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Definitions

• the present invention relates to synthesis procedures and synthesis intermediates of a macrocyclic protease inhibitor of the hepatitis C virus (HCV).
• HCV hepatitis C virus
• HCV Hepatitis C Virus
• liver transplantations hepatocellular carcinoma
• HCV NS3 serine protease and its associated cofactor, NS4A Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A.
• HCV NS3 serine protease and its associated cofactor, NS4A Various agents that inhibit this enzyme have been described.
• WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentane moiety.
• the macrocyclic derivatives are attractive by their pronounced activity against HCV and attractive pharmacokinetic profile.
• WO 2007/014926 describes macrocyclic cyclopentane and proline derivatives including the compound of formula I, with the structure represented hereafter.
• the compound of formula I is a very effective inhibitor of the HCV serine protease and is particularly attractive in terms
• the compound of formula I can be prepared starting from the bicyclic lactone carboxylic acid referred to as compound 39 in example 4, or in the general description of this reference as compound 17b, or as compound VII in this description and claims.
• the carboxylic acid in bicyclic lactone carboxylic acid is coupled with N-methylhex-5-enylamine 38, followed by lactone opening to 4-hydroxy- cyclopentane derivative 4L
• the latter derivative 4J_ is then coupled with aminocyclo- propylcarboxylic ester to cyclopentane dicarboxylic acid diamide 43, which is coupled with quinoline 36 in an Mitsunobu ether-forming reaction, which involves an inversion at the hydro xy-bearing carbon.
• the resulting intermediate 44 is cyclized via a metathesis reaction to a macrocyclic derivative, in which the ester group is hydro lysed and coupled with cyclopropylsulfonylamide to yield the desired end product of formula I.
• R represents Ci_ 4 alkyl and in example 4, R is ethyl.
• the enantiomerically pure bicyclic lactone 39 was prepared starting from an enantiomer of 3,4-bis(methoxycarbonyl)cyclo-pentanone, referred to as (17a) in WO 2007/014926. The latter was prepared as described by Rosenquist et al. in Acta Chemica Scandinavica 46 (1992) 1127 - 1129.
• Racemic cyclohexene dicarboxylic acid methyl ester was synthesized via a Diels- Alder reaction of 3-sulfolene and dimethyl fumarate, followed by oxidative cleavage of the double bond, cyclization, and decarboxylation, resulting in (+) 4-ketocyclopentane dicarboxylic acid dimethyl ester. Resolution of the latter by hydrolysis using pig liver esterase resulted in the corresponding (+)-monoacid and the (-) diester, which is intermediate (17a) of WO 2007/014926.
• the trans (3R,4R)-3,4-bis(methoxycarbonyl) cyclopentanone diester (17a) was converted to the bicyclic lactone 17b (also referred to as compound VII, see above), first by a keto to alcohol reduction, followed by hydrolysis of the esters, and lactone formation.
• the synthesis procedure for preparing I described in WO 2008/092955 starts from an intermediate D, wherein the ester function is hydrolysed, and coupled with cyclopropyl amino acid ester C.
• the resulting intermediate B is cyclized by an olefin metathesis reaction to the macrocyclic ester A, which is hydrolyzed and coupled with
• R is Ci_ 4 alkyl, in particular R is ethyl.
• R 1 is Ci_ 4 alkyl, in particular R 1 is methyl or ethyl.
• R 1 is in this scheme is as specified above and Bn represents benzyl.
• WO 2008/092955 furthermore describes procedures for preparing intermediate HJ_ starting from 4-oxo-l,2,-cyclopentanedicarboxylic acid O, by a keto to alcohol reduction, thus obtaining 4-hydroxy-l,2-cyclopentanedicarboxylic acid N, which in turn is cyclized to the bicyclic lactone M- Esterification of the carboxylic acid group in the latter yields the lactone benzyl ester L, wherein the lactone is opened by a transesterification reaction in the presence of a Ci_ 4 alkanol, thus yielding intermediate H, which is resolved in its enantiomers HJ_ and H2, as outlined in the following reaction scheme: OH OBn OR
• a disadvantage of the above process is that it involves a resolution of the enantiomers of H by chiral column chromatography, a cumbersome procedure that is difficult to run at large scale production. Another disadvantage is that the resolution takes place at a later stage of the synthesis, whereby half of the building block H has to be discarded.
• Compound HJ_ is one of the two enantiomers obtained by separation from the racemic compound H.
• the other enantiomer is compound H2.
• the bicyclic lactone (17b) is an interesting building block in the synthesis of the compound of formula I. Finding a synthesis path to obtain this lactone in good yield and high enantiomeric purity is a desirable goal to achieve.
• the present invention provides a process to prepare (lR,2R)-4-oxo-l,2-cyclopentanedicarboxylic acid, which can be readily converted to the bicyclic lactone (17b).
• the processes of the present invention are advantageous in that they are suitable for large scale production. Cumbersome purification steps, in particular by
• the present invention relates to a process for preparing [(li?,2i?)-4-oxo- 1 ,2-cyclopentanedicarboxylic acid II, by the resolution of racemic 4-oxo-l,2- cyclopentanedicarboxylic acid (V), said process comprising
• the invention also concerns the intermediate [(li?,2i?)-4-oxo-l,2-cyclopentane- dicarboxylic acid salt with brucine (1 : 2), having the structure III, and the
• the brucine salt III can be obtained by mixing brucine and tra/?s-4-oxo-l,2-cyclo- pentanedicarboxylic acid in the presence of a solvent, heating the mixture until all solids dissolve, and allowing the mixture to cool whereby the brucine salt crystallizes.
• Solvents include alcohols such as methanol or ethanol and aqueous alcohols, such as aqueous methanol or ethanol. Of interest are alcohol/water mixtures with a minor amount of water, e.g. a water content in the range of about 2% to about 20%, or about 5% to about 10% (w/w).
• a mixture of aqueous alcohol and brucine is made and slightly heated to a temperature in the range of about 30°C to about 50°C, e.g. at about 40°C whereupon a solution of tra/?s-4-oxo-l,2-cyclopentanedicarboxylic acid is added.
• the resulting mixture is heated until all solids are dissolved, in particular by heating to reflux temperature.
• the mixture is allowed to cool, preferably slowly, to room temperature.
• the solids that are formed are filtered. They may be recrystallized, e.g. from water.
• the (ii?,25)-(-)-ephedrine salt IV can be obtained similarly, but instead of aqueous alcohols, aqueous ketones such as aqueous acetone can be used.
• aqueous ketones such as aqueous acetone
• acetone/water mixtures with a minor amount of water e.g. a water content in the range of about 2% to about 25%, or about 10% to about 20% (w/w), e.g. about 16% (w/w).
• the resolution can also be performed with (7S,2R)-(+)-ephedrine yielding the
• brucine and (7R,2S)-(-)-ephedrine salts of (lR,2R)-4-oxo-l,2-cyclopentanedi- carboxylic acid can be converted to the free acid of formula II.
• brucine and (7R,2S)-(-)-ephedrine are removed by treating aqueous suspensions of the salts with a base, e.g. ammonium hydroxide. This is preferably done at increased temperature, for example at a temperature that is in the range of 60°C to 100°C, e.g. at 80°C. Cooling to room temperature results in crystallization of solid brucine, which can be isolated by filtration.
• the bisalkali metal salt form of II can also be prepared and isolated.
• the recovered brucine can be dried and recrystallized from water - ethanol (50:50) to purify the brucine, which can be re-used in the resolution.
• the (R,R)-4-oxo-l,2-cyclopentanedicarboxylic acid II obtained by the above process, or the brucine salt III or the (ii?,25)-(-)-ephedrine salt (IV), are used as a starting material in a process for preparing the bicyclic lactone (VII), by reducing the keto functionality to an alcohol resulting in 4-hydroxy-l,2-cyclopentane-dicarboxylic acid (VI), which is cyclized to the lactone (VII).
• the racemic 4-oxo-l,2-cyclopentanedicarboxylic acid V starting material can be prepared as described above in the Background of the Invention section.
• the keto to hydroxy reduction in II to VI can be done using a suitable reductant, in particular by hydrogen in the presence of a metal catalyst, e.g. rhodium on carbon or on alumina or Raney Ni, in a reaction- inert solvent, e.g. in an aqueous medium, such as water, in the presence of a base, e.g. NaOH, KOH, or an organic base such as triethylamine, N-methylmorpholine or Hunig's base (diisopropylethylamine).
• a suitable reductant in particular by hydrogen in the presence of a metal catalyst, e.g. rhodium on carbon or on alumina or Raney Ni, in a reaction- inert solvent, e.g. in an aqueous medium, such as water, in the presence of
• the resulting 4-hydroxycyclopentane-l,2-dicarboxylic acid VI can be converted to a salt, e.g. a bistertiary amine salt such as the bis-triethylamine salt, or a bisalkali metal salt such as the bis sodium or bis potassium salts.
• a salt e.g. a bistertiary amine salt such as the bis-triethylamine salt, or a bisalkali metal salt such as the bis sodium or bis potassium salts.
• Intermediate VI can be cyclized to form the lactone VII by reaction with a chloro- formate, e.g. with ethyl or methyl chloro formate.
• This reaction can be conducted in a reaction-inert solvent such as a ketone, in particular acetone, or an ether such as THF or MeTHF, or acetonitrile.
• a base can be added, e.g. a tertiary amine such as triethylamine or N-methylmorpholine (NMM).
• the lactone- forming agent is 2,4,6-trichloro-l,3,5-triazine (TCT) or a derivative thereof.
• intermediate II is converted to the 4-hydroxy-l,2-cyclo- pentane-dicarboxylic acid VI by a reduction reaction as described above, which is cyclized to the lactone VII using a triazine derivative, in a one-pot procedure without isolation of intermediary products.
• VI is obtained in water after the reduction step, to which an organic co-solvent might be added in the second step, for example acetone, methylethylketone (MEK), tetrahydrofuran (THF) or 2-methyltetrahydrofuran
• Triazine derivatives for this reaction comprise agents such as 2,4,6- trichloro-l,3,5-triazine (TCT), chloro-dimethoxytriazine (CDMT), N-(3,5-dimethoxy- triazinyl)-N-methylmorpholinium chloride (DMTMM) or dichloro-methoxytriazine (DCMT).
• TCT 2,4,6- trichloro-l,3,5-triazine
• CDMT chloro-dimethoxytriazine
• DTMM N-(3,5-dimethoxy- triazinyl)-N-methylmorpholinium chloride
• DCMT dichloro-methoxytriazine
• brucine and (ii?,25)-(-)-ephedrine salts of (li?,2i?)-4-oxo-l,2-cyclopentane- dicarboxylic acid III or IV can be converted directly to the dimethyl (li?,2i?)-4-oxo-l,2- cyclopentanedicarboxylate ester.
• brucine and (ii?,25)-(-)-ephedrine are removed as described above and solid brucine and (ii?,25)-(-)-ephedrine are isolated.
• the mother liquors after the recovery of brucine and (-)-ephedrine are evaporated to yield enantiomerically pure (li?,2i?)-4-oxo-l,2-cyclopentanedicarboxylic acid.
• This can be used to make I as described in WO 2007/014926.
• the residue that is obtained after evaporation is taken up in a methanol/ toluene mixture and a strong acid, e.g. sulfuric acid is added.
• the reaction mixture is heated up, preferably to reflux, whereafter the solvent is distilled off from the reaction mixture until an internal temperature of > 70°C is reached.
• the mixture is then cooled to about 30°C and water added.
• the resulting mixture is stirred at room temperature and further worked up by isolating the organic layer that is formed. Evaporation yields the desired dimethyl ester.
• the latter can be converted to dimethyl (li?,2i?)-4-oxo-l,2-cyclopentanedicarboxylate ester VIII as described above and further converted to other intermediates in the synthesis of the compound of formula I.
• the keto group in VIII is reduced yielding an intermediate IX, which is converted to X by a hydro xy-assisted transesterification reaction.
• the hydroxy- function in X is converted to a quinolinyl ether group in XI with a Mitsunobu reaction, which involves an inversion at the hydroxy-bearing carbon atom.
• compound XVIII a useful intermediate to prepare I, is obtained from intermediate X via the route described below:
• R 2 is hydrogen, Ci_ 4 alkyl, aryl, halogen,
• R 2 can be substituted in o, m, or in particular in p-position. Of interest is N0 2 , in particular p-N0 2 (4-N0 2 ). R 1 is as specified above and in particular is methyl.
• Compound X is reacted with an aromatic acid, an azodicarboxylate and a phosphine in a Mitsunobu reaction to give XIX, which is isolated as a crystalline solid from the reaction mixture, thereby providing an efficient purification from both impurities in X and those from the Mitsunobu reaction, as well.
• the synthesis procedures of the present invention offers the advantage that the correct stereochemistry at the cyclopentane moiety is obtained without using chiral chromatography.
• the brucine salt III and the ephedrine salt IV have been found to selectively crystallize with high diastereomeric purity (containing the acid II in high enantiomeric purity).
• the finding that the salts III and IV can be isolated by crystallization provides an elegant way to obtain (R,R)-4-oxo-l,2-cyclopentanedicarboxylic acid II and eventually the bicyclic lactone VII in high enantiomeric purity. Recrystallization or reslurrying allows further purification of these salts.
• the salts III and IV can be used as starting material in the further synthesis of the acid VI, as described above. The latter in turn can be converted to the lactone VII, an important building block in the preparation of the compound of formula I.
• the present invention relates to the compounds per se of formula III or IV.
• the cyclic lactone acid VII can be isolated, either as an acid or a salt thereof, but the resulting aqueous-organic solution of VII obtained in the reaction sequence described above can be used directly in a coupling reaction with the amine XVI to obtain the amide XVII.
• the bicyclic lactone acid VII or a salt thereof, either isolated or nonisolated, is used as a starting material in a process for preparing the cyclopentane derivative XVIII, by reacting the bicyclic lactone VII with N-methyl-5-hexen-l -amine (NMHA) XVI in an amide-forming reaction to yield the bicyclic lactone amide XVII, in which the lactone group is opened to yield the desired product XVIII.
• NMHA N-methyl-5-hexen-l -amine
• the further processing of the compound of formula XVIII to the end products of formula I are as outlined in the reaction schemes above and in particular as described in WO 2008/092955.
• the reaction of the bicyclic lactone VII with N-methyl-5-hexen-l- amine XVI is an amide forming reaction, which comprises reacting the starting materials with an amide-coupling reagent in a solvent, optionally in the presence of a base, as described in WO 05/073195 and WO 2007/014926.
• This reaction can be conducted, for example, by using N-ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline (EEDQ) as coupling agent, in dichloromethane (DCM), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF) as solvent, or can be performed by using TCT or a derivative thereof (CDMT, DCMT, DMTMM) in water or a mixture of water and an organic solvent.
• EEDQ N-ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline
• DCM dichloromethane
• THF tetrahydrofuran
• MeTHF 2-methyltetrahydrofuran
• Organic solvents to this purpose include acetone, methylethylketone (MEK), tetrahydrofuran (THF), MeTHF, CPME (cyclopentyl methyl ether), Ci_ 4 alkyl acetate, Ci_ 4 alkyl propionate, Ci_ 4 alkyl butyrate and toluene.
• Ci_ 4 alkyl defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl and ethyl; and also 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2 -methyl- 1 -propyl, 2-methyl-2- propyl.
• a compound represented without stereobonds is racemic or the configuration of the stereogenic center(s) is not defined.
• enantiomeric purity is given as enantiomeric ratio (e.r.).
• e.r. value refers to the ratio of the two enantiomers of the acid in the mixture of diastereomeric salts.
• Example 1 Resolution of 4-oxo-l,2-cyclopentanedicarboxylic acid with brucine.
• Example 3 (li?,2i?)-4-oxo-l,2-cyclopentanedicarboxylic acid and recovery of ephedrine.
• 2-Methyltetrahydrofuran (688 ml) was added and the mixture was stirred vigorously for 20 minutes. The two layers were separated and the aqueous phase was acidified with HC1.
• the 2-methyltetrahydrofuran organic phase contained the ephedrine, which could be recycled from that phase.
• the aqueous phase was then evaporated to dryness on the rotavapor and the residue recrystallized from water (50 ml) to yield 55.15 g (64 % yield) of (li?,2i?)-4-oxo-l,2-cyclopentane- dicarboxylic acid as an off white solid.
• the 2-methyltetrahydrofuran solution of ephedrine was evaporated to dryness on the rotavapor to yield crude ephedrine as a yellow oil, which solidified on standing after 3 days.
• the crude ephedrine was dissolved in 2-methyltetrahydrofuran (400 ml) and the mixture made acidic with HC1 in isopropanol. The solid material was filtered and washed with 2-methyltetrahydrofuran (50 ml). The solid ephedrine hydrochloride was dried under vacuum at 50°C before being dissolved in water (300 ml) at 40°C.
• Triethylamine (55.61 ml, 0.40 mol) was added and 80% of the solvent volume was distilled off under a pressure of 30 mbar.
• the reaction flask was fitted with a Dean-Stark trap filled with 2-methyltetrahydrofuran and 2-methyltetra- hydrofuran (100 ml) was added to the reaction mixture.
• the mixture was refluxed for 4 hours to remove the remaining water.
• 80% of the solvent volume was distilled off under ambient pressure.
• the mixture was cooled to 50°C and acetone (380 ml) was added.
• the mixture was cooled further to 22°C and additional acetone (760 ml) was added.
• Rhodium on alumina (5% wet, 25 g) was added to a solution of dimethyl (lR,2R)-4- oxo-l,2-cyclopentanedicarboxylate (100 g, 0.5 mol) in tetrahydrofuran (1000 ml).
• the reaction vessel was purged with hydrogen and then stirred under an atmosphere of hydrogen until complete conversion.
• the reaction mixture was filtered over Dicalite and the filter cake washed with tetrahydrofuran (10 ml).
• the combined filtrate and washings were evaporated to dryness to yield 95.9 g of dimethyl (li?,2i?)-4-hydroxy- 1 ,2-cyclopentanedicarboxylate as a colourless oil. This reduction could also be carried out using Raney - Ni as catalyst under hydrogen 6 bar pressure.
• Example 8 synthesis of XI, benzyl methyl (li?,2i?,45)-4-([2-(4-isopropyl-l,3-thiazol-2- yl)-7-methoxy-8-methyl-4-quinolinyl]oxy)-l,2-cyclopentanedicarboxylate
• Example 11 synthesis of XIV, (li?,2i?,4i?)-2-[[(li?,25)-l-(ethoxycarbonyl)-2-vinyl- cyclopropyl]carbamoyl]-4-[[2-(4-isopropyl-l,3-thiazol-2-yl)-7-methoxy-8-methyl-4- quinolinyl]oxy]cyclopentanecarboxylic acid
• Example 12 synthesis of XV, ethyl (lR,2S)-l-([[(lR,2R,4R)-2-[hex-5-en-l-yl(methyl)- carbamoyl] -4- [ [2-(4-isopropyl- 1 ,3 -thiazo l-2-yl)-7-methoxy-8-methylquino lin-4-yl] - oxy] cy clopentyl] carbonyl] amino)-2-vinylcyclopropanecarboxylate
• Diisopropyl azodicarboxylate (860 mg, 4.25 mmole) was added dropwise at such a rate that the temperature remained under 5°C. The mixture was stirred at 0°C a further 60 minutes before being allowed to warm to 22°C and stir for 16 hours. The reaction mixture was filtered and the solids washed with toluene.
• the weight% (w/w%) of salts in solution always refers to the w/w% of the parent acid in the solution.
• a 25 w/w% VI.2NMM solution a 25 w/w% VI.2NMM solution
• VI.2NMM referring to the (2 : 1) N-morpholine salt of compound VI) in a solvent refers to a solution of VI.2NMM in which 25 g of parent acid VI were present in 100 g of the solution).
• Example 19 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt
• Example 20 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt
• Example 21 728 of NMM (6.6 mmol) was mixed with 4 ml water and 406 mg (2.2 mmol) TCT was added. The mixture was stirred a few minutes before adding 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt (1 mmol). The resulting reaction mixture was further stirred overnight at room temperature before dilution to a final volume of 10 ml to give a 57 mM aqueous solution of VII ( yield: 57%).
• Example 22 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt
• Example 23 386 mg (2.2 mmol) CDMT was dissolved in 4 ml acetone and 463 ⁇ (4.2 mmol) NMMR was added. The mixture was stirred a few minutes then 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt was added. The resulting mixture was further stirred overnight at room temperature before dilution to a final volume of 10 ml to give a 69 mM solution of VII (yield: 69%).
• Example 24 386 mg (2.2 mmol) CDMT was dissolved in 4 ml MeTHF and 463 ⁇ (4.2 mmol) NMM was added. The mixture was stirred a few minutes then 735 mg of 23.7 w/w% aqueous solution of VI, bis-potassium salt was added. The resulting mixture was further stirred overnight at room temperature before dilution to a final volume of 10 ml to give a 54 mM solution of VII (yield: 54%).
• Example 25 5.66 g (32.2 mmol) CDMT was dissolved in 59 ml MeTHF. 3.7 ml (33.7 mmol) NMM was added and the mixture was stirred lh at 25°C.
• Example 26 5.66 g (32.2 mmol) CDMT was dissolved in 59 ml isopropyl acetate. 3.7 ml (33.7 mmol) NMM was added and the mixture was stirred lh at 25°C. 10.0 g of 25.5 w/w% aqueous solution of bis N-methylmorpholine salt of VI (14.6 mmol) was added and the resulting mixture was further stirred a few hours at 25°C. 15 ml water and 3 ml concentrated HC1 were added. The mixture was stirred a few minutes, the insoluble materials were filtered off, the filtrate was decanted and the water layer was extracted with 15 ml isopropyl acetate. The organic layers were combined and washed with 7 ml brine to give 56.6 g of 1.3 w/w% solution of VII in isopropyl acetate that also contained 0.18 w/w% VI (yield: 32%).
• Example 27 5.66 g (32.2 mmol) CDMT was dissolved in 59 ml acetone. 3.7 ml (33.7 mmol) NMM was added and the mixture was stirred lh at 25°C. 10.0 g of 25.5 w/w% aqueous solution of bis N-methylmorpholine salt of VI (14.6 mmol) was added and the resulting mixture was further stirred a few hours at 25°C. The insoluble materials were filtered off, 1 ml concentrated HC1 was added to the filtrate and the filtrate was decanted. The organic layer was washed with 7 ml brine to give 44.4 g of 1.44 w/w% solution of VII in MeTHF, which also contained 0.04 w/w% VI (yield: 28%).
• Example 28 19.80 g (113 mmol) CDMT was dissolved in 205 ml MeTHF. 13 ml (118 mmol) NMM was added and the mixture was stirred at 25°C for 2h. 35 g of 25.5 w/w% aqueous solution of bis N-methylmorpholine salt of VI (51.3 mmol) was added and the reaction mixture was stirred overnight at 25°C. 51 ml water and 10.6 ml concentrated HC1 were added and the mixture was stirred a few minutes at 25°C. The resulting solid was filtered off and the filtrate was decanted.
• Example 30 2.83 g (16 mmol) CDMT was dissolved in 29 ml MeTHF. 1.9 ml (18 mmol) NMM was added and the mixture was stirred at 20°C for 1 h. 52.01 g of 2.59 w/w% solution of VII in MeTHF (8.7 mmol) [from Example 25] was mixed with 1.82 g NMHA and 232 ⁇ (2.9 mmol) NMM and the resulting solution was added to the mixture of CDMT-NMM in MeTHF. The reaction mixture was stirred overnight at 20°C. 14.6 ml water and 1 ml concentrated HCl were added.
• Example 31 2.83 g (16 mmol) CDMT was dissolved in 29 ml isopropyl acetate. 1.9 ml (18 mmol) NMM was added and the mixture was stirred at 20°C for 1 h. 55.5 g of 1.3 w/w% solution of VII in isopropyl acetate (4.7 mmol) [from Example 26] was mixed with 1.82 g N-methyl-5-hexen-l -amine (NMHA) and 232 ⁇ (2.9 mmol) NMM and the resulting solution was added to the mixture of CDMT-NMM in isopropyl acetate. The reaction mixture was stirred overnight at 20°C. 14.6 ml water and 1 ml concentrated HCl were added.
• NMHA N-methyl-5-hexen-l -amine
• Example 33 9.90 g (56.4 mmol) CDMT was dissolved in 103 ml MeTHF. 6.8 ml (61.5 mmol) NMM was added and the mixture was stirred at 25°C for 2h. 162.2 g 2.13 w/w % solution of VII in MeTHF [from Example 28] was mixed with 0.71 ml (5.1 mmol) triethylamine and 6.38 g (56.4 mmol) NMHA then added to the mixture of CDMT -NMM. The reaction mixture was stirred for 3h at 25°C. 51 ml water and 3 ml concentrated HC1 were added and the mixture was stirred for a few minutes. The resulting solid was filtered off and the filtrate was decanted.
• Example 34 9.90 g (56.4 mmol) CDMT was dissolved in 103 ml MeTHF. 6.8 ml (61.5 mmol) NMM was added and the mixture was stirred at 25°C for 2h. 180.2 g 2.56 w/w % solution of VII in MeTHF [from Example 29] was mixed with 0.71 ml (5.1 mmol) triethylamine and 6.38 g (56.4 mmol) NMHA then added to the mixture of CDMT -NMM. The reaction mixture was stirred 3h at 25°C. 51 ml water and 3 ml concentrated HC1 were added and the mixture was stirred a few minutes. The resulting solid was filtered off and the filtrate was decanted.
• Example 36 81.4 g of 1.43 w/w% solution of XVII in isopropyl acetate [from Example 31] were concentrated under vacuum and the residue was redissolved in 59 ml toluene. 14.6 ml methanol and 76 methanesulfonic acid were added and the solution was refluxed overnight. 125 mg sodium carbonate was added and the mixture was refluxed lh more.
• Example 37 85.4 g of 1.45 w/w% solution of XVII in methyl isopropylketone (MIK) [from Example 31] were concentrated under vacuum and the residue was redissolved in 59 ml toluene. 14.6 ml methanol and 76 methanesulfonic acid were added and the solution was refluxed overnight. 125 mg sodium carbonate was added and the mixture was refluxed lh more.
• MIK methyl isopropylketone
• Example 38 To 73 g of 1.41 w/w% solution of XVII in toluene [from Example 32], were added 14.6 ml methanol and 76 methanesulfonic acid. The solution was refluxed overnight. 125 mg sodium carbonate was added and the mixture was refluxed for an additional one hour.
• Example 40 To 135 g of 2.51 w/w% solution of XVII in MeTHF [from Example 33], were added 154 ml toluene. 32 ml solvent were distilled off and the concentrate was cooled down to 60°C. 26 ml methanol and 84 ⁇ methanesulfonic acid were added and the solution was refluxed overnight. 136 mg sodium carbonate was added and the mixture was refluxed lh more.
• Example 41 To 126 g of 2.91 w/w% solution of XVII in MeTHF [from Example 34], were added 154 ml toluene. 190 ml solvent were distilled off and the concentrate was cooled down to 60°C. 26 ml methanol and 84 ⁇ methanesulfonic acid were added and the solution was refluxed overnight. 136 mg sodium carbonate was added and the mixture was refluxed lh more.

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