US3631021A - 7-halo lincomycin carbonate esters - Google Patents

7-halo lincomycin carbonate esters Download PDF

Info

Publication number
US3631021A
US3631021A US816417A US3631021DA US3631021A US 3631021 A US3631021 A US 3631021A US 816417 A US816417 A US 816417A US 3631021D A US3631021D A US 3631021DA US 3631021 A US3631021 A US 3631021A
Authority
US
United States
Prior art keywords
alkyl
carbonate
carbon atoms
lincomycin
acid addition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US816417A
Other languages
English (en)
Inventor
Anthony A Sinkula
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Application granted granted Critical
Publication of US3631021A publication Critical patent/US3631021A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof

Definitions

  • This invention relates to novel 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of 7-halogenated lincomycin compounds of the formula wherein R is alkyl of from 1 through 6 carbon atoms; R is alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, or aralkyl of up to 12 carbon atoms; R is hydrogen or alkyl of from 1 through 8 carbon atoms; X is chlorine, bromine or iodine; R is C Hzn'H OPJ- wherein n is an integer from 1 through and R is R or hydrogen; their acid addition salts; and novel synthesis processes.
  • alkyl carbonate esters of lincomycin compounds have antibiotic activity.
  • the 3-mono(alkyl carbonate) esters can be used to inhibit the growth of Staphylococcus aureus, Streptococcus hemolyticus and Streptococcus faecalis on medial and dental equipment contaminated with these bacteria.
  • the 2,3-bis(hexyl carbonate) ester of 7-deoxy-7(S)-chlorolincornycin is ad vantageous for oral administration as an antibiotic in that it lacks the bitter taste of the unesterified compound.
  • R is alkyl of from 1 through 6 carbon atoms; R is alkyl of from 1 through 8 carbon atoms, or aralkyl of up to 12 carbon atoms, and is located above the plane of the pyrrolidine ring as drawn to give the transconfigura- 3,631 ,ml Patented Dec.
  • R is hydrogen or alkyl from 1 through 8 carbon atoms
  • X is chlorine, bromine or iodine and is situated to the left of the vertical line as drawn to give the 7(R) configuration or to the right to give the 7(S) configuration
  • R is wherein n is an integer from 1 through 20 are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl, octadecyloxycarbonyl, eicosyloxycarbonyl and isomers of the alkyl moieties
  • novel 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of 7-halogenated lincomycin compounds of Formula I exist either in the nonprotonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization of the free base with suitable acids. Salts of 7-halo-7-deoxylincomycin-3-mono(alkyl carbonates) can be made by neutralizing the free base with the appropriate acid to below about pH 7.0 and advantageously to about pH 2 to pH 6.
  • Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic, glueonic, lactobionic, phthalic, tartaric, lauric, stearic, salicyclic, 3-phenylsa1icyclic, S-phenylsalicyclic, 3-methyl gluaric, orthosulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,2- cyclohexanedicarboxylic, 4-cyclohexenecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, azobenzenesul
  • novel 3-mono(alky1 carbonate) and 2,3-bis(a1kyl carbonate) esters of 7-ha1ogenated lincomycin compounds are prepared by mixing the appropriate 2,3-dihydroxy compound of Formula H:
  • R is selected independently from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and the isomeric forms thereof, with an appropriate alkyl halocarbonate of the Formula IV:
  • n has the meaning above and Y is fluorine, chlorine. bromine or iodine.
  • the starting compounds of Formula II are prepared in accordance with the procedures described in U.S. Pat. 3,380,992 and Belgian Pats. 676,154; 676,202 and 705,364.
  • the desired 7-halogenated lincomycin 3-mono(alkyl carbonate) or 2,3-bis(alkyl carbonate) compound of Formula I is one in which R is hydrogen, simultaneous undesirable acylation at 1-N atom is prevented by first shielding said l-N atom with a protective group subsequently removable by hydrogenolysis.
  • Suitable such groups are trityl, i.e., triphenylmethyl, diphenyl-(p-methoxyphenyl)-methyl, bis-(p-methoxyphenyl)-phenylmethyl, benzyl, or p-nitrobenzyl and hydrocarbyloxycarbonyl groups.
  • trityl i.e., triphenylmethyl, diphenyl-(p-methoxyphenyl)-methyl, bis-(p-methoxyphenyl)-phenylmethyl, benzyl, or p-nitrobenzyl and hydrocarbyloxycarbonyl groups.
  • W is hydrogen, allyl, or alkyl of not more than 4 carbon atoms, such as phenyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl, and p-allylphenyloxycarbonyl and the like.
  • the protective group is replaced by hydrogen by hydrogenolysis (in accordance with the procedure described in U.S. Pat. 3,380,992) to yield the desired 3-mono(alkyl carbonate) or 2,3-bis(alkyl carbonate) ester of the l'-N hydrogen lincomycin compound of Formula I.
  • amine bases of Formula III are known in the art and can be prepared by published methods.
  • Typical amine bases that can be used in the process of this invention include 3-ethylpyridine, 4-isopropylpyridine, S-butylpyridine, 3-ethyl-4-methylpyridine, 3,4-diisopropylpyridine, 3- methyl-4-dipropyl-5-propylpyridine, 3,5-dimethy1-4-sec.- butylpyridine, and the like.
  • alkyl halocarbonates of Formula IV are well known in the art and a wide variety of them have been prepared by known methods; a considerable number are commercially available.
  • alkyl halocarbonates (IV) that can be employed in the above invention process are methyl chlorocarbonate, ethyl bromocarbonate, propyl iodocarbonate, butyl fluorocarbonate, pentyl bromocarbonate, hexyl iodocarbonate, heptyl fluorocarbonate, undecyl chlorocarbonate, tridecyl bromocarbonate, tetradecyl iodocarbonate, pentadecyl fluorocarbonate, hexadecyl chlorocarbonate, heptadecyl bromocarbonate, octodecyl iodocarbonate, nonadecyl fiuorocarbonate and the like, and the isomeric forms thereof.
  • novel 7-halo-7-deoxylincomycin 3-mono(alkyl carbonate) and 2,3-bis(alkyl carbonate) esters of Formula I are prepared by merely mixing the free base or acid addition salt of a Z-hydroxy counterpart (Il) dissolved in an amine base (III), with an appropriate alkyl halocarbonate (IV). Inert solvents can be added, if desired. The reaction can be satisfactorily carried out between about 50 C. and +50 C., with heating of the reaction mixture being unnecessary.
  • reaction time required for the completion of the 3-monoesterification or 2,3-diesterification reaction depends upon such factors as the reaction temperature, the particular reactants employed, the relative amount of reactants, thoroughness of mixing, and the like. Therefore, it will be understood that optimum reaction time will vary for each set of reaction conditions. Ordinarily, reaction times ranging from about half an hour to about 48 hours are suitable. If desired, for example for purposes of time economy, the course of the reaction may be monitored by sampling and examining the reaction mixture by methods common to the art, for example by the use of thin-layer chromatography, during the reaction.
  • the desired product of Formula I is isolated from the reaction mixture in either its free base or acid addition salt form. Isolation of the product is carried out by conventional procedures such as filtration, solvent evaporation, solvent extraction; chromatography or crystallization; or a combination of these methods.
  • the desired product so obtained can be purified, e.g., by crystallization from a solvent or suitable mixture of solvents.
  • the product When the product is in the free base form, it can be converted to an acid addition salt by neutralization with an acid, e.g., any of those given above; when in the acid addition salt form it can be transformed to the free base, e.g., by treatment with a strongly basic anion exchange resin.
  • Lincomycin also named methyl 6,8 dideoxy-6-(trans-l-methyl-4-propyl-L-2-pyrrolidenecarboxamido) l thio D-erythro-a-D-galactooctopyranoside, is obtained as an elaboration product of a lincomycin-producing actinomycete in accordance with US. Pat.
  • EXAMPLE 1 7 (S -chl0r0-7-de0xylincomycin-3- pcntyl carbonate) hydrochloride A solution of 9.63 g. (0.02 mole) of 7(S)-chloro-7- deoxylincomycin hydrochloride [also named methyl 7- chloro-6,7,8-trideoxy 6-(trans 1 methyl-4-propyl-L-2- pyrrolidinecarboxamido) 1 thio-L-threo-a-D-galactooctopyranoside hydrochloride] (prepared as in Belgian Pat.
  • the ether layer is removed and discarded; the aqueous layer is extracted again with 800 m1. of ether and the ether extract removed and discarded.
  • the aqueous layer is next extracted with 780 ml. of chloroform (in two portions), and the chloroform extracts pooled, dried with anhydrous sodium sulfate, evaporated to dryness under vacuum at about 50 C. [he resulting residual light yellow oil is taken up in 80 ml. of chloroform, which is then saturated with anhydrous hydrogen chloride, and again reduced to dryness under vacuum at about 50 C., to give 2.65 g. of white solid 7 (S)-chlor0-7-deoxylincornycin-3-(pentyl carbonate) hydrochoride.
  • 7(S)-chloro-7-deoxy1incomycin 3 penentyl carbonate hydrochloride has antibacterial activity against Staphylococcus aureus equivalent to 180 micrograms of lincomycin per mg. Its relative molar CD is 0.37 times that of lin- 6 comycin when administered subcutaneously to mice infected with this organism.
  • 7(S) chloro-7-deoxylincomycin-3-(pentyl carbonate) hydrochloride is converted to its free base, 7(S)-chloro- 7-deoxylincomycin-3-(pentyl carbonate), by treatment with a strongly basic anion exchange resin.
  • Suitable anion exchange resins for this purpose are obtained by chlormethylating by the procedure given on pages 88 and 97 of Kunin, Ion Exchange Resins, 2nd edition (1958), John Wiley and Sons, Inc., polystyrene crosslinked, if desired, with divinylbenzene prepared by the procedure given on page 84 of Kunin, supra, and quaternizing with trimethylamine, or dimethylethanolamine by the procedure given on page 97 of Kunin, supra.
  • Anion exchange resins of this type are marketed under the trade names Dowex 2, DoWex 20, Amberlite IRA-400, Duolite A- 102, and Permutit 8-1.]
  • Dowex 2 DoWex 20
  • Amberlite IRA-400 Amberlite IRA-400
  • Duolite A- 102 Duolite A- 102
  • Permutit 8-1 The 7(S)-chloro-7-deoxylincomycin-3-(pentyl carbonate) is converted to other salts by contacting with other acids as previously disclosed.
  • EXAMPLE 2 Further 3-m0n0alkylcarb0nates Following the procedure of Example 1, especially as pertains to ratio of moles of alkyl halocarbonate to moles of starting 7-halogenated lincomycin compound or 1- protected-7-halogenated lincomycin compound but substituting for n-amyl chlorocarbonate another alkyl halocarbonate such as methyl bromocarbonate, ethyl fluorocarbonate, propyl iodocarbonate,
  • another amine base such as 3-methylpyridine, 4-propylidine, S-butylpyridine, 3-methyl-4-ethylpyridine, 3,4-dibutylpyridine, 3-ethyl-4-isopropylpyridine, 3-propyl- 5 4-isobutylpyridine, 3-ethyl-5-propylpyridine, 3,5-dimethylpyridine, 3-isopropyl-5-sec.
  • R is alkyl of from 1 through 6 carbon atoms
  • R is selected from the group consisting of alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, and aralkyl of up to 12 carbon atoms
  • R is selected from the group consisting of hydrogen and alkyl of from 1 through 8 carbon atoms
  • X is selected from the group consisting of chlorine, bromine and iodine
  • R is o n 2n+l wherein n is an integer from 1 through and the acid addition salts thereof.
  • R is methyl, R is trans-n-propyl, R is hydrogen, X is 7(S)-chloro, and R is hexyloxycarbonyl; and acid addition salts thereof.
  • a compound of claim 10 in which the acid addition pentyl-7(S)-chloro-7-deoxylincomycin and decyl iodocarbonate,
  • salt is the hydrochloride.
  • R is alkyl of from 1 through 6 carbon atoms
  • R is selected from the group consisting of alkyl of from 1 through 8 carbon atoms, cycloalkyl of from 3 through 8 carbon atoms, and aralkyl of up to 12 carbon atoms; R is selected from the group consisting of hydrogen and alkyl of from 1 through 8 carbon atoms; X is selected from the group consisting of chlorine, bromine and iodine; R and R are 0 0 H211 l'-0 wherein n is an integer from 1 through 20; and the acid addition salts thereof.
  • a compound of claim 19 in which the acid addition salt is the hydrochloride.
  • a compound of claim 23 in which the acid addition salt is a hydrochloride.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
US816417A 1969-04-15 1969-04-15 7-halo lincomycin carbonate esters Expired - Lifetime US3631021A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US81641769A 1969-04-15 1969-04-15

Publications (1)

Publication Number Publication Date
US3631021A true US3631021A (en) 1971-12-28

Family

ID=25220539

Family Applications (1)

Application Number Title Priority Date Filing Date
US816417A Expired - Lifetime US3631021A (en) 1969-04-15 1969-04-15 7-halo lincomycin carbonate esters

Country Status (9)

Country Link
US (1) US3631021A (fr)
JP (1) JPS4843349B1 (fr)
BE (1) BE748986A (fr)
CH (1) CH538503A (fr)
DE (1) DE2017482A1 (fr)
FR (1) FR2042328B1 (fr)
GB (1) GB1253323A (fr)
IL (1) IL34010A (fr)
NL (1) NL7005085A (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040105917A1 (en) * 2002-01-16 2004-06-03 Mannion Jeffrey T. Suspended containers

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3284438A (en) * 1964-04-20 1966-11-08 Upjohn Co Processes for making cyclic carbonate and cyclic thiocarbonate esters of lincomycin

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040105917A1 (en) * 2002-01-16 2004-06-03 Mannion Jeffrey T. Suspended containers
US7086545B2 (en) 2002-01-16 2006-08-08 Ajava Pinata, L.L.C. Suspended containers

Also Published As

Publication number Publication date
IL34010A (en) 1973-10-25
IL34010A0 (en) 1970-05-21
BE748986A (fr) 1970-10-15
CH538503A (de) 1973-06-30
DE2017482A1 (de) 1970-10-29
JPS4843349B1 (fr) 1973-12-18
FR2042328B1 (fr) 1974-01-11
FR2042328A1 (fr) 1971-02-12
GB1253323A (en) 1971-11-10
NL7005085A (fr) 1970-10-19

Similar Documents

Publication Publication Date Title
DE3852288T2 (de) K-252-Derivate mit Antitumorwirkung und diese enthaltende Arzneimittel.
US5182374A (en) Clindamycin phosphate synthesis
CH655728A5 (de) Erythromycin a-verbindungen, verfahren zu ihrer herstellung sowie ihre verwendung.
CH507970A (de) Verfahren zur Herstellung neuer desacylierter mehrkerniger Indole sowie deren Verwendung
Hodge et al. N-Glycosyl derivatives of secondary amines
DE3883387T2 (de) Bis(methylendioxy)biphenyl-Verbindungen.
US4464527A (en) Antibacterial 9-deoxo-9a-alkyl-9a-aza-9a-homoerythromycin A derivatives and intermediates therefore
US2851463A (en) Desalicetin and salts, and hydrocarbon carboxylic acid esters
US4188377A (en) Carminomycin derivatives, their preparation and use
CS235309B2 (en) Method of 20-aminotylosine derivatives production
US3631021A (en) 7-halo lincomycin carbonate esters
DE69424504T2 (de) Verfahren zur Herstellung von Etoposid-Phosphat und Etoposid
DE2502296A1 (de) Diaminocyclitol-derivate und verfahren zu ihrer herstellung
DE2537375A1 (de) 9,3'',4''-triacylester des antibiotikums sf-837 m tief 1 sowie verfahren zur herstellung derselben
EP0234348B1 (fr) Dérivés de N-glycosylamine, leur méthode de préparation et leur utilisation comme médicaments
DE602004002692T2 (de) Verfahren zur Herstellung von Topiramate
US3929761A (en) 3-Deoxykanamycin
DE69107431T2 (de) Deacetylcolchicinderivate.
US3551433A (en) Preparation of 4-phenyl-4-acyloxypiperidine
US4362866A (en) Aprosamine derivatives
US4101556A (en) Total synthesis of 2,5-dideoxystreptamines
EP0101951A1 (fr) 1,3-Dioxolo(4,5-g)quinoléines et leur préparation
US3598806A (en) Process for preparing lincomycin-3-monoacylates
US4220643A (en) Nitrosourea pentose compounds
US3655885A (en) Antibacterial compositions and methods of treating bacterial infections