EP0915699A4 - Synthese stereoselective d'antagonistes de recepteurs d'endothelines - Google Patents

Synthese stereoselective d'antagonistes de recepteurs d'endothelines

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Publication number
EP0915699A4
EP0915699A4 EP96939654A EP96939654A EP0915699A4 EP 0915699 A4 EP0915699 A4 EP 0915699A4 EP 96939654 A EP96939654 A EP 96939654A EP 96939654 A EP96939654 A EP 96939654A EP 0915699 A4 EP0915699 A4 EP 0915699A4
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EP
European Patent Office
Prior art keywords
formula
compound
alkyl
alkoxy
derivatives
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EP96939654A
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German (de)
English (en)
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EP0915699A1 (fr
Inventor
Robert John Mills
Conrad John Kowalski
Li-Jen Ping
Kerry Joseph Gombatz
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0915699A1 publication Critical patent/EP0915699A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to the stereoselective synthesis of aryl and heteroaryl ring-fused cyclopentane derivatives useful as endothelin receptor antagonists and to the preparation of chiral intermediates in the process.
  • Endothelin is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET-1. ET-2 and ET-3 (unless otherwise stated, "endothelin” shall mean any or all of the isoforms of endothelin). Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
  • WO 94/25013 is multi-step, low yielding and relies upon a chromatographic resolution of a racemic intermediate in order to prepare the named compounds in optically pure form.
  • a technique that needs to be developed in the synthetic art is the use of chiral aryl Grignard reagents. Chiral aryl Grignard reagents have seen some use as intermediates for the preparation of diastereomerically and enantiomerically pure compounds. Such chiral aryl Grignard reagents have been prepared, for example, from chiral oxazolidines derived from aryl aldehydes. See, e.g.. Real, S. D. et ai, U.S. Patent 5,332,840 and Tet.
  • a preferred stereoselective synthesis of aryl and heteroaryl ring-fused cyclopentane derivatives will be able to place substituents at the three contiguous, non-ring fused carbons of the cyclopentane ring in a stereocontroUed manner.
  • a preferred synthetic method will proceed in high overall yield, with minimal need to isolate and purify intermediates. This is a sophisticated challenge which is not met by any currently recognized synthetic methods.
  • the present invention is directed to a process for preparing aryl and heteroaryl ring fused cyclopentane derivatives of the formula:
  • R3', R4' and R5' are independently hydrogen, Cj-Cfc alkyl, Cj-Cs alkoxy, or hydroxy;
  • Rl2' is (CH 2 )2 ⁇ H or (CH 2 )p C0 2 H; p is an integer 1-3;
  • A, B, G and D are each carbon atoms or one of A, B, G and D is a nitrogen atom, and the remainder are carbon atoms;
  • Z' is hydrogen, hydroxy, C J-C5 alkoxy or C1-C5 alkyl;
  • These compounds of Formulae 7A and 7B are useful as endothelin receptor antagonists.
  • Examples of compounds useful is endothelin receptor antagonists that fall within the purview of these formula include (+)-(lS, 2R, 3S)-3-(2-carboxymethoxy-4- methoxyphenyl)-l-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylic acid and (+)-(lS, 2R, 3S)-3-[2-(2-hydroxyeth-l-yloxy)-4-methoxyphenyl]-l-(3,4- methylenedioxyphenyl)-5-propoxyindane-2-carboxylic acid.
  • the mixture of diastereomeric carbinols may be subjected to a crystallization process to provide the predominant isomer in essentially pure form.
  • a diastereomerically pure compound of Formula (6A) is converted to a compound of Formula ( 13 A) via a compound of Formula ( 11 A) by hydrolysis and epimerization of the carboxylate ester at C2 followed by cleavage of the chiral aryl ether component and re- esterification of the carboxylate group at C2.
  • a compound of Formula (13A) is then alkylated to afford an enantiomerically pure compound of Formula (14A) which is saponified to afford enantiomerically pure endothelin receptor antagonists of Formula (7A).
  • a diastereomerically pure compound of Formula (6A) is converted to a compound of Formula (8A) by cleavage of the chiral aryl ether OR 2 group.
  • Compounds of Formula (8A) are then alkylated to afford enantiomerically pure compounds of Formula (9A) which is then saponified to afford enantiomerically pure endothelin receptor antagonists of Formula (7A).
  • R3, R4 and R5 are independently hydrogen, C ]-Cg alkyl, Cj-Cg alkoxy, halide or protected hydroxy;
  • R ] is halide, especially bromide, chloride, or iodide;
  • R 2 is selected from the group consisting of anomers, enantiomers, and diestereomers of (1) carbohydrates and derivatives thereof, (2) terpenes and derivatives thereof and (3) amino acids and derivatives thereof, L is a leaving group;
  • A, B, G and D are independently carbon atoms or one of A, B, G and D is a nitrogen atom and the remainder are a carbon atoms;
  • Z is hydrogen, protected hydroxy, C1 -C5 alkoxy or C1-C5 alkyl
  • R ] 1 is unsubstituted 3,4-methylenedioxyphenyl or substituted 3,4-methylene- dioxyphenyl wherein the substituent is on the phenyl ring and is C1 -C5 alkyl, CJ-C5 alkoxy or protected hydroxy; R 10 is C ⁇ -C 5 alkyl;
  • R 12 is (CH 2 ) 2 OH or (CH 2 )p C0 2 R ] 3 ;
  • R13 is CJ-C5 alkyl or hydrogen; and p is an integer from 1 to 3.
  • alkyl when used alone or in combination, refers to an alkyl group which may be straight chained or branched. Preferred alkyl groups contain 1-8 carbon atoms, and even more preferred alkyl groups contain 1-6 carbon atoms. It is even more preferred that the alkyl group contains 1- 3 carbon atoms, with methyl being the most preferred. Examples include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, amyl, hexyl and the like.
  • alkoxy when used alone or in combination, refers to o-alkyl. The preferred alkoxy group contains 1-3 carbon atoms.
  • halide refers to fluoride, bromide, chloride, or iodide, with bromide and chloride being the most preferred halides.
  • protected hydroxyl as used herein and throughout this specification means hydroxyl groups that have been reacted with appropriate protecting groups, where appropriate protecting groups for hydroxyl groups are well known in the art.
  • Protecting groups which can be utilized are described in Greene, "Protecting Groups in Organic Synthesis", 1991, John Wiley and Sons, Inc., the contents of which are incorporated herein by reference.
  • a suitable method of protection is the transformation of the hydroxyl groups to an aryl ether, e.g., methyl ether, methoxymethyl ether, benzyloxy methyl ether or cyclopropyl methyl ether.
  • the preferred R ⁇ groups are iodo, and especially bromo and chloro.
  • R3, R4 and R5 as well as R3', R4' and R5' groups are independently hydrogen, Cj-Cg alkyl, or Cj-Cg alkoxy. It is more preferred that R3, R4 and R5 and R3', R4' and R5' are independently hydrogen or C j -Cg alkoxy. It is even more preferred that R3 and R5 and R3' and R5' are hydrogen and R4 and R4' are alkoxy, as defined herein, especially methoxy. Furthermore, it is preferred that R4 and R4' are each para to Rj and Rj ' , respectively and it is most preferred that R4 is alkoxy and is para to R j and that R4' is alkoxy and para to R j '.
  • L are halide, especially chlorides, iodides and bromides, tosylates, and mesylates.
  • A, B, G and D are either all carbon atoms or one of them is a nitrogen atom. If one is a nitrogen atom, it is preferred that the nitrogen atom be present in the one-position, i.e., it is preferred that D be a nitrogen atom. However, it is more preferred that A, B, G and D are all carbon atoms.
  • the ring containing A, B, G and D may either be substituted or unsubstituted. It is preferred that the ring is substituted.
  • the preferred values of Z and Z' are lower alkyl or lower alkoxy, and especially preferred values of Z and Z' are lower alkoxy. Moreover, it is preferred that Z and Z' are substituted on B.
  • the preferred Rj j substituent is unsubstituted 3,4-methylenedioxyphen l.
  • the preferred value of p is 1 or 2.
  • Rj J ' each have similar definition. Except when R3, R4, R5, Rj j and Z are a protected hydroxy, the definitions of R3, R4, R5, Rj j and Z are the same as R3', R4', R5', R j j ' and
  • R]2 and R12' also have similar definitions. Both R12 and R12' are (CH2)2 OH. However, Rj2 may also be (CH2)p COOH. In other words, Rj2 may also be an ester substituent, which, as described hereinbelow, is hydrolyzed to form the corresponding acid, i.e., R12 '•
  • R3-R5, and R3'- R5', Z and Z', R j i and R j j ' and R 12 and R ⁇ 2 - For example, if R3, R4, R5 or Z is a protected hydroxy, then the corresponding value of R3', R4', R5' and Z j ', respectively is hydroxy; on the other hand, if R3, R4 or R5, or Z is other than protected hydroxy, then each of R3, R4, R5 and Z have the same value as the corresponding R3', R4', R5' and Z ] ' .
  • R j j contains a protected hydroxy substituent
  • R ] ⁇ ' contains a hydroxy substituent
  • R ⁇ j and Rj j ' are the same.
  • R j 2 is (CH2)2 ⁇ H
  • R ⁇ ' is (CH2)2 ⁇ H
  • R J2 is (CH2)pC ⁇ 2Rj3
  • R]2' has the corresponding value (CH2)pCOOH.
  • the compounds 7A and 7B are synthesized in accordance with the present invention, as described hereinbelow.
  • the ortho-halo phenolic compounds of Formula I hereinbelow are useful precursors in the inventive methodology of the present invention.
  • Rj is chloride, bromide or iodide, and is bonded to a benzene ring.
  • a hydroxy group is located in an ortho position to R j .
  • the compounds of Formula ( 1 ) may be denoted as ortho-halo phenolic compounds.
  • the initially formed reactive organometallic intermediate may be subjected to one or more transmetallation reactions.
  • the so-formed reactive organometallic intermediate may be treated with a second metal-containing reagent, such as a magnesium compound, e.g., magnesium bromide, to effect transmetallation and thus form an organomagnesium intermediate from the initially formed organolithium intermediate.
  • a reactive organometallic intermediate is the result of halogen metal exchange, optionally followed by one or more transmetallation reactions or a result of direct treatment of compound of Formula (3) with a metal.
  • a suitable concentration of compounds of Formulae (5 A) and (5B) in the solvent is about 0.01 molar to about 0.3 molar, preferably about 0.1 molar to about 0.2 molar, and more preferably about 0.1 molar to about 0.15 molar which corresponds to about 100 g of compounds of Formulae (5A) and (5B) in one (1) liter of solvent.
  • Palladium on carbon catalysts are well known in the art, and may be obtained from many commercial supply houses, e.g., Aldrich Chemical Company
  • the hydrogenation catalyst preferably has a pH of greater than about 6, more preferably has a pH between about 6.5 and about 8, and still more preferably has a pH of about 6.8 to about 7.5. It is thus preferred that the Pd/C hydrogenation catalyst be neutral or slightly basic. Precious Metal Corp. will provide their Type # 1910 15% palladium on carbon as essentially a neutral catalyst, 50% water wet, and this catalyst is preferred for the hydrogenation reaction of the invention. Commercially available acidic catalysts may be used if washed sufficiently with water at about neutral pH to thereby provide a neutral catalyst.
  • the (6A):(6B) molar percent ratio of the compounds of Formulas (6A) and (6B) in the product will also be about (100-90): (0-10) (compound of Formula (6A) in excess when the starting composition had the compound of Formula (5A) in excess) or about (0-10):( 100-90) (compound of Formula (6B) in excess when the starting composition had the compound of Formula (5B) in excess).
  • the chemistry in Scheme 2 thus illustrates the process wherein a composition comprising compounds (5A) and (5B) in a (5A):(5B) molar percent ratio of from 100:0 to 0: 100 is selected and then contacted with hydrogen gas in the presence of a basic or neutral hydrogenation catalyst to achieve a hydrogenation reaction.
  • the hydrogenation catalyst is about 10 wt.% to about 15 wt.% palladium on carbon having a pH of about 6.8 to about 7.5, and the hydrogenation reaction is conducted in the presence of ethyl acetate as a solvent.
  • the molar percent ratio of compounds (5A):(5B) in the starting material is substantially the same as the molar percent ratio of compounds (6A):(6B) formed as products.
  • Suitable solvents for the crystallization include, without limitation, ethanol, optionally containing about 1% to about 5% of a second solvent such as toluene, methanol or ethyl acetate, and absolute ethanol, optionally containing up to about 10% of a second solvent such as toluene, methanol or ethyl acetate. Absolute ethanol with up to about 10% ethyl acetate is a preferred crystallization solvent, while absolute ethanol without any co- solvent is more preferred.
  • the crystallization process dissolves compounds (6A) and (6B) in a solvent at an elevated dissolution temperature, and then holds the mixture at a crystallization temperature lower than the dissolution temperature while crystals form.
  • the precise dissolution and crystallization temperatures can vary over wide ranges, and will depend on the solubility and concentration of the compounds (6A) and (6B) in the crystallization solvent.
  • a suitable crystallization temperature is less than about 40°C, is preferably about 20°C to about 40°C, and is more preferably about 30°C to about 40°C.
  • a single one of the diastereomerically-related compounds (6A) and (6B) may be obtained as crystals having very high diastereomeric excess, e.g., a diastereomeric excess greater than about 75%, preferably greater than about 90%, more preferably greater than about 95% and still more preferably greater than about 98% diastereomeric excess.
  • the invention further provides for a compound of Formula (6A) to be converted to a compound of Formula (7 A) according to the chemistry outlined in Scheme 3, Routes (A) and (B). While the chemistry outlined in Scheme 3 is illustrated starting with a compound of Formula (6A) for convenience, it should be understood that the same chemistry can be used to convert a compound of Formula (6B) to a compound of Formula (7B), and to convert a composition comprising compounds of Formulae (6A) and (6B), having a (6A):(6B) molar percent ratio of 100:0 to 0:100, to a composition comprising compounds of Formula (7A) and (7B), having a (7A):(7B) molar percent ratio of 100:0 to 0: 100. As explained previously, compounds of Formulas (7 A) and (7B) are useful as endothelin receptor antagonists.
  • a compound of Formula (6A) is treated with Br ⁇ nsted acid. This affects cleavage of the aryl ether -OR2 group in a compound of Formula (6A) and forms a phenolic -OH group in a compound of Formula (8A).
  • the preferred acid is hydrochloric acid, which is dissolved in water at a concentration of about 5 wt.% to about 37 wt.%.
  • concentrated (con.) hydrochloric acid i.e., 37 wt.% aqueous HCI, is the acid for the cleavage reaction.
  • the compounds of Formulae (6A) and (6B) are preferably slurried in a solvent prior to treatment with acid.
  • Aliphatic alcohols or polyols, and aliphatic ethers and polyethers are suitable solvents.
  • a preferred solvent is a C J-C4 alcohol, where methanol is a particularly preferred solvent.
  • An elevated temperature is preferably employed in Step ( 1 ) in order to obtain a commercially desirable rate for the reaction.
  • a temperature of about 50°C to about the reflux temperature is employed, while a more preferred temperature is at the reflux temperature of the reaction mixture. The reaction will be slower at lower temperatures.
  • Step (2) wherein a phenolic compound of Formula (8A) is alkylated to form a compound of Formula (9A).
  • R2 is particularly suited to allowing the formation of a composition comprising diastereomerically-related compounds (5A) and (5B) from compounds (3) and (4) where the composition is highly enriched in one of the two diastereomers due to the influence of R2, while R12 is particularly suited to enhancing the efficacy of a compound of Formula (7 A) as an endothelin receptor antagonist.
  • Exemplary leaving groups include chloride, bromide and iodide.
  • Many hydroxyl derivatives e.g., derivatives prepared by the conversion of a hydroxyl group into an ester of a relatively strong acid, are leaving groups according to the invention.
  • Exemplary hydroxyl group derived leaving groups include, without limitation, p ⁇ r ⁇ -toluenesulfonyl ester (tosylate group), methanesulfonyl ester (mesylate group) and alkyl esters, such as acetate ester, and the like.
  • the alkylation reaction is preferably conducted in the presence of base.
  • bases include, without limitation, sodium hydride, potassium hydride, potassium carbonate and the like.
  • the potassium carbonate may be in, e.g., powder or granular form.
  • Other bases could also be employed, where suitable bases are known to one of ordinary skill in the art.
  • the alkylating agent is ethylene carbonate
  • the base is preferably potassium carbonate, and is more preferably anhydrous powdered potassium carbonate.
  • About 2 to about 20 equivalents of base are suitably used per equivalent of compound of Formula (8A).
  • Preferably, about 2 to about 8 equivalents are employed, while more preferably about 4 to about 6 equivalents of base are employed.
  • the reaction mixture in the alkylation reaction of Step (2) is conducted at temperatures effective to produce the desired product.
  • the reaction mixture in the alkylation reaction of step (2) is taken to elevated temperature, such as about 50°C to about the reflux temperature of the reaction mixture, in order to achieve a satisfactory reaction rate.
  • the reaction temperature is about 100°C to about 120°C, and when toluene is the reaction solvent, the preferred temperature is about 110°C to about 1 15°C, which is the reflux temperature of the reaction mixture.
  • ethylene carbonate is the alkylating agent, it is preferred that a high temperature of about 100°C to about 120°C is preferably employed in order to obtain a reasonable rate for the alkylation reaction.
  • lactonization between the phenolic hydroxyl group and the carboxylate ester at position 2 of the indane ring may be a significant problem due to the particular stereochemistry of the compounds of Formulae (8A) and (8B).
  • extended reaction times at elevated temperatures may convert any lactone intermediate that does form into the desired alkylated product.
  • the chemistry used to convert a compound of Formula (8A) to a compound of Formula (9 A) according to Step 2 may be generally used to prepare a composition comprising compounds (9A) and (9B), having a (9A):(9B) molar percent ratio of from 100:0 to 0: 100, from a composition comprising compounds (8A) and (8B), having an (8A):(8B) molar percent ratio of from 100:0 to 0:100, where the compounds (9 A) and (9B) have the Formulae (9 A) and (9B), respectively.
  • compositions comprising compounds (9A) and (9B) having the Formulae (9A) and (9B) respectively, in a (9A):(9B) molar percent ratio of 100:0 to 0: 100, wherein R3, R4, R5, A, B, G, D, Z, RJQ, Ri 1 and Rj2 are as defined hereinabove.
  • a preferred composition of the compounds (9A) and (9B) are methyl (IS, 2S, 3S)- 1 -(3,4-methylenedioxyphenyl)-3-[2-(2-hydroxyeth- 1 -y loxy)-4-methoxyphenyl]-5- propoxyindane-2-carboxylate and methyl-(lR, 2R, 3R)-l-(3,4-methylenedioxyphenyl)-3- [2-(2-hydroxyeth- 1 -yloxy)-4-methoxyphenyl)-5-propoxyindane-2-carboxylate, respectively, and the molar percent ratio of (9A):9(B) is about (100-95): (0-5).
  • Such a composition may be prepared by selecting a composition comprising compounds (8A) and (8B), wherein the compounds (8A) and (8B) are methyl-(lS, 2S, 3S)-l-(3,4- methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate and methyl-(lR, 2R, 3R)-l-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)- 5-propoxyindane-2-carboxylate, respectively, and the molar percent ratio of (8A):(8B) is about (100-95):(0-5), and then treating the composition comprising compounds (8A) and (8B) with ethylene carbonate in the presence of potassium carbonate in toluene at a temperature of about 100°C to about 120°C.
  • the compound of Formula (9 A) is treated with base such as hydroxides, alkoxides, and the like, in the presence of water in a suitable solvent mixture such a methanol and tetrahydrofuran to achieve saponification and epimerization of the carboxylate group at position 2 of the compound, to thereby form a compound of Formula (7A) as shown in Route (A), Step (3) of Scheme 3.
  • Base such as hydroxides, alkoxides, and the like
  • a suitable solvent mixture such as a methanol and tetrahydrofuran
  • a composition comprising compounds (6A) and (6A), having a (6A):(6B) molar percent ratio of from 100:0 to 0:100 may be converted to a composition comprising compounds (7 A) and (7B), having a (7A):(7B) molar percent ratio of from 100:0 to 0:100.
  • R3 * , R 4 ', R 5 ⁇ A, B, D, G, Z ⁇ R ⁇ j/ and R ⁇ ' are as defined hereinabove.
  • the starting material compositions are significantly enriched in one of the diastereomerically-related compounds of Formulas (6A&B), (8A&B) or (9A&B).
  • the term "significantly enriched" means that the starting material compositions are not racemic, i.e., they do not contain equal molar amounts of the compounds (6A) and (6B), or equal molar amounts of the compounds (8A) and (8B), or equal molar amounts of the compounds (9A) and (9B).
  • the molar percent ratio of any two of the above-listed diastereomerically-related compounds is about (100-75):(0-25), more preferably is about (100-90): (0-10), still more preferably is about (100-95):(0-5), and yet still more preferably is about (100-98) :(0-2), where either of the diastereomerically-related compounds (6A)/(6B), (8A)/(8B) or (9A)/(9B) may be in excess of the other.
  • the conversion of a compound of Formula (6A) to a compound of Formula (7 A) may proceed through Route (B) as identified in Scheme 3, where the intermediates formed in the conversion according to Route (B) are more completely shown in Scheme 4.
  • a compound of Formula (6A) may be converted to a compound of Formula (10A) by epimerization of the carboxylate ester at position 2.
  • the epimerization reaction is preferably accomplished by treating a compound of Formula (6A) with base in the presence of solvent at an elevated temperature.
  • Suitable bases for the reaction of Step (4A) include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, as well as alkali metal alkoxides, such as sodium ethoxide and sodium methoxide. Alkali metal hydroxides are preferred, with lithium hydroxide being a particularly preferred base for the epimerization reaction.
  • a suitable reaction temperature is about 20°C to about the reflux temperature of the reaction mixture, preferably about 50°C to the reflux temperature of the reaction mixture, and more preferably about the reflux temperature of the reaction mixture.
  • the chemistry used to convert a compound of Formula (6A) to a compound of Formula (10A) according to Step (4A) may be generally used to prepare a composition comprising compounds (10A) and (10B), having a (10A):(10B) molar percent ratio of from 100:0 to 0:100, from a composition comprising compounds (6A) and (6B), having a (6A):(6B) molar percent ratio of from 100:0 to 0: 100, wherein the compounds (10A) and (10B) have the Formulae (10A) and (10B), respectively.
  • R3, R , R 5 , R 2 , A, B, D, G, Z, Ri 1 and R JQ are as defined hereinabove.
  • the basic conditions that cause the epimerization reaction for converting a compound of Formula (6A) to a compound of Formula (10A) according to Step (4 A) may subsequently cause hydrolysis of the ester compound of Formula (10A) to form the carboxylate compound of Formula (11 A) according to Step (4B).
  • some water must be present in the reaction mixture.
  • the basic conditions used in Step (4A) may cause not only the epimerization of the carboxylate ester at position 2, but also the hydrolysis of the carboxylate ester at position 2 to form a carboxylic acid as shown in Formula (11A). If water is not present in the solvent used to convert a compound of Formula (6A) to a compound of Formula (10A), then water should be added to a compound of Formula (10A) in order achieve its hydrolysis and the subsequent formation of a compound of Formula (HA).
  • the chemistry used to convert a compound of Formula (10A) to a compound of Formula ( 1 1A) according to Step (4B) may be generally used to prepare a composition comprising compounds (1 1A) and (1 IB), having an (11A):(1 IB) molar percent ratio of from 100:0 to 0: 100, from a composition comprising compounds (10A) and (10B), having a (10A):(10B) molar percent ratio of from 100:0 to 0: 100, wherein the compounds (11A) and (1 IB) have the Formulae (11A) and (1 IB), respectively.
  • a composition comprising compounds (6A) and (6B) and having a (6A):(6B) molar percent ratio of from 100:0 to 0:100 may be converted to a composition comprising compounds ( 1 1A) and (1 IB), having an ( 11 A):(l IB) molar percent ratio of from 100:0 to 0: 100, without need to isolate or purify the intermediate compounds (10A) or (10B).
  • the invention also provides for the conversion of a compound of Formula (1 1 A) to a compound of Formulas (12A), and the subsequent conversion of a compound of Formula (12A) to a compound of Formula (13A). It is not necessary to isolate the compound of Formula (12A). Indeed, a compound of Formula (11A) is preferably reacted under conditions that immediately convert a compound of Formula (12A) to a compound of Formula (13A) so that a compound of Formula (12A) is not isolated. Furthermore, it is preferred to carry out the conversion of a compound of Formula (6A) to a compound of Formula ( 13 A) in a single reaction kettle, without isolation of any of the intermediate compounds (10A), (11A) or (12A). While either of compounds of Formula (11A) or (12A) could be isolated and purified, these isolation steps are not preferred because they increase the expense of preparing the endothelin receptor antagonists of interest.
  • organic hydrophobic solvents include aliphatic and aromatic hydrocarbons and chlorohydrocarbons, and the like.
  • the preferred organic hydrophobic solvent preferably has a boiling point of less than about 150°C.
  • Xylenes, toluene and chlorobenzene are preferred solvents for the extraction step, with toluene being particularly preferred.
  • Alcohol is a preferred solvent for Step (5B), and alcohol is also a suitable solvent for Step (5A).
  • the invention provides for the organic hydrophobic solvent to be replaced with an alcohol solvent.
  • Suitable alcohol solvents have the Formula HO-R13, wherein R13 is C ⁇ alkyl.
  • Suitable solvents include methanol, ethanol, n-propanol and isopropanol.
  • the alcohol solvent is preferably a primary alcohol, and is more preferably methanol or ethanol.
  • Step (5A) In order to replace toluene, or whatever organic hydrophobic solvent has been used for the extraction of Step (5A), with an alcohol solvent, the solution of the compound of Formula ( 11 A) in an organic hydrophobic solvent is concentrated using distillation, and the compound of Formula (11A) redissolved in alcohol.
  • a preferred alcohol solvent is methanol, i.e., R13 is methyl.
  • the suitable and preferred temperatures at which the compound of Formula (11A) is converted to a compound of Formula ( 12 A) are the same as the suitable and preferred temperature set forth in connection with Scheme 3, Route (A), Step (1).
  • the ratio of acid to the aryl ether compound of Formula ( 11 A) is about 30 mL to about 100 mL acid per 0.1 to about 0.5 mol of aryl ether, and more preferably is about 40 mL to about 60 mL acid per 0.1 to about 0.15 mol aryl ether.
  • the reaction mixture from Step (5 A) is taken to a sufficient temperature to effect the conversion.
  • the temperature ranges from about 20°C to about 80°C, more preferably about 40°C to about 80°C, and most preferably about 50°C to about 70°C. It is typically the case that Step (5B) should be conducted at a higher temperature than is necessary for Step (5A), in order to achieve a commercially desirable rate for the conversion of a compound of Formula (11A) to a compound of Formula (13A).
  • Step (5A), used to convert a compound of Formula (1 1 A) to a compound of Formula (12A), can also generally be used to prepare a composition comprising compounds (12A) and (12B), having a (12A):(12B) molar percent ratio of from 100:0 to 0: 100, from a composition comprising compounds (11A) and (1 IB), having an ( 1 1A):(1 IB) molar percent ratio of from 100:0 to 0:100, wherein the compounds (12A) and (12B) have the Formulae (12A) and (12B), respectively.
  • R3, R4, R5, A, B, G, D, Z and R j ⁇ are as defined hereinabove.
  • the composition of compounds having Formulae (12A) or (12B) is converted to a composition of compounds having the Formulae (13A) or (13B), respectively.
  • the compounds of Formulae (11A) and (1 IB) can be converted directly to compounds of Formulas (13A) and (13B), without the isolation or purification of any (12A) or (12B) compounds.
  • the compounds (13A) and (13B) have the Formulae (13A) and (13B), respectively.
  • R3, R4, R5, A, B, G, D, Z, Rj j, and R 13 are as defined hereinabove.
  • Steps 4A, 4B, 5A and 5B are preferred to conduct Steps 4A, 4B, 5A and 5B (as outlined in Scheme 4), in a single reaction flask, without having isolated or purified any of the compounds of Formulae (10A), (11A) or (12A) by distillation, chromatography or the like.
  • This can be accomplished by treating a compound of Formula (6A) with base and water in a suitable solvent to provide a compound of Formula ( 11 A), then neutralizing the base with acid and treating the compound of Formula (11 A) with acid in the presence of an alcohol solvent.
  • the starting material compositions are significantly enriched in one of the diastereomerically-related compounds of Formulae (6A&B), (10A&B), (11A&B), (12A&B), (13A&B) or (14A&B).
  • the term "significantly enriched” has the same meaning as set forth above in connection with the compounds formed and used in Route (A).
  • the invention provides for compounds of Formulae (10A&B), ( 11A&B), ( 12A&B), ( 13 A&B) and (14A&B), where compounds of Formulae (14A&B) may be converted to endothelin receptor antagonists of Formulae (7 A&B).
  • compositions comprising diastereomerically-related compounds (15A) and (15B), having the Formulas (15A) and (15B) respectively, which encompass the compounds of Formulae (10A&B), (11A&B), (12A&B), (13A&B) and (14A&B).
  • compositions having one of the compounds (15A) or (15B) in essentially isomerically pure form are most preferred, where isomerically pure form means that at least about 98%, and preferably at least about 99% of the composition is a single one of (15A) or (15B).
  • R2, R3, R4, R5, A, B, D, G, Z, R ⁇ j are as defined hereinabove,
  • Rj2 is -(CH2)2 ⁇ H or -(CH2)pC ⁇ 2Rj3 where p is an integer from 1 to 3;
  • Rl3 is hydrogen or Ci ⁇ alkyl
  • R]4 is H, R2, or Rj2;
  • R 15 is H, R 10 or R 13 ; provided that when R15 is H, R 14 is H or R2.
  • Particularly preferred compounds of Formula (15A) are the following: methyl-OS, 2R, 3S)-l-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-0-isopropylidene- ⁇ - D-mannofuranosyloxy)-4-methoxyphenyl]-5-(prop-l-yloxy)indane-2-carboxylate; (IS, 2R, 3S)-l-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-0-isopropylidene- ⁇ -D- mannofuranosyloxy)-4-methoxyphenyl]-5-(prop-l-yloxy)indane -2-carboxylic acid; (IS, 2R, 3S)- l-(3,4-methylenedioxyphenyl)- 3-(4-methoxy-2-hydroxyphenyl)-5-(prop-l- yloxy)indane-2-car
  • 25 is reacted with acid followed by alkylation with L-(CH2)pC ⁇ 2Ri3 such as methyl bromoacetate, (wherein L is
  • compound 21 is synthesized, as another embodiment by reacting 25 with acid then by alkylating with ethylene carbonate in the presence of base, e.g., potassium carbonate and then reacting the product thereof with aqueous base, in accordance with the procedure described herein.
  • base e.g., potassium carbonate
  • the process of the present invention forms compounds of Formulae 7A and 7B as well as the precursors thereof as substantially pure compounds.
  • they are substantially enantiomerically pure and diasteromerically pure.
  • substantially it is meant that the purify is at least 75% and more preferably at least 90%, and even more preferably at least 95% pure, and most preferably 98% pure in the categories emphasized.
  • the reaction was quenched with 420 mL of water, then 5.0 L of toluene and 10.1 L of a 2.5 N aqueous sodium hydroxide solution was added and the reaction was stirred for 5 minutes. The aqueous layer was separated and the organic layer was washed twice with 2.5 L portions of 2.5 N aqueous sodium hydroxide solution. The organic solution was concentrated in vacuo to 50 % of it's original volume and 500 g of
  • the reaction was cooled to 25-27°C and quenched with 250 mL of water, then 1.75 mL of toluene and 1.50 L of a 2.5 N aqueous sodium hydroxide solution were added and the reaction was stirred for 5 minutes.
  • the aqueous layer was separated and the organic layer was washed twice with 1.50 L portions of 2.5 N aqueous sodium hydroxide solution.
  • the organic solution was then washed with 1.50 L of saturated sodium chloride solution and 1.5 L of water.
  • the organic layer was concentrated to approximately 2.0 L under vacuum and filtered. Isopropanol (1 L) was added and the solution was concentrated to a volume of approximately 1.0 L.
  • the reaction was quenched with 2 mL of water, then 25 mL of toluene and 50 mL of a 2.5 N aqueous sodium hydroxide solution were added and the reaction was stirred for 5 minutes.
  • the aqueous layer was separated and the organic layer was washed with 2 x 25 mL portions of 2.5 N aqueous sodium hydroxide solution.
  • the organic solution was concentrated in vacuo to 50 % of it's original volume and 5 g of FlorisilTM was added.
  • the solution was stirred 10 minutes then filtered through a pad of 10 g of Aluminum oxide and 5 g of FlorisilTM. The filter pad was washed with 100 mL o f 10% ethyl acetate in toluene.
  • MgBr2 # Et2 ⁇ 180 g, 697.1 mmol was added at -78 to -75°C.
  • MgBr2*Et2 ⁇ the resulting suspension was warmed to 22-25°C over 80 minutes so that the reaction mixture was a clear solution. This solution was stirred for another 2 hours before it was cooled back to -78°C.
  • the reaction was quenched with 100 mL of 20 % aqueous solution of NH4CI at about -72°C and warmed to 22-25°C.
  • the resulting mixture was concentrated from 3.5 L to 3.0 L by distillation. After concentration, 1 L of water was added and the mixture was stirred for 5 minutes. The aqueous layer was separated and back extracted with 300 mL of toluene.
  • a 5 gallon Hastelloy-C reactor and all necessary equipment was inspected for cleanliness and dryness.
  • the vessel was pressure tested to 100 psi to determine the leak rate. When an acceptable leak rate was established, the reactor was flushed with nitrogen and residual oxygen levels determined. When acceptable levels of oxygen were detected, the vessel was charged with 12 L of ethyl acetate, 1.26 kg (97.9%, 1.68 mol) of (R)-methyl-3-(3,4- methylenedioxyphenyl)-l-hydroxy-l-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy- 4-methoxyphenyl]-6-propoxy-lH-indene-2-carboxylate and 500 g of 15 % Pd/C 1910 (approximately 50 % water wet) purchased from Precious Metals Corporation.
  • the vessel was sealed, then pressurised to approximately 100 psi with nitrogen, then vented to the atmosphere. This procedure was repeated an additional 2 times.
  • the reactor leak rate was monitored for approximately 5 minutes. When a satisfactory leak rate was established, the nitrogen was vented to the atmosphere and the vessel pressurised to 100 psi with hydrogen. The hydrogen was released to the atmosphere and the cycle repeated an additional 2 times.
  • the vessel was re-pressurised with hydrogen to approximately 100 psi and the agitator started. The agitator was set at 700-750 rpm. The progress of the reaction was monitored by in-process HPLC analysis and by the recorded hydrogen uptake.
  • a 100 mL miniclave was charged with 15 mL of ethyl acetate, 15 mL of ethanol (200 proof), 130 mg of (S)-methyl-3-(3,4-methylenedioxyphenyl)-l-hydroxy-l-[2-(2,3:5,6- isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-lH-indene-2- carboxylate and 64 mg of 10 % Pd on Carbon (on a dry basis).
  • the vessel was sealed, then pressurised to approximately 400 psi with nitrogen, then vented to the atmosphere. This procedure was repeated an additional 2 times. After the third cycle, the reactor leak rate was monitored for approximately 5 minutes.
  • the nitrogen was vented to the atmosphere and the vessel pressurised to 100 psi with hydrogen.
  • the hydrogen was released to the atmosphere and the cycle repeated an additional 2 times.
  • the vessel was re-pressurized with hydrogen to approximately 400 psi, the internal contents warmed to 55 °C and the agitator started. The reaction was deemed complete after 24 hours.
  • the hydrogen was vented to the atmosphere and the vessel purged 3 times with nitrogen. After each purge, the nitrogen was vented to the atmosphere. The contents of the vessel were drained into a clean container and the reactor rinsed with 20 mL of ethyl acetate.
  • the reaction mixture was heated to reflux and monitored by HPLC. The reaction was complete in 2.5 hours.
  • the reaction was cooled to 20-25°C and 1.57 L of toluene and a solution of 100 g of citric acid in 1.5 L of water was added. The layers were separated and the aqueous layer was extracted with 1.57 L of toluene.
  • the combined toluene layers were washed with 2 portions of 5% aqueous sodium bicarbonate ( 1.2 L) and concentrated under reduced pressure to approximately 250 mL.
  • the solution was concentrated under reduced pressure to approximately 400 mL. Toluene (750 mL) and water (100 mL) were added, followed by 5% sodium bicarbonate solution (260 mL). The layers were separated and the organic layer was washed twice with 5% sodium bicarbonate solution (2 x 260 mL). The organic layer was concentrated to about 200 mL under reduced pressure, toluene (300 mL) was added, then the solution was filtered through Celite.
  • a 5 L 3 necked round-bottom flask equipped with an air driven stirrer, reflux condenser and a nitrogen inlet/outlet was charges with 375.0 g (96.1 % wt/wt, 501.4 mmol) methyl- (lS,2S,3S)-l-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-0-isopropylidene-a-D- mannofuranosyloxy-4-methoxyphenyI]-5-propoxyindane-2-carboxylate, 3750 mL of methanol and 37.5 mL of concentrated aqueous HCI.
  • the resulting slurry was heated to 60- 65 C C under an atmosphere of nitrogen over a period of approximately 60 minutes.
  • an additional 37.5 mL of concentrated aqueous HCI was added to the mixture and the solution maintained within the temperature range of 60-65°C.
  • the progress of the reaction was monitored by HPLC.
  • the reaction was deemed to be complete when no starting material was detected.
  • the resulting clear solution was allowed to cool towards ambient temperature over a period of approximately 3 hours.
  • 2.0 g of seed crystals of the title compound were added.
  • the resulting slurry was stirred at ambient temperature for approximately 18 hours, then cooled to 0-5 °C for an additional 4 hours.
  • An analytical sample could be obtained by recrystallization from 2-propanol. Mpt. 125-127 °C.
  • the resulting solution in 2-propanol was allowed to stir at ambient temperature for approximately 15 minutes to obtain a homogeneous mixture then diluted with an additional 1000 mL of 2-propanol.
  • the resulting solution was heated to approximately 60°C over a period of 15-20 minutes under a gentle purge of nitrogen. Heating was discontinued and ethylene diamine (11.6 g, 99.5 +%, 192.5 mmol) was added.
  • the reaction mixture was cooled to 30-35°C over a period of 4 hours. As the solution cooled to 57°C, precipitation of the title compound occurred.
  • the resulting slurry was stirred at ambient temperature for approximately 12 hours then cooled to 0°C an additional 3 hours before isolation of the title compound via filtration.
  • the concentrate was diluted with methanol (300 mL) and tetrahydrofuran (500 mL) then a solution of lithium hydroxide monohydrate (28 g, 654 mmol) dissolved in 300 mL of deionized water was added.
  • the resulting solution was heated to reflux (internal temperature 62-65 °C) over approximately 15 minutes and maintained at reflux while monitoring the reaction progress by HPLC.
  • the reaction was considered complete when no intermediates were detected by in-process HPLC analysis. After approximately 12 hours at reflux the reaction was considered complete and the resulting mixture cooled to ambient temperature. DI water (500 mL) was added and the reaction mixture concentrated under reduced pressure to a volume of approximately 1 L.

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Abstract

La présente invention concerne un procédé de préparation par synthèse d'antagonistes de récepteurs endothéliaux, lesquels antagonistes sont représentés par les formules générales (7A) et (7B). L'invention concerne également les intermédiaires chiraux correspondants.
EP96939654A 1995-11-08 1996-11-08 Synthese stereoselective d'antagonistes de recepteurs d'endothelines Withdrawn EP0915699A4 (fr)

Applications Claiming Priority (4)

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US634895P 1995-11-08 1995-11-08
US6348P 1995-11-08
CA002236924A CA2236924A1 (fr) 1995-11-08 1996-11-08 Synthese stereoselective d'antagonistes de recepteurs d'endothelines
PCT/US1996/018084 WO1997017071A1 (fr) 1995-11-08 1996-11-08 Synthese stereoselective d'antagonistes de recepteurs d'endothelines

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EP0915699A4 true EP0915699A4 (fr) 2008-06-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
WO1994025013A1 (fr) * 1993-04-27 1994-11-10 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389620A (en) * 1993-08-18 1995-02-14 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives
CN1049219C (zh) * 1993-08-18 2000-02-09 万有制药株式会社 具有内皮素拮抗活性的芳香杂环并环戊烯衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
WO1994025013A1 (fr) * 1993-04-27 1994-11-10 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ELLIOTT J D ET AL: "1,3-DIARYLINDAN-2-CARBOXYLIC ACIDS, POTENT AND SELECTIVE NON- PEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 11, 1994, pages 1553 - 1557, XP000652243, ISSN: 0022-2623 *
I.C.M.DEA: "Aryl glycosides of oligosaccharides Part II. Bromo-, chloro-, and iodo-phenyl beta-D-glycosides of some disaccharidestables I and II", CARBOHYDR. RES., vol. 12, 1970, pages 297 - 299, XP002452559 *
K. TAKEO ET AL.: "Synthesis of methyl alfa- and beta-maltotriosides and aryl beta-maltotriosides", CARBOHYD. RES., vol. 48, 1976, pages 197 - 208, XP002452560 *
See also references of WO9717071A1 *

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