Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to a process for obtaining a statin as well as to certain compounds used as intermediates in said process.
• the present invention relates to a process for obtaining atorvastatin calcium as well as 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo N-phenylpentanamide, 1 - [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5-oxohexyl] -5- (4 -fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide, 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3) dioxolan-4-yl) -3,5-dihydroxyhexyl) -5- (4-fluorophenyl) -2-
• the present invention relates to the method for obtaining a statin, preferably atorvastatin calcium.
• the present invention further relates to statins obtained from the method for obtaining a statin, preferably atorvastatin calcium.
• Atorvastatin calcium is a statin indicated as an adjunct to the diet to treat patients with elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides, to increase HDL-cholesterol levels in patients with primary hypercholesterolaemia and combined hyperlipidaemia. serum triglycerides and for patients with dysbetalipoproteinemia who do not respond adequately to the diet. Atorvastatin is also indicated for the reduction of total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolaemia.
• Atorvastatin is a selective and competitive inhibiting hypolipidemic agent of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the limiting enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols, including cholesterol.
• HMG-CoA 3-hydroxy-3-methylglutarylcoenzyme A
• the drug lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, increasing the number of hepatic LDL receptors on the cell surface, increasing LDL absorption and catabolism.
• the atorvastatin molecule generally has two main synthetic routes.
• the first route developed is completely linear and consists of 12 steps, starting from methyl 4-methyl-3-oxopentanoate, with an overall yield of 4.2%.
• the (R, R) - ⁇ - ⁇ -dihydroxy ester syn (10) is subjected to a basic hydrolysis reaction followed by acidification to provide the respective ⁇ - ⁇ -dihydroxy acid syn (11), which is immediately heated to refluxing toluene with azeotropic removal of water to yield the respective -hydroxy-6-lactone (atorvastatin lactone) (12) in 82% isolated yield after recrystallization (Scheme 7).
• the chiral auxiliary (A *) (Scheme 3) ((S) -2-hydroxy-1,2,2-triphenylethyl acetate) is a high cost reagent, greatly increasing the cost of the process;
• the transesterification step (Scheme 4) employing sodium methoxide (CH3 0Na) as a basis, which is expensive, corrosive and hygroscopic reagent.
• methoxide of sodium being a strong base, can generate unwanted byproducts;
• the cross-Claisen condensation reaction step employs n-butyllithium (n-BuLi) for the generation of LDA (lithium diisopropyl amide).
• n-BuLi n-butyllithium
• LDA lithium diisopropyl amide
• Olefin (16) is treated with ozone, followed by oxidation with chromium trioxide to provide carboxylic acid (17), which is treated with tert-butanol in the presence of 4-DMAP (4-dimethylaminopyridine) and DCC (dicyclo- dicyclohexylcarbodiimide) and subjected to catalytic hydrogenation (H 2 at 50 psi and oxide platinum (Pt02) as a catalyst) to obtain amino ester (18) (Scheme 9).
• 4-DMAP 4-dimethylaminopyridine
• DCC dicyclohexylcarbodiimide
• the nitrile reduction step (17) employs a catalytic hydrogenation reaction with high pressure hydrogen gas (50 psi) and platinum oxide (PtC> 2) as catalyst.
• high pressure hydrogen gas 50 psi
• platinum oxide PtC> 2
• the use of hydrogen gas is problematic due to the fact that it is a highly flammable gas and furthermore the catalyst (PtC> 2) has a high cost;
• n-butyllithium n-BuLi
• n-BuLi n-butyllithium
• O3 ozone gas
• the process employs potassium cyanide (KCN) and chromium trioxide (CrC> 3), which are highly toxic reagents and therefore difficult to use on an industrial scale, taking into account environmental aspects.
• KCN potassium cyanide
• CrC> 3 chromium trioxide
• NaCN sodium cyanide
• Aryl sulfonates (ArS0 2 Cl) employed in this process are costly;
• DMSO dimethyl sulfoxide
• the last step is a catalytic hydrogenation reaction employing high pressure (50 psi) molecular hydrogen and Raney nickel as catalyst which is very pyrophoric and hazardous;
• the cyano ester (25) is subjected to a sequence of two reactions without purification. Initially, a cross-Claisen condensation reaction is carried out, where cyano ester (25) reacts with lithium enolate derived from tert-butyl acetate in THF, providing the respective (R) -6-cyano-5-hydroxy -3-oxohexanoate (26), which is not isolated (Scheme 13).
• the ⁇ -keto ester (26) is selectively reduced with sodium boron hydride (NaBH 4 ) in the presence of diethyl methoxy borane (B (OMe) Et 2 ), providing the respective 1,3-syn diol (27) with high diastereoselectivity (Scheme 13).
• NaBH 4 sodium boron hydride
• B (OMe) Et 2 diethyl methoxy borane
• tert-butyl (3R, 5R) -6-cyano-3,5-dihydroxyhexanoate (27) is treated with 2,2-dimethoxypropane in acetone in the presence of a catalytic amount of methanesulfonic acid to provide the respective cyano acetonide ester (23) in 53% yield (Scheme 14).
• Product (23) is a highly crystalline white solid which is purified by recrystallization.
• cyano ester (20) is hydrogenated in the presence of Raney nickel, providing the respective amino ester (18) as a colorless viscous oil in 85% yield.
• NaCN sodium cyanide
• n-butyllithium (n-BuLi) is employed, which is expensive and highly flammable, representing a major operational risk in an industrial plant.
• t-BuOAc t-butyl acetate
• the last process step (Scheme 14) consists of a catalytic hydrogenation reaction employing high pressure (50 psi) hydrogen gas and Raney nickel as catalyst. Hydrogen gas is potentially flammable and Raney nickel is very pyrophoric and this process requires special equipment to be performed on an industrial scale.
• ⁇ -keto amide (29) is selectively reduced with sodium boron hydride in the presence of diethyl methoxy borane (B (OMe) Et 2 ), providing the corresponding 1,3-syn diol (30). with high diastereoselectivity (Scheme 16).
• 1,3-syn diol (30) is treated with 2,2-dimethoxypropane in acetone in the presence of catalytic amount of methanesulfonic acid to provide the respective cyano acetonide (23) (Scheme 17).
• cyano acetonide (23) is hydrogenated in the presence of Raney nickel, providing the respective amino acetonide (24) (Scheme 17).
• n-BuLi is used to obtain lithium diisopropylamide (LDA), which is expensive and highly pyrophoric, representing a major operational risk in an industrial plant;
• cyano ester (27) is treated with morpholine in MTBE (methyl tert-butyl ether) to provide the respective cyano amide (28), which is immediately subjected to catalytic hydrogenation reaction (50 psi hydrogen). in the presence of platinum catalyst (Pt / C) in acidic medium, providing the respective amine hydrochloride (29) (Scheme 20).
• hydrochloride (29) is deprotonated with sodium methoxide (MeONa) and reacted with phenylacetic acid to provide the respective ammonium carboxylate (30) (Scheme 21).
• pyrrol starch (31) is reacted with the ethyl acetoacetate sodium lithium dienolate (32) at low temperature to provide the respective 1,3-diketone (33) (Scheme 23).
• 1,3-Diketone (33) is subjected to selective reduction under hydrogen gas pressure in the presence of a chiral ruthenium catalyst (RuCl 2 (DMF) (R) (+) -Cl-MeO-BIPHEP) in acidic medium.
• 1,3-Diol (34) is obtained in this case as the 1: 1 diastereoisomeric mixture of syn / anti isomers (Scheme 24).
• 1,3-diol ester (34) is subjected to basic hydrolysis (KOH), followed by acidification with HCl, lactonization and disposal employing drastic reaction conditions (toluene reflux, 110 ° C, acetic anhydride, 60 ° C) to provide the respective ⁇ , ⁇ -unsaturated lactone (35) (Scheme 25).
• KOH basic hydrolysis
• HCl HCl
• lactonization and disposal employing drastic reaction conditions (toluene reflux, 110 ° C, acetic anhydride, 60 ° C) to provide the respective ⁇ , ⁇ -unsaturated lactone (35) (Scheme 25).
• the O, ⁇ -unsaturated lactone (35) is treated with benzyl alcohol in the presence of base (NaOH), followed by neutralization and catalytic hydrogenation (3 ⁇ 4 at 50 psi using carbon-supported palladium hydroxide) to provide atorvastatin lactone (12) after 8 reaction steps (Scheme 26).
• the 8 step linear reaction sequence employs long reaction times.
• the compounds are produced without any diastereoselectivity, that is, compound (34) is obtained as a 1: 1 mixture of syn / anti isomers. From a synthetic and economic point of view, these factors represent a major disadvantage;
• the process employs strong corrosive base (MeONa), n-BuLi and sodium hydride (NaH), which are expensive and highly flammable, posing a major operational risk in an industrial plant; and
• Ratio (R) :( S) 95: 5
• ⁇ -hydroxy acid is resolved by employing (R) - (+) -methyl benzyl amine to provide the respective ⁇ -hydroxy acid (36) with> 99% enantiomeric excess (Scheme 28).
• 1-diketone (39) is subjected to the Pall-Knorr reaction with chiral amino ester (18) under pivalic acid catalysis using a ternary solvent mixture.
• the benzyl ester (40) is subjected to the catalytic hydrogenation reaction (3 ⁇ 4 at 40 psi and carbon-supported palladium metal catalyst - Pd / C) to yield the respective carboxylic acid (41).
• Compound (41) is immediately treated with oxalyl - (COCl) 2 chloride and aniline in benzene as solvent, yielding amide (42) after purification on silica column chromatography (Scheme 32).
• Acetonide ester (42) is subjected to acid hydrolysis (HCl) followed by basic hydrolysis, neutralization and extraction with ethyl acetate to provide the respective carboxylic acid (43), which is purified on a silica chromatographic column.
• Carboxylic acid (43) is finally treated with sodium hydroxide solution followed by treatment with calcium acetate to produce calcium atorvastatin (14) (Scheme 33).
• the chiral amino ester (18) employed in the process has a high cost and its obtaining requires a 6 step linear reaction sequence.
• WO 2004/014896 describes the production of atorvastatin lactone (12) employing chiral ruthenium complexes in reduction reactions, as shown in Schemes 34-35.
• the ester (46) is subjected to basic hydrolysis, followed by neutralization and refluxing lactonization of toluene with azeotropic removal of water.
• Atorvastatin lactone (12) is obtained in enantiomeric excess of only 85% (Scheme 35).
• the ruthenium catalyst (45) has an excessively high cost, making the process economically unfavorable;
• the lactonization reaction employs toluene as a solvent, which is a solvent of high toxicity.
• WO 2005/012246 describes obtaining atorvastatin lactone (12) employing a convergent route as shown in Schemes 36-40.
• chlorine lactol (47) is protected as methyl acetal (48), which is subjected to reaction with benzyl bromide to protect secondary alcohol (49) (Scheme 36).
• Chlorine acetal (49) is treated with potassium cyanide.
• 1,4-diketone (52) is subjected to the Pall-Knorr reaction with amine (51) under acid catalysis, providing the respective pyrrole (53) (Scheme 38).
• Methyl acetal (55) is subjected to the reaction of acid hydrolysis to obtain atorvastatine lactol (56), which is further oxidized with Dess-Martin periodinane reagent (DMP) in dichloromethane as a solvent, to then produce atorvastatine lactone (12) (Scheme 40).
• DMP Dess-Martin periodinane reagent
• the synthetic route is long and involves the use of intermediates containing protecting groups employing high cost starting materials.
• the reaction sequence is long and some reactions require long time (e.g. 4 days) to complete (Scheme 37);
• atorvastatin lactone (12) from lactol employs an oxidation reaction with Dessartan periodinane reagent (DMP), which is extremely expensive for large-scale use.
• DMP Dessartan periodinane reagent
• the inventors use dichloromethane (CH 2 Cl 2) as a solvent, which is toxic and highly harmful to the environment; and
• atorvastatin acetonide (42) is treated with HCl (IN) in methanol as a solvent at room temperature, providing the respective diol ester, which is kept in solution.
• Subsequent treatment of the diol ester with 10% aqueous NaOH solution provides the respective sodium carboxylate which is treated with HCl to obtain the acid diol (43).
• Atorvastatin lactone (12) is obtained by treating acid diol (43) with refluxing toluene and azeotropic removal of water (Scheme 44).
• the lactonization step employs drastic reaction conditions and high temperatures (toluene reflux: 110 ° C).
• EP 1,834,944 describes the obtaining of some intermediates for the synthesis of calcium atorvastatin, as well as the production of atorvastatin lactone (12) and atorvastatin lactol.
• the ester (57) undergoes a basic hydrolysis reaction, providing the respective carboxylic acid (58).
• carboxylic acid (58) is homologated on two carbons to produce the respective ⁇ -ketoester (59), as shown in Scheme 45.
• ⁇ -Ketoester (59) is stereoselectively reduced by employing catalytic hydrogenation in the presence of chiral ruthenium catalyst (RuCl 2 (R) -BINAP), thus providing the respective ⁇ -hydroxy ester (60).
• the reaction of Claisen cross-condensation of the ⁇ -hydroxy ester (60) with the tert-butyl acetate-derived lithium enolate provided the respective 6-hydroxy-keto ester (61) (Scheme 46).
• the 6-hydroxy keto ester (61) is selectively reduced with sodium borohydride and diethyl methoxyborane at low temperature, followed by protection of the intermediate diol with 2,2-dimethoxypropane (2,2-DMP) under acid catalysis to yield the respective acetonide syn (62) (Scheme 47).
• the acetonide ester (62) is reduced with lithium aluminum hydride (LiAlH) to obtain its primary alcohol, which is then treated with tosyl chloride (Ts-Cl) in the presence of triethylamine to provide the respective compound.
• tosylate (63) is then treated with tosylate (63) in step Next, tosylate (63) is reacted with sodium azide (NaN 3 ) in dimethylsulfoxide to provide alkyl azide (64) (Scheme 48).
• alkyl azide (64) is reduced under catalytic hydrogenation to yield the respective primary amine (65) (Scheme 49).
• 1,4-diketone (4) is treated with amine (65) in the presence of pivalic acid as catalyst in a tertiary refluxing solvent system for 40 h.
• the respective pyrrolic compound (66) was obtained in only 42% of isolated yield after purification on silica column chromatography (Scheme 50).
• Methyl acetal (68) is treated with sodium hydride and benzyl bromide to protect secondary hydroxyl as benzyl ether (69) (Scheme 52).
• methyl acetal (69) is treated with acetic acid to yield the respective lactol (50) (Scheme 52).
• n-BuLi n-butyl lithium
• LDA lithium diisopropyl amide
• BuLi has a high cost and is highly pyrophoric, which represents a major operational risk in a pilot plant where it is employed in large volumes;
• LiAlH 4 lithium aluminum hydride
• This reagent is particularly hazardous when in its pure state as it is highly pyrophoric and may ignite spontaneously in the air. This poses a great risk of accident during handling.
• LiAlH4 tends to generate large amounts of aluminum salt and hydroxide, which make it difficult to filter and remove product from the reaction medium;
• pyrrolic acetonide (66) (Scheme 50) has a long reaction time and results in very low yield (only 42%). This means that larger quantities of starting materials must be used to obtain the desired mass of product.
• pyrrolic acetonide (66) is purified on silica column chromatography, a unit operation practically impossible to be applied on an industrial scale; and
• the synthesis route employed in this process is relatively long (18 steps), which demands more uptime and a greater number of unit operations, employing protection and deprotection steps. These factors tend to weigh negatively on choosing the ideal synthetic route.
• statins preferably atorvastatin calcium
• pyrophoric reagents such as n-butyllithium
• a process for obtaining atorvastatin calcium is provided.
• the compound 1- [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5-oxo -hexyl] -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide is provided as one of the intermediates in said process for obtaining calcium atorvastatin.
• 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3,5-dihydroxyhexyl compound ) -5- (4-fluorophenyl) -2-isopropyl-N,-diphenyl-1H-pyrrol-3-carboxamide is provided as one of the intermediates in said process for obtaining atorvastatin calcium.
• 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1 - ((3R, 7S) -3,5,7,8-tetrahydroxyoctyl) 1H-pyrrol-3-carboxamide is provided as one of the intermediates in said process for obtaining calcium atorvastatin.
• the use of the compound 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3 is provided. , 5-dihydroxyhexyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide.
• a seventh aspect of the present invention the use of the compound 5- (4-fluorophenyl) -2-isopropyl-N,-diphenyl-1 - ((3R, 7S) -3,5,7,8- tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide.
• a method for obtaining a statin is provided.
• intermediate compounds are provided in said method for obtaining a statin.
• a statin obtained by method of the ninth aspect of said invention.
• the attached Figure 2 shows the 13 C-NMR spectrum of 4-methyl-3-oxo-Î2-phenylpentanamide (2) in DMSO D6 at 63 MHz.
• Figure 3 attached has the NMR spectrum of 1 H (Z) -2-benzylidene-4-methyl-3-oxo-A7-phenylpentanamide (3) in acetone D6 at 250 MHz.
• Figure 5 attached shows the NMR spectrum of 1 H 2- [2- (4-fluorophenyl) -2-oxo-l-phenylethyl] -4-methyl-3-oxo-N- phenylpentanamide (4) in DMSO D6 at 250 MHz.
• Figure 7 shows the annexed H NMR spectrum of 1 [5- (4-fluorofenila) -1- (3-hydroxypropyl] -2-isopropyl-N, 4-diphenyl-l.J ⁇ -pyrrol-3-carboxamide (5) in 250 MHz CDCl 3 .
• the attached figure 8 shows the 13 C NMR spectrum of [5- (4-fluorofenila) -1- (3-hydroxypropyl] -2-isopropyl-iV, 4-diphenyl-LFI-pyrrole-3-carboxamide (5) in CDCl 3 to 63 MHz.
• FIG. 11 shows the 1 H NMR spectrum of 1- [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5 -oxohexyl] -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (13) at 250 MHz C0 Oe.
• FIG. 12 shows the 13 C-NMR spectrum of 1 - [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5 -oxohexyl] -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (13) in 63 MHz CDCl 3 .
• Figure 13 shows the annexed NMR spectrum of 1 H 1- ((3R, 5R) -6- ((S) -2, 2-dimethyl-l, 3-dioxolan-4-yl) -3, 5 - dihydroxyhexyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14) at C 6 D 6 at 250 MHz.
• FIG. 14 shows the 13 C-NMR spectrum of 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3,5) -dihydroxyhexyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14) at C 6 D 6 at 63 MHz.
• Figure 15 shows the annexed H NMR spectrum of 1 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-l- ((3R, 5R, 7S) - 3, 5, 7, 8 tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide (15) in 250 MHz MeOD.
• the attached Figure 16 shows the 13 C spectrum of the 5-
• Figure 17 shows the annexed NMR spectrum of 1 H 1- (2- ((2R, R) -4, 6-diidroxitetraidro-2H-pyran-2-yl) ethyl) - 5- (4-fluorophenyl) -2-Isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (26) in CDCl 3 at 250 MHz.
• FIG. 18 shows the 13 C NMR spectrum of 1- (2- ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-Isopropyl-N, -diphenyl-1H-pyrrol-3-carboxamide (26) in CDCl 3 at 63 MHz.
• FIG. 20 shows the 13 C-NMR spectrum of 5- (4-fluorophenyl) -1- (2- ((2R, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl) ethyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (31) in 63 MHz CDCl 3 .
• Figure 21 shows the annexed NMR spectrum of 1 H atorvastatin calcium (41) in DMSO-D6 at 250 MHz.
• the attached Figure 23 shows the diffractogram of amorphous calcium atorvastatin (41).
• the present invention is a process for obtaining atorvastatin calcium and its intermediates.
• the first part describes the steps for obtaining 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo-N-phenylpentanamide (4), the first key intermediate. for the synthesis of calcium atorvastatin (41).
• the steps for obtaining 5- (4-fluorophenyl) -2-isopropyl-1- (3-oxopropyl) -N, 4-diphenyl-1H-pyrrol-3-carboxamide (6) are described.
• the first part of the atorvastatin obtaining process of the present invention comprises obtaining 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo-N- phenylpentanamide (4).
• Said first part comprises three steps according to the following scheme.
• Step 1 is the reaction of methyl 4-methyl-3-oxo-pentanoate (1) with excess aniline (0.8 to 2.0 equivalents, preferably 1.2 equivalents) in the presence of NaOH as catalyst at a concentration which It varies from 0.5 to 20 mol%, preferably 2 mol%, in the absence of solvent and with concomitant removal of methanol, having as product 4-methyl-3-oxo-N-phenylpentanamide (2) (Scheme I).
• This product is purified only by extraction with aqueous HCl (1%) and can be used directly in step 2 without prior purification.
• the reaction of said step 1 is conducted for a period of 12 to 24 hours, preferably for 16 hours, at a temperature ranging from 90 ° C to 160 ° C, preferably 135 ° C.
• step 1 provides a yield in the range of 85% to 95%, preferably about 92%, which is higher than the yield described in the prior art (63%).
• the reaction described in step 1 of the present invention provides for the use of a lower amount of aniline, in addition to using NaOH as a catalyst rather than ethylenediamine, which is more expensive and much more toxic. Additionally, the reaction of the present invention occurs in the absence of solvent.
• Step 2 is the condensation reaction of 4-methyl-3-oxo-N-phenylpentanamide (2) with benzoic aldehyde (0.9 to 2.0 equivalents, preferably 1.05 equivalents) under reflux in hexane and azeotropic removal of water in the presence of p-aminophenol and acetic acid as catalysts in a concentration ranging from 5 mol% to 40 mol%, preferably 20 mol%, having as product 2-benzylidene-4-methyl-3-oxo-N- phenylpentanamide (3) (Scheme II).
• Said product (3) is purified by simple washing with hexane at 60 ° C, followed by cooling, washing with water, filtration and drying under high vacuum.
• Product (3) is a white solid with a melting point of 145 to 150 ° C.
• the reaction of said step 2 is conducted for a period of 18 to 36 hours, preferably for 24 hours.
• reaction of this step provides a yield in the range of 83% to 96%. preferably about 93%, which is higher than the yield described in the prior art (77%).
• reaction described in step 2 of the present invention provides for the use of p-aminophenol, which is a cheaper catalyst compared to that commonly employed in the reactions described in the prior art ( ⁇ -alanine).
• Step 3 consists of a Stetter reaction between 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (3) and 4-fluorobenzaldehyde (0.9 to 2.0 equivalents, preferably 1.05 equivalents). ), in the absence of solvent and in the presence of catalytic amount of 3-ethyl-5- (2-hydroxyethyl) -4-methyl-3-thiazolium bromide in a concentration ranging from 10 mol% to 30 mol%, preferably 20 mol%, and triethylamine (0.3 to 3.0 equivalents, preferably 1.0 equivalents) as a base, having 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4- methyl-3-oxo-N-phenylpentanamide (4) (Scheme III) in a yield ranging from 60% to 90%, preferably 73%, after recrystallization from isopropanol, ethanol or n-butanol,
• step 3 provides a higher yield than the yield described in the prior art (69%). Furthermore, the reaction described in step 3 of the present invention is performed without solvent as it does not use ethanol which is commonly employed in the reactions described in the prior art.
• the three steps of the first part of the process of obtaining atorvastatin calcium (41) of the present invention provide an overall yield in the range of 50% to 65%, preferably about 62.4%, which is higher than that. described in the prior art (33.4%). Additionally, it is important to mention that the reactions involved in this first part reduce the use of solvent and important reagents, as well as using cheaper reagents.
• the second part of the process for obtaining atorvastatin of the present invention comprises obtaining 5- (4-fluorophenyl) -2-isopropyl-1- (3-oxopropyl) -N, 4-diphenyl-1H-pyrrol-3-carboxamide (6). Said second part comprises two steps as described below.
• Step 4 consists of treating 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo-N-phenylpentanamide (4) with 1.0 to 3.0 equivalents preferably 1.7 equivalent of 3-amino-1-propanol under catalysis of pivalic acid (5 mol% to 40 mol%, preferably 20 mol%) in a 1: 1 mixture of refluxing toluene / THF with azeotropic removal of water over a period of 24 to 56 hours, preferably 48 hours, having as product [5- (4-fluorophenyl) -1- (3-hydroxypropyl] -2-isopropyl-N, 4-diphenyl-1H -pyrrol-3-carboxamide (5) (Scheme IV).
• reaction of said step 4 provides a yield in the range of 50% to 80%, preferably about 75%, which is higher than the yield described in the prior art (35%). Furthermore, the reaction described in step 4 of the present invention does not use heptane as a solvent, which represents an operational advantage.
• Step 5 consists of a selective oxidation reaction of [5- (4-fluorophenyl) -1- (3-hydroxypropyl] -2-isopropyl-
• reaction occurs in two sub-steps.
• compound (5) dissolved in dichloromethane is reacted with oxalyl chloride and dimethyl sulfoxide at a temperature ranging from -78 ° C to -40 ° C, preferably -50 ° C, over a period of 0.5 to 3 hours, preferably 1 hour.
• triethylamine is slowly added to the reaction mixture obtained in the first sub-step to provide compound (6).
• step 5 provides a yield in the range of 60% to 90% and is performed as described in the prior art (Indian patent document 2005-KO485), where a yield of about 84% is expected.
• the third part of the atorvastatin process of the present invention comprises obtaining (S) -1- (2,2-dimethyl-1,3-dioxolan-4-yl) propan-2-one (11). ) from L - (S) - malic acid (7).
• Said acid is a chiral organic substrate of natural origin and commercially available at relatively low cost.
• Said third part comprises three steps as described below.
• Step 6 consists of the transformation of the acid (L) - (7) in its corresponding methyl ester ((S) - dimethyl malate (8)) by an esterification reaction with methanol in the presence of catalytic amount of refluxing sulfuric acid over a period of 12 to 36 hours, preferably 24 hours (Scheme VI).
• the product (S) - dimethyl malate (8) does not require purification and can be employed directly in step 7 of the process of the present invention in its raw form, which reduces a unitary operation in said process.
• reaction of step 6 provides a yield in the range of 80% to 95%, preferably 91%, which is higher than the yield described in the prior art (90%).
• Step 7 consists of converting dimethyl (S) -malate (8) into (S) -methyl 2- (2,2-dimethyl-1,3-dioxolan-4-yl) (10) by a reaction regioselective reduction employing BH 3 .Se 2 (0.8 equivalent to 2.0 equivalent, preferably 1.05 equivalent) and NaBH 4 (1 mol% to 20 mol%, preferably 5 mol%) in the presence of THF, having as starting material the diol ester (9), which is not purified.
• Said diol ester (9) is employed directly in the ketalization reaction with 2,2-dimethoxypropane in acetone in the presence of catalytic amount of p-TsOH (Scheme VII).
• Said ketalization reaction is conducted at a temperature of 0 ° C to 50 ° C, preferably 25 ° C, for a period of 2 to 10 hours, preferably 4 hours.
• (S) -methyl 2- (2,2-dimethyl-1,3-dioxolan-4-yl) (10) can be easily purified by distillation under reduced pressure, although it can also be employed in the next step without prior purification.
• step 7 provides a yield in the range of 60% to 80%, preferably 75%, which is higher than the yield described in the prior art (74%).
• Step 8 is the reaction of (S) -methyl 2- (2,2-dimethyl-1,3-dioxolan-4-yl) (10) with MeMgCl (3.0 to 6.0 equivalents, preferably 4.0 equivalent) in the presence of methyl methoxy amine hydrochloride (Me (OMe) H.HCl) in THF, having as product (S) -1- (2,2-dimethyl-1,3-dioxolan-4-yl) propan-2-one (11) via Weinreb's amide (Scheme VIII).
• MeMgCl 3.0 to 6.0 equivalents, preferably 4.0 equivalent
• the reaction of said step 8 is conducted at a temperature in the range of -50 ° C to 35 ° C, preferably in the range of -10 ° C to 25 ° C, for a period of 4 to 16 hours, preferably 8 hours.
• Said (S) -1- (2,2-dimethyl-1,3-dioxolan-4-yl) propan-2-one (11) can be easily purified by distillation, although it can also be employed in the next step without purification. Preview.
• step 8 provides a yield in the range of 80% to 95%, preferably 92%, which is higher than the yield described in the prior art (90%). It is important to mention that the three steps of the third part of the process of obtaining atorvastatin calcium (41) of the present invention provide an overall yield of 55% to 65% and are performed as described in the prior art (Doroh, B.; Sulikowski, GA Org. Lett. 2006, 8, 903), where an overall yield of about 62.8% is predicted.
• the fourth part of the atorvastatin obtaining process of the present invention comprises the steps for joining fragments (6) and (11) and the final synthesis of calcium atorvastatin (41).
• Step 9 Obtaining 1- [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5-oxohexyl] -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (13)
• Step 9 initially consists of treating (S) -1- (2,2-dimethyl-1,3-dioxolan-4-yl) propan-2-one (11) with chloro dicyclohexyl borane (c-Hex 2) BCl) in Et 20 followed by triethylamine at a temperature of from -50 ° C to 25 ° C, preferably 0 ° C, for generation of kinetic boron enolate over a period of 10 minutes to 3 hours, preferably 1 hour.
• c-Hex 2 chloro dicyclohexyl borane
• the reaction of said step 9 provides a yield of 50% to 85%, preferably about 79%, with a stereo selectivity (ratio R, S / S, R) of about 92:08 in the generation of the first one. stereogenic center of the molecule. Both the yield and stereoselectivity obtained are higher than those described in the prior art (63% yield and 86:14 stereoselectivity).
• the reaction described in step 9 of the present invention does not employ the (S) -2-hydroxy-1,2,2-triphenylethyl chiral acetate auxiliary, which is expensive and does not use n-BuLi ( flammable) or diisopropylamine (high cost). These three compounds are widely used in the aldolic reactions described in the prior art.
• step 9 of the present invention already provides for the addition of all carbons of the atorvastatin structure and, after obtaining compound (13), only 5 further reaction steps provide atorvastatin calcium (41), whereas in the state of technique 7 more steps are required to obtain atorvastatin calcium.
• step 9 employs lower cost reagents, easy handling and low toxicity, and therefore more suited to the large scale synthesis employed in industrial processes.
• Step 10 Obtaining 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3,5-dihydroxyhexyl) -5- (4 - fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14)
• Step 10 is the diastereoselective reduction reaction of 1- [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5-oxohexyl ] -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (13) according to the conditions described in Narasaka, K .; Pai, FC Tetrahedron 1984, 40, 2233 and Chen, KM; Hardtmann, GE; Prasad, K .; Repic, Shapiro, MJ Tetrahedron Lett.
• Step 11 consists in the acid hydrolysis reaction (1N HCl and H 2 0 / MeOH or H 2 0 / THF) of 1- ((3R, 5R) -6- ((S) -2, 2-dimethyl- 1, 3-dioxolan-4-yl) -3,5-dihydroxyhexyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14), having as product 5 - (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl 1- ((3R, 7S) -3,5,7,8-tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide (15) (Scheme XI).
• the reaction of said step 11 is conducted over a temperature range of from -10 ° C to 50 ° C, preferably 25 ° C, over a period of 2 to 8 hours, preferably 4 hours.
• Said 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1 - ((3R, 7S) -3,5,7,8-tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide (15) may be employed in the next reaction step without prior purification since it is obtained in high purity even in its raw state.
• reaction of said step 11 provides a yield in the range of 80% to 97%, preferably 94%.
• Step 12 Obtaining 1- (2- ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4 -diphenyl-1H-pyrrol-3-carboxamide (26)
• Step 12 consists of the cleavage reaction of 5- (4- fluorophenyl) -2-isopropyl-N, 4-diphenyl-1- ((3R, 7S) -3, 5,7,8-tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide (15) with sodium periodate (NaIO, j) under very mild conditions
• step 12 ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide ( 26) (Scheme XII).
• the reaction of said step 12 is conducted over a temperature range of from -20 ° C to 15 ° C, preferably 0 ° C, over a period of 30 minutes to 3 hours, preferably 1 hour.
• reaction of said step 12 provides a yield in the range of 75% to 95%, preferably 88%.
• 1- (2- ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl -1H-pyrrol-3-carboxamide (26) was obtained after 9 steps with an overall yield in the range of 15% to 25%, preferably 22.3%.
• Step 13 is the selective oxidation reaction of 1- (2- ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-isopropyl -N, 4-diphenyl-1H-pyrrol-3-carboxamide (26) in the presence of excess manganese dioxide (activated MnO 2 (10 to 20 equivalents, preferably 15 equivalents) and dichloromethane, providing 5- (4) -fluorophenyl) -1- (2- ((2R, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl) ethyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3 carboxamide (31) (Scheme XIII)
• the reaction of said step 13 is conducted over a temperature range of 0 ° C to 40 ° C, preferably 25 ° C, for a
• reaction of said step 13 provides a yield in the range of 78% to 98%, preferably 95%.
• Step 14 is treating 5- (4-fluorophenyl) -1- (2- ((2R, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl) ethyl) -2-isopropyl N, 4-diphenyl-1H-pyrrol-3-carboxamide (31) with 10% sodium hydroxide in the presence of MeOH over a temperature range of 45 ° C to 65 ° C, preferably 55 ° C, over a period of 40 ° C. minutes to 3 hours, preferably 1 hour, followed by treatment of the resulting salt with calcium acetate over a temperature range of 40 ° C to 60 ° C, preferably 50 ° C, over a period of 40 minutes to 3 hours, preferably 1 hour. hour, supplying as an end product calcium atorvastatin (41).
• step 14 provides a yield in the range of 85% to 95%, preferably 92%.
• atorvastatin calcium (41) was obtained after 12 steps with an overall yield in the range of 15% to 22%, preferably 19.5%.
• the present invention deals with the compounds 1- [(R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3-hydroxy-5-oxohexyl] 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (13), 1- ((3R, 5R) -6- ((S) -2,2) -dimethyl-1,3-dioxolan-4-yl) -3,5-dihydroxyhexyl) -5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14) and 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1- ((3R, 7S) -3,5,7,8-tetrahydroxyoctyl) -1H-pyrrol-3-carboxamide
• the present invention addresses the use of said intermediates in steps 10, 11 and 12 of the process for obtaining calcium atorvastatin of the present invention.
• the present invention addresses the atorvastatin calcium obtained by the process for obtaining atorvastatin calcium of the present invention.
• the present invention further relates to a method for obtaining a statin (e.g. simvastatin, lovastatin, pravastatin, rosuvastatin or pitavastatin). and its intermediaries.
• a statin e.g. simvastatin, lovastatin, pravastatin, rosuvastatin or pitavastatin.
• step 1 compound II is treated with a dialkyl haloborane, followed by cooling of the reaction and slowly adding compound I:
• R may have a very large number of possibilities, such as:
• R Ar, HetAr, alkyl
• R 1 and R 2 H or C n H2n + i (with n ranging from 1 to 10)
• R 1 and R 2 H, aromatic ring (CeH 5 - represented generally by Ar) or heteroaromatic (hetAr) with different substituents on the aromatic or heteroaromatic ring.
• reaction compound III is diastereoselectively reduced by employing a dialkyl alkoxyborane and boron tetrahydride to provide compound IV:
• R 1 and R 2 H or C n H 2n + i (with n ranging from 1 to 10)
• R 1 and R 2 H, aromatic ring (CeH 5 - represented generally by Ar) or heteroaromatic (hetAr) with different substituents on the aromatic or heteroaromatic ring.
• step 3 corresponds to the acid hydrolysis of compound IV to obtain compound V:
• R may have a very large number of possibilities, such as for example:
• R Ar, HetAr, alkyl
• R 1 and R 2 H or C n H 2 n + i (with n ranging from 1 to 10)
• R 1 and R 2 H, aromatic ring (CeH 5 - represented generally by Ar) or heteroaromatic (hetAr) with different substituents on the aromatic or heteroaromatic ring.
• step 4 corresponds to cleavage of compound V with alkali metal periodate salt to provide compound VI:
• R may have a very large number of possibilities, such as:
• R Ar, HetAr, alkyl
• R 1 and R 2 H or C n H 2n + i (with n ranging from 1 to 10)
• R 1 and R 2 H, aromatic ring (C6H5- represented generically by Ar) or heteroaromatic (hetAr) with different substituents on the aromatic or heteroaromatic ring.
• step 5 corresponds to selective oxidation of compound VI in the presence of excess activated metal oxidant to provide compound VII:
• R may have a very large number of possibilities, such as:
• R Ar, HetAr, alkyl
• step 6 the obtained compound VII is treated with a base, and then the resulting salt is treated with a calcium salt to provide a statin (VIII):
• the present invention addresses the compounds obtained through steps 1, 2 and 3 which are used as intermediates in the method for obtaining a statin of the present invention.
• the present invention addresses the use of said intermediates in steps 2, 3 and 4 of the method for obtaining a statin of the present invention.
• the present invention addresses the statins obtained by the process for obtaining a statin of the present invention.
• Example 2 Procedure for obtaining 2-benzylidene-4-methyl-3-oxo-A7-phenylpentanamide (3) (Knoevenagel reaction).
• Example 3 Procedure for obtaining 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo-7-phenylpentanamide (4) (Stetter's reaction).
• Example 4 Procedure for obtaining [5- (4-fluorophenyl) -1- (3-hydroxypropyl] -2-isopropyl-Z-4,4-diphenyl-1 H -pyrrol-3-carboxamide (5) ( Pall-Knorr reaction) To a solution of 2- [2- (4-fluorophenyl) -2-oxo-1-phenylethyl] -4-methyl-3-oxo-N-phenylpentanamide (4) (20.0 g 47.8 mmol; 1.0 equivalent) and 3-amino-1-propanol (6.1 g; 81.2 mmol; 1.7 equivalent) in toluene / THF (1: 1) (100 mL) were added.
• Example 5 Procedure for obtaining 5- (4-fluorophenyl) -2-isopropyl-1- (3-oxopropyl) -N, 4-diphenyl-1 H- pyrrol-3-carboxamide (6) (Swern oxidation reaction).
• oxalyl chloride 5.0 g, 39.3 mmol; 1.2 equivalent
• DMSO 4.8 mL, 65.5 mmol, 2.0 equivalents
• Example 7 Procedure for obtaining (S) -methyl 2- (2,2-dimethyl-1,3-dioxolan-4-yl) acetate (10).
• dimethyl (8) -malate (8) 1.0 equivalent; 30.0 g; 185.1 mmol
• BH 3 .SMe 2 10 M
• the solution was kept under stirring for 30 minutes at 20 ° C until hydrogen evolution ceased.
• the reaction temperature was reduced to 10 ° C and the solution was kept for 10 minutes at this temperature.
• Example 8 Procedure for obtaining (S) -1- (2,2-dimethyl-1,3-dioxolan-4-yl) propan-2-one (11).
• a solution of MeMgCl (3M) in THF 168 mL; 504 mmol; 4.0 equivalents) for 50 minutes.
• Example 10 Procedure for obtaining 1- ((3R, 5R) -6- ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) -3,5-dihydroxyhexyl) -5- (4-Fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrol-3-carboxamide (14) (Narazaka reduction).
• Example 11 Procedure for obtaining 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1 - ((3R, 7S) -3,5,7,8-tetrahydroxyoctyl) -1H-pyrrolidin 3-carboxamide (15).
• Example 12 Procedure for obtaining 1- (2- ((2R, 4R) -4,6-dihydroxytetrahydro-2H-pyran-2-yl) ethyl) -5- (4-fluorophenyl) -2-isopropyl-N , 4-diphenyl-1H-pyrrol-3-carboxamide (26).
• Example 13 Procedure for obtaining 5- (4-fluorophenyl) -1- (2- ((2R, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl) ethyl) -2-isopropyl -N, 4-diphenyl-1H-pyrrol-3-carboxamide (31) (atorvastatin lactone).
• Example 14 Procedure for obtaining atorvastatin calcium (41).
• 5- (4-fluorophenyl) -1- (2 ((2R, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl) ethyl) -2-isopropyl-N, 4 -diphenyl-1H-pyrrol-3-carboxamide (31) (atorvastatin lactone) (1.0 equivalent; 2.0 g, 3.6 mmol) in methanol was added 10% aqueous NaOH until pH 12 and the resulting mixture was stirred for 1 hour at 55 ° C.
• the reaction was concentrated to 1/3 of the initial volume and distilled / deionized water (100 mL), methanol (20 mL) and ethyl acetate (100 mL) were added. The phases were separated and the aqueous phase was washed with ethyl acetate (2 x 50 mL). The aqueous phase was separated, the pH adjusted to 8.0 by the addition of aqueous HCl (1 N) solution and then heated to 50 ° C. The resulting mixture was treated with a solution of monohydrated calcium acetate (0.35 g, 1.98 mmol, 0.55 equivalent) in distilled / deionized water and the mixture was heated to 50 ° C.

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