Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/82—Purification; Separation; Stabilisation; Use of additives
  • C07C209/86—Separation
  • C07C209/88—Separation of optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to the field of organic synthesis, in particular to the racemisation of chiral by-products in the synthesis of optically active compounds.
• Racemisation techniques represent a practical method for regeneration of undesirable enantiomers.
• a-amines and a-alcohols There are a number of processes for racemisation of such chiral compounds unlimitedly listed in the following items.
• Transition metal catalyzed hydrogen transfer is the most often used approach for racemisation of ⁇ -amines or alcohols.
• the process utilizes a conversion of optically active a-benzyl amine compound to an imine by reaction with a metal catalyst (hydride storage), followed by recovery of the amine by in situ hydrogenation of the imine to get the racemic mixture.
• a metal catalyst hydrogen storage
• the process undergoes via the ketone intermediate (see Scheme 1 ).
• Such methodology is efficient but suffers especially from the use of hazardous and carcinogenic polycyclic hydrocarbon aromatics and also from the difficult handling of alkali metal complexes (low stability, toxicity etc.) and as such it is not so convenient for industrial applications especially in pharmaceutical development. It is also less suitable for cyclic amines where substrates under single electron transfer reduction conditions could follow cycle-cleavage reactions.
• the present invention provides a novel efficient, simple and economic racemisation methodology suitably adapted and applicable for the target compounds of optically active ⁇ -benzyl amine, hydroxy and thiol compound including cyclic ⁇ -benzazepines like lorcaserin.
• the present invention also provides new methods for inversion of the chirality and a method for increasing the yield of a desired enantiopure product, suitably used in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt.
• the present invention further provides novel intermediates of such new methods preferably applied in the manufacturing of the target molecule lorcaserin, or its salt, preferably its hydrochloride salt.
• R is represented by a linear, branched or cyclic Ci-Ci 2 -alkyl
• R' is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a d- Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a Ci-C 4 - alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
• X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
• one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C 6 -alkoxy group, a unsubstituted or Ci-Ci 2 -alkyl mono- or di-substituted amino group, a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a Ci-C 6 - alkyloxy carbonyl group, a CrC 4 -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl- sub
• R is preferably represented by hydrogen, an acetyl group, a trifluoracetyl group, a benzyloxycarbonyl, an allyloxycarbonyl group, a mesyl group, or a tosyl group.
• a high boiling polar aprotic solvent preferably selected from a group of amides, sulfoxides, and sulfones, more preferably ⁇ , ⁇ -dimethylacetamide (DMA), N,N- dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), and most preferably dimethylsulfoxide.
• DMA ⁇ , ⁇ -dimethylacetamide
• DMF N,N- dimethylformamide
• DMSO dimethylsulfoxide
• the strong base is selected from alkali or earth alkali hydroxides (preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide), alkali or earth alkali alkoxides (preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide), or alkali or earth alkali amides (preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)).
• alkali or earth alkali hydroxides preferably selected from alkali metal hydroxides, more preferably sodium or potassium hydroxide
• alkali or earth alkali alkoxides preferably alkali metal alkoxides, more preferably sodium or potassium ie f-butoxide
• alkali or earth alkali amides preferably silylamides, more preferably sodium hexamethyldisilazane (NaHMDS)
• R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
• step (f) isolating the product of the step (e'), which is preferably a racemate, according to the above step (b') to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively. 18. The method according to item 17, wherein the steps (b') to (f) are successively repeated several times.
• the present invention provides a very simple, efficient and economic technology for racemisation of amine, alcohol or thioalcohol compounds having chirality in the ⁇ - position. It was surprisingly found that this simple technology based on the use of appropriate base in appropriate solvent, enables efficient racemisation of amines, alcohols or thioalcohols where the chiral carbon (benzylic position) is located at the ⁇ -position of the heteroatom (amino, hydroxyl or mercapto group) or even more distant therefrom.
• enantiomerically enriched mixture/product/compound or “enantiomerical enrichment” as used herein mean a mixture, a product, a compound or a process having or achieving an enantiomerical excess by 10 to 70 % e.e, preferably 30 to 70 % e.e, more preferably 50 to 70 % e.e.
• enantiomerically pure means a compound having an enantiomerical excess by at least 70 % e.e., preferably having at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
• racemization refers to the converting of an enantiomerically enriched or enantiopure compound into a mixture where the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is reduced at least by one-third, more preferably at least by half, and still more preferably by at least by two- third. Most preferably, the racemization results in a mixture where the enantiomers are present in equal quantity (racemic or a racemate).
• salt refers to any suitable salt form from the respective compound.
• the salt is pharmaceutically acceptable.
• the invention provides a method for racemisation of a compound according to the formula la or lb:
• R is represented by a linear, branched or cyclic Ci-Ci 2 -alkyl
• R' is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a d- Ci2-alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a C1-C4- alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-subsituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one or more double and/or triple bond;
• X is selected from O, S or N-R", wherein R" is selected from groups as defined for R' and is the same or different from R';
• one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are optionally substituted with halo, nitro, nitroso, cyano, hydroxy or a group selected from a C C 6 -alkoxy group, a unsubstituted or Ci-Ci 2 -alkyl mono- or di-substituted amino group, a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a Ci-C 6 - alkyloxy carbonyl group, a CrC 4 -alkanesulfonyl group, and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl- sub
• the racemisation treatment reduces the enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration at least by one-third, more preferably at least by half, and still more preferably by at least by two-third. It is most preferred that no enantiomeric excess of the enantiomerically enriched or enantiopure starting configuration is detectable after the racemisation treatment thus achieving a racemic mixture of 0% e.e.
• the racemization method thus preferably yields the compound according to the formula Ha or Mb, respectivel :
• the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the enantiomerically enriched or enantiopure starting configuration.
• the racemisation treatment is preferably carried out in a high boiling polar aprotic solvent, which is preferably selected from the group of amides, sulfoxides, and sulfones
• the preferred solvents are ⁇ , ⁇ -dimethylacetamide (DMA), N,N-dimethylformamide (DMF), sulfolane and dimethylsulfoxide (DMSO), the most preferred one is dimethylsulfoxide.
• the solvent preferably consists only of high boiling polar aprotic solvents, which are preferably used anhydrous.
• One high boiling polar aprotic solvent may be used alone or a mixture of high boiling polar aprotic solvents may be used.
• the racemisation treatment is preferably carried out at elevated temperature, preferably at 80 °C or more, more preferably at 90 °C or more, most preferably 100 °C or more.
• the upper limit of the reaction temperature is not especially limited provided that the reaction temperature is lower than the degradation/decomposition temperature of the educts in the reaction mixture.
• the racemisation treatment is suitably accomplished in the presence of metal hydroxides, metal alkoxides or metal amides which are selected from bases the corresponding acid having a pKb of at least 12 in DMSO.
• the base is selected from alkali or earth alkali hydroxides, alkali or earth alkali alkoxides or alkali or earth alkali amides. More preferably the base is selected from alkali metal hydroxides (preferably sodium or potassium hydroxide), alkali metal alkoxides (preferably sodium or potassium ie f-butoxide), or alkali metal silylamides (preferably sodium hexamethyldisilazane (NaHMDS)).
• alkali metal hydroxides preferably sodium or potassium hydroxide
• alkali metal alkoxides preferably sodium or potassium ie f-butoxide
• alkali metal silylamides preferably sodium hexamethyldisilazane (NaHMDS)
• the strong base is added in an amount enabling suitable racemisation turnover.
• the conversion can be performed by submolar, equimolar or excess amounts of the base, but in order to increase the turnover and/or speed up the reaction time, it is preferred to apply the strong base at least equimolar, preferably with a molar excess of 1.25 or more, with respect to the compound according to formula la or lb.
• the upper limit of the amount of strong base is not particular limited provides that the used amount avoids the decomposition or degradation of the compound to be racemised. However, in the individual case, it may even be desirable to apply such an amount of strong base that leads to racemisation and de-protection of a protecting group at the heteroatom O, N, or S (i.e. groups R', R", R b or R c ) in one concerted reaction.
• the reaction of conversion is preferably prolonged to a full racemisation, in the case of very slow conversion a skilled person can optionally stop the reaction, when a reasonably reduced enantiomeric access, such 50 % e.e. or below, preferably 20 % e.e. or below, is reached.
• a full racemisation is usually achieved within 48 hours, preferably it takes 12 to 36 hours.
• the benzene ring may be substituted as defined above. If one or more of the positions 2, 3, 4, 5, and 6 of the aromatic ring are substituted, at least one of the substituents is preferably selected from an electron withdrawing group selected from halo, nitro, nitroso, cyano, or a group selected from a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxycarbonyl group, a Ci-C 4 -alkanesulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups and optional substituents of the carbon atoms are defined as above.
• Such electron withdrawing groups may have beneficial impact on the racemisation turnover in the racemisation treatment of the present invention. It is most preferred that a chloro substituent is present in the meta-position (i.e. position 3 or 5) of the benzene ring of formula la or lb with no further substitution on the benzene ring being present.
• R is preferably represented by methyl, ethyl, isopropyl, more preferably methyl.
• R' is preferably represented by hydrogen.
• R' is hydrogen
• R" is selected from hydrogen or a group selected from a Ci-Ci 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a CrC 4 -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-substituted and/or aryl-substit
• R" may be suitably selected to be the same or different from R', while such amine compounds being substituted by R' and R" may be represented by alkylamides, alkylsulfonamides, tertiary amines, etc.
• I a H, F, CI, Br, I, OH, MeO, N0 2 ; preferably H or CI (preferably in meta-position);
• R" is selected from hydrogen or a group selected from a CrCi 2 -alkyl group, a Ci-Ci 2 -alkanoyl group, a benzoyl group, a CrC 6 -alkyloxy carbonyl group, a CrC 4 -alkylsulfonyl group and a benzenesulfonyl group, wherein the alkyl chain of these groups is linear, branched or cyclic, wherein one or more carbon atom of these groups is optionally substituted with halo, hydroxy, CrC 6 -alkoxy, unsubstituted or substituted amino, CrC 6 -alkyl-substituted and/or aryl-substituted silyl, unsubstituted or substituted phenyl or heteroaryl, and wherein the alkyl chain of these groups is optionally in the dehydro form by containing one
• n is 1.
• the compound according to the formula lb features a benzazepine skeleton having a 7-membered ring annealed to the benzene ring.
• A is represented by -CH 2 -CH 2 -, -CH 2 -CO- or -CO-CH 2 -, more preferably -CH 2 -CH 2 -.
• Scheme 4 Another typical but not limited set of the cyclic benzylic compounds according to the formula lb for successful racemisation according to the invention is shown in Scheme 4 with respect to the compound according to the formula lb". Experimental details are more precisely shown in the example section, while table 1 in Example 10 teaches optimal conditions and reagents for racemisation.
• the substituents R b or R c may beneficially influence on ease and duration of racemisation conversion.
• the influence is empirical, a skilled person may decide according to experimental results whether the substitution of the heteroatom X, preferably nitrogen, is done in order to make racemisation easier, the reaction time shorter or temperature lower.
• the substituent(s) R a may also influence on ease and duration of racemisation conversion. Electron withdrawing substituents, such as chloro have a beneficial effect on duration and completeness of the racemisation, because they enhance acidity of the proton on the carbon atom attached to the aromatic ring.
• the heteroatom can be substituted by protecting groups from previous steps of the synthesis.
• a skilled person can decide whether the racemisation is performed on the substituted derivative or by an approach wherein the intermediate is first deprotected and then racemised.
• the present invention provides novel compounds according to the formulae 2* to 7* as shown in Scheme 5, wherein the compounds shown in Scheme 5 are enantiomerically enriched or enantiopure in (S) or (R) configuration, preferably the (R) configuration. More preferably, such compounds have an enantiomeric excess of 98 % e.e. or more.
• Such novel compounds represent suitable intermediates for the synthesis of pharmaceutically active agents, especially lorcaserin, or a salt thereof, preferably the hydrochloride salt thereof.
• Such intermediates can be achieved by substitution of the heteroatom, which can be done by routine methods well known to a skilled person using reactive alkylation or acylation reagents in the presence of a base or by dehydration techniques using dehydration reagents such as carbodiimides.
• the invention provides a method for inverting the chirality of a compound according to the formula la or lb
• the starting compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
• the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
• step (b) Following the steps (a) and (b) in a repeating manner, it is possible to successively convert almost all starting compound to the desired compound having inverted chirality.
• step (b) there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
• the invention provides a method for increasing the yield of a desired enantiopure product according to the formula la or lb
• R, R', A, n and the positions 2, 3, 4, 5, and 6 are defined as above and wherein the winding line ⁇ indicates that the enantiomeric excess of the (R)- or (S)- configuration, respectively, is less than 50 % e.e., preferably less than 20 % e.e., more preferably less than 2 % e.e., most preferably 0 % e.e. (full racemisation) in favor of the configuration of the undesired enantiomer;
• step (f) isolating the product of the step (e'), which is preferably a racemate, according to the procedure of the above step (b') in order to achieve a second batch of the enantiomerically pure desired enantiomer according to the formula la or lb, respectively.
• the resulting desired compound has preferably an enantiomeric excess of at least 90 % e.e., more preferably at least 95 % e.e., most preferably at least 98 % e.e.
• the reagents, reaction conditions and the compounds according to formula la or lb including the substituents are the same as for the method of the above first embodiment, while the above described preferences apply also for the method according to this embodiment.
• the steps (b') to (f) are preferably successively repeated several times. Thereby, it is possible to batch-wise increase the yield of the compound having the desired chirality.
• step (b') there can be used for instance an optical resolution approach as described in WO 05/019179 applying tartaric acid protocol or chiral chromatography as described by B. M. Smith et al. (J. Med. Chem. 2008, 57, 305-315).
• the above methods of the present invention can be suitable used in the synthesis of lorcaserin according to the formula (R)-" , or a salt thereof, preferably the hydrochloride salt thereof.
• the present invention is illustrated more precisely based on the following examples and with the table which presents a study of the effect of the reaction conditions on racemisation process using novel technology.
• the optical purity of the starting compounds and final products is indicated by enantiomeric excess (% e.e.).
• the enantiomeric excess as mentioned herein means an excess of one enantiomer over the racemic mixture.
• Optical purity is determined using chiral HPLC analysis or by chiral GC-FID.
• the % e.e. is calculated from percentage ratio of enantiomers x:y, wherein y>x by the mathematical formula 100 - 2x.
• the testing compound of the formula (S)-9 is commercially available.
• the testing compound (S)-2-(3-chlorophenyl)propan-1 -amine ⁇ (S)-5) was prepared according to the literature (J. Med. Chem. 56, 4786 (2013)) followed by separation of enantiomers by column chromatography on chiral supporter to its (S)- and (R)- enantiomer.
• Example 7 Racemisation of optical active (S)-/V-2-(3-chlorophenyl)propyl)-2- phenylacetamide in the presence of potassium ie f-butoxide
• the compound of the formula ⁇ (S)- ) was prepared following the procedures of examples 8, 9, 10, and 12 in WO 05/019179.
• the obtained crude racemate of the compound according to the formula 1 was submitted to triple crystallisation through the salt with D-(-)-tartaric acid according to the Example 13 of the same publication to give the title compound in 16 % yield and optical purity of over 98 % e.e.
• Example 10 Efficient racemisation of optical pure (S)-8-chloro-1 -methyl-2, 3,4,5- tetrahydro-1 /-/-benzo/c//azepine
• Example 12 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone using sodium hydroxide
• Example 13 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 /-/- benzo[c/]azepin-3(2/-/)-yl)ethanone in the presence of potassium ie f-butoxide
• Example 15 Racemisation of optical pure allyl (S)-8-chloro-1 -methyl-4,5-dihyd benzo[c/]azepine-3-(2/-/)-carboxylate in the presence of potassium ie f-butoxide
• Example 17 Racemisation of optical pure (S)-1 -(8-chloro-1 -methyl-4,5-dihydro-1 H- benzo[d]azepine-3-(2H)-yl)-2-phenylethanone)-2-phenylethanone
• a skilled person may combine different approaches of recovery, for example he may racemise only the liquor from tartaric salt preparation, which is much more enriched in undesired isomer and may treat recrystallisation liquors, which are rich in the desired isomer by other approaches. By repeatable recovery the yield may exceed 50 % before one crop of liquors must be discarded due to accumulation of degradation products.

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