DE1944379A1 - Carboxy-arylmethylpenicillin derivatives and processes for their preparation - Google Patents

Description

«C-carboxy-arylmethylpenicillin derivatives and Process for their manufacture

The present invention relates to antibiotics and their preparation, particularly arylmethylpenicillins having a carboxyl group. ο ^ in position and a process for the production of orally administrable Arylmethylper! linen with a "C-carboxy ester group.

Simple acylation of 6-Aminopenicilansäure by 1) acid chlorides and 2) or a mixed acid anhydride in the US Patents 3,270,009, 3,142,673 and described _f 3,173,916; and the derivative of a substituted malonic acid active by 3.) for the preparation of various esters of - ^ - carboxy-arylmethylpenicillins is described in British Patent 1,004,670. In addition, the production of such penicillins by acylation of 6-aminopenicillanic acid using aryl carboxy-acetene ester is described in the German patent application Aktζ. '1 900 195.1'.

009811/1625

It has now been found that the acylation of 6-Amin.openic ill anic acid with a reactive derivative of an aryl-substituted malonic acid runs easily and the Economical production of esters of -carboxy-aryl methylpenic illinen allowed, which can be administered orally Antibiotics are valuable.

The new compounds according to the invention are those of the general formula

CH-COOH

and their pharmaceutically acceptable salts in which R ^ is a thienyl, furyl, pyridyl, phenyl or substituted phenyl radical, the substituent being a lower: alkyl, lower alkoxy, di-lower-alkyl-amino or trifluoromethyl radical , or is a chlorine or bromine atom; _un a. Rp is one of the following:

substit.) -? iperidyl7 -

-CH ₂ -CH ₂ -CH ₂ -NB ₅ R ₆ -CH (CH ₃ J-CH ₂ - ^ JR ₅ E ₆

-CH ₂ -CH (CH ₃ ) -NR ₅ R ₆

where Ra is a water to ff atom, a lower AIk ^ or _y benzyl group, and Rg is a lower alkyl, lower alkanoyl, benzyl, phenyl or lower carbalkoxy group

009311/1625

represents, where Rg is a lower carboxy group, when R ₁ - is a hydrogen atom, t and R ^ and Rg are not at the same time an alkyl, / ^ - PhenylaTlyl-, / ^ - (substit. Phenyl) - allyl radical, in which the substituent at least one chlorine, bromine or fluorine atom, a lower alkoxy, lower alkyl, nitro or methyl endio xy group is a / ^ phenylpropargyl or y- (phenyl substit.) - propargyl radical, in which the substituent is a lower alkyl, lower alkoxy, or nitro group or a chloro or bromatoin; or one of the pension

or

in which X _{1 is} a chlorine, bromine or fluorine atom: a lower alkyl or lower alkoxy group, Xp is a chlorine atom or a lower alkyl group, X ^ is a phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower.Carboxyalk.vl- or lower carbalkoxy lower alkyl group, and X. is a nitro or di (lower alkyl) amino, or monosubstituted phenyl group in which the substituent is a phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower carbalkoxy lower alkyl - Or a lower carboxyalkyl group, or one of the radicals

or

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»944379

wherein X _{1 is} a chlorine, bromine or fluorine atom, a lower alkyl or lower alkay group, Xp is a lower alkyl group or a chlorine atom, X- is a phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower carboxyalkyl or lower carbalkoxy-lower alkyl group, and X »is a nitro or di (lower alkyl) amino or a monosubstituted aenyl group in which the substituent is an isyl, carboxyvinyl, lower carbalkoxy vinyl, lower carballoxy lower alkyl or is a lower carboxyalkyl radical.

The process according to the invention is characterized by the reaction of 6-aminopenicillanic acid or a suitable one Derivatives of the same in a reaction-inert solvent at .a temperature of about O - 50 ° C and a pH of about 5-8 with an aryl malona acid ester general formula

COX

R ₁ CH

COOR ₂

009811/1625

in which X is a chlorine or bromine atom »delr-OCOR *, in which R 1 is a benzyl or lower alkyl radical; RJ is a ihienyl, puryl, pyridyl, phenyl or substituted phenyl group in which the substituent is a lower alkyl, lower alkoxy, di-lower alkylamino or trifluoromethyl radical or a chlorine or bromine atom; and Rg is an isopropylphenyl radical or one of the radicals of the general formulas

or

. a chlorine, bromine or fluorine atom, a lower one

in the X alkyl or lower alkoxy group;

a lower alkyl

group or a chlorine atom; X-, a hydrogen atom, a Methyl, phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower carboxyalkyl or lower carbalkoxy lower alkyl group; and X. a nitro or di (lower alkyl) amino group are; also a monosubstituted phenyl group, where the substituent is a phenyl, carboxyvi ^ "! .-, lower CarbaJoxyvinyl-, lower Carbalkoxy-lowerriUcyX- or is a lower carboxyalkyl radical; a acyliertor indanyl radical or its substituted derivative, wherein the substituent is a methyl group or a chlorine or bromine atom; a tetrahydronaphthyl radical or its substituted derivatives, where the substituent is a methyl group or a chlorine or bromine atom; and Rp can also mean one of the following radicals:

009811/1625

i-low-alkoxy-2,2,2-trichloroethyl, -, 1-lower-alkoxy-2,2,2-trifluoroethyl, lower carbalkoxy-lower-alkoxymethyl-, di-lower-carbalkoxy-lower-alkoxymethyl-, 3- / _1- (R, - substit.) Piperidyl T -,

_2m56
-CH ₂ -CH (CH ₃ ) -NR ₅ R ₆ ,
-CH (CH ₃ ) -CH ₂ -NR ₅ R ₆ or lower-alkylCn-Y ₁

where m is an integer from 2 - 3 _t R _{5 is} a hydrogen atom, a lower alkyl or a benzyl group, and Rg is a ™ lower alkyl, lower alkanoyl, benzyl, phenyl or lower carbalkoxy group, and where R ^ - is a lower alkanoyl or lower carbalkoxy group when R ₁ - is an atom of what s he material; and Y .. one of the following remainders:

Azetido,
Aziridino,
Pyrrolidino,
Piperidino,
Morpholino,
Thiomorpholino,
Nn Mrig-Älkyl-piperazino-j,
Pyrrolo-,
W imidazolo,

2-imidazolino,

2,5-dimethylpyrrolidino,

1 * 4,5,6 -tetrahydropyrimidino,

4-methylpiperidino or

2,6-dimethylpiperidino- _f

wherein each of the lower alkoxy, alkanoyl and alkyl groups comprises 1 ~ 4 carbon atoms and the lower alkylene group has 1-3 carbon atoms; ■ also R ₂ the remainder

009811/1625

or a substituted derivative may be the same; v / q in Z. is an alkylene radical, namely a - (CH ₀ ) x or - (CH .-.), radical, and wherein the substituent is a methyl group or a chlorine or bromine atom ;

or a / * - I ^ fenylallyl-.y ^ -substit ^ -Pheiyl-allyl-, in which the substituent has at least one chlorine, bromine or fluorine atom, a lower alkoxy group , lower alkyl, nitro-oIe ^ methylenedioxy group, a ^^ - Phenylpro'pargyl-, ^ -substit.- Phsnyl-propargyl is where the Subctituent in Clil'U · - is niodera alkyl oi-r Hitrogruppe.? - or BrÖmatom, Oino lower alkoxy.

As a derivative of ö-aminopenicillanic can iusn boirpici ^ - Freise the sodium, potassium or tri-lower-slkyl-aminsal ζ use as Ausgangssub _# Stan2.

The degree of purity of the 6-aminopenicillanic acid is not critical for the success of the process. B19 6-aminopenicillanic acid can be used in pure, partially pure * οδ · 3Γ raw form, as it is in the fermentation broth The use of water as a solvent is preferred from an economic point of view of fermentation broths containing e-aminopenicillan acids.

A reaction-inert solvent is understood here to mean a solvent which under reaction conditions, especially with the reaction participants, still undergoes a noticeable reaction with the products. Aqueous and non- aqueous solvents can be used. The usage of

009811/1625

Of course, water as a solvent brings one with it some hydrolysis of the acid chloride. However, the hydrolysis proceeds under the appropriate temperature and time conditions as well as the pH below proportionately slow rate compared to the desired N-acylation reaction. Suitable solvents for the process according to the invention are e.g. methylene chloride, Benzene, chloroform, dioxane, water, acetone,

t
Tetrahydrofuran, diethyl ether and dimethyl ether. It can

also aqueous solvent systems, including the -P those in which an emulsion is formed, e.g. Water / non-water-miscible solvent is used will. Solvents that easily form emulsions with water are, for example, solvents that are immiscible with water such as benzene, n-butanol, methylene chloride, chloroform, methyl isobutyl ketone and lower alkyl acetates like ethyl acetate. The preferred ones immiscible with water Solvents are methyl isobutyl ketone and ethyl acetate.

The reaction will take place in a range of pH of about. 5 - about 8, preferably 6-7, performed. The pH value is about the IT neutral point by adding a suitable P acid acceptor such as an alkali metal or alkaline earth metal hydroxide maintained. But you can also, and this is preferred, the pH by using a Salt of 6-amine penicillic acid with an organic Maintain base. Any organic base that forms eijL RaIζ with dor C-aninopenicillanic acid can be used will. Suitable organic brooms are tri-low-alkylaaine, Dibenzylarr.in, IT, N'-Dibenzylathylenjdiamine, N-lower-alkyl-pireridino, N-lower alkyl-morpholine, N-benzyl- / -phenäthylamine, N, 11'-bis-dehydroabietylamine, Dehydroabietylan.in or 1-ephenamine.

009811/1625

However, it is advantageous to use a tri (lower alkyl) amine, preferably triethylamine, as the organic base. Such bases have the advantage of being a salt with 6-aminopenicillanic acid to form which is soluble in many of the aforementioned solvents. You are particular beneficial when using a non-aqueous solvent system used as methylene chloride.

The reaction can be carried out within a wide temperature range, for example in the range from about 0 to 50 C. In order to avoid decomposition of the products, however, temperatures of about 0 ° to about 30 ° C. are preferably used .

The preferred form of the aryl malonic acid esters as acylating agents is the respective acid monochloride due to its relatively easy production compared to the Anhydrides.

The Arylmäbnsäuremonoester are in a known manner Implementation of the corresponding Arylchlorocarbonylketene of the general formula

COCl

with the corresponding alcohols R ₀ OH, where R ₁ and Rp have the aforementioned meaning. The implementation is at a molar. Ratio of 1: 1 carried out at a temperature of about -70 ° to about + 30 ° C, advantageously in a reactive solvent, which allows better mixing and better regulation of the reaction.

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- 10 -

Suitable solvents are diethyl ether, dimethyl ether, Dioxane, methyl chloride and chloroform.

The reaction mixture is then mixed with water and an alkaline Reagent, e.g. I sodium bicarbonate treated. The reaction mixture if it is still at a temperature below the freezing point of water, to at least 0 C heated, namely ε-ntv / eder before or after the addition of the Water and the alkaline reagent. In order to neutralize the by-product hydrogen chloride and the aryl

To make a malonic acid mono esters becomes sufficiently alkaline Reagent, usually 2 to 3 equivalents added. That The mixture is stirred for about 1/2 hour and the organic solvent is reduced under pressure below 35 ° C deducted. The remaining solution is extracted with ether, cooled to 10 ° to 15 ° C and brought to a pH of set about 2. The acidic solution is extracted with a suitable solvent, e.g. methylene chloride, the extract is dried and the solvent is then drawn off under reduced pressure. The arylmalonic acid monoesters prepared in this way are converted into their acid monocchloride by treatment with transferred excess thionyl chloride, expedient-

"wisely in the presence of an inert solvent such as benzene, diethyl ether or methylene chloride at a temperature of about 0 ° to about 80 ° C, in a known manner.

The required Arylchlorearbonylketene are converted by reacting an arylmalonic acid with a halogenating agent such as PCl ₅ , PCl ₃ , POCl ₃ or SOCl ₂ at temperatures from about 0 to about 50 ° C. for one to about 10 hours. The reaction is carried out in the presence of a solvent system, preferably a reaction-inert solvent system. Suitable solvents are

009811/1625

BADORlSiNAL

Dialkyl ethers, such as diethyl ether, dipropyl ether, mono- and dimethyl ethers of ethylene glycol and propylene glycol, methylene chloride and chloroform.

The reaction time is of course dependent on the reaction temperature and the nature of the reactants. With a certain combination of respondents a lower temperature requires a longer reaction time than a higher temperature.

The molar ratios of the reactants, i. The arylmalonic acid can be used in a wide range of ways Ranges, e.g., 1:10 or higher; however, for sufficient yields they should be at least 3toichiometric be. In practice, a stoichiometric ratio of reactants is preferred.

The reactants can be added all at once or separately will. If they are added separately, the order in which they are added is not critical. However, it appears that. the Implementation runs smoother and fewer side actions is subject if the arylmalonic acid to the halogenating agent, what is the color of the reaction mixture, especially after distillation results. Under such conditions, the color of the reaction mixture will appear generally from yellow to red. However, the color progresses with the reverse addition, that is, with the addition of the halogenating agent to arylmalonic acid, from gold to black.

The arylhalocarbonyl ketenes are isolated by distillation in vacuo. Because of their high reactivity they are usually stored under a nitrogen atmosphere at low temperatures and with the exclusion of light.

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bath

The acid anhydri ^ derivato of the arylmalonic acid half-esters are such as by reacting the half-ester with a lower chloroalkyl carbonate in the presence of an acid acceptor Pyridine or a tri- (lower-alkyl) -amine prepared; (cf. J. / an. Chem. 3oc. Vol. 7 ^> Pp. 637-9 (1953) and J. Org. Chem. Vol. 2 £, p. 248 (1957)). Instead of the lower ones Chloralkyl carbonates can be other Chloreai ^ bonate, such as e.g. Use chlorobenzyl carbonate or chlorophenyl carbonate.

Diec ^ -Carboxyarylmethylpenicillinester are ίί-oliejt in a known manner. A typical method when using water is to adjust the pH of the reaction mixture to about 2-3 jin and extract the product with ethyl acetate; the ethyl acetate extract is washed with water, the product from this with 10 $ Oxygenated with aqueous sodium bicarbonate and then extracted again in ethyl acetate. The ethyl acetate extracts are extracted again with water, the aqueous extract is brought to a pH of 2 to 3 and then extracted 3 times with ethyl acetate. The product is obtained by removing the volatile components. The product can also be isolated as an alkali metal or amine felt by adding the appropriate inorganic or organic base to the dry ethyl acetate extract.

When wetting an aqueous. E.
Product .Two ck.T. äfii £: ^c r'.vei ^ o dur oh ^ xtrahierung des Heaktionr; -cr · .T.it eirxer. - · -: · _ οΙλτι ο tor. ir.it V / ater immiscible riiittel n / t'-r. It is adjusted to a pH of 2, with ethyl acetate being particularly useful. The extract is then getrockr .-; t- -; j :: 1 evaporated to dryness. The product Ύ / is transformed into a /jrir.- cd ».r .nlkaliraetallsalz. Addition of the corresponding η 5 a ?; ^. z. B. N-Ethylpiperiäjin or Kaliumäthylhexanoat z ~ x a solution of the ester product

00 9 811/16 2 5 BAD ORiQlNAL.

»944379

transferred in a suitable solvent such as ethyl acetate.

Another method of value when the acylation reaction is performed in a non-aqueous solvent, e.g. in methylene chloride, consists in the Adding water to the reaction mixture and then adjusting the pH of the aqueous phase to about 2-3 · The aqueous phase is separated, extracted with the non-aqueous solvent, and the combined non-aqueous solvent layers dried. The products are made from the non-aqueous solvent by adding a suitable organic base such as N-ethylpiperidine or sodium or potassium 2-ethylhexanoate, precipitated as their corresponding salts. The non-watery Solvent can also be distilled off after drying at a low temperature, the residue in added to a suitable solvent, and the product precipitated therefrom by adding a suitable base. With regard to the choice, this alternative method offers the bases have a greater width. The appropriate solvent will be determined by the solubility of the salt desired.

The esters are converted into the corresponding acids by known processes, for example a mild one Acid or alkali hydrolysis or enzymatically with an esterase such as liver homogenate.

The preferred esters are those in which R _{2 is} .ein. Is indanyl, 2-isopropylphenyl, dimethyl-substituted phenyl or chlorine-substituted tolyl radical. Such esters are, like the ester remaining in the scope of the present invention effective in vivo and in vitro antibiotics. They have, for example, a considerable effectiveness in the

009811/1625

Treatment ^of gram-positive and gram-negative infections in animals and humans. The pure substances or their mixtures with other antibiotics can be used for this purpose. They can be administered alone or in combination with a pharmaceutical carrier selected from the point of view of the chosen route of administration and standard pharmaceutical practice. They can also be administered orally in the form of elixirs or oral suspensions which contain flavorings and / or colorings, or they can be injected parenterally, ie for example intramuscularly or subcutaneously. For pg # nteral administration they can best be used in the form of a sterile solution, which can either be aqueous, such as water, an isotonic saline, isotonic dextrose or Ringer's solution, or which can be non-aqueous. In addition, compositions can advantageously be prepared which are suitable for the preparation of the solution immediately prior to administration.

The oral and parenteral dosages for the present compounds are typically on the order of up to 200 mg / kg and 100 mg / kg of body weight per day.

Many of the penicillin ester compounds of the present invention show improved absorption when administered orally versus those derived from the corresponding forms of the free acid or the alkali metal salts were manufactured. They therefore represent a common and effective dosage form of the C-carboxyarylmethylpenicillins represent.

QQS811 / 1825 6ADORfGFNAL

194A379

In addition, many are described above. Esters, although they are inherently inactive or relatively of low activity against gram-negative organisms are, through the metabolism to the underlying acid *, i.e. to the ** - Carbo xybenzylpenic ill in degraded, if they are injected parentcrial into the animal or human.

. Dnc antLmikrcbielle spectrum of different esters of Carboxybenzylpenicillin against Staphylococcus aureus \ "and ^ schorichia coli 2C6 is shown in Table I. The Verruche were performed under standardized conditions in which a nutrient broth untorschie · ^1. !! ^ - · :; Concentrations of the substance to be investigated, inoculated with the particular organism in question -tur-'lc ", and the minimal growth rate at which the growth of each organism no longer proceeded, observed and recorded. The substances examined have the following formulas; they were examined in the form of their sodium or potassium alale. The benzylpenicillin (potassium salt) investigated in this way gave values of 0.1 ^ 6 and> 100, respectively, for S. aureus and B. coli.

Table II contains the in vivo values for oral and subcutaneous Administration of numerous compounds of the invention to the mouse.

The value. ¹ were under stindar ^ isi-j-rter. Conditions- received. The ancestor consists in the formation of uiner akuxor. experimental infection with E. cell? of in the mouse by intrnperitoneal inoculation of the f-.ur with a. axandnrisierton (10 ~ °) KuItui * in front. S. coli Z66, which in 57 ° i €. «= Nemagennucin (hog gati'ic ir.ucin) was susj-cndicrt. The Tis-vöi bonds were made in the form of their ilatritin or potassium selenium

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dor infected mouse administered after one Multiple "dosiorungsvorschrift, with the first dose Is given 0.5 hours after inoculation, and this dose is repeated 4.24 and 48 hours later. Then the percentage of surviving mice is determined.

The LD. QQ of K. coli 266 (i.e. the lowest concentration,

which is necessary for a lOO ^ igo mortality of the mice

-7 ♦
is) is 10. In order to check for possible virulence migration, control animals received

-5 -6 -7
vaccinations of 10, 10 "and 10.

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TADELLE I In Vitro 3pectren

aureus E. coli

0.39

2- (T-T-LIe thylanilino) ethyl 2-n-t-ethyl-N-fomylariiinoethyl 2-n-ethyl-I-I-o-cetylariinoethyl 2-H-iithyl-IJ-foraylaminoethyl 2-H-ethyl-N-acetylaminoethyl 2-iy-isopropyl-If-formylarainoethyl 2-III'-isopropyl-IT-acetylaminoethyl 2-IT- (η-butyl) -I-foorinylaminoethyl 2-2T- (n-butyl) -n-acetylo, minoätiiyl 3-N- (isopropyl) -N-formylaminopropyl 3-N- (Isopropyl) -IT-acetylaninopropyl 2-III-IIethyl-N-carbomethox3raminoethyl 2-iI-I.Iethyl-ri-carTDo- (isobutoxy) -aminotylthyl 2-lT-ethyl-N-carlDoineth.oxyaninoethyl 2-N-Eth3'-1-H-carbo- (isobutoxy) -ar.iinoätlayl 2-Π- (n-butyl) -N-carbomethoxyarainoethyl 3-n-formylaminopropyl 3-N-Acetylinopropyl 3-IT-Carbo- (isobU'bo: cy) -aninopropyl

3-H-Isopropyl-N-carbo- (isobutoxy) -aminopropyl O.195

3- (i-Eth.ylpiperidyl) "6.78

3- (i-Benzylpiperidyl) O.10

H 1.25

4- (2-carboxyvinyl) phenyl 0.39

2-tert-butyl-4-niGtlioxyplienyl · O.O9O

2-biphenyl 0.012

2-Carbornethoxyne thylplienyl 0.392

4-Carbethoxyrne tliylphenyl 0.049

4- (2-Carbo ;; yethyl) -phenyl 1.56

4- (2-carbomethoxyethyl) phenyl 0.195

: vw ■: - ■ * -: .τ. · 009811/162 0.70

0.195
0.195
0.195
0.049
0.195
0.024
0.09C

0.39

0.90

1.56

0.73

1.56

0.39

0.7G-

0.39

6.25

100

50 100

25> 200

12.5

100

■ 50

50 25

25 100

3.12 3.12

■ 3.12

50

12.5 1.56 6.25 5.25

50 3,125

Tab _il _ _i 1_- continued ....

2-I.iethoxy-4- (2-carboxyvinyl) -pIienyl 1.56 25

2-l-ethoxy-4- (2-carbomethoxyvinyl) -phenyl 1.56 * 25

4- (2-Carboxy-2-carbobenzoxyaninoä.thyl) -phenyl 0.39 100

4-acetamidophenyl 0.70 50

4-Carboraethoxymethylphenyl ~ 1.56 12.5

2-I'etho :: y-4-f orny! Phenyl 0.195 12.5

In Vivo - \ .erte compared to E. coli at the house

Λ2 Oral subcutaneously

200 mz / lzz 100 200 ms / kg 100

2-II-r: ethyl-H-fornylaminoethyl 10 0 CO 90

2-rr-i.Iethyl-rT-acetyle .; - iinoethyl 40 40 90 70

2-IT-iitlayl-IT-foriviylaninoiitlijrl 0 0 100 70

2-W-Ethyl-N-acetylaninoLLthyl 90 20 ^

2-Ii-Isopropyl-IT-formylaninoethyl CO 60 ^ ° ^

2-lI-Isopropyl-N-acetylarainoäthyl GO 10 ^ ° '

2-tert-butyl-4-: iiethoxyphenyl 100 CO 100 100

2-biphenyl 100 100 100 CO ^ ⁰ ^

2-carbonethoxy]: aethylphenyl 70 20 90 9o ' ^e '

4-Carbethoxymethylphen3ri CO 0 90 50> ^e )

4- (2-carbonethoxyethyl) phenyl 50 0 80 70 ·

4-Carbonietlioxyne thy! Phenyl SO 30 100 100

4- (2-carbethoxyethyl) phenyl 00 0 90 50

2-Hydroxynethylphenyl 60 20 60 10 ^ ^c '

2-IIetlioxy-4-fornylphenyl 10 0 100 60 '

4-carbomethoxyethylphenyl 90 30 100 100

2-N- (n-Butyl) -II-fomylariinoethyl 70 "o ' ^c '

2-rr- (nr-butyl) -N-acetylaniinoethyl 90 O ^ ⁰ ^

3 -IT- (Isopr opyl) -Nf 0 rmjrlaminopropyl 70 10 ' ^c '

3-lI- (Isopropyl) -IJ-acetyl-aininopro- _{1Q Q} (c) _{1 (χ)} go ^ ⁰ ^

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Table II - continued ...

- ■ - ■ ■ ■ r- τι w ι ■ η ι ■■ **

Oral sublo.it at

200 his /▶.- :; ioo 200 ^ A :;

ar.iinoc.thyl 10 0 ^K "' ^J 100

= 50 ins / IvS

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n (c)

2-Π-ΐ; οΐ1ιγ1-Ι! -ΟηΓϋθ- (5> .3ονΛ \ ΐο :: ^ ') - / χ / χ

aiiiiioLithyl '0 0 ^KC) 70 (Λ'

2-H-ethyl-II-carbomctho :: y- ₍ \ _f \

am-noäthyl 20 O ^ ^; GO IO ^v;

2-Ii-i'lthyl-II-car oo- (isobvvtoxy) -

ιοΜτΙν / 1 10 ro JO 0

2-N- (n-butyl) -i: -carboj: iotIio: cy- _fn \ '/. \

aminoLthyl 0 0 ^K} 00 C ^ ^;

ropyl 0 0 ^(c) TC 0 ^(c)

3-N-Acotylaninoprop _: ι ο G ^v * 70 20V ^;

3-.:-Carbo(isobv.to::;/)-:r,.-iinoprop:0 0 10 ^v ' ! 00 · "0 ^{v ;}

3-if-isopropyl-Ii-cr.rbc- (iccbuto: cy) - <·> />

aninopropyl 0 0 * '70 ''C ^K *

2-ϊI, Ii-DibΘnzJ ^ laniΓ-O>ii; l · _ι 3Ί ".-C n ^ ⁿ '· 70 O ^ '

2 ~ iMIcthyl-i * -bennylä "ohyl 0 0 ^v ^ V GO- 20 ^{v - /}

3- (1-Mthylpiporiö ;. '!) ^{10 10} O ■ (^' ^c Vo ^ ⁰ ^

2- (1-Benzylpipri-idyl) ".Ο SC u ^ ^c ^ ^r > c ' ^c '

Ϊ944379

example 1

N-ethylpiperidine salt of pC - / ~ "Carbo (5-iridan.y3.oxy) penicillin

A mixture of 17.3 g of 6-amir; openicillane acid (0.08 mol) in ethylene chloride (125 ml) and 1ή,? β Triethylamine (0.16 mol) was. Stirred at room temperature under nitrogen for 2 hours in a flask (creased flask). The mixture was then ^{cooled to 0} ° C. (with a supply of nitrogen) and mixed with 21.9 g of 2-phenyl -2- (5-iridanyloxycarbonyl) acetyl chloride (0.07 mol) in 30 ml methyl chloride by means of a dropping funnel is added quickly as: ηο like, the exothermic reaction being kept below 15 ° C in an ice bath . The ice bath was removed and the mixture stirred vigorously for 1.5 hours. 135 ml of water were then added and the mixture was stirred for a further 2 minutes. The pH value (8.8) was adjusted to pH 2 by adding 6N HCl (15 ml). The mixture was stirred vigorously for 10 minutes and the natural layer separated. The acidic aqueous layer was extracted with methyl en chlorid (2 x 67 ml). Γ-ie Iwethylenchloridschichten were combined, dried, filtered and concentrated to 35 ⁰ C under reduced pressure over magnesium sulfate, concentrated to dryness. The slightly gelatinous foam obtained was dried and 34.4 g of crude penicillin (9%) were obtained. 17 g of crude penicillin (0.0344 mCi) in 40 ml of acetone was cooled to 1O ⁰ C and treated with 3.96 g of IT ÄthylpiT. ^ Ri-Un. '(C-, C35 mol) added. The mixture became. '"inut&g-;r'J.hr ⁺ jr: i the white crystalline salt formed atfiltri ^ r * ,,.". it Ac ^ - .. n. gnv / assee and dried. Yield: 8C f ("17.9 g);" ohmic melting point 143-145 ° C (decomposed),

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ÖAD ORfGIWAL

By slurrying in 10 g per 100 ml of acetone at 4G ⁰ C, cooling to room temperature, filtering and drying was further purified, 80? ' of the salt were recovered. Melting point 149-151 ° C (decomposed).

Conversion into the potassium pala: A suspension of 5 g of the R-ethylpiperidine salt (8.2 mol) in 75 ml. 1.93 g of Kaliuraathylhexano.it (10.6 mol) were added to ethyl acetate at room temperature. The mixture was then added 2 minutes at 45 ⁰ G erwM.rr.it, sum cooling to room temperature and then cooled to 0 C in an ice bath. The potassium salt was filtered off, washed with ethyl acetate and dried. Yield 4.2 g ($ 96.1); Melting point 198-199 ⁰ C (decomposed).

The sodium salt: was made in a similar manner from sodium ethylhexanoate produced and melted at 182-184 ° C (decomposed).

Example 2

N-Ethy lpipe ridinsa lz vontC- / ~ Ca rbo (2-isopropylphenoxy) "J benzylpenicillin

A mixture aur? 3.74 g of 6-aminopenicillanic acid (17.3 mol ⁰ C cooled. A solution of 4,3 & 2-Pheny1-2- (2-isopropylphenoxycarbonyl) acetyl chloride (14.4 mmol) in 5 ml of methylene chloride was quickly added and prepared; Eeaktionsgemisch 1 hour at room temperature ze stirred. Then the mixture was varsetzt with 20 ml water, stirred for 2 Minutfin, cooled to 10 ⁰ C, followed by addition of hydrochloric acid the pH 6 η

009811/1625

Ϊ944379

set. The mixture was stirred for 5 minutes, after which the methylene chloride layer was separated, dried and dried evaporated to dryness, with the crude penicillin as a cream colored foam (4.4 g) was obtained.

550 mg of crude penicillin (1.12 mmol) in 1 ml of ethyl acetate was treated at room temperature with 147 mg of N-ethylpiperidine, stirred for 2 minutes, then ^{cooled to 0} ° C., filtered and dried to give the salt. Yield 625 mg (92 #); Melting point 139-14O ⁰ C The total yield of the amine salt is, based on the acid chloride participant, 84.2 ^.

The N-ethylpiperidine salt was converted into the potassium salt in the following manner: 100 ml of benzene were placed in a 250 ml three-necked flask and 50 ml of benzene were distilled off. The benzene was heated under reflux with 3 g of N-Äthylpiperidinsalu (5 mmol} was added and then cooled to room temperature. 3.2 ml of a 26 $ strength Aeetonlösung of Kaliumäthylhexanoat was added and the mixture was heated 3 minutes at 45 ⁰ C. The mixture was stored to cool to room temperature, then ^{quenched to 0} ° C., filtered and dried. Yield: 2.1 g ($ 78); melting point 180-182 ° C. (decomposed).

The sodium salt was prepared in a similar manner by replacing the potassium ethylhexanoate with the sodium ethylhexanoate. Melting point 170-172 ° C (decomposed) from isopropanol or ethyl acetate.

009811 / 1S25

BATH ORIGINAL

Example 3

The filing esters of ^ T -Cardoxylbenzylpenicillin were as their N-ethylpiperidine salts by the method of Example 1 produced.

OH-C-NH-CH-CH

O = C

CH.

-CH- COC "

2, ^ - Pimethylphc-nyl 2 , 4-

2 j 3-Pi: nethyiphonyl 2 5 6-pine thy! Phenyl ^, 4-PiUiC thylphenyl 3,5-dimethylphenyl 2-chloro-4-nit t; iylp ^ cii3 ^r l 4-chloro-2-mt: thylphenyl • 6-chloro-2-r .; _t ethylphenyl 4-chloro - "? -! Tc + hylrlicnyl 2-iie thoxy - * '- -" - j tiiy 1 phenyl 3-methoxy-3-butethylphoiiyl 4-indenyl

2- (5,6,7, B-Te trahyironaphthyl) 1- (5, C, 7,8-Te trahydronaphthyl) melting point ( ⁰ C)

144-150 142-144 151-153 150-151 145-147 147-149 144-145 149-151 153-154 141-142 150-152 150-152 136-13S 138-139 136-139

009811/1625

BAD ORJQjjs / _AL

4-chloro-3 f5-dimethylphenyl 4-chloro-2,3-dimethylphenyl 3,4-methylenedioxyphenyl

Example 4

Melting point ( ⁰ C)

140-142 144-147 146-148

This example illustrates the preparation of X- _/ / ~ carbo (2-isopropylphenoxy) -7benzylpenicillin from a fermentation broth containing 6-arrainopenicillanic acid. A fermentation broth containing 6-aminopenicillanic acid was prepared according to the procedure of Example 1 of TJ.SA Patent 3,239,427 which comprises the enzymatic hydrolysis of benzylpenicillin by Proteus rettgeri.

1.5 l of broth were treated with 0.5 g of calcium chloride and ^ _x g of diatomaceous earth at room temperature for TO minutes

liter
then filtered. A • clarified, 5.4 g (0.024 mol) 6-Ajninopenicills.npäur; Broth containing v / urdc brought into a three-necked flask equipped with a high-speed stirrer. Then 10 g of 2- (2-isopylphonoxycarbonyl) acetyl chloride (0.0: 15% 1) were added dropwise over the course of one hour at room temperature. . Kontinuierliche- by addition of 10 tigern aqueous KaliuinhydroKyd the pH was ert ^w between pH. 6.3 and 6.5 are maintained. Then I-iinchur.f- 'was stirred for 1 hour at room temperature urii the pH value of 6.3 to 6.5 then by 6 r. Hydrochloric acid adjusted to pH2.

The acidic reading was extracted with ethyl acetate (3 × 200 ml). The combined extracts were washed with water, filtered and the filtrates with 10 / igem aqueous

009811/1625

BADORtGiNAL

Extracted potassium bicarbonate (500 ml). The aqueous layer was separated, saturated with potassium chloride and extracted with ethyl acetate (2 × 200 ml). The combined ethyl acetate extracts were extracted with water (3 × 100 ml), the water extracts were combined and acidified to pH2 with 6 η hydrochloric acid. The precipitate formed was washed with ethyl acetate (2 χ 75 ml), the extract with anhydrous sodium sulfate, filtered and then evaporated under reduced pressure at 35 ⁰ C to dryness,

The residue (5.4 g), an oily-looking foam, was dissolved in 10 ml of ethyl acetate and treated with 1.13 g of N-ethylpiperidine (0.01 mol) at room temperature. A crystalline product separated out immediately. The mixture was quenched, then filtered and the product washed with ethyl acetate and dried. Yield: 5.85 g (40 <$) ; Melting point 146-148 ⁰ C (decomposed).

This procedure was carried out at pH values of 3.0 to 3.3, ^ am 5.3 and 8.5 to 8.8 repeated during the acelation step, wherein the desired product was also obtained. However, the yields were lower.

Example 4

Kai iumsnlZ νοη <£ - / ~~ Carbo (2- i sopropylphenogy) 7benzylpenicillin

The pH of an aqueous suspension of 10.8 g of 6-amino penicillanic acid (0.05 mol) in 500 ml of water was adjusted to pH 6.4 by adding 6 η sodium hydride solution. The resulting solution was treated dropwise at room temperature over 1 hour with 19 g of 2- (2-isopropylphonoxycarbonyl) acetyl chloride (0.06 mol) added.

009811/1625

- 26 -

By continuously adding 10 # sodium hydroxide solution the pH was kept at 6.3 to 6.5. The renktionsgemissch was stirred at room temperature for 1.25 hours and the pH of 6.3 to 6.5 is then adjusted to pH2 by adding 6 η hydrochloric acid. Subsequently was. 500 ml of ethyl acetate were added and the mixture was stirred for 5 minutes. The ethyl acetate layer was separated 200 nl concentrated and with potassium ethylhexanoate (0.07 mol) treated. The mixture was concentrated to a small volume (about 50 ml) with 100 ml of fresh ethyl acetate shifted and concentrated again. This step was repeated, then the crystalline salt filtered with ethyl acetate washed and dried. Yield: 6.8 g ($ 25.4).

Example 6

Acelation of 6-aminopenicillanic acid in an aqueous solution emulsion

A solution of 6-aminopenicillanic acid (10.8 g, 0.05 mol) in 1000 ml of water was treated at pE 6.4 and 25 ° C with a solution of 31.6 g of 2-phenyl-2- (2-isopropylphenoxycarbonyl) acetyl chloride (0.1 mol) is added to 250 ml of methyl isobutyl ketone (in one portion). The mixture was then vigorously stirred and the pH was kept at 6 by continuous addition of 10 aqueous sodium hydroxide.

250 ml of methyl isobutyl ketone were added to the compartment for 6 minutes, the emulsion was stirred and adjusted to pH 2 with dilute hydrochloric acid. The solution was made with ethyl acetate extracted (3 × 200 ml) and the combined extracts washed with water and then with anhydrous sodium sulfate dried. The dry extract was evaporated to dryness, the residue was taken up in ethyl acetate and used for

BAD ORIGINAL 009811/1625 ~~~

Formation of the corresponding salt with 6 g of N-ethylpiperidine treated, the salt being recovered by filtration.

Similarly, by replacing the isopropylphenyl ester with the acid chloride of the corresponding Phenylmnlonuäurehnlbesters the corresponding 5-indanyl, 2,4-dimothylphenyl , 2-methyl-4-chlorophenyl, 3,4-dimethylphynyl and 4-indanyl esters obtain.

The above procedure was repeated below Use of 2-phenyl-2- (2-isopropylphenoxycarbonyl) acetyl chloride however at pH values of 3.5 and 8.0, with the desired products, however, in lower yield were obtained.

Example 7

The following connections were made by the method of Example 2 from the corresponding arylmalonic acid half-esters • ^ Ip ye & N-ethylpiperidine salts manufactured.

CH C -NH OH-Ώ

. H ₊ C ₀ H, \ /

CH-ceo->;

009811/1625

o-Dirae thylaminophenyl o-Di-n-butylaminophenyl m-dimethylaminophenyl m-di-n-propylaminophenyl p-methylethylaminophenyl p-methylisopropylaminophenyl 2,3-diethylphenyl 2,6-diethy! Phenyl 2,4-ui-n-propylphynyl 5-methyl-3-methylphenyl 2-M e thy 1-4 - rje-k. -but y lph eny 3-methyl-4-t-butylphenyl 2,4,6-trimethylphenyl 2,6-dimethyl-4-ether, ylphenyl 4,5 - üiiTie thyl-2-isopropyljihoriy 2,6-dichloropheny1 4-l-propylphenyl ; <- chloro-2-fluorophenyl 2-Bro: n-s - i'luorpher, yl 2-Ke thoxy-4-methylpheny-i-2-Chlcr-f-methox "ph.:; Nyl 3-iiothcxy-2i: ic thylphcr.; /!

2-H c th ο xy- 6- r, ro py Ip} icny L (r-chloro-2-rao thylphenyl 2-fluoro-4-! Tiuthylphenyl ■ 2-3Γοη-6 — meth-y lph tiny I 2- I <ROM "r- t-buty 1 phonyI _{2-chloro-5-fluorpher;} 4-yl-2-CSilcr iscprGr-, phenyl 1 - (5,6,7,8-T e · occurred.!. / d ronäph-

thyl) -

5-chloro-2,4-dimethylphenyl 2-chloro-3, A -dimethylphenyl 2-chloro-4-isopropylphenyl 2-1-butyl-4-fluorophonyl 6-bromo-3,4-dimethylphenyl 4-chloro-2,6-dimethylphenyl 4-chloro-6-isopropyl-3-methylphenyl

4,6-dichloro-2-methylphenyl 5-methyl-4-indanyl 1-methyl-4-indanyl 1-methyl-5-indanyl 7-methyl-5-indanyl 6-t-butyl-5-indanyl 1,1 -Di: ir, thyl-4-indanyl 1,1-, 2-trimethyl-4-indanyl r-chloro-4-indanyl / -bromo-;.- i-ride ^! -.nyl '.'— Chior - ^ - indanyl', 1,7-ΤτΙη, οthy 1-4-indanyl 1-irien.nyl
'- -Indanyl

''. -ΓΊ ο thy 1- 5 - in d ° η 7/1 2-rier / riyl-1 -in deny I 2, 2-I3iir.tthyi- '-indanyl ^, 3 - ^ i-itluyl-1 - in danyl. ? -C'hlo r- ': - ir. Dany-1 I'-Br-τη- ¹ -: L ^ dC'"-'iyi' -ChI or-i! - 'r. N ^ .ri_yl

2-Piperldiricäthyl

0038U / 162

BATH ORIGINAL

2- (5,6,7,8-tetrahydronaphthyl) 2-pyrrolidinoethyl 1 - (4-Methyl-5,6,7,8-tetra-2-imidazo] ^ ethyl

hydronaphtyl) 2-morpholinoethyl

2- (1-Me-üiyl -5,6,7,8-totra-2-Azetidinoethyl

hydronaphthyl) 2- (2,5-dimethylpyrrolidiiD) -

1- (4,! - dimethyl-5,6,7,8-ethyl

tetrahydronaphthyl) 2-aziridinoethyl

2- (1,6-dimethyl-5,6,7,8-2-thiomorpholinoethyl

tetrahydronaphthyl). 2- (4-methylpiperidine ^ ethyl

1- (2,4,6-trimethyl-5,6,7,8-pyrrolidinomethyl

tetraliydronaphthyl) aziridinomethyl

2- (5,5,8,8-tetramethyl-5,6, (2-imidazolino) methyl

7,8-tetrahydronaphthyl) (1,4,5,6-tetrahydropyrimi-

1- (2-methyl-1,2,3,4-tetradino) methyl

hydronaphthyl) pyrrolidinome thyl

1- (3,4-dimethyl-1,2,3,4-tetra-piperidinomethyl

hydronaphthyl) Morpholinorae thyl

2- (6-methyl-1,2,3,4-tetra-thiomorpholinomethyl

hydronaphthyl) 2-acetamic "" ethyl

2- (2,6-dimethyl-1,2,3,4-2-butyramidoethyl

tetrahydronaphthyl) 2- (ethylisopropyl-

1- (2-chloro-1,2,3,4-tetra-amino) ethyl

hydronaphthyl) 2- (2,6-Diniethylpi-

2- (1-bromo-1,2,3,4-tetrahydropperidiro) ethyl

naphthyl) 2-methylanilino) ethyl

2-diraethylamiroethyl 2-N-isopropylanilino) -

2-dibutylaminoethyl

2- (2 ~ Iim3.azolincJäthyl - "" "" "" "" "3-pyrrolidine-

2- (N-n-butylaniline)) ethyl 2-propyl

2- (methylbutylamine _o ) -1-propyl 3-piperidino-2-propyl

3-aziridino-2-propyl 3-morpholino-2-propyl

2-piperidino-1-propyl 3-di- (n ~ butyl) amino-2-propyl

009811/162 5

2 - (! T-ethyl) piperazino-1-propyl 2-Bi- (n-propyl) amino-1-propy1 3- (IT-A thylanilino) -2-propyl 2- (IT-methylanilino) -1-propyl 1-ethoxy-2,2,2-trichloroethyl 1-butoxy-2,2,2-trichloroethy1 1-ethoxy-2,2,2-trifluoroethyl 1-isopropoxy-2,2,2-trichloroethyl

Dica.rbomethoxyäthoxymethyl 1-Dimethylamino- 2-methy I phenyl 2-methyl-6-nitro phenyl 3-diethylaminopropyl 3-dibutylaminopropyl 3- (2-imidazolino) propyl 3-piperidinopropyl 3-pyrrolopropyl
2- (1,4, 5, 6-tetrahydropyrimidino) ethyl

2- (N-methyl) pipera_zinoethyl 3-IT-butylpiperazinopropyl 3-dimethylaminopropyl 3-di- (n-propyl) aminopropyl 3-di- (n-propyl) amino-2-propyl 2-diethylamino-1-propyl 2-Ni trοpheny1
2-methyl-5-nitrophenyl 4-biphenyl
2-chloro-3-phenyl 2-bromo-4-mnenyl
2-nitro-4-biphenyl - 3-DiiiiC; thylamino-2-propyl 2-pyrrolidino-1-propyl 2-thiomorpholino-1-propyl 2- (imidazolino) -1-propyl 3-imidazolidino-2-propyl 3- ( Methylpropylamino) propyl 3- (ethylisopropylaraino) propyl

3- (He thyläthylamin ο) -2-propyl

3-inidazolo-2-propyl 3-pyrrolo-2-propyl 2-ioropholino-1-propyl 3- (2-Irnidazolir) o) -2-propyl 3- (li-methylanilino) propyl 3- (N-Me thylan i 1 ine) -2-propyl

2_ (Ii-n-Pr opy ianilino) -1 propyl

1-methoxy-2,2, 2-trichloroethyl 1-butoxy-2,2,2-trifluoroethyl

Carbethoxyethoxymethyl 1-t-butoxy-2,2,2-trichloroethyl

2-IT-Me thyl-IT-ace tylaminoäthyl 2-N- (n-Butyl) -N-formylaminoäthyl '

2-Έ- (η-butyl) -N-acetylaminoethyl

009811/1625

BATH ORIGINAL

2-Pimethylamino-5-binhenyl 2-Oarbomethoxyme.thylphenyl ·! - (2-Cnrboxyäthy 1) phenyl 4- (2-0 ?? rbätho xyäthy1) phenyl A ~ { 2-Carboxyvinyl) phenyl 2-Methoxy- · ' . - (2-carboxy vinyl) phenyl

2-methoxy -] - (2-carbone thoxyvinyl) phenyl

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

2-chloro-3- (2-carbcxyvinyl) -phunyl

2- (2-Cr \ rboxy vinyl) -6-nit 1-4-biphynyl

2, t-Pdmethyl-C- (cirboxymethyl) phenyl

.'- t-Putyl-2-biphfnyl 3-methoxy-2-biphonyl 2-isopropyl - "- mt-thoxyphenyl * 5-dimethylamine-2-isopropylphynyl

2-H-T'ethyl-ii-foi-! Nyla; nino. ^: ithyl

2-K-On rbome thoxy * rrtinoethyl 2-T5-i3en2yl-II-earOc :: ie tho xyaminoSthyl

2-N-benzyl-: 5-'ic tylirainoethyl 3-piperidyl

3_ (1-HethyIp ipe ri dy1) 3- (1-n-Butylriperidyl) 3-N- (Isopropy1) -N- a coty1-aminopropyl

2 -N -Me thy 1-K - c ^r ; rb ome th ο xyaminolithyl

2-il-Mc thy 1-lT-cnrbo (i f obut oxy) aminoethyl 3-M-pormylaminopropyl 3-N-Act-tylimincpropyl 3-iJ-Carbo (isobutoxy) aniinoprctiyl

Jf-phenyl propargyl

Y- (2-chlorophenyl) prop · ⁷ : rgyl i "- (--- Ni trcphc-nyl) propargyl 2-Ti , N-dibunzyl ^ .niinoethyl 2-11-methyl-R-be nzylaininou thyl

■■ 3-N, iT-libenzylnmino-2-propyl

2-K- (η-butyl) -N-benzy1-r.jnincät-liyl

2 -:; - (n-Uutyl) -N-butyryl araincethyl

y_ (.; _ i "e thy lphc nyl) a lly 1 γ- ( 2-Chlcr -'.-methylphenyl) allyl
! "" - (--Isopropylphenyl) -allyl

Y- { 2,5-dimethy1-1-me: thoxyphenyl) allyl

009811/1625

3- (1-Benzylpiporidyl) YVPhenylallyl T- (· '-Ohio rpheny1) ally y- - (4-Methoxyphynyl) "-r- (3, C-Methy] ondioyyphynyl) allyl

T- (2-Ni trof.hcnyl ) illyi

phenyl) allyl

r- (3-Fluorophir.yl) ". 1IyI 3T- (?, Λ, 5_Tri ch Iornh cnyl; allyl

JT- (3-bromophenyl) -siIy 1 Example 8

γ-_ (3-f-Tethoxy-4-ethoxyphynyl) allyl
If- (3-chloro- ' ¹ -methoxy-

Ϋ- ( 3-Hethyl-6-nitrophcnyl) -

Τ- (2,6-Dinitrophenyl *) allyl T- (4-n-Butoxyphenyl) allyl V- (rn-Tolyl) propargyl

The following penicillins were gcmä'i the procedure de ?? Example 1 prepared from the corresponding arylmalonic acid half-esters and e-aminopenicillanic acid.

R ₁ -CH-CO-ITHR ^

COGR,

For each of R ₂ listed in the following table R ₁ .bedeuten 2-thienyl, 3-thienyl, 2-Fyridyl, 2-Puryl and o-tolyl and R, the PenicillanBäurerest.

009811/1625 BAD ORiQlNAU

19U379

1-I.Iethoxy-2,2,2-trichloroethyl, 2-chloro-6-propylphenyl

i-butoxy-2,2,2-trichloroethyl o-dimethylaminophenyl

1-ethoxy-2,2,2-trifluoroethyl o-di-n-butylaminophenyl

2-isopropylphenyl p-IIethylethylaminophenyl

2,6-dimethylphenyl 2- (N-methylanilino) ethyl

3-methyl-4-t-butylphenyl 2-diisopropylaminoethyl 4,5-diraethyl-2-isopropylphenyl3-diethylaminopropyl

2, 4-Mmethyl-3-äthylph.enyl 2- (IT TIethyl) piperazinoäthyl

2,6-dichlorophenyl 2- (1,4,5,6-tetrahydropyrimi-

2-Dimethylarainoäthyl dino) ethyl

2-dibutylaminoethyl 3-imidazolopropyl

2-C 2-imidazolino) ethyl 3-di- (n-propylanino) -2-

2-piperidino-ethyl propyl

3-IIorpholinopropyl 3-Paetrolidino-2-propyl

3-thiomorpholinopropyl, 3-diethylamino-2-propyl

2-pyrrolidino ethyl 3-IIorpholino-2-propyl

2- (2-Inidazolino) ethyl 3-Difflethylanino-2-propyl

2-pyrroloethyl 3-diisopropylaminopropyl 4-dimethylamino-2-methylphenyl3-piperi dinopropy1

2- (ethylbutylamino) ethyl 3-pyrrolidinopropyl

2-arizidinoethyl 3- (Hethylethylamino) -2-propyl

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

2-chloro-6-yne ethoxypheny 3. 3- (2-I.nidazolino) -2-propyl

2-ethoxy-3-diethylphenyl 3-inidazola-2-propyl

2-chloro-5-diethylphenyl 2-dimethylamino-1-propyl

2-chloro-4-isopropylphenyl 2-pyrrolo-1-propyl

4-chloro-2, 3-dineth5'-lphenyl 2- ( 2, 5-diinethylpyrrolidino) -

2-isobutyryl-4, δ-dimethyl-1-propyl

phenyl

/ Vziridinomethyl 2- (1-IIethyl-1,2,3 _t 4-tetra-

Piperidinomethyl hydronaphthyl

(2-Inidazolino) methyl 2- (1,2,3,4-tetrahydronaphthyl.

(4-Hethylpiperidino) nGthyl 1- (3-Uethyl-5 »6 _f 7, C-tetra-

Pyrrolomethyl hydronaphthyl '

; ". .- ₊₁ , · _Ί . χ - -, 00981 1/1625 2- (I ^t i-uethylanxlino) -1-propyl

2-nitrophenyl 4-ethyl-2-nitrophenyl Dicarburethoxyethoxynethyl C arbethoxyethoxync thyl 4-indanyl

5-indanyl

1-IIIethyl-4-indanyl 7-IIGthyl-4-indanyl 1 -I Ie thyl- 5- indanyl 5-rt-butyl-5-indanyl S-chloro-4-indanyl 3-ethyl-1-indanyl 2-chloro-1-indanyl 1-chloro-2-indanyl 1-indanyl

2-indanyl

2-IIe thyl-1-indanyl 2-lIe thyl-2-indanyl 1- (5,6,7, o-tetrahydronaphthyl) 2- (5,6,7, O-tetrahydronaphthyl)

1- (5,3-dimethyl-1,2,3,4-tetrahydronaphthyl)

2-IIethyl-4-biphGnyl 5-Diaethylamino-2-isopropyl-

phenyl

2-IM-methyl-N-formylaninoethyl 2-N-I.Iethyl-N-acetylaninoethyl

2 — IT— (η-Butyl) -II-acetylaminoethyl

3-N- (Isopropyl) -N-acetylanino-

propyl

2-II-III-ethyl-II-carbonothoxyaninoethyl 2-biphenyl

4-biphenyl

2-chloro-3-biphenyl, 2-bromo-4-biphenyl 2-IIitro-4-biphonyl 2-Dineth3 ^r laraino-5-biphenyl 2-t-butyl-4-aethozyphenyl 4-Carbätho; ynGthy phenyl 2-C! ar bom e tho;: ym e thylp h enyl 4- (Carbo-n-butoxy) methyl-

phenyl

4- (2-Carbone tho :: y & thyl) -

phenyl

4-carbon tho xyn e thylph enyl

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

phenyl

2- (2-carboxy / ynyl) -6-ni ^J ; ro-

4-phenyl

3-

4 · 3-

3-

IIethyl-4- (2-carbo; cyathyl) ·

phenyl

t-butyl-2-biphenyl I Ie thoxy- 2-biphenyl (1-benzylpiporidyl) Phenylallyl

(4-chlorophenyl) allyl (2-; Ictho; cyp "henyi) allyl

(3,4-Dinethoxyohenyl) - * allyl

(4-nitrophenyl) ellyl (3-? Luophenyl) allyl (4-methylphenyl) allyl (2-chloro-4-nothvlphenyl)

allyl

009811/1625 BAD

19U379

2-Π-ίIethyl-N-carboC'isobutoxy) - / - (3-LIethoxy-4-ethoxyphenyl)

aminoethyl allyl

2-N- (n-butyl) -N-carbomethoxy- '-O-chloro ^ -methoxyphcnyl)

aminoethyl allyl

3-II-Poraylaninopropyl -O-IIethyl-ö-nitrophenyl)

3-N-acetyl arainopropyl allyl

2-H, il-Dibcnzylaminoäthyl * - (2-Nitro-4-chlorophynyl) 3-N-Ethyl-n-benzylaminopropyl allyl

3-Iipertdyl '"-Phenylpropar ^ yl 3- (1-butylpiperidyl) - (4-chlorophenyl) proparsyl

»- (4-! Iethoxyphenyl) -pro-

pargyl

- - (4-IIitrophenyl) propar3yl

Pci game " 9 ...

The following penicillins, where R ₁ denotes the 3-furyl-i B-IVi'ieyl * »4- ^ ridyl-, p-tolyl-, o-ethoxyphenyl- f p-ilethoxyphenyl-, p-iTrifluormothylphenyl-, p- Chlorophenyl, o-dimethylaminophenyl and p-dimethylaminophenyl radicals for each of the R ₂ -Hestc listed in the table below were used according to the method of Example 4

the appropriate aryliaalonic acid half-yeast and 6-aainoponicitlancüure produced.

2-Isopropylphenyl i- (5,6,7 »G-Tetrahydro-1-ethoxy-2,2,2-trichloroethyl naphthyl

1-butoxy-2,2, 2-trifluoroethyl 2- (5,6,7 »3-tetrahydro-naphthyl Dicarbäthoxyäthoxymethyl

Carbylthoxyathoxymethyl 1 ~ (2-chloro-1.2 _t 3 »4-tetra-1-isopropoxy-2,2,2-trichlorohydronaphthyl)

ethyl 1- (1,2,3 »4-tetrahydronaph-1-t-butoxy-2,2,2-trichloro ^t ^

009811/1625

-ethyl

o-dimethylaminophenyl o-di-n-butylaminophonyl p-IlGthyläthylaminophenyl 2,3-dimethylphenyl 2,4-di-n-propylphonyl 4i5-dimethyl-2-icopropylphenyl 2,6-dichlorophynyl. 4- Whore thylanino-2-rne thy lphenyl 4-nitrophenyl ♦ S-chloro-ö-nethoxyphonyl 3-I.Ie ~ thoxy-2-methylph.cnyl 5-fluorine-2-ncthoxyphenyl 2-Isobutyl-4-fluorophynyl-4-chloro-2,3-diethylphenyl-1 4-chloro-2,3-diethylphenyl 3- (2-imidazqlinopropyl) 3- (2,5-Dinethylpyrrolidino) -

propyl

^3-r Pj rrolopropyl Aziridinonicthyl Pyrrolidinor.iethyl i lorpholinomcthyl 2, G Di: ac thy lphenyl 3 -) iioopropylarainö-2-propyl 2-propyl-1 Diiricthyloxiino 3-aziridino-2-propyl 2- (iI-IIothylpjiilino) ethyl-3- (II-LlGthylanilino) propyl 2- (li-I.iethylcJiilino) -1-propyl 3- (imidazolino) -2-propyl 3_ (4-i.ie tliylpip er i dino) - 2-

propyl

- 2-1 iOrpholino-1-propyl 2- (1,2,3,4-tetrahydronaph-

thyl

2- Irai dazolo-1-propyl 2-Bu ty r ani do c. t la; / l -Indanyl

-Chlor-1-indanyl -indanyl

-Indanyl

-Iicthyl-5-indanyl -Indanyl

-Ilethyl-1-indanyl -Dinothylaminoäthyl -Pipcridinoäthyl -I.Iorpholinopropyl -PjTrolidinoäthyl -lyrroloethyl

-Di- (n-rvropyl) arainoethyl -Diisopropyl arainopropyl

-Di (n-butyl) amino-2-propyl

-Dimethylamino-2-propyl -C hlοr-4-racethylpheny1 -I I e thoxy-4-r.iG thylphynyl -Diphonyl

-Chlor-3-biphenyl-III-nitro-4-biphenyl -Dime thy laraino-5-biphonyl - (Carbo-n-butoxy) methyl-

phonyl

-Car bon ο tho xyrnc thylphcnyl - (2-carbethoxyethyl) -

phenyl

4- (2-Co.rboxyvinyl) phenyl 2

JJGthoxy-4- (2-carbomethoxyvinyl) phenyl

Chl ο r- 3 - (2- carbo xy vinyl) -

phcnyl

1 lGthyl-4- (2-carbo;: yäthyi-

phcnyl

0 0 9 811/16 2 BAD

19U379

3 -Diä tliylaraino ätliyl 3-piporidinopropyl 2-pyrrolidinoethyl

2- (1,4, 5 f 6-Tc t rally dropyrimidino) ethyl

2-dietliylanino-1-propyl 3-pyrrolidio-2-propyl 3-Pipcridino-2-propyl 2-II-i Ic tliyl-H- car bon ο t ho xy-

aminoethyl

2-lWJethyl ~ rI-carbo (isobutoxy)

amino ethyl

3-N-acctylaminopropyl 3-II-carbo (isobutoxy) amino

propyl

2-1I ₇ Π-Dibenzylaminoethyl 2-Ii-I.Icthyl-H-benzylauinoethyl 3-M, n-dibenzylanino-2-propyl 1-ri-benzyl-H-acctylaminoethyl 3-pipcridyl

3- (1-i-ethylpiperyl) 3- (1-Bonzylpiperidyl) -; - '' Phcnylallyl

3-I.Icthoxy-2-biphynyl

plicnyl

DimcthylaiTiino-3-isopropoxyphcnyl

N-r.Icthyl-N-fornylamino-

ätliyl

N- (n-butyl) -DT-ac c tylamino-

ätliyl

f- (4-chlorophenyl) allyl $ - (2-I, Icthoxyphcnyl) allyl f- (3,4-Dinitlioxyphcnyl) -

allyl

# * - (4-Ni trophynyl) allyl f- (3-J ^ lUO rphcnyl) allyl ) f- (2-Clilor-4-nctliylphnyl)

allyl

it- (4-IsOPrOPyIpIiOnJrI) allyl ίΓ - (2-ITi tro-4-chlorophenyl) -Phcnylproparsyl ^allyl - (4-Chlorplionyl Jpropargjri

- (4-llc thoxyphynyl) propargyl

- (4-nitrophenyl

Example 10

According to the procedure of Example 2, the ". -Carboxycrylpnicillin esters, where the aryl group, R ^, for each the given Rp - '. Jortc denotes n-tolyl-, m-Hethoxyphenyl-, ω-Trifluornotliylphonyl-', o-Isopropylplionyl-, o-Chlorplienyl-, o-Browplienyl-j m-bromophenyl-, n-chlorophenyl-, o-butoxyphonyl-, o-Butylplienyl-, o-Dietliylaminophenyl-, p-Di- (npropyl) aninopliciiyl-, o-dibutylaminophenyl and m-dinethyl

QÜ9811 / 1625

aininophonyl-Rcst means, from the suitable reaction

participants made.

R,

1-i.icthoxy-2, 2, 2-trichloroethyl

1-ethoxy-2 _f 2, 2-trifluoroethyl-dicarbethoxyethoxymethyl carbethoxyethoxynothyl dicarbonethoxyethoxymethyl 2-isopropylphenyl

o-dimothylarainoplionyl n-Di-n-propylaninophenyl 3,4-dimethylphynyl 2,6-di-n-propylplienyl 4,5-Dinethyl-2-isopropylphenyl 2,6-dichlorophonyl

2-nitrophenyl

4-dimethylaniino-2-methylphenyl 2-I.Ie t'ho xy- 4-m e thy Iph enyl 4-chloro-2-mene tliylplionyl

.2-Bromo-4-t-butylphenyl 4-chloro-2 _? 3-diraothylphenyl 1- (5,6,7, G-tetrahydronaphthyl) 2- (5,6,7, G-tetrahydronaphthyl)

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

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

2-indanyl

4-indanyl

5-indanyl

5-i.Iethyl-4-indanyl 1 -IIethyl-5-indanyl 6-Clilor-5-indanyl 2-piperidinoethyl 2-LIorpholinoäthyl 2-Pyrrolidinoäthyl 3-pyrrolopropyl 2- (1,4,5,6-tetrahydro-

pyriraidino) ethyl

3-pyrroleidinopropyl 2-dibutylaminoethyl 2-Ityrroloäthyl 2-Irai dazoloäthyl 2-Az e t i dino ethyl 3-dimethylaminopropyl 3-aziridinopropy1

3- (N-Iicthylpiperazino) propyl

3- (2-iridazolino) propyl (inidazolino) meth.yl Pipcridinomothyl 2-pyrrolidino-1-propyl 2-1Io rpholino-1-propyl 2-pyrrolo-T-propyl 3-iridazolo-2-propyl 3- (2-irnidazolino) -2-propyl 2- (LIe thyläthylanino) ethyl 3- (llethyläthylamino) -2-

propyl

00 9811/162

BAD ORlQfNAL

2-

2-

3 2

3 3

2- (Dietliylainino-1-propyl 3-pyrrolidino-2-propyl 3-diethylamino-2-propyl 3-liorpholino-2-propyl 3-Dir.iothylainino-2-propyl 3-piporidinopropyl

2- (n-Icthylanilino) ethyl

3- (Ιϊ-Πο thylanilino) -2-propyl 4-biphenyl

2-bromo-4-biphcny1

2-i! Itro-4-biphenyl

2-dittothylanino-5-biphynyl

4- (Carbo-n-buto3: y) me thy 1-

phcnyl

4- (2-Carbor.icthoxyäthy-1) -

phcnyl

4-Carboi.icthoxynothylphynyl

2-i ictho :: y-4- (2-carbon oxyvinyl) phenyl

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

phenyl ^,

3 -;. * E thy 1-4- (2-carboxyethyl) -

phcnj'l

3-1 icthoxy-2-bisphon3rl 2-isopropyl-4-methoxyphynyl 5-dinothylanino-2-isopropylphenyl . 2-N- ^ ethyl-II-acctylaninoethyl 2-i: -Isopropyl - ^ - fornylacinoethyl IT- (n-butyl) -H-ac e tylaraino-

ätliyl

H-Uethyl-K-earborjcthoxyaminoethyl

Π- (n-butyl) -H-carboracthoxy aLiinoethyl

If-acetylaminopropyl N-LIcthyl-IT-bcn2ylainino-

ethyl

Ii, II-dibenzylaminopropyl Pipcridyl

(1-benzylpiporidyl)

it- (4-chlorophenyl) allyl (4-iicthoxyphcnyl) allyl.

(3,4-Hethylcndioxyphenyl)

allyl

(3-fluorophynyl) allyl Phenylpropnyl (2-chlorophenyl) propar3yl

009811/1625

Example 11 '

₁ g-Carbo (2-isopropylphenoxy) benzylpenicillin - anhydride method

A stirred solution of 2.5 g of mono- (2-isopropylpheny]) phenylmalonate in 10 ml of dry acetone was cooled to ^{0 ° C. in an ice bath.} Within 15 minutes was added dropwise triethylamine and then added with 1 _r 27 g anhydrous with 900 mg of dry Chloräthylcarbonat. A precipitate of triethylamine hydrochloride immediately formed. The mixed anhydride was treated at the same time with a solution of 1.6 g of 6-aminopenicillanic acid in 2C in a 5% solution of sodium bicarbonate and 5 ml of acetone. The equipment was ^{stirred at 0} ° C. for half an hour, then extracted with ether (3 × 50 ml) and acidified to pH 1.0 with concentrated Sslzryrarc. The acidic solution was extracted with mix ethyl acetate (3 × 50 ml). Pie extracts were combined, with water, saturated Pnlzlcsun ,? gcv / ash and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the product was obtained as a yellow oil. Yield; O'C mr (21, 650.

r by dissolving in 1 ir.l Ϊ. thy lace did and the addition of a light "jberpchus? e- £ an I ¹ T - \ + hylpiperidine, the product was converted into the crystalline li-ethyl piperidine salt. The salt was collected, washed with ethyl acetate and dried.

Similarly, the following penicillins were prepared from the appropriate participants in the exercise.

009 811/1625

BA1D OFHÖINÄL

R ₁ -CH-CO-NH-R ₄

COOR.

(R. = the penicillanic acid residue)

R.

5-indanyl (Cl-COOR ¹ ) Phenyl 4-Indn.nyl ethyl Phenyl 2-1sopropylphenyl Isobutyl Phenyl 3,4-dimethylphenyl Benzyl Phenyl -CH ₂ -CH ₂ -N (Ii-C ₃ R ₇ ) 2 ethyl Phenyl -CH p-CH p-rao rpho lino
5-indanyl n-propyl Phenyl
3-thienyl 2-isopropylphenyl n-propyl
ethyl 3-thienyl 2-methoxy ----- methyl-
phenyl ethyl 3-thienyl -CH p-piperidino
-CH ₂ -CH ₂ -CH ₂ -N- ethyl 3-thienyl
3-thienyl -CHp-iraidnzolo ethyl
ethyl 3-thienyl 5-indanyl Ethyl ■ o-chlorophenyl 5-indanyl ethyl P-methoxyphenyl 5-indanyl ethyl ρ - T ri ι luo rme th y 1-
phenyl 5-indanyl ethyl p-E'imethylamino-
phtnyl 2-isopropylphenyl ethyl p-chlorophenyl 5-indanyl ethyl 2-th.iunyl 4-chloro-2-methyl
phenyl n-propyl 2-thicnyl 5-indanyl n-propyl 2-pyridyl ethyl

009811/1625

-Hz-

R,

5-indanyl (Cl-COOR ') 4-pyridyl 5-indanyl ethyl 2-furyl -CH ₂ CH ₂ -NCn-C ₃ H ₇ ) ₂ ethyl A pyridyl 2-isopropylphenyl Benzyl ■ 1-pyridyl 2-3iphenyl ethyl Phenyl 3-kethoxy-2-biphenyl ethyl Phenyl 2-nitro-4-biphenyl ethyl Phenyl 4- (2-carbomethylethyl) -
phenyl ethyl Phenyl 2-methoxy-4- (2-carbo-
raethoxyvinylphenyl methyl Phenyl 2-biphenyl methyl 3-thienyl 2-biphenyl methyl p-chlorophenyl 2-biphenyl methyl 4-pyridyl 2-t-butyl-; -mexhoxy-
phenyl. methyl 3-thienyl 2- t-butyl-4-αε-thoxyphenyl methyl ρ-methoxyphenyl 2-t-butyl-4-methoxyphenyl methyl 4-pyridyl 2-1 ?, IT-Ia benzylaminoethyl JTethyl Phenyl 3- (1-3enz; / lpiperidyl) ethyl Phenyl 3-TT-acetylaminopropyl ethyl Phenyl S- phenylP.llyl Ethyl Phenyl T -phenylpropargyl methyl Phenyl methyl Example 12 Potassium salt νόη ~ «Γ-Carbo (2-tsipheriyloxy) benzylpenicillin c £ -Carbo (2-biphenyloxy) phenyl acetic acid

90 g of phenylmalonic acid (0.5 mol), 85 g of o-phenylphenol (0.5 mol), 0.8 ml of T _f 5F-dimethylformaride, 725 ml of isopropyl ether and 59.5 g of thionyl chloride (0.5 mol) were combined , stirred and refluxed in a steam bath for 2 hours tx-hi

009811/1625

6AD ORIGINAL

-H3-

The mixture was cooled to room temperature, then washed with water (3 × 50 ml) and extracted with saturated aqueous sodium bicarbonate solution (3 × 100 ml). The combined aqueous extracts were washed with ether (2 χ 25 ml), then acidified with 6 η hydrochloric acid to pH 3 and extracted again with ether (50 ml). The extracts were gown first with water (2 × 15 ml) and then with saturated aqueous salt solution (2 × 15 * nl), then dried over anhydrous sodium sulfate and evaporated to dryness. Yield: 90.3 g of tL -carbo (2-biphenyloxy) phenylene acetic acid

Acid chloride of carbon color (^ -

In c in ari equipped with a kuhi he and Trockenrchrehcn dry flask -OG "C-Carbc (2-foiphenylc xy) were phcnyl-. acetic acid (0.135 McI) ₁ -50 nil! • ■ ethylt.r.chloride, 0.1 ml anhydrous. Ιϊ, Κ-Γ-int thylfonn.-a-iid and 16,6G g ühicn; '! - chlcrid (0,1-'C McI; gtLiricht. Da? Gt. Mi sch v / urät 3? Do the. Under Heated reflux. Γ- · ί ^; T. '^ Thyienchlcridlönungsritt * · :! was under rcdu? Icrtt.m I ^ ick cntfon: ⁴ ", an sohl ic ϊί-ηΐ nit additional: r. 200 rl dtr Lcs'inrsr. ittc-lr - / tvcttzz and: I .--. f vfcn wiedorhclt, v.'cb ".: - ^ g -jir.t?" rub Γ1? -rwere.

tC -Carbu (2-biphenylcxy) bcr .. ^ ylpt-ni ji "Eint slurry vcr,? 9, .1f g '; -Anii: icpenic-illanoic acid (0.1 ^ 5 mol) in? 0C- T ₁ I! "Ethyler.ekleri'd -.vur-ie at R ^ uritt-peratur under echr.i-iiKoiire-r. mixed with 27.27 g of triethylamine (0.27 mol), after Z hours. was there ?. Mixture was filtered at 5 "G gtkühiyand with '3 g of the acid chloride vcn JL-carbo (2-biphenyl-rxy) i: heTiylfcssigsäurc (? 0, ¹ 5 mCi) in 2OC rrl Kethlynechlcrid offset, wherein the speed of Zagrzbe held se v -was when the tem-

009811/1625

ρ "era door The residue did not exceed 1O ⁰ C. The mixture was then stirred for 1 hour- diluted ml at 100, stirred at pH 2 adjusted c and vigorous. The methylene chloride phase was separated, dried and evaporated over sodium sulfate to dryness. was taken up in 300 nil ethyl acetate, the solution was washed with water (3 × 15.0 ml) and extracted with saturated aqueous sodium bicarbenate (3 × 150 ml), the aqueous extract was washed with ethyl acetate and then in the presence of 300 ml of freshly distilled ethyl acetate - acidified to pH 2..

Lid suspension was mixed vigorously, the ethyl acetate - "" ■ oh'-ipe "ürra one after the other with V-'asser (3 x 150 ml) and more saturated Brine (3 x 150 ml). Then ■ dried (anhydrous sodium sulfate) and under reduced Truck evaporated to dryness.

The residue was dissolved in 1.0 ml of ethyl acetate, and 2 g of F-ethylpiperidine were added. The residue was inoculated and left to stand overnight. The product was filtered, washed with ethyl acetate and air-dried. Yield; 37.5 g; melting point 131-133 ⁰ C (decomposed).

By "adding 16 ml of an ethyl acetate solution, which is 0.283 g Kaliura-2-ethylhexanoate per ml contained to form a slurry of 10 g ϊϊ-ethylpiperidine salt in 100 ml dry Benzene, the product was converted to the potassium salt. D. The mixture cleared. It was based on a steam room 45 C heated, inoculated and kept at room temperature. The product was filtered off and washed with 5.37 g of ether

009811/1625

- 45 -

"Example 13

The above procedures were repeated, but using the following phenol derivative instead of o-Phenylphenol: butylated hydroxyanisole

A -carbornethoxyethylphenol

4-carb: i thoxy methylphenol

4-carbonomethoxyraethylphenol

The following esters have been used as their N-ethylpiperidine salts C'NÄP) produced:

Penicillins (as NAP Sal 2) melting point ( ⁰ C.)

<£ -Carbo (2-t-butyl-4-: nethoxyphene-

oxy) benzylpenicillin 148-52 (decomp.)

oC-Carbo (4-carbomethoxyethylphen

oxy) benzylpenicillin 94-96.5 (decomp.)

ef -Ca.rbo (4- carbä thoxyme thylphen-

οχγ) benzylpenicillin 104-06 (decomp.)

eC-Carbo (4-carbome thoxyme thy 1-phenoxy) benzylpenicillin 89-92 (decomp.)

The products were made using or sodium Potassium 2-ethylhexanoate, as described above, in converted to their sodium or potassium salts.

Phosphorus oxychloride rather than thionyl chloride is used to produce the half-esters of malonic acid with these phenol derivatives used,

00981.1 / 1625

Example 14

By following the procedure of Example 2, the products of Examples 3 and 7-11 were converted into the sodium and potassium salts converted.

Example 15

According to the methods of Examples 1 to 3 and 7 to 11, iedoch replacing vcn TT-Xthylpiperidin by the appropriate amine the following ^ Salje of the described compounds were prepared: IT Hethylpiperidin-, Triäthylamin-, tributylamine, Ν, Ν'- Bibenzylethylenediamine, procaine and dibensylamine salt.

Preparation A

Malonic acids ■

The following arylmalonic acids, not previously described in the literature, were prepared by the Wallingford method et.al, J. Am. Chcm. Soc. 63, 2056-2059 (1964), where an alkyl carbonate, usually diethyl carbonate, with an equiinol / ren amount of the desired ethylarylacetate in the presence of an excess (4-8 times) of P sodium ethylate with continuous removal of the than By-product resulting / ilkchols from the reaction mixture was condensed. The esters so produced were hydrolyzed to the acid by known methods.

COOH
COOH

009811/1625

19A4379

»1 ^R 1

o-methoxyphenyl 3-pyridyl

m-Mcthexyphenyl! pyridyl

p-Methoxyphynyl o-Butoxyphenyl

o-Trifluoromethylphonyl o-Dimethylaminophynyl

m-Tri fluorine thylphenyl c-diethylaminophenyl

p-Trifluorrae thy lphenyl ni-Diiae thylaminophenyl

c-isopropylphenyl p-dimethylaminophenyl 3-furyl

"! ic required o-Trifluort> henylessigsäure was prepared by the method yon Corse et al, J. Am. Chem, Sec. 70, p? .B ^ (1948) Pure c-Trifluorberizonitri-1, where ( a) the nitrile * by Grignard reaction with methyl magnesium3cdid · ^{4 "+} was added to o-Trifluormethylace tophencn umgewandc I and (b) the acetophenone reacted for 16 hours at 135 C with sulfur and Mcrphclin and was subsequently treated with glacial acetic acid and hydrochloric acid.

Preparation B

Phenylchlorocarbonyl ketene

1. 20 ft of phenylmalonic acid in 100 ml of ethyl ether was admixed with A £ ρ Phesphcrpentachlorid. The reaction mixture was heated under reflux for 4 hours and then partially removed by heating in a steam bath. The reaction mixture turned black after about half of the ether had been removed .

⁺ and subsequent hydrolysis

009811/1625

BAD ORIQfNAL

The remaining ether was removed under reduced pressure (at 100 mm). The pike stand was distilled under vacuum and collected at 75 to 9O ⁰ C for 1.5 to 4 mm fraction boiling. The product, a yellow liquid, was demonstrated at 74 ⁰ C and 1.5 mm destilliert.Das infrared spectrum again at 4.69 myu a staken peak.

When this procedure was repeated, however, using 10 g of phenylmalonic acid instead of 20 g, the reaction was less violent when phosphorus pentachloride was added. P instead. The same product was obtained.

2. A stirred solution of 10 g of phenylmalonic acid in 50 ml ethyl ether was initially cured at a temperature of 0 ° to 5 ⁰ C within von.5 minutes with 23 g of phosphorus pentachloride. The temperature rose to 13 ° C. during the addition. The mixture was then refluxed for 5 hours and stored overnight at room temperature. By removing the ether at 20 mm vmrde, a dark concentrate was obtained which was distilled in vacuo, where the desired product was obtained: boiling point 80 to 88 ° at 1.5 to 2 mm and 74 ⁰ C. at 0.2 ram. , - ■■ -, '. ι. ·> ...: '

* 3 · 10 g of phenylmalonic acid were added within 2 minutes to a stirred solution of <] 6 g of phosphorus pentachloride in 100 ml of ethyl ether. The mixture was 4 hours; stirred at room temperature, then heated under reflux for 4 hours and stored overnight at room temperature. The excess phosphorus pentachloride was filtered off and the ether boiled off at atmospheric pressure. The reaction mixture gradually changed color from dark yellow to red. The residue was distilled in vacuo to give the product. Boiling point 83 to 86 ° at

009811/1625

BAD OFHGINÄU

1.5 well. The product was obtained as a yellow liquid,

The .Vorfahren for the production of the preparation B-3 was repeatedly, but using the appropriate malonic acid derivatives instead of the phenylmalonic acid esters to give the following compounds.

R ₁ -C = O

O = C-Cl

^L 1

2-thienyl 3-thienyl 2-furyl o-tolyl m-tolyl P-tolyl o-methoxyphenyl m-methoxyphenyl p-Methoxyphenyl o-! Tri fluorine thylphenyl p-Trifluoromethylphenyl ra-Trifluoromethylphenyl o-isopropylphenyl

3-puryl

2-pyridyl 3-pyridyl 4-pyridyl o-bromophenyl o-chlorophenyl p-chlorophenyl m-chlorophenyl o-But oxyphenyl ο-dimethylaminophenyl o-Diethylaminophenyl m-Dimethylaminophenyl p-dirnethylaminophenyl

Preparation C

Arlycarboxy-acetene esters - general manufacture

A solution of 0.1 mole of the appropriate aryl halocarbonyl ketene in meth ^ lene chloride (sufficient to produce a clear solution and generally from about 5 to 10 ml per gram of retentene) was mixed with the appropriate alcohol R _? OH (0.1 mol) added. The reaction mixture was under a

009811/1625

Maintained a nitrogen atmosphere and stirred for 20 minutes to 3 hours, working with the exclusion of moisture. The temperature range was between about -70 C to -2O ⁰ O.

The reaction mixture was mixed with 200 ml of water and then with 3 equivalents of sodium bicarbonate. The mixture was ^{warmed to 0} ° C. and stirred for 1/2 hour, a strong emulsion being obtained. The methylene chloride was removed under reduced pressure at a temperature below 35 ⁰ C and the remaining aqueous solution with "4ther extracted The Jitherextrakt was washed with water (made it with sodium bicarbonate to pH 8 alkali was) washed (back-washed), with anhydrous sodium sulphate dried and evaporated leaving the unreacted alcohol »

The basic aqueous solution was ^{cooled to 10 °} C., adjusted to pH 2.0 with dilute hydrochloric acid and then extracted with methylene chloride. The extract was dried with anhydrous sodium sulfate and evaporated to dryness to give the malonic acid half ester.

The esters were made ready for use without further purification the cC-carboxyarylpnicillin esters described above were used.

Preparation D

Acid chlorides of arylmalonic acid half-esters rn - General ^;

Manufacturing

A solution of malonic acid half-ester in methylene chloride (approximately 10 ml per g ester) and tionyl chloride (1 equiva-

009811/162 5 " _A _

BAD ORiQiNAL

equivalents) were heated for 3 hours under gentle reflux .. The methylene chloride - solvent and other volatiles were removed by evaporation under reduced pressure _t removes the acid chloride product was obtained. The acid chirides were used without further purification.

Preparation E ■ * *.
Aminoisopropanols

The following aminopropanols were prepared by reacting propylene oxide with the appropriate amine. In general, the process consists in reacting the propylene oxide with an aqueous solution of the amine in a molar ratio of 1.0 to 1.4 in a closed tube. The sealed tube was shaken and stored overnight, after which it was heated to .80% for 6 hours. And then heated ^{at 95 °} C. for 4 hours. Dae pipe v / urdr _; then cooled, the contents removed and the aminoisopropanol salted out with potassium carbonate.

The product was, in the fall; a liquid, separated. dried with solid potassium hydroxide and then urr.fc * - distilled under reduced pressure. FpIIg> Ias product as If solid was present, it was filtered off and unacrystallized from a suitable solvent.

Dime thy lm & ino

Diethylamiiio

Di-n-propy! Amino

Diieopropy! Amino

Di-n-butylamino

1 »415,6-tetrahydropyrimidino n-A * thy lpiperazine ο

009811/1625

19U379

im -r>

5

Piperidino Pyrrolidino Pyrrolo

Morphclino

Thiomorpholines Imidazoline Imidazolino

Preparation F 2-aminopropanol The following 2- / uninoprop''inols of the general formula

in which NR ^ R ₆ denotes a di- (lower alkyl) amine or a hetero-ocyclic radical, are produced according to the method of Moffett, Org.Syn., Volume IV, p. 834, the

Lithium aluminum hydride reduction of the appropriate ester the formula,

H ₅ C ₂ OOC-CH-NR ₅ R ₀

CH-,

comprises, the esters according to the method - / or, lioffot-j, Org.Syn., Volume ivy p. 466 by reaction of the g with ethyl C -bromopropion? .t hcr / 5-.stollt beo./

00981 1 / t625 _i;

BADÖRIGiNÄL,

19U379

Di (n-propyl) amino Oi (η-butyl) amino Diisopropylamino

1,4,5,6-tetrahydropyrimidino

N-methylpiρeraζinο N-n-Butylp ip e raz in ο Piperidino Morpholine Thi ο mo r rrtio 1 ino Pyrrolo Imidazolino Imidazolidino

009811 / Iff25

Claims (11)

Claims · ^, ■■.-......, -. ■ - ^ ■ ». r 1. -Carboxy-arylmethylpenicillin derivatives of the general formula '' ■ _ '. " OH - - .- S - - ■■ - III / \ R ₁ ^ CH-CN-CH CH C (CHO ₀ II! I ³ ι C = O O = C-N CH-COOH 'Ro and their pharmaceutically acceptable salts, in which R. a Thienyl, furyl, pyridyl, phenyl or substituted Is phenyl, the substituent being a lower alkyl, lower alkoxy, di-lower-alkyl-amino or trifluoromethyl radical, or is a chlorine or bromine atom; and Rp is one of the following radicals; 3 -, / 1- (Rr-. Substit.) -Piperidyl / - ₂₂₅ g
-CH (CH.) - CH ₂ -NR ₅ R ₆ . -CH ₂ -CH (CH ₃ ) -NR ₅ R ₆ where Rp- is a hydrogen atom, a lower alkyl or benzyl group, and Rg is a lower alkyl, lower k alkanoyl, benzyl, phenyl or lower carbalkoxy group, where R ^ is a lower carbalkoxy group when R _{c is} hydrogen is atom, and R _n . and R _{r are} not at the same time an alkyl, if'-phenylallyl, ^ * - (substit. Phenyl) -allyl radical, in which the substituent has at least one chlorine, bromine or fluorine atom, a lower alkoxy, lower alkyl, T is nitro or methylenedioxy; a ^ ■ Phenylpropargyl- or iJF * - (phenyl-substit.) -Propargylrest, in which the substituent is a lower alkyl, lower 009811/1625 BAD OFHGlNAl. Is alkoxy or nitro group or a chlorine or bromine atom; or one of the leftovers -Ci- ν . odor in which X ₁ is a chlorine, bromine or fluorine atom, a lower alkyl or lower "lkox" ygruppe, _X? is a chlorine atom or a lower alkyl group), U represents a phenyl, carboxyvinyl, lower Carbalkoxyvinyl-, lower Carboxyalkyloier lower Carbalkoxy lower alkyl group, and X ^. A nitro or di (lower aikyl) amino, or monosubstituted phenyl group, in which the oubstituent is a phenyl, carboxy vinyl, lower carbalkoxy vinyl, 'Carbalkoxy lower alkyl or a lower carboxyalkyl group.' 2. Compounds according to claim 1, in which-E _{1 is} a p-chlorophenyl, and R _? are an alkynyl group, as well as their pharmaceutically acceptable salts. 3. Compounds according to · Claim -1, in which R _{1 is} a phenyl and R _{1 is} a'-phenylpropargyl group, and their pharmaceutically usable salts. 4. Compounds according to claim 1, in which R _{1 is} a phenyl group and Rp is a phenylallyl group, and their pharmaceutically acceptable salts. 009811/1625 Γ ^BAD OR _mHAL 5. Compounds according to .Anspruch 1, in which R: "fine" p-chlorophenyl and R ₀ a propargyl group siride, and their pharmaceutically useful salts. 6. Compounds according to claim 1, in which R. is a phenyl group and R _{0 is} a substituted phenyl group, at least one substituent being a phenyl radical, as well as their pharmaceutically acceptable salts. _; 7. Compounds according to claim 1, in which R _{1 is} a phenyl group and Rp is a substituted phenyl group, at least one substituent being a lower carbalkoxy-lower alkyl group, and their pharmaceutically acceptable salts. i. '. ■ ".. '. ■■■. ■■■. 8. Compounds according to claim 1, where R _{1 is} a phenyl and Rp is a ^ -tert. 9. Connections g? M | 3i ?. Claim 1, in which R _{1 is} a phenyl group and R ^ _{- is} an S-bisphonyl group, as well as the pharmaceutically usable "SaI z ^: e» 10. Compounds according to claim 1, in which R _{1 is} a phenyl and Rp is a P-Cerborethoxymethylphenylgruppe, and their • pharmaceutically acceptable salts. ■ - / ■! . ■ ■■ ■ ■■■■ .- ψ 11. Compounds according to /jnn.pruoh 1, in which R. is a phenyl group and R ^ de.r FiOPt -GH ₀ -CH.-NR _r Rg, in which R, - a lower alkyl and Ty a lower one Alkanoyl group means, as well as their pharmaceutically acceptable salts. Ί 2 ^ compounds according to claim 1, in which L is a phenyl and R _{2 is} a 3- (l-benzylpiperidy] ^ group, as well as their pharmaceutically acceptable salts. 009811/1625 13. Compounds according to claim 1, in which R. is a phenyl group and Ep is the radical -CH ₀ -CHp-NRcR'- Bind, in dom Rj- and Rg are benzyl groups, and their pharmaceutically acceptable salts. 14. Compounds according to claim 1, in which K _{1 is} a phenyl group and Rp is the remainder -CH ₂ -CH ₂ -?!; 'CO-CH are, as well as their pharmaceutically acceptable salts. 15. ^ - Carbo- (2-biphenyloxy) -benzylpenicillin. 16; . </ "- Carbo- (4-carbomethoxymethylphenoxy) -benzylpenicillin. 17 · ds- 'Carbo- (2-tert-butyl-4-methoxyphenoxy) -benzylpenicillin. 18. Process for the preparation of - -.- Carbox ^ -ary! Methyl penicillin derivatives the general formula CH-C -NH -CH - CH ( CH-, COOR, CIi ⁽ -COOM in which M is a hydrogen atom, sodium, potassium or am Tri- (lower-alkyl) -amine means, characterized in that in a reaction-inert solvent at a Temperature of about 0-50 ° C and a pH value of about 5-8 a compound of the formula 009811/1825 CH- -CH -CH CH -COOH reacts with an acylating agent of the general formula CH COX OOK in which X ssin is Clilor or bromine or the radical -OGORy , in which R _{7 is} a benzyl or lower alkyl group, and R. is a thienyl, furyl, pyridyl, phenyl or substituted pnenyl group, in which the Sufcstituent is a lower alkyl, lower alkoxy, di-lower-alkylamino or trifluoromethyl radical or a chlorine or eromatic atom and R 1 is an isopropylphenyl radical or one of the radicals of the general formulas "4 il 009811/1625 BATH in. the X- a chlorine, bromine or fluorine atom, a lower alkyl or lower alkoxy group; X _{2 is} a lower alkyl group or a chlorine atom; X ^ is a hydrogen atom, a methyl, phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower carboxyalkyl or lower carbalkoxy- lower alkyl group; and X. are a Nijfcrö or di (lower alkyl) amino group; furthermore a monosubstituted phenyl group, the substituent being a phenyl, carboxyvinyl, lower carbalkoxyvinyl, lower carbalkoxy, lower alkyl or lower carboxyalkyl radical; an aylated indanyl radical or a dessin-substituted derivative, the substituent being a methyl group or a chlorine or bromine atom; denotes a tetrahydronaphthyl radical or its substituted derivatives, where the substituent represents a methyl group or a chlorine or broro atom? and R _{7 can} also mean one of the following radicals:. 1-lower- * 1-koxy-, 2, c, 2-triehloroethyl-, 1-lower-alkoxy-c, 2,2-trifluoroethyl-, lower carbalkoxy-lower-alkoxymethyl-, di-lower-c arbalkoxy-low-alkoxymethyl-, 3- / 5 - (E ₅ -SUbSt it ») piperidyl / -, -CII ₂ -CH (CH,) - HRcK ₆ 1 - (Sl (CH,) - CK ₂ -Krt5R ₆ or lower-alkylene-Y., where m is a whole ^ c number of 2-3, R ^ is a hydrogen atom, a lower alkyl or a benzyl group, and Rg is a lower alkyl, lower alkanoyl, benzyl, phenyl or lower carbalkoxy group, and where Rg is a lower alkanoyl or lower carbalkoxy group when R ₆ . is a hydrogen atom; and T ". erner of the following residues; 009811/162 1944373 . . ■ ■■ "■■■■" ■■■ 'Asetido—, - ■. "■■" " Aairidino,
Pyrrolidino,
Piperidino,
Morpholine,
m "■ -" ■ ".- ■. Thiomorpholine- * • TI-lower-alkyl-piperazino-, - "Pyrrole-,. ■ · '-". Iraidazolo-,
2-Imidaaolino ~,
2,5-Mmathyl pyrrolidino-, 4-methylpiperidino or . 2,6-Dimotiiylpiperidino- means that v / p in each of the lower alkoxy, alkanoyl and alkyl groups comprises 1 to 4 carbon atoms and the lower alkylene radical has 1 to 3 carbon atoms furthermore 'dp the rest. "- or a substituted derivative thereof, where Z is an alkylene radical, namely a. - (CHp) -.- or - (GHp) / - Eest, 'and wherein the substituent is a methyl group or a chlorine or bromine atom; or eihe / ^ phenylallyl-, ./-'-substit.-Phenyl-allyl-, in the the substituent is at least one chlorine, bromine or fluorine atom, a lower alkoxy group, lower alkyl, nitro or Methyl end iöxy group, a / - ^ phenyl propargyl, / * - substit, -phenyl-propargyl group is in which the substituent is a chlorine or bromine atom, a lower alkoxy, lower alkyl or Is nitro group. : 009811/16 25 ^Bm 19 · Method according to claim 1, characterized in that an acylating agent of the general formula COCl RfXTI '■ COOR ₂ - used, in which R. and R _{0 have} the meaning given in claim 18. For Chas. Pfizer & Co., Ine, New York, H.Yr, V.St.A. (Dr.H.Chr. Beil) Lawyer 0 0981 YJ 1625