DE1020348B - Process for converting D-erythro- or L-threo-1-phenyl- (or 1-p-nitrophenyl) -2-amino-1,3-propanediol into D, L-threo-1-phenyl- (or. 1-p-nitrophenyl) -2-amino-1,3-propanediol - Google Patents

Description

GERMAN

It is known that chloramphenicol D-threo-1-p-nitrophenyl ^ -dichloroacetamido-ljS-propanediol is. Since synthetic methods always give racemic compounds, it is at some stage of the chloramphenicol synthesis required to make a cleavage into optical isomers in order to the derivative of the D-threo series reach. If the cleavage into optical isomers is carried out on threo-phenylaminodiols, it becomes the D-isomer used to continue the synthesis, while so far the ΐ, -isomer remained unused; in the event of a split from erythro-phenylaminodiols, on the other hand, come with the l-isomer for use and the D-isomer not. It is obvious to the chemist that the use of the Hitherto unused forms becomes possible as soon as it is possible to racemize them.

So far, however, any attempt to racemize them has remained fruitless. The thermal methods failed because the substance decomposes before the racemization temperature is reached; with others, Racemization does not occur with less energetic methods.

The new invention is based on the following considerations: Those of the general formula

Process of conversion,

of D-erythro- or L-threo-1-phenyl-

(or 1-p-nitrophenyl) -2-amino-1,3-propanediol in D, L-threo-1-phenyl- (or 1-p-

Nitrophenyl) -2-amino-1,3-propanediol

Applicant:
Farmaceutici Italia SA _f Milan (Italy)

Representative:

Dipl.-Ing. Dipl.-Chem. Dr. phil. Dr. techn. J. Reitstötter, Patent attorney, Munich 15, Haydnstr. 5

Claimed priority:
Italy from May 30th and August 8th 1953

-CH-CH-CH ₉ OH

OH NH,

Carlo G. Alberti, Luigi Bernardi, Giovanni Larini

and Alberto Vercellone, Milan (Italy),
(I) have been named as the inventor

Phenylaminopropanediols corresponding to (Y = NO ₂ or H) have the two asymmetric carbon atoms 1 and 2, and this is one of the reasons for their resistance to direct racemization. By eliminating one or both centers of asymmetry, for example by introducing double bonds, it might be possible to arrive at a substance without asymmetric carbon atoms, on which the aminodiol chain would have to be rebuilt, or at a substance with only one center of asymmetry, whose racemization as a result would be relieved.

For example, by converting the secondary alcoholic group of the phenylaminodiols into a Keto group canceled the asymmetry of the carbon atom in position 1 and obtained a substance that only has more of a single asymmetric carbon atom and this in α-position to a keto group and therefore suggests that this will make its racemization easier. It is in fact known that substances that are a Center of asymmetry in the vicinity of a group that has a hydrogen atom on the asymmetric one Mobilize carbon (e.g. the α-amino acids) are in their majority racemizable.

In the present case it was found that the ketones obtained by oxidizing the α-acylamino - ^ - acyloxyderivate of phenylaminopropanediols show the disappearance of the rotational ability, but that in reality this disappearance of the rotational ability is essentially due to the formation of a new compound in which the centers of asymmetry have disappeared because the acyloxy group in the / 3-position was split off by combining with the hydrogen atom in the α-position to form an unsaturated compound with a double bond between the carbon atoms in the a- and in / 3-position.

It is easy to establish that precisely those substituents favor this cleavage reaction which can theoretically be assumed in advance that they have a beneficial effect, namely the electron affinity (2nd class substituents) in the para position rather than in the meta position, as well as the acyl radicals stronger acids, both in a- and in ^ -position to the keto group.

But there are substances that greatly increase the speed of the above-mentioned cleavage reaction, such as that this reaction takes place in a few hours at room temperature. All fabrics have this property basic character, be it inorganic compounds such as sodium hydrate, potassium hydrate, etc., or organic Compounds, such as primary, secondary, tertiary, cyclic,

709 808/292

heterocyclic and aliphatic amines (pyridine, diethylamine etc.), alkaline alcoholates and enölate, alkaline salts of organic acids, organometallic derivatives of Alkali metals and a multitude of various other basic agents not listed here by name will.

If caustic alkalis are used in a stoichiometric ratio to the (possibly phenyl-substituted, e.g. p-nitro-) α-acylamino - ^ - acyloxypropiophenones, so is the cleavage reaction is almost instantaneous, i.e. the compounds (I) behave like weak acids; but it is preferable to work with milder catalysts, such as organic bases or traces of alkaline alcoholates; it is also preferable to work anhydrous.

We have also now surprisingly found that when treating the a-acylamino-je-hydroxypropiophenones (including those substituted in the core or including p-nitropropiophenones) among the same ones mentioned above Conditions the racemization reaction outweighs the cleavage so far that it occurs Racemization allows.

On the basis of these findings, according to the invention for the conversion of the aminodiols into the relevant Hh H

oxidized. The products of the cleavage reactions can either be used as α-acyliminopropiophenones

-CO-C-CH ₈

γ X - COR

react or as a-acylaminoacrylphenone

CO-C = CH,

NH-COR

They react with aqueous hydrohalic acid in the former form and give the phenylmethylglyoxals

> —CO - CO-CH,

by hydrolysis reaction, while they (the compounds V) with anhydrous hydrohalic acid (HCl, HBr, HJ), dissolved in an ether such as ethyl ether, propyl ether, tetrahydrofuran, dioxane, at temperatures between

the racemic compounds mainly after 25 O and 10O ⁰ C can react as acrylophenones

two paths taken: first path: racemization of the (substituted or unsubstituted) α-acylamino - /? - hydroxypropiophenones; second way: restoration of the aminodiol chain on (substituted or unsubstituted) α-acylamino-acrylophenones.

For the first way, it is essential to obtain the a-acylamino- / I-hydroxypropiophenones as starting materials, the preparation of which is known by means of N-acylation of the salts of the α-amino-jS-hydroxypropiophenones.

/ J-hydroxypropiophenone by immediate selective oxidation of the D-erythro- and L-threo-N-acylamino derivatives of the (possibly phenyl-substituted) Phenylaminopropanediols.

This process can be achieved by treating the N-acylaminodiols with halogens in aqueous solution Carry out temperatures between 0 and 50 ° C, preferably in the presence of actinic light. Instead of

and a reaction takes place which adds the elements of the hydrohalic acid to the double bond, such that the cc-acylamino - /? - halogenpropiophenone form.

These can with boron-sodium hydride as well as with boron-potassium hydride in alcoholic or aqueous or aqueous-alcoholic solution can be reduced so that the keto group is transformed into an alcoholic group will. According to the invention, however, a more rapid method has been developed for alcoholate in the presence of an excess of alcohol Developed to use the aforementioned d- and L-a-acylamino- (e.g. with aluminum isopropylate and isopropyl alcohol)

be carried out or with another selective reducing agent that does not attack the nitro group, such as boron-lithium hydride or lithium-aluminum hydride 40 in ethyl ether or in tetrahydrofuran solution. With the Reduction of the keto group becomes a second in addition to the asymmetric carbon atom of the / 3-halopropiophenones Center of asymmetry introduced, which is why the obtained D.L-l-phenyl ^ -acylamino-S-halogen-propan-l-olebzw.die A corresponding phenyl-substituted one, e.g. the D, L-l-p bond, can expediently be halogenated in this reaction Find use, which releases halogen, nitrophenyl compounds, mixtures of the forms threo especially an alkali bromate. So one can be beneficial and erythro.

z. B. with sodium bromate, in the presence of a little.

Work hydrogen bromide. cation from a suitable solvent, e.g. B. off

The racemization of the n- or L-a- 50 methanol, ethanol, chloroform, benzene, represented in this way, into its two Acylamino- / 3-hydroxypropiophenone is done by breaking down components; or it can be like it under the same conditions and with the same, are used in the following work step, Catalysts work as it does for the elimination of the halogen derivative in alcohol reaction were specified. For this racemization lischer or aqueous or aqueous-alcoholic solution are suitable as substances of a basic character, as found 55 with an alkali hydroxide (NaOH, KOH, etc.) in the especially the alkali bicarbonates - especially cold for 10 to 15 hours or at boiling temperature Sodium bicarbonate - in aqueous solution. Reacted for 5 to 30 minutes

One arrives at the racemic a-acyl- replacing the halogen with a hydroxyl, amino-ß-hydroxypropiophenones, which then after

known methods can be converted back into aminodiols 60 1,3-propanediol, phenyl-substituted (e.g. pN O ₂ -phenyl-). or not, threo or erythro, depending on whether

For the second way, one uses the one from the Abspal- from the relevant threo- or erythro-halogen derivative reaction resulting compounds, which was assumed by. If a mixture of the halogens Formula V of the scheme must be shown and the derivatives threo and erythro used can be obtained by using the threo and erythro derivatives of the acyl known per se Way (see C. G. Alberti et al., La Chimica aminodiole by fractional crystallization from e rindustria, 33, 5 [1951]; and gazz. Chim. It. 82, 53 methanol, ethanol or water separated from one another [1952]) D-erythro- or L-threo-1-phenyl- (or phenyl- become.

substituted) 2-acylamino ~ 3-acyloxypropan-l-ols (see To obtain the corresponding aminodiols,

C. G. Alberti et al., Gazz.Chim.lt. 82, 63 [1952]) 70 one then uses the ones already known for this

Methods (L. M. Long and H. D. Trautmann, J. Am. Chem. Soc. 71, 2473 [1949]; C. G. Alberti et al., La Chimica e l'Industria 33, 5 [1951]; J. Controulis et al., J. Am. Chem. Soc. 71, 2463 [1949]). The present invention in Substances that can be considered, each containing 1 or 2 asymmetric carbon atoms, can be used in dextrorotatory, levorotatory or racemic form occur and, moreover, in each case in erythro- and in threo-form; they are therefore all or any in the present description and in the associated claims of the said forms are intended, unless a specific one of them is expressly stated.

First way

D-erythro-
or L-threo- '

D-erythro- / _x Second way

• or L-threo-ν ) —CH — CH — CH ₂ OH —r

_l

~ Γ "

(I)

OH NH ₂

(X)

-CH-CH-CH ₂ OH

OH NH-COR D-erythro- or L-threo-

(II)

-CH CH-CH ₂ OCOR '

OCOR NH ₉ -HCl

D- or L-- / KsKJ V ^ JLi. OJLJL ₂ V

\ ._ l / j

NH ₂ - HCl D- or χ-; % —CH —CH — CH ₂ —OCOR 'threo or erythro \ -] -' | [

γ OH NHCOR

(III) -CO-CH-CH ₉ OH

(XI)

V-CO-CH-CH ₈ OH

D or L- '; - \ j \ J - v ^ jlt. · - OJiX ₂ V

γ NH-COR

D- or L- C

(XII)

> —CO —CH — CH ₂ OCOR '

γ NH-COR

(IV)

(V)

(VI)

-CO-C = CH ₂ NH-COR

-CO-CH-CH ₂ X NH-COR

^ -CH-CH-CH ₂ OH

-j- '' it

γ OH NH-COR

(VIII)

Y
(XIII)

CO-CH-CH ₂ OH

NH-COR

D-, L- <

threo and erythro ^v - {- or only threo γ

(IX) D-, L-

threo and erythro or just threo

-CH-CH-CH ₂ OH

OH NH ₉ CH-CH ₂ X

γ OH NH-COR

(VII)

X = Cl, Br, J; Y = NO ₂ or H; R identical to or different from R '= alkyl, haloalkyl, aryl aralkyl, H.

Some embodiments of the invention follow. The Roman numerals refer to the reaction scheme.

example 1

= + 6.7 4-1 ° C (c = 4; methanol). 11.0 g of L-threol-phenyl ^ -acetamino-S-acetoxypropan-l-ol (III) are dissolved in 69 cm ^{3 of} chloroform and oxidized with sodium dichromate and sulfuric acid in an aqueous solution. Da-acetamino - /? - acetoxypropiophenone (IV), melting point 106 to 108 ° C. (from ethanol): (a) _D = -36.5 (c = 4; methanol). 25.5 g of da-acetamino-ß-aeetoxypropiophenone (IV) with 40 cm ^{3 of} concentrated HCl, diluted with 32 cm ^{3 of} water, are heated on the water bath until everything has dissolved. It is distilled in vacuo and the residue is taken up in methanol: The hydrochloride of Na-amino - /? - hydroxypropiophenone (XI) crystallizes out, melting point 179 to 180 ^° C .; (a) _D = -42.5 ± 0.5 ⁰ C (c = 2; methanol). 8 g

28.2 g of L-threo-l-phenyl-2-amino-l, 3-propanediol (I) are boiled for ₂ hours under reflux I ¹ Z with 25 cm ³ of methanol and 26 cm ⁸ Methyldichloroacetat to L-threo 1-phenyl-2-dichloroacetamino-1,3-propanediol (X), melting point 92 to 93 ° C (from benzene); (a) _D = + 2.5 ± 2 ° C (c = 4; methanol). 10.0 g of L-threo-1-phenyl-2-dichloroacetamino-1,3-propanediol (X) are dissolved in 10 cm ^{3 of} dioxane, and 3.4 cm ^{3 of} acetic anhydride are added at ⁰ ° C. After one night

is poured into concentrated hydrochloric acid and ice and extracted with 15 of the hydrochloride thus obtained in 70 g of ethyl acetate. The crude oily residue, a mixture of crushed ice and water, and the mixture of L-threo-1-phenyl ^ -dichloroacetamino-S-acetoxy- are added 6.5 cm ^{3 of} benzoyl chloride. At a

At a temperature between 0 and 5 ^° C., 10.5 g of sodium acetate, dissolved in 15 cm ^{3 of} water, are added, and the mixture is stirred for 3 hours, then the crystallized Da-benzoylamino- / 3-hydroxypropiophenone (XII): melting point 138 is filtered up to 140 ^c C (from ethanol); (a) _D = + 32.5 +1.5 [c = 2; Methanol). 10 g of da-benzoylamino- / j-hydroxypropiophenone are dissolved in a mixture of pyridine and triethylamine. After 3 hours, it is poured into ice and concentrated hydrochloric acid and the nL-α-benzoylamino-β-hydroxypropiophenone (XIII), melting point "141 to 142" ° C. (ethanol) is filtered. 10 g D, La-Benzoylamino-jiJ-hydroxypropiophenone (XIII)

shaped hydrogen chloride. After one night, after adding a small amount of Raney nickel, it is poured into ice and the product which has crystallized out is ^{filtered off in 100 cm 3 of} methanol at 10 atm until it is complete; it is D, La-dichloroacetamino-ß-chloropropio-hydrogen would take on hydrogenated. After filtering off the phenone (VI) with melting point of 129 to 13O ⁰ C, the residue (from the catalyst, the ethanolic solution is concentrated and methanol) .20,0 gD ^ -a-Dichloroacetamino-ß-chloropropio- crystallized from a mixture of the phenone ( VI) are dissolved in 80 cm ³ of methanol, and 35 ^v 'n nL-threo and erythro-l-phenyl-2-benzoylamino-1,3 g boron hydride at 20 to 25 ° C reduced. One 1,3-propanediol (VIII) _ consists of which by diluting with water and extracted with ethyl acetate; Crystallize from ethanol - water the D, i, -threoes is an oily residue, which is separated from a mixture of l-phenyl-2-benzoylamino-1,3-propanediol from D.i-erythro-and threo-l-phenyl ^ -dichloroacetamino - Is, melting point 165 to 167 ° C, which consists of boiling 3-chloropropan-l-ol (VII), which is not purified 40 at 20 °. ₀ hydrochloric acid saponifying the r>, L-threo-1 -Phenylwird, but that one in 60 cm ³ of methanol and dissolved 2-amino-l, 3-propanediol (IX) yields, melting point 82

propan-1-ol (III) is oxidized with sodium dichromate and sulfuric acid to obtain da-dichloroacetamino - /? - acetoxy-propiophenone (IV). This is dissolved in pyridine without first being cleaned and left overnight at room temperature. On pouring into ice and concentrated hydrochloric acid to obtain a oily-crystalline precipitate from the obtained by extraction with ethyl acetate and crystallization from ethyl acetate undPetroläther, the a-Dichloroacetaminoacrylophenon (V) obtained, melting point 118 to 12O ⁰ C.

25.0 g of a-dichloroacetamino-acrylophenone (V) are dissolved in 100 cm ^{3 of} anhydrous dioxane, the 28 g of gas

takes up dropwise with 18 cm ^{3 of} 20% NaOH at the boiling point. The crystallized sodium chloride is filtered off and the methanol is evaporated off. The residue is dissolved in 10% HCl and ^{heated to 60 to 70 °} C. for 5 minutes. After cooling the mixture is made alkaline to p _H = 7.5 and extracted with ethyl acetate. The residue from evaporation is crystallized from water, and DL-threo-1-Phenvlbis84 ^: C.

Example 3

10 g of i .- (-) - lp-nitrophenyl-2-amino-1,3-propanediol (I) are ^{suspended in 24 cm 3 of} saturated solution of HCl in acetic acid (about 11 ⁰ Z ₀ Ig), and there are 16 cm ^{3 of} acetyl chloride added. After one night, L - (+) - lp- nitrophenyl -1,3 - diacetoxy - 2 - aminopropan

2-dichloroacetamino-l, 3-propanediol (VIII) an, melted chlorohydrate (II) filtered off, which from methanol — ether point 95 to 97 ° C. This is purified by known methods, melting point 170 to 172 ° C and ( a) _D = + 6.5 ° C

saponified

D, L-threo-1-phenyl-2-amino-1,3-propanedioI (see example 2).

Example 2

20.0 L-threo-1-phenyl-2-amino-1,3-propanediol (I) are dissolved in 30 cm ^{3 of} glacial acetic acid; 100 cm ^{3 of a} saturated solution of hydrogen chloride in glacial acetic acid are added, followed by 100 cm ^{3 of} acetyl chloride, and the mixture is left to stand overnight. Then it is diluted with 500 cm ³ of ether to give L-threo-l-phenyl-LJS-diacetoxy ^ -amino-propanchlorhvdrat (II) crystallize out to leave, which is thereafter filtered: mp 153.5 to 154.5 ⁰ C; (a) _D = - 13.8 ± 3 ° C (c = 4; methanol). 10.5 g of L-threo-1-phenyl-l, S-diacetoxy ^ -aminopropane chlorohydrate (II) are dissolved in 21 cm ^{3 of} water, and 3.6 g of NaHCO ₃ , dissolved in 300 cm ^{3 of} water, are dissolved at room temperature admitted. The crystallized L-threol-phenyl-2-acetamino-3-acetoxy-propan-l-ol (HI), (methanol, c = 4.18) is filtered. 13 g of L-threo-1-p-nitrophenyl -1,3-diacetoxy-2-amino-propane chlorohydrate (II) are dissolved in 100 cm ^{3 of} water; 120 cm ^{3 of} acetone are added; then at 0 ^: C 25 cm ³ N, 2-NaO H. After hours, the mixture is neutralized at ⁰ C with Nl-H Cl and the acetone is distilled off in vacuo. By extracting with ethyl acetate and subsequent evaporation, L-threo-lp-nitrophenyl-2-acetamino-l, 3-propanediol (X), melting point 134 to 136 ⁰ C; (a) _D = - 7.65 ⁰ C (c = 5.22; ethanol) .25,0gL-threo-lp-nitrophenyl-2-acetamido-1,3-propanediol (X) dissolved in 200 cm ³ of water , 5 cm ^{3 of} bromine are added in sunlight at 30 ° C. with stirring. One pulls out with ethyl acetate, and out

the solution in ethyl acetate is obtained by evaporation of the Dp-nitro-a-acetamino- / 3-hydroxypropiophenone (XII), melting point 142 to 144 ^a c "; (a) _D = + 32 ° C (c = 13; pyridine) or +22.5 C ^0. (c = 2.0; ethanol). to this ketol can be reached also by on a water bath

Melting point 121 to 122 ° C (from water); (a) r> 70 a mixture of 30g Dp-nitro-a-acetamino- / S-acetoxy ~

9 10

propiophenone (IV) and 40 cm ^{3 of} concentrated HCl, trium bromate in 120 cm ^{3 of} water and 0.6 g is added

thinned with 32 cm ^{3 of} water, warmed. Once everything is in 48% hydrobromic acid too. One leaves a day

Solution is gone, one cools down so that the chlorine is long in the sunlight; then you filter the

hydrate of Dp-nitro-a-acetamino - ^ - hydroxypropiophe- crystallized Dp-nitro -a -acetamino -SS- hydroxypropio-

NONS (XI) crystallizes, mp 192 ⁰ C, (a) _D 5 phenone (XII), melting point 140 to 142 ⁰ C. 10 g

= -55 ° C (c = 4; H ₂ O). 17 g of this chlorohydrate Dp-nitro-a-acetamino-ß-hydroxypropiophenone (XII)

are mixed with 50 cm ^{3 of} water, 100 g of ice and 8 cm ^{3 of} vinegar in 150 cm ^{3 of} 5% sodium bicarbonate solution

acid anhydride mixed, and there are suspended the solution and shaken from time to time. To

22 g of sodium acetate in crystals in 30 cm ^{3 of} water one night one nitrates the d, Lp-nitro-a-acetamino-

admitted. D-p-nitro-α-acetamino- ίο / 3-hydroxypropiophenone (XIII), melting point 158 bis, crystallizes

^ -hydroxypropiophenone (XII) from, melting point 142 159 ⁰ C.

up to 144 ° C. This is analogous to Example 2 on Di-threo Example 8
1-p-Nitrophenyl-2-amino-1,3-propanediol for further processing

tet. 2.5 g of D-p-nitrophenyl-a-acetamino - ^ - hydroxypropio-

• Rpiqnipi 4 i5 phenon (XII), melting point 142 to 144 ⁰ C, (a) _D

^y = +22.5 ⁰ C (c = 2; ethanol), are in 20 cm ^{3 of} ethanol

Proceed as in Example 3, but starting from and 75 cm ^{3 of} N-ethylpiperidine dissolved. After a few

D-threo-l-p-nitrophenyl-2-acetamino-l, 3-propanediol (X), minutes is the one showing the racemization that has taken place

this gives L-p-nitrophenyl-a-acetamino-ß-hydroxy separation of the Β, ι-ρ-nitrophenyl-a-acetamino-jS-hy-

propiophenone (XII), melting point 142 to 144 ° C, 20 droxypropiophenones (XIII) in the form of tiny yellow ones

(a) /) = -32 ^° C. (c = 13; pyridine), or -22.5 ^° C. crystals. The product is collected after 3 hours

(c = 2.0; ethanol). This is analogous to Example 2 and washes it with a little ether, melting point 160 bis

D, L-threo-1-p-nitrophenyl-2-amino-l, 3-propanediol continue 163 ⁰ C. This is further processed as in Example 6. FIG.

processed. ". . , _n

Example 9

2.5 g D-p-nitrophenyl-a-acetamino-jS-hydroxypropio-

5 g Da-acetylamino - ^ - hydroxy-p-nitropropiophenone phenone (XII), (m.p. 142-144 ⁰ C), (ajo (XII), melting point 142 ° to 144 ° C, (a) z> = + 32 ° C = + 22.5 ° C (c = 2; ethanol), in 25 cm ³ Piper-

(c = 13; pyridine) are dissolved in 40 cm ^{3 of} anhydrous pyridine idine. An intense red color is dissolved and appears for 30 hours at room temperature. After 5 minutes it is poured into 100 g of ice and

(about 20 ° C). From the beginning, 100 cm ^{3 of} concentrated hydrochloric acid can be used. They divorce

Sampling and control found that the umpteen yellowish crystals of D, L-p-nitrophenyl-a-acet-

Rotational ability according to a logarithmic curve from amino- / 3-hydroxypropiophenone (XIII), which can be sam-

decreases. When the racemization is well advanced, it gathers and dries. Melting point 164 to 166 ° C.

D, La-acetylamino-jS-hydroxy-p-nitropropio- 35 This is processed as in Example 6,
phenone (XIII) in the form of tiny yellowish crystals

to be deposited, which can be found at the end of work step Example 10

collects, washes with a little ether and in the air S ^ gD-p-Nitrophenyl-a-acetamino - ^ - hydroxypropiophe-

dries. 25.2 g of DL-p-nitro-a-acetamino-ß-hydroxypropyl non (XII), melting point 142-144 ⁰ C, (a) _D = +22.5 ⁰ C

piophenone (XIII) is suspended in 80 cm ^{3 of} deacidified 40 (c = 2; ethanol) and is in 140 cm ^{3 of} absolute ethanol

Methanol, and 2 g of 91% strength solution are added with stirring. After that, 10 cm ^{8 become} one in the cold

Potassium borohydride, dissolved in 10 cm ^{3 of} boiled water, was added to an ethanolic solution of sodium ethylate

to, the temperature being kept between 25 and 30 ⁰ C (obtained by dissolving 0.25 g of sodium in 100 cm ³

will. After 20 minutes, 4 cm ^{3 of} concentrated ethanol are added). One soon appears

HCl to and leaves the erythro-1-p-nitrophenyl-2-acet-45 intense red color. After 5 minutes, vinegar

Crystallize amino-1,3-propanediol (VIII), neutralize the melting acid, and disperse the ethanol in vacuo.

point 184 to 185 ° C, which after cleaning evaporates at 195 ° C, and the residue is crystallized out

melts. The crystallization mother liquor is purified from dioxane. This gives the r>, L-p-nitro-

Evaporated dry, and the residue is with phenyl -α- acetamino - /? - hydroxypropiophenone (XIII),

Ethyl acetate extracted. By concentrating the solution 50, melting point 162 to 163 ° C. This is

the threo-1-p-nitrophenyl game 6 is further processed in ethyl acetate.
2-acetamido-1,3-propanediol (VIII), melting point 157 bis

162 ° C, which melts at 166 ° C after recrystallization. Example 11
This is saponified by known methods to D, L-threo- 5 g of Dp-nitrophenyl-a-propionamino-ß-hydroxy-propiol-p-nitrophenyl-2-amino-1,3-propanediol (cf. 55 phenone (XII) , Melting point 135 to 136 ⁰ C, (α) = 26.5 ⁰ C Example 2). (c = 4; ethanol) are dissolved in 30 cm ^{3 of} piperidine at room temperature, example 6. After 5 minutes, it is poured into 100 g

Ice and 100 cm ^{3 of} concentrated hydrochloric acid. It part

Proceed as in Example 5, but starting from Lp-nitrophenyl-2-acetamino-1,3-propanediol (X), (a) # 60, the DjL-p-nitrophenyl-a-propionamine, in the form of a glue mass which soon crystallizes - ^ - hydroxypropio- = -32 ⁰ C (c = 13; pyridine), melting point 142 to phenon (XIII). It is collected and dried, melting point 144 ^° C., this again gives D, L-cc-acetylamino point 115 to 116 ^{° C. This is processed further as in Example 6} /3-hydroxy-p-nitropropiophenone (XIII), melting point.
162 to 164 ° C. This is carried out using the method described in Example 2 on », L-threo-lp-nitrophenyl-65 Example Iz
2-amino-1,3-propanediol processed further. 4 g of Dp-nitrophenyl-a-chloroacetamino-jS-hydroxy-

propiophenone (XII), melting point 101 to 102 ⁰ C,

Example 7 (a) i> = + 6.4 ° C (c = 4; acetone), in 25 cm ³

10 g of i-threo-1-p-nitro-pyridine are dissolved in a flask at room temperature. If the Rota-

phenyl-2-acetamino-1,3-propanediol (X) and 2.2 g of nativity has disappeared, it is poured into 100 g

11 12

Ice and 75 cm ^{3 of} concentrated hydrochloric acid. It separates 2-acetamino-3-chloropropane-l-ol (VII) crystallizes out, the BL-p-nitrophenyl-a-chloroacetamino-p'-hydroxy- melting point of 133 to 14O ⁰ C. Fractional propiophenone (XIII) from , melting point 128 to 13O ⁰ C. crystallization of this mixture from methanol is obtained, this is further processed as in example 6. FIG. as a less soluble derivative the D, L-threo-lp-nitro-

5 phenyl ^ -acetamino-S-chloropropan-1-ol, melting point

Example 13 169 to 17O ⁰ C, and from the crystallization mother liquor

the D, L-erythro-l-p-nitrophenyl ^ -acetamino-S-chloro-

3 g Dp-nitrophenyl-a-benzamino JSS-hydroxypropiophe- propan-1-ol, melting point 153-154 ° C. The reduction of non (XII), melting point 149-150 ° C, [o) d - +60 ⁰ C of the D, Lp-nitro-a-acetamino - /; i-chloropropiophenone (VI) (c = 2; acetone), are dissolved in 30 cm ^{3 of} piperidine at room- i ° can also be dissolved with lithium aluminum hydride at the following temperature. After 10 minutes it is poured into ice. To be carried out: 5.0 g of chloroketone (VI) and concentrated hydrochloric acid. It separates in shape are dissolved in 50 cm ^{3 of} anhydrous tetrahydrofuran, tiny crystals the d, Lp-nitrophenyl-a-benzamino- and it is stirred, at a temperature of / 3-hydroxypropiophenone (XIII), melting point 157 40 ' C., 0.20 g of H ₄ AlLi up to 159 ° C. over a period of 30 minutes. This is processed further as in Example 6, dissolved in 20 cm ^{3 of} anhydrous tetrahydrofuran. given. After a further 30 minutes at ^40.degree. C., one adds

Example 14 5 cm ^{3 of} water are added and nitrated from the precipitated

Hydrates of lithium and aluminum. Of the

15 g! - (+ Jlp-nitrophenyl-IS-diacetoxy ^ -aminopro- filter cake of the hydrates is then extracted with boiling panchlorhydrate (II), which is extracted from methanol and ether, and the methanolic solution is purified to the melting point 170 to 172 ⁰ C, (α) χ »= + 6.5 ° C combined with the solution in tetrahydrofuran; by (c = 4.18; methanol) and, as in Example 3, evaporation of the combined solutions is obtained A mixture of D, L-threo- and -erythreo-lp-nitrophenyl is dissolved in 60 cm ^{3 of} water and made alkaline with 5 g of sodium bicarbonate.2-acetamino-3-chloropropan-l-ol (VII) , 0 g B, L-threo-Man receives l - (-) - lp-nitrophenyl-2-acetylamino-3-acet-25 lp-nitrophenyl ^ -acetamino-S-chloropropan-l-ol (VII) oxypropan-1 ol (III), purified from ethyl acetate, wherein are dissolved in 150 cm ³ of ethanol and melting with 10 cm ³ NaOH 134 to 136 ° C, (a) _D = -19.7 ° C (c = 3.86 ; Treated. After one night, acidification on methanol). 12.6 g L-threo- lp-nitrophenyl-2-acetamino p _H observed between 5 and 6, the ethanol evaporated 3-acetoxy-propan-l-ol (III) are dissolved in 110 cm ³ of acetic acid and the residue treated with water. The solution is dissolved in acid. At 15 ⁰ C., 9 g of chromic anhydride, extracted 30 with ethyl acetate and dissolved therefrom by evaporation in 9 cm ³ of water and diluted with 5 g of acetic acid, the d, L-threo-lp-nitrophenyl ^ -acetammo-lS-propanzu. It is left at 15 ° C. for a further 3 hours, and then diol (VIII) crystallizes out; 4.0 g sodium bisulfite solution. The acetic acid Bi-erythreo-lp-nitrophenyl - ^ - acetamino-S-chloroproin is evaporated, taken up with water and extracted with 35 pan-l-ol are dissolved in 110 cm ^{3 of} ethanol, and it is chloroform. ^{3.5 cm 3 of} 5N NaOH are added by evaporation of the chloroform solution. The bp-nitro-a-acetamino- / 5-acetoxypropio- is boiled and then refluxed for 5 minutes and then phenone (IV), which, recrystallized from ethanol, is allowed to stand for 2 hours. Sodium chloride is filtered off from low-140 to 141 ° C, (a) r> = -37 ° C (c = 5.0; metha blow off and the ethanol evaporates; nol crystallizes). 50 g of Dp-Nitro-a-acetylamina-jS-acetoxypropiophe- 40 B, L-erythro-lp-Nitrop_henyl-2-acetamino-1,3-propanediol non (IV) are dissolved in 190 cm ^{3 of} methanol, and it (VIII ) from, which, recrystallized from ethanol, at 192 10 cm ^{3 of} 0.5% sodium alcoholate solution melts up to 193 ° C. 3.3 g mixture of Β, ι-threo- and given (5 g of metallic sodium dissolved in 100 cm ^{3 of} absolute -erythro-lp-nitrophenyl ^ -acetamino-S-chloropropane-methanol). After standing for 4 days at room temperature, l-ol (VII) is dissolved in 30 cm ^{3 of} methanol, the solution shows a rotational ability equal to 45 at boiling temperature, 12 cm ^{3 of} N / l NaOH are added, and zero. 10 cm ³ l, 3% strength aqueous acetic acid solution are added and the mixture is left to stand overnight. After evaporation, add and concentrate to half volume, then pour the methanol, extract with ethyl acetate and pour in 800 cm ^{3 of} ice-water, whereby p-nitro-a-acetamino crystallizes the mixture of B, L-threo- and -erythroacrylophenone (V) crystallized out. After um-lp-nitrophenyUZ-acetamido-IS-propanediol (VIII) fracture from ethanol, the compound (V) emerges in 50 ionized form from water. 63 g of BL-erythro-1-p-nitro yellow prismatic needles with a melting point of 120 to phenyl-2-acetamino-1,3-propanediol are raised to 121 ° C. ^{in 130 cm 3.} If B-p-nitro-a-acetamino-jS-acetoxypropio-chloroform is suspended and phenone (IV) with 5 parts of pyridine 30 cm ^{3 of} thionyl chloride are added with stirring at room temperature, the temperature being brought to reaction, the reaction is already complete after being kept at 25 to 30 ^° C. Stirring is ended for a further 18 hours. It is then sufficient, in ice and con- 55 for 30 minutes always at 25 to 3O ⁰ C and then filtered to pour centered acid so that the p-nitro It falls to a crude product which a- by boiling with 700 cm ³ acetaminoacrylophenone (V) crystallized out. 50 g of methanol is purified; After cooling, the p-nitro-α-acetaminoacrylophenone (V) is filtered and the D, i-erythro-lp-nitrophenyl-2-acetamino-cold is dissolved in 10 cm ^{3 of} dioxane, and the 24 g of gaseous 1,3-propanediol are dissolved cyclic sulfite, melting point 143 ⁰ C contain hydrogen chloride per 100 cm ^{3 of} dioxane. After 60 (decomp.). 50 g of Bt-erythro-lp-nitrophenyl ^ -acetamino one night is poured into water, and 1,3-propanediol cyclic sulfite is crystallized in a small BL-p-nitro-a-acetamino - ^ - chloropropiophenone (VI), Flask melted by heating in a small oil bath with the kept at 150 ^{0 C after recrystallization from ethanol.} If the product is completely white needles, m.p. 120 to 120.5 ⁰ C (decomp.) Is melted, so it provides a heating and triggers occurs. 5.0 gb, Lp-nitro-a-acetamino-ß-chloropropio- 65 the residue with ethanol at boiling temperature. When phenone (VI) in 25 cm ³ of methanol are suspended, cooling, crystallizing the B, L-threo-2-methyl-4-oxy- and 0.31 g of boron hydride in 71.3 ° / ₀ sodium methyl 5-p-nitrophenyl-ZI ² -oxazoline from that added from ethanol solution in 5 cm ^{3 of} methanol. This gives a clean, melts at 161 to 162 ⁰ C. 50 g of B, L-threo-brown solution, from which, as a result of dilution with water, 2-methyl-4-oxymethyl-5-p-nitrophenyl- / I ² -oxazoline were a mixture of B, i-threo and erythreo-1-p- Nitrophenyl- 70 den heated at 50 to 6O ⁰ C with 220 cm ³ N / l HCl. the

solution treated with carboraffin is cooled and then 20 g of sodium bicarbonate is added. D, Llp-nitrophenyl-2-acetamino-1,3-propanediol crystallizes out. Melting point 164 to 165 ^° C. (from water). 20 g DJL-threo-lp-nitrophenyl ^ -acetamino-lS-propanediol are heated on a water bath with 60 cm ³ 10 ° / ₀ HCl solution. Is decolorized with Carboraffin and basified to p _H 11 with NaOH (36 ° Be). It crystallizes D, L-threo-lp-nitrophenyl ^ amino-lS-propanediol (IX) from which is purified of water, melting point 140-141 ⁰ C.

Example 15

54.0 g of L-threo-lp-nitrophenyl-2-amino-1,3-propanediol (I) are ^{dispersed in 100 cm 3 of} dioxane and 100 cm ^{3 of} pyridine. The mixture is cooled to + 5 ^° C. and 60 cm ^{3 of} benzoyl chloride are added, the temperature being kept between +5 and + 10 "C. After one night in the refrigerator, 400 g of ice and 200 cm ^{3 of} concentrated HCl are poured with stirring . The mixture is filtered and washed with water; a ° by recrystallization from ethanol is obtained L-threol-p-nitrophenyl ^ -benzamino-S-benzoxypropan-l-ol (III), melting point 173-174 ⁰ C, {a) _D = ⁰ +23.3 C (c = 2; _CHCl3). 41.0 g of L-threo-lp-nitrophenyl-2-benzamino-3-benzoxypropan-l-ol (III) are dispersed cm ³ of acetic acid in 335, and 11.6 g of chromic anhydride, dissolved in 12 cm ^{3 of} water, are added. After 3 hours, 32 cm ^{3 of} sodium bisulfite (32 ° Be) and 340 cm ^{3 of} water are added. The Bp-nitro-α-benzamino- / ? -benzoxypropiophenon (IV), which, recrystallized from methanol, melts at 145 to 146 ° C, {a) _D = -22.9 ⁰ C (c = 2.0; methanol) 5 g Da-Benzamino- / 3 system. -benzoxyp-nitropropiophenon (IV), melting point 145 to 146 ° C, (a) _D = - 22.9 ° C (c = 2.06; methanol), are dissolved in a mixture of 60 cm ³ of chloroform, and 60 cm ³ of ethanol, is added and 3.5 cm ³ of 0.5 ° / ₀ sodium alcoholate to (5 g of metallic sodium dissolved in 100 cm ³ of absolute ethanol). After 24 hours, 3 _^0/0 aqueous acetic acid is added 3.5 cm ³ l, and concentrated to dryness in vacuo. Is taken up in ethanol and filtered, the p-nitro-a-benzamido-acrylophenon (V), which melts after recrystallization from methanol at 135 to 137 ⁰ C. 5.0 g of p-nitro-a-benzamido-acrylophenone (V) are dissolved in the cold in 10 cm ^{3 of} dioxane, which contains 28 g of gaseous hydrogen chloride per 100 cm ^{3 of} dioxane. After a night you pour in water; The B, ip-nitro-a-benzamino-zS-chloropropiophenone (VI) crystallizes out, melting point 144 to 146 ° C. (decomp.), from methanol. 5.0 gd, Lp-nitro-a-benzamino-ß-chloropropiophenon (VI) are reduced in methanolic suspension with 0.25 g of 73 ° / _o sodium boron hydride. As a result of dilution with water, a mixture of D, L-threo- and -erythro-lp-nitrophenyl-2-benzamino-3-chloropropan-l-ol (VII) crystallizes out, melting point 90 to 145 ° C, which is dissolved in ethanol and is treated with 1.5 equivalents of 2 N-Na OH. After one night, the ethanol is evaporated and the mixture of B, L-threo- and -erythro-1-p-nitrophenyl ^ -benzamino-IS-propanediol (VIII) crystallizes out, the D, L- erythro-lp-nitrophenyl ^ -benzamino-lS-propanediol, melting point 210 to 211 ⁰ C, supplies as a less soluble compound, and from the mother liquor the B ^ -threo-lp-nitrophenyl-2-benzamino-1,3-propanediol , M.p. 157-161 ° C. (You can also carry out the reduction of the b, Lp-nitro-a-benzarninojß-chloropropiophenone (VI) with aluminum isopropylate. For this purpose, 5.0 g of chloroketone are heated with 8 g of aluminum ^{isopropylate in 125 cm 3 of} isopropanol in such a way that the Acetone formed in the reaction is distilled off by a rectifying column. When acetone no longer distills over, the mixture is cooled and 45 cm ^{3 of} 2 η-sulfuric acid + 200 cm ^{3 of} water are added. A precipitate forms, which is extracted with ethyl acetate, after which the crude is evaporated BL-lp-Nitropnenyl ^ -benzamino-S-chloropropan-1-ols (VII), which are subjected to treatment with caustic alkalis as they arise.) 20.0 g of B, L-erythro-lp-nitrophenyl- 2-benzamino-l, 3-propanediol are suspended in 100 cm ³ of chloroform, and ³ are SOCl ₂ were added at +5 to + 1O ⁰ C 10 cm. After standing for one night at room temperature with stirring, the cyclic sulfite of D, L-erythro-1-ρ-nitrophenyl-2-benzamino-1,3-propanediol is filtered off, melting point 177 to 178 ° C. (decomp.). 23.0 g of the cyclic sulfite BL-erythro-lp-nitrophenyl ^ -benzamino-1,3-propanediol are melted, and 106 cm ³ 20 ° / ₀ sodium HCl after cooling added. The mixture is refluxed for 12 hours and the aqueous solution is washed with ethyl ether. After evaporation in vacuo, the mother liquor 60 is added cm ³ of water and made alkaline with 36 ll ⁰ Be NaOH to p _H. The d, L-threo-1-p-nitrophenyl-2-amino-1,3-propanediol (IX), which melts ^{at 140 to 141 ° C. after recrystallization from water, is filtered off.}

Example 16

5.0 g of p-nitro-α-acetaminoacrylophenone (V) are dissolved in 10 cm ³ (21 g of HBr per 100 cm ^{3 of} containing) dioxane in the cold. After standing overnight, it is poured into water and the BL-p-nitro-α-acetaminoß-bromopropiophenone (VI), which crystallizes out, is filtered off; purified from ethanol, it appears in small needles with melting point 168 ⁰ C (dec.). The B, Lp-nitro-a-acetamino - /? - brornopropiophenone (VI) is reduced with boron-sodium hydride in a similar manner as described in the preceding examples, and the resulting mixture of D, L-threo- and -erythro- 1-p-Nitrophenyl-2-acetamino-3-bromo-propan-1-ol (VII) is reacted with NaOH in an aqueous-ethanolic solution, again analogously to what has already been said. The resulting products b, L-erythro- and -threo-lp-nitrophenyl-2-acetamino-1,3-propanediol (VIII) are separated by fractional crystallization from water; the erythro derivative is the less soluble in water. The further processing to B, L-threo-lp-nitrophenyl ^ -amino-ljS-propanediol takes place according to Example 14.

Claims (2)

Patent claims: 1. Process for the conversion of D-erythro- or L-threo-1-phenyl- (or 1-p-nitrophenyl) -2-aminol, 3-propanediolinB, L-threo-1-phenyl- (or -1 -p-nitrophenyl) -2-amino-1,3-propanediol, characterized in that either B-erythro- or i-threo-1-phenyl- (or. 1-p-Nitrophenyl) ^ -a propanediol of the general formula - CH-CH-CH ₂ OH OH NH-COR (Y = NO ₂ or H; R = alkyl, haloalkyl, aryl, aralkyl) by direct and selective oxidation by means of compounds releasing halogens or halogens, preferably by means of sodium bromate in the presence of hydrogen bromide, in aqueous solution at a temperature between 0 and +5 ⁰ C, preferably in the presence of actinic light, in the corresponding D- or i-a-acylamino-ß-oxypropiophenone the general formula Y - < > —CO —CH — CH ₂ OH NH-COR (Y, R as above) transferred and this by treatment at a temperature between 0 and 60 ° C with a substance of basic character, in particular pyridine, N-ethylpiperidine or piperidine in anhydrous State or environment, or with alkali bicarbonate, preferably sodium bicarbonate, in aqueous Solution, racemized, the racemate reduced by known methods and the diols thus obtained also by known methods to D, L-threo-1-phenyl- or (1-p-nitrophenyl) ^ -amino-1- ^ -propanediol saponified, or from the optically active aminodiols mentioned above by methods known per se obtained d- or i ^ -acylamino-S-acyloxypropan-1-ols using chromic acid in acetic acid solution to D- or L-a-acylamino - ^ - acyloxypropiophenones the general formula CO-CH-CH ₂ OCOR '«5 NH-COR (Y and R as above, R 'identically or differently from R == alkyl, haloalkyl, aryl, aralkyl) oxidizes, the deposited product by treatment with a substance of basic character, in particular pyridine or Sodium alcoholate, preferably at room temperature, into the corresponding α-acylaminoacrylophenone general formula C = CH ₂ NH-COR (Y and R as above) transferred, this with the solution of a hydrohalic acid in anhydrous medium, such as ether, tetrahydrofuran or dioxane 40 Brings temperatures between 0 and 100 ⁰ C to the reaction, the thus obtained d, La-acylamino - ^ - halogenpropiophenone of the general formula Y- ^ -CO —CH- -CH ₂ X NH-COR (Y and R as above; X = Cl, Br, J) in a manner known per se by selective reduction to D.L-threo- or D, i-erythro-1-phenyl- (or 1-p-nitrophenyl) -2-acylamino-3-halogenpropan-1-ols the general formula ■ - CH-CH-CHo-X OH NH-COR (R, X, Y as above) reduced by treating in alcoholic solution with alkali hydroxide in a known manner Way in d, l ~ (mixture of threo and erythro or only threo -) 1 - phenyl - (or 1 - ρ - nitrophenyl) - 2 - acylamino-1,3-propanediols Y - <' ^X - CH-CH-CHoOH \ ■ 1 OH NH-COR (R, Y as above) transferred, which the latter in turn according to known methods in D.L-threo-l-phenyl- or l-p-nitrophenyl-2-amino-1,3-propanediol are saponified. 2. The method according to claim 1, characterized in that the relevant d- or L-a-acylarnino / 3-oxypropiophenone from the starting compound to be converted instead of via 1-phenyl- (or 1-p-nitrophenyl) -2-acylamino-1,3-propanediol (D-erythro resp. L-threo), according to methods known per se via <z-acylamino - /? - acyloxypropiophenone (d- or L-) and the corresponding a-amino-z-oxypropiophenone chlorohydrate is obtained. Considered publications:
German patent application F 7340 IVc / 12q. © 709 808/292 11.