PROUD Indian WORLD RECORD VIEWS holder on THIS BLOG, ………live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 45 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, [THIS BLOG HOLDS WORLD RECORD VIEWS ] A PROUD INDIAN
DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
MOLECULAR FORMULA C231H386N64O67S5 + (C2H4O)4n MOLECULAR WEIGHT approx. 45 kDa
The structure of navepegritide (YUVIWEL®) is built using a “prodrug” design. It is not a simple small molecule, but rather a complex conjugate consisting of three distinct components designed to release the active drug slowly over time.
1. The Active Part: C-Type Natriuretic Peptide (CNP)
The core of the molecule is a synthetic 38-amino acid peptide (CNP-38).
Sequence: This peptide mimics the natural human C-type natriuretic peptide, which is essential for bone growth.
Function: Once released, this peptide binds to the natriuretic peptide receptor B (NPR-B) on the surface of chondrocytes (cartilage cells) in the growth plates, stimulating bone formation.
2. The Carrier: Polyethylene Glycol (PEG)
To prevent the body from clearing the small peptide too quickly, it is attached to a large, inert carrier.
Type: It uses a multi-arm, branched 40 kDa Polyethylene Glycol (PEG) molecule.
Purpose: The PEG carrier acts as a shield and a “weight,” making the molecule too large to be filtered out rapidly by the kidneys. This is what allows for once-weekly dosing instead of daily injections.
3. The Linker: TransCon™ Technology
This is the most critical part of the structure. The peptide is attached to the PEG carrier via a cleavable linker.
Mechanism: This linker is designed to break down spontaneously at a predictable rate under physiological conditions (neutral pH and body temperature).
The Result: As the linker slowly breaks, it releases the unmodified, active CNP-38 into the bloodstream. Because the peptide is released in its natural state, it retains its full biological activity.
Summary Table: Structural Components
Component
Description
Role
Peptide
CNP-38 (38 amino acids)
The “payload” that stimulates bone growth.
Linker
pH-sensitive cleavable bond
Controls the slow release of the peptide.
Carrier
40 kDa PEG
Increases the half-life and prevents rapid clearance.
Note: This structure is technically a prodrug because the large PEG-bound version is inactive; only the released CNP-38 peptide performs the therapeutic work.
C-Type natriuretic peptide (CNP), human, (89-126)-fragment (1-38) (CNP-38), conjugated at N6 of Lys26 with four O-methylpoly(ethylene glycol) chains (approx. 10 kDa each) via a cleavable tetra-antennary linker; L-leucyl-L-glutaminyl-L-?-glutamyl-L-histid
Poly(oxy-1,2-ethanediyl), ?-hydro-?-methoxy-, 26,26,26,26-tetraether with L-leucyl-L-glutaminyl-L-?-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-sery
FDA 2026, APPROVALS 2026, 2/27/2026, Yuviwel, Y3BH8M899D, MN-266, TRANSCON CNP, PA (224-233), Influenza, DA-66438, ACP-015, WHO 11981,
To increase linear growth in pediatric patients 2 years and older with achondroplasia with open epiphyses
Navepegritide is a prodrug consisting of a 38-amino acid C-type natriuretic peptide (CNP) moiety conjugated to a multi-arm polyethylene glycol (PEG) carrier via a cleavable linker. This structure allows for the once-weekly dosing approved by the FDA for children with achondroplasia.
Key Details
Purpose: It is designed to increase linear growth by providing continuous exposure to C-type natriuretic peptide (CNP), a protein that helps regulate bone growth.
Mechanism: As a prodrug, it uses Ascendis Pharma’s TransCon technology to release active CNP slowly into the body over a week, maintaining steady levels and avoiding high peaks.
Clinical Benefits: In the pivotal ApproaCH trial, patients treated with navepegritide showed a significant improvement in annualized growth velocity (AGV) compared to those on a placebo. It also showed potential improvements in body proportionality and lower-limb alignment.
Administration: It is administered via a once-weekly subcutaneous injection, offering a less frequent alternative to daily treatments like vosoritide.
Safety: Most common side effects include injection site reactions (redness, itching, or swelling) and a risk of low blood pressure (hypotension).
25 Feb 2026Vanda Pharmaceuticals has patent protection for an improved method of treatment with milsaperidone in USA
25 Feb 2026Vanda Pharmaceuticals has patents pending for an improved method of treatment with milsaperidone in China, Australia, Israel, Mexico and worldwide
56.36 g of boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1 ,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0°C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone (iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0°C ± 2°C. After the addition is complete, the mixture is stirred at 0°C for 20 hours. The reaction mixture is then poured into precooled methanol (0-5°C) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50°C and an additional hour at 0CC. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50°C. The title compound is obtained (white crystals).
[α]D20– 19.3° (c=1 in chloroform) Mp: 138.2 – 138.8°C
The boran complex used as starting material can be obtained as follows:
200 ml of a solution of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (1M in toluene) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling to -12°C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40°C. The boran complex is obtained /white crystals).
Copper histidinate, sold under the brand name Zycubo, is a medication used for the treatment of Menkes disease.[1] Copper histidinate is a copper replacement therapy given by subcutaneous injection.[1][2]
The most common side effects include infections, respiratory problems, seizures, vomiting, fever, anemia and injection site reactions.[2]
Copper histidinate was approved for medical use in the United States in January 2026.[2]
Menkes disease is a neurodegenerative disorder caused by a genetic defect that impairs a child’s ability to absorb copper.[2] The disease is characterized by seizures, failure to gain weight and grow, developmental delays, and intellectual disability.[2] It leads to abnormalities of the vascular system, bladder, bowel, bones, muscles, and nervous system.[2]
SYN
A275388 — Flores-Pulido AA, Jimenez-Perez VM, Garcia-Chong NR: Sintesis y uso de histidinato de cobre en ninos con enfermedad de Menkes en Mexico. Gac Med Mex. 2019;155(2):191-195. doi: 10.24875/GMM.18004310. [PubMed:31056589]
World Health Organization (2025). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 94”. WHO Drug Information. 39 (3). hdl:10665/383022.
Clinical trial number NCT00811785 for “Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency” at ClinicalTrials.gov
Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
RegisteredAtopic dermatitis
27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)
Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).
Synthesis of Oxazole Compound (Type A Crystal)
Compound (5) (white powder) was prepared in accordance with the method disclosed in Example 352 of PTL 1 (WO2007/058338).
Synthesis of difamilast commenced with the monobenzylated protocatechuic acid ethyl ester 15.1. Phenol 15.1 was first converted into the corresponding isopropyl ether, which was subsequently debenzylated under palladium-catalyzed hydrogenation conditions to generate the phenolic intermediate 15.3. Difluoromethylation of 15.3 was accomplished by introducing sodium chlorodifluoroacetate 15.4 in the presence of potassium carbonate at an elevated temperature. The decarboxylative C− O bond-forming reaction presumably proceeded via a difluorocarbene species. The difluoromethylated product was treated with acid followed by ester hydrolysis under a basic medium to furnish benzoic acid derivative 15.5. Benzoic acid 15.5 was subsequently transformed into benzamide 15.6 via a benzoyl imidazole intermediate. Condensation of benzamide 15.6 with 1-acetoxy-3-chloroacetone 15.7 produced an oxazole derivative, which was subsequently saponified and recrystallized from 50% aqueous MeOH to generate alcohol 15.8.
First, an activation−displacement process transformed alcohol 15.8 into bromide 15.9 via a mesylate intermediate. Alkyl bromide 15.9 was then treated with potassium phthalimide to incorporate the nitrogen center via an SN2-type displacement. Methylamine-mediated phthalimide deprotection and subsequent salt formation produced amine 15.11 as a hydrochloride salt in 69% yield over 3 steps. Finally, hydrochloride salt 15.11 was treated with aqueous sodium bicarbonate to generate a free amine, which was subjected to amide bond formation with 2-ethoxybenzoic acid 15.12 to deliver difamilast after recrystallization from aqueous EtOH.
Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.
[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).
[0072]
[Chem. 6]
[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).
[0074]
[Chem. 7]
[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).
[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).
Using the compound obtained in Example 347 and 2-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
[0146]
[Chem. 11]
[0147]
10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 ml of N,N-dimethylformamide and 6 ml of water, and the mixture was stirred until exotherm subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was added thereto, and the mixture was reacted at 95 to 110°C for 3 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the solution was partitioned. 80 ml of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of 20°C or below, followed by pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder.
Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
[0149]
[Chem. 12]
[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.
[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.
[0152]
[Chem. 13]
Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.
[0160]
[Chem. 14]
[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.
Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).
[0072]
[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).
[0074]
[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.
[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).
PATENT
WO2014034958A1
WO2007058338A2
WO2007058338A9
WO2007058338A3
US9181205B2
US2015239855A1
USRE46792E
US2020078340A1
US2017216260A1
US2019070151A1
US2009221586A1
US8637559B2
US2014100226A1
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AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
Mechanism of Action Sodium-bile acid cotransporter-inhibitors
Highest Development Phases
Phase II Primary biliary cirrhosis; Pruritus; Type 2 diabetes mellitus
Phase I Cholestasis
Most Recent Events
01 Jan 2017 Phase-II clinical trials in Pruritus in USA (PO) (NCT02966834)
14 Nov 2016 GlaxoSmithKline completes a phase I trial for Cholestasis in Healthy volunteers in Japan (PO, Tablet) (NCT02801981)
11 Nov 2016 Efficacy, safety and pharmacodynamic data from a phase II trial in Primary biliary cirrhosis and Pruritus presented at The Liver Meeting® 2016: 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2016)
GSK2330672 , an ileal bile acid transport (iBAT) inhibitor indicated for diabetes type II and cholestatic pruritus, is currently under Phase IIb evaluation in the clinic. The API is a highly complex molecule containing two stereogenic centers, one of which is quaternary
GSK-2330672 is highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor for treatment of type 2 diabetes.
More than 200 million people worldwide have diabetes. The World Health Organization estimates that 1 .1 million people died from diabetes in 2005 and projects that worldwide deaths from diabetes will double between 2005 and 2030. New chemical compounds that effectively treat diabetes could save millions of human lives.
Diabetes refers to metabolic disorders resulting in the body’s inability to effectively regulate glucose levels. Approximately 90% of all diabetes cases are a result of type 2 diabetes whereas the remaining 10% are a result of type 1 diabetes, gestational diabetes, and latent autoimmune diabetes of adulthood (LADA). All forms of diabetes result in elevated blood glucose levels and, if left untreated chronically, can increase the risk of macrovascular (heart disease, stroke, other forms of cardiovascular disease) and microvascular [kidney failure (nephropathy), blindness from diabetic retinopathy, nerve damage (diabetic neuropathy)] complications.
Type 1 diabetes, also known as juvenile or insulin-dependent diabetes mellitus (IDDM), can occur at any age, but it is most often diagnosed in children, adolescents, or young adults. Type 1 diabetes is caused by the autoimmune destruction of insulin-producing beta cells, resulting in an inability to produce sufficient insulin. Insulin controls blood glucose levels by promoting transport of blood glucose into cells for energy use. Insufficient insulin production will lead to decreased glucose uptake into cells and result in accumulation of glucose in the bloodstream. The lack of available glucose in cells will eventually lead to the onset of symptoms of type 1 diabetes: polyuria (frequent urination), polydipsia (thirst), constant hunger, weight loss, vision changes, and fatigue. Within 5-10 years of being diagnosed with type 1 diabetes, patient’s insulin-producing beta cells of the pancreas are completely destroyed, and the body can no longer produce insulin. As a result, patients with type 1 diabetes will require daily administration of insulin for the remainder of their lives.
Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, occurs when the pancreas produces insufficient insulin and/or tissues become resistant to normal or high levels of insulin (insulin resistance), resulting in excessively high blood glucose levels. Multiple factors can lead to insulin resistance including chronically elevated blood glucose levels, genetics, obesity, lack of physical activity, and increasing age. Unlike type 1 diabetes, symptoms of type 2 diabetes are more salient, and as a result, the disease may not be diagnosed until several years after onset with a peak prevalence in adults near an age of 45 years. Unfortunately, the incidence of type 2 diabetes in children is increasing.
The primary goal of treatment of type 2 diabetes is to achieve and maintain glycemic control to reduce the risk of microvascular (diabetic neuropathy, retinopathy, or nephropathy) and macrovascular (heart disease, stroke, other forms of cardiovascular disease) complications. Current guidelines for the treatment of type 2 diabetes from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [Diabetes Care, 2008, 31 (12), 1 ] outline lifestyle modification including weight loss and increased physical activity as a primary therapeutic approach for management of type 2 diabetes. However, this approach alone fails in the majority of patients within the first year, leading physicians to prescribe medications over time. The ADA and EASD recommend metformin, an agent that reduces hepatic glucose production, as a Tier 1 a medication; however, a significant number of patients taking metformin can experience gastrointestinal side effects and, in rare cases, potentially fatal lactic acidosis. Recommendations for Tier 1 b class of medications include sulfonylureas, which stimulate pancreatic insulin secretion via modulation of potassium channel activity, and exogenous insulin. While both medications rapidly and effectively reduce blood glucose levels, insulin requires 1 -4 injections per day and both agents can cause undesired weight gain and potentially fatal hypoglycemia. Tier 2a recommendations include newer agents such as thiazolidinediones (TZDs pioglitazone and rosiglitazone), which enhance insulin sensitivity of muscle, liver and fat, as well as GLP-1 analogs, which enhance postprandial glucose-mediated insulin secretion from pancreatic beta cells. While TZDs show robust, durable control of blood glucose levels, adverse effects include weight gain, edema, bone fractures in women, exacerbation of congestive heart failure, and potential increased risk of ischemic cardiovascular events. GLP-1 analogs also effectively control blood glucose levels, however, this class of medications requires injection and many patients complain of nausea. The most recent addition to the Tier 2 medication list is DPP-4 inhibitors, which, like GLP-1 analogs, enhance glucose- medicated insulin secretion from beta cells. Unfortunately, DPP-4 inhibitors only modestly control blood glucose levels, and the long-term safety of DPP-4 inhibitors remains to be firmly established. Other less prescribed medications for type 2 diabetes include a-glucosidase inhibitors, glinides, and amylin analogs. Clearly, new medications with improved efficacy, durability, and side effect profiles are needed for patients with type 2 diabetes.
GLP-1 and GIP are peptides, known as incretins, that are secreted by L and K cells, respectively, from the gastrointestinal tract into the blood stream following ingestion of nutrients. This important physiological response serves as the primary signaling mechanism between nutrient (glucose/fat) concentration in the
gastrointestinal tract and other peripheral organs. Upon secretion, both circulating peptides initiate signals in beta cells of the pancreas to enhance glucose-stimulated insulin secretion, which, in turn, controls glucose concentrations in the blood stream (For reviews see: Diabetic Medicine 2007, 24(3), 223; Molecular and Cellular Endocrinology 2009, 297(1-2), 127; Experimental and Clinical Endocrinology & Diabetes 2001 , 109(Suppl. 2), S288).
The association between the incretin hormones GLP-1 and GIP and type 2 diabetes has been extensively explored. The majority of studies indicate that type 2 diabetes is associated with an acquired defect in GLP-1 secretion as well as GIP action (see Diabetes 2007, 56(8), 1951 and Current Diabetes Reports 2006, 6(3), 194). The use of exogenous GLP-1 for treatment of patients with type 2 diabetes is severely limited due to its rapid degradation by the protease DPP-4. Multiple modified peptides have been designed as GLP-1 mimetics that are DPP-4 resistant and show longer half-lives than endogenous GLP-1 . Agents with this profile that have been shown to be highly effective for treatment of type 2 diabetes include exenatide and liraglutide, however, these agents require injection. Oral agents that inhibit DPP-4, such as sitagliptin vildagliptin, and saxagliptin, elevate intact GLP-1 and modestly control circulating glucose levels (see Pharmacology & Therapeutics 2010, 125(2), 328; Diabetes Care 2007, 30(6), 1335; Expert Opinion on Emerging Drugs 2008, 13(4), 593). New oral medications that increase GLP-1 secretion would be desirable for treatment of type 2 diabetes.
Bile acids have been shown to enhance peptide secretion from the
gastrointestinal tract. Bile acids are released from the gallbladder into the small intestine after each meal to facilitate digestion of nutrients, in particular fat, lipids, and lipid-soluble vitamins. Bile acids also function as hormones that regulate cholesterol homeostasis, energy, and glucose homeostasis via nuclear receptors (FXR, PXR, CAR, VDR) and the G-protein coupled receptor TGR5 (for reviews see: Nature Drug Discovery 2008, 7, 672; Diabetes, Obesity and Metabolism 2008, 10, 1004). TGR5 is a member of the Rhodopsin-like subfamily of GPCRs (Class A) that is expressed in intestine, gall bladder, adipose tissue, liver, and select regions of the central nervous system. TGR5 is activated by multiple bile acids with lithocholic and deoxycholic acids as the most potent activators {Journal of Medicinal Chemistry 2008, 51(6), 1831 ). Both deoxycholic and lithocholic acids increase GLP-1 secretion from an enteroendocrine STC-1 cell line, in part through TGR5
{Biochemical and Biophysical Research Communications 2005, 329, 386). A synthetic TGR5 agonist INT-777 has been shown to increase intestinal GLP-1 secretion in vivo in mice {Cell Metabolism 2009, 10, 167). Bile salts have been shown to promote secretion of GLP-1 from colonic L cells in a vascularly perfused rat colon model {Journal of Endocrinology 1995, 145(3), 521 ) as well as GLP-1 , peptide YY (PYY), and neurotensin in a vascularly perfused rat ileum model {Endocrinology 1998, 139(9), 3780). In humans, infusion of deoxycholate into the sigmoid colon produces a rapid and marked dose responsive increase in plasma PYY and enteroglucagon concentrations (Gi/M993, 34(9), 1219). Agents that increase ileal and colonic bile acid or bile salt concentrations will increase gut peptide secretion including, but not limited to, GLP-1 and PYY.
Bile acids are synthesized from cholesterol in the liver then undergo conjugation of the carboxylic acid with the amine functionality of taurine and glycine. Conjugated bile acids are secreted into the gall bladder where accumulation occurs until a meal is consumed. Upon eating, the gall bladder contracts and empties its contents into the duodenum, where the conjugated bile acids facilitate absorption of cholesterol, fat, and fat-soluble vitamins in the proximal small intestine (For reviews see: Frontiers in Bioscience 2009, 74, 2584; Clinical Pharmacokinetics 2002,
41(10), 751 ; Journal of Pediatric Gastroenterology and Nutrition 2001 , 32, 407). Conjugated bile acids continue to flow through the small intestine until the distal ileum where 90% are reabsorbed into enterocytes via the apical sodium-dependent bile acid transporter (ASBT, also known as iBAT). The remaining 10% are deconjugated to bile acids by intestinal bacteria in the terminal ileum and colon of which 5% are then passively reabsorbed in the colon and the remaining 5% being excreted in feces. Bile acids that are reabsorbed by ASBT in the ileum are then transported into the portal vein for recirculation to the liver. This highly regulated process, called enterohepatic recirculation, is important for the body’s overall maintenance of the total bile acid pool as the amount of bile acid that is synthesized in the liver is equivalent to the amount of bile acids that are excreted in feces.
Pharmacological disruption of bile acid reabsorption with an inhibitor of ASBT leads to increased concentrations of bile acids in the colon and feces, a physiological consequence being increased conversion of hepatic cholesterol to bile acids to compensate for fecal loss of bile acids. Many pharmaceutical companies have pursued this mechanism as a strategy for lowering serum cholesterol in patients with dyslipidemia/hypercholesterolemia (For a review see: Current Medicinal Chemistry 2006, 73, 997). Importantly, ASBT-inhibitor mediated increase in colonic bile acid/salt concentration also will increase intestinal GLP-1 , PYY, GLP-2, and other gut peptide hormone secretion. Thus, inhibitors of ASBT could be useful for treatment of type 2 diabetes, type 1 diabetes, dyslipidemia, obesity, short bowel syndrome, Chronic Idiopathic Constipation, Irritable bowel syndrome (IBS), Crohn’s disease, and arthritis.
Certain 1 ,4-thiazepines are disclosed, for example in WO 94/18183 and WO 96/05188. These compounds are said to be useful as ileal bile acid reuptake inhibitors (ASBT).
Patent publication WO 201 1/137,135 dislcoses, among other compounds, the following compound. This patent publication also discloses methods of synthesis of the compound.
The preparation of the above compound is also disclosed in J. Med. Chem, Vol 56, pp5094-51 14 (2013).
Patent publication WO 201 1/137,135 dislcoses general methods for preparing the compound. In addition, a detailed synthesis of the compound is disclosed in Example 26. J. Med. Chem, Vol 56, pp5094-51 14 (2013) also discloses a method for synthesising the compound.
The present invention discloses an improved synthesis of the compound.
The synthetic scheme of the present invention is depicted in Scheme 1 .
Treatment of 2-methoxyphenyl acetate with sulfur monochloride followed by ester hydrolysis and reduction with zinc gave rise to thiophenol (A). Epoxide ring opening of (+)-2-butyl-ethyloxirane with thiophenol (A) and subsequent treatment of tertiary alcohol (B) with chloroacetonitrile under acidic conditions gave chloroacetamide (C), which was then converted to intermediate (E) by cleavage of the chloroacetamide with thiourea followed by classical resolution with dibenzoyl-L-tartaric acid.
Benzoylation of intermediate (E) with triflic acid and benzoyl chloride afforded intermediate (H). Cyclization of intermediate (H) followed by oxidation of the sulfide to a sulphone, subseguent imine reduction and classical resolution with (+)-camphorsulfonic acid provided intermediate (G), which was then converted to intermediate (H). Intermediate (H) was converted to the target compound using the methods disclosed in Patent publication WO 201 1/137,135.
Scheme 1
Dibenzoyl-L-tataric acid
The present invention also discloses an alternative method for construction of the quaternary chiral center as depicted in Scheme 2. Reaction of intermediate (A) with (R)-2-ammonio-2-ethylhexyl sulfate (K) followed by formation of di-p-toluoyl-L-tartrate salt furnished intermediate (L).
The present invention also discloses an alternative synthesis of intermediate (H) as illustrated in Scheme 3. Acid catalyzed cyclization of intermediate (F) followed by triflation gave imine (M), which underwent asymmetric reduction with catalyst lr(COD)2BArF and ligand (N) to give intermediate (O). Oxidation of the sulfide in intermediate (O) gave sulphone intermediate (H).
The present invention differs from the synthesis disclosed in WO 201 1/137,135 and J. Med. Chem, Vol56, pp5094-51 14 (2013) in that intermediate (H) in the present invention is prepared via a new, shorter and more cost-efficient synthesis while the synthesis of the target compound from intermediate (H) remains unchanged.
Intermediate A: 3-Hydroxy-4-methoxythiophenol
A reaction vessel was charged with 2-methoxyphenyl acetate (60 g, 0.36 mol), zinc chloride (49.2 g, 0.36 mol) and DME (600 mL). The mixture was stirred and S2CI2 (53.6 g, 0.40 mol) was added. The mixture was stirred at ambient temperature for 2 h. Concentrated HCI (135.4 mL, 1 .63 mol) was diluted with water (60 mL) and added slowly to the rxn mixture, maintaining the temperature below 60 °C. The mixture was stirred at 60 °C for 2 h and then cooled to ambient
temperature. Zinc dust (56.7 g, 0.87 mol) was added in portions, maintaining the temperature below 60 °C. The mixture was stirred at 20-60 °C for 1 h and then concentrated under vacuum to -300 mL. MTBE (1 .2 L) and water (180 mL) were added and the mixture was stirred for 10 min. The layers were separated and the organic layer was washed twice with water (2x 240 mL). The layers were separated and the organic layer was concentrated under vacuum to give an oil. The oil was distilled at 1 10-1 15 °C/2 mbar to give the title compound (42 g, 75%) as colorless oil, which solidified on standing to afford the title compound as a white solid. M.P. 41 -42 °C. 1 H NMR (500 MHz, CDCI3)$ ppm 3.39 (s, 1 H), 3.88 (s, 3H), 5.65 (br. S, 1 H), 6.75 (d, J – 8.3 Hz, 1 H), 6.84 (ddd, J – 8.3, 2.2, 0.6 Hz, 1 H), 6.94 (d, J – 2.2 Hz).
Intermediate E: (R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol, dibenzoyl-L-tartrate salt
A reaction vessel was charged with 3-hydroxy-4-methoxythiophenol (5.0 g, 25.2 mmol), (+)-2-butyl-2-ethyloxirane (3.56 g, 27.7 mmol) and EtOH (30 mL). The mixture was treated with a solution of NaOH (2.22 g, 55.5 mmol) in water (20 mL), heated to 40 °C and stirred at 40 °C for 5 h. The mixture was cooled to ambient temperature, treated with toluene (25 mL) and stirred for 10 min. The layers were separated and the organic layer was discarded. The aqueous layer was neutralized with 2N HCI (27.8 mL, 55.6 mmol) and extracted with toluene (100 mL). The organic layer was washed with water (25 mL), concentrated in vacuo to give an oil. The oil was treated with chloroacetonitrile (35.9 mL) and HOAc (4.3 mL) and cooled to 0 °C. H2SO4 (6.7 mL, 126 mmol, pre-diluted with 2.3 mL of water) was added at a rate maintaining the temperature below 10 °C. After stirred at 0 °C for 0.5 h, the reaction mixture was treated with 20% aqueous Na2CO3 solution to adjust the pH to
7-8 and then extracted with MTBE (70 ml_). The extract was washed with water (35 ml_) and concentrated in vacuo to give an oil. The oil was then dissolved in EOH (50 ml_) and treated with HOAc (10 ml_) and thiourea (2.30 g, 30.2 mmol). The mixture was heated at reflux overnight and then cooled to ambient temperature. The solids were filtered and washed with EtOH (10 ml_). The filtrate and the wash were combined and concentrated in vacuo, treated with MTBE (140 ml_) and washed successively with 10% aqueous Na2C03 and water. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in MeCN (72 ml_), heated to -50 °C and then dibenzoyl-L-tartaric acid (9.0 g, 25.2 mmol) in acetonitrile (22 ml_) was added slowly. Seed crystals were added at -50 °C. The resultant slurry was stirred at 45-50 °C for 5 h, then cooled down to ambient temperature and stirred at ambient temperature overnight. The solids were filtered and washed with MeCN (2x 22 ml_). The wet cake was treated with MeCN (150 ml_) and heated to 50 °C. The slurry was stirred at 50 °C for 5 h, cooled over 1 h to ambient temperature and stirred at ambient temperature overnight. The solids were collected by filtration, washed with MeCN (2 x 20 ml_), dried under vacuum to give the title compound (5.5 g, 34% overall yield, 99.5% purity, 93.9% ee) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.78 (m, 6H), 1 .13 (m, 4H), 1 .51 (m, 2H), 1 .58 (q, J – 7.7 Hz, 2H), 3.08 (s, 2H), 3.75 (s, 3H), 5.66 (s, 2H), 6.88 (m, 2H), 6.93 (m, 1 H), 7.49 (m, 4H), 7.63 (m, 2H), 7.94 (m, 4H). EI-LCMS m/z 284 (M++1 of free base).
A suspension of (R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol, dibenzoyl-L-tartrate salt (29 g, 45.2 mmol) in DCM (435 mL) was treated with water (1 16 mL) and 10% aqueous Na2C03 solution (1 16 mL). The mixture was stirred at ambient temperature until all solids were dissolved (30 min). The layers were separated. The organic layer was washed with water (2 x 60 mL), concentrated under vacuum to give (R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol (free base) as an off-white solid (13.0 g, quantitative). A vessel was charged with TfOH (4.68 ml, 52.9 mmol) and DCM (30 mL) and the mixture was cooled to 0 °C. 5 g (17.6 mmol) of (R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol (free base) was dissolved in DCM (10 mL) and added at a rate maintaining the temperature below 10 °C. Benzoyl chloride (4.5 mL, 38.8 mmol) was added at a rate maintaining the temperature below 10 °C. The mixture was then heated to reflux and stirred at reflux for 48 h. The mixture was cooled to 30 °C. Water (20 mL) was added and the mixture was concentrated to remove DCM. EtOH (10 mL) was added. The mixture was heated to 40 ° C, treated with 50% aqueous NaOH solution (10 mL) and stirred at 55 °C. After 1 h, the mixture was cooled to ambient temperature and the pH was adjusted to 6-7 with cone. HCI. The mixture was concentrated in vacuo to remove EtOH. EtOAc (100 mL) was added. The mixture was stirred for 5 min and the layers were separated. The organic layer was washed successively with 10% aqueous Na2CO3 (25 mL) and water (25 mL) and then concentrated in vacuo. The resultant oil was treated with DCM (15 mL). The resultant thick slurry was further diluted with DCM (15 mL) followed by addition of Hexanes (60 mL). The slurry was stirred for 5 min, filtered, washed with DCM/hexanes (1 :2, 2 x 10 mL) and dried under vacuum to give the title compound (7.67 g, 80%) as a yellow solid. 1 NMR (500 MHz, DMSO-d6) δ ppm 0.70 (t, 7.1 Hz, 3 H), 0.81 (t, 7.1 Hz, 3H), 1 .04-1 .27 (m, 8H), 2.74 (s, 2H), 3.73 (s, 3H), 6.91 (s, 1 H), 7.01 (s, 1 H), 7.52 (dd, J – 7.8, 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 2H). EI-LCMS m/z 388 (M++1 ).
Intermediate G: (3R,5R)-3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1 ,4]thiazepine 1 ,1 -dioxide, (+)-camphorsulfonate salt
A vessel was charged with (R)-(2-((2-amino-2-ethylhexyl)thio)-4-hydroxy-5-methoxyphenyl)(phenyl)methanone (1 .4 g, 3.61 mmol), toluene (8.4 ml_) and citric acid (0.035 g, 0.181 mmol, 5 mol%). The mixture was heated to reflux overnight with a Dean-Stark trap to remove water. The mixture was concentrated under reduced pressure to remove solvents. Methanol (14.0 ml_) and oxone (2.22 g, 3.61 mmol, 1 .0 equiv) were added. The mixture was stirred at gentle reflux for 2 h. The mixture was cooled to ambient temperature, and filtered to remove solids. The filter cake was washed with small amount of Methanol. The filtrate was cooled to 5 °C, and treated with sodium borohydride (0.410 g, 10.84 mmol, 3.0 equiv.) in small portions. The mixture was stirred at 5 °C for 2 h and then concentrated to remove the majority of solvents. The mixture was quenched with Water (28.0 ml_) and extracted with EtOAc (28.0 ml_). The organic layer was washed with brine, and then concentrated to remove solvents. The residue was dissolved in MeCN (14.0 ml_) and concentrated again to remove solvents. The residue was dissolved in MeCN (7.00 ml_) and MTBE (7.00 ml_) at 40 °C, and treated with (+)-camphorsulfonic acid (0.839 g, 3.61 mmol, 1 .0 equiv.) at 40 °C for 30 min. The mixture was cooled to ambient temperature, stirred for 2 h, and filtered to collect solids. The filter cake was washed with MTBE/MeCN (2:1 , 3 ml_), and dried at 50 °C to give the title compound (0.75 g, 32% overall yield, 98.6 purity, 97% de, 99.7% ee) as white solids. 1 NMR (400 MHz, CDCI3) δ ppm 0.63 (s, 3H), 0.88 (t, J – 6.9 Hz, 3H), 0.97 (m, 6H), 1 .29-1 .39 (m, 5H), 1 .80-1 .97 (m, 6H), 2.08-2.10 (m, 1 H), 2.27 (d, J – 17.3 Hz, 1 H), 2.38-2.44 (m, 3H), 2.54 (b, 1 H), 2.91 (b, 1 H), 3.48 (d, J – 15.4 Hz, 1 H), 3.79 (s, 3H), 4.05 (d, J – 17.2 Hz, 1 H), 6.45 (s, 1 H), 6.56 (s, 1 H), 7.51 -7.56 (m, 4H), 7.68 (s, 1 H), 7.79 (b, 2H), 1 1 .46 (b, 1 H). EI-LCMS m/z 404 (M++1 of free base).
Method 1 : A mixture of (3R,5R)-3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1 ,4]thiazepine 1 ,1 -dioxide, (+)-camphorsulfonate salt (0.5 g, 0.786 mmol), EtOAc (5.0 mL), and 10% of Na2C03 aqueuous solution (5 mL) was stirred for 15 min. The layers were separated and the aqueous layer was discarded. The organic layer was washed with dilute brine twice, concentrated to remove solvents. EtOAc (5.0 mL) was added and the mixture was concentrated to give a pale yellow solid free base. 1 ,4-Dioxane (5.0 mL) and pyridine (0.13 mL, 1 .57 mmol) were added. The mixture was cooled to 5-10 °C and triflic anhydride (0.199 mL, 1 .180 mmol) was added while maintaining the temperature below 15 °C. The mixture was stirred at ambient temperature until completion deemed by HPLC (1 h). Toluene (5 mL) and water (5 mL) were added. Layers were separated. The organic layer was washed with water, concentrated to remove solvents. Toluene (1 .0 mL) was added to dissolve the residue followed by Isooctane (4.0 mL). The mixture was stirred at rt overnight. The solids was filtered, washed with Isooctane (4.0 mL) to give the title compound (0.34 g, 81 %) as slightly yellow solids. 1 NMR (400 MHz, CDCI3) δ ppm 0.86 (t, J – 7.2 Hz, 3H), 0.94 (t, J – 7.6 Hz, 3H), 1 .12-1 .15 (m, 1 H), 1 .22-1 .36 (m, 3H), 1 .48-1 .60 (m, 2H), 1 .86-1 .93 (m, 2H), 2.22 (dt, J = 4.1 Hz, 12 Hz, 1 H), 3.10 (d, J – 14.8 Hz, 1 H), 3.49 (d, J – 14.8 Hz, 1 H), 3.64 (s, 3H), 6.1 1 (s, 1 H), 6.36 (s, 1 H), 7.38-7.48 (m, 5), 7.98 (s, 1 H).
Method 2: A mixture of (R)-3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3-dihydrobenzo[f][1 ,4]thiazepin-8-yl trifluoromethanesulfonate (0.5 g, 0.997 mmol), ligand (N) (0.078 g, 0.1 10 mmol) and lr(COD)2BArF (0.127 g, 0.100 mmol) in DCM (10.0 mL) was purged with nitrogen three times, then hydrogen three times. The mixture was shaken in Parr shaker under 10 Bar of H2 for 24 h. The experiment described above was repeated with 1 .0 g (1 .994 mmol) input of (R)-3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3-dihydrobenzo[f][1 ,4]thiazepin-8-yl
trifluoromethanesulfonate. The two batches of the reaction mixture were combined,
concentrated to remove solvents, and purified by silica gel chromatography
(hexanes:EtOAc =9:1 ) to give the sulfide (O) as slightly yellow oil (0.6 g, 40% yield, 99.7% purity). The oil (0.6 g, 1 .191 mmol) was dissolved in TFA (1 .836 mL, 23.83 mmol) and stirred at 40 °C. H202 (0.268 mL, 2.62 mmol) was added slowly over 30 min. The mixture was stirred at 40 °C for 2 h and then cooled to room temperature. Water (10 mL) and toluene (6.0 mL) were added. Layers were separated and the organic layer was washed successively with aqueous sodium carbonate solution and wate, and concentrated to dryness. Toluene (6.0 mL) was added and the mixture was concentrated to dryness. The residue was dissolved in toluene (2.4 mL) and isooctane (7.20 mL) was added. The mixture was heated to reflux and then cooled to room temperature. The mixture was stirred at room temperature for 30 min. The solid was filtered and washed with isooctane to give the title compound (0.48 g, 75%).
Intermediate L: (R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol, di-p-toluoyl-L-tartrate salt
To a mixture of (R)-2-amino-2-ethylhexyl hydrogen sulfate (1 1 .1 g, 49.3 mmol) in water (23.1 mL) was added NaOH (5.91 g, 148 mmol). The mixture was stirred at reflux for 2 h. The mixture was cooled to room temperature and extracted with MTBE (30.8 mL). The extract was washed with brine (22 mL), concentrated under vacuum and treated with methanol (30.8 mL). The mixture was stirred under nitrogen and treated with 3-hydroxy-4-methoxythiophenol (7.70 g, 49.3 mmol). The mixture was stirred under nitrogen at room temperature for 1 h. The mixture was concentrated under vacuum, treated with acetonitrile (154 mL) and then heated to 45 °C. To the stirred mixture was added (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid (19.03 g, 49.3 mmol). The resultant slurry was
stirred at 45 °C. After 2 h, the slurry was cooled to room temperature and stirred for 5 h. The solids were filtered, washed twice with acetonitrile (30 mL) and dried to give the title compound (28.0 g, 85%) as white solids. 1 NMR (400 MHz, DMSO-d6) δ (ppm): 0.70-0.75 (m, 6H), 1 .17 (b, 4H), 1 .46-1 .55 (m, 4H), 2.30 (s, 6H), 3.71 (s, 3H), 5.58 (s, 2H), 6.84 (s, 2H), 6.89 (s, 1 H), 7.24 (d, J – 1 1 .6 Hz, 4H), 7.76 (d, J – 1 1 .6 Hz, 4H).
A flask was charged with (R)-(2-((2-amino-2-ethylhexyl)thio)-4-hydroxy-5-methoxyphenyl)(phenyl)methanone (3.5 g, 9.03 mmol), citric acid (0.434 g, 2.258 mmol), 1 ,4-Dioxane (17.50 mL) and Toluene (17.50 mL). The mixture was heated to reflux with a Dean-Stark trap to distill water azetropically. The mixture was refluxed for 20 h and then cooled to room temperature. EtOAc (35.0 mL) and water (35.0 mL) were added and layers were separated. The organic layer was washed with aqueous sodium carbonate solution and concentrated to remove solvents to give crude imine as brown oil. The oil was dissolved in EtOAc (35.0 mL) and cooled to 0-5 °C. To the mixture was added triethylamine (1 .888 mL, 13.55 mmol) followed by slow addition of Tf2O (1 .831 mL, 10.84 mmol) at 0-5 °C. The mixture was stirred at room temperature for 1 h. Water was added and layers were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude triflate was purified by silica gel chromatography
Journal of Medicinal Chemistry (2013), 56(12), 5094-5114.
The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.
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Example 26: 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl- 2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid
Method 1 , Step 1 : To a solution of (3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-5- phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine-8-carbaldehyde 1 ,1 -dioxide (683 mg, 1 .644 mmol) in 1 ,2-dichloroethane (20 mL) was added diethyl 3- aminopentanedioate (501 mg, 2.465 mmol) and acetic acid (0.188 mL, 3.29 mmol). The reaction mixture was stirred at room temperature for 1 hr then treated with NaHB(OAc)3 (697 mg, 3.29 mmol). The reaction mixture was then stirred at room temperature overnight and quenched with aqueous potassium carbonate solution. The mixture was extracted with DCM. The combined organic layers were washed with H2O, saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give diethyl 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5- phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioate (880 mg, 88%) as a light yellow oil: MS-LCMS m/z 603 (M+H)+.
Method 1 , Step 2: To a solution of diethyl 3-({[(3R,5R)-3-butyl-3-ethyl-7- (methyloxy)-l ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8- yl]methyl}amino)pentanedioate (880 mg, 1 .460 mmol) in a 1 :1 :1 mixture of
THF/MeOH/H2O (30 mL) was added lithium hydroxide (175 mg, 7.30 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under reduced pressure. H2O and MeCN was added to dissolve the residue. The solution was acidified with acetic acid to pH 4-5, partially concentrated to remove MeCN under reduced pressure, and left to stand for 30 min. The white precipitate was collected by filtration and dried under reduced pressure at 50°C overnight to give the title compound (803 mg, 100%) as a white solid: 1 H NMR (MeOH-d4) δ ppm 8.05 (s, 1 H), 7.27 – 7.49 (m, 5H), 6.29 (s, 1 H), 6.06 (s, 1 H), 4.25 (s, 2H), 3.60 – 3.68 (m, 1 H), 3.58 (s, 3H), 3.47 (d, J = 14.8 Hz, 1 H), 3.09 (d, J = 14.8 Hz, 1 H), 2.52 – 2.73 (m, 4H), 2.12 – 2.27 (m, 1 H), 1 .69 – 1 .84 (m, 1 H), 1 .48 – 1 .63 (m, 1 H), 1 .05 – 1 .48 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 547 (M+H) Method 2: A solution of dimethyl 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-
1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8- yl]methyl}amino)pentanedioate (~ 600 g) in THF (2.5 L) and MeOH (1 .25 L) was cooled in an ice-bath and a solution of NaOH (206 g, 5.15 mol) in water (2.5 L) was added dropwise over 20 min (10-22°C reaction temperature). After stirring 20 min, the solution was concentrated (to remove THF/MeOH) and acidified to pH~4 with concentrated HCI. The precipitated product was aged with stirring, collected by filtration and air dried overnight. A second 600g batch of dimethyl 3-({[(3R,5R)-3- butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4- benzothiazepin-8-yl]methyl}amino)pentanedioate was saponified in a similar fashion. The combined crude products (~2 mol theoretical) were suspended in CH3CN (8 L) and water (4 L) and the stirred mixture was heated to 65°C. A solution formed which was cooled to 10°C over 2 h while seeding a few times with an authentic sample of the desired crystalline product. The resulting slurry was stirred at 10°C for 2 h, and the solid was collected by filtration. The filter cake was washed with water and air-dried overnight. Further drying to constant weight in a vacuum oven at 55°C afforded crystalline 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 – dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8- yl]methyl}amino)pentanedioic acid as a white solid (790 g).
Method 3: (3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-5-phenyl-2,3,4,5-tetrahydro- 1 ,4-benzothiazepine-8-carbaldehyde 1 ,1 -dioxide (1802 grams, 4.336 moles) and dimethyl 3-aminopentanedioate (1334 grams, 5.671 moles) were slurried in iPrOAc (13.83 kgs). A nitrogen atmosphere was applied to the reactor. To the slurry at 20°C was added glacial acetic acid (847 ml_, 14.810 moles), and the mixture was stirred until complete dissolution was observed. Solid sodium triacetoxyborohydride (1424 grams, 6.719 moles) was next added to the reaction over a period of 7 minutes. The reaction was held at 20°C for a total of 3 hours at which time LC analysis of a sample indicated complete consumption of the (3R,5R)-3-butyl-3-ethyl- 7-(methyloxy)-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepine-8-carbaldehyde 1 ,1 – dioxide. Next, water (20.36 kgs) and brine (4.8 kgs) were added to the reactor. The contents of the reactor were stirred for 10 minutes and then settled for 10 minutes. The bottom, aqueous layer was then removed and sent to waste. A previously prepared, 10% (wt/wt) aqueous solution of sodium bicarbonate (22.5 L) was added to the reactor. The contents were stirred for 10 minutes and then settled for 10 minutes. The bottom, aqueous layer was then removed and sent to waste. To the reactor was added a second wash of 10% (wt/wt) aqueous, sodium bicarbonate
(22.5 L). The contents of the reactor were stirred for 10 minutes and settled for 10 minutes. The bottom, aqueous layer was then removed and sent to waste. The contents of the reactor were then reduced to an oil under vacuum distillation. To the oil was added THF (7.15 kgs) and MeOH (3.68 kgs). The contents of the reactor were heated to 55°C and agitated vigorously until complete dissolution was observed. The contents of the reactor were then cooled to 25°C whereupon a previously prepared aqueous solution of NaOH [6.75 kgs of water and 2.09 kgs of NaOH (50% wt wt solution)] was added with cooling being applied to the jacket. The contents of the reactor were kept below 42°C during the addition of the NaOH solution. The temperature was readjusted to 25°C after the NaOH addition, and the reaction was stirred for 75 minutes before HPLC analysis indicated the reaction was complete. Heptane (7.66 kgs) was added to the reactor, and the contents were stirred for 10 minutes and then allowed to settle for 10 minutes. The aqueous layer was collected in a clean nalgene carboy. The heptane layer was removed from the reactor and sent to waste. The aqueous solution was then returned to the reactor, and the reactor was prepared for vacuum distillation. Approximately 8.5 liters of distillate was collected during the vacuum distillation. The vacuum was released from the reactor, and the temperature of the contents was readjusted to 25°C. A 1 N HCI solution (30.76 kgs) was added to the reactor over a period of 40 minutes. The resulting slurry was stirred at 25°C for 10 hours then cooled to 5°C over a period of 2 hours. The slurry was held at 5°C for 4 hours before the product was collected in a filter crock by vacuum filtration. The filter cake was then washed with cold (5°C) water (6 kgs). The product cake was air dried in the filter crock under vacuum for approximately 72 hours. The product was then transferred to three drying trays and dried in a vacuum oven at 50°C for 79 hours. The temperature of the vacuum oven was then raised to 65°C for 85 additional hours. The product was off-loaded as a single batch to give 2568 grams (93.4% yield) of intermediate grade 3-({[(3R,5R)-3- butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4- benzothiazepin-8-yl]methyl}amino)pentanedioic acid as an off-white solid.
Intermediate grade 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5- phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid was dissolved (4690 g) in a mixture of glacial acetic acid (8850 g) and purified water (4200 g) at 70°C. The resulting solution was transferred through a 5 micron polishing filter while maintaining the temperature above 30°C. The reactor and filter were rinsed through with a mixture of glacial acetic acid (980 g) and purified water (470 g). The solution temperature was adjusted to 50°C. Filtered purified water (4230 g) was added to the solution. The cloudy solution was then seeded with crystalline 3-({[(3 5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl-2,3 ,4,5- tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid (10 g). While maintaining the temperature at 50°C, filtered purified water was charged to the slurry at a controlled rate (1 1030 g over 130 minutes). Additional filtered purified water was then added to the slurry at a faster controlled rate (20740 g over 100 minutes). A final charge of filtered purified water (3780 g) was made to the slurry. The slurry was then cooled to 10°C at a linear rate over 135 minutes. The solids were filtered over sharkskin filter paper to remove the mother liquor. The cake was then rinsed with filtered ethyl acetate (17280 g) then the wash liquors were removed by filtration. The resulting wetcake was isolated into trays and dried under vacuum at 50°C for 23 hours. The temperature was then increased to 60°C and drying was continued for an additional 24 hours to afford crystalline 3-({[(3R,5R)-3-butyl-3-ethyl- 7-(methyloxy)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8- yl]methyl}amino)pentanedioic acid (3740 g, 79.7% yield) as a white solid.
To a slurry of this crystalline 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 – dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8- yl]methyl}amino)pentanedioic acid (3660 g) and filtered purified water (3.6 L) was added filtered glacial acetic acid (7530 g). The temperature was increased to 60°C and full dissolution was observed. The temperature was reduced to 55°C, filtered, and treated with purified water (3.2 L). The solution was then seeded with crystalline 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl-2,3,4,5- tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid (18 g) to afford a slurry. Filtered purified water was charged to the slurry at a controlled rate (9 L over 140 minutes). Additional filtered purified water was then added to the slurry at a faster controlled rate (18 L over 190 minutes). The slurry was then cooled to
10°C at a linear rate over 225 minutes. The solids were filtered over sharkskin filter paper to remove the mother liquor. The cake was then rinsed with filtered purified water (18 L), and the wash liquors were removed by filtration. The resulting wetcake was isolated into trays and dried under vacuum at 60°C for 18.5 hours to afford a crystalline 3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl- 2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid (3330 g, 90.8% yield) as a white solid which was analyzed for crystallinity as summarized below.
Paper
Cowan, D. J.; Collins, J. L.; Mitchell, M. B.; Ray, J. A.; Sutton, P. W.; Sarjeant, A. A.; Boros, E. E.Enzymatic- and Iridium-Catalyzed Asymmetric Synthesis of a Benzothiazepinylphosphonate Bile Acid Transporter InhibitorJ. Org. Chem.2013, 78 ( 24) 12726– 12734, DOI: 10.1021/jo402311e
A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.
Paper
Scheme 1. Current Route to Chiral Intermediate 4 in the Synthesis of GSK2330672
Development of an Enzymatic Process for the Production of (R)-2-Butyl-2-ethyloxirane
†Synthetic Biochemistry, Advanced Manufacturing Technologies, ‡API Chemistry, ∥Protein and Cellular Sciences, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
§API Chemistry, ⊥Synthetic Biochemistry, Advanced Manufacturing Technologies, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States
# Biotechnology and Environmental Shared Service, Global Manufacturing and Supply, GlaxoSmithKline, Dominion Way, Worthing BN14 8PB, United Kingdom
∇ Molecular Design, Computational and Modeling Sciences, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States
An epoxide resolution process was rapidly developed that allowed access to multigram scale quantities of (R)-2-butyl-2-ethyloxirane 2 at greater than 300 g/L reaction concentration using an easy-to-handle and store lyophilized powder of epoxide hydrolase from Agromyces mediolanus. The enzyme was successfully fermented on a 35 L scale and stability increased by downstream processing. Halohydrin dehalogenases also gave highly enantioselective resolution but were shown to favor hydrolysis of the (R)-2 epoxide, whereas epoxide hydrolase from Aspergillus nigerinstead provided (R)-7 via an unoptimized, enantioconvergent process.
REFERENCES
1: Nunez DJ, Yao X, Lin J, Walker A, Zuo P, Webster L, Krug-Gourley S, Zamek-Gliszczynski MJ, Gillmor DS, Johnson SL. Glucose and lipid effects of the ileal apical sodium-dependent bile acid transporter inhibitor GSK2330672: double-blind randomized trials with type 2 diabetes subjects taking metformin. Diabetes Obes Metab. 2016 Jul;18(7):654-62. doi: 10.1111/dom.12656. Epub 2016 Apr 21. PubMed PMID: 26939572.
2: Wu Y, Aquino CJ, Cowan DJ, Anderson DL, Ambroso JL, Bishop MJ, Boros EE, Chen L, Cunningham A, Dobbins RL, Feldman PL, Harston LT, Kaldor IW, Klein R, Liang X, McIntyre MS, Merrill CL, Patterson KM, Prescott JS, Ray JS, Roller SG, Yao X, Young A, Yuen J, Collins JL. Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. J Med Chem. 2013 Jun 27;56(12):5094-114. doi: 10.1021/jm400459m. Epub 2013 Jun 6. PubMed PMID: 23678871.
Form I may be prepared according to the procedures in WO2011/137135, Example 26.
Method 2
Form I of linerixibat was prepared according to the following procedure at a large scale (> 500 g). All charges were based on input linerixibat.
An intermediate grade linerixibat was dissolved in acetonitrile / Water (12 vols / 8 vols) at reflux (~76 °C). The solution was seeded at 70°C with Form I (2% w/w), cooled to 60 °C over 15 mins and aged at 60 °C for 2 hrs. Water (14 vols) was added over 8 hrs and aged for 1 hr. The suspension was cooled to 20 °C over 1 hr and aged for >30 mins. The slurry was filtered, washed with acetonitrile: water (6:11 v/v) (3.5 vols), then twice with water (2 vols) and blown down with nitrogen 8-18 hrs. Drying was carried out under vacuum at 40-50 °C without agitation until the Karl Fisher measurement (KF) was < 10% w/w. The batch was agitated at 4 rpm for 2 mins every 3 hrs until the KF <1 % w/w to provide Form I.
Form I can also be prepared by the above procedure without the step of seeding. Method 3
Form I of linerixibat was prepared according to the following procedure at a large scale (> 50 kg). A reactor (Reactor 1) was charged with 55.84 kg GSK2330672B (1.0 wt) intermediate grade (IG) followed by acetonitrile (12 vol) and purified water (8 vol). The mixture was heated to reflux (74-79°C), and held until complete dissolution is observed. The solution was then transferred to a reactor (Reactor 2) that had been pre-heated to 74-79°C via filter (0.22pm pipe-line filter). Reactor 1 was rinsed with acetonitrile (MeCN) (0.3 vol) and purified water (0.2 vol), and the solution in Reactor 1 was transferred to Reactor 2 via filter (0.22pm pipe-line filter). The contents of Reactor 2 were held until complete dissolution is observed. The solution in Reactor 2 was cooled to 69-72°C, then seeded with 2 w/w% (based on pure GSK2330672B input). The suspension was cooled to 58-62°C within 10-20 min. The suspension was held at 58-62°C for 2h. Purified water (14 vol) was added over 8 hrs. After the addition was complete, the slurry was held at 58-62°C for 60 min, then cooled to 18-25°C over 50-70 min. The slurry was stirred at 18-25°C for not less than 30 min, then the suspension filtered under vacuum. The reactor was rinsed with MeCN/water (6/11 v:v, 3.5 vol) and the rinse used to wash the cake. The cake was washed twice with water (2 vol). The cake was blown down with nitrogen and dried at 60°C under vacuum to give 46.35 kg GSK2330672B Form 1 solid.
Method 4
10.94g of GSK2330672B was charged and washed into a vessel using 131mL of acetonitrile (MeCN) and 88mL of water. The slurry was then heated to reflux. 4mL of 3:2v/v MeCN/water was charged followed by 5.5mL of 3:2v/v MeCN/water. The contents were cooled to 70 °C, then cooled to 60°C over 15 minutes and held stirring for 2 hours. 153 mL water was added over 8 hours, the contents were cooled to 20°C over 1 hour, and held stirring for 1 hour. The product was isolated, washed with 38mL of 6:11 MeCN/water, then washed twice with 22mL of water. After deliquoring, the product was dried at 45°C under vacuum, to give 9.35g (85.5%w/w) Form I GSK2330672B.
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, Peter W. Sutton*‡, Rebecca Splain§, Christopher Morgan§, Andrew Fosberry∥, Katherine Honicker⊥, Paul Homes∥, Cyril Boudet#, Alison Dann#, Jiasheng Guo§, Kristin K. Brown∇, Leigh Anne F. Ihnken⊥, and Douglas Fuerst⊥
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