GB1590433A

GB1590433A - Process for the production of penam and cephem derivatives

Info

Publication number: GB1590433A
Application number: GB28346/76A
Authority: GB
Original assignee: Novo Industri AS
Current assignee: Novo Nordisk AS
Priority date: 1976-07-07
Filing date: 1976-07-07
Publication date: 1981-06-03
Also published as: NL7707523A; PT66774B; NO772396L; FR2357565A1; DK300277A; DE2730548A1; FI772114A; SE7707824L; ES460514A1; JPS537699A; ATA490277A; PT66774A; FR2357565B3

Description

(54) A PROCESS FOR THE PRODUCTION OF PENAM AND CEPHEM DERIVATIVES (71) We, NOVO INDUS?'RI A/S, a company organized under the Jaws of Denmark, of Novo All', DK-2880 Bagsvaerd, Denmark, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a process for the preparation of penam and cephem derivatives by reacting a phosphite amide of the general formula:

wherein X represents a group of the general formula::

wherein the carbon atom adjacent to the COOR' group is connected to the nitrogen atom, R1 represents a substituted or non-substituted alkyl or aralkl group or an organo-metallic group, R2 represents a hydrogen atom, an acetoxy group or -5-Het, wherein Het represents a heterocyclic group, and Z represents a group having the formula:

wherein Rs represents an alkyl group, R4 and Rd are the same or different and each represents an alkyl group, n represents 1 or 2, and m represents 0, 1, or 2, with. an acyl halide in an aprotic solvent.

The specification of Belgian Patent No. 8099110 and the cognate British Patent Applications Nos. 12788/75 and 26826/75 (Serial No. 1,546,385) disclose a process for the preparation of penam and cephem derivatives by reacting a phosphite amide of 6-aminopenicillanic acid of 7-aminocephalosporanic acid with an acvl halide in an anrotic 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 (as hereinafter defined), optionallv 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 phosphite halide, as exemplified in the following reaction scheme for the synthesis of the trimethylsilyl ester of amipicillin: Scheme 1

Phosphite halides, such as the compound having the formula A, while quite stable under aprotic conditions, react with hydroxylic reagents like water and alcohols.During synthesis. therefore, hydroxyl groups and similar substituents should be properly protected. Problems may also arise when a hydrolytic step is included in a synthesis of such sensitive compounds as penicillins and cephalosporins, unless the violent reaction between the phosphite and halide and water is adequately controlled. Surprisinply it has now been found that these obstacles may be overcome by adding a phosphite halide scavenger to the reaction mixture.

Herein, the term "weak tertiary amine" means a tertiary amine having a pK,value not exceeding 6.0.

Thus, according to this invention, the reaction between the phosphite amide of the general formula I and formula R14 Hal, wherein R14 represents an acyl group and Hal represents a halogen atom, in an aprotic solvent is carried out in the presence of a phosphite halide scavenger, for the preparation of a penam or cephem derivative having the general formula:

As mentioned above, R1 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 the organometallic groups are trialkylsilyl and, preferably, the trimethylsilyl group. Throughout the present specification, the term alkyl, when used alone or in combination with other groups, designates a straight or branched alkyl group, preferably containing at the most 6 carbon atoms, more preferably at the most 4 carbon atoms, such as a methyl, ethyl, propyl, isopropyl or 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 R5 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: R'-CO-Hal (11) wherein Rs represents a naphthyl group; an amino-substituted group having the general formula:

wherein R'2 and RlS are identical or different and each represents an alkylene group or a bond, and Y represents a bond or an oxygen atom or a 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: phenoxy, amino, cyclohexenyl, cyclohexadienyl, triazo, substituted or non-substtuted phenoxycarbonyl, substituted or non-substituted phenyl, alkyl, thienyl, cyano, hydroxy, nonsubstituted or halogen-substituted pyridylthio or 1H-tetrazolyl-1-yl; or a corresponding group containing a hydroxy or amino protecting group on a hydroxy or amino group, and Hal represents halogen.Preferably, R6 represents a l-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetrahydrothiopyran-4-yl, l-aminocyclopentyl, phenoxymethyl, 1-(1,4-cyclohexadienyl)aminomethyl, a-triazobenzyl, a- (2,3 -dihydroinden-5- yloxycarbonyl)benzyl, a-aminobenzyl or a 3-phenyl-5-methyl-isoxazol-4-yl group which optionally is substituted witb. halogen in the 2- and 6-positions of the phenyl group, a 2,6-dimethoxyphenyl, p-hydroxy-a-aminobenzyl, 1 phenoxypropyl, thien-2ylmethyl, 1-naphthyl, 1-(thien-3-yl)aminomethyl, 1H-tetrazol-l-ylmethyl, or pyrid-4ylthiomethyl group which optionally is substituted with halogen in the 2- and 6positions, a cyanomethyl, a-hydroxybenzyl, or p-(3,4,5,6-tetrahydropyrimidin-2-yl)- benzyl group, or a corresponding group containing a hydroxy or amino protecting group on a hydroxy or amino group. More preferably, R6 is a 1-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetrahydrothiopyran-4-yl, 1-aminocyclopentyl, phenoxymethyl, 1- ( 1,4-cyclohexadienyl ) aminomethyl, a-triazobenzyl, a- (2,3 - dihydroinden-S-yloxycarbonyl )benzyl, fr-aminobenzyl or a 3 -phenyl-5 -methyl-iso- oxazol-4-yl group which optionally is substituted with halogen in the 2- and 6positions, of the phenyl group, a 2,6-dimethoxyphenyl, p-hydroxyta-aminobenzyl l-phenoxypropyl, thien-2-ylmethyl, 1-naphthyl, 1 - (thien-3 -yl) aminomethyl, 1 H- tetrazol-l-ylmethyl, or pyrid-4-ylthiomethyl group which optionally is substituted with halogen in the 2- and 6-positions, a cyanomethyl, a-hydroxybenzyl, or p-(3,4,5,6 tetrahydropyrimidin-2-yl)phenylmethyl group, or a corresponding group containing a hydroxy or amino protecting group on a hydroxy or amino group.

As mentioned above, R2 may be a -5-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, carboxymethyltetrazole, and 2-methyl1,3,4-thiadiazole groups.

Herein, the term "halogen", when used alone or in combination with other groups, designates bromine, chlorine and fluorine, most preferably chlorine.

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 -NH,+Z- wherein HZ is an organic or inorganic acid. Preferably, HZ represents HCI. An example of a hydroxy protecting group is a trialkylsilyl, preferably trimethylsilyl, group, which means Rss contains a p-trialkylsilyloxy, preferably p-trimethylsilyl, group. It is also possible to use other compounds containing a protecting group, provided that the protecting group subsequently can be readily split off yielding the desired penam or cephem compound.

Examples of scavengers suitable for use in the presence of the invention are epoxides and vinyl ethers which are capable of reacting quantitatively or almost quantitatively with the phosphite halide as demonstrated in Example 1, in which 2 chloro-1,32-dioxaphospholane and propylene oxide are used as reactants in a control reaction. This reaction may be illustrated by the following scheme:

Scheme 2. CH3 o ICH3 + H3 ,0 ~~~~~ o L X PC I cH2-o-P00Th CH2 2 (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 1, 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-hydroxyphenylglycyl chloride, hydrochloride which is used in the preparation of p-hydroxyampicillin.

A preferred subclass of phosphite halide scavengers suitable for use in the process according to the present invention is compounds of the general formula: R'-R8 (III) wherein Q represents a moiey 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 RS connected to the oxygen atom in the moiety Q of the formula -CH= CH-O- does not represent hydrogen.

A preferred subclass of compounds of the general formula III is compounds of the general formula:

wherein Rg 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 com- pounds of 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, and preferably compounds wherein Rll represents hydrogen, and R10 represents an ethyl or butyl group, or R10 and R1l together represent a trimeth.ylene 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 group) is performed even in the presence of an excess of a weakly basic tertiary amine, a reaction with the unprotected hydroxyl group would ensue, resulting in the production of tertiary phosphite ester. The efficiency of the phosphite halide scavenger to block this reaction in the presence of a weak base, viz. N,Ndimethylaniline, is demonstrated in the following Example 9.

The process according to the present invention is further illustrated by the following non-limiting Examples, Examples 2 to 4 and 6 to 9 specifically exemplifying the present invention.

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 temperature, 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. 31-PNMR spectra of the reaction mixture shows two signals at 8 = 143 ppm and at i'8 = 134 ppm and indicate that the two compounds formed have the formulae VI and VII, respectively. No signal from the starting material (.6 = 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 2:1 of the two propylene chlorohydrins corresponding to Compounds VI and VII stated in Scheme 2 was demonstrated by GLC.

Example 2.

p-Hydroxyampicillin.

Diisopropylamine (84 ml, 0.6 mole), dissolved in dry methylene chloride (400 ml), is cooled to 0 C, and 2-chloro-1,3,2-dioxaphospholane (27 ml, 0.3 mole) is added dropwise at this temperature. 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 0 C and filtered to remove the precipitated amine hydrocloride. To the cooled filtrate pyridine hydrochloride 2.32 g, 20 millimoles), propylene oxide (70 ml, 1 mole) and D-( - )-p-hydroxy- phenylglycyl chloride, hydrochloride (54.5 g, 0.2 mole) are added with vigorous stirring. The reaction is completed under 40 minutes.The yield is estimated to be 94 pent cent by titration following hydrolysis by means of B. cereus penicillinase. 31P-NMR spectra of this solution showed the two signals at 8 = 143 and ss =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 sodium 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. Further 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-hydroxyphenylglycyl chloride, hydrochloride (2.72 g, 10 rnillimoles) and propylene oxide (3.5 ml, 50 millimoles) but omitting the addition of pyridine hydrochloride. This reaction is called reaction A.

In the same way another reaction mixture was prepared, this time with the addition of pyridine hydrochloride (116 mg, 1 millimole). This reaction is called reaction B.

These reactions were followed by enzymatic tritration of the penicillin content at intervals:

Yield per cent: Time minutes Reaction A Reaction B 5 3 47 15 18 80 35 65 90 60 77 95 90 85 95 120 1 90 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 follows: Reaction A: 116 mg (1 millimole) Reaction B: 1.74 g (15 millimoles) The reactions were followed titrimetrically:

Yield per cent: Time 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 minutes Yield per cent 3 66 6 68 15 44 30 31 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 propvlene oxide was replaced by 4 ml of epichlorohydrin (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 OOC, and 0.9 ml (10 millimoles) of 2-chloro-1,3-dioxaphospholane, dissolved in 5 ml of methylene chloride, was added dropwise. After stirring for 30 minutes, the temperature was raised to 20"C, and 2.16 g of 6-aminopenicillanic acid were added, followed by 1.2 ml (10 millimoles) of trimethylchlorosilane. After stirring for 3 yours at room temperature the mixture was cooled to OOC, and the precipitated diisopropylamine, hydrochloride was removed by filtration.The filtrate was cooled to --1SOC, and 0.93 ml of a 2N solution of N,N-dimethylaniline, hydrochloride in methylene 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-hydroxyphenylglycyl chloride, hydrochloride. The cooling bath was removed, and the temperature raised to 15"C during 10 minutes. After reacting for 30 minutes the above-mentioned compounds VI and VII were identified in the reaction mixture by gas chromatography. The yield, calculated against a reference standard solution, was 65%. The yield of penicillin, as estimated by enzymatic titration, was 70%.

WHAT WE CLAIM IS: 1. A process for the preparation of a penam or cephem derivative having the general formula:

wherein X represents a group of the general formula:

wherein the carbon atom adjacent to the COOR 1 group is connected to the nitrogen atom, R' represents a substituted or non-substituted alkyl or aralkyl group, or an organometallic group, R2 represents a hydrogen atom, an acetoxy group or -5-Het, wherein Het represents a heterocyclic group and R'4 represents an acyl group, by reacting a phosphite amide having the general formula

wherein X has the meaning defined above and Z represents a group having the formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 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 OOC, and 0.9 ml (10 millimoles) of 2-chloro-1,3-dioxaphospholane, dissolved in 5 ml of methylene chloride, was added dropwise. After stirring for 30 minutes, the temperature was raised to 20"C, and 2.16 g of 6-aminopenicillanic acid were added, followed by 1.2 ml (10 millimoles) of trimethylchlorosilane. After stirring for 3 yours at room temperature the mixture was cooled to OOC, and the precipitated diisopropylamine, hydrochloride was removed by filtration.The filtrate was cooled to --1SOC, and 0.93 ml of a 2N solution of N,N-dimethylaniline, hydrochloride in methylene 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-hydroxyphenylglycyl chloride, hydrochloride. The cooling bath was removed, and the temperature raised to 15"C during 10 minutes. After reacting for 30 minutes the above-mentioned compounds VI and VII were identified in the reaction mixture by gas chromatography. The yield, calculated against a reference standard solution, was 65%. The yield of penicillin, as estimated by enzymatic titration, was 70%. WHAT WE CLAIM IS:

1. A process for the preparation of a penam or cephem derivative having the general formula:

wherein X represents a group of the general formula:

wherein Rt represents an alkyl group, R4 and R5 are the same or different, and each represent an alkyl group, n represents 1 or 2 and m represents 0, 1, or 2, with an acyl halide, having the formula R14 Hal, wherein R14 has the meaning defined above and Hal represents a halogen atom, in an aprotic solvent, the reaction being carried out in the presence of a phosphite halide scavenger.

2. A process according to Claim 1, wherein R1 represents a trialkylsilyl group.

3. A process according to Claim 2, wherein R 1represents a trimethylsilyl group.

4. A process according to Claim 3, wherein X represents a group of the general formula (Al), wherein R1 represents a trimethylsilyl group and Z represents a 1,3,2dioxaphospholan-2-yl group.

5. A process according to any one of the preceding claims, wherein the acyl halide has the general formula: ReCOHal (II), wherein Rt represents a naphthyl group; an amino-substituted group having the general formula:

wherein R12 and R13 are identical or different and each represents an alkylene group or a bond, and Y represents a bond or an oxygen atom or a sulphur atom; a phenyl group substituted by one or more alkoxy group(s); a substituted beterocyclyl group; or a methyl group substituted with one or two of the following substituents: phenoxy, amino, cyclohexenyl, cyclohexadienyl, triazo, substituted or non-substituted phenoxycarbonyl, substituted or non-substituted phenyl, alkyl, thienyl, cyano, hydroxy, nonsubstituted or halogen-substituted pyridylthio or 1H-tetrazolyl-1-yl; or a corresponding group containing a hydroxy or amino protecting group or a hydroxy or amino group, and Hal represents halogen.

6. A process according to Claim 5, wherein R6 represents a 1-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetrahydro-thiopyran-4-yl, 1-aminocyclopentyl, phenoxymethyl, 1-(1,4-cyclohexadienyl)aminomethyl, a-triazobenzyl, a-(2,3-dihydro inden-5-yloxycarbonyl )benzyl, a-aminobenzyl or a 3-phenyl-5-methyl-isoxazol-4-yl group which optionally is substituted with halogen in the 2- and 6-positions of the phenvl group, a 2,6-dimethyloxyphenyl, p-hydroxy-a-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-positions, a cyanomethyl, a-hydroxybenzyl, or p- ( 3,4,5,6-tetrahydropyrimidin-2-yl) - benzyl group, or a corresponding group containing a hydroxy or amino protecting group on a hydroxy or amino group.

7. A process according to claim 5 or 6, wherein R6 represents a group containing a group having the formula -NH,+Cl-.

8. A process according to Claim 6, wherein Rss represents an a-aminobenzyl group or a p-hydroxy-a-aminobenzyl group, the hydroxy and/or the amino group being protected by a removable protecting group, and Hal represents a chlorine atom.

9. A process according to any one of claims 1-7, wherein Hal represents chlorine.

10. A process according to any one of the preceding claims, wherein the phosphite halide scavenger is an epoxide or a vinyl ether.

11. A process according to Claim 10, wherein the phosphite halide scavenger has the general formula: R7~Q~R8 (III) wherein Q represents a moiety of the formula -CH = CH-O- or

and R7 and RS are the same or different and each represents a hydrogen atom, 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 R7 or R3 connected to the oxygen atom in the moiety Q of the formula CH=CH-O- does not represent a hydrogen atom.

12. A process according to Claim 11, wherein the scavenger has the general formula:

wherein R9 represents a hydrogen atom, a substituted or non-substituted alkyl group or an aryl group.

13. A process according to Claim 12, wherein R9 represents a methyl, chloromethyl or phenyl group.

14. A process according to Claim 11, wherein the scavenger has the general formula: R11-CH = CH-O-R10 (V), wherein R11 represents a hydrogen atom or an alkyl group, and R10 represents an alkyl group, or R10 and R11 together with the --CH=CHH--O- moiety form a heterocyclic ring.

15. A process according to Claim 14, wherein R10 and R1l together represent a trimethylene group.

16. A process according to Claim 14, wherein R1l represents a hydrogen atom, and R10 represents an ethyl or butyl group.

17. A process according to any one of the preceding claims, wherein a proton donor is added to the reaction mixture.

18. A process according to Claim 17, wherein the proton donor is an acid addition sale of a weak tertiary amine (as hereinbefore defined).

19. A process according to Claim 17, wherein the proton donor is a mixture of an acid addition salt of a weak tertiary amine (as hereinbefore defined), and said weak tertiary amine.

20. A process according to Claim 18, wherein the amine is pyridine or N,N dimethylaniline.

21. A process according to Claim 18 or 19, wherein the acid addition salt is a hydrochloride.

22. A process for the preparation of a penam or cepbem derivative, substantially as described in any one of the foregoing Examples 2 to 4 and 6 to 9.

23. A penam of cephem derivative whenever prepared by the process of any one of the preceding claims.