DE1089768B - Process for the preparation of substituted acid hydrazides - Google Patents

Description

GERMAN

The present invention relates to the manufacture of substituted acid hydrazides of the general formula

R ₁ -CO-NH-NH-R ₂ (I)

wherein R _{1 is} a saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon radical substituted by halogen, hydroxy or alkoxy groups containing up to 4 carbon atoms, and R _{2 is} an aralkyl radical or an alicyclic or saturated, straight-chain or branched aliphatic hydrocarbon radical containing up to 6 carbon atoms , as well as salts of these acid hydrazides.

According to the invention, the above-defined acid hydrazide compounds are either by condensation of an acid of the general formula

R ₁ -COOH (II)

with a substituted hydrazine of the general formula

H ₂ N-NH-R ₂

(III)

where R ₁ and R _{2 have} the meaning defined above, prepared in the presence of a Ν, Ν'-disubstituted carbodiimide or by the methods known per se given below and optionally converting the free acid hydrazide obtained into a salt.

On the one hand, the invention relates to a process for the preparation of certain, characterized by the formula I, substituted acid hydrazides. According to this procedure, a carboxylic acid becomes the general Formula II with a substituted hydrazine of the general formula III in the presence of a carbodiimide condensed. To implement the acids or their salts, eg. B. the alkali metal salts are used will. A conversion into the more reactive esters, halides, anhydrides, etc. is unnecessary. As Condensing agents used N, N'-disubstituted carbodiimides can known, for. B. by treating disubstituted urea derivatives with p-toluenesulfochloride be made in pyridine. The corresponding urea derivatives are used in the reaction according to the invention recovered. By using suitably substituted carbodiimides, by-products are obtained Urea derivatives, which can be easily separated from the reaction product.

As Ν, Ν'-disubstituted carbodiimide, for example Use N.N'-dicyclohexyl-carbodnmide Reaction can e.g. B. between 0 and 50 ° C, preferably at room temperature or slightly elevated temperature, carried grazing. It is convenient to use a solvent. It can be both organic Solvents such as B. methylene chloride, chloroform, dioxane, tetrahydrofuran, dimethylformamide or acetonitrile, and water can be chosen.

Method of manufacture
substituted acid hydrazides

Applicant:

F. Hoffmann-La Roche & Co.

Corporation,

Basel, Switzerland)

Representative: Dr. G. Schmitt, lawyer,
Lörracti (Bad.), Friedridistr. 3

Claimed priority:
Switzerland from July 3 and October 11, 1957

Dr. Hugo Gutmann, Birsfelden,

Dr. Otto Sträub, Bottmingen,

and Dr. Paul Zeller, Neuallschwil (Switzerland),

have been named as inventors

The use of dicyclohexylcarbodiimide to form the peptide bond between a carboxylic acid and a free amino group is described in J. Am. Chem. Soc, 77 (1955), p. 1067, and in J. Org. Chem., 21 (1956), P. 439, already described.

On the other hand, the invention relates to the preparation of substituted acid hydrazides of the formula I according to the following methods known per se. A reactive derivative of an acid of the formula II is condensed, such as an ester, a halide, the anhydride or the amide, optionally with heating, with a substituted one Hydrazine of formula III. According to a further embodiment of the invention, the from the Heat acids of the formula II with the salts formed with the hydrazines of the formula III to high temperatures. To Another method is to react the hydrazide of an acid of the formula II with a carbonyl compound and reduces the hydrazone formed, for example by catalytic hydrogenation using Platinum or palladium carbon as a catalyst or by reaction with lithium aluminum hydride. As a carbonyl compound you can use, for example, acetone, methyl ethyl ketone or benzaldehyde. The two Reactions can take place simultaneously or one after the other.

009 609/417

3 4

Other non-present invention present in the molecule cannot have any effect against those saturated with tubercles Groups are also hydrogenated. After a bacilli on. The administration of the latter is therefore Another method does not use the hydrazide of an acid with the disadvantageous effect of creating resistance of the formula II with a carbonyl compound.

treats the hydrazone formed with a Grignard 5 Example 1
compound and hydrolyzes the resulting addition

product. The Grignard compound used is 8.8 g of methoxyacetic acid and 10.1 g of triethylamine

preferably methyl or ethyl magnesium halide. are dissolved in 150 ecm acetonitrile. After adding

According to the process according to the invention, 11.05 g of isopropylhydrazine monohydrochloride can be stirred

For example, the following substituted acid hydrazides io for 1 hour at room temperature and then adds

are prepared: 20.7 g of NjN'-dicyclohexyl-carbodiimide are added. Well will

1- (Hydroxyacetyl) -2-isopropylhydrazine,! - (Hydroxy- for 3 to 4 hours, the

acetyl) - 2 - benzyl - hydrazine, 1 - (α - hydroxypropionyl) - reaction temperature by intermittent cooling between

2-tert-butylhydrazine, 1- (a-hydroxypropionyl) -2-iso-25 and 30 ^° C. is maintained. Then the selected

propyl - hydrazine, 1 - (α - hydroxypropionyl) - 2 - benzyl- 15 precipitated dicyclohexylurea filtered off and the filtrate

hydrazine, 1- (a-hydroxypropionyl) -2-phenethylhydrazine, concentrated in vacuo at a maximum of 60 ° C. The residue

l- (y-Hydroxybutyryl) -2-phenätnyl-hydrazine, l- (y-Hy- is extracted with ether, whereby triethylamine-hydro-

droxybutyryl) -2-sec.butylhydrazine, l- (methoxyacetyl) chloride remains undissolved. The ethereal solution becomes

2-isopropyl-hydrazine, l- (ethoxyacetyl) -2-benzyl-hydra- first with saturated sodium bicarbonate solution and

zin, l- (ethoxyacetyl) -2-isopropylhydrazine, l- (diethoxy- 20 then in portions with 70 ecm 2 n-chlorinated water-

acetyl) -2-isopropylhydrazine, l- (diethoxyacetyl) -2-benzoic acid extracted. The combined hydrochloric acid extracts

zyl-hydrazine, 1 - (^ - hydroxypropionyl) -2-isopropyl-hydrazine are with concentrated sodium hydroxide solution to p _H 7 to 8

zin, l- (2-ethoxypropionyl) -2-isopropylhydrazine, l- (a-di- adjusted, saturated with table salt and several times with

ethoxypropionyl) -2-isopropylhydrazine, l- (chloroacetyl) ether extracted. The combined and dried

2-isopropylhydrazine and! - (/ S-chlorocrotonyl ^ -isopropyl- 25 ether extracts are freed from the solvent, whereby

hydrazine. l-methoxyacetyl-2-isopropylhydrazine is obtained;

From a pharmacological point of view, »ff = 1.4587; Boiling point: 105 to 106 ° C / 12 mm.
those acid hydrazides in which R _{1 is} a through

Hydroxy- or alkoxy-substituted lower aliphatic example 2

table hydrocarbon radical with 1 to 4 carbon 30

atoms and R _{2 is} the isopropyl or benzyl radical. As from 44 g / 3-ethoxypropionic acid ethyl ester and 21 g

especially interesting representatives of this group of particular hydrazine hydrate by heating to 100 ⁰ C 2ständiges

Preferred compounds are, for example, those obtained from and then distilled at 80 ° C / 0.005 mm

of lactic acid and dialkoxyacetic acids, especially j8-ethoxypropionyl hydrazide, is obtained by boiling with

the diethoxyacetic acid, derived, according to claim 35 acetone into the l - (/ S-ethoxypropionyl) -2-isopropylidene-

Highlight hydrazides. hydrazine transferred, which at 48.5 to 50.5 ⁰ C

The substituted acid obtainable according to the invention melts. A solution of this hydrazone in ethanol. B. at temperature and at atmospheric pressure with water-hydrohalic acids, such as hydrochloric acid, 40 material shaken until the hydrogen uptake comes to the still-hydrobromic acid, hydroiodic acid, with others. After filtering off the catalyst and mineral acids, such as sulfuric acid, phosphoric acid, and concentrating the filtrate, the residue is vacuum-distilled in high-pitric acid and with organic acids such as tartaric acid. L- (| 8-ethoxypropionyl) -2-iso-salicylic acid, ascorbic acid, maleic acid, mandelic acid 45 propyl hydrazine is obtained as a fraction with a boiling point of citric acid, camphor sulfonic acid, ethanesulfonic acid, 65 ° C / 0.03 mm, which solidifies on cooling ; etc. Preferred salts are the hydrohalides, melting point 31.5 to 32.5 ° C; »Ff = 1.4506.
especially the hydrochloride. The acid addition salts are prepared in an analogous manner using, preferably in an inert solvent, methyl methoxyacetate in place of the β-ethoxide by treating the hydrazine derivative with an ethyl propionate over the methoxyacetic acid excess of the corresponding acid. 50 hydrazide (melting point 50 to 51 ⁰ C, boiling point 71 ⁰ C

The substituted acid available according to the invention at 0.01 mm) and the corresponding l- (methoxyacetyl) -

hydrazides and their salts inhibit the monoamine 2-isopropylidene hydrazine (melting point after the

oxidase; individual representatives are characterized by their crystallization from acetone-petroleum ether 73 to 74 ⁰ C) that

pronounced antidepressant effectiveness and l- (methoxyacetyl) -2-isopropylhydrazine (boiling point 105

weight-increasing in cachexia. You thus set a 55 to 106 ° C / 12mm, n ² ^ = 1.4587) obtained, which is

valuable enrichment of the drug treasure. solidified at lower temperatures.

By determining the weakening of the ethanol

Anesthesia potentiation in the mouse was found in Example 3

that glycol hydrazide, lactic acid hydrazide and "

Propoxyacetic acid hydrazide no monoamine oxidase- 60 that from 160.8 g ß-propiolactone in 650 ecm acetonitrile

develop an inhibiting effect. In contrast, was charged and 122 g of 100 ° / _o hydrazine hydrate by concentration

round that the / 3-hydroxypropionyl obtained by a dose of 5 mg / kg 2-hydroxy of the reaction mixture

2-ethyl-3-isobutyl-9,10-dimethoxy-l, 2,3,4,6,7-hexa- hydrazine is a melting point of 102.5 to 104 ⁰ C.

hydro - HbH - benzo [a] quinolizine - hydrochloride reacted by heating with excess acetone,

Called reinforcement of the ethanol effect already by 65 By concentration of the resulting reaction mixture

Administration of the sub- obtainable according to the invention is obtained 1 - (/? - hydroxypropionyl) -2-isopropylidene-

Substituted acid hydrazide in a low dose prevents hydrazine, which occurs after recrystallization

will. Unlike existing substances with acetone at 94 melts to 95.5 ^0C. One solution to this

similar effectiveness, e.g. B. the l-isonicotinoyl-2-iso- hydrazone in ethanol is in the presence of platinum

propyl hydrazide, the process products of the 70 catalyst exhibit in the manner described in Example 2

hydrogenated to give l - (/? - hydroxypropionyl) -2-isopropylhydrazine, which crystallizes from ethyl acetate in fine, colorless needles with a melting point of 99 to 100 ° C.

Example 4

Glycolic hydrazide with a melting point of 91.5 to 92.5 ° C is reacted by boiling with excess acetone. 1- (Hydroxyacetyl) -2-isopropylidene hydrazine with a melting point of 113 to HS ⁰ C. 20 g of this hydrazone are dissolved in ethanol and hydrogenated with 0.1 g of platinum catalyst at room temperature and atmospheric pressure. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is concentrated in vacuo. The resulting crude 1- (hydroxyacetyl) -2-isopropylhydrazine is recrystallized from ethyl acetate, giving colorless prisms with a melting point of 96 to 97.degree.

In an analogous manner, starting from γ-Άγ -hydroxybutyric acid hydrazide, l- (γ-hydroxybutyryl) -2-isopropylhydrazine with a melting point of 69 ° to 71 ° C. is obtained.

Example 5

15 g of lactic acid hydrazide are boiled in 150 ecm acetone for 3 hours, whereupon the reaction mixture is evaporated to dryness and the yellowish sticky residue, after drying briefly on clay, is boiled again with 100 ecm acetone for 2 hours. After renewed concentration and drying, the residue is recrystallized from benzene or ethyl acetate. 24 g of the l- (a-hydroxypropionyl) -2-isopropylidene-hydrazine with a melting point of 86 to 91 ⁰ C obtained in this way are dissolved in 700 ecm of ethanol in the presence of platinum catalyst at room temperature and atmospheric pressure until the calculated amount of hydrogen (1 mol per Mol of the substance to be hydrogenated) hydrogenated. The solution freed from the catalyst is evaporated to dryness in a vacuum. The residue is recrystallized from ethyl acetate. 15 g of 1- (a-hydroxypropionyl) -2-isopropylhydrazine with a melting point of 102 to 103 ° C. are obtained.

Example 6

20.8 g Milchsäurehydrazid be with 62 g of a 50 ° / ₀ aqueous alcoholic Phenylacetaldehydlösung and 20 cc of ethanol, boiled for 1 hour. The product which has precipitated after the reaction mixture has stood in the cold for several hours is suction filtered and recrystallized from a mixture of ethyl acetate and ethanol (6: 1). 10.3 g of the resulting l- (a-hydroxypropionyl) -2- ( _j 5-phenylethylidene) hydrazine with a melting point of 160 to 163 ° C. are dissolved in 500 ecm of ethanol with 0.3 g of platinum oxide at room temperature and atmospheric pressure up to Taking up the calculated amount of hydrogen hydrogenated. The solution filtered off with suction from the catalyst is concentrated to dryness in vacuo, whereupon the residue is recrystallized from benzene. The melting point of the l - (<z-hydroxypropionyl) -2-phenethylhydrazine obtained in this way is 111.5 to 114.degree.

Example 7

20 g of Diäthoxyessigsäureäthylester and hydrazine hydrate (100 ° / _o ig) obtained Diäthoxyessigsäure hydrazide (boiling point 103 ° C / 0.02 mm, n = 1.4635%) are boiled with 20 cc of acetone for 1 hour under reflux. The excess acetone is then distilled off, the residue is dissolved in 50 ecm of alcohol and, after the addition of a little platinum catalyst, is hydrogenated at room temperature and at atmospheric pressure until the uptake of hydrogen has stopped. After filtering off the catalyst, the filtrate is concentrated in vacuo and the residue is distilled. 1-Diethoxyacetyl-2-isopropylhydrazine is obtained with a boiling point of 78 to 80 ° C./0.1 mm, ^ j = 1.4470.

Example 8

22.3 g of the diethoxyacetic acid hydrazine prepared according to Example 7 are heated with 50 ecm of alcohol and g of benzaldehyde for 1 hour on a water bath. Subsequently, hydrogenation is carried out in the presence of platinum catalyst at room temperature and atmospheric pressure as in the preceding example, and thus arrives to the l-Diäthoxyacetyl-2-benzyl-hydrazine, which melts after recrystallization from benzene-petroleum ether at ⁰ C 8S.

Example 9

A mixture of 23.6 g of ethyl lactate and 14.8 g of isopropylhydiazine is used for about 60 hours heated to reflux at an oil bath temperature of 120 ° C. The reaction mixture is then in a water jet vacuum constricted. The solid residue is recrystallized from ethyl acetate. This gives 15 g 1- (α - hydroxypropionyl) - 2 - isopropyl - hydrazine with a melting point of 102 to 103 ° C.

Claims (13)

Patent claims: 1. Process for the preparation of substituted acid hydrazides of the general formula R ₁ -CO-NH-NH-R ₂ wherein R _{1 is} a saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon radical substituted by halogen, hydroxy or alkoxy groups containing up to 4 carbon atoms and R _{2 is} an aralkyl radical or an alicyclic or saturated, straight-chain or branched aliphatic hydrocarbon radical containing up to 6 carbon atoms, and salts of these acid hydrazides, characterized in that an acid of the general formula R ₁ - COOH with a substituted hydrazine of the general formula H ₂ N - NH - R ₂ , in which R ₁ and R _{2 have} the meaning defined above, in the presence condensed a Ν, Ν'-disubstituted carbodiimide and optionally converted the free acid hydrazide obtained into a salt. 2. The method according to claim 1, characterized in that the condensation in one Solvent between 15 and 30 ° C. 3. The method according to claim 1 and 2, characterized in that the carbodiimide is dicyclohexylcarbodiimide is used. 4. The method according to claim 1 to 3, characterized in that the acid or lactic acid Diethoxyacetic acid used. 5. A process for the preparation of the substituted acid hydrazides mentioned in claim 1, characterized in that a reactive functional derivative of an acid of the general formula R ₁ - COOH with a substituted hydrazine of the general formula H ₂ N - NH - ■ R ₂ , wherein R ₁ and R _{2 has} the meaning defined in claim 1, condensed. 6. The method according to claim 5, characterized in that the functional derivative is an ester, a halide, the amide or the anhydride of an acid of the formula R ₁ - COOH, wherein R _{1 is} the im Claim 1 has a defined meaning, used. 7. The method according to claim 5 and 6, characterized in that that one uses a functional derivative of lactic acid or diethoxyacetic acid. 8. The method according to claim 1 to 7, characterized in that the substituted hydrazine Isopropyl hydrazine or benzyl hydrazine is used. 9. A process for the preparation of the substituted acid hydrazides mentioned in claim 1, characterized in that the hydrazide of an acid of the general formula R ₁ - COOH, wherein R _{1 has} the meaning defined in claim 1, with an aromatic, araliphatic or up to 6 Alicyclic or saturated, straight-chain or branched aliphatic caibonyl compounds containing carbon atoms are condensed and the hydrazone which is formed is reduced at the same time or subsequently. 10. The method according to claim 9, characterized in that the hydrazone is catalytically hydrogenated. 11. The method according to claim 9 and 10, characterized in that the hydrazide of lactic acid or diethoxyacetic acid is used. 12. The method according to claim 9 to 11, characterized in that the carbonyl compound Acetone or benzaldehyde is used. 13. A process for the preparation of the substituted acid hydrazides mentioned in claim 1, characterized in that the hydrazide of an acid of the general formula R ₁ - COOH, wherein R _{1 has} the meaning defined in claim 1, with an aromatic, araliphatic or up to ίο 5 carbon atoms containing alicyclic or saturated, straight-chain or branched aliphatic carbonyl compound condenses, the formed Reacts hydrazone with methyl or ethyl magnesium halide and hydrolyzes the addition product formed. Considered publications: Beilstein's Handbook of Organic Chemistry, 4th edition, main work: Vol. 3, pp. 285, 343; Supplementary work I: Vol. 3, p. 94, UO; Supplementary work II: Vol. 3, p. 209;
British Patent No. 782,420;
Journal of the Am. Chem. Soc, 77, p. 1067 (1955);
Journal of Organic Chemistry, 21, p. 439 (1956). A test report was displayed when the registration was announced.