GB2268176A - Erythromycin fragments useful in the synthesis of macrolide and azalide antibodies - Google Patents

Erythromycin fragments useful in the synthesis of macrolide and azalide antibodies Download PDF

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GB2268176A
GB2268176A GB9312316A GB9312316A GB2268176A GB 2268176 A GB2268176 A GB 2268176A GB 9312316 A GB9312316 A GB 9312316A GB 9312316 A GB9312316 A GB 9312316A GB 2268176 A GB2268176 A GB 2268176A
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hydrogen
methyl
alkyl
oxo
covalent bond
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Sherman T Waddell
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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Abstract

Compounds of the formulae <IMAGE> Such compounds are made by cleaving the macrolide rings of erythromycin and certain of its dervatives. For the above structural formula, n = 0 or 1; R<1> is hydrogen, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsufonyl; when n = 0, R<2> is hydrogen or methyl and R<3> is hydrogen, methyl, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsufonyl; when n = 1, R<2> and R<3> are methyl; one of R<4> and R<5> is hydrogen, the other is OR<1> or NR<2>R<3> where R<1> is as defined before and R<2> and R<3> are defined as before for when n = 0; R<6> is hydrogen, Me3SiCh2CH2-,C1-10 alkyl or aralkyl; R<7> is hydrogen or C1-3 alkyl; when R<7> is hydrogen, R<9> is methyl and R<10> is hydrogen, when R<7> is alkyl, either R<9> is methyl and R<10> is hydrogen or R<9> is hydrogen and R<10> is methyl. Such compounds are useful as intermediates to the synthesis of modified macrolide and azalide antibiotics.

Description

TITLE OF THE INVENTION ERYTEROMYCIN FRAGMENTS USEFUL IN SYNTHESIS OF MACROLIDE AND AZALIDE ANTIBIOTICS BACKGROUND OF THE INVENTION The present invention relates to novel compounds that are intermediates useful in the synthesis of macrolide and azalide antibiotics, which are useful in the therapy of bacterial infections in mammals.
The synthesis of the novel compounds of the invention starts with the well-known macrolide antibiotic, erythromycin A, (or modified versions of erythromycin A, such as clarithromycin, etc.) which have the structural formula
where R7 = H for erythromycin and R7 = CH3 for clarithromycin.
This macrolide ring is cleaved at two points to produce two fragments. The larger fragment is a linear C1 to C10 fragment characterized by having an intact cladinose sugar moiety, an intact desosaminyl moiety, either a 9-ketone or a cyclic hemiketal and a backbone from carbon 1 to carbon 10 of erythromycin A that is essentially unchanged with regard to substituents or stereochemistry. Two cases exist, depending upon whether R7 is H or is alkyl.
Embodiment A; the case when R7 is H:
Embodiment B; the case when R7 is alkyl;
where R8 and R9 are hydrogen and methyl respectively or methyl and hydrogen respectively.
When R7 is hydrogen, then an equilibrium exists between the ketone form and the 9-R and 9-S diastereomers of the hemiketal form. In general the hemiketal form predominates over the ketone form.
The mixture can, however, be used as a starting material in reactions of either ketones or hemiketals because the two structures interconvert rapidly. If the mixture is being used as the starting material in a reaction of a ketone, as the ketone is consumed in the reaction it will be constantly regenerated from the hemiketal form, so that in effect the mixture behaves as the ketone Conversely, if the mixture is used as the starting material in a reaction of a hemiketal it will be constantly regenerated from the ketone form, so that in effect the mixture is behaving as a hemiketal.These ketone and hemiketal structures will be referred to as the "eastern fragment1'. The smaller fragment produced by the cleavage, which will be referred to as the western fragment", can be separated and modified by subsequent chemical reactions, and then cyclized with the eastern fragment to yield an erythromycin macrolide having one or more structural modifications from carbons 11 to 14. Preferably, after cleavage and separation, a new western fragment can be synthesized de novo to any desired sequence with any desired pattern of substitution, and cyclized with the eastern fragment to form novel lactams or lactones of 10 members or larger.It. will readily be seen that throughout the process, the eastern fragment has remained unchanged, obviating the need for protecting groups or for subsequent synthesis steps to replace moieties on the sugars or the C1-C10 backbone.
Almost all macrocyclizations to give erythromycin-like molecules which have been reported to date have been conducted on precursors in the aglycone form, that is, without the sugars intact.
By the method used to make the compounds of the present invention, an eastern fragment is produced with the sugars intact, eliminating subsequent synthesis steps to attach such sugars.
Alternatively, one can, of course, subsequently modify the sugars as desired, as by introducing acyl derivatives, amines, and so forth.
SUMMARY OF THE INVENTION The present invention comprises compounds of the formulae
when R7 is hydrogen
ighen R7 is alkyl.
In the foregoing formulae, n - O or 1; R1 is hydrogen, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 0, R2 is hydrogen or methyl and R3 is hydrogen, methyl, C1-l0 alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 1, R2 and R3 are methyl; one of R4 and R5 is hydrogen, the other is OR1 or NR2R3 where R1 is as defined before and R2 and R3 are defined as before for when n = 0; R6 is hydrogen, C1-10 alkyl, or aralkyl; R7 is hydrogen or C13 alkyl; when R7 is hydrogen, R8 is methyl and R9 is hydrogen; when R7 is alkyl, either R8 is methyl and R9 is hydrogen or R8 is hydrogen and R9 is methyl.
The compounds of the invention can be readily prepared according to the following flow charts, detailed descriptions, examples and modifications thereof, using readily available starting materials, reagents and conventional synthesis techniques. The overall process is illustrated in the following flow sheet. In these reactions it is also possible to use variants that are themselves known to those of ordinary skill in this art, but which are not mentioned in greater detail.
These flow charts and details likewise serve to illustrate the utility of the ketone and hemiketal compounds of the present invention.
FLOW CHART
FLOW CHART (CONT'D)
FLOW CHART (CONT'D)
where n = O or 1; R1 is hydrogen, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsufonyl; when n = 0, R2 is hydrogen or methyl and R3 is hydrogen, methyl, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 1, R2 and R3 are methyl; one of R4 and R5 is hydrogen, the other is OR1 or NR2R3 where R1 is as defined before and R2 and R3 are defined as before for when n = 0; R6 is C1-10 alkyl or aralkyl;R7 is hydrogen or C13 alkyl; when R7 is hydrogen, R8 is methyl and R9 is hydrogen; when R7 is alkyl, either R8 is methyl and R9 is hydrogen or R8 is hydrogen and R9 is methyl; R10 is hydrogen, alkyl, acyl, arylsufonyl or aralkoxycarbonyl X = O, NH, CH2 A = a chain of 2-7 carbon atoms which may be substituted with a variety of carbon, oxygen and nitrogen-containing functional groups, and which may be interrupted by a heteroatom.
DETAILED DES.CRIPTION OF THE INVENTION The compounds of formula I can be prepared readily according to the following detailed descriptions and accompanying examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures.The overall process is illustrated by the following reaction:
Alternatively:
where n = O or 1; R1 is hydrogen, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 0, R2 is hydrogen methyl and R3 is hydrogen, methyl, C1-10 alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 1, R2 and R3 are methyl; one of R4 and R5 is hydrogen, the other is OR1 or NR2R3 where R1 is as defined before and R2 and R3 are as defined as before for when n = 0; R6 is C1-10 alkyl or aralkyl;R7 is hydrogen or C1-3 alkyl; when R7 is hydrogen, R8.is methyl and R9 is hydrogen; when R7 is alkyl, either R8 is methyl and R9 is hydrogen or R8 is hydrogen and R9 is methyl. M is K+, Na+ or Li+.
X is halogen, methanesulfonate, toluenesulfonate or trifluoromethanesulfonate.
Appropriate starting materials for the fragmentation reaction include erythromycin and a large subset of its derivatives. The fragmentation is a retro-aldol process and requires the hydroxy function at position 11 and the ketone function (or other a-anion stabilizing function including but not limited to oximino, imino, hydrazono, etc.) at position 9. Modification of erythromycin at other sites should in general not affect the course of the fragmentation reaction.
Although not intending to be limited by a single theory of the invention, the fragmentation reaction is believed to occur by retro-aldol rupture of the C10-Cll bond and saponification of the ester function at carbon 1. The smaller fragment, comprised of carbons 11-13, can retroaldol further and/or polymerize under the reaction conditions, and is normally not isolated. The larger fragment, a carboxylate salt comprised of carbons 1-10 of the macrocycle, is essentially the sole isolated product of the reaction.
The retroaldol reaction is a well known base catalyzed reaction, and can in general be carried out with a large number of bases under a variety of reaction conditions. For derivatives of erythromycin the situation is complicated by the fact that several pathways for base catalyzed reaction exist. Most combinations of alkali and alkaline earth metal hydroxides and alkoxides in protic solvents give predominantly or exclusively another style of reaction and little or no retroaldol style reaction.
Preferably the retroaldol reaction is done in a polar aprotic solvent (most preferably THF but including and not limited to DNF, DMSO, DME, etc.) with a strong base which has good solubility in the chosen solvent (most preferably KOTMS but including and not limited to KOH, NaOH, LDA, etc.) Preferably the fragmentation reaction is carried out at a concentration of 0.01 to 0.10 M, with 0.02 M most preferred. The amount of base used is preferably from 1 to 10 equivalents based on starting material, with 5 to 6 equivalents most preferred.The reaction is usually run at a temperature of from 0 C to 50 , preferably at 22-25"C). The reaction can be allowed to run-from 2 hours to 5 days; but is preferably carried out over 6 - 18 hours.
The immediate product of the fragmentation reaction is a carboxylate salt, which is generally not isolated or purified but subjected immediately to conditions which form an ester at position 1.
Esterification of a carboxylate can be accomplished in a very large number of ways, including but not limited to acid catalyzed condensation with alcohols and nucleophilic displacement on electrophilic alkyl species by the carboxylate ion. Acid catalyzed condensation is not preferred for derivatives of erythromycin due to the potential labile nature of the attached carbohydrates under acid conditions, but if carefully optimized these methods could be used.
Nucleophilic displacent by carboxylate on species of the general form R-X where R is a suitable alkyl group and X is a leaving group (including but not limited to CI, Br, I, N2, triflate, methanesulfonate, benzenesulfonate, tosylate, etc.) is the preferred method of esterification, and reaction with diazomethane is the most preferred of these methods.
Because diazomethane must be protonated to form the active methyl diazonium species, the reaction mixture must be neutralized prior to reaction with diazomethane. For most other R-X species the derivatization can be carried out without prior neutralization.
Preferably the diazomethane reaction is done in an aprotic solvent (most preferably methylene chloride but including and not limited to DMF, DMSO, DME, ether, etc.) in which the neutralized (presumably zwitterionic) crude product of the fragmentation reaction is dissolved to a concentration of between 0.01 M and 0.25 M with 0.07 M most preferred. A crude solution of diazomethane in a suitable solvent (preferably ether) is dripped in until the yellow color persists, and then after being allowed to stir from 5 minutes to one hour the excess diazomethane is quenched with a suitable carboxylic acid (preferably acetic acid). The reaction is usually run at a temperature of from 0 C to 25"C, preferably at 22-25"C.
The following examples further illustrate details for the practice of the invention. Those skilled in the art will readily understand that known variations, when taken with the alternative reagents, bases and solvents taught above, can be used in the practice of the invention.
Example 1 Preparation of an equilibrium mixture of 11,12,12a,13,14,15-hexanorerythromycin A seco acid methyl ester and the two C-9 diasteriomeric 11,12,12a,13,14,15-hexanorerythromycin A-6.9-hemiketal seco acid methvl esters
To a 2 L flask was introduced 10 g of erythromycin A (ca. 13.6 mmol, ca. 957. pure, available from Aldrich Chemical Company, Milwaukee, WI) and 10 g of tech. potassium trimethylsilanoate (70 mmol, ca. 907. pure, available from Aldrich Chemical Company, Milwaukee, WI). The two powdery compounds were thoroughly mixed by agitation, and then 800 ml of Aldrich Sure-Seal tetrahydrofuran was poured quickly into the flask with shaking to insure rapid mixing.The reaction was allowed to stir at room temperature for three hours, during which time the color changed from clear to greenish yellow, and a bit of fine precipitate formed and clung to the walls of the flask. At this time the reaction was judged to be complete by thin layer chromatography (silica plates, 93:7:1 CH2C12 : MeOH : aq. NH3 as eluent, p-anisaldehyde stain). The.tetrahydrofuran was removed under vacuum and the residue was dried further under high vacuum at room temperature for 30 minutes. Next, 300 ml of water was added to the residue and the pH was adjusted to 7.0 using 2N HC1 and monitoring continuously with a -pH meter. The water was then removed under high vacuum, and the residue was dried overnight under high vacuum. The residue was then triturated repeatedly with CH2C12, each time decanting the organic from the gummy salts (centrifugation can be used here if necessary.) When it was judged-that all of the compound had been removed from the salts, the methylene chloride solution was dried with MgS04 and concentrated to about 250 ml.
Diazomethane was prepared from 4 g N-nitroso-N-methylurea, 12 ml 40% KOH and 100 ml ether in the manner- described in Org. Syn. Coll. Vol.
2 165 (1943). This ether solution of diazomethane was poured into the methylene chloride solution of the carboxylic acid from above, and allowed to stir for 5 minutes, after which time acetic acid was added until the excess diazomethane was decomposed (as judged by the disappearance of the yellow color.) TLC (silica plates, 93:7:1 CH2C12 : MeOH : aq. NH3 as eluent, p-anisaldehyde stain) at this point showed'a major spot with an Rf of approximately 0.6, along with a substantial baseline spot, Extraction with water effectively removed the baseline material, which could. be reneutralized and subjected again to the diazomethane reaction. The organic layer was extracted with sat. aq. NaHC03, dried over MgS04, and rotovapped to yield 5.8 g of crude hemiketal 2.The product of this reaction was sufficiently pure to be used in a subsequent step, but could be further purified by flash chromatography on silica gel, eluting with 92 : 8 : 1 CH2C12 : MeOH : aq. NH3.
NMR shows predominantly the hemiketal form of the product.
Selected spectral data: 1H NMR (400 MHz, CDCL3) 6 4.54 (d, H-i"), 4.47 (d, H-I1), 4.15 (dd, H-3), 3.96 (dq, H-5"), 3.63 (s, COOCH3), 3.49 (m, H-5'), 3.26 (dd, H-2'), 3.24 (s, OCH3), 2.93 (d, H-4"), 2.73 (dq, H-2), 2.50 (m, H-3'), 2.27 (s, N(CH3)2), 1.43 (d, H-2" ax), 1.08 (d), 0.89 (t, CH3-11), 13C NMR (CDCL3) 6 176.6, 107.1, 102.6 EXAMPLE 2 Preparation of 11,12,12a,13,14,15-hexanorerythromycin A seco acid methyl ester N-oxide and the two diastereomeric 11,12,12a,13,14,15-hexanorerythromycin A-6.9-hemiketal seco acid methyl ester N-oxides
To a 250 ml flask was introduced 270 mg of erythromycin A N-oxide (0.360 mmol, prepared following the procedure given by Jones and Rowley in Org. Chem. 1968, 33, 665 the entire disclosure of which is incorporated herein by reference) and 233 mg of tech. potassium trimethylsilanoate (2.56 mmol, ca.
907o pure, available from Aldrich Chemical Company, Milwaukee, WI). The two powdery compounds were thoroughly mixed by agitation, and then 27 ml of Aldrich Sure-Sealo tetrahydrofuran was poured quickly into the flask with shaking to insure rapid mixing.
The reaction was allowed to stir at room temperature for three hours, during which time the color changed from turbid white to translucent yellow, and a bit of fine precipitate formed and clung to the walls of the flask. At this time the reaction was judged to be complete by thin layer chromatography silica plates, 93:7:1 CH2C12 : MeOH : aq. NE3 as eluent, p-anisaldehyde stain). The tetrahydrofuran was removed under vacuum and the residue was dried further under high vacuum at room temperature for 30 minutes. Next, 10 ml of water added to the residue and the pH was adjusted to 7.0 using 2 N HC1 and monitoring continuously with a pH meter. The water was then removed under high vacuum, and the residue was dried overnight under high vacuum.The residue was then triturated repeatedly with CH2C12, each time decanting the organic from the gummy salts (centrifugation can be used here if necessary.) When it was judged that all of the compound had been removed from the salts, the methylene chloride solution was dried with MgS04 and concentrated to about 250 ml.
An ether solution of diazomethane prepared as described in Example 1 was added at room temperature to the methylene chloride solution of the carboxylic acid until the yellow color of diazomethane persisted, and allowed to stir for 5 minutes, after which time acetic acid was added until the excess diazomethane was decomposed (as judged by the disappearance of the yellow color.) TLC (silica plates, 90:10:1 CH2C12 : MeOH : aq. NH3 as eluent, p-anisaldehyde stain) at this point showed two spots with Rf's of approximately 0.75 and 0.5, along with a small baseline spot. The organic layer was extracted with sat. aq. NaHC03, dried over MgS04, and rotovapped'and purified by flash chromatography on silica gel, eluting with 92 : 8 : 1 CH2C12 : MeOH aq. NH3.In this manner there was obtained 26 mg of the faster eluting compound which was shown to be 11,12,12a,13,14,15-hexanorerythromycin A-6,9-hemiketal seco acid methyl ester (the preparation of which is described in Example 1 above), and 67 mg of the more slowly eluting compound which proved to be 11,12,12a,13,14,15- hexanorerythromycin A-6 , 9-hemiketal seco acid methyl ester N-oxide. NMR shows predominantly the hemiketal form of the product.
Selected spectral data: 1H NMR (400 MHz, CDCL3) 6 4.61 (d, H-l"), 4.61 (d, H-1'), 4.23 (dd, H-3), 4.00 (dq, H-5"), 3.84 (dd, H-2'), 3.70 (s, COOCH3), 3.31 (s, OCH3), 3.22 (s, N)CH3)2), 2.80 (dq, H-2), 2.30 (d, H-2" eq), 1.47 (dd, H-2" ax), 0.94 (t, CH3-11), 13C NMR (CDCL3) 6 176.8, 107.1, 102.3, 95.7, 84.5, 80.6, 79.6, 78.0, 72.8, 67.8, 65.3, 54.0 51.8, 49.4, 41.7, 40.9, 39.8, 39.5, 35.2, 34.2, 30.8, 25.1, 21.6, 21.0, 18.0, 13.1, 11.0, 10.4, 9.4 EXAMPLE 3 Preparation of 6-0-methyl-11,12,12a,13,14,15- hexanorerythromycin A seco acid methyl ester and 6-0-methyl-8-epi-11,12,12a,13,14,15-hexanorerythro- mvcin A seco acid methvl ester
To a 1 L flask was introduced 3 g of 6-O-methylerythromycin A (4.01 mmol, ca. 95% pure, prepared according to procedures given in 3. Am.
Chem. Soc. 1955, 77, 3104 and J. Antibiotics, 90, 286) and 2.9 g of tech. potassium trimethylsilanoate (70 mmol, ca. 90% pure, available from Aldrich Chemical Company, Milwaukee, WI). The two powdery compounds were thoroughly mixed by agitation, and then 300 ml of Aldrich Sure-Seale tetrahydrofuran was poured quickly into the flask with shaking to insure rapid mixture. The reaction was allowed to stir at room temperature for three hours, during which time the color changed from clear to greenish yellow, and a bit of fine precipitate formed and clung to the walls of the flask. At this time the reaction was judged to be complete by thin layer chromatography (silica plates, 93:7:1 CH2C12 : MeOH : aq. NH3 as eluent, p-anisaldehyde stain). The tetrahydrofuran was removed under vacuum and the residue was dried further under high vacuum at room temperature for 30 minutes. Next, 300 ml of water was added to the residue and the aqueous solution was agitated with 150 ml of ethyl acetate. The aqueous layer was separated and brought to pH 7 using acetic acid. The water was then removed under high vacuum, and the residue was dried overnight under high vacuum. The residue was then triturated repeatedly with CH2Cl2, each time decanting the organic from the gummy salts (centrifugation can be used here if necessary.) When it was judged that all of the compound had been removed from the salts, the methylene chloride solution was dried with MgS04 and concentrated to about 250 ml.
An ether solution of diazomethane prepared as described in Example 1 was added at room temperature to the methylene chloride solution of the carboxylic acid until the yellow color of diazomethane persisted, and allowed to stir for 5 minutes, after which time acetic acid was added until the excess diazomethane was decomposed (as judged by the disappearance of the yellow color.) TLC (silica plates, 93:7:1 CH2C12 : MeOR : aq. NH3 as eluent, p-anisaldehyde stain) at this point showed one spot with an Rf of approximately 0.6, along with a small baseline spot. The organic layer was extracted with sat. aq. NaHC03, dried over MgS04, and rotovapped and purified by flash chromatography on silica gel, eluting with 965 : 35 : 5 CH2C12 : MeOH : aq. NH3.
In this manner was obtained 1.61 g of the product, approximately a 50:50 mixture of 6-0-methyl-11,12,12a, 13,14,15-hexanorerythromycin A seco acid methyl ester and 6-0-methyl-8-epi-11,12,12a,13,14,15-hexanoreryth- romycin A seco acid methyl ester.
Selected spectral data for the mixture: 1H NMR (400MHz, CDCL3) 6 4.62 (apparent t, H-1"), 4.37 (apparent t, H-1'), 3.61 & 3.60 (s, COOCH3), 3.25 & 3.23 (s, OCH3), 3.09 & 3.01 (s, OCH3), 2.27 & 2.24 (s, N(CH3)2) 13C NMR (CDCL3) 6 215.22, 215.11, 175.98, 175.95, 102.80, 102.38, 95.16, 94.80, 79.84, 79.58, 79.39, 78.87, 78.70, 77.89, 72.66, 72.63, 70.27, 68.84, 65.32, 65.22, 65.18, 51.53, 51.47, 50.18, 50.05, 49.23; 41.97, 41.50, 41.25, 41.22, 40.27, 40.22, 39.30, 37.41, 36.71, 35.00, 34.31, 32.41, 29.02, 28.80, 21.45, 21.37, 21.13, 20.11, 19.01, 18.78, 17.98, 17.94, 10.86, 10.78, 10.65, 10.59, 7.72, 7.60 EXAMPLE 4 Preparation of an equilibrium mixture of 4"-deoxy- 4"-amino-11,12,12a,13,14,15 hexanorerythromycin A and the two C-9 diastereomeric 4"-deoxy-4"-amino 11,12,12a,13,14,15-hexanorerythromycin A-6.9-hemiketal seco acid methvl esters
To a 2 L flask is introduced 10 g of 4"deoxy-4"amino-erythromycin A (13.6 mmol) and 10 g of tech. potassium trimethylsilanoate (70 mmol, ca. 90% pure, available from Aldrich Chemical Company, Milwaukee, WI).The two powdery compounds are thoroughly mixed by agitation, and then 800 ml of Aldrich Sure-Sealo tetrahydrofuran is poured quickly into the flask with shaking to insure rapid mixing.
The reaction is allowed to stir at room temperature for three hours. The tetrahydrofuran is removed under vacuum and the residue is dried further under high vacuum at room temperature for 30 minutes.
Next, 300 ml of water is added to the residue and the pH is adjusted 7.0 using 2 N HC1 and monitoring continuously with a pH meter. The water is then removed under high vacuum, and the residue is dried overnight under high vacuum. The residue is then triturated repeatedly with CH2Cl2, each time decanting the organic from the gummy salts (centrifugation is used here if necessary.) When it is judged that all of the compound has been removed from the salts, the methylene chloride solution is dried with MgS04 and concentrated to about 250 ml.
Diazomethane is prepared from N-nitroso N-methylurea and 40% KOH in ether in the manner described in Org. Syn. Coll. Vol 2 165 (1943). This ether solution of diazomethane is poured into the methylene chloride solution of the carboxylic acid from above, and allowed to stir for 5 minutes, after which time acetic acid is added until the excess diazomethane is decomposed (as judged by the disappearance of the yellow color.). The organic layer is extracted with sat. aq. NaHC03, dried over MgS04, and rotovapped to yield crude product, which is purified by flash chromatography on silica gel.
EXAMPLE 5 General Procedure for the Preparation of Fragments of Ervthromycin-like Molecules
Using the procedure taught in Example 4, an erythromycin derivative X is converted to an equilibrating mixture of erythromycin fragments Y wherein values for R1 to R9 are defined as follows: n = O or 1; R1.is hydrogen, Cl~lO alkylcarbonyl, aralkoxycarbonyl or arylsulfonyl; when n = 0, R2 is hydrogen or methyl and R3 is hydrogen, methyl, C1~10 alkylcarbonyl, aralkoxycarbonyl or arylsufonyl; when n = 1, R2 and R3 are methyl; one of R4 and R5 is hydrogen, the other is OR1 or NR2R3 where R1 is as defined before and R2 and R3- are as defined as before for n = 0; R6 is hydrogen, C1-10 alkyl or aralkyl;R7 is hydrogen or C13 alkyl; when R7 is hydrogen, R8 is methyl and R9 is hydrogen; when R7 is alkyl, either R8 is methyl and R9 is hydrogen or R8 is hydrogen and R9 is methyl. It will be recalled that when R7 is hydrogen the ketone form will exist in equilibrium with the mixture of C-9 diastereomeric hemiketals.
A representative but non-limiting sampling of the compounds which may be produced in this manner include those in the following table: EXAMPLE 5 TABLE
Example 5 Table (Contld)
Conpound R1 R2 R3 R' Rs Rf R7 n 5a H Ma b OH H s s tI 5b H Mr 1ER OH H bH2 H O 5e H Me Pb OH H s3SiCH2CH2 H O 5d H Mr 1X OH H } Pr 0 5e H s fez H OH H O 0 0 II ii PhCH2oC M3 PhCH20C OH H Nb H O H H s PESO2 OH H s H O Ph= phenyl : net hyl Per= propyl While the invention has been described, exemplified and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention.
It is intended, therefore, that the invention be limited only by the scope of the 'claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims (9)

WHAT IS CLAIMED IS:
1. A compound of the formula
wherein R1 is hydrogen, C1-10 alkylcarbonyl, aralkoxycarbonyl, or arylsulfonyl; R2 is hydrogen or methyl; R3 is hydrogen, methyl, C1-10 alkylcarbonyl, aralkoxycarbonyl, or arylsulfonyl; one of R4 and R5 is hydrogen and the other is OR1 or NR2R3 where R1, R2 and R3 are as defined above; R6 is hydrogen, C1-10 alkyl or aralkyl; R7 is hydrogen or 'C1-3 alkyl when R8 is oxo;R7 is a convalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H or alkyl; R8 is a hydroxy group of either stereochemical orientation when R7 is a covalent bond to the C-9 carbon atom; R9 is methyl and R10 is hydrogen when R7 is hydrogen or when R7 is a covalent bond to the C-9 carbon; one of R9 and R10 is hydrogen and the other is methyl when R7 is C13 alkyl; n is O or 1 when R2 and R3 are both methyl; n is 0 for all other definitions of R2 and R3 given above.
2. A compound as claimed in claim 1 wherein R1 is hydrogen or benzyloxycarbonyl; R2 is methyl; R3 is methyl, benzyloxycarbonyl, or benzenesulfonyl; one of R4 and R5 is hydrogen and the other is OH or NH2; R6 is hydrogen, methyl, benzyl, or Me3SiCH2CH2; R7 is hydrogen, methyl, or propyl when R8 is oxo; R7 is a covalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H or alkyl; R8 is a hydroxy group of either stereochemical orientation when R7 is a covalent bond to the C-9 carbon atom; R9 is methyl and R10 is hydrogen when R7 is hydrogen or when R7 is a covalent bond to the C-9 carbon; one of R9 and R10 is hydrogen and the other is methyl when R7 is alkyl; n is O or 1 when R2 and R3 are both methyl; n is 0 for all other definitions of R2 and R3 given above.
3. A compound as claimed in claim 1 wherein R1 is hydrogen; R2 is methyl; R3 is methyl; R4 is OH and R5 is hydrogen; R6 is hydrogen or methyl; R7 is hydrogen or methyl when R8 is oxo; R7 is a covalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H or alkyl; R8 is a hydroxy group of either stereochemical orientation when R7 is a covalent bond to the C-9 carbon atom; R9 is methyl and R10 is hydrogen when R7 is hydrogen or when R7 is a covalent bond to the C-9 carbon atom; one of R9 and R10 is hydrogen and the other is methyl when R7 is alkyl; n is O or 1.
4. A compound as claimed in claim 1 wherein R1 is hydrogen; R2 is methyl; R3 is methyl; R4 is OH and R5 is hydrogen; R6 is hydrogen or methyl; R7 is hydrogen when R8 is oxo; R7 is a covalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H; R8 is a hydroxy group of either stereochemical orientation when R7 is a covalent bond to the C-9 carbon atom; R9 is methyl and R10 is hydrogen; n is 0.
5. A compound as claimed in claim 1 wherein R1 is hydrogen; R2 is methyl; R3 is methyl; R4 is OH and R5 is hydrogen; R6 is hydrogen or methyl; R7 is hydrogen when R8 is oxo; R7 is a covalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H; R8 is a hydroxy group of either stereochemical orientation when R7 is a covalent bond to the C-9 carbon atom; R9 is methyl and R10 is hydrogen; n is 1.
6. A compound as claimed in claim 1 wherein R1 is hydrogen; R2 is methyl; R3 is methyl; R4 is OR and R5 is hydrogen; R6 is hydrogen or methyl; R7 is methyl; R8 is oxo; one of R9 and R10 is hydrogen and the other is methyl; n is 0.
7. A compound as claimed in claim 1 wherein R1 is hydrogen; R2 is methyl; R3 is methyl; R4 is NR2 and R5 is hydrogen; R6 is hydrogen or methyl; R7 is hydrogen when R8 is oxo; R7 is a covalent bond to the C-9 carbon atom when R8 is hydroxy; R8 is oxo when R7 is H; R8 is a hydroxy group of either stereochemical -conriguratlon when R7 is a covalent bond to the C-9 carbon atom R9 'is methyl and R10 is hydrogen; is 0.
8. A compound as claimed in any one of claims 1 to 7 for use as an intermediate in the synthesis of a corresponding macrolide or azalide.
9. A process for preparing a compound as claimed in any of claims 1 to 8 which process comprises cleavage at C10 and C13 of the corresponding macrolide.
GB9312316A 1992-06-24 1993-06-15 Erythromycin fragments useful in the synthesis of macrolide and azalide antibodies Withdrawn GB2268176A (en)

Applications Claiming Priority (1)

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US90362592A 1992-06-24 1992-06-24

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GB2268176A true GB2268176A (en) 1994-01-05

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Tetrahedron Lett., 1992, Vol. 33(51), pages 7827-7830 & CA 118: 124924d *

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