Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

• Desacetyl 7-aminocephalosporanic acid is obtained chemically in reasonable yield from desacetyl 7- aminocephalosporanic acid lactone by subjecting the lactone in a basic water-containing medium to a pH of ll-l3 for 5 seconds to 5' minutes.
• the amino group of alcohol I can be acylated by known' methods with any of a number of known-acylating agents to produce desacetyl cephalosporins; which are antibiotic agents.
• the lactone II is also a known compound (U.S. Pat. No. 3,207,755); but there has heretofore been no means for con-. verting the lactone to the useful alcohol 1.
• the alcohol product has thus not up to this time been obtainable from the lactone chemically in yields high enough to be adaptable to commercial production.
• the alcohol has been obtainable only by enzymatic hydrolysis of the acetoxy group of a compound such as 7-aminocephalosporanic acid.
• the present invention therefore, has as its principal object the provision of a method of chemically hydrolyzing the lactone of desacetyl 7-aminocephalosporanic acid (11) to desacetyl 7-aminocephalosporanic acid (I) in yields high enough to offer promise of commercial feasibility.
• the availability of the lactone 11 by total synthesis (French Pats. Nos.
• the process of the present invention generally consists of subjecting the lactone 11, or a salt thereof, to a water-containing basic medium of pH 11-13 for about seconds to 5 minutes.
• the critical variables are the time and the pH. Use of longer periods of times will result in ring-opening of the B-lactam in addition to the lactone ring.
• some lactam ring-opening does occur, limitation of the time as stated above enables one to obtain a sufficient amount of the desired product in which the lactam ring is v intact, while the lactone ring has been hydrolyzed.
• the pH is i also a critical factor, since below pH 1 l, lactam-opening is extensive with little lactone-opening, and above pH 13, extensive secondary decomposition occurs.
• the preferred conditions are pH 11.5-12.5 for 5-60 seconds.
• the temperature of the reaction when conducted at pH 11-13 for 5 seconds to 5 minutes should be approximately room temperature (20-30 C., preferably 25-27 C. Variation between 0-l00 C. is possible, but the optimal pH and time of reaction will be shifted.
• the solvent for the reaction is not critical, provided it contains some water for hydrolysis and provided also that it dissolves the starting material.
• aqueous alcohols, acetone, dimethylformamide, or tetrahydrofuran are satisfactory.
• the reaction is most preferably conducted by dissolving a salt (including the hydrochloride, acetate, sulfate, etc.) of the lactone in water, quickly adjusting the pH to about 12 with aqueous base, and 15-30 seconds later, adding acid to pH 7 to terminate the reaction.
• a salt including the hydrochloride, acetate, sulfate, etc.
• the desired pH for the hydrolysis reaction is attained by use of such conventional basic materials as hydroxides, including sodium or potassium hydroxide; quaternary ammonium hydroxides, including ion exchange resins; and buffers capable of maintaining the desired pH.
• the alcohol product may be isolated by any convenient method, since the invention resides in the particular hydrolytic conditions, rather than in any manner of isolation.
• a preferred method of isolation consists of lyophilizing a mixture of the reaction solution and cellulose and then chromatographing this material on a cellulose column at 5 C., percent acetronitrile in water being the eluant. Starting material, if any remains, will be eluted first, any lactam ringopened byproductnext, and the desired hydroxy acid last.
• the product can be isolated by ion exchange chromatography. Evaporation of solvent under'reduced pressure gives. the crude product, which can be further purified by conventional means.
• EXAMPLE 2 The procedure in example 2 is the same as that described in example 1, except that the pH is adjusted to 1 1.0 and the reaction is allowed to proceed for 5 minutes. When desacetyl 7- aminocephalosporanic acid was estimated by bioassay, the conversion was approximately 10 percent.
• EXAMPLE 3 The procedure in example 3 is the same as that described in example 1, except that the pH is adjusted to 1 1.5 and the reaction is allowed to proceed for 15-30 seconds. When desacetyl 7-aminocephalosporanic acid was estimated by bioassay, the conversion was approximately 15 percent.
• EXAMPLE 4 The procedure is example 4 is the same as that described in example 1, except that the pH is adjusted to 13.0 and the reaction is allowed to proceed for 5-10 seconds.
• desacetyl 7-aminocephalosporanic acid was estimated by bioassay, the
• a process for hydrolyzing desacetyl 7- aminocephalosporanic acid lactone to desacetyl 7- aminocephalosporanic acid comprising subjecting the said lactone in a water-containing medium to a pH of 1 1-13 for 5 seconds to 5 minutes.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=25370056

Family Applications (1)

Country Status (11)

Cited By (1)

• 0
  • BE BE757176D patent/BE757176A/xx unknown
• 1969
  • 1969-11-17 US US877481A patent/US3607869A/en not_active Expired - Lifetime
• 1970
  • 1970-09-23 ZA ZA706510A patent/ZA706510B/xx unknown
  • 1970-10-10 JP JP45089234A patent/JPS4932550B1/ja active Pending
  • 1970-10-13 CA CA095364A patent/CA918656A/en not_active Expired
  • 1970-10-29 FR FR707039082A patent/FR2067328B1/fr not_active Expired
  • 1970-10-29 NL NL7015871A patent/NL7015871A/xx unknown
  • 1970-11-10 DE DE19702055336 patent/DE2055336A1/de active Pending
  • 1970-11-13 LU LU62058D patent/LU62058A1/xx unknown
  • 1970-11-13 GB GB54155/70A patent/GB1276413A/en not_active Expired
  • 1970-11-17 CH CH1698270A patent/CH534181A/de not_active IP Right Cessation

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