CA1087184A - 1-aminocycloalkanealkanoic acids - Google Patents

Abstract

ABSTRACT
There are described acids of the formula (I) wherein R and R1 are, independently, hydrogen or lower alkyl; X is hydrogen or methyl; Z
is an amino group or an amino group protected with a removable blocking group and n is an integer from 1 to 5, and when n is 3 R2 is hydrogen, their salts and their derivatives useful as acylating agents for introducing the acyl group of the acid. The compounds are useful for the preparation of 6-[2-(1-aminocycloalkyl)acetamido-penicillanic acids end their salts which are anti-bacterial agents. The amino acids are prepared by hydrolysis of a B-lactam of formula

Description

AHP-5749-Can*
~ ` 1087184 This invention relates to 1-aminocycloalkanoic acids, their salts and acylating derivatives, for example, the N-carboxy amino acid anhydrides which compounds are intermediates in the preparation of new penicillins. The penicillins possess 5 broad-spectrum antibacterial activity, are highly soluble in ~ -water, and provide high and prolonged blood levels after - parentaral or oral administration.
The 1-aminocycloalkanoic acids of tha present invention and corresponding compounds with a protected amino group are compounds of the ganeral formula (I) R

CH\ Z
(C~ /c < 1l CH CHC~H (I) ¦ R2 R~ ~
: -wherein R and R are, independently, hydrogen or lower alkyl;
R2 is hydrogen or methyl; Z i9 an amino group, optionally protected with a removable blocking group and n is sn integer from 1 to 5, and ths salts thereof, with the proviso that when n i9 3! R must be hydrogen.
The amino acids of formula I possess the inherent general physical properties of being high melting solids, substantially soluble in water, methanol and ethanol, and insoluble in ether, benzene, and chloroform. Examination of the comoounds produced -20 according to the hereinafter described process raveals upon infrarsd spectographic analysis, spectral data supporting the molecular structures herein set forth. The afor6mentioned AHP-5749 -Can*

physical characteristics, taken together with the elemental analyses, nature of the starting materials, and the mode of synthesis, eon~irm the structure of the new compounds.
The N-carboxyamino acid anhydridss of the present invention are eompounds of general formula (II):

O

CH / NH-C

CH~2)n C ; (II) CH ~ ~ CH-C~

wherein R and R1 are independently, hydrogen and (lower)-alkyl; R2 is hydrogen and methyl; and n is an integer from 1 to 5, with the proviso that when n is 3, R2 must be hydrogen.
The compounds of formula II possess the general physical -10 characteristics of being crystalline solids, soluble ~n ethyl aeetate, chloroform, and benzene and substantially insoluble ~ -in hexane. In water the compounds will hydrolyse to afford the amino acids of formula I.
Examination of the N-carboxyamino acid anhydrides 15 produced according to the hereinafter deseribed proeesses reveals upon infrared spectroscopic analysis spectral data conPirming the molecular strueture hereinbefore set forth.
` The aforementioned physical characteristics, taken together with the elemental analyses, nature of the starting material, 20 and the mode of synthesis, confirm the structure of the .,, . . .
.

^ AHP-5749-Can*
10~7184 compositions to be patented. ~.
The aminocycloalkaneacetic acids of formula I
and the N-carboxy amino acid anhydrides of formula II, are useful as intermediates for the synthesis of novel penicillins, namely the 6-[2-aminocycloalkyl)acetamido]
penicillanic acids of formula III

I I II / S \ / Ch3 CH C - CNH--~H - CH ¦ \CH3 f H \ NH2 ll l R1 . C02H

(III) and their acid sa~ts, where R, R1,R2 and n are as defined above.
The invention provides a process for the preparation o~ a compound of formula I or a salt thereof, wherein (a) a ~-lactam of formula R

C NH

C ~ ~ CH

where R, R1,R2and n are as defined above is hydrolysed and, if desired, a removable blocking group for the amino function is introduced.

AHP-5749-Can*

The invention also provides a process of preparation of a derivative of a compound of formula I possessing utility as an acylating agent, which comprises converting the compound of formula I into its derivative in manner 5 known per se.
The amino compounds of formula I ~hich are used in the synthesis of the penicillin of formula III, may be prepared according to the following reaction sequence, which illustrates schematically the preparation of a 10 specific embodiment, namely 1-aminocyclohexaneacetic acid:

S02Cl I
N

2 (A) VI VIII
Na2503 ; .: `

NH2HCl 0<~ C~,--IX VIII

The starting material for the synthesis is a methylene cycloalkane(VI),compounds ~hich are readily available or obtainable by well kno~n procedures. In the first ~ AHP-5749-Can*

step (A), a methylene cycloalkane (VI) is treated with N-chlorosulphonyl isocyanate in a raaction-inert organic solvent, such as ethyl ether, at 0-10C to give a N-chlorosulphonyl ~-lactam (VII). The N-chloro-sulphonyl ~-lactam (VII) is isolated and uséd directly for the next step (9) which involves reduction of the N-chloro-sulphonyl group to afford the ~-lactam (VIII). The reduction may conveniently be performed by dissolving the N-chlorosulphonyl ~-lactam (VII) in a reaction-inert organic solvent, preferably ethyl ether, and treating the solution with aqueous sodium sulphite. During the reduction, the aqueous phase is kept slightly basic (pH-7-a) by the addition of sodium hydroxide. The product is recovered from the organic phase by conventional procedures. Stepa (A) and (9) are described by T. Durst and M.J. O'Sullivan in J. Orq. Chem., 35, 2043 (1970). The ~-lactam (VIII) is then hydrolysed in an aqueous acid, such as concentrated hydrochloric acid, to give the l-aminocycloalkane acetic acid (IX) in the form of ` 20 the acid addition salt. The acid addition salt can be isolated by conventional procedures, for example, removing the solvent and recrystallising the residue, or, if desired, it can be converted to the free zwitterion form by passing a ~ater solution of the salt through a suitable ion exchange column, 2~ such as Dowex 50/HI, eluting with ammonium hydroxide, and evaporating the water from the eluant.

.
~:

AHP-5749-Can*
1~87184 It ~ill be obvious that 1-aminocycloalkanacetic acids other than 1-aminocyclohexaneacetic acid can be prepared by using an appropriats methylene cycloalkane in place of methylene cyclohexane and performing the 5 subsequent reactions using the intermediates produced therefrom.
It ~ill be obvious to those skilled in the art of chemistry that the 1-aminocycloalkane acetic acids may exist in solution as different ionic species, 1û that is, as a neutral dipolar ion (z~itterion),a cation, `
or an anion -- depending upon the pH of the solution. Such forms are readily interconvertible by adjusting the pH of ~
the solution with a suitable acidic or basic substance. -The 1-aminocycloalkaneacetic acids may be isolated 15 in the form of their salts, including acid addition salts at the amino group e.g., the hydrochloride, sulphate, fumarate, maleate, citrate, or the like; or the salts at the carboxyl group, such as alkali or alkaline earth metal, e.g., sodium, potasslum, calcium, magnesium and 20 aluminium salts; and as organic salts, e.g., salts of '' AHP-5749-Can*
10871~34 ;

primary, secondary or tertiary amines, such as triethyl-amine, dibenzylamine, N,N~-dibenzylethylenediamine, N-(lower alkyl) piperidine, and the like. Methods for preparing the salts ~ill be apparent to those skilled 5 in the art.
The N-carboxy amino anhydrides of formula II
are preparsd from the 1-aminocycloalkaneacetic acids of formula I by procedures well known in the art. A preferred method involves reaction of the 1-aminocycloalkaneacetic 10 acid with phosgene under anhydrous conditions in a reaction-inert organic solvent, as p-dioxane; this procedure is generally described in United States Patent 3,194,802.
The penicillins may be prepared by a process characterised in that 6-aminopenicillanic acid, or a 15 functional derivative thereof, is coupled with an acid, of general formula (I) -R O

' CH - CH-~OH
/ \ / 'R2 (C ~ ~n / C

~ CH ~ \ (I) .: I . .Z

or a functional derivative thereof, wherein R, R1, R2 and n have the same meanings defined above, and Z is an amino group or a group convertible to an amino group, such as a protected amino group, or, where necessary, the product obtained is subjected to treatment, for example by hydrolysis or alcohololysis, to remove a blocking group or, if necessary the protecting group (Z) is removed in known manner; and, if desired, a salt is formed nr a salt is converted to -; a compound of formula III.

--AHP-5749-Can*

The eoupling reaction between 6-aminopeniecillanic acid, or a functional derivative thereof, and a carboxylic acid of formula I, or a functional derivative thereof, may be carried out using methods generally known to form amide 5 bonds in peptide and penicillin chemistry. Such methods ~ -are diselosed by E. Schroder and K. Lubke, The Peptides, Vol. 1, Academic Press, 1965 and by J. Greenstein and ~ ~ -M. Winitz, Chemistry of the Amino Acids, Vol. 2, Oohn wiley and Sons, Inc., 1961.
When a functional derivative of an acid of formula I is employed for the coupling raaction, suitable derivatives are, acy1ating derivatives, for example: an anhydride or mixed anhydride ~ith an organie or inorganie aeid, an aeid halide, or a functional ester (e.g. p-nitro phenyl ester) derived from the acid. Moreover, the acid (I) itsslf may be used in the presenee of a dehydrating or functionalising agent such as carbodiimide (e.g. dicyclohexyl carbodiimide), N,N'-carbonylidiimidazole, or an alkoxyaeetylene. The acylating derivatives of compounds of formula I ean be prepared in known manner. To prepare an anhydride, the acid is treated with a dehydrating agent; to prepare a mixed anhydride it is treated with an aeylating agent derived from an organic or inorganic aeid; and to prepare a corresponding acyl halide it is reacted with a halogenating agent such as a thionyl halide or phophorus pentahalide.
When using such derivatives for the coupling reaction, free amino groupsare proteeted. After the penicillin is obtained, the proteeting group is removed in known manner. When an amino group is protected, it is much preferred to use an ~' AHP-5749-Can*

N-carboxyamino acid anhydride since a separate step for removing the protecting group is thereby rendered unnecessary.
Protection can be by any of the protecting groups kno~n in the penicillin and peptide arts: for instance, (a) a 5 benzyloxycarbonyl radical which can, for example, be substituted such as with halo, nitro, or alkoxy in the benzene ring, particularly at the para position: (b) a benzhydryloxy-carbonyl radical; (c) trityl radical; (d) an alkoxycarbonyl radical particularly t-butyloxycarbonyl, allyloxycarbonyl or 10 ~ -trichloroethyloxycarbonyl; (e) a sulphur-containing radical such a~ tritylsulphenyl, o-nitrophenylsulphenyl or other arylsulphenyl radical; (f) or a radical obtained by reacting the ~ree amino group with a ~-dicarbonyl compound such as acstylacetone, acetoacetic ssters or benzoylacetone to 15 form enamines of Schiff bases or with an aldehyde, e.g.
an aromatic hydroxyaldehyde, to form a Schiff base; or a trifluoroacetyl or p-tolylsulphenylethoxycarbonyl group.
Protection can also be by protonation for instance as a hydrohalide or other acid addition salt. The removal or 20 protecting groups after the coupling reaction is accomplished by known methods, for instance, by mild or base catalysed hydrolysis or by hydrogenolysis over a noble metal or Raney nickel çataLyst. aenzyloxycarbonyl and relatad groups and trityl groups can be removed by catalytic hydrogenation or 25 electrolytic reduction; and a ~ -trichloroethyloxycarbonyl group can be readily removed by zinc in a lower alkanoic acid.

~ AHP-5749-Can*

~087~84 In the case of sulphur containing radicals, enamines, -and Schiff bases the protecting group is preferably removad by mild acid hydrolysis, for instance at a pH of about 2.
A tertiary butoxycarbonyl group is also preferably re~oved 5 by mild acid hydrolysis, especially with formic acid. An o-nitrophenylsulphenyl or related group can be removed by nueleophilic attaek on the sulphur atom of the sulphenamido group for instanee using thioaeetamide, an alkali metal iodide, a dithionite, or a thiocyanate.
A preferred compound for preparing the eompounds of formula I is a l-aminocycloalkaneacetie acid chloride hydroehloride having the formula (V) R -.

CH
/ \ j H2-(CH ~ / C

CH HCCl R1 ~2 (V) .
wherein R, R1, R2 and n are as hereinbefore defined. These eompound~ are prepared by treating 1-aminocycloalkane-15 acetic acid hydrochloride with a halogenating agent such as phosphorus pentachloride, in a reaction inert solvent, such as benzene.
The preparation of the penieillins is deseribed in more detail in our eopending Applieation Number 159,118.
As employed herein, the term "eyeloalkyl" means eyclic aliphatic carbon radical sueh as cyclobutyl, eyelopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

~. .

~~ AHP-5749-Can*
~0~71~4 The term also includes a cycloalkyl radical containing one or two (lo~er)alkyl group such as methyl, ethyl, or propyl substituted on tha carbon atoms adjacent to the carbon at which the cycloalkyl radical is attached to an adjacent 5 moiety. The term "lower alkyl" means an aliphatic radical -~
containing one to three carbon atoms, namely methyl, ethyl, and propyl.
The invention is illustrated by means of the fallouing Examples:-ExamPle I

~ solution of 1-azaspiro [3,5]nonane-2-one (9 9., 64.5 meq.) in concentrated hydrochloric acid (40 ml.) is stirred at room temperature for one-half hour. The solution is diluted with~water to a volume of 200 ml., and the solution extracted twice with ether. The water solution is then passed through a column containing Dowex 50/H+* ion exchange resin, and the column eluted uith 1N ammonium hydroxide. The eluent is evaporated to yield 12.6 9. of 1-aminocyclohexaneacetic acid.

ExaMple II

A solution of 1-azaspiro [3,5]nonan-2-one (4.6 9., 32.2 meq.) in concentrated hydrochloric acid (25 ml.) is Ytirred for one-half hour. The solvant is then evaporated to give a residue which is dried in a vacuum over KOH. The rssidue is dissolved in methanol. Ether is added to initiate crystallisation o~ a solid, m.p. 206-208C, which is l-aminocyclohexaneacetic acid, hydrochloride, hydrate.

AnalYsis for C8H1 N02.HCl 1/4 H O

Calculated:C,48.48; H,8.39; N,7.07; Cl,17.89 Found: C,48.74; H,8.13; N,6.77; Cl,18.08 *Trade Mark -12-^ AHP-5749-Can*
1087~4 Example III

8y employing the procedure described in Example I
and using appropriate starting materials in place of 1-azaspiro [3,5]nonan-2-one, the following amino acids 5 are preparad.
(a) 1-Amino-2,6-trans-dimethylcyclohexaneacetic acid, hydrate, m.p. 225-227C(d).
Analysi9 for C10Hl9No2- /4 H20 Calculated: C, 65.24; H, 10.36; N, 7.38 Found: C, 62.99; H, 10.34; N, 7.63 (b) 1-Aminocyclobutaneacetic acid, m.p. 243-244C(d).
Analysis for C6H11N02 Calculated: C, 55.79; H, 8.58; N, 10.85 Found: C, 55.27; H, 8.41; N, 10.a7 (c) 2-(1-Aminocyclooctyl)-2-msthylacetic acid (d) 1-Aminocyclooctaneacetic acid Analysis for CgH17N02 Calculated: C, 63.13; H, 10.00; N, 8.18 Found: C, 62.93; H, 10.C6; N, 8.18 Example IV

; A suspension of 1-aminocyclohexaneacetic acid (4.7 g.j30 meq.) in dioxane (500 ml.) is haated undar reflux while phosgene is passed 910wly through the .
~13-'~

' ,-~ AHP-5749-Can*
. :
10871~34 mixture. The flow of phosgene is stopped one-half hour after the reactants become completely dissolved.
Removal of solvent under vacuum yields an oily rssidue ~hich is crystallised from ethyl acetate-hexane to give 1-aminocyclohexanecarboxylic acid, N-carboxyanhydride, m.p. 132-133C.
Analysis for CgH13N03 Calculated: C, 59.00; H, 7.15; N, 7.65 Found: C, 59.20; H, 7.16; N, 7.59 Example V

9y employing the procedure of Example IV and using J appropriate starting materials in place of 1-amino-cyclohexaneacetic acid, the follo~ing N-carboxy-anhydrides , are obtained:
(a) 1-Amino-2,6-trans-dimethylcyclohexaneacetic acid, N-carboxyanhydride Analysis for C11H17N3 Calculated- C, 62.54; H, 8.11; N, 6.63 Found: C, 61.76; H, 8.02; N, 6.62 (b) 1-Aminocyclobutaneacetic acid, N-carboxy-anhydride (c) 1-Aminocyclooctane--methylacetic acid, l N-carboxyanhydride Analysis for C12H19N3 Calculated: C, 63.97; H, 8.50; N, 6.22 Found: C, 63.45; H, 9.25; N, 7.51 ~ AHP-5749-Can*
. .
10~71~34 (d) 1-Aminocycloheptaneacetic acid, N-carboxy-anhydride Analysis for C10H15N03 Calculated: C, 60.99; H, 7.67; N, 7.10 Found: C, 60.29; H, 7.86; N, 7.02 (e) 1-Aminocyclopentaneacetic acid, N-carboxy-anhydride -(f) 1-Aminocyclooctaneacetic acid, N-carboxy-anhydride Examplè VI

1-Aminocyclohexaneacetic acid, hydrochloride (86.0 9. 0.44 mole) is suspended in benzene (1050 ml.).
To the suspension is added with stirring phosphorus pentachloride (186 9., 0.9 mole) over a period of 5-10 minutes. During the addition the temperature is kept at 15-2bC. The mixture is stirred at this temperature range for 26 hours, after which benzene (400 ml.) is removed by evaporation at temperatures not sxceeding 30C. The concentrate is cooled to 8C and the crystalline -material present in the mixture is filtered. The precipitate iswashed three times with 75 ml. portions of benzene, and , '.

~ AHP-5749-Can*
10~7184 .
then dried undar vacuum at room temperature. Yield:
89.5 9. of the compound, 1-aminocyclohexaneacetic acid chloride hydrochlorida.

Example VII

N-(o-nitrophenylsulphenyl)-1-aminocyclobutaneacetic acid . . . ~
1-Aminocyclobutaneacetic acid (2.6 9., 0.02 mnle) is dissolved in 1N sodium hydroxide (20 ml.) and the resulting solution diluted with dioxane (30 ml.). To the solution is added o-nitrophenylsulphenyl chloride (4.2 9., 0.22 mole) while the pH of the mixture is maintained between 9 and 11 by addition of 2N alkali. The mixture is then stirred for 20 minutes after which it is diluted with water (200 ml.) and filtered. The filtrate is cooled to 0C, the pH is ! adjusted to 3.0 with dilute su~phuric acid, and is extracted with several portions of ethyl acetate (until the final extract is colourless). The pooled extracts are ~ashad ~ith water until neutral and finally dried over anhydrous sodium sulphate.
Removal of solvent gives 6.3 9. of the compound, N-(o-~ nitrophenylsulphenyl)-1-aminocyclobutaneacetic acid.
j 20 Recrystallisation from athyl acatate gives a sample having the following analysis:
Analysis for C12H14N2045 /4 H20 Calculated: C, 50.77; H, 5.07; N, 9.56%
Found: C, 50.26; H, 5.09; N, 9.71%

Claims (22)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the general formula (I) wherein R and R1 are independently hydrogen or lower alkyl; Z is an amino group or an amino group protected with a removable amino-protecting group, and n is an integer from 1 to 3;
or a salt or acyl halide thereof, or an N-carboxyan-hydride of the formula (II) wherein R, R1, and n are as defined above wherein:

(a) a .beta.-lactam of the general formula (III) (III) wherein R, R1, and n are as defined above, is hydrolysed; or (b) a .beta.-lactam of the general formula III is hydrolysed and the acid obtained is reacted to introduce a removable amino-protecting group to protect the amino group; or (c) step (a) or step (b) as set forth above is carried out and the acid obtained is reacted with a halogenating agent to form the acyl halide; or (d) a .beta.-lactam of the general formula III is hydrolysed and the acid so formed is reacted with phosgene to form the N-carboxyan-hydride of the general formula II.

2. A process for the preparation of a compound of the general formula (I) of Claim 1, wherein R, R1, and n are as de-fined in Claim 1, and Z is an amino group, wherein a .beta.-lactam of the general formula III

(III) is hydrolysed.

3. A process for the preparation of a compound of the general formula I of Claim 1, wherein R, R1, and n are as de-fined in Claim 1, and Z is an amino group protected with a remov-able amino-protecting group, wherein a .beta.-lactam of the general formula III is hydrolysed, and the acid obtained is reacted to introduce a removable amino-protecting group to protect the amino group.

4. A process for the preparation of an acyl halide of the compounds of the general formula I

(I) wherein the product of the process of Claim 3 is further treated by reaction with a halogenating agent.

5. A process for the preparation of an N-carboxyanhydride of the general formula II

(II) wherein R and Rl are independently methyl or hydrogen; and n is 1 to 3; wherein the product of the process of Claim 2 is further treated by reacting it with phosgene.

6. A process for the preparation of a compound of the general formula wherein R, R1, and n are as defined in Claim 1, wherein a .beta.-lactam of the general formula III of Claim 1 is hydrolysed, and the amino acid obtained is reacted in the form of its hydro-chloride to afford the acyl chloride.

7. A process for the preparation of 1-aminocyclohexane-acetic acid, or a salt thereof, wherein 1-azaspiro [3,5] -nonane-2-one is hydrolysed.

8. A process for the preparation of l-amino-2,6-trans-dimethylcyclohexaneacetic acid, or a salt thereof, wherein a .beta.-lactam of the formula is hydrolysed.

9. A process for the preparation of 1-aminocyclobutane-acetic acid, or a salt thereof, wherein a .beta.-lactam of the formula is hydrolysed.

10. A process for the preparation of 1-aminocyclohexane-acetic acid, N-carboxyanhydride, wherein 1-aminocyclohexane-acetic acid is prepared by hydrolysis of 1-azaspiro [3,5]nonane-2-one and reacted with phosgene.

11. A process for the preparation of 1-aminocyclohexaneacetic ?cid chloride hydrochloride, wherein 1-azaspiro [3,5]nonan-2-one is hydrolysed and the amino acid so obtained is reacted in the form of its hydrochloride with phosphorus pentachloride.

12. A compound of the general formula (I) wherein R and Rl are independently, hydrogen or lower alkyl;
Z is an amino group or an amino group protected with a removable amino-protecting group, and n is an integer from 1 to 3;
or a salt or acyl halide thereof, or an N-carboxy-anhydride of the formula (II) wherein R, R1, and n are as defined above whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

13. A compound of the general formula (I) of Claim 1, wherein R, R1, and n are as defined in Claim 1, and Z is an amino group, whenever prepared by the process of Claim 2 or an obvious chemical eguivalent thereof.

14. A compound of the general formula I of Claim 1, wherein R, R1, and n are as defined in Claim 1, and Z is an amino group protected with a removable amino-protecting group, whenever pre-pared by the process of Claim 3 or an obvious chemical equivalent thereof.

15. An acyl halide of a compound of the general formula I of Claim 4, whenever prepared by the processes of Claim 4 or obvious chemical equivalent thereof.

16. An N-carboxyanhydride of the general formula II of Claim 5, whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.

17. A compound of the general formula wherein R, R1, and n are as defined in Claim 1, whenever prepared by the process of Claim 6 or an obvious chemical equivalent thereof.

18. 1-Aminocyclohexaneacetic acid or a salt thereof, when-ever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.

19. 1-Amino-2,6-trans-dimethylcyclohexaneacetic acid or a salt thereof, whenever prepared by the process of Claim 8 or an obvious chemical equivalent thereof.

20. 1-Aminocyclobutane acetic acid or salt thereof, whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.

21. 1-Aminocyclohexaneacetic acid, N-carboxyanhydride derivative, whenever prepared by the process of Claim 10 or an obvious chemical equivalent thereof.

22. 1-Amino-cyclohexaneacetic acid chloride hydrochloride, whenever prepared by the process of Claim 11 or an obvious chemical equivalent thereof.