CA1082171A - Process for the production of penam and cephem derivatives - Google Patents

Abstract

Abstract of the Disclosure A process for the preparation of penam and cephem deriva-tives by reacting a phosphite amide of a 6-aminopenicillanic acid or 7-aminocephalosporanic acid with an acyl halide in an aprotic solvent in the presence of a phosphite halide scavenger.

Description

~0823 7~

This invention relates to a process for the preparation of penam and cephem derivatives by reacting a phosphite amide of the general formula:

Z-NH-CH-CH-S
I I I (I) CO-N -X
wherein X represents a group of the general formula:
ICH3 --Cl H2 f - CH3 or - f -CH2R
- CH-COOR - C-COOR

(Al) (A2) wherein the carbon atom adjacent to the COOR group is connected to the nitro-gen atom, Rl represents a substituted or non-substituted alkyl or aralkyl group, or a metal organic group, R represents hydrogen, an acetoxy group, cr -S-Het, wherein Het represents a heterocyclic group, and Z represents a group having the formula:

(CH~ ~ O / R -O /

(A3) (A4) (A5) wherein R3 represents an alkyl group, R4 and R5 are the same or different, and each represents an alkyl group, n represents 1 or 2, m represents 0, 1, or 2, with an acyl halide in an aprotic solvent.
Belgian Patents Nos. 809,110 and 840,060 disclose a process for the preparation of penam and cephem deriva-

-2-: , . .
~-. : -: : ~. .:

. . . , : . , ,, : .-. :
.
. .
: - : : : :

: ' 1~)82171 tives by reacting a phosphite amide of 6-aminopenicillanic acid or 7-aminocephalosporanic acid with an acyl halide in an aprotic solvent. This reaction produces penam or cephem compounds in high yields. The reaction is proton catalysed, and the reaction rate may be controlled by varying the proton concentration in the reaction medium, for example by adding as a proton source varying amounts of an acid addition salt of a weak tertiary amine option-ally in admixture with the weak tertiary amine itself. Examples of such amines are pyridine and N,N-dimethylaniline and examples of acid addition salts are hydrochlorides. The overall reaction proceeds with elimination of a phopshite halide, as exemplified in the following reaction scheme for the synthesis of the trime-thylsilyl ester of amipicillin:

Scheme 1 S CH3 ~ CH-COCl P-NH ~ ~ 3 ~ NH2,HCl O ~ N COOSi(CH3)3 O

C~-CO-NH ~ CH + C / P-Cl NH2,HCl N COOSi(CH3)3 (A) Phosphite halides, such as the compound having the formula A, while quite stable under aprotic conditions, react with hydrox-ylic reagents like water and alcohols. During synthesis, there-fore, hydroxyl groups and similar substituents should be properly protected. Problems may also arise when a hydrolytic step is in-cluded in a synthesis of such sensitive compounds as penicillinsand cephalosporins, unless the violent reaction between the phosphite halide and water is adequately controlled. Surprisingly, it has now been found that these obstacles may be overcome by adding a - ' . ~ ' .' 1082~71 phosphite halide scavenger to the reaction mixture.
Thus, according to this invention, the reaction be-tween the phosphite amide of the general formula I and an acyl halide in an aprotic solvent is carried out in the presence of a phosphite halide scavenger having the general formula R7 - Q - R8 (III) wherein Q represents a moiety of the formula -CH=CH-0- or -CH / CH- and R7 and R8 are the same or different and each o represents hydrogen, a substituted or non-substituted alkyl group, or an aryl group, or R7 and R8 together with Q form a heterocyclic ring, with the proviso that any symbol R7 and R8 connected to the oxygen atom in the moiety Q of the formula -CH=CH-0- does not represent hydrogen.
As mentioned above, Rl may be a substituted alkyl or aralkyl group. Examples of substituted alkyl groups are 2,2,2-trichloroethyl, p-bromophenacyl, pivaloyloxymethyl, and phthalidyl groups. Examples of substituted aralkyl groups are benzhydryl and benzyl groups which optionally are substituted by a nitro group in the benzene ring. Examples of a metal organic group are trialkylsilyl and, preferably, trimethylsilyl groups. Throughout the present specification and claims, the term alkyl, when used alone or in combination with other groups, designates a straight or branched alkyl group, preferably con-taining at the most 6 carbon atoms, more preferred 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, and tert.butyl .
.
,. . .
: .

. . . - .. : : . :
, .
, .
. .

group. Examples of groups having the formula A3 are 1,3,2-dioxaphospholan-2-yl and groups of the general formula A4 wherein R4 and R each represent an ethyl group.
It is preferred that the acyl halide to be used in the process according to the present invention has the general formula:

R6 _ CO - Hal (II) wherein R6 represents a naphthyl group; a cycloalkyl group sub-stituted with an amino group and optionally containing an oxygen or sulphur atom; a phenyl group substituted by one or more alkoxy group(s); a substituted heterocyclyl group; or a methyl group substituted with one or two of the following substituents:
a phenoxy, amino, cyclohexyl group containing one or two unsat-urated bond(s), a triazo, a substituted or non-substituted phenoxycarbonyl group, a substituted or non-substituted phenyl, alkyl, thienyl, cyano, hydroxy group, or a non-substituted or halogen substituted pyridylthio group, or corresponding groups containing a hydroxy or amino protecting group on a hydroxy or amino group, if any, and Hal represents halogen. Preferably R6 is a l-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetra-~ - 4a -" ' ' ' '': ' :

10~32~71 hydrothiopyran-4-yl, l-aminocyclopentyl, phenoxymethyl, 1-tl,4-cyclohexadienyl)aminomethyl, a-triazobenzyl, -(2,3-dihydroinden-5-yloxycarbonyl)benzyl, a-aminobenzyl or a 3-phenyl-5-methyl-iso-oxazol-4-yl group which optionally is substituted with halogen in the 2- and 6-position of the phenyl group, a 2,6-dimethoxyphenyl, p-hydroxy-a-aminobenzyl, l-phenoxypropyl, thien-2-ylmethyl, 1-naphthyl, l-(thien-3-yl)aminomethyl, lH-tetrazol-l-ylmethyl, or pyrid-4-ylthiomethyl group which optionally is substituted with halogen in the 2- and 6-position, a cyanomethyl, a-hydroxybenzyl, or p-(3,4,5,6-tetrahydropyrimidin-2-yl)phenylmethyl group, or corresponding groups containing a hydroxy or amino protecting group on a hydroxy or amino group, if any.
As mentioned above, R may be a -S-Het group, wherein Het represents a heterocyclic group. Examples of such heterocyclic groups are tetrazole, 1,2,3-triazole, 1,3,4-thiadiazole, and alkyl or carboxyalkyl substituted tetrazole, 1,2,3-triazole, and 1,3,4-thiadiazole groups such as methyltetrazole, carboxymethyl-tetrazole, and 2-methyl-1,3,4-thiadiazole groups.
Throughout the present specification and claims, the term halogen, when used alone or in combination with other groups, designates bromine, chlorine, and fluorine, most preferred chlor-ine.
An example of a compound containing an amino protecting group is a compound of the formula II wherein R6 contains a group of the formula -NH3 Z wherein HZ is an organic or inorganic acid.
Preferably, HZ represents HCl. An example of a hydroxy protecting group is a trialkylsilyl, preferably trimethylsilyl group, which means R6 contains a p-trialkylsilyloxy, preferably p-trimethyl-silyloxy group. It is also possible to use other compounds con-taining a protecting group, provided that said protecting group subsequently can be readily split off yielding the desired penam or cephem compound. -Examples of scavengers suitable for use in the process of the invention are epoxides and vinyl ethers which are capable of reacting quantitatively or almost quantitatively with the phos-phite halide as demonstrated in Example 1, in which 2-chloro-1,3,2-dioxaphospholane and propylene oxide are used as reactants in a control reaction. This reaction may be illustrated by the following scheme:

- . -: , . . ~ . : . , .- ~. : . : ,' - :~' , -- '' , ' . .

10~3Z173.

Scheme 2 0 CH3 1 3 ~ 0 ~ 1 3 O CH2~ CH2C1 CH -0-P / J
~VI) (VII) which, however is merely illustrative, not restrictive as to the scope of the invention.
Since the phosphite halide scavenger does not interfere with the amide forming reaction according to Scheme 1J the presence of a scavenger such as an epoxide or a vinyl ether will permit the reaction to be performed also with a reactant carrying an unprotected hydroxyl group, such as D-(-)-p-hydroxy-phenylglycylchloride, hydrochloride which is used in the preparation of p-hydroxyampicillin.
As indicated above, the phosphite halide scavengers suitable for usein the process according to the present invention are compounds of the general formula:
R7_Q_R8 (III) wherein Q represents a moiety of the formula -CH=CH-O- or -CH-CH- and R7 O
and R are the same OT different and each represents hydrogen, a substituted or non-substituted alkyl group, or an aryl group, or R7 and R8 together with Q form a heterocyclic ring, with the proviso that any symbol R7 or R8 connect-ed to the oxygen atom in the moiety Q of the formula -CH=CH-O- does not repre-sent hydrogen.
A preferred subclass of compounds of the general formula III is compounds of the general formula:

. . .. . . ~ . . ~, ~ .-: . :

.
: . . ~ .: :
- : - . ..
.. -- . . :' - . :

108Z17~
R -CH\
I / (IV) CH

wherein R9 represents hydrogen, a substituted or non-substituted alkyl group or an aryl group, and preferably compounds wherein R9 represents a methyl, chloromethyl, or phenyl group.
A further preferred subclass of compounds of the general formula III is compounds of the general formula:

R -CH=CH-O-R (V) wherein Rll represents hydrogen or an alkyl group, and R10 repre-sents an alkyl group, or R10 and Rll together with the -CH=CH-O-moiety form a heterocyclic ring, and preferably compounds wherein R 1 represents hydrogen, and R10 represents an ethyl or butyl group, or R10 and Rll together represent a trimethylene group.
It might have been expected that when the acylation of a phosphite amide with an acyl halide containing a free hydroxy group (e.g. when R6 represents a p-hydroxy-a-aminobenzyl gro~uF) is performed even in the presence of an excess of ~ ~ c tertiary amine, a reaction with the unprotected hydroxyl group would ensue, resulting in the production of a tertiary phosphite ester. The efficiency of the phosphite halide scavenger to block this reaction in the presence of a weak base, viz. N,N-dimethyl-aniline, is demonstrated in thé following Example 9.
The process according to the present invention is further il-lustrated by the following non-limiting examples.

:, . ., .- . . ., .:
. . : - -- : : . : . . . .: . . -.
- . . .:
: . , : ,, . .: . : - -, '' ' '. : .. ' . , : :. ' ' ' '-,, , . ~ . ' :
' . '- . , : , : .:: ' , ' .: .

Example 1 2-Chloro-1,3,2-dioxaphospholane (0.9 ml, 0.1 millimole) is dissolved in dry methylene chloride (5.6 ml) at room tempera-ture, and propylene oxide (3.5 ml, 50 millimoles) is added. A
slightly exothermic reaction ensues, producing a mixture of two compounds as shown by GLC. lP-NMR spectra of the reaction mix-ture shows two signals at ~ = 143 ppm and at ~ = 134 ppm and in-dicate that the two compounds formed have the formulae ~1 and III, respectively. No signal from the starting material (~ = 168 ppm) could be observed. Spectra were recorded at 36.43 MHz, and 85 per cent phosphoric acid was used as an external standard.
Upon addition of water to the reaction mixture chloride ions could not be detected by the addition of silver nitrate solution, but precipitation of metallic silver was observed.
The formation in a ratio of about 2:1vlof the t~wlo propylene chlorohydrins corresponding to Compounds VI~ and VIII stated in Scheme 2 was demonstrated by GLC.

Example 2 p-Hydroxyampicillin.
Diisopropylamine (84 ml, 0.6 mole), dissolved in dry methyl-ene chloride (400 ml) is cooled to 0C, and 2-chloro-1,3,2-dioxa-phospholane (27 ml, 0.3 mole) is added dropwise at this tempera-ture. After 30 minutes the temperature is allowed to rise to room temperature and 6-aminopenicillanic acid (64.8 g, 0.3 mole) and trimethylchlorosilane (38 ml, 0.3 mole) are added. When the slightly exothermic reaction has subsided, the mixture is stirred for three hours, cooled to 0C and filtered to remove the preci-pitated amine hydrochloride. To the cooled filtrate pyridine hy-drochloride (2.32 g, 20 millimoles), propylene oxide (70 ml, 1 mole) and D-(-)-p-hydroxyphenylglycylchloride,hydrochloride (54.5 g, 0.2 mole) are added with vigorous stirring. The reaction is completed after 40 minutes. The yield is estimated to be 94 per cent by titration following hydrolysis by means of B. cereus penicillinase. P-NMR spectra of this solution showed the two signals at ~ = 143 and ~ = 134 mentioned in Example 1.

'' ' ' ~ . , -:
.
- ~ - , The reaction mixture is poured onto ice-water with vigorous stirring, while the pH of the mixture is adjusted to 2 with so-dium hydroxide solution. After stirring for 30 minutes, the organic phase is removed, the aqueous phase washed twice with methylene chloride, and the product precipitated by adjusting the pH to 4.9 with aqueous ammonia solution. After two hours the product is isolated by filtration and washed on the filter with water. Yield: 69.2 g (82.5 per cent) of crude material of 83 per cent purity as estimated biologically against Sarcina lutea. Fur-ther purification may be performed by known methods.

Example 3 A reaction mixture is prepared as described in Example 2 from 6-aminopenicillanic acid (3.18 g, 15 millimoles), D-(-)-p-hydroxyphenylglycylchloride,hydrochloride (2.72 g, 10 millimoles) and propylene oxide (3.5 ml, 50 millimoles) but omitting the addi-tion of pyridine hydrochloride. This reaction is called reaction _ -In the same way another reaction mixture was prepared, this time with the addition of pyridine hydrochloride (116 mg, 1 mil-limole). This reaction is called reaction B.
These reactions were followed by enzymatic titration of the penicillin content at intervals:
.
Time Yield per cent:
minutes Reaction A Reaction B

3 47 ... ... . - : ., ,. :. .

.
. . . ~ . :
,:. ' ' ' :

108'~17~
Example 4 Two reaction mixtures were prepared as described in Example 3 B, except that the propylene oxide was replaced by dihydropyran (4.5 ml) and the amounts of pyridine hydrochloride were as fol-lows:

Reaction A: 116 mg (1 millimole) Reaction B: 1.74 g (15 millimoles) The reactions were followed titrimetrically:

Time Yield per cent Reaction A Reaction B

5 minutes 2 80 10 minutes 15 80 60 minutes 60 80 2 hours 74 3 hours 85 24 hours 85 Example 5 A reaction mixture as described in Example 3 B was prepared except that the addition of propylene oxide was omitted. The amount of pyridine hydrochloride was 116 mg (1 millimole). The reaction was followed titrimetrically:

Time Yield per cent minutes .
- . :
- - :

.
- . : . . . ,..... : .
- , : ,, . : .

108~

Example 6 A reaction mixture as described in Example 3 B was prepared, except that the propylene oxide was replaced by ethyl vinyl ether ~4.8 ml). The yield was estimated titrimetrically after 2 and 4 hours to be 77 per cent.
Example 7 In a reaction mixture as described in Example 2, the propylene oxide was replaced by 4 ml of epichlorhydrin (1-chloro-2,3-epoxypropane). The yield (obtained by titration) of amoxycillin was 90 per cent after 45 minutes.
Example 8 In a reaction mixture as described in Example 2, the propylene oxide - was replaced by 10.5 ml of styrene oxide. The yield (obtained by titration) of amoxycillin was 85 per cent after 45 minutes.
Example 9 2.8 ml (20 millimoles) of diisopropylamine dissolved in 15 ml of dry methylene chloride was cooled to 0C, and 0.9 ml (10 millimoles) of 2-chloro-1,3-dioxaphospholane dissolved in 5 ml of methylene chloride was added drop-wise. After stirring for 30 minutes, the temperature was raised to 20C, and 2.16 g of 6-aminopenicillanic acid were added, followed by 1.2 ml (10 milli-moles) of trimethylchlorosilane. After stirring for 3 hours at room tempera-ture the mixture was cooled to 0C, and the precipitated diisopropylamine,hydrochloride was removed by filtration. The filtrate was cooled to -15C, and 0.93 ml of a 2N solution of N,N-dimethylaniline, hydrochloride in methy-lene chloride, 1.3 ml of N,N-dimethylaniline and 3.5 ml of propylene oxide were added, followed by 2.4 g (9 millimoles) of p-hydroxyphenylglycylchloride, hydrochloride. The cooling bath was removed, and the temperature raised to 15C during 10 minutes. After reacting for 30 minutes the above-mentioned compounds VI and VII were identified in the reaction mixture by gas chromato-graphy. The yield, calculated against a reference standard solution, was 65%.
lhe yield of penicillin, as estimated by enzymatic titration, was 70%.

, . . . . . . . . . .
- . . ; ~ : . , , .
~ : ~
. .

Claims (19)

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 penam or cephem deriv-atives by reacting a phosphite amide of the general formula:

(I) , wherein X represents a group of the general formula:

or , (A1) (A2) wherein the carbon atom adjacent to the COOR1 group is connected to the nitrogen atom, R1 represents a substituted or non-substi-tuted alkyl or aralkyl group, or a metal organic group, R2 repre-sents hydrogen, an acetoxy group, or -S-Het, wherein Het repre-sents a heterocyclic group, and Z represents a group having the formula:

, or , (A3) (A4) (A5) wherein R3 represents an alkyl group, R4 and R5 are the same or different, and each represent an alkyl group, n represents 1 or 2, m represents 0, 1, or 2, with an acyl halide in an aprotic solv-ent; c h a r a c t e r i z e d in that the reaction is carried out in the presence of a phosphite halide scavenger/

# - 12 -having the general formula R7 - Q - R8 (III) wherein Q represents a moiety of the formula - CH = CH - O - or and R7 and R8 are the same or different and each represents hydrogen, a substituted or non-substituted alkyl group, or an aryl group, or R7 and R8 together with Q form a heterocyclic ring, with the proviso that any symbol R7 or R8 connected to the oxygen atom in the moiety Q of the formula -CH=CH-O- does not represent hydrogen.

- 12a -

2. A process according to claim 1, c h a r a c t e r -i z e d in that R1 represents a trialkylsilyl group.

3. A process according to claim 2, c h a r a c t e r -i z e d in that R1 represents a trimethylsilyl group.

4. A process according to claim 3, c h a r a c t e r -i z e d in that X represents a group of the general formula Al wherein R1 represents a trimethylsilyl group and Z repre-sents a 1,3,2-dioxaphospholan-2-yl group.

5. A process according to claim 1, c h a r a c t e r -i z e d in that the acyl halide has the general formula:

R6-CO-Hal (II) , wherein R6 represents a naphthyl group; a cycloalkyl group sub-stituted with an amino group and optionally containing an oxygen or sulphur atom; a phenyl group substituted by one or more alk-oxy group(s); a substituted heterocyclyl group; or a methyl group substituted with one or two of the following substituents:
a phenoxy, amino, cyclohexyl group containing one or two unsa-turated bond(s), a triazo, a substituted or non-substituted phen-oxycarbonyl group, a substituted or non-substituted phenyl, alkyl, thienyl, cyano or hydroxy, or a non-substituted or halogen substituted pyridylthio group; or corresponding groups containing a hydroxy or amino protecting group on a hydroxy or amino group, if any, and Hal represents halogen.

6. A process according to claim 5, c h a r a c t e r -i z e d in that R6 represents a 1-aminocyclohexyl, 4-aminotetra-hydropyran-4-yl, 4-aminotetrahydrothiopyran-4-yl, 1-aminocyclo-pentyl, phenoxymethyl, 1-(1,4-cyclohexadienyl)aminomethyl, .alpha.-triazobenzyl, .alpha.-(2,3-dihydroinden-5-yloxycarbonyl)benzyl, .alpha.-ami-nobenzyl or a 3-phenyl-5-methyl-isoxazol-4-yl group which optionally is substituted with halogen in the 2- and 6-position of the phenyl group, a 2,6-dimethoxyphenyl, p-hydroxy-.alpha.-aminobenzyl, 1-phenoxy-propyl, thien-2-ylmethyl, 1-naphthyl, 1-(thien-3-yl)aminomethyl, 1H-tetrazol-1-ylmethyl, or pyrid-4-ylthiomethyl group which optionally is substituted with halogen in the 2- and 6-position, a cyanomethyl, .alpha.-hydroxybenzyl, or p-(3,4,5,6-tetrahydropyrimidin-2-yl)phenylmethyl group, or corresponding groups containing a hydroxy or amino protecting group on a hydroxy or amino group, if any.

7. A process according to claim 5, characterized in that Hal represents chlorine.

8. A process according to any of the claims 5 - 7, characterized in that R6 represents a group containing a group having the formula -NH3+Cl-.

9. A process according to claim 6, characterized in that R6 represents an .alpha.-aminobenzyl group or a substituted or non-substituted p-hydroxy-.alpha.-aminobenzyl group, and Hal represents chlorine.

10. A process according to claim 1, characterized in that the scavenger has the general formula:
(IV) wherein R9 represents hydrogen, a substituted or non-substituted alkyl group, or an aryl group.

11. A process according to claim 10, characterized in that R9 represents a methyl, chloromethyl, or phenyl group.

12. A process according to claim 10, characterized in that the scavenger has the general formula:

R11 - CH = CH - O - R10 (V) wherein R11 represents hydrogen, or an alkyl group, and R10 represents an alkyl group, or R10 and R11 together with the -CH=CH=O-moiety form a heterocyclic ring.

13. A process according to claim 12, characterized in that R10 and R11 together represent a trimethylene group.

14. A process according to claim 12, characterized in that R11 represents hydrogen, and R10 represents an ethyl or butyl group.

15. A process according to claim 1, characterized in adding a proton donor to the reaction mixture.

16. A process according to claim 15, characterized in that the proton donor is an acid addition salt of a weak tertiary amine.

17. A process according to claim 15, characterized in that the proton donor is a mixture of an acid addition salt of a weak tertiary amine and said weak tertiary amine.

18. A process according to claim 16, characterized in that the amine is pyridine or N,N-dimethylaniline.

19. A process according to claim 16 or 17, characterized in that the acid addition salt is a hydrochloride.