DE2059451A1 - Process for the production of penicillins - Google Patents

Description

cHEWL waiter BEH 2. Da ^. 197 <J

Dlli-C ^ I H-J. WOLFP

DR. JUR. HANS C.-iii. DuIL j

FRANKFURTAM MAIN-HOCHST

Our no.16 697

Pfizer Inc.

New York, N.Y., V.St.A.

Process for the production of penicillins

The invention relates to a process for the production of antibiotics, in particular of arylmethylpenicillins with a cC -carboxyester group. These antibiotics can be taken orally administered.

The acylation of 6-aminopenicillanic acid with the formation of various JZ -carboxyarylmethylpenicillin "esters using acid chlorides or simple or mixed acid anhydrides is described in U.S. Patents 3,270,009, 3,142,673 and 3,173,916, while such an acylation is described under Use of active derivatives of a substituted malonic acid is disclosed in British patent specification 1 004 670. Furthermore, the concurrent patent application P 19 00 195.7 describes the preparation of such penicillins by acylating 6-aminopenicillanic acid with the aid of aryl carboxy-ketene esters.

1 0! J '', '/ ¹ J / 7 7 1 1

It has now been found that the acylation of 6-aminopenicillanic acid can be carried out using a reactive derivative of an aryl-substituted malonic acid and that esters of cf * -carboxyarylmethylpenicillins, which are valuable antibiotics for oral administration, can be prepared in this way.

The process according to the invention relates to the condensation of 6-aminopenicillanic acid or one of its derivatives, e.g. the sodium, potassium or tri-lower alkyl amine salt, which in an inert solvent system at about 0 to 50 ° C and a pH of about 5 to 8 with an acylating agent of the formula

R-

CH

CO-O-SO ₃ B

COOR.

in the

B denotes a lithium, sodium or potassium atom, R _{1 is} a thienyl, puryl, pyridyl, phenyl or substituted phenyl group, the substituent of which is a lower alkyl group, a chlorine or bromine atom, a lower alkoxy group, a lower dialkylamino group or a trifluoromethyl group

represents, and Rp is a group of the formula

or

in which X is a chlorine, bromine or fluorine atom, a lower alkyl group or a lower alkoxy group,

1 (J Ü ίί ? ^L > /?? 1 7

X _{2 represents} a lower alkyl group or a chlorine atom, X, a hydrogen atom or a methyl, phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carboxy-lower alkyl or carbo-lower alkoxy-lower alkyl group, Xk means a nitro group, a di -lower alkyl-amino group or a monosubstituted phenyl group, the substituent of which is a phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carbo-lower alkoxy-lower alkyl or carboxy-lower alkyl group; or an isopropylpheny group; or an indanyl or substituted indanyl group whose substituent is a methyl group or a chlorine or bromine atom, or a tetrahydronaphthyl or substituted tetrahydronaphthyl group whose substituent is a methyl group or a chlorine or bromine atom, or

a l-lower alkoxy-2,2,2-trichloroethyl group, a l-lower alkoxy-2,2,2-trifluoroethyl group, a carbo-lower alkoxy-lower alkoxymethyl group, a dicarbo-lower alkoxy-lower alkoxymethyl group, a 3- £ L- (R, - -substituted) -Piperidylgruppe_7 or the group - (CH ₂ J _1n -NR ₅ R ₆ ,
-CH ₂ -CH (CH ₃ ) -NR ₅ R ₆ ,

-CH (CH 'J-CH ₂ NR ₅ R ₆ or - (lower alkyleneJ-Y ^ where m is the integer 2 or 3,

R ₁ - denotes a hydrogen atom, a lower alkyl group or the benzyl group, R ₆ denotes a lower alkyl group, a lower alkanoyl group, the benzyl or phenyl group or a carbo-lower alkoxy group, with the proviso that if R _{5 is} a hydrogen atom, R ₆ denotes a lower one Represents alkanoyl group or a carbo-lower alkoxy group and

Y _{1 is} an azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N- (lower alkyl) piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethylpyrrolidino, 1 , 4,5,6-tetrahydropyrimidino, 4-methylpiperidino or 2,6-dimethylpiperidino group;

1 0 ^f J " / 5 /?? 1 7

each lower alkoxyl, lower alkanoyl or lower alkyl group having 1 to 4 carbon atoms and each lower alkylene group Contains 1 to 3 carbon atoms; or the group

(CH ₂ ) _n

or a substituted derivative derived therefrom, where η denotes the integer 3 or 4 and the substituent Xf is a methyl group, a chlorine or a bromine atom; or a -T'-phenylallyl or phenylallyl substituted .Y phenylallyl group of the formula

CH = CH-CH ₂ -

where the substituent Xg is at least one chlorine, bromine or Represents fluorine atom and / or at least one lower alkoxy, lower alkyl, nitro and / or methylenedioxy group; or a tf ^ -phenylpropargyl- or in the phenyl radical -substituierte λ ^ -phenylpropargyl group of the formula

C-CH ₂

- cc «.

where the substituent X _{7 is} a chlorine or bromine atom, a lower alkoxy, lower alkyl or nitro group.

The degree of purity of the 6-aminopenicillanic acid is not decisive for the success of the process. The 6-aminopenicillanic acid can be used in pure or partially pure form or as a crude product, such as is contained in fermentation solutions will. If water is used as the solvent, fermentation solutions containing 6-aminopenicillanic acid are economical Point of view preferred.

The term "inert solvent" means that under the process conditions it does not undergo any noticeable reaction with either the reactants or the products. Aqueous and non-aqueous solvents can be used. The use of water as a solvent naturally leads to some hydrolysis of the acyl sulfate used as a reactant. However, under the appropriate conditions of temperature, pH and time, the hydrolysis takes place at a relatively slow rate compared to the desired N-acylation. According to the invention, suitable solvents include dimethylformamide, dimethylsulfoxide, dioxane, water, acetone, tetrahydrofuran and hexamethylphosphoric λ

phoramid. It is also possible to use aqueous solvent systems, including those in which an emulsion is formed, for example one composed of water and a water-immiscible solvent. Solvents that quickly form emulsions with water are, for example, water-immiscible solvents such as benzene, n-butanol, methylene chloride, chloroform, methyl isobutyl ketone and lower alkyl acetates (e.g. ethyl acetate). Preferred water-immiscible solvents are methyl isobutyl ketone and ethyl acetate ^.

The method according to the invention is surprising to this extent exceptional in that there is no ester interchange between the

1 7

2053451

^ -Carboxyester grouping and that in the state of tension brings about the four-membered lactam ring, with a less strained ring system of the formula

MO — CvCH ' ^λ0Η 3

would arise in the R ,, Rp and M in the already specified Meaning exist.

The reaction takes place in the pH range from about 5 to about 8, preferably from 6 to 7. The pH is kept at approximately neutral by adding a suitable acid acceptor such as alkali or alkaline earth metal hydroxides. However, it is also possible, and this is the preferred way, to maintain the pH by using a salt of 6-aminopenicillanic acid with an organic base. Any organic base that forms a salt with 6-aminopenicillanic acid can be used for this, ^{e.g. tri-lower alkylamine, dibenzylamine, N, N 1} -dibenzylethylenediamine, M- (lower alkyl piperidines, N- (N-lower alkyl morpholines, N- Benzyl-ß-phenethylamine, N, N'-bis-dehydroabietylamine, dehydroabietylamine and 1-ephenamine. However, a tri-lower alkylamine, preferably triethylamine, is expediently used as the organic base. Such bases have the advantage that they merge with 6-aminopenicillanic acid Form salt which is soluble in many of the aforementioned solvents.

1 0 ^C J V »'? f> /? ? 1 7

They are particularly useful when working with a non-aqueous solvent system such as methylene chloride.

The reaction can take place over a wide temperature range take place. Temperatures are between about 0 and about 50 C. applicable, but it is preferred to operate at about 0 to about 30 ° C. in order to prevent degradation of the products.

The acyl sulfates are preferred as acylating agents in the form of the aryl malonic acid esters because they are relatively easy to prepare.

The arylmalonic acid monoesters are best obtained by reacting the corresponding aryl chlorocarbonyl ketene

COCl

R ₁ -C = C = O

with a suitable alcohol RpOH, where R 1 and R _{2 have the} aforementioned meanings. The reaction erfolt using a molar ratio of 1: 1 and a temperature of about -70 to 30 ⁰ C and, to achieve useful to better mixing and reaction control in a presence of an inert solvent. Suitable solvents are diethyl ether, dimethyl ether, dioxane, methylene chloride and chloroform.

The reaction mixture is then treated with water and a base, for example sodium carbonate, is added. If the reaction mixture has a temperature below the freezing point of water, the mixture is heated ^{to at least 0 ° C. either before or after the addition of water and base.} The base is added in a sufficient amount, that is to say generally using two to three equivalents thereof, in order to neutralize the hydrogen chloride obtained as a by-product and to form the salt of the arylmalonic acid monoester.

1 0 L "; ? ^r W? ? 1 7

The mixture is stirred for about half an hour and then the organic solvent is evaporated under reduced pressure less than 35 ° C. The remaining solution is extracted with ether, cooled to 10 to 15 ° C and adjusted to about pH 2. The acidic solution is extracted with a suitable solvent such as methylene chloride, and the extract is dried and then the solvent is removed under reduced pressure.

The arylmalonic acid monoesters formed in this way are converted into the required acyl sulfate acylating agent, that the sodium, potassium or lithium salt of the aforementioned arylmalonic acid monoester with a 1: 1 complex compound from sulfur trioxide and dimethylformamide as follows:

/ ^C0 2 ^B CO-O-SO, B

R-CH SO. (CH) _? NCHO / ^

CO ₂ R ₂

In practice, the acyl sulfate is not isolated as such, but is formed in situ by adding the sulfur trioxide / dimethylformamide complex to a solution or suspension of the sodium, potassium or lithium salt of the corresponding arylmalonic acid monoester. The reaction takes place in the presence of a preferably inert solvent system, for example dimethylformamide, dimethyl sulfoxide and hexamethylphosphoramide, at a temperature of about 0 to 50 ^° C. The reaction time is five minutes to one hour.

The molar ratio of the reactants, ie the 1: 1 dimethylformamide / sulfur trioxide complex and the arylmaloic acid monoester salt mentioned, can be 1: 1 up to H :.

10:

For the production of the required salt of the arylmalonic acid monoester a solution of 6-aminopenicillanic acid in an inert solvent such as methanol with an equivalent Amount of the required metal hydroxide, i.e. sodium, potassium or lithium hydroxide, added and then the solvent evaporated under reduced pressure.

The 1: 1 dimethylformamide / sulfur trioxide complex can be used, for example, by the method of Garbrecht, J. Org . Chem., £ 4, 368 (1959). I.

The required Arylchlorcarbonylketene is obtained by reaction of arylmalonic acid with a halogenating agent in the form of PCl ₁ -, PCI, POCl, or SOCIp at a temperature of about 0 to about 50 ⁰ C; the reaction time is about 1 to about 10 hours. The reaction takes place in the presence of a preferably inert solvent system. Dialkyl ethers such as diethyl ether, dipropyl ether, mono- and dimethyl ethers of ethylene glycol and propylene glycol, methylene chloride, chloroform, toluene and xylene are suitable for this purpose.

The duration of the reaction depends, of course, on the temperature and the nature of the reactants. Given the combination " of reactants, however, the lower temperatures require longer reaction times than the higher ones.

The molar ratio of the reactants, i.e. the arylmalonic acid and the halogenating agent, can be further Limits, e.g. up to 1:10 or higher, should at least fluctuate in order to achieve satisfactory yields be stoichiometric. In practice, a stoichiometric ratio of reactants is preferred.

The reactants can be added all at once or separately. In the latter case, the order of addition is not critical.

100825/2 2 17

Yet it seems that the reaction is smoother and with fewer side reactions - like the color of the reaction mixture especially after distillation - proceeds when the arylmalonic acid is added to the halogenating agent. Under Under these conditions, the reaction mixture changes color from yellow to red. If the addition is done in reverse Manner, i.e. if the halogenating agent of the arylmalonic acid is added, the reaction mixture turns yellow too black.

The arylhalocarbonyl ketenes are isolated by distillation in vacuo. Since they are very reactive, they are generally stored under a nitrogen atmosphere at low temperatures and with the exclusion of light.

The ^ -Carboxyarylmethylpenicillinester are known according to traditional method isolated. According to one of these methods, when water is used as the solvent, the pH the reaction mixture adjusted to about 2 to 3 and the product extracted with ethyl acetate. The ethyl acetate extract is washed with water and the product is extracted therefrom with 10 # aqueous potassium carbonate and then in ethyl acetate back extracted. The ethyl acetate extracts are extracted again with water and the pH of the aqueous extract is adjusted to 2 to 3 and the latter extracted again with ethyl acetate. The product is made by removing the volatiles won. But you can also isolate the product as an alkali metal or amine salt by adding the dry ethyl acetate extract mixed with the corresponding inorganic or organic base.

When using an aqueous emulsion as the solvent, the product is advantageously isolated in such a way that one this extracted after adjusting the pH to 2 with a suitable, water-immiscible solvent. Ethyl acetate is particularly suitable for this. The extract is then dried and evaporated to dryness.

1 0 9 fJ ') ^l - /? ? 1 7

To convert the product into an amine or alkali metal salt, a solution of the ester in a suitable Solvent such as ethyl acetate with the appropriate base, e.g. with N-ethylpiperidine or potassium octoate (potassium ethylhexanoate) offset.

Another way of working that is applicable when the If acylation is carried out in a non-aqueous solvent, e.g. in methylene chloride, the reaction mixture is with Water is added and the pH of the aqueous phase is then adjusted to about 2 to 3. The aqueous phase is separated off, extracts them with the non-aqueous solvent and dries the combined non-aqueous solvent layers. The products are by adding a suitable organic base such as N-ethylpiperidine or by adding sodium or Potassium octoate precipitated in the form of their corresponding salts from the non-aqueous solvent. But one can also use the θρ-nonaqueous Distill the solvent off after drying at a lower temperature, the residue in one absorb suitable solvent and precipitate the product from it by adding a suitable base. This alternative method offers more leeway with regard to the selection of the base. The solubility of the desired salt is crucial for choosing the right solvent.

The ester is converted into the corresponding acids according to known processes, e.g. by mildly acidic or mildly alkaline hydrolysis or enzymatically with HÜLfe an esterase such as liver homogenate.

Preferred according to the invention are those esters in which R _{2 is} an indanyl, 2-isopropylphenyl, dimethylphenyl or chlorotoluyl group. These esters, as well as the other esters falling within the scope of the invention, are antibiotics that are effective both in vivo and in vitro. For example, they are remarkably effective in treatment

2053451

numerous infections caused by responding gram-positive and gram-negative bacteria in animals and humans. For The pure substances or mixtures thereof with other antibiotics can be used for this purpose. You can as such or in conjunction with a pharmaceutical carrier, which according to the particular mode of administration and the selected according to standard pharmaceutical practice. For example, they can be taken orally in the form of tablets Excipients such as starch, lactose, certain types of clay, etc., or as capsules either alone or in a mixture with the be administered with the same or with equivalent excipients. Orally they can also be in the form of elixirs or corresponding Suspensions, which can be provided with flavoring or coloring agents, are administered. You let yourself also inject parenterally, e.g. intramuscularly or subcutaneously. For parenteral administration, one is best used sterile aqueous solution, which can either be aqueous (e.g. water, isotonic saline solution, isotonic dextrose solution or Ringer's solution) or is non-aqueous such as fatty oils of vegetable origin (cottonseed oil, peanut oil, corn oil, Sesame oil or other non-aqueous carriers that do not affect the therapeutic effect of the preparation are used and are non-toxic in the amount or ratio used (glycerine, propylene glycol, sorbitol). In addition, compositions for the ex tempore preparation of solutions prior to administration can also expediently be used getting produced. Such compositions can include liquid diluents such as propylene glycol, diethyl carbonate, glycerin, Sorbitol, etc., then buffering agents as well as local anesthetics and inorganic ones Contain salts to ensure desired pharmacological properties.

The oral and parenteral dosage for the present compounds is generally up to about 200 mg / kg or 100 mg / kg body weight per day.

1 U ^f J 8? K /? ? 1 7

Compared to the corresponding forms of the free acids or of the alkali metal salts, many of those according to the invention show Penicillin esters improved absorption when administered orally. They thus provide convenient, effective dosage forms. the ^ -Carboxyarylmethylpenicillins.

In addition, although inactive as such or of relatively low activity against gram-negative organisms, many of the esters described here are metabolized after parenteral injection in animals and humans with the formation of mother acid, namely ^ -carboxybenzylpenicillin. i

The following examples serve to illustrate the invention.

example 1

N-ethylpiperidine salt of &, - Z £ arbo- (5-indanyloxyl7-benzylpenicillin.

Working method A

A solution of 29.63 g (100 millimoles) of 2-phenyl-2- (5-indanyloxycarbonyl) acetic acid in 500 ml of methylene chloride p.a. was ™ with a solution of 1.20 g (100 millimoles) of lithium hydroxide monohydrate in 250 ml of methanol p.a. added. The resulting solution was concentrated under reduced pressure at 35 to 40 ° C. The lithium salt was obtained in the form of an oil which crystallized out after the addition of 30.2 g of pentane.

30.2 g (0.1 mol) of this lithium-2-phenyl-2- (5-indanyloxycarbonyl) acetates in 20 ml of dimethylformamide was cooled to 0 ⁰ C and maintained under nitrogen while 200 ml of dimethylformamide with a content of 12 , 2 g (0.08 mol) of a dimethylformamide / sulfur trioxide complex were added dropwise.

1 0 9 a '/ ^f >f> ? 1 7

After the addition was complete, a suspension of 21.6 g (0.1 mol) of 6-aminopenicillanic acid in 200 ml of methylene chloride with a triethylamine content of 10 g (0.1 mol) was added dropwise, the temperature of the mixture being kept at 0 g became. The temperature of the reaction mixture was allowed to rise to room temperature and, after 30 minutes, it was treated with 200 ml of water and 200 ml of saturated sodium chloride solution. The pH of the aqueous phase was adjusted to 2 with 6N hydrochloric acid solution, and the methylene chloride layer was separated and washed with water. 300 ml of water were added to the organic phase and the pH of the mixture was adjusted to 8.2 by adding saturated sodium bicarbonate solution. The aqueous layer was separated, adjusted to pH 2 with 6N hydrochloric acid solution and extracted with methyl isobutyl ketone (MIBK). The MIBK was separated off, dried over magnesium sulfate and treated with 11.3 g (0.1 mol) of N-ethylpiperidine. The MIBK-N-ethylpiperidine solution was stirred for 30 minutes at 0 C and the precipitate formed was filtered and dried. This gave 3 _S 8 g of a product having a melting point 138-140 ⁰ C (with decomposition).

Neutralization equivalent:

calculated: 607
found: 607.

Further purification was carried out by trituration with acetone; Melting point 142 - 144 ° C with decomposition.

The N-ethylpiperidine salt was converted into the potassium salt as follows over; e leads:

50 ml of benzene was placed in a 250 ml three-neck flask and heated to the boiling point.

1 OMi; ν ί. / 'f 1 7

3.04 β (5 millimoles) of the N-ethyl piperidine salt was added to the refluxing benzene, followed by cooling to room temperature. They gave Kaliuraoctoat (3.2 ml of a 26 # acetone solution) are added and the mixture was heated three minutes 45 ⁰ C. This was allowed to cool to room temperature and then cooled it to ⁰ C. The precipitated potassium salt of the desired product was filtered and dried.

The sodium salt is obtained in the same way by using sodium octoate instead of potassium octoate.

Example 2

N-ethylpiperidine salt from <£ - / Carbo- (5-indanyloxy ^ -benzylpenicillin.

Working method B

Following the general procedure of Example 1, 31 g of sodium 2-phenyl-2- (5-indanyloxycarbonyl) acetate _} 20.8 g of dimethylformamide / sulfur trioxide complex and 21.6 g of 6-aminopenicillanic acid were reacted with one another to form the desired product .

Example 3

N-ethylpiperidine salt of t £ .- /. Carbo- (5-indanyloxy ) 7 -benzylpenicillin.

Working method C

According to Example 1 and 2, using Potassium 2-phenyl-2- (5-indanyloxycarbonyl) acetate in turn the desired product.

1 0 '; - r / -> 9 1 7

Example 4

Following the procedure of Example 1, the following compounds are obtained from the corresponding arylmalonic acid half-esters in the form of their N-ethylpiperidine salts obtained:

CH-C-NH-CH-CH

0 —C — OR ₂ O = C N_

CH ₃ CH — COO-

^H ^ ⁺ ^ ^C 2 ^H 5

o-dimethylaminophenyl o-di-n-butylaminophenyl m-dimethylaminophenyl p-dimethylaminophenyl p-methylethylaminophenyl 2,3-diethylphenyl 2,6-diethylphenyl 2,6-di-n-propylphenyl 2,6-dimethyl-4-ethylphenyl 2,6 -Diäthyl-4-mtfethylphenyl 4, 5-dimethyl-2-isopropylphenyl, 2,6-dichlorophenyl ¹ ^ - Is opropy lphenyl 2-chloro-6-methoxyphenyl 2-ethoxy-3 ~ methylphenyl 6-chloro-2-methylphenyl, 2-chloro -5-methylphenyl 2-fluoro-4-methylphenyl 4-fluoro-3-methylphenyl 6-ethyl-2-methylphenyl 2-methyl-6-n-propylphenyl 4-isopropyl-3-methylphenyl 2-methyl-4-sec.- butylphenyl 3-Methy1-4-t-butylphenyl 2,3,4-trimethylphenyl 2,4,6-trimethylphenyl 3,4,5-trimethylphenyl 2-methoxy-4-methylphenyl 3-methyl-4-indanyl 2-methyl-5 -indanyl 6-t-butyl-5-indanyl 1, l-dimethyl-4-indanyl ljl ^ -trimethyl-il-indanyl 1,1,5,6-tetramliethyl-4-indanyl, 7-dimethyl-4-indanyl 5 ~ chloro-4-indanyl 7-bromo-4-indanyl 6-chloro-5-indanyl

2-bromo-6-methylphenyl, 2-bromo-4-t-butylphenyl 2-chloro-5-fluoropheny1 4-chloro-2-isopropylphenyl 5-chloro-2,4-dimethylphenyl 2-isopropyl-4-methylphenyl 2-chloro-3,4-dimethylphenyl 2-chloro-4-isopropylphenyl 2-ethyl-4-fluorophenyl 6-bromo-3,4-dimethylphenyl 4-chloro-2,5-dimethylpheny1 4-chloro-6-isopropy1-3-methylphenyl

2-chloro-4,5-dimethylphenyl 4,6-dichloro-2-methylphenyl 5-methyl-4-indanyl 3-chloro-2-fluorophenyl 2-bromo-4-fluorophenyl 2- (1-methyl-5,6,7,8-tetrahydronaphthyl)

2- (3-methyl-5,6,7,8-tetrahydronaphthyl)

2- (5-methyl-5,6,7,8-tetrahydronaphthy1)

1- (4,4-dimethyl 1-5,6,7,8-tetra hydronaphthy1)

2- (1,6-dimethyl-5,6,7,8-tetra hydronaphthyI)

l-methyl-4-indanyl 6-methyl-4-indanyl 7-methyl-4-indanyl 1- (2,4,7-trimethyl-5,6,7,8-tetrahydronaphthyl)

1 0 9 'i ? ^£ » 1,1,7-trimethyl-4-indanyl 1-indanyl

2-indanyl

6-methyl-5-indanyl 3-ethyl-1-indanyl 7-methyl-1-indanyl 2,3 ~ Dimethyl-1-indanyl 3,3-Dimethyl-1-indany1 4-chloro-1-indanyl 2-bromo-1-indanyl 3-bromo-1-indanyl 1-chloro-2-indanyl 1- (5,6,7,8-tetrahydronaphthyl)

2- (5,6,7,8-tetrahydronaphthyl

1- (3-methyl-5,6,7,8-tetrahydronaphthyl 1- (1,3-dimethyl-1,2,3,4-tetrahydronaphthyl l- (5,8-dimethyl-1,2,3,4-tetrahydronaphthyl) l- (4,5,7-trimethyl-1,2,3,4-tetrahydronaphthy1) 1- (1,5,8-trimethyl-1,2,3,4-tetrahydronaphthyl) 2- (l-methyl-1,2,3,4-tetrahydronaphthy1) 2- (2,6-dimethyl-1,2,3,4-tetrahydronaphthyl) 2- (4,4-dimethyl-1,2,3,4-tetrahydronaphthyl) l- (3-chloro-1,2,3,4-tetrahydronaphthy1)

2Q59451

1- (3,4,6-trimethyl-5,6,7,8-tetrahydronaphthyl) 2- (1,5,6-trimethy1-5,6,7,8-tetrahydronaphthyl) 2- (3, ¹ *, 7-trimethyl-5,6,7,8-tetrahydronaphthy1) 1- (1,2,4-triethy1-5,6,7,8-tetrahydronaphthy1) 2 ~ (5,5,8,8-tetramethyl-5, 6,7,8-tetrahydronaphthyl) 1- (2-methyl-1,2,3,4-tetrahydronaphthyl)

l- (7-methyl-1,2,3,4-tetrahydronaphthyl)

2- (2-imidazolino) ethyl 2-piperidinoethyl 2-pyrrolidinoethyl 2-pyrroloethyl 2-imidazoloethyl 2-morpholinoethyl 2-azetidinoethyl 2- (2,5-dimethylpyrrolidino) ethyl

2-aziridinoethyl 2-diisobutylaminoethyl 2-thiomorpholinoethyl

2- (4-methylpiperidino) ethyl pyrrolidinomethyl ^ ziridinomethyl (2-Imidazolino) methyl (1,4,5,6-tetrahydropyrimidino) methyl

2- (1-bromo-1,2,3,4-tetrahydronaphthy1)
l- (2-bromo-1,2,3,4-tetrahydronaphthyl)
3-dibutylaminopropyl 3- (2-imidazolino) propyl 3-piperidinopropyl 3-pyrrolidinopropyl 2- (3-bromo-1,2,3,4-tetrahydronaphthyl)
2-dimethylaminoethyl 2-diisopropylaminoethyl 2-di (n-propyl) aminoethyl 2- (N-isopropylanilino) ethyl

2- (N-n-butylanilino) ethyl 2- (methylbutylamino) propyl

3 ~ aziridino-2-propyl 3-thiomorpholino-2-propyl 2-piperidino-1-propyl 3-pyrrolopropy L azetidinomethyl 3-morpholinopropyl 3-thiomorpholinopropyl 2- (1,4,5,6-tetrahydropyrimidino ) ethyl 2- (N-methyl) piperazinoethyl

3-N-butylpiperazinopropyl 3-dimethylaminopropyl 3-di (n-propy1) aminopropyl

1 0 :!

'> 1

Pyrrolidinomethyl

Piperidinomethyl

Morpholinomethyl

Thiomorpholinomethyl 2-acetamidoethyl

2-butyramidoethyl

2- (methylethylamino) ethy1 2- (ethylisopropylamino) ethyl 2- (2,6-dimethylpiperidino) ethyl

2- (N-ethylanilino) ethyl

2-di- (η-butyl) amino-1-propyl 2-thiomorpholino-l-propyl 2- (imidazolino) -l-propyl 3- (1,4, 5,6-Tetrahydropyrimidino) · 2-propyl

3-thiomorpholino-2-propyl 3-imidazolidino-2-propyl 2-diisopropylamino-1-propyl 3- (methylpropylamino) propyl 3- {methylethylamino) -2-propyl 2- (methylethylamino) -1-propyl 3-imidazolo- 2-propyl 3-pyrrolo-2-propyl 3- (N-methyl) -piperazino-2-propyl 2-morpholino-1-propyl 3- (2-imidazolino) -2-propyl 3- (N.methylanilino) propyl 3- (N-methylanilino) -2-propyl 3- (N-butylanilino) -2-propyl-1-methoxy-2,2,2-trichloroethyl 2- (N-ethyl) -piperazino-1-pr ^ yI 2 -Di- (n-propyl) -amino-1-propyl 3-aziridinopropyl 3-di- (n-propyl) -amino-2-propyl 2-diethylamino-1-propyl 3-pyrrolidino-2-propyl 3-diethylamino- 2-propyl 3-morpholino-2-propyl 3-di- (n-butyl) amino-2-propyl 2.-pyrrolidino-1-propyl 4-dimethylamino-2-methylphenyl 2-methyl-6-nitrophenyl 3-biphenyl ^ -Biphenyl 2-chloro-3-biphenyl 2-bromo - ^ - biphenyl 2-dimethylamino-5-biphenyl 4-carbomethoxymethylphenyl ^ -Carbo-n-butoxymethylphenyl 4- (2-carboxyethyl) -phenyl ⁱ l- (2-carbomethoxyöthyl) -phenyl H- (2-Carbrfäthoxyäthy1) -phenyl 2-chloro-3- (2-carboxyethyl) -phenyl 2, k-Oimethyl- 6- ( carboxymethyl) phenyl

10 '..' ./9917

3- (NI sopropy land, lino) -propyl-1-butoxy-2,2,2-trichloroethyl-1-ethoxy-2,2,2-trifluoroethyl-dicarbethoxyethoxymethyl-1-isopropoxy-2,2,2-trichloroethyl-1-isobutoxy-2 , 2,2-trichloroethyl dicarbomethoxyethoxymethyl 2-chloro-3- (2-carboxyvinyl) -phenyl 2- (2-carboxyvinyl) -6-nitro-4-biphenyl 3-methyl-4- (2-carboxyethyl) -phenyl 2, 4-dimethyl-6- (carboxymethyl) -phenyl 4-t-butyl-2-biphenyl 3-methoxy-2-biphenyl 2-t-butyl- ⁱ J-biphenyl 2-isopropyl - ^ - methoxyphenyl 2-t-butyl- 4-ethoxyphenyl 5-dimethylamino-2-isopropyl-phenyl l-propoxy-2,2,2-trichloroethyl l-methoxy-2,2 _J 2-trifluoroethyl Carbäthoxyäthoxymethyl 1-sec-butoxy-2,2,2-trichloroethyl lt-butoxy -2,2,2-trichloroethyl 2-nitrophenyl ^ -nitrophenyl 4- (2-carboxyvinyl) -phenyl 2-methoxy-4- (2-carbomethoxyvinyl) -phenyl 2,5-dimethyl-4- (2-carboxyvinyl) - phenyl

2 ₃ 6-Dimethoxy-i} - (2-carboxyvinyl) phenyl 3-N, N-dibenzylaminopropyl 2-N-methyl-N-benzylaminoethyl

3-N, N-dibenzylamino-2-propyl

2-NjN-dibenzylamino-propyl

2-N- (n-butyl) -N-benzylaminoethyl

2-N- (n-butyl) -N-butyrylaminoethyl

2-N-carbomethoxyaminoethyl, 2-N-benzyl-N-carbomethoxyaminoethyl

3-N-Benzyl-N-carbo- (isopropoxy) aminopropyl 2-N-carbobutoxyaminoethyl 2-N-Benzyl-N-acetylaminoethyl

3-piperidyl

3- (1-ftthylpiperidyl) 3- (l-Iso ^ propylpiperidyl) 3- (1-n-Butylpiperidyl) Y - phenylallyl

1 V

2-methyl-5-nitrophenyl 3-methyl-4-nitrophenyl 2-N-ethyl-N-carbo- (isopropyl> xy) -aminoethyl

2-N, N-dibenzylaminoethyl Y- (3-nitrophenyl) allyl Y- (4-isopropoxy-3-methoxyphenyl) allyl

Y- (3-fluorophenyl) allyl Y- (2,6-diehlophenyl) -ally1 2-N-Methy1-N-acetylaminoethyl 2-N-Ethyl-N-formylaminoethyl 2-N-Ethy1-N-acetylaminoethyl. 2-N-Isopropyl-N-formylaminoethyl 2-N-Isopropyl-N-acetylaminoethyl 2-N- (n-Buty1) -N-acetylaminoethyl 3-N- (isopropyl) -N-formylaminopropyl

3-N- (isopropyl) -N-acetylaminopropyl

2-N-methyl-N-carbo- (isobutoxy) -aminoethyl

2-N-Ethy1-N-carbomethoxyaminoethyl

2-N- (n-Buty1) -N-carbomethoxyaminoethyl

3-N-pormylaminopropyl 3-N-acetylaminopropyl 3-N-carbo- (isobutoxy) -amino-, propyl

Y-phenylpropargyl

Y- (p-tolyl) propargyl Y- (3,4-dimethoxyphenyl) propargyl

Y- (4-chloropheny1) -allyI Y- (4-methoxyphenyl) allyl Y- (3,4-methylenedioxyphenyl) allyl Y- (2-nitrophenyl) allyl Y- (4-chlorophenyl) propargyl Y- (4-methoxyphenyl) propargyl Y- (4-nitrophenyl) propargyl 3- (N-ethylanilino) -2-propyl

2- (N-methylanilino) propyl

3- (N-ethylanilino) propyl

Y- (2,4,5-trichlorophenyl) -allyl Y- (3-bromophenyl) -allyl Y- (2-methylphenyl) allyl Y- (2-chloro-4-methylphenyl) -allyl Y- (4-isopropylphenyl) -allyl

Y- (2,4,6, -trimethylphenyl) -allyl Y- (2,5-dimethyl-4-methoxyphenyl) -allyl Y- (3-chloro-4-methoxyphenyl) -allyl Y- (3-methyl-6-nitrophenyl) -allyl Y- (2,6-dinitrophenyl) allyl

1 Ü! J Ii? * I '> ? 1

R.

Y- (2-ethoxy-5-nitrophenyl) -allyl Y- (4-n-butoxyphenyl) -allyl Y- (2,4-xylyl) propargyl Y- (m-tolyl) propargyl Y- (3-chlorophenyl) propargyl Y- (3-methoxyphenyl) propargyl Y- (3-nitrophenyl) propargyl

Example 5

Following the procedure of Example 2, the corresponding arylmalonic acid half-esters and 6-aminopenicillane are obtained acid the following penicillins:

R-CH-CO-NHR ₁

¹ I.

COOR,

where Rp denotes all of the radicals listed below, R ₁ denotes ex; ,, —Tlilenyl, 3-thienyl, 2-pyridzyl, 2-puryl and o-tolygroups and R ₁ . the penicillan acid residue is,

1-methoxy-2,2,2-trichloroethyl 1-butoxy-2,2,2-trichloroethyl 1-methoxy-2,2,2-trifluoro-ethyl 1-ethoxy-2,2,2-trifluoroethyl 2-isopropyl / pylphenyl 2,3-dimethylphenyl 2,6-dimethylphenyl 2,4-di-n-propylphenyl 2 _J ⁱ ID.imethyl-3-ethylphenyl 2,6-dichlorophenyl 3-isopropylphenyl 2-dibutylaminoethyl 2- (2-imidazolino) - ethyl 2-piperidinoethyl 3-morpholinopropyl 3-thiomorpholinopropyl 2-pyrrolidinoethyl 2- (2-iraidazolino) ethyl 2-pyrroloethyl Ί -dirne thy! amino-2-methy! phenyl

5-ethyl-3-methylphenyl 3-methyl-4-t-butylphenyl 2, k, 6-trimethylphenyl 2-methoxy-6-propylphenyl 6-chloro-2-methylphenyl 2-chloro-5-methylphenyl JJ-chloro-2, 3-dimethylphenyl 4-chloro-6-isopropyl-3-methylphenyl

2-isobutyryl ⁱ i, 6-dimethylphenyl

2-chloro-6-propylphenyl o-dimethylaminophenyl o-di-n-butylaminophenyl m-di-n-propylaminophenyl p-methylisopropylaminophenyl 2- (N-methylanilino) -ethyl 3-diethylaminopropyl 2- (N-methyl) -piperazinoethyl 3- (N-Butyl) -piperazinopropyl 2- (1, * J j 5 3 6-Te tr ahydropyrimidino) -ethyl
3-Pyrrolopropyl 3-Imidazolopropyl 3-di (n-propyl 3 aifiino) -2-propyl 2 -]) iäthylamino- 1 -propyl 2-Diäthylam: INC: i hyl - (Methyläthy1 r ■ ino) -äthy1?. '- (Ethylbutyl ίγ rio) -thyl ^: ~ (methyl isopr'i; vlami no) -ethyl

- ('' "ijtlv / 1 propy I -:; ino) -propyl

- (Ath, v 1 i "'ipropv ι amino) -propyl

2-methoxy - ^ - methylphenyl 2-chloro-6-methoxyphenyl 2-ethoxy-3-methylphenyl 2-arizidinoethyl 2-thiomorpholinoethyl 2- (lj-niethylpiperidino) ethyl

3- (2,6-Dimethy! Piperidino) ■ propy1

2- (N-ethylanilino) -ethyl 3- (methylethylaraino) -2-propyl

3 ~ pyrrolo-2-propyl 3- (2-imidazolino) -2-propyl 3-imidazolo-2-propyl 2-dimethylamino-1-propyl 2-di (n-butyl) -amino-l-

2-pyrroio-1-propyl 2- (2-imidazolino) -1-propyl Piperidinomethyl (2-imidazolino) methyl N -ethylpiperazinoraethyl Pyrrolomethyl

3- (N-Isopropylanilino) -propyI

2- (N-methylanilino) propyl

3-methyl-2-nitrophenyl dicarbethoxyethoxymethyl Carbethoxyethoxymethyl ^ -Indanyl

1 ■ ·

5-indanyl

5-methyl-4-indanyl 1-methyl-4-indanyl 4,6-dimethyl-5-indanyl 1,1-dimethyl-4-indanyl 1,1,2-triethyl-4-indanyl l, l, 2,3-tetramethyl-4-indanyl

5-chloro-4-indanyl 3-pyrrolidino-2-propyl 3-piperidino-2-propyl 3-morpholino-2-propyl 3-di (n-butyl) amino-2-propyl

3-dimethylamino-2-propyl 3-diisopropylaminopropyl 3-piperidinopropyl 3-pyrrolidinopropyl 3- (1,4,5,6-tetrahydropyrimidino) propyl 3- (N-methylanilino) propy1 1-indanyl

2-indanyl

2-methyl-2-indanyl 1-ethyl-1-indanyl 1- (5,6,7,8-tetrahydronaphthyl)

2- (5,6,7,8-tetrahydronaphthyl)

5-methyl-1-indanyl 7-methyl-1-indanyl 2,3-diethyl-1-indanyl 2-chloro-1-indanyl 1- (2-methyl) -l, 2,3,4-tetrahydronaphthyl) l- (7-methyl-1,2,3,4-tetrahydronaphthyl) 1- (1,3-dimethyl-1,2,3,4-tetrahydronaphthyl) l- (5,8-dimethyl-1,2,3,4-tetrahydronaphthy1) 1- (1,2,7-trimethyl-1,2,3,4-tetrahydronaphthyl) 1- (1,5,8-trimethyl-1,2,3,4-tetrahydronaphthyl) 2- (l-methyl-1,2,3,4-tetrahydronaphthyl) 2- (2,6-dimethyl-1,2,3,4-tetrahydronaphthy1) 2- (l, l, 4,4-tetramethyl-l, 2, -3,4-tetrahydronaphthyl) l- (3-methyl-5,6,7,8-tetrahydronaphthy1) 2- (4-methyl-5,6,7,8-tetrahydronaphthyl) 2- (1,6-dimethyl-5,6,7,8-tetrahydronaphthyl ') 2- (1,5,6-trimethyl-5,6,7,8-tetrahydronaphthyl) 7-Bromo-4-indanyl 1,1,7-Trimethyl-4-indanyl 3-Methyl-1-indanyl 2- (2-carboxyvinyl) -6-nitro-4-biphenyl 2,4-dimethyl 1-6- (carboxymethyl) phenyl

1 0 5: '■ / ''^I'>? 1 7

3-bromo-1-indanyl 4-chloro-1-indanyl 2-biphenyl
2-chloro-3-biphenyl 2-bromo-4-biphenyl 2-dimethylamino-5-biphenyl 2-t-butyl-4-methoxyphenyl 4-carbethoxymethylphenyl 2-carbomethoxymethylphenyl 4- (carbo-n-butoxy) methylphenyl 4- ( 2-carboxyethyl phenyl 4- (2-carbomethoxyethyl) phenyl 4-carbomethoxymethylphenyl 2-chloro-3- (2-carboxyethyl) phenyl

2,4-dimethyl-6- (carboxymethyl) phenyl

4- (2-carboxyvinyl) phenyl 2-methoxy-4- (2-carboxyvinyl) phenyl

2-methoxy-4- (2-carboromethoxyvinyl) phenyl

2,6-dimethoxy-4- (2-carboxyvinyl J-alijci phenyl 2-chloro-3- (2-carboxyvinyl) phenyl

Y- (3-bromopheny1) -ally1 Y- (2-methylphenyl) allyl Y- (2-chloro-4-methylphenyl) allyl

Y- (4-isopropy-phenyl) -ally1 Y- (2, S-dimethyl- ^ - methoxyphenyD-allyl

Y- (3-methoxy-4-ethoxypheny1) allyl

3-methoxy-2-biphenyl, 2-isopropyl-4-methoxyphenyl

4-dimethylamino-3-isopropoxyphenyl

2-N-methyl-N-formylaminoethyl

2-N- (n-butyl) -N-acetylaminoethyl

3-N- (Isopropyl) -N-acetylaminopropyl

2- (3,4,7-trimethyl-5,6,7,8 · tetrahydronaphthyl) 2- (5,5,8,8-tetramethyl-5,6-7,8-tetrahydronaphthyl) Y-phenylallyl

Y- (4-chlorophenyl) -ally1 Y- (2-methoxyphenyl) -allyl y- (If-methoxyphenyl) -allyl Y- (3,4, -Methylenedioxyphenyl) allyl

Y- (3,4-dimethoxyphenyl) allyl

Y- (3-fluoropheny1) -ally1 Y- (2,6-dichloropheny1) allyl

2-methyl-4-biphenyl, 2-t-butyl-4,5-dimethoxyphenyl

5-dimethylamino-2-isopropylphenyl

2-N-methyl-N-acetdylaminoethyl

3-N- (isopropyl) -N-formylaminopropyl

1 0 '.! ii 2 B /? ? 1

Y- (3-chloro-4-methoxyphenyl) allyl Y- (3-methyl-6-nitrophenyl) -allyl Y- (2-nitro- ⁱ l-chlorophenyl) -allyl Y- (3-nitro-5-bromophenyl) -allyl Y- (2-ethoxy-5-nitrophenyl) -allyl Y- (4-n-butoxyphenyl) -allyl Y-phenylpropargyl Y- (p-tolyl) -propargyl Y- (3,4-dimethoxyphenyl) -propargyl Y - (4-Chloropheny1) -propargyl Y- (4-methoxypheny1) -propargyl 3-methyl-4- (2-carboxyethyl) -phenyl-4-t-butyl-2-biphenyl 2-N-methyl-N-carbo "(isobutoxy ) -aminoethyl 2-N- (n-butyl) -N-carbomethoxyaminoethyl 3-N-acetylaminopropyl 2-N, N-dibenzylaminoethy1 3-N-methyl-N-benzylaminopropyl

3- (1-butylpiperidyl) 1-methyl-5-indanyl 3-N-Pormylaminopropyl 3-N-Carbo- (isobutoxy) -aminopropyl

3-N-Isopropyl-N-carbo- (isobutoxy) aminopropyl 3-piperidyl

3- (l-benzylpiperidyl)

Example 6

The following penicillins are obtained by following the procedure of Example 3 from the corresponding arylmalonic acid half-ester and 6-aminopenicillanic acid. This applies to all of the following Rp residues:

R ₁ = 3-furyl, 3-pyridyl, 4-pyridyl, p-tolyl, o-methoxyphenyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-chlorophenyl, o-dimethylaminophenyl or p-dimethylaminophenyl.

For the sake of simplicity, only the Rp residues are listed:

2 ~ isopropylphenyl l-ethoxy-2,2,2-trichloro ethyl

l-methoxy-2,2,2-trifluoroethyl

1-butoxy-2,2,2-trifluoroethyl

Di c arätho xyäthoxymethyI Carbethoxyethoxymethyl l-isopropyl-2,2,2-trichloroethyl

Di carbomethoxyethoxymethy1 o-dimethylaminophenyl o-di-n-butylaminophenyl p-methylisopropylaminophenyl 2,3-dimethylphenyl 2, iJ-di-n-propylphenyl 6-ethyl-2-methyl-phenyl-2-methyl-4-sec.-butylphenyl 3-methyl-4-t-butylphenyl

4-Bromo-3-isopropyl-3-methylphenyl

2-chloro-3, ⁱ * -dimethylphenyl 1- (5,6,7,8-tetrahydronaphthyl)

2- (5,6,7,8-tetrahydronaphthyl)

l- (4-methyl-5,6,7,8-tetrahydronaphthyl)

1- (i |, 4-dimethyl 1-5,6,7,8-tetrahydronaphthyl) 2- (1,6-dimethyl-5,6,7,8-tetrahydronaphthyl) 2,3, iJ-trimethylpheny 1 2,6-dimethyl-4-ethylphenyl ^, 5-dimethyl ~ 2-isopropy1-phenyl

4-butyl-5-isopropyl-2-methylphenyl
2,6-dichlorophenyl ^i- 1-dimethylamino-2-methylphenyl

3-methyl-5-nitrophenyl 2-chloro-6-methoxyphenyl 3-methoxy-2-methylphenyl 2-methoxy-6-propylphenyl 5-fluorine-2-methoxyphenyl 2-chloro-4-isopropylphenyl

2-isobutyl-l ^{i-fluorophenyl} 6-bromo-3,4-dimethylphenyl

4-chloro-2,3-dimethylphenyl
1-indanyl

4-chloro-2-methylphenyl 2-bromo-6-methylphenyl 2-bromo-4-t-butylphenyl 6-methyl-4-indanyl 7-methyl-5-indanyl 6-t-butyl-5-indanyl or 6-dimethyl -5-indanyl 1,1-dimethy1-4-indany1 1,1,2-triethyl-if-indanyl 1,1,2,3-tetramethy1-4-indany 1
5,7-dimethyl-4-indanyl

2- (1,5,6-trimethyl-5,6,7,8-tetrahydronaphthyl) 2- (3, ⁱ », 6-trimethyl-5,6,7,8-tetrahydronaphthyl) 1- (1,2, 1-triethyl-5,6,7,8-tetrahydronaphthyl) 2- (5,5,8,8-tetramethyl-5,6-7,8-tetrahydronaphthyl) 1- (l-methyl-1,2,3, 4-tetrahydronaphthy1) ^{1- (2-chloro-1,2,3, i} »-tetrahydronaphthyl 4-isopropylphenyl 1- (1,2,3,4-tetrahydronaphthyl)

2- (1,2,3,4-tetrahydronaphthyl)

2-di- (n-propyl) aminoethyl, 2-di- (n-butyl) aminoethyl, 3-diisopropylaminopropyl 3-imidazolopropyl 3- (2-imidazolinopropyl) 3- (2,5-dimethy! Pyrrolidino) propyl

3-aziridinopropylin 3-pyrrolopropyl aziridinomethyl Pyrrolidinomethyl morpholinomethyl 2-chloro-1-indanyl 3-bromo-1-indanyl ^ -Indanyl

5-indanyl

5-methyl - ^ - indanyl (1,1,5,6-tetrahydropyrirnidino) methyl - ^ I-indanyl 7-bromo- ⁱ i-indanyl 6-chloro-5-indanyl

2-indanyl

l-ethyl-1-indanyl 2-dimethylaminoethyl 3-dietyhylaminopropyl 2-piperidinoethyl 3-morpholinopropyl 3-thiomorpholinopropyl 2-pyrrolidinoethyl 2- (2-ImidazolinO) ethyl 2-pyrroloethyl 3- (N-methyl) piperazinopropyl

3- (Imidazolino) -2-propyl 3- (4-methylpiperidino) -2-propyl

2-aziridino-1-propyl 2-morpholino-1-propyl 2-thiomorpholino-1-propyl 2-iridazolo-1-propyl 2- (1,4,5,6-tetrahydropyrimidino) -1-propyl 2-dipropylamino-1-propyl 2-butyramidoethyl, 2-pyrrolo-1-propyl 2-piperidinoethyl 3-piperidinopropyl 2-pyrrolidinoethyl 2- (1, I, 5,6-tetrahydropyrimidino) ethyl 2-diethylaniino-1-propyl 3-pyrrolidino-2-propyl

10

1 7

Pyrrolomethyl

3-diisopropylamino-2-propyl 2-dimethylamino-1-propyl 3-aziridino-2-propyl 2- (N-ethylanilino) ethyl 3- (N-methylanilino) propyl 3- (N-Isopropylanilino) propyl 3- (N-methylanilino) -2-propyl 2- (N-methylanilino) -1-propyl 3- (N-ethylpiperazino) -2-propyl

4- (Carbo-n-butoxy) methylphenyl

4- (2-carboxyethyl) phenyl 4-carbomethoxymethylphenyl 4- (2-carboethoxyethyl) phenyl 2-chloro-3- (2-carboxyethyl) phenyl

4- (2-carboxyvinyl) phenyl 2-methoxy-4- (2-carboXjEmethoxy vinyl) phenyl

2,6-dimethoxy-4- (2-carboxyvinyl) phenyl

2-chloro-3- (2-carboxyvinyl) phenyl

3-methyl-4- (2-carboxyethyl) phenyl

2,4-dimethyl-6- (carboxymethyl) -phenyl

3-methoxy-2-biphenyl 3-piperidino-2-propyl 3-diethylamino-2-propyl 3-morpholino-2-propyl 2,4-dimethylphenyl 3,4-dimethylphenyl 3,5-dimethylphenyl 3-biphenyl

2-chloro-3-biphenyl, 2-bromo-4-biphenyl, 2-dimethylamino-5-biphenyl

2-N- (n-butyl) -N-acetyl arainoethyl

2-N-methyl-N-carbomethoxy aminoethyl

2-N-methyl * N-carbo (iso- butoxy) -arainoethyl 2-N- (n-butyl) -N-carbo methoxyarainoethyl 3-N-acetylaminopropyl 3- (1-isopropylpiperidyl) 3-di- (inn-butyl) amino-2- propyl

3-dimethylamino-2-propyl 2-azetidinoethyl 3-azetidino-2-propyl 6-chloro-2-methylphenyl 2-methoxy-4-methylphenyl 4-chloro-3,5-dimethylphenyl Y-phenylallyl

10 !;

2-methyl- ¹ »-biphenyl, 2-isopropyl-4-methoxyphenyl, 4-dimethylamino-3-isopropoxyphenyl

5 ~ Dimethylamino-2-isopropyl-2-N-Me thy 1-lJ-formylaminoethyl 2-N-methyl-N-acetäylaminoethyl 2-N- (η-butyl) -N-formylaminoethyl

Y- (2-methylphenyl) -allyl Y- (2-chloro-4-methylphenyl) -allyl

Y- (4-isopropylphenyl) -allyl Y- (3-chloro-4-methoxyphenyl) -allyl

Y- (2-nitro-4-chlorophenyl) allyl

Y- (i »-n-butoxyphenyl) allyl Y-phenylpropargyl

Y- (p-tolyl) propargyl Y- (4-chlorophenyl) propargyl Y- (4-methoxyphenyl) propargyl Y- (4-chlorophenyl) allyl Y- (2-methoxypheny1) -alIy1 Y- (3,4-methylenedioxyphenyl) allyl

Y- (3-i ^{| 1} luorpheny 1) -ally 1 Y- (2,4,5-triehlorpheny1) -allyl

Y- (3-bromophenyl) -allyl 3- (N-carbo- (isobutoxy) * - aminopropyl

3-N-Isopropyl-N-carbo- (isobutoxy) -aminopiipropy 1 2-N, N-dibenzylaminoethyl, 2-N-methyl-N- benzylaminoethyl

3-N-butyl-N-benzylamino propyl

2-N-Benzyl-N-acetylamino ethyl

3-piperidyl

3- (1-methylpip * eridy1)

Example 7

The products from Examples 2 to 4 are according to the procedure from Example 1 converted into the sodium and potassium salts.

Example 8

Proceeding as in Example 4, but replacing the N-ethylpiperidine with the appropriate amine, the following are obtained Salts of the compounds described:

N-methylpiperidine, triethylamine, tributylamine, N, N'-dibenzyl • ithy Lend i win, procaine and dibenzyiamine salts.

ίο.

Preparation A

Malonic acids

The following arylmalonic acids, not previously described in the specialist literature, are obtained according to the method of Wallingford et. al., J_. At the,. Chem . Soc ., 63 , 20 56-2059. According to this process, an alkyl carbonate, usually diethyl carbonate, is condensed in the presence of a (4- to 8-fold) excess of sodium ethylate with an equimolar amount of the desired ethylarylacetate, the alcohol obtained as a by-product continuously is removed from the reaction mixture. The esters obtained in this way are hydrolyzed in a known manner to form the acid.

- CH

COOH

^S COOH

o-methoxyphenyl m-methoxyphenyl p -hethoxyphenyl o-trifluoromethylphenyl m-trifluoromethylphenyl p-Trifluoromethylphenyl o-Isopropylphenyl 3-furyl

3-pyridyl

4-pyridyl

o-butoxyphenyl o-dimethylaminophenyl o-Diä thylaminophenyl m-dimethylaminophenyl p-dimethylaminophenyl

υ i .ο erf or'cvLiclie o-Trif 1 uorplionylessi / räure receives nn, o-Tri f] Uo · 'i:; oni ti-il after the V';i'fahi'en of Corse et β

1 0 Mi; I h ί V? 1 7

BATH ORIGINAL

J_. At the. Chem . Soc. , 70_, 2841 (1948) by

a) Conversion of the nitrile into o-trifluoromethylacetophenone by Grignard reaction with methyl magnesium iodide and subsequent hydrolysis;

b) Reaction of acetophenone with sulfur and morpholine at 13 5 C for 16 hours and subsequent treatment with glacial acetic acid and hydrochloric acid.

Preparation B

Phenyl chlorocarbonyl ketene

1) 20.g of phenylmalonic acid in 100 ml of ethyl ether were added with 46 g Phibsphorpentachlorid added. There was a violent reaction a. The reaction mixture was refluxed for four hours and then the ether was removed by heating in the Partial steam bath. After about half of the ether was removed, the reaction mixture turned black. Of the remaining ether was drawn off under reduced pressure (at 100 mm). The residue was distilled under vacuum and caught the fraction with a boiling range of 75 - 90 C / 1.5 - 4 mm on. The yellow liquid obtained as the product was redistilled at 74 ° C. and 1.5 mm. In the infrared part of the spectrum it peaked at 4.69.

When this procedure was repeated using 10 g of phenylmalonic acid instead of 20 g of the same occurred a less strong reaction after the addition of the phosphorus pentachloride. The same product was obtained.

2) A three-necked flask equipped with a condenser, dropping funnel, thermometer, stirrer and gas inlet was charged with 1 mol of phenylmalonic acid and 250 ml of toluene and the mixture was cooled to 0.degree. To the mixture, which was stirred well, 3 moles of thionyl chloride were added dropwise over 15 minutes and refluxed for 18.5 hours under a slowly flowing nitrogen stream. (During this time the reflux temperature increased gradually from 77 to 124 C). The excess thionyl chloride and most of the toluene were then removed under reduced pressure at a temperature below 35.degree. The residue was then distilled in vacuo and 170.5 g (yield 94.7 %) of product with boiling point 95 102 e at 175 mm were obtained. The product solidified after cooling to 0 ° C.

Preparation B

Following the procedure of preparation B 2), the corresponding malonic acid derivative was used instead of phenylmalonic acid the following connections established:

L ₁ - CC = O
O = A-Cl

2-thienyl
3-thienyl
2-FuryI
o-tolyl

3-puryl
2-pyridyl 3-pyridyl k -pyridyl

109Ö25 / ?? 17

m-tolyl o-bromophenyl

p-tolyl o-chlorophenyl

o-methoxyphenyl p-chlorophenyl

m-methoxyphenyl m-chlorophenyl

p-methoxyphenyl o-butoxyphenyl

o-trifluoromethylphenyl o-dimethylaminophenyl

p-Trifluoromethylphenyl o-diethylaminophenyl

m-trifluoromethylphenyl m-dimethylaminophenyl

o-isopropylphenyl p-dimethylaminophenyl

Preparation G

Esters of aryl carboxy-ketenes - General manufacturing process

A solution of the corresponding aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient for the formation of a clear solution, usually about 5 to 10 ml / g ketene) was treated with the corresponding alcohol RpOII (0.1 mol). The reaction mixture was kept under a nitrogen atmosphere and stirred for 20 minutes to three hours, careful attention to the exclusion of moisture. The temperature range was between about -70 and about -20 C.

The reaction mixture was treated with water (200 ml) and then with three equivalents of sodium bicarbonate. The mixture was brought to 0 ° C. and stirred for half an hour until a thick emulsion was formed. The methylene chloride ..mde removed under reduced pressure at a temperature below "3 ¹ > 0 and the remaining aqueous solution extracted with ether. The ether extract was washed with water (adjusted to pH 8 alkaline with sodium bicarbonate), over water

10 9 3? S / 7717 ^{BAD 0RIGINAU}

3?

dried free sodium sulfate and evaporated to give not converted alcohol.

The basic aqueous solution was cooled to 10 ° C. by means of diluted hydrochloric acid adjusted to pH 2 and then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate dried and evaporated to dryness, the malonic acid half ester stayed behind.

The esters are used without further purification for the preparation of the <t -carboxyarylpenicillin esters described here.

Preparation D

Aminoi s propanols

The following aminoisopropanols were obtained by reacting Propylene oxide with the corresponding amine. General became like that method that the propylene oxide with an aqueous solution of the amine using a molar ratio of 1.0 to 1.4 reacted in a sealed tube. The latter was shaken, set aside overlooked, then at 80 ° C for six hours and then heated to 95 ° C. for four hours. You cool them down Tube, took out the contents and salted the aminoisopropanol with potassium carbonate.

If the product is in liquid form, it is separated off, dried over solid potassium hydroxide and then

-J Q α. -; rv / ο? 1 7

distilled under reduced pressure. If the product is solid, it is filtered off and removed from a suitable solvent recrystallized.

Dimethylamine?

DiUthyIamiηο Di-n-propylamino diisopropylamino di-n-butylamino 1,4,5,6-tetralydropyrimidino n-Ethylpiperazino Piperidino Pyrrolidino Pyrrole ο

Morpholines?

Thiomorpholine Imidazolino Imidazolidine

Preparations

2-aminopropanols

The following 2-aminopropanols of the formula

HO-CIL ₁ -CH-NRJ-L <- ι 5

CH ₃ in the NR _r R. a Di-Niedera] kylainino- or a hote.rocyc-

■ '? 'Ί

Lische group is obtained according to the method of Moffett Org. Syn., Coil. Volume IV_, page 834, by lithium aluminum hydride reduction of the corresponding ester precursor of the formula

H ₅ C ₂ OOC-CH-NO

CH ₃

where the acid esters according to Moffett, Org. Syn., Coll. Volume IV , page 466, can be prepared by reacting the desired amine with ethyl X -bromopropionate. "

-NR ₅ R ₀

Di (n-propyl) amino

Di (n-butyl) amino

Diisopropyamino

1> 4,5,6-tetrahydropyrlmidino

N-methylpiperazino

II-n-butylpiperazino

Piperidino

Morpholino

Thiomorpholine ™

Pyrrolο

Imidazolino

Imidazolidines

ü Γ; ij? S /? ? 1

Claims (10)

Patent claims Process for the preparation of penicillins of the formula R- QU- C-NH-CH-CH COOR, C -N CII COOM in which M is a hydrogen, sodium or potassium atom or a Tri-lower alkyl ~ am.inruppe, characterized in that one in an inert solvent system at etv; a 0 to 50 ° C and a pH of about 5 to 8 a compound of the formula H ₂ N- qw ^c \ CIL O = C N- CH- CH- COOM with an acylating agent of the formula CO-O-SO ₃ B R ₁ -CH XOOR ₂ in which B is a lithium, sodium or potassium atom, R is a thienyl, puryl, pyridyl, phenyl or substituted one Phenyl group means whose substituent is a lower alkyl group, a chlorine or a bromine atom, a lower alkoxy group, a dialkyl loweramino group or a trifluoroethyl group 1 0 i3 ΙΪ? f »/? ? 1 7 represents, and R- is a group of the formula or in which X is a chlorine, bromine or fluorine atom, a lower alkyl group or is a lower alkoxy group, X is a lower alkyl group or a chlorine atom, X is a hydrogen atom or a methyl, phenyl, carboxyviriyl, Carbon-lower ^^ alkoxyvinyl, carboxy-lower alkyl or carbon-lower alkoxy-lower alkyl group means, X is a nitro group, a di-lower alkylamino group or an inono-substituted phenyl group, the substituent of which is a phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carbo-lower alkoxy-lower alkyl or carboxy-lower alkyl group; <C- or an isopropylphenyl group; od: t> a an indanyl or substituted indanyl group, the substituent of which is a methyl group or a chlorine or bromine atom; or a tetrahydronaphthyl or substituted tetrahydronaphthyl group, whose substituent is a methyl group or a chlorine or bromine atom; or a 1-lower alkoxy-2,2,2-trichloroethyl group; a 1-lower alkoxy-2,2,2-trifluoroethyl group; a (carbo-lower alkoxy) -nxederalkoxymethyl group; a (dicarbo-lower alkoxy) -lower alkoxymethyl group; a 3- / T- (Rr-substituted) piperidyl group7; or the group d. 1 Γ / ■? ι 7 -CH (CH ₃ ) -CH ₂ NR R ₆ or - ^ iiederalkylen) -Y ₁ , where m is the integer 2 or 3, R represents a hydrogen atom, a lower alkyl group or a benzyl group and R, a lower alkyl group, a lower alkanoyl group, denotes a benzyl group, a phenyl group or a carbo-lower alkoxy group with the proviso dai3 if R is a hydrogen atom, R ^ represents a lower alkanoyl group or a carbo-lower alkoxy group, and Y is an azetidino, aziridino, pyrrolidino, piperidino, Morpholino-, thiomorpholino-, N- (lower alkyl) -piperazino-, pyrrolo-, imidazolo-, 2-imidazolino-, 2,5-dimethylpyrrolidino-, 1,4,5,6-tetrahydropyrimidino-, 4-methylpiperidino or 2,6-dimethylpiperidino group means; wherein each lower alkoxy, lower alkanoyl or lower alkyl group has 1 to 4 carbon atoms and each lower alkylene group contains 1 to 3 carbon atoms; or the group
X, or a substituted derivative derived therefrom, wherein η denotes the integer 3 or 4 and the substituent X is a methyl group, a chlorine or a bromine atom; or a T-phenylallyl or substituted in the phenyl radical , ^ - phenylallyl group of the formula 10: / S / *? > 1 7 where the substituent X, - at least one chlorine, bromine or Represents fluorine atom and / or at least one lower alkoxy, lower alkyl, nitro and / or methylenedioxy group; or a .Γ-phenylpropargyl or phenyl-substituted ■ ^r -phenylpropargyl group of the formula C = C- where the substituent X _{7 is} a chlorine or bromine atom, a lower alkoxy, lower alkyl or nitro group. 2. The method according to claim 1, characterized in that there is an acylating agent of the formula co - 0SO ₃ Li Ä CH COOR ₂ used, wherein R. and R _{2 have} the meaning given in claim 1. 3. The method according to claim 2, characterized in that the reaction is carried out in a non-aqueous, inert solvent system in the presence of a lower tri-alkylamine. 1 0 9 3 2! *, /? ? 1 7 4. The method according to claim 3, characterized in that the solvent is dimethylformamide and the lower trialkylamine Triethylamine used. 5. The method according to claim 4, characterized in that an acylating agent of the formula III is used in which R _{1 is} a phenyl group and R _{2 is} a 2-isopropylphenyl group. 6. The method according to claim 4, characterized in that an acylating agent of the formula III is used in which R _{1 is} a phenyl group and R of the formula corresponds in which the two symbols X ₁ and X _{2 represent} a lower alkyl group and X _{3 is} a hydrogen atom, or X is a chlorine atom, X _{2 is} a lower alkyl group and X _{3 is} a hydrogen atom, or X _{1 is} a lower alkoxy group, X ₂ represents a lower alkyl group and X represents a hydrogen atom. 7. The method according to claim 4, characterized in that an acylating agent of the formula III is used in which R is a phenyl group and R is either of the formula corresponds to, in which η is the number 3 or 4 bodeut. or the biphenyl radical or of the formula 101. ? . ', / > ?. 1 7 ^r c ■ ■ ■■ ■ ■. ■■ ■■■ '· - ■ ■■,. . corresponds, in which R, a hydrogen atom and R. a carbon-lower alkoxy-lower alkyl group means. 8. The method according to claim 4, characterized in that the
7 holds. the temperature at 0 to 30 ° C and the pH at 6 to 9. The method according to claim 6, characterized in that an acylating agent of the formula III is used in which R "of the formula corresponds, in which X is a 2-methyl group and X "is a 4-methyl group or X. is a 4-chlorine atom and X "is a 2-methyl group means. 10. The method according to claim 6, characterized in that an acylating agent of the formula III is used in which R _{2 of} the formula corresponds, in which X. is a 2-methoxy group and X_ is a Is 4-methyl group. For: Pfizer Inc. New York, N.Y., V.St.A. (Dr H.J. Wolff) Lawyer 0 9 3 2 f> / / 2 1 7