compact, glass-glimmering plates, M. P.=56-58 0., easily soluble in ethanol, ether and benzene, nearly insoluble in water.
7.895 'mg. of the substance gave 0.376 cc. of N:
(20 C., 748 mm. Hg.).
0.3411 g. substance used 13.12 00. of 11/10 HCl=0.04784 g. HCI.
CrzHnON calc. N=5.49% mol. weight=255.
found N=5.46% mol. weight=260.0.
Hydrochloride: needles from ethanol-ether or ethanol-ethylacetate. M. P.=181-l83 C,
Picrate: yellow needles from a 50% aqueous ethanol solution. M. P.=149-l51 0.
Example 7 Q i To a boiling solution of 124.5 parts (0.5 mol.) of N-acetyl-benzyl-a-aminopropionic acid ethylester of the formula CHs-CH-COOCJH N-CHa-Cflh OCH:
in 1000 parts of absolute ethanol are added 100 parts of sodium cut in small pieces and the solution is boiled until all sodium has been dissolved. After cooling down to about 70 0., 200 parts of ice are addedthereto and the solution is neutralized with dilute hydrochloric acid under further cooling to about 30' C. The precipitated sodium chloride is filtered oil, washed with ethanol and the filtrate evaporated in vacuo in order to produce a further precipitation of sodium chloride. After dilution with absolute ethanol, new filtration'from sodium chloride and working up as described in Example 1, the d,l-N-benzylalaninol described in- Example 1 will be obtained.
Example 8 110.5 parts (0.5 mol.) of N-methyl-benzyl-aaminopropionic acid ethylester of the formula are reduced in the manner described in Examples 1-3, whereby after working up the reduced material the d,l-N-methylbenzylalaninol of the formula will be obtained in form of a colorless oil of boiling point 138-140 C. (14 mm.) easily soluble in ethanol, ether and benzene, very difilcultly soluble in water.
5.263 mg. of substance gave 0.355 cc. of N: (19 0., 749 mm. Hg). 0.2893 g. of substance used 15.76 cc. of 12/10 H01 (=0.0574 8. RC1). CnHrzON calc. N=7.82% mol. weight=179;
found N=7.77% mol. weight =183.6. 10 parts of d,l-N-methy1benzylalaninol are dissolved in 100 parts of ethanol. a solution of 3.5 parts of crystallized oxalic acid (1 equivalent) in 50 parts of water and 3 parts of palladium sponge are added thereto and the solution shaken with hydrogen under a weak pressure. After 8 hours the absorption of hydrogen is achieved. The solution is then filtered from the catalyst and evaporated in vacuo to a syrup. By dissolving in ethanol the neutral oxalate of the di- N-methylalaninol crystallizes out with a yield of 6.6 parts=88% of the theory, in form of fine needles of M.p. 174 0. (corn). On recrystallization from water and dilution with ethanol the melting point is no more altered. The base contained in the oxalate has the composition C4HuON and the formula O Caron-onion NIH-CH:-
Eaxlmple 9 110.5 parts (0.5 mol.) of N-(p-methylbenzyD- a-aminopropionic acid ethylester CHr-CH-C 0 0 02m NH'CHICOHLCHI(Q CHPCHCHIOH NH-CHr-CsHt-CH:
is obtained in form of needles from cyclohexane or ethylacetate of M=75-77 (3., which are easily 75 soluble in ethanol and chloroform. diificultly soluble'in water.
4.886 mg. of substance gave 0.323 cc. of N:(19
C., 749 mm...H'g).'
0.2347 g. of substance used 13.11 cc. of n/ 10- 15.5 parts of d,l-N-(p-methylbenzyl) -alaninol are dissolved in 150 parts of ethanol, 5.45 parts of crystallized oxalic acid in '15 parts of water are added thereto and hydrogenated in the manner described in the preceding example, After the calculated quantity of hydrogen (1 mol. of hydrogen for 1 mol. of base) has been taken up, the hydrogenation ceases. After filtration from the catalyst and evaporation of the solvent, the residual syrup begins to crystallize on treatment with ethanol. Yield: 10.0 parts of d,l-alaninoloxalate=97% of the theory. After one recrystallization from some water in presence of ethanol the compound shows the right melting point 182 0. (corn).
- Example 10 100 parts of sodium cut in large pieces are placed in a round flask possessing a reflux condenser and a thermometer and covered with 300 parts of dry tetrahydronaphthalene. The whole is heated on an oil bath at 120 C. and a solution of 140.5 parts (0.5 mol.) of N-(3-methoxy- -ethoxybenzyl) -a-aminopropionic ester in 400 parts of absolute ethanol is allowed to run in in such a manner that the inner temperature remains at 106-108 C. After the whole solution has been introduced into the flask, about 700 parts of absolute ethanol are slowly added to the solution, which is then heated to boil until the metal is completely dissolved. After cooling down to about 80 0., 200 parts of ice are added, the solution is cooled down to about 30 C. and neutralized with dilute hydrochloric acid. The precipitated sodium chloride is filtered and washed with ethanol. The tetrahydronaphthalene layer is then separated from the alcoholic solution which is then evaporated in vacuo until precipitation of sodium chloride takes place. The residue is diluted with abso-- lute ethanol, filtered and evaporated. The dark brown syrup is then dissolved in some water and mixed with an excess of a concentrated sodium hydroxide solution. The new compound separates out in form of a dark oil, that is then taken up with ether. The separated ethereal solution is mixed with half its volume of chloroform, dried over sodium sulphate. The solvents are then evaporated in vacuo and the still warm residue is dissolved in 100 parts of ether. On cooling with cold water, crystallization takes place immediately, especially after inoculation. The crystals are then filtered and washed with ether. For complete purification they may be twice recrystallized from ethylacetate in presence of some charcoal.
The dJ-N-(3-methoxy-4-ethoxybenzyl) alaninol of the formula OCH:
acid ethyl is obtained in form'of fine, felted needles of M. P.=94-96 C., which are easily soluble in ethanol and chloroform, difiicultly soluble in ether, difllcu-ltly soluble in cold, but better in hot water. I
4.747 mg. of substance gave 0.248 cc. of N: (21
0., 750 mm. Hg). 0.3424 g. of substance used 14.22 cc. of n/lO HCl (=0.05185 g. HCl) C13H21O3N calc. N=5.85% mol. weight 239.
. found N=5.99% mol. weight 240.8.
Hydrochloride: plates from ethanol-ether of M.
P.=l32.l34 C., easily soluble in water.
The reductive splitting of the d,'l-N-(3-methoxy-4-ethoxy-benzyDal-aninols takes place slower than this is the case with the derivatives of the above examples. 12.2 parts of the base are dissolved in 150 parts of ethanol, 3.2 parts of oxalic acid in 75 parts of water are added thereto and shaken with hydrogen in presence of 8 parts of palladium sponge. After a day about of the calculated hydrogen quantity had been taken up and the hydnogenation did no more progress. After filtration from the catalyst 8 parts of fresh catalyst have 'been added to the solution, whereby the hydrogenation was terminated after 13 hours. The obtained reaction mixture is then worked up in the usual manner, whereby .5 parts of the neutral alaninol oxalate=82% of the theory are obtained. After one recrystallisation the salt had the correct melting point 182 (corn) What I claim is:
1. A process for the manufacture of aminoa-lcohols, comprising the step of treating with hydrogen compounds of the general formula wherein X stands for a member of the group consisting of hydrogen, lower alkyl and lower alkoxy, Y stands for a member of the group consisting of lower alkyl and phenyl-lower alkyl, Z stands for a carbethoxy group and R stands for a member of the group consisting of hydrogen, lower alkyl and phenyl-lower alkyl.
2. .A process for the manufacture of aminoalcohols, comprising the step of.'treating with hydrogen compounds of the general formula alcohols, comprising the step of' treating with,
hydrogen compoimds of the general formula wherein x stands for a member of the group consisting of hydrogen, lower alkyl and lower aikoxy, Y stands for a member of the group consisting of lower alkyl and phenyl-lower alkyl, Z stands for a carbethoxy group and R stands for a member or the group consisting of hydrogen, lower alkyl and phenyi-lower alkyl, in presence of a solvent selected from the group consisting of ethanol, butanol, toluene, tetrahydroand components "by fractional crystallization of its salts with d-dibenzoyltartaric acid.
6. A process for the manufacture of aminoalcohols, comprising the steps oi treating with hydrogen the a-benzylamino-fl-phenylpropionic acid ethyl ester in presence of butanol, and separating the d,l-2-N-benzylamino-3-phenylpropanel-1 into its optically active components by fractional crystallization of its salts with anoptically active acid.
7; The benzylaminoalcohols selected from the class consisting of racemic and optical forms, possessing the general formula.
4 N-CH x wherein X stands for a member oi! the group consisting or hydrogen, lower alkyl and lower alkoxy, .Y stands for a member of the group consisting of lower alkyl and phenyl-lower alkyl, and It stands for a member of the group consisting of hydrogen, lower alkyl and phenyl-lower alkyi.
8. The benzylaminoaloohols selected from the class consisting of racemi'c and optical forms, possessing the formula cm-cu-cmon H-crncm.
9. The henzylaminoalcohols selected from the class consisting of racemic and optical forms, possessing the formula (club-on-om-cn-cmon NH CH CJL 10. The benzylaminoalcohols selected from the class consisting of racemic and optical forms, possessing the formula Cc rCHrCHCH|OH Nn-cmhar,
JULIUS PEYER.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2490834A (en) * 1946-07-15 1949-12-13 Parke Davis & Co Benzhydryl beta hydroxy alkyl amines
US2503652A (en) * 1947-06-21 1950-04-11 Burroughs Wellcome Co Nu-phenethyl-beta-alanine derivatives
US2534567A (en) * 1947-06-21 1950-12-19 Burroughs Wellcome Co N-phenethyl-beta-alanine derivatives
US2540636A (en) * 1947-11-12 1951-02-06 Mallinckrodt Chemical Works Separation of nitrile intermediates in amidone synthesis
US2584589A (en) * 1948-09-27 1952-02-05 Du Pont Preparation of diacyl 1,3-amino alcohols and their hydrolyzed products, 1,3-amino alcohols
US2597248A (en) * 1948-08-06 1952-05-20 Smith Kline French Lab Nu-substituted amino-ethanols
US2597247A (en) * 1948-08-02 1952-05-20 Smith Kline French Lab Nu-substituted amino-ethanols
US2717263A (en) * 1952-10-03 1955-09-06 Leonard L Mckinney Condensation products of alpha-amino acids and phenols
US2790830A (en) * 1954-10-21 1957-04-30 Pittsburgh Plate Glass Co Nu-aminoalkanol substituted alkylaromatic compounds
US2820827A (en) * 1953-11-02 1958-01-21 Hoechst Ag Process of separating l- and d-aminomethyl-(3, 4-dihydroxyphenyl)-carbinol
US4312861A (en) * 1974-03-09 1982-01-26 Hoechst Aktiengesellschaft Pharmaceutical compositions containing N-alkyl-N-(nuclearly-substituted) benzylamines having vasotonia-regulating activity

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2490834A (en) * 1946-07-15 1949-12-13 Parke Davis & Co Benzhydryl beta hydroxy alkyl amines
US2503652A (en) * 1947-06-21 1950-04-11 Burroughs Wellcome Co Nu-phenethyl-beta-alanine derivatives
US2534567A (en) * 1947-06-21 1950-12-19 Burroughs Wellcome Co N-phenethyl-beta-alanine derivatives
US2540636A (en) * 1947-11-12 1951-02-06 Mallinckrodt Chemical Works Separation of nitrile intermediates in amidone synthesis
US2597247A (en) * 1948-08-02 1952-05-20 Smith Kline French Lab Nu-substituted amino-ethanols
US2597248A (en) * 1948-08-06 1952-05-20 Smith Kline French Lab Nu-substituted amino-ethanols
US2584589A (en) * 1948-09-27 1952-02-05 Du Pont Preparation of diacyl 1,3-amino alcohols and their hydrolyzed products, 1,3-amino alcohols
US2717263A (en) * 1952-10-03 1955-09-06 Leonard L Mckinney Condensation products of alpha-amino acids and phenols
US2820827A (en) * 1953-11-02 1958-01-21 Hoechst Ag Process of separating l- and d-aminomethyl-(3, 4-dihydroxyphenyl)-carbinol
US2790830A (en) * 1954-10-21 1957-04-30 Pittsburgh Plate Glass Co Nu-aminoalkanol substituted alkylaromatic compounds
US4312861A (en) * 1974-03-09 1982-01-26 Hoechst Aktiengesellschaft Pharmaceutical compositions containing N-alkyl-N-(nuclearly-substituted) benzylamines having vasotonia-regulating activity

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