TW201811811A - Processes for preparing fluoroketolides - Google Patents

Abstract

Processes and intermediates for preparing fluoroketolide compounds are described herein.

Description

Method for preparing fluoroketone lactone

The invention described herein relates to methods and intermediates for the preparation of fluoroketone lactone compounds.

Fluoroketone lactone compounds have been reported to be very effective in treating bacterial and protozoal infections. In addition, fluoroketone lactone compounds have been reported to be particularly effective in treating drug-resistant bacteria and protozoal infections compared to other macrolides and azalides, including corresponding non-fluoroketone lactones. With the monotonous increase in global bacterial and protozoal resistance, fluoroketone lactone compounds will play an increasingly important role in the treatment of diseases. However, the reported method of producing fluoroketone lactones is carried out in many cases with low yield or low conversion. Low conversion results in purification that is very difficult to resolve, in which case it is difficult to separate the fluorinated product from the non-fluorinated starting material. In addition, the reported ketolactone manufacturing process tends to produce high levels of undesirable by-products, such as N-demethylated by-products, and undesirable adducts with fluorinating agents or their reaction by-products. . Since fluoroketone lactones (as with all antibiotics) are administered at high doses, such manufacturing limitations make it more difficult to prepare the desired metric tons. In addition, bacterial and protozoal infections are not only a worldwide problem, but are also more prevalent in the poorest countries. As a result, such manufacturing constraints can result in high product costs and hinder the treatment of more vulnerable groups in the world. Because of the importance of such compounds to the health of humans and other animals, alternative and/or improved methods of preparing them are needed. There is a need for high yield and high conversion fluoroketone lactones on a commercial scale to meet the unmet needs of these important human and animal health compounds. It has been unexpectedly discovered herein that the process comprising hydrazine and/or phosphazene provides high conversion to fluoroketone lactone with fewer by-products. Further, the method of using hydrazine and/or phosphazene can be carried out at a temperature higher than a conventional fluorination reaction. The flexibility of the temperature allows the methods to be carried out on a larger scale to ensure adequate supply to meet the worldwide need to treat bacterial infections, and at a lower input cost. Due to the high conversion and fewer by-products, the methods described herein can be used to prepare metric tons of fluoroketone lactones, which can be separated by simple precipitation rather than by chromatography or fractional recrystallization, each of which It is expensive and/or may result in significant loss in isolated yield.

In an exemplary embodiment of the invention described herein, a method of preparing a fluoroketone lactone compound by fluorination at C2 of a macrocycle is described. In another embodiment, the methods described herein include the following chemical transformations: A salt comprising each of the foregoing, wherein: R ¹ is H or a thiol group, or R ¹ is a monosaccharide such as a monosaccharide containing a methylamino group or a dimethylamino group; R ⁶ is H or an alkyl group; V is CH _2- N(R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is independently selected from hydrogen or in each case a substituted alkyl group; and Q ¹ is a hydroxyl group or a derivative thereof or an amine group or a derivative thereof; and W ¹ is a hydroxyl group or a derivative thereof; and W ² is H, or a hydroxyl group or a derivative thereof; or W ¹ And W ² together with the carbon atom to which they are attached form an oxygen-containing and/or nitrogen-containing heterocyclic ring, each of which is optionally substituted. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein: R ¹ is H or a thiol group, or R ¹ is a monosaccharide such as a monosaccharide containing a methylamino group or a dimethylamino group; R ⁶ is H or an alkyl group; V is CH _2- N(R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is independently selected from hydrogen or in each case a substituted alkyl group; and Q ¹ is a hydroxyl group or a derivative thereof or an amine group or a derivative thereof; and A is a bond, or A is composed of O, C(O), CR, CR ₂ and NR, and combinations thereof Forming a linking group as appropriate, wherein each R is independently selected in each case to be absent to form a double bond or a bond, which is hydrogen, or an optionally substituted alkyl group; and B is one The bond, or B, is optionally substituted alkyl, optionally substituted alkenyl or, as appropriate, substituted alkynyl. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein: R ^1a is H or fluorenyl; R ⁶ is H or alkyl; V is CH ₂ -N(R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ is hydroxy or a derivative or amine thereof or a derivative; and A is a bond, or A is a linking group selected from the group consisting of O, C(O), CR, CR ₂ and NR, and combinations thereof, wherein each R is independently selected in each case a non-existent to form a double bond or a bond, a hydrogen, or an optionally substituted alkyl group; and B is a bond, or B is an optionally substituted alkyl group, optionally substituted alkylene An alkynyl group substituted or substituted as appropriate. In another embodiment, the methods include the following chemical transformations: or A salt comprising each of the foregoing, wherein: R ¹ is H or a thiol group, or R ¹ is a monosaccharide such as a monosaccharide containing a methylamino group or a dimethylamino group; R ⁶ is H or an optionally substituted alkane A is a bond, or A is a linking group selected from O, C(O), CR, CR _2, and NR, and combinations thereof, wherein each R is independently selected in each case as not Existing to form a double bond or a para-bond, a hydrogen, or an optionally substituted alkyl; and B is a bond, or B is optionally substituted alkyl, optionally substituted alkenyl or An alkynyl group substituted as appropriate. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein R ^1a is H or a thiol group. In another embodiment, the methods include the following chemical transformations: A salt according to each of the foregoing, wherein R ^1a is H or a thiol group; and R ⁶ is H or an optionally substituted alkyl group. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein R ^1a is H or a thiol group. In another embodiment, a method of preparing a fluoroketone lactone compound by in situ N-methylation is described herein. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein: R ^1a is H or fluorenyl; R ⁶ is H or alkyl; V is CH ₂ -N(R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ is hydroxy or a derivative or amine thereof or a derivative; and W ¹ is a hydroxyl group or a derivative thereof; and W ² is H, or a hydroxyl group or a derivative thereof; or W ¹ and W ² together with the carbon atom to be bonded form an oxygen-containing and/or nitrogen-containing heterocyclic ring, Each of them is replaced as appropriate. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein: R ^1a is H or fluorenyl; R ⁶ is H or alkyl; V is CH ₂ -N(R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ is hydroxy or a derivative or amine thereof or a derivative; and A is a bond, or A is a linking group selected from the group consisting of O, C(O), CR, CR ₂ and NR, and combinations thereof, wherein each R is independently selected in each case a non-existent to form a double bond or a bond, a hydrogen, or an optionally substituted alkyl group; and B is a bond, or B is an optionally substituted alkyl group, optionally substituted alkylene An alkynyl group substituted or substituted as appropriate. In another embodiment, the methods include the following chemical transformations: or A salt comprising each of the foregoing, wherein: R ^1a is H or a fluorenyl group; R ⁶ is H or an alkyl group; A is a bond, or A is O, C(O), CR, CR ₂ and NR and a bond group optionally formed by combination, wherein each R is independently selected in each case to be absent to form a double bond or a bond, which is hydrogen or an optionally substituted alkyl group; and B is A bond, or B, is optionally substituted alkyl, optionally substituted alkenyl or, as appropriate, substituted alkynyl. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein R ^1a is H or a thiol group. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein R ^1a is H or a thiol group; and R ⁶ is H or an alkyl group. In another embodiment, the methods include the following chemical transformations: A salt comprising each of the foregoing, wherein R ^1a is H or a thiol group. In another embodiment, an intermediate for the preparation of a fluoroketone lactone compound is described herein. An exemplary intermediate has the following formula And a salt thereof, wherein R ^1a , V, W ¹ , W ² , A and B are as defined herein. In each of the embodiments described herein, exemplary oxygen and/or nitrogen containing heterocycles include And analogs thereof, wherein R is hydrogen or alkyl. X is illustratively a substituted alkylene group, a substituted alkenyl group or a substituted alkynyl group such as an alkyl group, an alkenyl group or an alkynyl group substituted with an aryl group. In such embodiments, the aryl group can be, for example, an imidazolyl group, a triazolyl group, and the like, and the aryl group is optionally substituted with a group C, as described herein. In another embodiment, a pharmaceutical composition comprising one or more of the compounds is also described herein. It will be understood that the compositions may include other components and/or ingredients including, but not limited to, other therapeutically active compounds and/or one or more carriers, diluents, excipients, and the like, and combination. In another embodiment, methods of treating a host animal having a bacterial or protozoal infection are also described herein, wherein the methods comprise administering to the host animal one or more compounds and/or compositions described herein. In another embodiment, the use of the compounds and compositions in the manufacture of a medicament for treating a host animal having a bacterial or protozoal infection is also described herein. In another embodiment, the medicament comprises a therapeutically effective amount of one or more compounds and/or compositions to treat a host animal having a bacterial or protozoal infection.

Certain fluoroketone lactones and methods of preparing such fluoroketone lactones are described in WO 2004/080391. Processes for the preparation of fluoroketone lactones are also described in WO 2009/055557. The method described in the aforesaid publication for fluorination at C2 of the macrolide lactone core structure has been found to be incomplete. In addition, it has been found that attempts to achieve complete fluorination at C2 result in reduced yields and the formation of increasingly higher levels of by-products such as N-demethylation of sugars at C5, such as demethylation of deoxyglycosides. And as the reaction conditions become more severely decomposed. Furthermore, it has been found that when the disclosed method is carried out at a higher temperature in an effort to increase the conversion, the yield is also lowered and a large increase in by-product formation occurs. One such by-product is an adduct formed from a fluorinating reagent. Therefore, the search for solving the problem of incomplete conversion leads to at least two other problems, formation of by-products and a decrease in overall yield. In addition, it has also unexpectedly been found that the unfluorinated starting materials and fluorinated products are substantially inseparable, especially using commercially available purification techniques required for large scale production of antibiotics for use in the global market. Since the only difference between the starting material and the desired product is a single fluorine atom, the separation of the two compounds is very difficult and can only be achieved by careful column chromatography or fractional recrystallization, each causing a large amount of Material loss, and thus overall loss of yield. It has also unexpectedly been found that N-demethyl byproducts are also extremely difficult to remove using commercially available purification techniques required for large scale production of antibiotics for use in the global market. Commercially available purification techniques include evaporation, precipitation, and crystallization, while advantageously avoiding chromatography or fractional crystallization, each being more expensive and resulting in a substantial reduction in yield. In addition, it has been found that in many cases, the corresponding unfluorinated analog of the desired fluoroketone lactone is substantially less active than the desired fluorinated compound, particularly against drug pathogens. Similarly, the corresponding N-demethylated analog of the desired fluoroketone lactone in almost all of the examples is substantially less active than the desired N,N-dimethyl compound. Thus, it should be understood that complete fluorination is required to ensure product purity and is not contaminated by less active analogs that may affect drug efficacy, especially when the relative amount of less active analogs may vary widely in multiple batches. Similarly, it will be appreciated that demethylation needs to be avoided to ensure product purity and is not contaminated by less active analogs that may affect drug efficacy, especially when the relative amount of less active analogs may vary widely from batch to batch. Time. Such batch-to-batch variations complicate precise ingredients and can even hinder regulatory approval. Addressing the problem of incomplete fluorination requires more vigorous reagents and reaction conditions, such as higher temperatures, higher equivalents of base, and/or higher equivalents of fluorinating agents. However, these same methods modify the problems associated with weighting, adding undesirable N-demethylated products (initial unfluorinated compounds (eg, (1-DM)) and product fluorinated compounds (eg, (2-DM) )) The amount of both). In addition, the use of their same relatively harsh reagents and reaction conditions can cause decomposition and other undesirable by-products, such as NFSi adducts of the formula And inevitably, causing an overall loss in yield. For example, higher temperatures and/or excess fluorinating reagents achieve better conversion, but are also accompanied by increased formation of NFSi adducts and/or increased demethylation. Similarly, solving the problem of undesirable N-demethylation requires less aggressive reagents and reaction conditions. However, this same solution exacerbates the attendant problems of reducing the conversion of unfluorinated compounds to product fluorinated compounds. It has also been found that in situ remethylation fails even when known methods, such as those reported in WO 2009/055557, are optimized to facilitate transformation and concomitant N-demethylation. Therefore, it is desirable to separate multiple products from the reaction mixture and perform separate remethylation, which causes additional material loss, overall yield reduction, higher cost, and longer manufacturing time. The need for fluoroketolides for the treatment of bacterial and protozoal infections worldwide requires a manufacturing process that is both cost effective and can be carried out on a large kilogram or metric ton scale. Without any of these attributes, the supply of fluoroketone lactone will not be sufficient to meet the needs of the world and/or hinder the use of fluoroketone lactone in poorer areas where bacteria or protozoal infections are often more prevalent in the world, and The result of poverty. There is a need for a new process for the preparation of fluoroketone lactones. In the absence of such improved methods of providing higher yields of high purity fluoroketone lactone antibiotics, there are millions of patients with bacterial or protozoal infections that may suffer from supply shortages, manufacturing delays, and/or treatment costs. High and unable to get treatment. It has been unexpectedly discovered herein that the fluorination process described herein provides substantially higher conversion of the unfluorinated starting material to the desired fluoroketone lactone. It has also been unexpectedly discovered herein that the fluorination process described herein provides a substantially lower amount of N-demethylated by-product. It has also been unexpectedly discovered herein that the fluorination process described herein can be carried out at higher temperatures without the formation of an excess of fluorinating agent adduct. Moreover, it has been unexpectedly discovered herein that the fluorination process described herein can be adapted to include in situ remethylation to further increase overall yield by recapture of N-demethylated byproducts. Thus, undesirable N-demethylated products, including, for example, (1-DM) and (2-DM), can be used as starting materials for the preparation of fluoroketone lactones. The process described herein provides high purity fluorinated ketone lactone in high yields and is adaptable to larger commercial scales of kilograms and metric tons. Several exemplary embodiments of the invention are described using the following items: A method of preparing a fluoroketone lactone of formula (I), The method comprises formulating a compound of the formula Contact with fluorinating agents and hydrazine or phosphazene; where R ¹ H or thiol, or R ¹ Is a monosaccharide, such as a monosaccharide containing a methylamino group or a dimethylamino group; V is CH ₂ -N(R), C(O)-N(R), C=Q or C=NQ ¹ Wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ Is a hydroxyl group or a derivative thereof or an amine group or a derivative thereof; and W ¹ Is a hydroxyl group or a derivative thereof; and W ² Is H, or a hydroxyl group or a derivative thereof; or W ¹ And W ² Together with the carbon atoms to which they are attached, oxygen- and/or nitrogen-containing heterocycles are formed, each of which is optionally substituted. Any one of the aforementioned methods, wherein the purine base is 1,1,3,3-tetramethylguanidine (TMG), 2-tert-butyl-1,1,3,3-tetramethylguanidine, 7 -Methyl-1,5,7-triazabicyclo(4.4.0)non-5-ene (MTBD), 1,1,2,3,3-pentamethylindole, anthracene, and combinations thereof. Any one of the aforementioned methods, wherein the phosphazene base is a tert-butylimine-paraxyl (dimethylamino)phosphane, P ₁ -t-Bu-para (butylene), 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorus Benzene, trioctylimido-sodium (dimethylamino)phosphane, 1-tert-butyl-2,2,4,4,4-penta(dimethylamino)-2λ ⁵ , 4λ ⁵ - bis(phosphazene) and combinations thereof. Any one of the aforementioned methods, wherein the phosphazene base is selected from the group consisting of And their combinations. Any one of the aforementioned methods, wherein the guanidine or phosphazene base is 1,1,3,3 tetramethylguanidine or a tert-butylimido-ginxyl (dimethylamino)phosphane (also known as Phosphazene base P ₁ - t -Bu) and its combination. A method according to any one of the preceding claims wherein the fluorinating agent is selected from the group consisting of NFSi, Selectfluor and F-TEDA, and combinations thereof. A method according to any one of the preceding claims wherein the fluorinating agent is selected from the group consisting of NFSi and Selectfluor, and combinations thereof. A method according to any one of the preceding claims wherein the fluorinating agent is a combination of NFSi and Selectfluor. A method according to any one of the preceding claims wherein the fluorinating agent is NFSi. A method according to any one of the preceding claims wherein the temperature is between about -40 ° C and about 20 ° C; between about -30 ° C and about 20 ° C; between about -20 ° C and about 20 ° C; Between 15 ° C and about 20 ° C; between about -10 ° C and about 20 ° C; between about -5 ° C and about 20 ° C; or between about 0 ° C and about 20 ° C. A method according to any one of the preceding claims wherein the temperature is between about -40 ° C and about 10 ° C; between about -30 ° C and about 10 ° C; between about -20 ° C and about 10 ° C; Between 15 ° C and about 10 ° C; between about -10 ° C and about 10 ° C; between about -5 ° C and about 10 ° C; or between about 0 ° C and about 10 ° C. Or any one of the preceding methods, wherein the temperature is between about -40 ° C and about 5 ° C; between about -30 ° C and about 5 ° C; between about -20 ° C and about 5 ° C; Between 15 ° C and about 5 ° C; between about -10 ° C and about 5 ° C; between about -5 ° C and about 5 ° C; or between about 0 ° C and about 5 ° C; or at about 5 ° C under. A method according to any one of the preceding claims wherein the temperature is between about -40 ° C and about 0 ° C; between about -30 ° C and about 0 ° C; between about -20 ° C and about 0 ° C; Between 15 ° C and about 0 ° C; between about -10 ° C and about 0 ° C; or between about -5 ° C and about 0 ° C; or at about 0 ° C. Or any one of the preceding methods, wherein the temperature is between about -40 ° C and about -5 ° C; between about -30 ° C and about -5 ° C; between about -20 ° C and about -5 ° C; Between about -15 ° C and about -5 ° C; between about -10 ° C and about -5 ° C; or at about -5 ° C. It has been found herein that phosphazene bases can be used at higher temperatures. Or any one of the preceding methods, wherein the temperature is between about -40 ° C and about -10 ° C; between about -30 ° C and about -10 ° C; between about -20 ° C and about -10 ° C; Between about -15 ° C and about -10 ° C; or at about -10 ° C. A process for the preparation of a compound of formula (I), which process comprises or further comprises a compound of formula (DM) a salt comprising each of the foregoing, in contact with a methylating agent; wherein: R ^1a H or thiol; V is CH ₂ -N(R), C(O)-N(R), C=Q or C=NQ ¹ Wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ Is a hydroxyl group or a derivative thereof or an amine group or a derivative thereof; and W ¹ Is a hydroxyl group or a derivative thereof; and W ² Is H, or a hydroxyl group or a derivative thereof; or W ¹ And W ² Together with the carbon atoms to which they are attached, oxygen- and/or nitrogen-containing heterocycles are formed, each of which is optionally substituted. It will be appreciated that this methylation process can be carried out in situ after any of the fluorination processes described herein, wherein no separation step is required prior to carrying out the methylation process. Any one of the aforementioned methods, wherein the methylating agent is CH ₂ O/HCO ₂ H. Any of the foregoing methods, which are carried out in a solvent, wherein the solvent comprises a ketone such as acetone, MEK or MTBK. Any one of the preceding methods, which is carried out in a solvent, wherein the solvent comprises an ether such as MTBE, THF, Me-THF or a glycol ether such as dimethoxyethane, diethoxyethane, or R ¹ O-(CH ₂ ) ₂ -OR ² Compound, where R ¹ Is an alkyl group such as methyl, ethyl, propyl, isopropyl or butyl; and R ² Is H, methyl, ethyl, propyl, isopropyl or butyl; or formula R ¹ [O-(CH ₂ ) ₂ -] ₂ OR ² Compound, where R ¹ Is an alkyl group such as methyl, ethyl, propyl, isopropyl or butyl; and R ² Is H, methyl, ethyl, propyl, isopropyl or butyl. Any of the foregoing methods, which are carried out in a solvent, wherein the solvent comprises an ester such as EtOAc, iPrOAc. Any of the foregoing methods, which are carried out in a solvent, wherein the solvent comprises a guanamine such as DMF, DMA, NMP. Any of the preceding methods, which are carried out in a solvent, wherein the solvent comprises a mixture of guanamine and an ester, such as iPrOAc/DMF, or iPrOAc/DMF, illustratively ranging from about 1:2 to about 2:1. , or about 3:2 to about 2:3, or about 1:1. Any of the preceding methods, which are carried out in a solvent, wherein the solvent is substantially free or free of chlorinated solvents, such as CH ₂ Cl ₂ (DCM), CHCl ₃ And / or CCl ₄ . Any of the foregoing methods, wherein W ¹ And W ² Forming a urethane with the attached carbon atom, wherein the nitrogen is via the formula N ₃ -BA group substitution, where A is a bond, or A is O, C(O), CR, CR ₂ And NR and combinations thereof, optionally selected as a linking group, wherein each R is independently selected in each case to be absent to form a double bond or a bond, which is hydrogen or an optionally substituted alkyl group. And B is a bond, or B is an optionally substituted alkyl group, optionally substituted alkenyl group or optionally substituted alkynyl group. Any of the foregoing methods, wherein W ¹ And W ² Forming a urethane with the attached carbon atom, wherein the nitrogen is substituted by a group of the formula TBA, wherein A is a bond, or A is O, C(O), CR, CR ₂ And NR and combinations thereof, optionally selected as a linking group, wherein each R is independently selected in each case to be absent to form a double bond or a bond, which is hydrogen or an optionally substituted alkyl group. And B is a bond, or B is an optionally substituted alkyl, optionally substituted alkenyl or, as the case may be, substituted alkynyl; T is optionally substituted aryl, including Not limited to) imidazolyl, 1,2,3-triazolyl, phenyl, benzimidazolyl, benzotriazolyl and the like, and wherein substitutions are optionally included, including but not limited to, as appropriate Substituted aryl groups such as phenyl, aminophenyl, benzimidazolyl, benzotriazolyl, benzimidazolylmethyl, benzotriazolylmethyl and the like. Any one of the aforementioned methods, wherein the compound of formula (I) is Or its salt. Any one of the aforementioned methods, wherein the compound of formula (I) is Or its salt. Any one of the aforementioned methods, wherein the compound of formula (I) is Or its salt. Any one of the aforementioned methods, wherein the compound of formula (I) is Or its salt. Any one of the aforementioned methods, wherein the compound of formula (I) is Or its salt. A method according to any one of the preceding claims, wherein the compound of formula (I) is solithromycin or a salt thereof. Any one of the aforementioned methods, wherein the compound of the formula (DM) is Or its salt. Any one of the aforementioned methods, wherein the compound of the formula (DM) is Or its salt. Any one of the aforementioned methods, wherein the compound of the formula (DM) is Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the compound has the formula Or its salt. Any one of the aforementioned methods, wherein the compound has the formula Or its salt. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the starting compound has the formula Or a salt thereof, or a C2-fluoro analogue as described above. Any one of the aforementioned methods, wherein the compound has the formula Or its salt. Any of the foregoing methods, wherein R ⁶ H. Any of the foregoing methods, wherein R ⁶ Is a methyl group. A method according to any one of the preceding claims wherein the monosaccharide is a hexose such as D-glucose, D-mannose, D-xylose, D-galactose, L-trehalose and the like; a pentose sugar such as D- Ribose, D-arabinose and the like; ketose, such as D-ribulose, D-fructose and the like; including amine methyl and dimethylamino derivatives thereof, such as glucosamine, galactosamine Sugar, acetylglucose, acetylgalactose, N-ethinylglucosamine, N-ethinyl-galactosamine, galactosyl-N-ethyl glucosamine, N-ethyl fluorenyl Neuroglycolic acid (sialic acid), carnimelose, deoxyglycosamine, L-vancoamine, 3-desmethyl-vancoamine, 3-episo-vancoamine, 4-episo-vancoamine, icocarbamide Acosamine), 3-amino-glucose, 4-deoxy-3-amino-glucose, actinosamine, daunosamine, 3-episo-dose amine, ritosamine N-methyl-D-reducing glucosamine and its analogues; and its amine methyl and dimethylamino derivatives. Any of the foregoing methods, wherein OR ¹ With the following formula Where each R ^N1 In each case independently selected from H and decyl and alkyl, cycloalkyl, arylalkyl and heteroarylalkyl, each of which is optionally substituted; and R ^O It is H or a mercapto group or an alkyl group, a cycloalkyl group, an arylalkyl group and a heteroarylalkyl group, each of which is optionally substituted. In another embodiment, at least one R ^N1 Is a methyl group. In another embodiment, R ^N1 All are methyl. In another embodiment, R ^O H or thiol. In another embodiment, R ^O H. Any of the foregoing methods, wherein R ¹ It is a deoxyglycosyl group. Any of the foregoing methods, wherein R ¹ It is an N-desmethyl deoxyglycosyl group. Any one of the aforementioned methods, wherein the heterocyclic ring containing oxygen and/or nitrogen is Wherein X is a substituted alkylene group, a substituted alkenyl group or a substituted alkynyl group, such as an alkyl group substituted with an aryl group, an alkenyl group or an alkynyl group, wherein the aryl group is an imidazolyl group or a tris Azolyl and its analogs, and the aryl group is optionally substituted with a group C as described herein. Any one of the aforementioned methods, wherein the heterocyclic ring containing oxygen and/or nitrogen is Wherein R is hydrogen or an alkyl group; X is a substituted alkylene group, a substituted alkenyl group or a substituted alkynyl group, such as an alkyl group substituted with an aryl group, an alkenyl group or an alkynyl group, wherein The aryl group is an imidazolyl or triazolyl group and the like, and the aryl group is optionally substituted with a group C as described herein. A composition comprising solimycin which is substantially free or free of defluastolic. A composition comprising solimycin comprising less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.15%, less than About 0.1%, less than about 0.05% or less than about 0.03% deflusorubicin. A composition comprising solimycin which is substantially free or free of fluorinating agent adducts. A composition comprising solimycin comprising less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.15%, less than About 0.1%, less than about 0.05% or less than about 0.03% fluorinating agent adduct. A composition comprising solimycin which is substantially free or free of N-desmethylsomycin. A composition comprising solimycin comprising less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.15%, less than About 0.1%, less than about 0.05% or less than about 0.03% N-desmethylsomycin. Also described herein is a method of preparing a benzoic acid benzoic acid or a salt thereof, wherein the method comprises The salt of each of the foregoing is included. Also described herein is a method of preparing solimycin or a salt thereof, wherein the method comprises preparing a fluorinated compound described herein, and converting the fluorinated compound to solimycin or a salt thereof. In each of the foregoing and each of the following examples, unless otherwise specified, it is to be understood that the chemical formula includes not only the pharmaceutically acceptable salts of all the compounds but also any and all of the compounds. Hydrates and/or solvates. It will be appreciated that certain functional groups, such as hydroxyl groups, amine groups and the like, form complexes and/or coordination compounds with water and/or different solvents, in different physical forms of the compounds. Accordingly, the above formulae are to be understood as references to such hydrates and/or solvates, including pharmaceutically acceptable solvates. In each of the foregoing and each of the following examples, unless otherwise specified, it is understood that the chemical formula includes and represents any and all crystalline forms, partially crystalline forms, and amorphous and/or amorphous forms of the compound. form. In each of the foregoing and each of the following examples, unless otherwise indicated, it is to be understood that the formula includes and represents every possible isomer, such as stereoisomers and geometric isomers, Both are independent and in any and all possible mixtures. As used herein, the term "solvate" refers to a compound described herein that is complexed with a solvent molecule. It will be appreciated that the compounds described herein may form such complexes with a solvent only by mixing the compound with a solvent, or by dissolving the compound in a solvent. It will be appreciated that when a compound is to be used as a medicament, such a solvent is a pharmaceutically acceptable solvent. It should also be understood that when a compound is to be used as a medicament, the relative amount of solvent forming the solvate should be less than the established guidelines for such pharmaceutical use, such as less than the International Conference on Harmonization (ICH) guidelines. It will be appreciated that the solvate can be separated from the excess solvent by evaporation, precipitation and/or crystallization. In some embodiments, the solvate is amorphous, and in other embodiments, the solvate is crystalline. It will be understood that each of the foregoing embodiments can be combined in a chemically related manner to produce a subset of the embodiments described herein. Therefore, it should be further understood that all such subsets are also illustrative embodiments of the invention described herein. The compounds described herein may contain one or more pairs of palmitic centers, or may additionally be capable of being present in multiple stereoisomers. It should be understood that in one embodiment, the invention described herein is not limited to any particular stereochemical requirements, and that the compounds, and compositions, methods, uses, and medicaments thereof, may be optically pure, or may be a variety of stereoscopic Any of a mixture of the enantiomers, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It will also be understood that mixtures of such stereoisomers may comprise a single stereochemical configuration in one or more pairs of palmar centers, and a mixture of stereochemical configurations in one or more other pair of palmar centers. Similarly, the compounds described herein can include geometric centers such as cis, trans, E, and Z double bonds. It should be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments thereof, may be pure, or may be of a variety of geometries Any of a mixture of isomers. It will also be understood that mixtures of such geometric isomers may comprise a single configuration in one or more double bonds and a geometrical mixture in one or more other double bonds. As used herein, the term "alkyl" includes a chain of carbon atoms, which branches as appropriate. As used herein, the terms "alkenyl" and "alkynyl" each include a chain of carbon atoms, which are optionally branched and each include at least one double bond or a bond. It should be understood that an alkynyl group can also include one or more double bonds. It should also be understood that in certain embodiments, the alkyl group advantageously has a limited length, including C. ₁ -C _{twenty four} , C ₁ -C ₁₂ , C ₁ -C ₈ , C ₁ -C ₆ And C ₁ -C ₄ And C ₂ -C _{twenty four} , C ₂ -C ₁₂ , C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And similar groups. Illustratively, such specific restricted length alkyl groups (including C ₁ -C ₈ , C ₁ -C ₆ And C ₁ -C ₄ And C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And similar groups) may be referred to as lower alkyl groups. It is further understood that in certain embodiments, alkenyl and/or alkynyl groups may each advantageously have a limited length, including C. ₂ -C _{twenty four} , C ₂ -C ₁₂ , C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And C ₃ -C _{twenty four} , C ₃ -C ₁₂ , C ₃ -C ₈ , C ₃ -C ₆ And C ₃ -C ₄ And similar groups. Illustratively, such specific restricted length alkenyl and/or alkynyl groups (including C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And C ₃ -C ₈ , C ₃ -C ₆ And C ₃ -C ₄ And similar groups) may be referred to as lower alkenyl and/or alkynyl groups. It will be appreciated herein that shorter alkyl, alkenyl and/or alkynyl groups may add less lipophilicity to the compound and thus will have different pharmacokinetic properties. In the examples of the invention described herein, it is to be understood that, in each case, an alkyl group refers to an alkyl group, as defined herein, and optionally a lower alkyl group. In the examples of the invention described herein, it is to be understood that in each case, the enumeration of alkenyl refers to an alkenyl group, as defined herein, and optionally a lower alkenyl group. In the examples of the invention described herein, it is to be understood that in each case, the enumeration of alkynyl refers to an alkynyl group, as defined herein, and optionally a lower alkynyl group. Exemplary alkyl, alkenyl and alkynyl groups are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl , 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like, and the corresponding groups containing one or more double bonds and/or reference bonds, or a combination thereof. As used herein, the term "alkylene" includes a divalent chain of carbon atoms, which branches as appropriate. As used herein, the terms "alkenyl" and "alkenyl" include divalent chains of carbon atoms, which are optionally branched and each include at least one double or para-bond. It will be understood that an alkynyl group may also include one or more double bonds. It should also be understood that in certain embodiments, the alkylene group advantageously has a limited length, including C. ₁ -C _{twenty four} , C ₁ -C ₁₂ , C ₁ -C ₈ , C ₁ -C ₆ And C ₁ -C ₄ And C ₂ -C _{twenty four} , C ₂ -C ₁₂ , C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And similar groups. Illustratively, such specific restricted length alkyl groups (including C ₁ -C ₈ , C ₁ -C ₆ And C ₁ -C ₄ And C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And similar groups) may be referred to as low carbon alkylene groups. It is further understood that in certain embodiments, the alkenyl and/or exetylene groups may each advantageously have a limited length, including C. ₂ -C _{twenty four} , C ₂ -C ₁₂ , C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And C ₃ -C _{twenty four} , C ₃ -C ₁₂ , C ₃ -C ₈ , C ₃ -C ₆ And C ₃ -C ₄ And similar groups. Illustratively, such specific restricted length extended alkenyl and/or alkynyl groups (including C ₂ -C ₈ , C ₂ -C ₆ And C ₂ -C ₄ And C ₃ -C ₈ , C ₃ -C ₆ And C ₃ -C ₄ And similar groups) may be referred to as lower carbon and alkenyl groups. It will be appreciated herein that shorter alkyl, alkenyl and/or alkynyl groups may add less lipophilicity to the compound and will therefore have different pharmacokinetic properties. In the examples of the invention described herein, it is to be understood that in each case, the alkyl, alkenyl and alkynyl groups are taken to mean alkyl, alkenyl and alkyne as defined herein. And, as the case may be, a lower alkyl, an alkenyl and an alkynyl group. Exemplary alkyl groups are, but are not limited to, methylene, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl, pentyl, 1,2- It has a pentyl group, a 1,3-pentyl group, a hexyl group, a heptyl group, a octyl group and the like. As used herein, the term "cycloalkyl" includes a chain of carbon atoms, optionally branched, wherein at least a portion of the chain is cyclic. It will be understood that a cycloalkylalkyl group is a subset of a cycloalkyl group. It should be understood that a cycloalkyl group can be a polycyclic ring. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentylethyl-2-yl, adamantyl, and the like. As used herein, the term "cycloalkenyl" includes a chain of carbon atoms, optionally branched, and includes at least one double bond, wherein at least a portion of the chain is cyclic. It will be understood that one or more double bonds may be in the acyclic portion of the cycloalkenyl group and/or the acyclic portion of the cycloalkenyl group. It will be understood that the cycloalkenylalkyl and cycloalkylalkenyl groups are each a subset of a cycloalkenyl group. It should be understood that a cycloalkyl group can be a polycyclic ring. Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexylvinyl-2-yl, cycloheptenylpropenyl, and the like. It should also be understood that the chain forming the cycloalkyl and/or cycloalkenyl group preferably has a limited length, including C. ₃ -C _{twenty four} , C ₃ -C ₁₂ , C ₃ -C ₈ , C ₃ -C ₆ And C ₅ -C ₆ . It will be understood herein that shorter alkyl and/or alkenyl chains which form a cycloalkyl and/or cycloalkenyl group, respectively, may provide lower lipophilicity to the compound and will therefore have different pharmacokinetic properties. As used herein, the term "heteroalkyl" includes a chain of atoms including carbon and at least one heteroatom, and branches as appropriate. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In some variations, exemplary heteroatoms also include phosphorus and selenium. As used herein, the term "cycloheteroalkyl" includes heterocyclic and heterocyclic rings, including a chain of atoms, including carbon and at least one hetero atom, such as a heteroalkyl group, and optionally branched, wherein at least a portion of the chain is ring. Exemplary heteroatoms include nitrogen, oxygen, and sulfur. In some variations, exemplary heteroatoms also include phosphorus and selenium. Exemplary cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, Pyridyl and its analogous groups. As used herein, the term "aryl" includes both monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Exemplary aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes an aromatic heterocyclic group, each of which may be optionally substituted. Exemplary aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazole Base, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl , benzoisoxazolyl, benzisothiazolyl and the like. As used herein, the term "amine group" includes the group NH. ₂ And an alkylamino group and a dialkylamino group, wherein the two alkyl groups of the dialkylamino group may be the same or different, that is, an alkylalkylamino group. Illustratively, the amine group includes a methylamino group, an ethylamino group, a dimethylamino group, a methylethylamino group, and the like. In addition, it is to be understood that when an amine group is modified by another term or by another term, such as an aminoalkyl or amidino group, the above variations of the term amine are included. Illustratively, the aminoalkyl group includes H ₂ N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl and the like. Illustratively, the guanamine group includes a mercaptomethylamino group, a mercaptoethylamino group, and the like. As used herein, the term "amine group and its derivatives" includes amine groups as described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino, heteroalkenylamino groups. , alkynylamino, cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamine Alkyl, arylalkynylamino, heteroarylamino, heteroarylalkylamino, heteroarylalkenylamino, heteroarylalkynylamino, decylamino and the like, each of which Replaced as appropriate. The term "amino derivative" also includes urea, urethane and the like. As used herein, the term "hydroxyl and its derivatives" includes OH, and alkoxy, alkenyloxy, alkynyloxy, heteroalkoxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkoxy, ring Alkenyloxy, cycloheteroalkoxy, cycloheenyloxy, aryloxy, arylalkoxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkoxy, Heteroarylalkenyloxy, heteroarylalkynyloxy, decyloxy and the like, each of which is optionally substituted. The term "hydroxy derivative" also includes urethanes and analogs thereof. As used herein, the term "thio and its derivatives" includes SH, and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio , cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroylthio, arylthio, arylalkylthio, arylalkenylthio, arylalkynyl Thio, heteroarylthio, heteroarylalkylthio, heteroarylalkenylthio, heteroarylalkynylthio, arylthio and the like, each of which is optionally substituted. The term "thio-based derivatives" also includes thiocarbamates and the like. As used herein, the term "mercapto" includes a fluorenyl group, and an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a heteroalkylcarbonyl group, a heteroalkenylcarbonyl group, a heteroalkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkene group. Carbocarbonyl, cycloheteroalkylcarbonyl, cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkynylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, hetero An arylalkenylcarbonyl group, a heteroarylalkynylcarbonyl group, a fluorenylcarbonyl group, and the like, each of which is optionally substituted. As used herein, the term "carbonyl and its derivatives" includes the groups C(O), C(S), C(NH), and substituted amino derivative thereof. As used herein, the term "carboxylic acid and its derivatives" includes groups CO ₂ H and its salts, as well as its esters and guanamines, and CN. As used herein, the term "sulfinic acid or its derivatives" includes SO ₂ H and its salts, as well as its esters and guanamines. As used herein, the term "sulfonic acid or its derivatives" includes SO ₃ H and its salts, as well as its esters and guanamines. As used herein, the term "sulfonyl" includes alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, heteroalkylsulfonyl, heteroalkenylsulfonyl, heteroalkynylsulfonyl. , cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloheteroalkylsulfonyl, cycloheteroylsulfonyl, arylsulfonyl, arylalkylsulfonyl, arylalkenyl Mercapto, arylalkynylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl, heteroarylalkynylsulfonyl, fluorenylsulfonyl And similar groups, each of which is substituted as appropriate. As used herein, the term "monophosphonic acid or a derivative thereof" includes P(R)O. ₂ H and its salts, as well as esters and guanamines thereof, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, Aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of which is optionally substituted. As used herein, the term "phosphonic acid or a derivative thereof" includes PO ₃ H ₂ And its salts, as well as its esters and guanamines. As used herein, the term "hydroxylamine and its derivatives" includes NHOH, and alkyloxy NH, alkenyloxy NH, alkynyloxy NH, heteroalkyloxy NH, heteroalkenyloxy NH , alkynyloxy NH, cycloalkyloxy NH, cycloalkenyloxy NH, cycloheteroalkyloxy NH, cycloheteroalkenyloxy NH, aryloxy NH, arylalkyloxy NH, arylalkenyloxy NH, arylalkynyloxy NH, heteroaryloxy NH, heteroarylalkyloxy NH, heteroarylalkenyloxy NH, heteroarylalkynyloxy NH, a decyloxy group and the like, each of which is optionally substituted. As used herein, the term "mercapto and its derivatives" includes alkyl NHNH, alkenyl NHNH, alkynyl NHNH, heteroalkyl NHNH, heteroalkenyl NHNH, heteroalkynyl NHNH, cycloalkyl NHNH, cycloalkenyl NHNH, cycloheteroalkyl NHNH, cycloheteroyl NHNH, aryl NHNH, arylalkyl NHNH, arylalkenyl NHNH, arylalkynyl NHNH, heteroaryl NHNH, heteroarylalkyl NHNH, heteroaryl Alkenyl NHNH, heteroarylalkynyl NHNH, fluorenyl NHNH and the like, each of which is optionally substituted. The term "optionally substituted" as used herein includes the replacement of a hydrogen atom with another functional group on an optionally substituted group. Such other functional groups illustratively include, but are not limited to, amine groups, hydroxyl groups, halo groups, thiols, alkyl groups, haloalkyl groups, heteroalkyl groups, aryl groups, aralkyl groups, aryl heteroalkyl groups, miscellaneous Aryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, amine, hydroxy, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroaryl Any of the heteroalkyl and/or sulfonic acids are optionally substituted. As used herein, the term "optionally substituted aryl" and "optionally substituted heteroaryl" include the replacement of a hydrogen atom with another functional group on an optionally substituted aryl or heteroaryl group. Such other functional groups are also referred to herein individually as aryl substituents or heteroaryl substituents, illustratively including, but not limited to, amine groups, hydroxyl groups, halo groups, thio groups, alkyl groups, halo Alkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and derivatives thereof, carboxylic acid And derivatives thereof and the like. Illustratively, amine, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroaryl Any of the alkyl and/or sulfonic acids are optionally substituted. Exemplary substituents include, but are not limited to, groups - (CH ₂ ) _x Z ^X , where x is an integer from 0 to 6 and Z ^X Is selected from the group consisting of halogen, hydroxy, alkoxy, including C ₁ -C ₆ Alkyloxy, optionally substituted methoxy, alkyl (including C ₁ -C ₆ Alkyl), alkoxy (including C ₁ -C ₆ Alkoxy), cycloalkyl (including C ₃ -C ₈ Cycloalkyl), cycloalkoxy (including C ₃ -C ₈ Cycloalkoxy), alkenyl (including C ₂ -C ₆ Alkenyl), alkynyl (including C ₂ -C ₆ Alkynyl), haloalkyl (including C ₁ -C ₆ Haloalkyl), haloalkoxy (including C ₁ -C ₆ Haloalkoxy), halocycloalkyl (including C ₃ -C ₈ Halocycloalkyl), halocycloalkoxy (including C ₃ -C ₈ Halocycloalkoxy), amine, C ₁ -C ₆ Alkylamino group, (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ Alkyl)amino, alkylcarbonylamino, N-(C ₁ -C ₆ Alkyl)alkylcarbonylamino, aminoalkyl, C ₁ -C ₆ Alkylaminoalkyl, (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ Alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C ₁ -C ₆ Alkyl)alkylcarbonylaminoalkyl, cyano and nitro; or Z ^X From -CO ₂ R ⁴ And -CONR ⁵ R ⁶ , where R ⁴ , R ⁵ And R ⁶ Each time it is independently selected from hydrogen, C ₁ -C ₆ Alkyl, aryl-C ₁ -C ₆ Alkyl and heteroaryl-C ₁ -C ₆ alkyl. The term "protecting group" as used herein generally refers to any group that is reversibly bonded to a functional group and that is used to block or partially block the reactivity of a functional group to a predetermined set of conditions, such as reaction conditions. Illustratively, the nitrogen protecting group is reversibly bonded to the amine to block or partially block the reactivity of the amine under a predetermined set of conditions. Exemplary nitrogen protecting groups include, but are not limited to, urethanes such as t-Boc, Fmoc, and the like. As used herein, the term "leaving group" refers to a reactive functional group that produces an electrophilic site at the atom to which it is attached such that a nucleophile can be added to an electrophilic site on the atom. Exemplary leaving groups include, but are not limited to, halogen, optionally substituted phenol, decyloxy, sulfonoxy, and the like. It will be understood that such leaving groups may be on alkyl, sulfhydryl and the like. Such leaving groups can also be referred to herein as activating groups, such as when a leaving group is present on a sulfhydryl group. Additionally, conventional peptides, guanamine and ester coupling agents such as, but not limited to, PyBop, BOP-Cl, BOP, pentafluorophenol, isobutyl chloroformate, and the like, are formed on the carbonyl group as defined herein. The various intermediates that leave the base. It will be understood that in each instance disclosed herein, the recitation of the range of integers of any variable is intended to describe each individual member within the scope, the range, and every possible sub-range of the variable. For example, an integer that ranges from 0 to 8 is used to describe the range, and individual and optional values of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n being 0, or n being 1, Or n is 2, etc. Furthermore, the enumeration n is an integer from 0 to 8, and each and every sub-range is also described, each of which may be based on another embodiment, such as n being 1 to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to 3, an integer of 2 to 4, and the like. As used herein, the term "treatment", "contact" or "reaction" when referring to a chemical reaction generally means adding or mixing two or more reagents under appropriate conditions to cause chemical or chemical reactions. And/or produce specified and/or desired products. It will be appreciated that the reaction to produce the indicated and/or desired product may not be directly caused by the combination of the two agents initially added. In other words, there may be one or more intermediates produced in the mixture which ultimately result in the formation of the designated and/or desired product. As used herein, the term "composition" generally refers to any product comprising the specified ingredients in the specified amounts, and any product that results, directly or indirectly, from the combination of the specified ingredients. It will be understood that the compositions described herein can be prepared from isolated salts, solutions, hydrates, solvates, and other forms of the compounds described herein or the compounds described herein. It will also be appreciated that the compositions may be prepared from different amorphous, crystalline, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It will also be appreciated that the compositions may be prepared from different hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that cite the compounds described herein are to be understood to include each or any combination of the various morphological forms and/or solvates or hydrate forms of the compounds described herein. Furthermore, it is to be understood that the compositions can be prepared from different co-crystals of the compounds described herein. Illustratively, the composition can include one or more carriers, diluents, and/or excipients. The compounds described herein, or compositions containing the same, can be formulated in a therapeutically effective amount in any of the conventional dosage forms suitable for the methods described herein. The compounds described herein, or compositions containing the same, including such formulations, can be administered by a wide variety of conventional routes for use in the methods described herein and in a wide variety of dosage forms using known procedures ( See generally Remington: The Science and Practice of Pharmacy, (21st ed., 2005)). The term "therapeutically effective amount" as used herein refers to a biological or medical response (which includes amelioration of a disease or condition being treated by a researcher, veterinarian, doctor or other clinician in a tissue system, animal or human). Symptom) The amount of active compound or agent. In one aspect, a therapeutically effective amount is an amount that treats or reduces the symptoms of a disease or disease at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions described herein can be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular patient will depend on a number of factors, including the severity of the condition or condition being treated; the activity of the particular compound employed; the particular composition employed; the age, weight, General health, sex and diet: time of administration, route of administration and excretion rate of the particular compound used; duration of treatment; combination with or concurrent use of the particular compound used; and researcher, veterinarian, doctor or other skilled Similar factors well known to clinicians. It will also be appreciated that a therapeutically effective amount, whether monotherapy or combination therapy, is selected with reference to any toxic or other undesirable side effects that may occur during administration of one or more of the compounds described herein. In addition, it is to be understood that the co-therapy described herein may allow for the administration of lower doses of a compound exhibiting such toxicity or other undesirable side effects, wherein the lower doses are below the threshold of toxicity or in the therapeutic window. The amount is lower than the amount otherwise administered in the absence of co-therapy. In addition to the exemplary dosages and dosing regimens described herein, it is to be understood that the effective amount of any of the compounds described herein, or mixtures thereof, may be observed by the attending physician or physician by using known techniques and/or by observing It is easily determined by the results obtained in a similar situation. When determining an effective amount or dose, the attending physician or physician considers a number of factors including, but not limited to, the species of the mammal (including humans), their size, age and general health, the particular disease or condition involved, the disease Or the extent or severity of the condition, the response of the individual patient, the particular compound being administered, the mode of administration, the bioavailability characteristics of the formulation being administered, the chosen dosage regimen, the use of the concomitant medication, and other related circumstances. The dosage of each compound in the claimed combination will depend on a number of factors, including, the method of administration, the condition being treated, the severity of the condition, the treatment or prevention of the condition, and the age, weight and health of the individual being treated. situation. In addition, information about the pharmacogenomics of a particular patient (the effect of genotype on the pharmacokinetics, pharmacodynamics, or efficacy profile of the treatment) can affect the dosage used. The term "administering" as used herein includes all means of introducing the compounds and compositions described herein into a host animal, including but not limited to oral (po), intravenous (iv), intramuscular (im) ), subcutaneous (sc), transdermal, inhalation, buccal, transocular, sublingual, transvaginal, transrectal and the like. The compounds and compositions described herein can be administered in unit dosage form and/or formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and/or vehicles. Exemplary forms for oral administration include lozenges, capsules, elixirs, syrups, and the like. Exemplary routes for parenteral administration include intravenous, intraarterial, intraperitoneal, epidural, intraurethral, intrasternal, intramuscular, and subcutaneous, as well as any other technically recognized route of parenteral administration. EXAMPLES The following examples further illustrate specific embodiments of the invention; however, the following illustrative examples are not to be construed as limiting the invention in any way. EXAMPLES General procedure for the preparation of fluoroketone lactones. a compound of formula (I) wherein R ¹ , V, W ¹ And W ² The solution of the precursor compound as defined in the various embodiments described herein is cooled to a temperature in the range of from about -40 °C to about +20 °C. The hydrazine or phosphazene base (2 to 3 equivalents) described herein is added. A solution of fluorinating reagent or fluorinating agent (1 to 2 equivalents) is added. After obtaining acceptable or complete conversion, water is added. The compound of formula (I) is isolated from the organic layer by evaporation or, if the compound of formula (I) is a solid, is optionally precipitated from an organic layer or other solvent system. Example. (11-N-(4-Azido-butyl)-5-(2'-benzylidene-deoxyglycosyl)-3-oxo-2-fluoro-6-O- Methyl-erythrew lactone A, 11,12-cyclic urethane) (Compound (2)). Compound (1) (1.0 eq.) was added to a mixture of DMF, isopropyl acetate or DMF/isopropyl acetate (2 to 10 vol) and stirred at ambient temperature to obtain a clear solution. It should be understood that the aforementioned concentrations are not critical. Cool with stirring and maintain the solution at -20 ° C to -30 ° C. TMG (2 to 3 equivalents) was added followed by a solution (1 to 3 volumes) of NFSI (1.1 to 1.5 equivalents) in a mixture of DMF, isopropyl acetate or DMF/isopropyl acetate. The mixture is stirred until an acceptable or complete conversion is observed, such as by TLC, HPLC, and the like. Isopropyl acetate (2 to 7 volumes) and chilled water (2 to 10 volumes) are added, and are carried out in stages as appropriate. The organic layer was removed and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water. Add formaldehyde (37%, 0.1 to 0.3 equivalents) and formic acid (0.5 to 1.0 equivalents) to the solution at ambient temperature, then heat the mixture to 45-50 ° C until acceptable or complete conversion is observed, such as by TLC, HPLC and It is done in a similar way. The solution was cooled to ambient temperature, water was added, and the pH was adjusted to 7-8 with aqueous ammonia. The aqueous layer was removed and the organic layer was washed with water. The organic layer was concentrated under vacuum. Isopropanol (IPA) was added and the mixture was heated. Water was added and the resulting slurry was cooled to ambient temperature and filtered. The resulting solid was washed with water and dried under vacuum to give CEM-276. Example. (11-N-(4-Azido-butyl)-5-(2'-benzylidene-deoxyglycosyl)-3-oxo-2-fluoro-6-O- Methyl-erythrew lactone A, 11,12-cyclic urethane) (Compound (2)). Compound (1) (300 g, 1.0 equivalent) was added to iPrOAc (3 vol) and stirred at room temperature. Once a clear solution was obtained, DMF (3 vol) was added and the solution was cooled to -30 °C. TMG (2.67 equivalents) was added over 15 minutes and the solution was stirred at -30 °C for an additional 15 minutes. A solution of NFSI (1.29 equivalents) in DMF (2 vol) was slowly added over 60 min to the reaction. The reaction mass was stirred at -30 ° C for further 30 minutes. The reaction mixture was checked by HPLC. Isopropyl acetate (2 volumes) was added to the reaction mass over 15 minutes at -30 °C. Water (2 volumes) was added over 30 minutes at -30 °C. The reaction mixture was diluted with isopropyl acetate (4 vol) and water (8 vol) at -30 °C. The reaction mixture was allowed to warm slowly to room temperature. The organic layer was separated, washed with water (3 vol) and dried by distillation. 37% formaldehyde (0.21 equivalent) and formic acid (0.71 equivalent) were added sequentially to the solution, and then heated to 50 ° C for 2 hours. The solution was cooled to room temperature and water (3 vol) was added over 30 min. The pH was adjusted to 8.0 with aqueous ammonia (0.2 volume) over 60 minutes. The reaction mixture was stirred for a further 30 minutes; the organic layer was separated and washed with water (3). The iPrOAc was removed in vacuo at no higher than 50 °C and degassed in vacuum for 10 minutes. IPA (1 volume) was added and the slurry was heated to 70-75 ° C for 30 minutes. The IPA was completely removed in vacuo at no higher than 60 °C and fresh IPA (4 volumes) was added. The resulting slurry was stirred at 55-60 ° C for 30 minutes and then cooled to room temperature and stirred at this temperature for a further 60 minutes. Water (5 vol) was slowly added over 2 hours and the resulting slurry was stirred for 1 hour. The slurry was filtered and washed with water (1 vol) and dried under vacuum. Compound (2) purity: 98.83 A%, yield: 292 g, 95.1% Purified (2) HPLC: The above method was also carried out at -30 ° C on a scale of 300 g, followed by in situ methylation to obtain (9) 95.1% isolated yield, HPLC purity 98.8%, with 0.11% fluorinating agent adduct, and wherein Each of (1), (1-DM), and (2-DM) was not detected (below the limit of quantitation). The above method was also carried out at -10 ° C on a scale of 2.5 g, yielding 98.5% conversion according to HPLC, having 1.49% (1), wherein no fluorinating agent adduct, (1-DM) and (2- Each of DM) (below the limit of quantitation). The above method was also carried out at a temperature of 2.5 g at 0 ° C, followed by in situ methylation to obtain 97.6% HPLC purity of (2) with 1.43% (1), wherein no fluorinating agent adduct was detected, Each of 1-DM) and (2-DM) (below the limit of quantitation). The above procedure was also carried out at 0 °C using 2.5 equivalents of BTPP instead of TMG on a 1 g scale, yielding 100% conversion according to HPLC, where no fluorinating agent adduct was detected (below the limit of quantitation). Example. 11-N-(3-Amino-phenyl-1-yl-[1,2,3]-triazol-1-yl]butyl)-5-(2'-benzylidene deoxygenation Glycosyl)-3-oxo-2-fluoro-erythrew lactone A, 11,12-cyclic urethane. 11-N-(4-azidobutyl)-5-(2'-benzylidenyldeoxyglycosyl)-3-oxooxy-2-fluoro as described in WO 2009/055557 -6-O-methylerythryrolactone A, 11,12-cyclic urethane, 3-ethynylphenylamine, copper iodide and diisopropylethylamine were reacted in acetonitrile to prepare 11 -N-(3-Amino-phenyl-1-yl-[1,2,3]-triazol-1-yl]butyl)-5-(2'-benzylidene-deoxyglycosylamino --3-Alkyloxy-2-fluoro-erythrewactone A, 11,12-cyclic urethane. Examples. Solimycin. 11-N-(3-Amino-phenyl-1-yl-[1,2,3]-triazol-1-yl]butyl)-5-(2) as described in WO 2009/055557 '-Benzyl decyl deoxyglycosyl)-3-oxo-2-fluoro-erythrew lactone A, 11,12-cyclic urethane was dissolved in methanol and heated under reflux Preparation of solimycin. Comparative Example. The method of (2) preparation (2) is disclosed in WO 2009/055557. As described, the process was carried out on a 10 g scale (2 independent operations) to give (2) a 65% yield with a purity of 89% HPLC and a 9.9% unreacted starting material (1). Comparative Example. The above method was adapted by using NFSI and lithium terp-butoxide as a base. Conversion to (2) is incomplete with 9-11% residual (1). Comparative Example. The method disclosed in WO 2009/055557 was modified by using potassium pentanol as a base. Conversion to (2) is extremely low or unobservable. In addition, one or more unknown by-products are formed. Comparative Example. The method disclosed in WO 2009/055557 was modified by using lithium t-butoxide as a base. The conversion to (2) is extremely low, and the remaining 9-11% is unreacted (1). In addition, unknown by-products are formed. Comparative Example. The method disclosed in WO 2009/055557 was modified by using NaH as a base. The conversion to (2) is extremely low and decomposes in large amounts into unknown by-products. Comparative Example. The method disclosed in WO 2009/055557 was modified by using Selectfluor as a fluorinating agent. The conversion to (2) is comparable and the remaining 29% is unreacted (1). Comparative Example. The method disclosed in WO 2009/055557 was modified by using NaHMDS as a base. The conversion to (2) is extremely low and decomposes in large amounts into unknown by-products. Comparative example. By using K ₂ CO ₃ The method disclosed in WO 2009/055557 is modified as a base. No conversion was observed to (2). Instead, a large amount of decomposition into one or more unknown by-products was observed. Comparative example. By using K ₂ CO ₃ The process disclosed in WO 2009/055557 is modified as a base in toluene/water with a tetra-n-butylammonium bromide (TBAB) phase transfer catalyst. No conversion was observed to (2). In addition, one or more unknown by-products are formed. Comparative example. By using NFSI or Selectfluor and Lewis Acid or a transition metal catalyst such as MgClO ₄ , Ti(iOPR) ₄ , Pd(OAc) ₂ And analogs thereof) modify the method disclosed in WO 2009/055557 instead of a base. No conversion was observed to (2). In addition, one or more unknown by-products are formed. Comparative Example. The method disclosed in WO 2009/055557 was modified by using DMF as a solvent. Conversion to (2) is low and the remaining 24% is unreacted (1). Comparative Example. The method disclosed in WO 2009/055557 was modified by using 1:1 THF/DCM as a solvent. Conversion to (2) is low and the remaining 12-15% unreacted (1). In addition, unknown by-products are formed. Comparative Example. The method disclosed in WO 2009/055557 was modified at 0.25 g scale using NFSI (1.5 eq.), DBU (2.67 eq.), DMF (3 vol) and iPrOAc (3 vol) at 0 °C. After standard treatment, HPLC of the crude product showed 78.9 A% (2), 1.8 A% (1), 7.3 A% 2-DM, 7.8% fluorinating agent adduct and two other impurities (5.85 A% and 2.05) A%). Each of the publications cited herein is incorporated herein by reference.

Claims (18)

A method for preparing a fluoroketone lactone of the formula (I), The method comprises formulating a compound of the formula Contact with a fluorinating agent and a hydrazine or a phosphazene base; wherein R ¹ is H or a thiol group, or R ¹ is a monosaccharide such as a monosaccharide containing a methylamino group or a dimethylamino group; and V is CH ₂ -N ( R), C(O)-N(R), C=Q or C=NQ ¹ ; wherein Q is O or (NR, H); wherein R is independently selected from hydrogen in each case or optionally substituted An alkyl group; and Q ¹ is a hydroxyl group or a derivative thereof, or an amine group or a derivative thereof; and W ¹ is a hydroxyl group or a derivative thereof; and W ² is H, or a hydroxyl group or a derivative thereof; or W ¹ and W ² A heterocyclic ring containing oxygen and/or nitrogen is formed together with the carbon atom to be bonded, and is optionally substituted. The method of claim 1, wherein the purine base is 1,1,3,3-tetramethylguanidine (TMG), 2-tert-butyl-1,1,3,3-tetramethylguanidine, 7- Methyl-1,5,7-triazabicyclo(4.4.0)non-5-ene (MTBD), 1,1,2,3,3-pentamethylindole, anthracene, and combinations thereof. The method of claim 1, wherein the phosphazene base is a phosphazene base P ₁ -t-Bu-para (butylene), 2-tert-butylimino-2-diethylamino-1 , 3-dimethylperhydro-1,3,2-diazaphosphorine, third octylimido-parade (dimethylamino)phosphorane, 1-third Butyl-2,2,4,4,4-penta(dimethylamino)-2λ ⁵ ,4λ ⁵ -catenadi (phosphazene) and combinations thereof. The method of claim 1, wherein the phosphazene base is selected from the group consisting of And their combinations. The method of claim 1, wherein the guanidine or phosphazene base is 1,1,3,3 tetramethylguanidine or a tert-butylimine-paraxyl (dimethylamino)phosphane or a phosphazene base P ₁ - t -Bu or a combination thereof. The method of claim 1, wherein the purine base is 1,1,3,3 tetramethylguanidine. The method of claim 1, wherein the phosphazene base is a tert-butylimido-gin(dimethylamino)phosphane. The method of any one of claims 1 to 7, wherein the fluorinating agent is selected from the group consisting of NFSi, Selectfluor, and F-TEDA, and combinations thereof. The method of claim 8, wherein the compound of formula (I) is Or its salt. The method of claim 8, wherein the compound of formula (I) is Or its salt. The method of claim 8, wherein the compound of formula (I) is solitromycin or a salt thereof. The method of claim 8, wherein the starting compound has the formula Or its salt. The method of claim 8, wherein the starting compound has the formula Or its salt. A process for the preparation of a compound of formula (I), which process comprises or further comprises a compound of formula (DM) a salt comprising each of the foregoing, in contact with a methylating agent; wherein: R ^1a is H or a thiol group; V is CH ₂ -N(R), C(O)-N(R), C=Q or C =NQ ¹ ; wherein Q is O or (NR, H); wherein R is, in each case, independently selected from hydrogen or optionally substituted alkyl; and Q ¹ is hydroxy or a derivative thereof, or an amine group or a derivative; and W ¹ is a hydroxyl group or a derivative thereof; and W ² is H, or a hydroxyl group or a derivative thereof; or W ¹ and W ² together with the carbon atom to be bonded form an oxygen-containing and/or nitrogen-containing heterocyclic ring, Each case is replaced. The method of claim 14, wherein the compound of the formula (DM) is Or its salt. The method of claim 14, wherein the compound of the formula (DM) is Or its salt. A composition comprising solimycin which is substantially free or free of defluastolic. A composition comprising solimycin which is substantially free or free of N-desmethylsomycin.