# US 4,391,975 A · Process for 1-oxacephem derivatives

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- Number: US 4,391,975 A
- Document ID: US4391975A
- Status: Granted
- Kind: A
- Application number: 06/356,236
- Filed: 1982-03-08
- Granted: 1983-07-05
- Earliest claimed: 1981-12-15
- Assignees: Queen's University at Kingston
- Inventors: Saul Wolfe; Chia-Cheng Shaw
- Web page: https://patentgrep.com/patent/US4391975A

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 205/085: with a nitrogen atom directly attached in position 3
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 505/00: Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-C07D-0995.gif] , e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A process for preparing compounds of the formula ##STR1## in which R is hydrogen or methoxy, R.sub.1 is a hydroxyl group, R.sub.2 is chlorine, bromine, OAc or SHET, R.sub.3 is hydrogen or a cleavable carboxy-protecting group preferably selected from loweralkyl, benzyl, benzhydryl, loweralkoxyloweralkyl, loweralkoxybenzyl, phenacyl, trimethylsilyl, 2,2,2-trichloroethyl or pivaloloxy, R.sub.4 is hydrogen or a cleavable amino-protecting acyl group, or R.sub.4 NH represents phthalimido, and HET is a five or six membered aromatic heterocycle containing 1-4 heteroatoms and optionally substituted with loweralkyl, and from which the corresponding 1-oxacephem derivatives can be prepared is described. The novel intermediate compounds of the formula 1 are produced from a penicillin derivative of formula 1 wherein R, R.sub.3 and R.sub.4 are as above described and R.sub.1 and R.sub.2 are both the same halogen, by treatment with a formylating agent in a halogenated hydrocarbon solvent to obtain the corresponding compound in which R.sub.1 and R.sub.2 are both OCHO which is then treated with less than one molar equivalent of a boron halide to obtain a 2:1 to 4:1 mixture of the corresponding compounds of formula 1 in which R.sub.1 is OCHO and R.sub.2 is the corresponding halogen or R.sub.1 is halogen and R.sub.2 is OCHO, and in which the former compound predominates. This mixture is separated and the compound in which R.sub.1 is OCHO and R.sub.2 is halogen is isolated. This last compound is hydrolyzed and the desired intermediate compound in which R.sub.1 is OH and R.sub.2 is a halogen is isolated. Alternatively, the compound of formula 1 in which R.sub.1 is OCHO and R.sub.2 is halogen is subjected to displacement by .sup.- OAc or HSHET prior to the hydrolysis.

## Claims

### Claim 1

A process for preparing a 1-oxacephem derivative of the formula I
in which R.sub.4 is hydrogen or a cleavable amino-protecting acyl group, or R.sub.4 NH represents phthalimido, R.sub.3 is hydrogen or a cleavable carboxy-protecting group, R.sup.2 is hydrogen or methoxy, W is NH, O, or S and Z is selected from lower acyl groups and from five membered heterocycles containing 1-4 hetero atoms and optionally substituted with loweralkyl, which comprises treating a compound of the formula II ##STR26## in which R.sub.4, R.sub.3, R.sub.2, W and Z are as defined above with fluoride ions, and isolating the corresponding compound of formula I.

### Claim 2 (depends on 1)

A process as claimed in claim 1 wherein the compound of formula II is prepared by treating a compound of the formula IIIa: ##STR27## in which R.sub.4, R.sub.2, R.sub.3, W and Z are as defined in claim 1 and R.sub.1 is hydrogen with t-butyldiphenylsilyl chloride, and isolating the corresponding compound of formula II.

### Claim 3 (depends on 2)

A process as claimed in claim 2 wherein the compound of formula IIIa is prepared by treating a compound of the formula IIIb ##STR28## in which R.sub.4, R.sub.3 and R.sub.2 are as defined in claim 2, R.sub.1 is CHO, and Y is a halogen, with a compound of the formula HWZ in which W and Z are as defined in claim 2, and isolating the corresponding compound of formula IIIa in which R.sub.1 is CHO; treating said last-named compound of formula IIIa with a hydrolyzing agent, and isolating the corresponding compound of formula IIIa in which R.sub.1 is hydrogen.

### Claim 4 (depends on 3)

A process as claimed in claim 3 in which the compound of formula IIIb in which R.sub.1 is hydrogen is prepared by treating a compound of formula III ##STR29## in which R.sub.4, R.sub.3, R.sub.2 and Y are as defined above and X is the same halogen as Y
(a) with a formylating agent in a halogenated hydrocarbon solvent to obtain the corresponding compound of formula III in which X and Y are both OCHO;
(b) treating said last-named compound with less than one molar equivalent of a boron halide, to obtain a 2:1 to 4:1 mixture of the corresponding compounds of formula III in which X is OCHO and Y is the corresponding halogen with the corresponding compound of formula III in which X is the corresponding halogen and Y is OCHO; separating said last-named mixture, and isolating the corresponding compound of formula III in which X is OCHO and Y is the corresponding halogen;
(c) treating said last-named compound of formula III in which X is OCHO and Y is the corresponding halogen with a hydrolyzing agent and isolating the corresponding compound of formula III in which X is OH and Y is the corresponding halogen;
(d) alternatively, treating the last-named compound of formula III of (b) with a tetraalkylammonium acetate or with a heterocyclic mercaptan of the general formula HSHET, where HET is a five or six membered aromatic heterocycle containing 1-4 heteroatoms and optionally substituted with lower alkyl, and isolating the corresponding product of formula III in which X is OCHO and Y is OAc or SHET prior to the hydrolysis step of (c).

### Claim 5 (depends on 4)

A process as claimed in claim 4 wherein HET is selected from furyl, thienyl, ##STR30##

### Claim 6 (depends on 4)

A process as claimed in claim 4 in which the formylating agent is selected from tetra(lower alkyl)guanidinium formates and tetra(lower alkyl)ammonium formates.

### Claim 7 (depends on 4)

A process as claimed in claim 4 in which the formylating agent is selected from tetramethylguanidinium formate and tetra-n-butylammonium formate.

### Claim 8 (depends on 4)

A process as claimed in claim 4 in which the halogenated hydrocarbon solvent has 1-2 carbon atoms and 2-4 halogen atoms in which the halogen has an atomic weight greater than 19.

### Claim 9 (depends on 4)

A process as claimed in claim 4 in which the halogenated hydrocarbon solvent is methylene (di)chloride.

### Claim 10 (depends on 4)

A process as claimed in claim 4 in which the boron halide is used in quantities of 0.3 to 0.7 molar equivalents.

### Claim 11 (depends on 1)

A process as claimed in claim 1 in which the hydrolyzing agent is a mineral acid dissolved in a lower alkanol.

### Claim 12 (depends on 4)

A process as claimed in claim 4 in which the hydrolyzing agent is hydrochloric acid dissolved in methanol.

### Claim 13 (depends on 4)

A process as claimed in claim 4 in which the treatment with the formylating agent is carried out at ambient temperature, the treatment with the boron halide is carried out within a temperature range of from -10.degree. C. to 2.degree. C., and the hydrolysis is carried out with a temperature range of from -5.degree. C. to 5.degree. C.