Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
  • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
  • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the invention relates to a process for preparing obeticholic acid with a reduced number of synthetic steps.
• the essence of the present invention consists in conversion of the 7-keto-litocholic acid amide protected in position 3 of formula II, wherein R 1 , R 2 are a Ci - C 6 n-alkyl, or together a C 5 - C 6 cycle (for example piperidide, pyrrolidide, morpholide), to 7-trimethylsilyl enol ether of formula III, which is then converted by reaction with an alkylation agent to the 6- ethylidene derivative of formula IV, which is reduced to the compound of formula V and then simultaneously hydrolyzed and deprotected in position 3 to the compound of formula VI and then reduced to obeticholic acid of formula VII.
• R 1 , R 2 are a Ci - C 6 n-alkyl, or together a C 5 - C 6 cycle (for example piperidide, pyrrolidide, morpholide), to 7-trimethylsilyl enol ether of formula III, which is then converted by reaction with an al
• the amide of formula II is prepared in such a way to protect position 3 by carbamoylation at the same time in one common step (which will shorten the process).
• Step 1 The conversion of 7-keto-litocholic acid to the amide with simultaneous protection of the hydroxyl in position 3 can be carried out by reaction of this acid, after suitable activation, with the respective amine.
• the activated intermediate is prepared by reaction of 7-keto-lithocholic acid with, e.g., DCC-carbonyl diimidazole, hydroxybenzotriazole, or by another method described in the amide preparation literature (Houben-Weyl: Methoden der Organischen Chemie, Bd. E5, G. Thieme, Stuttgart 1985) under the conditions described therein.
• CDI and a suitable amine can be preferably used because the carbamate protection in position 3 can then be achieved in one step.
• Step 2 The preparation of 7-silyl enol ether is conducted via a lithio or sodio enolate by means of an alkali amide, while the basicity of the secondary amine used for preparing the amide must be lower than the basicity (pKa) of LDA and higher than pKa of the ketolithocholic acid 7-enolate itself.
• the absolute value of pKA depends on the environment (solvent used), advantageously ethers, especially THF.
• HMDS diphenylamine, ditolylamine, dinaphthylamine, hexamethyldisilazane, /V-methylaniline, N- methyltoluidine, /V-isopropylaniline, /V-tertbutylaniline and other secondary aromatic and silylated amines, preferably HMDS and diphenylamine.
• Step 3 - The 6-ethylation can be conducted with common alkylation agents: ethyl bromide, ethyl iodide, ethyl triflate, ethyl mesylate, ethyl tosylate, diethyl sulphate, preferably EtJ and Et triflate with an auxiliary base, e.g. a tertiary amine, preferably HUnig's base.
• auxiliary base e.g. a tertiary amine, preferably HUnig's base.
• An alternative comprises two-stage alkylation (aldolization with acetaldehyde and its derivatives) and subsequent reduction, which provides higher yields, does not work with alkylation agents, which are carcinogenic, but adds one step (reduction in the synthetic process).
• Acetaldehyde or its cyclic derivatives (metaldehyde, paraldehyde) in DCM or ethers are used, preferably in DCM, being catalyzed with strong Lewis acids (BF3 etherate, TiCl and SnCl 4 ), preferably TiCI 4 in DCM.
• the process is conducted at low temperatures, in the range of -80 to -20°C, preferably -60 to -40°C, to prevent retroaldolization.
• the aldolization is fast, and at the same time slow dehydration to the 6-ethylidene derivative proceeds, which is accelerated by addition of ACN, catalysis with J2, HCI, TMSCI, NaHS0 3 , ZnCI 2 and other weak Lewis acids, preferably with a combination of ACN and ZnCI 2 .
• Titanium salts soluble in the organic phase are removed by precipitation either as Ti0 2 or Ti 4+ -2DMF or by extraction with a-hydroxy acids into the aqueous phase (tartaric, hydroxyacetic, lactic, citric and other acids, best tartaric acid).
• Step 4 - The hydrogenation is conducted in an autoclave on a Pd catalyst (5-10% Pd/C, with or without Cu modification) under the pressure of 1-10 atmospheres, best 5% Pd/C and 3 atmospheres at RT to 100°C, in a solution of methanol, HCI or HAC, best at 40 to 60°C in HAC. After completed hydrogenation the catalyst is filtered off and returned to recycling and the solution is evaporated or neutralized and extracted, after dilution with water, to the organic phase.
• a Pd catalyst 5-10% Pd/C, with or without Cu modification
• Step 5 The hydrolysis of the amide and deprotection in position 3 is conducted by alkaline hydrolysis (KOH, NaOH, KOt-Bu, Cs 2 C0 3 , KOEt and NaOEt).
• the hydrolysis is carried out in higher boiling alcohols miscible with water under reflux (n-butanol, amyl alcohol, hexanol, cyclohexanol, ethylene glycol, propylene glycol, ethyl cellosolve, best glycols, KOH, 120°C).
• DCM toluene
• MTBE EtOAc
• the final product (6-ethyl-7- ketoacid) can be purified by crystallization in the form of salts with amines (diethylamine, diisopropylamine, dibutylamine, te/t-butylamine, octylamine, tert-octylamine, cyclohexylamine, dicyclohexylamine, morpholine, benzylamine, dibenzylamine, N- benzylmethylamine, (S)-a-methylbenzylamine, (R)-a-methylbenzylamine, preferably t- octylamine, (S)-a-methylbenzylamine).
• amines diethylamine, diisopropylamine, dibutylamine, te/t-butylamine, octylamine, tert-octylamine, cyclohexylamine, dicyclohexylamine, morpholine
• Step 6 The process of final reduction with NaBH is identical with the basic patent (US7138390).
• the final product can be crystallized via a t-octylamminium salt in an environment of methanol or isopropanol.
• the preparation of the lithioenolate can also be carried out with the commercially available lithium bis(trimethylsilyl) amide.
• a 1L sulfonation flask with a mechanical stirrer was annealed in vacuo and purged with nitrogen. After cooling off the flask, 120 ml of dried dichloromethane (dried using an A4 molecular sieve) and 1.75 ml (13.2 mmol, 0.37 equiv.) of paraldehyde were charged in a nitrogen atmosphere. The solution was cooled down to -60°C.
• the temperature of the reaction mixture was adjusted to the room temperature within 15 min and then 1.93 ml of distilled water (106.97 mmol, 3 equiv.) and 486 mg (3.57 mmol, 10 mol %) of zinc chloride were added.
• the product got completely dehydrated to (IVb).
• 300 ml of MTBE and 300 ml of water were poured to the mixture, stirred, the phases were separated and the organic layer was stirred with 14.12 ml (106.97 mmol, 3 equiv.) of triethanolamine for 10 min. 200 ml of water were then added to the mixture, and stirred for 10 min.
• reaction mixture was extracted with lx 150 ml and 2x 50 ml of EtOAc. The combined organic fractions were washed with 2x 100 ml of water, 100 ml of brine and dried with Na 2 S0 4 . The desiccant was filtered off and the filtrate was concentrated using an RVE. Reaction yield 13.5 g (83%) of crude (VI). Crystallization of the intermediate via the amminium salt: 10 ml MeOH, 1.02 equiv. of (S)-a-methylbenzylamine for 1 g of (VI), 10 ml of H 2 0 added under reflux. Then, the mixture was refluxed for 30 minutes, and left to cool down freely.
• MeOH come to theoretical 20.1 g. Purification of the final product was made by crystallization in the form of a salt with 1,1,3,3-tetramethylbutylamine. 3 ml of MeOH, 1.02 equiv. of 1, 1,3,3- tetramethylbutylamine (tert-octylamine) for 1 g of (VII); 10 ml of H 2 0 added under reflux. Then, the mixture was refluxed for 30 minutes, and left to cool down freely. The product after isolation was converted back to the free acid via the sodium salt with NaOH, then extracted into /-PrOAc using 1M HCI.

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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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