MXPA00011136A - Process for preparation of 4,5-epoxymorphinan-6-oxyglucuronides - Google Patents

Abstract

Conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides in the presence of Zinc containing compounds as activator under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides is disclosed. This novel approach provides an efficient method for preparation of both anomers of 4, 5-Epoxymorphinan-6-oxyglucuronides. The deprotected end products are useful as analgesic agents.

Description

PROCESS TO PREPARE 4.5-EPOXY1VIORFINAN-6- OXIGLUCURONATOS BACKGROUND OF THE INVENTION According to recent publications, the morphine metabolite Morphine-6-β-D-glucuronate (M6G) [6] is an analgesic drug that lasts more and more effectively than Morphine [5] with few effects and, therefore, there is a lot of interest in using M6G, instead of Morphine, as a drug that eliminates Morphine Morphine-6-ß-D-glucuronate (M6G) [5] [6] The traditional approach for the glycosylation of 4,5-Epoxymorfinan-6-ols explores the Bromoglucuronates as donors of glycoside and the Koenings-Knorr procedure for the activation of Bromoglucuronates (Berrang, B., et al., Synthesis, 1997, p. 1 1 65 and references cited therein).

Another approach (Scheinmann, F. et al., US Pat No. 5621087, see Claims 1, 2, 5 and 6, abstract, examples, column 4, line 5-line 45) explores the use of Lewis acids (of the type BF3 and TMSOTf) instead of Lewis acids based on heavy metals (March, J., "Advanced Organic Chemistry", 4th edition, A Whiley-Interscience publication, pp. 260-3) for the activation of Bromoglucuronates. Unfortunately, we did not succeed in obtaining 4,5-Epoxymorfinan-6-oxyglucuronate from Bromoglucuronates using activators proposed in Pat. From E.U. No. 5621087 and no such examples were found in the literature. Unexpectedly, we found that the O-glycosylation of 4,5-Epoxymorfinan-6-ols with Bromoglucuronates was accelerated by Zinc-containing compounds to give 4,5-Epoxymorfinan-6-oxyglucuronates of the formula [1] with high production. wherein: position 7 and 8 can be olefin as shown or dihydro adduct; R is alkyl, haioalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl, R 2 is alkyl, haloalkyl or aralkyl; R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or hydrogen; R 4 is alkyl, haloalkyl, arylmethyl, 2- (4-morpholinyl) ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl We also find that the anomeric and β selectivity of the conjugation product can be controlled using different protection groups Or in aglycon and Bromoglucuronates as well as varying the ratio between 4,5-Epoxymorfinan-6-ols and Zinc-containing compounds It is important to note that only the β-anomer of 4,5-Epoxymorfinan-6-oxyglucuronates was obtained according to to the Koenings-Knorr procedure and the procedure of the Patent of E.U. No. 5621 077 (but then with another glycoside donor from Bromogiucuronate). All previously described methods have serious disadvantages for producing material to be used as a pharmaceutical medicament. A desirable objective, satisfied by the present invention, has been to devise a synthetic process without using costly and commercially inaccessible reagents, and to neatly produce the desired 4,5-Epoxymorfinan-6-oxygluuronates, avoiding the costly and tedious purification steps.

SUMMARY OF THE INVENTION The present invention provides a commercially acceptable process for the conjugation of 4,5-Epoxymorfinan-6-ols of the formula [3] with bromoglucuronates of the formula [2] in the presence of compounds containing zinc under capable conditions. of forming 4,5-Epoxymorfinan-6-oxyglucuronates [1]. 12] m wherein the position 7 and 8 can be olefin as shown or dihydro adduct; R1, R2, R3 and R4 are as defined above. This new approach was used for the preparation of the known analgesic agent Morphine-6-β-glucuronate [4] and its isomer.

Other features and advantages will be apparent from the specification and claims.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new process for the conjugation of 4,5-Epoxymorfinan-6-ols with bromoglucuronates. Particularly, the present invention relates to the use of Zinc-containing compounds for the activation of Bromoglucuronates in the O-glycosylation reaction of 4,5-Epoxymorfinan-6-ols. This new approach has the following advantages: • Compounds containing Zinc as activating reagents of Bromoglucuronates are cheap and commercially available. • The use of different protection groups O in the aglycon and in the Bromoglucuronate as well as the different proportion of 4,5- Epoxymorfinan-6-ols and Zinc-containing compounds allows to obtain high anomeric selectivity and produce at will with a high degree of preference either ei ao or ß anomer. Although any 4,5-Epoxymorfinan-6-oIs is suitable for this O-glycosylation, preferably, the compounds of the formula [3] are used. wherein the 7 and 8 position can be olefin as shown or dihydro adduct; R3 and R4 are as previously defined. More preferably, said 4,5-Epoxymorfinan-6-ols are selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-0-Acylnalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O- Benzylmorphine, 3-O-Benzyldihydromorphine, N, O3-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Folcodin, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine, N, O3- Bis (benzyloxycarbonyl) normorphine. Although any Bromoglucuronate can be used, it is preferred that the compounds of the formula [2] are used. [2] wherein R1 and R2 are as previously defined. More preferably, the bromoglucuronates of the present invention are selected from the compounds of the formula [2a]. [2a] wherein R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl; R2 is as previously defined. More preferably, the bromoglucuronates of the formula [2b] are used. [2b] where R is as previously defined. Although any Zinc-containing compound as activating reagents for this O-glycosylation can be used, Zinc Bromide is preferably used. It is preferred that about 0.01 equivalents to about 4 equivalents and especially preferred that about 0.5 equivalents to about 2 equivalents of Zinc-containing compound be used. Preferably about 1 equivalent to about 2 equivalents of the Bromoglucuronate [2] is used. It is especially preferred that about 1 equivalent to about 1.5 equivalents of Bromoglucuronate [2]. Said 4,5-Epoxymorfinan-6-ol [3] can be used as a single compound or alternatively as corresponding salts thereof or complexes. Especially preferred is the use of said salt containing Zinc or complexes of [3] without using additional compounds containing Zinc as promoters for said coupling. It is preferred that said complexes can be prepared in situ. It may also be preferred to conduct said Zinc-activated O-glycosylation in the presence of additives to buffer or promote said Zinc-containing compounds. The above additives can be selected from molecular sieves, tertiary amines, tretralkylureas, salts and organic and inorganic acids. Any solvent inert to the reaction can be used. As used above and elsewhere herein, the term "reaction-inert solvent" refers to a solvent that does not react or decompose with starting materials, reagents, intermediates or products in a manner that adversely affects the production of the desired product. In general, the solvent may comprise a single entity, or contain multiple components. Preferably, the solvent is a solvent inert to the non-protic reaction and it is especially preferred that the solvent is Dichloromethane due to the excellent esteroselectivity it provides. Another solvent can be Chloroform or Dichloroethane. Any environment or conditions (eg, temperature, time, solvent) suitable for (i.e. capable of) forming the desired 4,5-Epoxymorphinan-6-oxygluuronates can be used. However, it is preferred that the reaction occurs at a temperature of from about -20 ° C to about 100 ° C and preferably from about 40 ° C to 65 ° C. Below about -20 ° C the reaction may be slow and above about 100"" C unwanted side reactions may occur (e.g., anomerisation). The reaction is conveniently carried out at about 0.5 to about 3 atmospheres, however, high pressures are especially preferred for such coupling. The present invention could be used as a general method to produce a large number of new compounds. As a result of said coupling also the salts and complexes of 4,5-epoxymorfinan-6-oxyglucuronates [1] could be obtained in a convenient manner. This invention makes a significant advance in the field of 4,5-Epoxymorfinan-6-oxyglucosides by providing efficient methods for preparing both anomers of 4,5-Epoxymorfinan-6-oxyglucuronates. The unprotected end products are useful as analgesic agents. It is to be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of this new concept as defined by the following claims.

Examples Example 1. Preparation of Codeine-β-glucuronate [4a] 1. 1 Preparation of Methyl (3-O-methyImorfin-6-yl-2 ', 3', 4'-tr'-O-acetyl-β-D-glucopyranoside) uronate [1 e] A mixture of methyl acetobromo-aD- glucuronate [2c] (0.20 g), Codeine [3b] (0.10 g), Molecular Sieve 3A (0.3 g) and Dichloromethane (10 mL) was stirred at room temperature for 5 hours. . Anhydrous Zinc Bromide (0.08 g) was added in one portion and the resulting mixture was refluxed for 48 hours. D? Chloromethane (20 mL) and saturated aqueous solution of Sodium Hydrogencarbonate (10 mL) were added to the cooled reaction mixture. After stirring for 30 min the organic layer was separated and rinsed with saturated aqueous solution of Sodium Hydrogencarbonate and Water. The aqueous layers were combined and washed with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. After purification of the residue the desired product was obtained in the production of 58% (0.1 2 g). Its structure was confirmed by 1 H NMR (CDCI) 3. 1.2 Hydrolysis of compound [1 e] The hydrolysis of compound [1 e] was carried out according to the known procedure (Carrupt, P.-A, -e. Al., J. Med. Chem, 1 991, v. 34 , 1272). Codeine-β-glucuronate was obtained with 50% yield. Its structure was confirmed by 1 H NMR (D 2 O), 13 C NMR, HR-MS.

Example 2. Preparation of Morphine-6-β-glucuronate [M6G] [4] 2. 1 Preparation of Methyl (3-O-methoxycarbonylmorfin-6-yl-2 ', 3', 4'-tri-0-acetyl-β-D-glucopyranoside) uronate [1 f] A mixture of methyl acetobromo-aD -glucuronate [2c] (39.7 g, 100 mmol), 3-O-methoxycarbonylmorphine [3c] (22.8 g, 66.5 mmol), Molecular Sieve 3A (50.0 g) and Chloroform (300 mL) was stirred at room temperature for 1 hour . Anhydrous Zinc Bromide (16.1 g, 71.4 mmol) was added in one portion and the resulting mixture was stirred at 50-55 ° C for 60 hours under Argon. Saturated aqueous sodium hydrogencarbonate solution (200 mL) was added to the reaction mixture cooled to room temperature and stirring was continued for a further 30 min. The organic layer was separated, rinsed with water, dried over anhydrous Sodium Sulfate, filtered through a short Silica gel column and evaporated under reduced pressure to give 35.0 g (80%) of the crude product. After recrystallization from iso-Propanol, 20.3 g (46.4% yield) of Methyl (3-O-methoxycarbonylmorphin-6-yl-2 ', 3', 4'-tri-O-acetyl-β-D- were obtained. glucopyranoside) uronate [1 f]. Its structure was confirmed by 1 H NMR (CDCI) 3. 2.2 Hydrolysis of compound [1 f] The hydrolysis of compound [1 f] was carried out according to the known procedure (Carrupt, P.-A, et al., J. Med. Chem, 1991, v. 34, 1272 ) and gave M6G [4] with 56% yield. Its structure was confirmed by 1 H NMR (D 2 O), 13 C NMR.

Example 3. Preparation of Morphine-6-a-glucuronate [4b] [2c] [3c] ZnBr2, CH2Cl2 MS 3Á [igj [4b] 3. 1 Preparation of Methyl (3-O-acetylmorphon-6-yl-2 ', 3', 4'-tri-O-acetyl- / β-D-glucopyranoside) uronate [1 g] A mixture of methyl acetobromo- α-D-glucuronate [2c] (6.0 g, 15 mmol), 3-O-Acetylimorphine [3c] (3.23 g, 10 mmol) and Molecular Sieve 3A (9.0 g) and Dichloromethane (50 mL) was stirred at room temperature for 5 hours. hours. Anhydrous Zinc Bromide (4.50 g, 20 mmol) was added in one portion and the resulting mixture was refluxed for 48 hours. Sodium hydrogencarbonate solution (8.0 g) in 80 mL of water and Dichloromethane (80 mL) was added to the cooled solution. After stirring for 30 min the organic layer was separated and the aqueous layer was rinsed with dichloromethane. The combined organic solution was rinsed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a short silica gel column (Dichloromethane - »Dichloromethane / Methanol 30: 1 v / v) and after concentration under reduced pressure, 5.7 g yellowish powder of Methyl (3-0-acetylmorphine) was obtained. 6-yl-2 ', 3', 4'-tri-O-acetyl-Dg! Ucopyranoside) uronate [1 g] desired (mixture a /? 6: 1 according to 1 H NMR spectrum) (91% yield) ). 3.2 Hydrolysis of compound [1 g] Sodium Hydroxide Solution (0.40 g, 10.0 mmol) in 7.5 mL of water was added to a stirred solution of Methyl (3-O-acetylmorphin-6-yl-2 ', 3', 4, -tri-O-acetyl-a / β-D-glucopyranoside. ) uronate (1.6 g, 2.0 mmol) in 30 mL of methanol and the mixture was stirred overnight at room temperature. The solution was then acidified with glacial acetic acid (5.25 g, 87.3 mmol) at pH 5.5. The solution was cooled to 0 ° C, Ethanol (20 mL) was added and the obtained mixture was stirred for 1.5 hours. The white precipitate formed under these conditions was filtered and rinsed with Ethanol (2 mL). After drying under reduced pressure at 80 ° C, 0.63 g (62% yield) of Morphine-6-a-glucuronate [4b] was obtained. Its structure was confirmed by 1 H NMR (D 2 O), 13 C NMR, HR-MS Example 4-20. Preparation of compound of the formula [1 b] The syntheses are described by the following Scheme. The procedures set forth in Example 3 were followed with the apparent exceptions of Table 1. The ß / a ratio was determined according to 1 H NMR and / or HPLC The procedures set forth in Example 3 were followed with the apparent exceptions of Table 1. The ß / a ratio was determined according to 1 H NMR and / or HPLC Table 1 Example 21. Preparation of Methyl (3-O-Acetylmorphin-6-yl-2 ', 3', 4'-tri- O-acetyl-β-D-glucopyranoside) uronate of the formula [8] Í8] [93 A suspension of 6.00 g of Methyl Tri-O-acetyl-1-a-bromo-1-deoxy-D-glucopyranuronate of the formula [9], 3.23 g of 3-0-Acetylmorphine6 dried in vacuum, freshly prepared and 9.00 g of 3A Molecular Sieve in CH2Cl2 was stirred at room temperature for 5 hours. 2.20 g of Anhydrous Zinc Bromide was added in one portion and the resulting mixture was refluxed for 24 hours. Then an additional 0.30 g of anhydrous Zinc Bromide was added and the mixture was refluxed for a further 24 hours. After this period, the red solution was cooled to room temperature and the mixture of Methylene Chloride (150 mL) and saturated aqueous solution of Sodium Hydrogencarbonate (80 mL) was added to the reaction mixture. After stirring for 30 min, the organic layer was separated and rinsed accordingly with saturated aqueous solution of Sodium Hydrogencarbonate and Water. The combined aqueous layers were rinsed with Methylene Chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. After purification of the residue, the desired product was obtained in the 91% yield (5.7 g).

References: 1. Osborne, R., e. Al. Br. J. Clin. Pharm. 1992, v.34, 130 2. French, B., eí al .. J. Pharm. Exp. Ther., 1992 v.262, 25

Claims (2)

CLAIMS 1. A process for the synthesis of a protected 4.5-Epoxymorfinan-6-oxyglucan of the formula [1] or a salt or complex thereof. [13 where the position 7 and 8 are olefin as shown or dihydro adduct; R1 is alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl, R2 is alkyl, haloalkyl or aralkyl; R3 is alkyl, arymethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R 4 is alkyl, haloalkyl, arylmethyl, 2- (4-morpholinyl) ethyl, acyl, alkoxycarbonyl. aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl. comprising the reaction of a Bromoglucuronate of the formula [2] [2] wherein R1 and R2 are as previously defined; with a 4,5-Epoxymorphinan-6-ols of the formula [3] or a salt or complex thereof [3] R3 and R4 are as previously defined; in the presence of a Zinc-containing compound under conditions capable of forming said protected 4,5-Epoxymorfinan-6-oxyglucanonate [1] or a salt or complex thereof. 2. A process according to claim 1, characterized in that said 4,5-Epoxymorfinan-6-ol is selected from the compounds of the formula [3a] [3a] wherein R4 is as previously defined 3. A process according to claim 1, characterized in that said 4,5-Epoxymorfinan-6-ol is selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O -Alkalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine, N, O3-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Folcodin, 3-O-Alkoxycarbonylmorphine, 3-O -Benzyloxycarbonylmorphine, N, O3-Bis (benzyloxycarbonyl) normorphine. 4. A process according to claim 1, characterized in that said Bromoglucuronate is selected from the compounds of the formula [2a] [2a] wherein R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R2 is as previously defined. 5. A process according to claim 1, characterized in that said Bromoglucuronate is selected from the compounds of the formula [2b] [2b3 where R is as previously defined. 6. A process according to claim 1, characterized in that said protected 4,5-Epoxymorfinan-6-oxyglucanide is an N-Methyl-4,5-epoxymorphinan-6-oxyglucuronate of the formula [1 a] or derivative. [1a] wherein the 7 and 8 position can be olefin as shown or dihydro adduct; R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, nitrobenzyloxycarbonyl, methoxybenzylcarbonyl or aroxycarbonyl; R 2 is alkyl, haloalkyl or aralkyl; . R 4 is alkyl, haloalkyl, arylmethyl, 2- (4-morpholinyl) ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl. 7. A process according to claim 1, characterized in that R2 and R3 are methyl. 8. A process according to claim 1, characterized in that said protected 4,5-epoxymorphinan-6-oxygluuronate is of the formula [1 b]. [i] where R and R4 are as previously defined. 9. A process according to claim 1, characterized in that said reaction occurs in the presence of molecular sieves. 10. A process according to claim 1, characterized in that the reaction occurs in a solvent inert to the non-protic reaction. eleven . A process according to claim 10, characterized in that the inert solvent is selected from Chloroform, Dichloromethane or Dichloroethane. 12. A process according to claim 1, characterized in that the Zinc-containing compound is Zinc Bromide.

1 3. The use of a Zinc complex of a general formula [3b] [3b] wherein R3 and R4 are as previously defined; X is a halogen or a cyano group; n 0.5 - 2 for the preparation of a protected 4.5-Epoxymorfinan-6-oxyglucanonate of a general formula [1] or a salt or complex thereof [13 wherein R1, R2, R3 and R4, are as previously defined. 14. A process for the synthesis of a protected 4,5-Epoxymorfinan-6-oxyglucuronate of the formula [1] or a salt or complex thereof [13 where the position 7 and 8 are olefin as shown or dihydro adduct; R1 is alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl, R2 is alkyl, haloalkyl or aralkyl; R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R 4 is alkyl, haloalkyl, arylmethyl, 2- (4-morpholinyl) ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl. comprising the reaction of Bromoglucuronate of the formula [2]

[2] wherein R1 and R2 are as previously defined; with complex of the formula [3b] under conditions capable of forming said protected 4,5-Epoxymorfinan-6-oxyglucuronate of the formula [1] or a salt or complex thereof. A compound having the following formula: [1c] wherein the 7 and 8 position is olefin as shown or dihydro adduct; R2 and R3 are as previously defined; R 6 is selected from alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, alkyloxycarbonyl and R 5 is selected from alkyl, haloalkyl, arylmethio, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or R 6 is selected from alkyl, haloalkyl, arylmethyl, 2- (4 -morpholinyl) ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl when one of R5 is selected from alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 16. A compound having the following formula: wherein the 7 and 8 position is olefin as shown or dihydro adduct; R7 is hydrogen, alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl, R8 is hydrogen, alkyl, haloalkyl or aralkyl; R9 is hydrogen, alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R10 is hydrogen, alkyl, haloalkyl, arylmethyl, 2- (4-morpholinyl) ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl. 17. A compound of the formula [1 c] according to claim 1 wherein R2 and R3 are both Me. 1 8. A protected 4, 5-Epoxymorfinan-6-oxyglucuronate synthesized according to any of claims 1 to 12 or 14. 1 9. A process for synthesizing M6G comprising: synthesizing a protected 4,5-Epoxymorfinan-6-oxyglucuronate according to any of claims 1 to 12 or 14; and hydrolyze protected 4,5-Epoxymorfinan-6-oxyglucanide to form M6G. 20. M6G synthesized according to claim 19. 21. M6G synthesized using a zinc complex according to claim 13.